var title_f0_36_576="B12 and folate in DNA synthesis";

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" Effects of cobalamin and folic acid on DNA synthesis",
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MFQgAOw==);\">",
" </div>",
" <div class=\"lgnd\">",
" Interdependent cofactor activity of cobalamin and folate in intracellular DNA
synthesis and metabolism. The + signs indicate enhancement, and the - signs
indicate inhibition. Demethylation of methyl-tetrahydrofolate (CH3-THF) to THF is a
critical step in DNA synthesis because THF is the substrate for the enzyme that
converts (THF)-1 to the polyglutamated form (THF)n. Only polyglutamated (THF)n
participates in purine synthesis.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Reproduced with permission from Tefferi, A, Pruthi, RK. The Biochemical Basis
of Cobalamin Deficiency. Mayo Clin Proc 1994; 69:181",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f0_36_576=[""].join("\n");
var outline_f0_36_576=null;
var title_f0_36_577="Open hernia groin incision";
var content_f0_36_577=[" <div id=\"graphicsToolbar\">",
" <div id=\"graphicsCopy\">",
" &copy;2013 UpToDate",
" ^{",
" &reg;",
"}",
" </div>",
" <div id=\"graphicsLinks\">",
" <a href=\"?imageKey=SURG
%2F51599&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=1\" onclick=\"\">",
" <img alt=\"Print this page\" src=\"./../images/icn_print.myextg\"
title=\"Print this page\"/>",
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=SURG
%2F51599&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=1\" onclick=\"\"
title=\"Print this page\">",
" Print",
" </a>",
" <a class=\"etacLink\" href=\"#\">",
" <img alt=\"Email graphic(s)\" src=\"./../images/icn_email.myextg\"
title=\"Email graphic(s)\"/>",
" </a>",
" <a class=\"icontxt textLink etacLink\" href=\"#\" title=\"Email graphic(s)\">",
" Email",
" </a>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 482px\">",
" <div class=\"ttl\">",
" Incision for open inguinal hernia repair",
" </div>",
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" <div class=\"lgnd\">",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f0_36_577=[""].join("\n");
var outline_f0_36_577=null;
var title_f0_36_578="Postpolypectomy bleeding";
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%2F82749&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=1\" onclick=\"\"
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" <a class=\"etacLink\" href=\"#\">",
" <img alt=\"Email graphic(s)\" src=\"./../images/icn_email.myextg\"
title=\"Email graphic(s)\"/>",
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" <a class=\"icontxt textLink etacLink\" href=\"#\" title=\"Email graphic(s)\">",
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" Delayed postpolypectomy bleeding in the colon",
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" </div>",
" <div class=\"lgnd\">",
" (A) Brisk bleeding in the ascending colon one week following polypectomy. (B)
Bleeding has diminished following submucosal epinephrine injection. (C) Bleeding
has completely stopped following heater probe application - note the heater
probe \"footprint.\"",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
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" <dd>",
" <a href=\"UTD.htm?1/40/1667\">",
" Patient information: Managing loss of appetite and weight loss with
cancer (The Basics)",
" </a>",
" </dd>",
" <dd>",
" <a href=\"UTD.htm?11/6/11363\">",
" Patient information: Narcotic pain medicines (The Basics)",
" </a>",
" </dd>",
" <dd>",
" <a href=\"UTD.htm?39/15/40178\">",
" Patient information: Nonsteroidal antiinflammatory drugs (NSAIDs) (The
Basics)",
" </a>",
" </dd>",
" <dd>",
" <a href=\"UTD.htm?36/16/37121\">",
" Patient information: What are clinical trials? (The Basics)",
" </a>",
" </dd>",
" <dd>",
" <a href=\"UTD.htm?29/4/29762\">",
" Patient information: When your cancer treatment makes you tired (The
Basics)",
" </a>",
" </dd>",
" <dt class=\"beyondthebasics\">",
" Beyond the Basics",
" </dt>",
" <dd>",
" <a href=\"UTD.htm?20/51/21300\">",
" Patient information: Complementary and alternative medicine treatments
(CAM) for cancer (Beyond the Basics)",
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" Patient information: Managing pain when you have cancer (The Basics)",
" </div>",
" <span class=\"view\">",
" View in",
" <a class=\"lang\" href=\"./es-419/managing-pain-when-you-have-cancer-the-
basics?source=topic_page\">",
" Spanish",
" </a>",
" </span>",
" <a class=\"contributor contributor_credentials\" href=\"./authors-and-
editors/patient-information\">",
" Written by the doctors and editors at UpToDate",
" </a>",
" <div id=\"topicText\">",
" <p class=\"headingAnchor\" id=\"H1568106\">",
" <span class=\"h1\">",
" What can cause pain in people with cancer?",
" </span>",
" &nbsp;&mdash;&nbsp;People with cancer can have pain from the cancer or from
the cancer treatments. People can also have pain from other conditions, such as
arthritis, that have nothing to do with their cancer.",
" </p>",
" <p class=\"headingAnchor\" id=\"H1568113\">",
" <span class=\"h1\">",
" Is there anything I can do on my own to feel better?",
" </span>",
" &nbsp;&mdash;&nbsp;Yes. To feel better, first try to avoid doing the things
that make your pain worse. You can also try to relax. For example, you can do
relaxation exercises or meditate.",
" </p>",
" <p>",
" If you have pain, it&rsquo;s important to keep track of your pain and how
you treat it. That way, your doctor can use this information to treat your pain
better. Keep a list of the medicines you take, how much they ease the pain, and how
long the pain relief lasts. When you describe your pain, you can give it a number
from 1 to 10. One (1) would be &ldquo;no pain,&rdquo; and 10 would be
&ldquo;unbearable&rdquo; (the worst pain ever) (",
" <a class=\"graphic graphic_figure graphicRef58567 \" href=\"UTD.htm?
1/2/1069\">",
" figure 1",
" </a>",
" ).",
" </p>",
" <p class=\"headingAnchor\" id=\"H1568120\">",
" <span class=\"h1\">",
" When should I call my doctor or nurse?",
" </span>",
" &nbsp;&mdash;&nbsp;Call your doctor or nurse if you have:",
" </p>",
" <p>",
" <ul class=\"bulletCompact-block\">",
" <li>",
" Any change in the type of pain you have or where your pain is",
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" Long-term pain that gets worse or does not get better with treatment",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H1568127\">",
" <span class=\"h1\">",
" Which medicines work best on cancer pain?",
" </span>",
" &nbsp;&mdash;&nbsp;Doctors usually use medicines called
&ldquo;narcotics&rdquo; to treat cancer pain. Narcotics are a group of medicines
that includes",
" <a class=\"drug drug_patient\" href=\"UTD.htm?14/33/14870?
source=see_link\">",
" morphine",
" </a>",
" (sample brand names: MS Contin&reg;, MSIR&reg;),",
" <a class=\"drug drug_patient\" href=\"UTD.htm?6/3/6198?source=see_link\">",
" oxycodone",
" </a>",
" (sample brand names: OxyContin&reg;, Oxy IR&reg;), and",
" <a class=\"drug drug_patient\" href=\"UTD.htm?0/29/472?source=see_link\">",
" fentanyl",
" </a>",
" (sample brand names: Duragesic&reg;, Fentora&reg;).",
" </p>",
" <p>",
" In general, narcotics can work in 2 ways. They can:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Start to work slowly and treat pain over many hours &mdash; These
medicines usually come as a slow-acting (called &ldquo;sustained release&rdquo;)
pill, or as a patch that goes on the skin.",
" </li>",
" <li>",
" Start to work quickly, to treat pain that starts or gets worse suddenly
&mdash; These medicines usually come as a fast-acting (called &ldquo;immediate
release&rdquo;) pill, liquid, or tablet that melts under the tongue.",
" </li>",
" </ul>",
" </p>",
" <p>",
" Doctors usually prescribe both types of narcotics to treat pain in people
with cancer. Most people use a slow-acting narcotic every day to prevent pain. If
they have episodes of pain while they are taking the slow-acting narcotic, then
they can also take a fast-acting narcotic to control the pain.",
" </p>",
" <p>",
" Depending on your symptoms and other conditions, your doctor might prescribe
other types of medicines. Most of the time, people take these medicines in addition
to their narcotics. Other medicines can include:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" <a class=\"drug drug_patient\" href=\"UTD.htm?19/35/20021?
source=see_link\">",
" Acetaminophen",
" </a>",
" (brand name: Tylenol&reg;) or a group of medicines called
&ldquo;NSAIDs.&rdquo; NSAIDs include",
" <a class=\"drug drug_patient\" href=\"UTD.htm?14/17/14614?
source=see_link\">",
" ibuprofen",
" </a>",
" (sample brand names: Advil&reg;, Motrin&reg;) and",
" <a class=\"drug drug_patient\" href=\"UTD.htm?43/35/44597?
source=see_link\">",
" naproxen",
" </a>",
" (sample brand names: Aleve&reg;, Naprosyn&reg;).",
" </li>",
" <li>",
" Medicines that are not usually used to treat pain but can help treat
certain types of pain in people with cancer",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H1568134\">",
" <span class=\"h1\">",
" What else should I know about my pain medicines?",
" </span>",
" &nbsp;&mdash;&nbsp;You should know that:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" It&rsquo;s important to take your slow-acting narcotics as prescribed,
even if you aren&rsquo;t in pain. The goal of treatment is to keep your pain under
control all the time, and not just treat it when it happens. If you aren&rsquo;t in
pain, it means that the treatment is working.",
" </li>",
" <li>",
" You need to let your doctor or nurse know if your medicine isn&rsquo;t
helping enough with your pain. Your doctor can increase your dose, increase how
often you take your medicine, or prescribe a different medicine.",
" </li>",
" <li>",
" Narcotics can have side effects. Common side effects include having
trouble having a bowel movement, feeling sleepy, and nausea. Let your doctor or
nurse know if you have any side effects. That way, he or she can treat your side
effects or change your medicine.",
" </li>",
" <li>",
" You need to keep your narcotics in a safe place so that people don&rsquo;t
steal them. People might try to steal your narcotics so that they can make money by
selling them illegally.",
" </li>",
" <li>",
" You will not get addicted to your narcotics. People often worry that they
are getting addicted to their medicine when they need higher and higher doses to
treat their pain. This is not the case. Your body might need higher doses because
your condition is getting worse, or because you have a higher
&ldquo;tolerance&rdquo; for the medicine. Tolerance is when a body gets used to a
medicine, so the medicine doesn&rsquo;t work as well as it used to. Tolerance is
not the same as addiction.",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H1568141\">",
" <span class=\"h1\">",
" Are there other kinds of treatments that can help with pain?",
" </span>",
" &nbsp;&mdash;&nbsp;Yes. If your medicines don&rsquo;t ease your pain enough,
talk with your doctor or nurse about other possible treatments. Depending on your
symptoms and the cause of your pain, he or she might recommend a procedure. This
could include getting a shot of medicine into the painful area.",
" </p>",
" <p>",
" He or she might also recommend that you work with a physical therapist,
mental health expert, or alternative medicine expert. Alternative medicine includes
treatments such as acupuncture and massage.",
" </p>",
" <p class=\"headingAnchor\" id=\"H1568148\">",
" <span class=\"h1\">",
" More on this topic",
" </span>",
" </p>",
" <p>",
" <a class=\"medical medical_basics\" href=\"UTD.htm?29/4/29762?
source=see_link\">",
" Patient information: When your cancer treatment makes you tired (The
Basics)",
" </a>",
" <br/>",
" <a class=\"medical medical_basics\" href=\"UTD.htm?1/40/1667?
source=see_link\">",
" Patient information: Managing loss of appetite and weight loss with cancer
(The Basics)",
" </a>",
" <br/>",
" <a class=\"medical medical_basics\" href=\"UTD.htm?39/15/40178?
source=see_link\">",
" Patient information: Nonsteroidal antiinflammatory drugs (NSAIDs) (The
Basics)",
" </a>",
" <br/>",
" <a class=\"medical medical_basics\" href=\"UTD.htm?11/6/11363?
source=see_link\">",
" Patient information: Narcotic pain medicines (The Basics)",
" </a>",
" <br/>",
" <a class=\"medical medical_basics\" href=\"UTD.htm?36/16/37121?
source=see_link\">",
" Patient information: What are clinical trials? (The Basics)",
" </a>",
" </p>",
" <p>",
" <a class=\"medical medical_patient\" href=\"UTD.htm?20/51/21300?
source=see_link\">",
" Patient information: Complementary and alternative medicine treatments
(CAM) for cancer (Beyond the Basics)",
" </a>",
" </p>",
" </div>",
" <div id=\"reviewProcess\">",
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" </h1>",
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" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H1568106\">",
" What can cause pain in people with cancer?",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H1568113\">",
" Is there anything I can do on my own to feel better?",
" </a>",
" </li>",
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" <a class=\"outlineLink\" href=\"#H1568120\">",
" When should I call my doctor or nurse?",
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" Which medicines work best on cancer pain?",
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" <a class=\"outlineLink\" href=\"#H1568134\">",
" What else should I know about my pain medicines?",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H1568141\">",
" Are there other kinds of treatments that can help with pain?",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H1568148\">",
" More on this topic",
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" </h1>",
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" <ul>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_patient\" href=\"UTD.htm?20/51/21300?
source=related_link\">",
" Patient information: Complementary and alternative medicine treatments (CAM)
for cancer (Beyond the Basics)",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_basics\" href=\"UTD.htm?1/40/1667?
source=related_link\">",
" Patient information: Managing loss of appetite and weight loss with cancer
(The Basics)",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_basics\" href=\"UTD.htm?11/6/11363?
source=related_link\">",
" Patient information: Narcotic pain medicines (The Basics)",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_basics\" href=\"UTD.htm?39/15/40178?
source=related_link\">",
" Patient information: Nonsteroidal antiinflammatory drugs (NSAIDs) (The
Basics)",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_basics\" href=\"UTD.htm?36/16/37121?
source=related_link\">",
" Patient information: What are clinical trials? (The Basics)",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_basics\" href=\"UTD.htm?29/4/29762?
source=related_link\">",
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Basics)",
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" </ul>",
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" </div>"].join("\n");
var title_f0_36_580="Recombinant human chorionic gonadotropin: Patient drug
information";
var content_f0_36_580=[" <noscript>",
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JavaScript is required in order for our site to behave correctly. Please enable
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" Official reprint from UpToDate",
" ^{",
" &reg;",
"}",
" <a href=\"file://www.uptodate.com\">",
" www.uptodate.com",
" </a>",
" <br>",
" &copy;2013 UpToDate",
" ^{",
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" <div id=\"topicContent\">",
" <div id=\"disclaimer\">",
" The content on the UpToDate website is not intended nor recommended as a
substitute",
"for medical advice, diagnosis, or treatment. Always seek the advice of your own
physician or",
"other qualified health care professional regarding any medical questions or
conditions. The",
"use of this website is governed by the",
" <a href=\"/home/terms-use\" target=\"_blank\">",
" UpToDate Terms of Use",
" </a>",
" &copy;2013 UpToDate, Inc.",
" </div>",
" <div id=\"drugTitle\">",
" Recombinant human chorionic gonadotropin: Patient drug information",
" </div>",
" <div id=\"lexiTitleImg\">",
" <img height=\"17\" src=\"./../images/lexiComp/Lexicomp_2012_71x17.myextg\"
width=\"71\"/>",
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" </div>",
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" Copyright 1978-2013 Lexicomp, Inc. All rights reserved.",
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" <div id=\"topicText\">",
" <p>",
" (For additional information",
" <a class=\"drug drug_general\" href=\"UTD.htm?42/18/43299?source=see_link\">",
" see \"Recombinant human chorionic gonadotropin: Drug information\"",
" </a>",
" )",
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xmlns=\"file://www.w3.org/1999/xhtml\">",
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" Brand Names: U.S.",
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" <ul>",
" <li>",
" Ovidrel&reg;",
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" <div class=\"list cbnlist drugH1Div drugBrandNames\" id=\"F855132\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
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" <li>",
" Ovidrel&reg;",
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" <div class=\"ord-stmt yya-os drugH1Div\" id=\"F10014392\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" What is this drug used for?",
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" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2691380",
" </span>",
" </span>",
" <span class=\"content\">",
" It is used to help you get pregnant.",
" </span>",
" </li>",
" </ul>",
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" <div class=\"ord-stmt coi-os drugH1Div\" id=\"F10014391\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" What do I need to tell my doctor before I take this drug?",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2701799",
" </span>",
" </span>",
" <span class=\"content\">",
" If you have an allergy to chorionic gonadotropin (recombinant) or any other
part of this drug.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2705171",
" </span>",
" </span>",
" <span class=\"content\">",
" If you are allergic to any drugs, foods, or other substances. Tell your
doctor about the allergy and what signs you had, like rash; hives; itching;
shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or
any other signs.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2703442",
" </span>",
" </span>",
" <span class=\"content\">",
" If you have any of these health problems: Brain tumor, cancer where
hormones make it grow, ovarian cysts, adrenal gland disease, thyroid gland disease,
or vaginal bleeding.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2701080",
" </span>",
" </span>",
" <span class=\"content\">",
" If you are pregnant or may be pregnant.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yye-os drugH1Div\" id=\"F10014396\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" What are some things I need to know or do while I take this drug?",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699677",
" </span>",
" </span>",
" <span class=\"content\">",
" Keep a list of all your drugs (prescription, natural products, vitamins,
OTC) with you. Give this list to your doctor.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2696717",
" </span>",
" </span>",
" <span class=\"content\">",
" Check all drugs you are taking with your doctor. This drug may not mix well
with some other drugs.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2696618",
" </span>",
" </span>",
" <span class=\"content\">",
" Avoid beer, wine, or mixed drinks.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2697565",
" </span>",
" </span>",
" <span class=\"content\">",
" Limit working out while undergoing ovarian stimulation.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2697636",
" </span>",
" </span>",
" <span class=\"content\">",
" Tell your doctor if you are breast-feeding. You will need to talk about any
risks to your baby.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyf-os drugH1Div\" id=\"F10014397\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" What are some side effects of this drug?",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698189",
" </span>",
" </span>",
" <span class=\"content\">",
" Irritation where the shot is given.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698292",
" </span>",
" </span>",
" <span class=\"content\">",
" Ovarian cyst.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698272",
" </span>",
" </span>",
" <span class=\"content\">",
" Upset stomach or throwing up. Many small meals, good mouth care, sucking
hard, sugar-free candy, or chewing sugar-free gum may help.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyh-os drugH1Div\" id=\"F10014399\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" What are some side effects that I need to call my doctor about right away?",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698721",
" </span>",
" </span>",
" <span class=\"content\">",
" If you think there has been an overdose, call 1-800-222-1222 (the American
Association of Poison Control Centers), your local poison control center
(file://www.aapcc.org), or emergency room (ER) right away.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699066",
" </span>",
" </span>",
" <span class=\"content\">",
" Signs of an allergic reaction, like rash; hives; itching; red, swollen,
blistered, or peeling skin with or without fever; wheezing; tightness in the chest
or throat; trouble breathing or talking; unusual hoarseness; or swelling of the
mouth, face, lips, tongue, or throat.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698640",
" </span>",
" </span>",
" <span class=\"content\">",
" Trouble breathing.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699008",
" </span>",
" </span>",
" <span class=\"content\">",
" Very bad belly pain.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699062",
" </span>",
" </span>",
" <span class=\"content\">",
" A big weight gain.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698603",
" </span>",
" </span>",
" <span class=\"content\">",
" Any rash.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698977",
" </span>",
" </span>",
" <span class=\"content\">",
" Side effect or health problem is not better or you are feeling worse.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyc-os drugH1Div\" id=\"F10014394\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" How is this drug best taken?",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2696011",
" </span>",
" </span>",
" <span class=\"content\">",
" It is given as a shot.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2696360",
" </span>",
" </span>",
" <span class=\"content\">",
" Your doctor may teach you how to give the shot.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2696257",
" </span>",
" </span>",
" <span class=\"content\">",
" Wash your hands before and after use.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2696118",
" </span>",
" </span>",
" <span class=\"content\">",
" Throw away needles in a needle/sharp disposal box and take the box back to
your doctor when it is full.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyd-os drugH1Div\" id=\"F10014395\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" What do I do if I miss a dose?",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2696446",
" </span>",
" </span>",
" <span class=\"content\">",
" Call your doctor to find out what to do.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyi-os drugH1Div\" id=\"F10014400\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" How do I store and/or throw out this drug?",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699398",
" </span>",
" </span>",
" <span class=\"content\">",
" Store in the original container at room temperature or in a refrigerator.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699264",
" </span>",
" </span>",
" <span class=\"content\">",
" Protect from light.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyj-os drugH1Div\" id=\"F10014401\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" General drug facts",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699675",
" </span>",
" </span>",
" <span class=\"content\">",
" If your symptoms or health problems do not get better or if they become
worse, call your doctor.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699673",
" </span>",
" </span>",
" <span class=\"content\">",
" Do not share your drugs with others and do not take anyone else's drugs.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699678",
" </span>",
" </span>",
" <span class=\"content\">",
" Keep all drugs out of the reach of children and pets.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699709",
" </span>",
" </span>",
" <span class=\"content\">",
" If you have any questions about this drug, please talk with your doctor,
pharmacist, or other health care provider.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s3302581",
" </span>",
" </span>",
" <span class=\"content\">",
" In Canada, take any unused drugs to the pharmacy. Also, visit
file://www.hc-sc.gc.ca/hl-vs/iyh-vsv/med/disposal-defaire-eng.php#th to learn about
the right way to get rid of unused drugs.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699677",
" </span>",
" </span>",
" <span class=\"content\">",
" Keep a list of all your drugs (prescription, natural products, vitamins,
OTC) with you. Give this list to your doctor.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699671",
" </span>",
" </span>",
" <span class=\"content\">",
" These are not all of the side effects that may occur. If you have questions
about side effects, call your doctor. Call your doctor for medical advice about
side effects.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699683",
" </span>",
" </span>",
" <span class=\"content\">",
" Talk with the doctor before starting any new drug, including prescription
or OTC, natural products, or vitamins.",
" </span>",
" </li>",
" </ul>",
" </div>",
" </div>",
" <div id=\"topicAgreement\">",
" Use of UpToDate is subject to the",
" <a class=\"licenseLink\" href=\"./license\" id=\"sla_in_page\"
target=\"_blank\">",
" Subscription and License Agreement",
" </a>",
" .",
" </div>",
" <div id=\"topicVersionRevision\">",
" Topic 12136 Version 33.0",
" </div>",
" </div>",
" <div id=\"footer\">",
" <div id=\"supportFooter\">",
" <span class=\"sfInfo\">",
" &copy; 2013 UpToDate, Inc. All rights reserved.",
" </span>",
" <span class=\"pipeSpace\">",
" |",
" </span>",
" <a class=\"licenseLink\" href=\"./license\" id=\"sla_footer\">",
" Subscription and License Agreement",
" </a>",
" <span class=\"sfInfo\">",
" <span class=\"pipeSpace\">",
" |",
" </span>",
" Release: 21.3 - C21.34",
" </span>",
" <br/>",
" <span class=\"sfInfo\">",
" Licensed to:",
" <span class=\"emphasis\">",
" Morehouse School of Medicine",
" </span>",
" </span>",
" <span class=\"sfInfo\">",
" <span class=\"pipeSpace\">",
" |",
" </span>",
" Support Tag: [0603-125.39.66.150-851E2265C2-S473950.14]",
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" <h1>",
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" </h1>",
" <div id=\"outline\">",
" <ul>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F151156\">",
" Brand Names: U.S.",
" </a>",
" </li>",
" <li class=\"plainItem\">",
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" How do I store and/or throw out this drug?",
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" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#F10014401\">",
" General drug facts",
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" </li>",
" </ul>",
" </div>",
" <h1>",
" RELATED TOPICS",
" </h1>",
" <div id=\"relatedTopics\">",
" <ul>",
" <li class=\"plainItem\">",
" <a class=\"drug drug_general\" href=\"UTD.htm?42/18/43299?
source=related_link\">",
" Recombinant human chorionic gonadotropin: Drug information",
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" </div>",
" <div class=\"lgnd\">",
" Ganglioneuroma is predominantly composed of Schwannian cells studded with
maturing or fully mature ganglion cells.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Courtesy of MJ Hicks, MD.",
" </div>",
" </div>",
" </div>",
" </div>",
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var outline_f0_36_581=null;
var title_f0_36_582="Bismuth-Corlette classification of biliary tumors";
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title=\"Email graphic(s)\"/>",
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" </div>",
" <div class=\"graphic\">",
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" Bismuth-Corlette classification of biliary tract cancers",
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" </div>",
" <div class=\"lgnd\">",
" The Bismuth-Corlette classification of biliary tract.&nbsp;White areas
represent tumor and green areas normal bile duct.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Modified&nbsp;from de Groen PC, Gores GJ, LaRusso NF, et al. N Engl J Med
1999; 341:1368.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
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var outline_f0_36_582=null;
var title_f0_36_583="Acute Raynaud phenomenon PI";
var content_f0_36_583=[" <div id=\"graphicsToolbar\">",
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" &copy;2013 UpToDate",
" ^{",
" &reg;",
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" <a class=\"etacLink\" href=\"#\">",
" <img alt=\"Email graphic(s)\" src=\"./../images/icn_email.myextg\"
title=\"Email graphic(s)\"/>",
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" <a class=\"icontxt textLink etacLink\" href=\"#\" title=\"Email graphic(s)\">",
" Email",
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" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 595px\">",
" <div class=\"ttl\">",
" Acute Raynaud phenomenon",
" </div>",
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" </div>",
" <div class=\"lgnd\">",
" The symptoms of Raynaud disease flare up when the blood vessels \"constrict,\"
meaning they get very narrow. When that happens, the fingers or toes do not get
enough blood, and they can turn blue or white.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Reproduced from: the National Heart Lung and Blood Institute. What is
Raynaud's? Additional information available at:",
" <br>",
" <a
href=\"file://www.nhlbi.nih.gov/health/dci/Diseases/raynaud/ray_what.html\"
target=\"_blank\">",
" file://www.nhlbi.nih.gov/health/dci/Diseases/raynaud/ray_what.html",
" </a>",
" .",
" </br>",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f0_36_583=[""].join("\n");
var outline_f0_36_583=null;
var title_f0_36_584="Intermediate case 14 answer";
var content_f0_36_584=[" <div id=\"graphicsToolbar\">",
" <div id=\"graphicsCopy\">",
" &copy;2013 UpToDate",
" ^{",
" &reg;",
"}",
" </div>",
" <div id=\"graphicsLinks\">",
" <a href=\"?imageKey=CARD
%2F62688&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=1\" onclick=\"\">",
" <img alt=\"Print this page\" src=\"./../images/icn_print.myextg\"
title=\"Print this page\"/>",
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=CARD
%2F62688&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=1\" onclick=\"\"
title=\"Print this page\">",
" Print",
" </a>",
" <a class=\"etacLink\" href=\"#\">",
" <img alt=\"Email graphic(s)\" src=\"./../images/icn_email.myextg\"
title=\"Email graphic(s)\"/>",
" </a>",
" <a class=\"icontxt textLink etacLink\" href=\"#\" title=\"Email graphic(s)\">",
" Email",
" </a>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 525px\">",
" <div class=\"ttl\">",
" Ventricular aneurysm",
" </div>",
" <div class=\"cntnt\" style=\"width: 505px; height: 211px; background-image:
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+vRRS5n3F/Z+Ftb2Uf/AV/kEPjrxHCEEeo4CMGX9xHwQmwfw/3eKZb+NfEFvbxQQ6htiiSONF8mM4WM5Qfd
7f/rooo5n3H9Qwv/PqP/gK/wAgk8a+IHiSNtQyieVgeTHx5bbk/h7EZ9+
+aefHXiMlSdR5Viw/cR9Swc/w/wB4A0UUKT7h9Qwv/PqP/gK/yGP418QO+9tQywjljz5Mf3ZCGcfd7lR9Mc
U+Tx14jkaVn1HJlVlf9xHyGCg/w+ir+VFFHM+4fUML/wA+o/8AgK/yBPHPiKOeSZNRxJJL5zHyI+X2CPP3f
7oA/wDr0Q+OvEcIQR6jgIwZf3EfBCbB/D/d4ooo5n3F/Z+Ff/LqP/gK/wAhlv418QW9vFBDqG2KJI40XyYz
hYzlB93t/wDrok8a+IHiSNtQyieVgeTHx5bbk/h7EZ9+
+aKKOZ9x/UMLe/so39F/kPPjrxGSpOo8qxYfuI+pYOf4f7wBpj+NfEDvvbUMsI5Y8+TH92QhnH3e5UfTHFF
FPmfcFgMKtqUf/AV/kPk8deI5GlZ9RyZVZX/cR8hgoP8AD6Kv5UJ458RRzyTJqOJJJfOY+RHy+wR5+7/dAH
/16KKXM+4v7Pwtreyj/wCAr/IIfHXiOEII9RwEYMv7iPghNg/h/u8VzVFFDbe5tSw9Kjd0oqN+ySP/2Q==)
;\">",
" </div>",
" <div class=\"lgnd\">",
" Electrocardiogram showing anterior wall myocardial infarction with probable
ventricular aneurysm. Persistent ST segment elevation in leads V1 to V4 three or
more weeks after a Q-wave myocardial infarction is a relatively specific but not
highly sensitive sign of severe ventricular motion abnormality and sometimes frank
aneurysm formation. Note also that the rhythm is sinus. There is borderline left
axis deviation (about -30&deg;) with an intraventricular conduction delay.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Courtesy of Ary Goldberger, MD.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f0_36_584=[""].join("\n");
var outline_f0_36_584=null;
var title_f0_36_585="Antimicrobial prophylaxis for bacterial endocarditis";
var content_f0_36_585=[" <noscript>",
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" Antimicrobial prophylaxis for bacterial endocarditis",
" </div>",
" <div id=\"topicContributors\">",
" <div>",
" <a id=\"authors\">",
" </a>",
" <a class=\"contributor contributor_credentials contributorType\"
href=\"UTD.htm?0/36/585/contributors\">",
" Author",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
0/36/585/contributors\">",
" Daniel J Sexton, MD",
" </a>",
" <br/>",
" </div>",
" <div>",
" <a class=\"contributor contributor_credentials contributorType\"
href=\"UTD.htm?0/36/585/contributors\">",
" Section Editor",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
0/36/585/contributors\">",
" Catherine M Otto, MD",
" </a>",
" <br/>",
" </div>",
" <div>",
" <a class=\"contributor contributor_credentials contributorType\"
href=\"UTD.htm?0/36/585/contributors\">",
" Deputy Editors",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
0/36/585/contributors\">",
" Elinor L Baron, MD, DTMH",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
0/36/585/contributors\">",
" Susan B Yeon, MD, JD, FACC",
" </a>",
" <br/>",
" </div>",
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" <div id=\"literatureReviewDate\">",
" <span class=\"emphasis\">",
" Literature review current through:",
" </span>",
" Oct 2013.",
" <span class=\"pipeSpace\">",
" |",
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" This topic last updated:",
" </span>",
" Oct 18, 2012.",
" </div>",
" <div id=\"topicText\">",
" <p class=\"headingAnchor\" id=\"H1\">",
" <span class=\"h1\">",
" INTRODUCTION",
" </span>",
" &nbsp;&mdash;&nbsp;Antimicrobial prophylaxis for bacterial endocarditis has
become standard in most developed countries, despite the fact that no prospective
randomized trial has proven that such therapy is beneficial. Furthermore, given the
extremely low incidence of endocarditis following procedures such as dental surgery
and the medicolegal climate in the United States and Europe, it is unlikely that
such a study will ever be undertaken. It has been estimated that a randomized trial
to assess the effectiveness of prophylaxis after dental procedures would require at
least 6000 patients in each study group [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/1\">",
" 1",
" </a>",
" ].",
" </p>",
" <p>",
" The theoretical basis for antimicrobial prophylaxis for endocarditis and the
most recent guideline that was published by the American Heart Association (AHA) in
2007 on the prevention of infective endocarditis will be reviewed here [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/2\">",
" 2",
" </a>",
" ]. As will be seen, this guideline made important revisions to previous
guidelines. (See",
" <a class=\"local\" href=\"#H8\">",
" 'AHA guideline'",
" </a>",
" below.)",
" </p>",
" <p class=\"headingAnchor\" id=\"H2\">",
" <span class=\"h1\">",
" THEORETICAL BASIS FOR PROPHYLAXIS",
" </span>",
" &nbsp;&mdash;&nbsp;The pathogenesis of infective endocarditis (IE) is presumed
to involve the following sequence of events [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/3\">",
" 3",
" </a>",
" ]:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Formation of a small noninfected thrombus on an abnormal endothelial
surface",
" </li>",
" <li>",
" Secondary infection of this nidus with bacteria that are transiently
circulating in the bloodstream",
" </li>",
" <li>",
" Proliferation of bacteria resulting in the formation of vegetations on the
endothelial surface",
" </li>",
" </ul>",
" </p>",
" <p>",
" Since the occurrence of bacteremia is crucial to the initiation of an episode
of IE, it is theoretically reasonable to conclude that preventing or promptly
treating transient bacteremia will prevent the above sequence even if a
predisposing valvular lesion is present.",
" </p>",
" <p class=\"headingAnchor\" id=\"H3\">",
" <span class=\"h2\">",
" Animal studies",
" </span>",
" &nbsp;&mdash;&nbsp;Bacterial endocarditis can be predictably induced
experimentally if bacteria with a known ability to cause endocarditis (eg,
streptococci) are injected into laboratory animals after their heart valves have
been traumatized using vascular catheters [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/4\">",
" 4",
" </a>",
" ]. However, endocarditis does not occur if antibiotics with activity against
streptococci are given immediately before or for up to 30 minutes after bacteria
are injected [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/3,5\">",
" 3,5",
" </a>",
" ]. In contrast, endocarditis is not prevented if such therapy is delayed for
six hours after the injection of bacteria. Protection can also be abolished if
penicillinase is given after the combination of",
" <a class=\"drug drug_general\" href=\"UTD.htm?41/10/42152?source=see_link\">",
" amoxicillin",
" </a>",
" and streptococci have been injected into susceptible animals.",
" </p>",
" <p>",
" These data suggest that antimicrobial therapy can prevent endocarditis either
by killing bacteria before they establish a nidus of infection on a susceptible
heart valve or by killing bacteria after they adhere to a localized area of damaged
valvular endothelium [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/3\">",
" 3",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H4\">",
" <span class=\"h2\">",
" Human studies",
" </span>",
" </p>",
" <p class=\"headingAnchor\" id=\"H5\">",
" <span class=\"h3\">",
" Prevention of bacteremia",
" </span>",
" &nbsp;&mdash;&nbsp;Bacteremia is common after invasive procedures. The
frequency, time course, and effect of",
" <a class=\"drug drug_general\" href=\"UTD.htm?41/10/42152?source=see_link\">",
" amoxicillin",
" </a>",
" on bacteremia after dental procedures were evaluated in a careful study of 100
children ages one to eight years (mean 3.5 years) who underwent endotracheal
intubation, dental restoration and cleaning, and tooth extractions [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/6\">",
" 6",
" </a>",
" ]. Children who had conditions considered to require antibiotic prophylaxis
were excluded; those enrolled were randomly assigned to receive amoxicillin or
placebo. Blood cultures were obtained at eight time points before and after
procedures, ranging from two minutes postintubation to 45 minutes after the last
extraction.",
" </p>",
" <p>",
" The following observations were made:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" The highest incidence of positive blood cultures occurred 1.5 minutes after
the last extraction (46 percent).",
" </li>",
" <li>",
" The majority of the 152 positive cultures and the 29 different bacteria
identified was gram-positive cocci, especially viridans streptococci.",
" </li>",
" <li>",
" The overall incidence of positive blood cultures was significantly lower
among patients receiving",
" <a class=\"drug drug_general\" href=\"UTD.htm?41/10/42152?
source=see_link\">",
" amoxicillin",
" </a>",
" than placebo (33 versus 84 percent).",
" </li>",
" </ul>",
" </p>",
" <p>",
" A second study of 500 children aged 3 to 16 determined the duration of
bacteremia following a dental extraction [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/7\">",
" 7",
" </a>",
" ]. Children were randomly allocated to 1 of 10 post-procedure time groups, and
blood samples were taken both pre- and post-extraction (time point determined
according to the assigned group) for the isolation of bacteria. The difference
between the pre-procedure blood sample and the post-procedure sample was used to
estimate the duration of bacteremia, which was found to be 11 minutes, considerably
less than previously thought.",
" </p>",
" <p>",
" The specific antibiotics used for antimicrobial prophylaxis are dependent upon
the bacteremia-causing procedure the patient is undergoing. Standard guidelines
have suggested",
" <a class=\"drug drug_general\" href=\"UTD.htm?32/21/33104?source=see_link\">",
" clindamycin",
" </a>",
" as an alternative in the penicillin-allergic patient at risk for endocarditis
who is undergoing a dental extraction.",
" </p>",
" <p>",
" Researchers in Spain have investigated whether",
" <a class=\"drug drug_general\" href=\"UTD.htm?32/21/33104?source=see_link\">",
" clindamycin",
" </a>",
" is effective in this setting, given the increasing resistance of oral bacteria
to this antibiotic. In a randomized, controlled trial, 221 adults who underwent
dental extractions were assigned to one of the following: 2 g",
" <a class=\"drug drug_general\" href=\"UTD.htm?41/10/42152?source=see_link\">",
" amoxicillin",
" </a>",
" , 600 mg clindamycin, 400 mg",
" <a class=\"drug drug_general\" href=\"UTD.htm?32/51/33584?source=see_link\">",
" moxifloxacin",
" </a>",
" , or no antibiotic, orally one to two hours before the procedure [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/8\">",
" 8",
" </a>",
" ].",
" </p>",
" <p>",
" Blood cultures were drawn at 30 seconds, 15 minutes, and one hour after the
dental extraction. At all time points,",
" <a class=\"drug drug_general\" href=\"UTD.htm?32/21/33104?source=see_link\">",
" clindamycin",
" </a>",
" was ineffective in preventing bacteremia, with similar bacteremia rates as the
no antibiotic control patients (85 versus 96, 70 versus 64, and 22 versus 20
percent at 30 seconds, 15 minutes, and one hour, respectively). In contrast, both",
" <a class=\"drug drug_general\" href=\"UTD.htm?41/10/42152?source=see_link\">",
" amoxicillin",
" </a>",
" and",
" <a class=\"drug drug_general\" href=\"UTD.htm?32/51/33584?source=see_link\">",
" moxifloxacin",
" </a>",
" significantly reduced bacteremia rates (46 and 57, 11 and 24, and 4 and 7
percent at 30 seconds, 15 minutes, and one hour, respectively).",
" </p>",
" <p>",
" The results of this study may not be generalizable to all populations, as a
high prevalence of resistant oral flora is a particular concern in this geographic
region. In addition, the baseline (before dental extraction) rates of bacteremia, 5
to 13 percent in the study groups, may in part be due to drawing the blood for
culture from an indwelling catheter. Reports of antibiotic prophylaxis failure
with",
" <a class=\"drug drug_general\" href=\"UTD.htm?32/21/33104?source=see_link\">",
" clindamycin",
" </a>",
" for dental extractions remain rare [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/9,10\">",
" 9,10",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H6\">",
" <span class=\"h3\">",
" Prevention of endocarditis",
" </span>",
" &nbsp;&mdash;&nbsp;Although biologic plausibility is very high, no study in
humans has definitively demonstrated that prophylactic antibiotics prevent
endocarditis after invasive procedures. Only observational studies are available,
with conflicting evidence of treatment benefit [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/11,12\">",
" 11,12",
" </a>",
" ].",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" A case control study compared 273 patients with community-acquired
endocarditis, who were not injection drug users, and an equal number of controls
matched for age, sex, and neighborhood to assess the risk of endocarditis following
dental procedures [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/13\">",
" 13",
" </a>",
" ]. Dental procedures were not more frequent in case patients than controls
during one, two, or three months before the diagnosis of the infection, even in
patients with endocarditis caused by recognized dental flora. The type of dental
procedure also did not appear to affect the risk of infection, although the number
of extractions among cases and controls were not sufficient to include this in the
analysis. Known valvular abnormality, not the dental procedure, was the major risk
factor for endocarditis in this study with prior cardiac valve surgery and a
previous episode of endocarditis being the two most significant (adjusted odds
ratios of 75 and 37, respectively).",
" <br/>",
" <br/>",
" The authors concluded that dental treatment does not seem to be a risk
factor for infective endocarditis, even in patients with valvular abnormalities,
and that few cases of infective endocarditis would be preventable with antibiotic
prophylaxis. An editorial accompanying this study suggested that the time had
arrived to refine guidelines for antimicrobial prophylaxis to markedly reduce the
number of patients for whom prophylaxis is recommended [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/14\">",
" 14",
" </a>",
" ].",
" </li>",
" <li>",
" A small observational study published in the 1980s evaluated 304 patients
with prosthetic heart valves who received antibiotics immediately prior to
undergoing invasive procedures thought to be capable of causing bacteremia with
organisms known or likely to cause endocarditis; the outcome was compared with that
in 229 similar patients with prosthetic heart valves who did not receive
antimicrobial therapy [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/15\">",
" 15",
" </a>",
" ]. Endocarditis developed in none of the 304 treated patients compared with
6 of the 220 (2.7 percent) untreated patients. The risk of endocarditis in this
nonrandomized study was higher than in subsequent epidemiological studies.",
" </li>",
" <li>",
" An epidemiologic study from France estimated that the risk of developing IE
following a dental procedure in adults with predisposing cardiac conditions was 1
in 11,000 for patients with prosthetic valves and no prophylaxis, 1 in 54,000 for
patients with native valves and no prophylaxis, and 1 in 150,000 for patients who
received prophylaxis [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/16\">",
" 16",
" </a>",
" ]. Thus, a large number of prophylaxis doses would be necessary to prevent a
very small number of IE cases, suggesting that only the highest-risk procedures and
populations should receive prophylaxis.",
" </li>",
" <li>",
" Two other studies that attempted to demonstrate the efficacy of IE
prophylaxis prior to dental work provided conflicting results: one suggested
benefit [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/17\">",
" 17",
" </a>",
" ] and the other did not [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/18\">",
" 18",
" </a>",
" ]. However, both studies had serious limitations in design or lacked
statistical power to demonstrate efficacy [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/3\">",
" 3",
" </a>",
" ].",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H7\">",
" <span class=\"h3\">",
" Failure of prophylaxis",
" </span>",
" &nbsp;&mdash;&nbsp;Given the limited evidence of benefit, it is not surprising
that failure of currently recommended prophylactic antibiotic regimens occasionally
occurs. One report, for example, evaluated 52 cases of IE that occurred despite
receipt of antimicrobial therapy prior to invasive surgical procedures [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/9\">",
" 9",
" </a>",
" ]. Approximately two-thirds of the pathogens causing endocarditis were
susceptible in vitro to the prophylactic antimicrobial agents that were
administered.",
" </p>",
" <p>",
" It has been estimated that, even if antimicrobial prophylaxis were assumed to
be 100 percent effective, less than 10 percent of all cases of endocarditis could
be prevented by the proper use of antimicrobial therapy before invasive procedures
[",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/10\">",
" 10",
" </a>",
" ]. Various epidemiologic studies have shown that between 2.7 and 5 percent of
all cases of endocarditis are preceded by a dental procedure [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/1\">",
" 1",
" </a>",
" ]. However, even in cases in which there is a close temporal relationship
between a dental procedure and the occurrence of endocarditis, it is impossible to
know whether this is a causal relationship, as it is possible that endocarditis
occurred as a consequence of the dental condition that led to the procedure or from
daily activity such as tooth brushing.",
" </p>",
" <p class=\"headingAnchor\" id=\"H22969468\">",
" <span class=\"h1\">",
" GUIDELINES",
" </span>",
" </p>",
" <p class=\"headingAnchor\" id=\"H8\">",
" <span class=\"h2\">",
" AHA guideline",
" </span>",
" &nbsp;&mdash;&nbsp;The 2007 American Heart Association (AHA) guideline for the
prevention of infective endocarditis (IE) [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/2\">",
" 2",
" </a>",
" ] made major revisions to the 1997 AHA guideline, the 2005 update of those
guidelines published by the Medical Letter [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/19\">",
" 19",
" </a>",
" ], and the 2006",
" <span class=\"nowrap\">",
" ACC/AHA",
" </span>",
" guideline on the management of valvular heart disease [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/20\">",
" 20",
" </a>",
" ]. Since the publication of the 2007 AHA guideline, the",
" <span class=\"nowrap\">",
" ACC/AHA",
" </span>",
" guideline was updated in 2008 [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/21\">",
" 21",
" </a>",
" ]. The 2009 European Society of Cardiology (ESC) guidelines are largely in
agreement with the American guidelines [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/22\">",
" 22",
" </a>",
" ].",
" </p>",
" <p>",
" The recommendation for antimicrobial prophylaxis for dental and other
procedures (and others) is now limited to those patients with cardiac conditions
with the highest risk of adverse outcome from IE [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/2\">",
" 2",
" </a>",
" ]. In contrast, the prior guidelines recommended prophylaxis for patients at
moderate to high risk of IE, a much larger population [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/19,20\">",
" 19,20",
" </a>",
" ]. (See",
" <a class=\"local\" href=\"#H9\">",
" 'Patients at highest risk'",
" </a>",
" below.)",
" </p>",
" <p>",
" The rationale for this change was to make guidelines more evidence-based
since, as noted above, there is no convincing evidence that antimicrobial
prophylaxis provides significant benefit in most patients in terms of prevention of
IE. This change has the added advantage of simplifying care for practitioners and
patients. (See",
" <a class=\"local\" href=\"#H6\">",
" 'Prevention of endocarditis'",
" </a>",
" above.)",
" </p>",
" <p>",
" The following points were made by the AHA in support of their recommendation
for the important change [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/2\">",
" 2",
" </a>",
" ]:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" IE is much more likely to result from frequent exposure to random
bacteremias associated with daily activities (eg, tooth brushing) than from
bacteremia caused by a dental, gastrointestinal, or genitourinary procedure.",
" </li>",
" <li>",
" Prophylaxis may prevent an exceedingly small number of cases of IE, if any,
in individuals who undergo these procedures.",
" </li>",
" <li>",
" The risk of antibiotic-associated adverse events exceeds the benefit, if
any, from prophylactic antibiotic therapy.",
" </li>",
" <li>",
" Maintenance of optimal oral health and hygiene may reduce the incidence of
bacteremia from daily activities and is therefore more important than prophylactic
antibiotics for a dental procedure to reduce the risk of IE.",
" </li>",
" </ul>",
" </p>",
" <p>",
" The guideline recommendations were based upon results of in vitro studies,
clinical experience, data from experimental animal models, and assessment of both
the bacteria most likely to produce bacteremia from a given site and those most
likely to result in endocarditis. An analysis of data collected between 1999 and
2010 in a Minnesota county concluded that there was no increase in incidence of IE
due to S. viridans following publication of the 2007 guidelines [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/23\">",
" 23",
" </a>",
" ].",
" </p>",
" <p>",
" The guidelines are not intended to be the standard of care in all instances in
which prophylactic antibiotic therapy might be considered [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/2\">",
" 2",
" </a>",
" ]. Clinicians can exercise their own judgment in selecting the dose and
duration of antibiotic therapy in individual cases or in special circumstances.",
" </p>",
" <p class=\"headingAnchor\" id=\"H9\">",
" <span class=\"h3\">",
" Patients at highest risk",
" </span>",
" &nbsp;&mdash;&nbsp;Prophylaxis was recommended only in those settings
associated with the highest risk of developing an adverse outcome if IE was to
occur [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/2\">",
" 2",
" </a>",
" ]. Patients with the following cardiac conditions were considered to meet this
criterion:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Prosthetic heart valves, including bioprosthetic and homograft valves.
(See",
" <a class=\"medical medical_review\" href=\"UTD.htm?14/56/15238?
source=see_link&amp;anchor=H7#H7\">",
" \"Management of patients with prosthetic heart valves\", section on
'Endocarditis prophylaxis'",
" </a>",
" .)",
" </li>",
" <li>",
" Prosthetic material used for cardiac valve repair",
" </li>",
" <li>",
" A prior history of IE.",
" </li>",
" <li>",
" Unrepaired cyanotic congenital heart disease, including palliative shunts
and conduits.",
" </li>",
" <li>",
" Completely repaired congenital heart defects with prosthetic material or
device, whether placed by surgery or by catheter intervention, during the first six
months after the procedure.",
" </li>",
" <li>",
" Repaired congenital heart disease with residual defects at the site or
adjacent to the site of the prosthetic device.",
" </li>",
" <li>",
" Cardiac \"valvulopathy\" in a transplanted heart. Valvulopathy is defined as
documentation of substantial leaflet pathology and regurgitation [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/24\">",
" 24",
" </a>",
" ].",
" </li>",
" </ul>",
" </p>",
" <p>",
" Similar limited criteria for prophylaxis were proposed in 2006 by the Working
Party of the British Society for Antimicrobial Chemotherapy [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/24\">",
" 24",
" </a>",
" ]. \"Valvulopathy\" in a transplanted heart was not included, but these
guidelines also included complex left ventricular outflow abnormalities including
aortic stenosis and bicuspid aortic valves, or acquired valvulopathy or mitral
valve prolapse with echocardiographic evidence of substantial leaflet pathology and
regurgitation [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/24\">",
" 24",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H10\">",
" <span class=\"h4\">",
" No longer indicated",
" </span>",
" &nbsp;&mdash;&nbsp;Common valvular lesions for which antimicrobial prophylaxis
is no longer recommended in the 2007 AHA guidelines include bicuspid aortic valve,
acquired aortic or mitral valve disease (including mitral valve prolapse with
regurgitation), and hypertrophic cardiomyopathy with latent or resting
obstruction.",
" </p>",
" <p class=\"headingAnchor\" id=\"H11\">",
" <span class=\"h3\">",
" Procedures that may result in transient bacteremia",
" </span>",
" &nbsp;&mdash;&nbsp;The 2007 AHA guidelines recommend that antimicrobial
prophylaxis be given to patients with the cardiac lesions cited above when they
undergo procedures likely to result in bacteremia with a microorganism that has the
potential ability to cause endocarditis [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/2\">",
" 2",
" </a>",
" ]. (See",
" <a class=\"local\" href=\"#H9\">",
" 'Patients at highest risk'",
" </a>",
" above.)",
" </p>",
" <p class=\"headingAnchor\" id=\"H12\">",
" <span class=\"h4\">",
" Dental",
" </span>",
" &nbsp;&mdash;&nbsp;The risk of IE is generally considered to be the highest
for dental procedures that involve manipulation of gingival tissue or the
periapical region of the teeth, or perforation of the oral mucosa; this does not
include routine cleaning [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/2,24\">",
" 2,24",
" </a>",
" ].",
" </p>",
" <p>",
" All individuals at risk for developing IE should establish and maintain a
program of oral health care including regular professional care, the regular use of
manual or powered toothbrushes, dental floss, and other plaque removing devices.",
" </p>",
" <p class=\"headingAnchor\" id=\"H13\">",
" <span class=\"h4\">",
" Respiratory tract",
" </span>",
" &nbsp;&mdash;&nbsp;Although a variety of organisms may cause bacteremia during
respiratory tract procedures, there is no direct evidence that such bacteremias
cause IE. The AHA guideline does not recommend routine antimicrobial prophylaxis
for procedures unless they involve incision or biopsy of the respiratory tract
mucosa [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/2\">",
" 2",
" </a>",
" ]. Examples of such procedures include tonsillectomy, adenoidectomy, or
bronchoscopy with biopsy.",
" </p>",
" <p>",
" In patients who undergo an invasive respiratory tract procedure as part of the
treatment of an established infection:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" The ongoing antibiotic regimen should include an agent that is active
against viridans group streptococci.",
" </li>",
" <li>",
" In patients who have a respiratory tract infection that is known or
suspected to be caused by Staphylococcus aureus, the regimen should include an
agent active against S. aureus.",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H14\">",
" <span class=\"h4\">",
" Genitourinary and gastrointestinal tracts",
" </span>",
" &nbsp;&mdash;&nbsp;The risk of bacteremia is significantly lower for invasive
genitourinary (GU) procedures such as dilation of strictures, insertions of
catheters, and prostatectomy compared with dental or respiratory tract infections.
Invasive gastrointestinal (GI) procedures, such as lower bowel endoscopy with
biopsy or endoscopic retrograde cholangiopancreatography, have an even lower risk
of IE since bacteremia due to organisms capable of causing endocarditis occurs in
less than 5 to 10 percent of cases.",
" </p>",
" <p>",
" The AHA guidelines no longer consider any GI (including diagnostic colonoscopy
or esophagogastroduodenoscopy) or GU procedures high risk and therefore do not
recommend routine use of IE prophylaxis even in patients with the highest risk
cardiac conditions defined above [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/2\">",
" 2",
" </a>",
" ]. Data evaluating the risk of IE associated with GI endoscopy are discussed
in detail elsewhere. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?40/25/41367?
source=see_link\">",
" \"Antibiotic prophylaxis for gastrointestinal endoscopic procedures\"",
" </a>",
" .)",
" </p>",
" <p>",
" Some patients with established infections of the GI or GU tract may have
enterococcal bacteremia. For patients with the highest risk cardiac conditions who
have ongoing GI or GU tract infection or who are undergoing a procedure for which
antibiotic therapy to prevent wound infection or sepsis is indicated, the AHA
suggests an antibiotic regimen that includes an agent active against enterococci.
(See",
" <a class=\"local\" href=\"#H17\">",
" 'Choice of antimicrobial agent'",
" </a>",
" below.)",
" </p>",
" <p>",
" For those patients with an enterococcal urinary tract infection or
colonization scheduled to undergo elective cystoscopy or urinary tract
manipulation, eradication of the organism prior to the procedure should be
attempted.",
" </p>",
" <p class=\"headingAnchor\" id=\"H15\">",
" <span class=\"h4\">",
" Vaginal or cesarean delivery",
" </span>",
" &nbsp;&mdash;&nbsp;Vaginal or cesarean delivery is not an indication for
routine antibiotic prophylaxis since the rate of bacteremia with these procedures
is low [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/3,25\">",
" 3,25",
" </a>",
" ]. The 2007 AHA guidelines specify that prophylaxis is not indicated for
vaginal delivery or cesarean section [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/2,26\">",
" 2,26",
" </a>",
" ], and the 2008",
" <span class=\"nowrap\">",
" AHA/ACC",
" </span>",
" guidelines note that antibiotic prophylaxis is not recommended for
genitourinary procedures [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/21\">",
" 21",
" </a>",
" ].",
" </p>",
" <p>",
" The American College of Obstetricians and Gynecologists (ACOG), Committee on
Obstetic Practice has endorsed the 2007 AHA recommendations, noting that infective
endocarditis prophylaxis is not recommended for vaginal or cesarean delivery in the
absence of infection [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/27\">",
" 27",
" </a>",
" ]. In patients with the highest risk lesions with established infection that
could cause bacteremia (such as chorioamnionitis or pyelonephritis) the underlying
infection should be treated in the usual fashion; treatment should include an
intravenous regimen effective for infective endocarditis prophylaxis. (See",
" <a class=\"local\" href=\"#H9\">",
" 'Patients at highest risk'",
" </a>",
" above and",
" <a class=\"medical medical_review\" href=\"UTD.htm?41/48/42761?
source=see_link\">",
" \"Intraamniotic infection (chorioamnionitis)\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?42/40/43657?
source=see_link&amp;anchor=H18#H18\">",
" \"Urinary tract infections and asymptomatic bacteriuria in pregnancy\",
section on 'Acute pyelonephritis'",
" </a>",
" .)",
" </p>",
" <p>",
" The 2008",
" <span class=\"nowrap\">",
" ACC/AHA",
" </span>",
" guidelines for management of adults with congenital heart disease contain
antibiotic prophylaxis recommendations that generally agree with the 2007 AHA
prophylaxis guidelines [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/28\">",
" 28",
" </a>",
" ]. However, the 2008",
" <span class=\"nowrap\">",
" ACC/AHA",
" </span>",
" adult congenital heart disease guidelines include a recommendation that is it
reasonable to consider antibiotic prophylaxis against infective endocarditis before
vaginal delivery at the time of membrane rupture in select patients with the
highest risk of adverse outcomes. This includes patients with prosthetic cardiac
valve or prosthetic material used for cardiac valve repair and patients or
unrepaired or palliated cyanotic heart disease, including surgically constructed
palliative shunts and conduits. However, proof of efficacy of prophylaxis in this
setting is not available.",
" </p>",
" <p class=\"headingAnchor\" id=\"H16\">",
" <span class=\"h4\">",
" Skin or musculoskeletal tissue",
" </span>",
" &nbsp;&mdash;&nbsp;Patients with infected skin, skin structure, or
musculoskeletal tissue may have polymicrobial infections. When such patients
undergo a surgical procedure, only bacteremia with staphylococci or beta-hemolytic
streptococci are likely to cause IE. The appropriate antibiotic regimen is
discussed below. (See",
" <a class=\"local\" href=\"#H23\">",
" 'Special circumstances'",
" </a>",
" below.)",
" </p>",
" <p class=\"headingAnchor\" id=\"H22969737\">",
" <span class=\"h2\">",
" NICE guideline",
" </span>",
" &nbsp;&mdash;&nbsp;The United Kingdom National Institute for Health and
Clinical Excellence (NICE) published a guideline in 2008 recommending that NO
antimicrobial prophylaxis for IE be administered prior to dental or other invasive
procedures [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/29\">",
" 29",
" </a>",
" ]. In the two years following the issuance of these guidelines, a
&lsquo;before and after&rsquo; study noted a 78 percent reduction in antibiotic
prophylaxis prescriptions after the guidelines were introduced, with no significant
increase in the incidence of infective endocarditis [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/30\">",
" 30",
" </a>",
" ].",
" </p>",
" <p>",
" These findings do not exclude the possibility that antibiotic prophylaxis may
benefit some high risk patients (eg those with prosthetic valves, congenital heart
disease or a history IE), for whom prophylaxis is still recommended in Europe and
the United States.",
" </p>",
" <p class=\"headingAnchor\" id=\"H17\">",
" <span class=\"h1\">",
" CHOICE OF ANTIMICROBIAL AGENT",
" </span>",
" &nbsp;&mdash;&nbsp;Among the selected patients for whom antimicrobial
prophylaxis is suggested, the antimicrobial regimen recommended by the AHA
guidelines varies with the procedure being performed (",
" <a class=\"graphic graphic_table graphicRef57182 \" href=\"UTD.htm?
39/63/40956\">",
" table 1",
" </a>",
" )&nbsp;[",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/2\">",
" 2",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H18\">",
" <span class=\"h2\">",
" Dental, oral, or upper respiratory tract procedures",
" </span>",
" &nbsp;&mdash;&nbsp;The primary antibiotic regimen for most patients, including
those with prosthetic valves, is",
" <a class=\"drug drug_general\" href=\"UTD.htm?41/10/42152?source=see_link\">",
" amoxicillin",
" </a>",
" , 2 g orally 30 to 60 minutes before the procedure; a second dose is not
necessary [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/2,31\">",
" 2,31",
" </a>",
" ].",
" </p>",
" <p>",
" A different regimen is warranted in the following circumstances; all drugs are
given 30 to 60 minutes before the procedure [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/2\">",
" 2",
" </a>",
" ]:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Patients who are allergic to penicillins or",
" <a class=\"drug drug_general\" href=\"UTD.htm?12/51/13112?
source=see_link\">",
" ampicillin",
" </a>",
" can be treated with",
" <a class=\"drug drug_general\" href=\"UTD.htm?36/37/37462?
source=see_link\">",
" cephalexin",
" </a>",
" (2 g) or",
" <a class=\"drug drug_general\" href=\"UTD.htm?32/43/33456?
source=see_link\">",
" azithromycin",
" </a>",
" or",
" <a class=\"drug drug_general\" href=\"UTD.htm?9/57/10138?
source=see_link\">",
" clarithromycin",
" </a>",
" (500 mg) or",
" <a class=\"drug drug_general\" href=\"UTD.htm?32/21/33104?
source=see_link\">",
" clindamycin",
" </a>",
" (600 mg).",
" </li>",
" <li>",
" Patients who are unable to take oral medications can be treated with 2 g of
intravenous or intramuscular",
" <a class=\"drug drug_general\" href=\"UTD.htm?12/51/13112?
source=see_link\">",
" ampicillin",
" </a>",
" . Patients allergic to penicillin can be given",
" <a class=\"drug drug_general\" href=\"UTD.htm?4/2/4136?source=see_link\">",
" cefazolin",
" </a>",
" or",
" <a class=\"drug drug_general\" href=\"UTD.htm?10/17/10521?
source=see_link\">",
" ceftriaxone",
" </a>",
" (1 g intravenously) OR 600 mg of intravenous or intramuscular",
" <a class=\"drug drug_general\" href=\"UTD.htm?32/21/33104?
source=see_link\">",
" clindamycin",
" </a>",
" .",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H19\">",
" <span class=\"h2\">",
" Genitourinary or gastrointestinal procedures",
" </span>",
" &nbsp;&mdash;&nbsp;For those high risk patients who undergo gastrointestinal
or genitourinary procedures at a time of ongoing gastrointestinal or genitourinary
infection, antibiotic coverage for enterococcal bacteremia should be provided
with",
" <a class=\"drug drug_general\" href=\"UTD.htm?41/10/42152?source=see_link\">",
" amoxicillin",
" </a>",
" or",
" <a class=\"drug drug_general\" href=\"UTD.htm?12/51/13112?source=see_link\">",
" ampicillin",
" </a>",
" or, in the patient unable to tolerate these drugs,",
" <a class=\"drug drug_general\" href=\"UTD.htm?41/41/42649?source=see_link\">",
" vancomycin",
" </a>",
" . (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?40/25/41367?
source=see_link\">",
" \"Antibiotic prophylaxis for gastrointestinal endoscopic procedures\"",
" </a>",
" and",
" <a class=\"local\" href=\"#H11\">",
" 'Procedures that may result in transient bacteremia'",
" </a>",
" above.)",
" </p>",
" <p class=\"headingAnchor\" id=\"H20\">",
" <span class=\"h2\">",
" Skin and musculoskeletal tissue",
" </span>",
" &nbsp;&mdash;&nbsp;Although infection of the skin or musculoskeletal tissue is
often polymicrobial, only staphylococcal or beta-hemolytic streptococcal bacteremia
is likely to cause endocarditis in such circumstances. Thus, an antistaphylococcal
penicillin or a cephalosporin is appropriate (",
" <a class=\"graphic graphic_table graphicRef57182 \" href=\"UTD.htm?
39/63/40956\">",
" table 1",
" </a>",
" ). In patients undergoing procedures involving infected skin and
musculoskeletal tissue (eg, incision and drainage of skin abscess), the treatment
regimen should include drugs active against these organisms.",
" <a class=\"drug drug_general\" href=\"UTD.htm?32/21/33104?source=see_link\">",
" Clindamycin",
" </a>",
" or",
" <a class=\"drug drug_general\" href=\"UTD.htm?41/41/42649?source=see_link\">",
" vancomycin",
" </a>",
" may be used when the patient is unable to take a beta-lactam or is known or
suspected to have an infection caused by a methicillin-resistant staphylococcus.
(See",
" <a class=\"medical medical_review\" href=\"UTD.htm?42/51/43831?
source=see_link\">",
" \"Skin abscesses, furuncles, and carbuncles\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H21\">",
" <span class=\"h2\">",
" Pregnancy",
" </span>",
" &nbsp;&mdash;&nbsp;As noted above, uncomplicated vaginal or cesarean delivery
is not a routine indication for antibiotic prophylaxis although prophylaxis may be
considered in certain circumstances. (See",
" <a class=\"local\" href=\"#H15\">",
" 'Vaginal or cesarean delivery'",
" </a>",
" above.)",
" </p>",
" <p>",
" If antibiotic prophylaxis is given to prevent enterococcal endocarditis,",
" <a class=\"drug drug_general\" href=\"UTD.htm?41/10/42152?source=see_link\">",
" amoxicillin",
" </a>",
" ,",
" <a class=\"drug drug_general\" href=\"UTD.htm?12/51/13112?source=see_link\">",
" ampicillin",
" </a>",
" , and",
" <a class=\"drug drug_general\" href=\"UTD.htm?41/41/42649?source=see_link\">",
" vancomycin",
" </a>",
" are appropriate agents and they should be administered at the time of
delivery.",
" </p>",
" <p class=\"headingAnchor\" id=\"H22\">",
" <span class=\"h2\">",
" Children",
" </span>",
" &nbsp;&mdash;&nbsp;Children given endocarditis prophylaxis should receive the
same antibiotic regimens and dosing intervals as noted above. Equivalent pediatric
doses for oral therapy are as follows:",
" </p>",
" <p>",
" <ul class=\"bulletCompact-block\">",
" <li>",
" <a class=\"drug drug_general\" href=\"UTD.htm?41/10/42152?
source=see_link\">",
" Amoxicillin",
" </a>",
" &mdash; 50",
" <span class=\"nowrap\">",
" mg/kg",
" </span>",
" to a maximum dose of 2 g",
" </li>",
" <li>",
" <a class=\"drug drug_general\" href=\"UTD.htm?32/43/33456?
source=see_link\">",
" Azithromycin",
" </a>",
" or",
" <a class=\"drug drug_general\" href=\"UTD.htm?9/57/10138?
source=see_link\">",
" clarithromycin",
" </a>",
" &mdash; 15",
" <span class=\"nowrap\">",
" mg/kg",
" </span>",
" to a maximum dose of 500 mg",
" </li>",
" <li>",
" <a class=\"drug drug_general\" href=\"UTD.htm?32/21/33104?
source=see_link\">",
" Clindamycin",
" </a>",
" &mdash;20",
" <span class=\"nowrap\">",
" mg/kg",
" </span>",
" to a maximum dose of 600 mg",
" </li>",
" <li>",
" <a class=\"drug drug_general\" href=\"UTD.htm?36/37/37462?
source=see_link\">",
" Cephalexin",
" </a>",
" &mdash; 50",
" <span class=\"nowrap\">",
" mg/kg",
" </span>",
" to a maximum dose of 2 g",
" </li>",
" </ul>",
" </p>",
" <p>",
" Equivalent pediatric doses for intramuscular or intravenous therapy are as
follows:",
" </p>",
" <p>",
" <ul class=\"bulletCompact-block\">",
" <li>",
" <a class=\"drug drug_general\" href=\"UTD.htm?12/51/13112?
source=see_link\">",
" Ampicillin",
" </a>",
" &mdash; 50",
" <span class=\"nowrap\">",
" mg/kg",
" </span>",
" to a maximum dose of 2 g",
" </li>",
" <li>",
" <a class=\"drug drug_general\" href=\"UTD.htm?4/2/4136?source=see_link\">",
" Cefazolin",
" </a>",
" or",
" <a class=\"drug drug_general\" href=\"UTD.htm?10/17/10521?
source=see_link\">",
" ceftriaxone",
" </a>",
" &mdash; 50",
" <span class=\"nowrap\">",
" mg/kg",
" </span>",
" to a maximum dose of 1 g",
" </li>",
" <li>",
" <a class=\"drug drug_general\" href=\"UTD.htm?32/21/33104?
source=see_link\">",
" Clindamycin",
" </a>",
" &mdash; 20",
" <span class=\"nowrap\">",
" mg/kg",
" </span>",
" to a maximum dose of 600 mg",
" </li>",
" <li>",
" <a class=\"drug drug_general\" href=\"UTD.htm?41/41/42649?
source=see_link\">",
" Vancomycin",
" </a>",
" &mdash; 15",
" <span class=\"nowrap\">",
" mg/kg",
" </span>",
" to a maximum dose of 1 g",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H23\">",
" <span class=\"h1\">",
" SPECIAL CIRCUMSTANCES",
" </span>",
" &nbsp;&mdash;&nbsp;The following four situations require special attention:",
" </p>",
" <p class=\"headingAnchor\" id=\"H24\">",
" <span class=\"h2\">",
" Patients on antibiotics",
" </span>",
" &nbsp;&mdash;&nbsp;If patients are receiving antibiotics for other indications
at the time that dental or invasive procedures are undertaken, an alternate
antibiotic of a different class is often chosen. As an example, if a patient
receiving penicillin for rheumatic fever prophylaxis undergoes an invasive dental
procedure and requires IE prophylaxis,",
" <a class=\"drug drug_general\" href=\"UTD.htm?32/21/33104?source=see_link\">",
" clindamycin",
" </a>",
" ,",
" <a class=\"drug drug_general\" href=\"UTD.htm?36/37/37462?source=see_link\">",
" cephalexin",
" </a>",
" , or",
" <a class=\"drug drug_general\" href=\"UTD.htm?32/43/33456?source=see_link\">",
" azithromycin",
" </a>",
" is often chosen.",
" </p>",
" <p class=\"headingAnchor\" id=\"H25\">",
" <span class=\"h2\">",
" Patients receiving anticoagulants",
" </span>",
" &nbsp;&mdash;&nbsp;Intramuscular injections of antibiotics should be avoided
in patients receiving anticoagulation therapy. Oral antibiotic regimens are
preferred, and intravenous therapy should be used when oral treatment is not
possible.",
" </p>",
" <p class=\"headingAnchor\" id=\"H26\">",
" <span class=\"h2\">",
" Surgery for placement of prosthetic valves or intracardiac/intravascular
materials",
" </span>",
" &nbsp;&mdash;&nbsp;Patients undergoing surgery for placement of prosthetic
valves or intracardiac or intravascular materials are at risk for the development
of bacterial endocarditis [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/32\">",
" 32",
" </a>",
" ]. In this setting the morbidity and mortality of infection is high and
antimicrobial prophylaxis directed against staphylococci is advisable. First
generation cephalosporins are often used, but local hospital susceptibility
patterns need to be taken into account, and if methicillin-resistant staphylococci
are common or prevalent local pathogens,",
" <a class=\"drug drug_general\" href=\"UTD.htm?41/41/42649?source=see_link\">",
" vancomycin",
" </a>",
" should be substituted for cephalosporins.",
" </p>",
" <p class=\"headingAnchor\" id=\"PATIENT_INFORMATION\">",
" <span class=\"h1\">",
" INFORMATION FOR PATIENTS",
" </span>",
" &nbsp;&mdash;&nbsp;UpToDate offers two types of patient education materials,
&ldquo;The Basics&rdquo; and &ldquo;Beyond the Basics.&rdquo; The Basics patient
education pieces are written in plain language, at the 5",
" ^{",
" th",
"}",
" to 6",
" ^{",
" th",
"}",
" grade reading level, and they answer the four or five key questions a patient
might have about a given condition. These articles are best for patients who want a
general overview and who prefer short, easy-to-read materials. Beyond the Basics
patient education pieces are longer, more sophisticated, and more detailed. These
articles are written at the 10",
" ^{",
" th",
"}",
" to 12",
" ^{",
" th",
"}",
" grade reading level and are best for patients who want in-depth information
and are comfortable with some medical jargon.",
" </p>",
" <p>",
" Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also
locate patient education articles on a variety of subjects by searching on
&ldquo;patient info&rdquo; and the keyword(s) of interest.)",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Basics topics (see",
" <a class=\"medical medical_basics\" href=\"UTD.htm?25/48/26370?
source=see_link\">",
" \"Patient information: Endocarditis (The Basics)\"",
" </a>",
" )",
" </li>",
" <li>",
" Beyond the Basics topics (see",
" <a class=\"medical medical_patient\" href=\"UTD.htm?30/37/31314?
source=see_link\">",
" \"Patient information: Antibiotics before procedures (Beyond the
Basics)\"",
" </a>",
" )",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H27\">",
" <span class=\"h1\">",
" SUMMARY AND RECOMMENDATIONS",
" </span>",
" &nbsp;&mdash;&nbsp;Despite the devastating consequences of bacterial
endocarditis, evidence to support antimicrobial prophylaxis as an effective
preventative measure is weak and inconclusive. The 2007 AHA guideline for the
prevention of infective endocarditis, with which we agree, has narrowed the
indications for bacterial endocarditis prophylaxis, compared with prior versions,
in recognition of the absence of strong supportive evidence [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/2\">",
" 2",
" </a>",
" ]. Similar indications were proposed in 2006 by the Working Party of the
British Society for Antimicrobial Chemotherapy [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/585/abstract/24\">",
" 24",
" </a>",
" ]. (See",
" <a class=\"local\" href=\"#H8\">",
" 'AHA guideline'",
" </a>",
" above.)",
" </p>",
" <p>",
" Despite a lack of evidence supporting the necessity of antimicrobial
prophylaxis for IE, we believe that it is reasonable to prescribe antimicrobial
prophylaxis for patients with the highest risk medical conditions undergoing
procedures likely to result in bacteremia with a microorganism that has the
potential ability to cause bacterial endocarditis (",
" <a class=\"grade\" href=\"._grade_6?title=Grade 2C\">",
" Grade 2C",
" </a>",
" ).",
" </p>",
" <p class=\"headingAnchor\" id=\"H28\">",
" <span class=\"h2\">",
" Which patients",
" </span>",
" &nbsp;&mdash;&nbsp;The following are the highest risk conditions (see",
" <a class=\"local\" href=\"#H9\">",
" 'Patients at highest risk'",
" </a>",
" above):",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Prosthetic heart valves, including bioprosthetic and homograft valves.",
" </li>",
" <li>",
" A prior history of IE.",
" </li>",
" <li>",
" Unrepaired cyanotic congenital heart disease, including palliative shunts
and conduits.",
" </li>",
" <li>",
" Completely repaired congenital heart defects with prosthetic material or
device, whether placed by surgery or by catheter intervention, during the first six
months after the procedure.",
" </li>",
" <li>",
" Repaired congenital heart disease with residual defects at the site or
adjacent to the site of the prosthetic device.",
" </li>",
" <li>",
" Cardiac valvulopathy in a transplanted heart.",
" </li>",
" </ul>",
" </p>",
" <p>",
" The following are the highest risk procedures (see",
" <a class=\"local\" href=\"#H11\">",
" 'Procedures that may result in transient bacteremia'",
" </a>",
" above):",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" All dental procedures that involve manipulation of either gingival tissue or
the periapical region of teeth or perforation of the oral mucosa.",
" </li>",
" <li>",
" Procedures of the respiratory tract that involve incision or biopsy of the
respiratory mucosa.",
" </li>",
" <li>",
" Procedures in patients with ongoing GI or GU tract infection.",
" </li>",
" <li>",
" Procedures on infected skin, skin structure, or musculoskeletal tissue.",
" </li>",
" <li>",
" Surgery to place prosthetic heart valves or prosthetic intravascular or
intracardiac materials. (See",
" <a class=\"local\" href=\"#H23\">",
" 'Special circumstances'",
" </a>",
" above.)",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H29\">",
" <span class=\"h2\">",
" Which antibiotic",
" </span>",
" &nbsp;&mdash;&nbsp;The choice of antibiotic is patient and procedure
specific.",
" </p>",
" <p>",
" For patients undergoing a dental procedure, who will be the majority of
individuals for whom prophylaxis is appropriate, the preferred regimen is oral",
" <a class=\"drug drug_general\" href=\"UTD.htm?41/10/42152?source=see_link\">",
" amoxicillin",
" </a>",
" 2 grams given 30 to 60 minutes before the procedure. Alternative regimens for
patients with penicillin allergy or who are unable to take oral medication are
shown above.",
" </p>",
" <p>",
" Regimens for non-dental procedures are described in detail above. Patients
with skin or musculoskeletal infections undergoing procedures should receive agents
active against staphylococci and beta-hemolytic streptococci. In patients with GI
or GU tract infection, antibiotic therapy to prevent associated wound infection or
sepsis should include an agent active against enterococci. (See",
" <a class=\"local\" href=\"#H17\">",
" 'Choice of antimicrobial agent'",
" </a>",
" above.)",
" </p>",
" </div>",
" <div id=\"topicAgreement\">",
" Use of UpToDate is subject to the",
" <a class=\"licenseLink\" href=\"./license\" id=\"sla_in_page\"
target=\"_blank\">",
" Subscription and License Agreement",
" </a>",
" .",
" </div>",
" <div class=\"headingAnchor\" id=\"references\">",
" <h1>",
" REFERENCES",
" </h1>",
" <ol id=\"reference\">",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/1\">",
" Duval X, Leport C. Prophylaxis of infective endocarditis: current
tendencies, continuing controversies. Lancet Infect Dis 2008; 8:225.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/2\">",
" Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis:
guidelines from the American Heart Association: a guideline from the American Heart
Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council
on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology,
Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and
Outcomes Research Interdisciplinary Working Group. Circulation 2007; 116:1736.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/3\">",
" Durack DT. Prevention of infective endocarditis. N Engl J Med 1995;
332:38.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/4\">",
" Glauser MP, Francioli P. Relevance of animal models to the prophylaxis of
infective endocarditis. J Antimicrob Chemother 1987; 20 Suppl A:87.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/5\">",
" Durack DT, Petersdorf RG. Chemotherapy of experimental streptococcal
endocarditis. I. Comparison of commonly recommended prophylactic regimens. J Clin
Invest 1973; 52:592.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/6\">",
" Lockhart PB, Brennan MT, Kent ML, et al. Impact of amoxicillin prophylaxis
on the incidence, nature, and duration of bacteremia in children after intubation
and dental procedures. Circulation 2004; 109:2878.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/7\">",
" Roberts GJ, Jaffray EC, Spratt DA, et al. Duration, prevalence and intensity
of bacteraemia after dental extractions in children. Heart 2006; 92:1274.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/8\">",
" Diz Dios P, Tom&aacute;s Carmona I, Limeres Posse J, et al. Comparative
efficacies of amoxicillin, clindamycin, and moxifloxacin in prevention of
bacteremia following dental extractions. Antimicrob Agents Chemother 2006;
50:2996.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/9\">",
" Durack DT, Kaplan EL, Bisno AL. Apparent failures of endocarditis
prophylaxis. Analysis of 52 cases submitted to a national registry. JAMA 1983;
250:2318.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/10\">",
" van der Meer JT, Thompson J, Valkenburg HA, Michel MF. Epidemiology of
bacterial endocarditis in The Netherlands. II. Antecedent procedures and use of
prophylaxis. Arch Intern Med 1992; 152:1869.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/11\">",
" Seto TB. The case for infectious endocarditis prophylaxis: time to move
forward. Arch Intern Med 2007; 167:327.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/12\">",
" Morris AM. Coming clean with antibiotic prophylaxis for infective
endocarditis. Arch Intern Med 2007; 167:330.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/13\">",
" Strom BL, Abrutyn E, Berlin JA, et al. Dental and cardiac risk factors for
infective endocarditis. A population-based, case-control study. Ann Intern Med
1998; 129:761.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/14\">",
" Durack DT. Antibiotics for prevention of endocarditis during dentistry: time
to scale back? Ann Intern Med 1998; 129:829.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/15\">",
" Horstkotte D, Rosin H, Friedrichs W, Loogen F. Contribution for choosing the
optimal prophylaxis of bacterial endocarditis. Eur Heart J 1987; 8(Suppl J):379.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/16\">",
" Duval X, Alla F, Hoen B, et al. Estimated risk of endocarditis in adults
with predisposing cardiac conditions undergoing dental procedures with or without
antibiotic prophylaxis. Clin Infect Dis 2006; 42:e102.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/17\">",
" Imperiale TF, Horwitz RI. Does prophylaxis prevent postdental infective
endocarditis? A controlled evaluation of protective efficacy. Am J Med 1990;
88:131.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/18\">",
" Van der Meer JT, Van Wijk W, Thompson J, et al. Efficacy of antibiotic
prophylaxis for prevention of native-valve endocarditis. Lancet 1992; 339:135.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/19\">",
" Antibacterial prophylaxis for dental, GI, and GU procedures. Med Lett Drugs
Ther 2005; 47:59.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/20\">",
" American College of Cardiology, American Heart Association Task Force on
Practice Guidelines (Writing Committee to revise the 1998 guidelines for the
management of patients with valvular heart disease), Society of Cardiovascular
Anesthesiologists, et al. ACC/AHA 2006 guidelines for the management of patients
with valvular heart disease: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines (writing
Committee to Revise the 1998 guidelines for the management of patients with
valvular heart disease) developed in collaboration with the Society of
Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular
Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll
Cardiol 2006; 48:e1.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/21\">",
" Nishimura RA, Carabello BA, Faxon DP, et al. ACC/AHA 2008 guideline update
on valvular heart disease: focused update on infective endocarditis: a report of
the American College of Cardiology/American Heart Association Task Force on
Practice Guidelines: endorsed by the Society of Cardiovascular Anesthesiologists,
Society for Cardiovascular Angiography and Interventions, and Society of Thoracic
Surgeons. Circulation 2008; 118:887.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/22\">",
" Habib G, Hoen B, Tornos P, et al. Guidelines on the prevention, diagnosis,
and treatment of infective endocarditis (new version 2009): the Task Force on the
Prevention, Diagnosis, and Treatment of Infective Endocarditis of the European
Society of Cardiology (ESC). Endorsed by the European Society of Clinical
Microbiology and Infectious Diseases (ESCMID) and the International Society of
Chemotherapy (ISC) for Infection and Cancer. Eur Heart J 2009; 30:2369.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/23\">",
" Desimone DC, Tleyjeh IM, Correa de Sa DD, et al. Incidence of infective
endocarditis caused by viridans group streptococci before and after publication of
the 2007 American Heart Association's endocarditis prevention guidelines.
Circulation 2012; 126:60.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/24\">",
" Gould FK, Elliott TS, Foweraker J, et al. Guidelines for the prevention of
endocarditis: report of the Working Party of the British Society for Antimicrobial
Chemotherapy. J Antimicrob Chemother 2006; 57:1035.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/25\">",
" Tower C, Nallapeta S, Vause S. Prophylaxis against infective endocarditis in
obstetrics: new NICE guidance: a commentary. BJOG 2008; 115:1601.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/26\">",
" Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial
endocarditis. Recommendations by the American Heart Association. Circulation 1997;
96:358.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/27\">",
" American College of Obstetricians and Gynecologists Committee on Obstetric
Practice. ACOG Committee Opinion No. 421, November 2008: antibiotic prophylaxis for
infective endocarditis. Obstet Gynecol 2008; 112:1193.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/28\">",
" Warnes CA, Williams RG, Bashore TM, et al. ACC/AHA 2008 Guidelines for the
Management of Adults with Congenital Heart Disease: a report of the American
College of Cardiology/American Heart Association Task Force on Practice Guidelines
(writing committee to develop guidelines on the management of adults with
congenital heart disease). Circulation 2008; 118:e714.",
" </a>",
" </li>",
" <li>",
" Prophylaxis against infective endocarditis. National Institute for Health and
Clinical Guidance, 2008. file://www.nice.org.uk/CG064 (Accessed on June 09,
2011).",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/30\">",
" Thornhill MH, Dayer MJ, Forde JM, et al. Impact of the NICE guideline
recommending cessation of antibiotic prophylaxis for prevention of infective
endocarditis: before and after study. BMJ 2011; 342:d2392.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/31\">",
" Dajani AS, Bawdon RE, Berry MC. Oral amoxicillin as prophylaxis for
endocarditis: what is the optimal dose? Clin Infect Dis 1994; 18:157.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/585/abstract/32\">",
" Baddour LM, Bettmann MA, Bolger AF, et al. Nonvalvular cardiovascular
device-related infections. Circulation 2003; 108:2015.",
" </a>",
" </li>",
" </ol>",
" </div>",
" <div id=\"topicVersionRevision\">",
" Topic 2147 Version 10.0",
" </div>",
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" <h1>",
" TOPIC OUTLINE",
" </h1>",
" <div id=\"outline\">",
" <ul>",
" <li>",
" <a class=\"sr_button\" href=\"#H27\" id=\"summRecButton\">",
" <span>",
" SUMMARY &amp; RECOMMENDATIONS",
" </span>",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H1\">",
" INTRODUCTION",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H2\">",
" THEORETICAL BASIS FOR PROPHYLAXIS",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H3\">",
" Animal studies",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H4\">",
" Human studies",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H5\">",
" - Prevention of bacteremia",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H6\">",
" - Prevention of endocarditis",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H7\">",
" - Failure of prophylaxis",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H22969468\">",
" GUIDELINES",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H8\">",
" AHA guideline",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H9\">",
" - Patients at highest risk",
" </a>",
" </li>",
" <li class=\"bulletItem2\">",
" <a class=\"outlineLink\" href=\"#H10\">",
" No longer indicated",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" <a class=\"outlineLink\" href=\"#H11\">",
" - Procedures that may result in transient bacteremia",
" </a>",
" </li>",
" <li class=\"bulletItem2\">",
" <a class=\"outlineLink\" href=\"#H12\">",
" Dental",
" </a>",
" </li>",
" <li class=\"bulletItem2\">",
" <a class=\"outlineLink\" href=\"#H13\">",
" Respiratory tract",
" </a>",
" </li>",
" <li class=\"bulletItem2\">",
" <a class=\"outlineLink\" href=\"#H14\">",
" Genitourinary and gastrointestinal tracts",
" </a>",
" </li>",
" <li class=\"bulletItem2\">",
" <a class=\"outlineLink\" href=\"#H15\">",
" Vaginal or cesarean delivery",
" </a>",
" </li>",
" <li class=\"bulletItem2\">",
" <a class=\"outlineLink\" href=\"#H16\">",
" Skin or musculoskeletal tissue",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H22969737\">",
" NICE guideline",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H17\">",
" CHOICE OF ANTIMICROBIAL AGENT",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H18\">",
" Dental, oral, or upper respiratory tract procedures",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H19\">",
" Genitourinary or gastrointestinal procedures",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H20\">",
" Skin and musculoskeletal tissue",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H21\">",
" Pregnancy",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H22\">",
" Children",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H23\">",
" SPECIAL CIRCUMSTANCES",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H24\">",
" Patients on antibiotics",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H25\">",
" Patients receiving anticoagulants",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H26\">",
" Surgery for placement of prosthetic valves or intracardiac/intravascular
materials",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#PATIENT_INFORMATION\">",
" INFORMATION FOR PATIENTS",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H27\">",
" SUMMARY AND RECOMMENDATIONS",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H28\">",
" Which patients",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" <a class=\"outlineLink\" href=\"#H29\">",
" Which antibiotic",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a href=\"#references\">",
" REFERENCES",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" <div class=\"openRelatedGraphics\" id=\"ID/2147\" rel=\"outline_link\">",
" GRAPHICS",
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" TABLES",
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" </li>",
" <li class=\"bulletItem\">",
" <a class=\"graphic graphic_table\" href=\"UTD.htm?39/63/40956\" title=\"table
1\">",
" Antibiotic regimens dental",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" RELATED TOPICS",
" </h1>",
" <div id=\"relatedTopics\">",
" <ul>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_review\" href=\"UTD.htm?40/25/41367?
source=related_link\">",
" Antibiotic prophylaxis for gastrointestinal endoscopic procedures",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_review\" href=\"UTD.htm?41/48/42761?
source=related_link\">",
" Intraamniotic infection (chorioamnionitis)",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"medical medical_review\" href=\"UTD.htm?14/56/15238?
source=related_link\">",
" Management of patients with prosthetic heart valves",
" </a>",
" </li>",
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var title_f0_36_586="Aplastic anemia: Pathogenesis; clinical manifestations; and
diagnosis";
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" <div id=\"topicTitle\">",
" Aplastic anemia: Pathogenesis; clinical manifestations; and diagnosis",
" </div>",
" <div id=\"topicContributors\">",
" <div>",
" <a id=\"authors\">",
" </a>",
" <a class=\"contributor contributor_credentials contributorType\"
href=\"UTD.htm?0/36/586/contributors\">",
" Author",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
0/36/586/contributors\">",
" Stanley L Schrier, MD",
" </a>",
" <br/>",
" </div>",
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" <a class=\"contributor contributor_credentials contributorType\"
href=\"UTD.htm?0/36/586/contributors\">",
" Section Editor",
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" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
0/36/586/contributors\">",
" William C Mentzer, MD",
" </a>",
" <br/>",
" </div>",
" <div>",
" <a class=\"contributor contributor_credentials contributorType\"
href=\"UTD.htm?0/36/586/contributors\">",
" Deputy Editor",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
0/36/586/contributors\">",
" Stephen A Landaw, MD, PhD",
" </a>",
" <br/>",
" </div>",
" </div>",
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" <a href=\"UTD.htm?0/36/586/contributor-disclosure\" target=\"_blank\">",
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" Literature review current through:",
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" Oct 2013.",
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" This topic last updated:",
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" Mar 12, 2013.",
" </div>",
" <div id=\"topicText\">",
" <p class=\"headingAnchor\" id=\"H1\">",
" <span class=\"h1\">",
" INTRODUCTION",
" </span>",
" &nbsp;&mdash;&nbsp;Aplastic anemia is characterized by diminished or absent
hematopoietic precursors in the bone marrow, most often due to injury to the
pluripotent stem cell. The designation \"aplastic anemia\" is a misnomer because
the disorder is defined as pancytopenia rather than anemia [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/1\">",
" 1",
" </a>",
" ]. The disease is estimated to occur in two to four subjects per million
population per year [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/1,2\">",
" 1,2",
" </a>",
" ].",
" </p>",
" <p>",
" This topic will review the pathogenesis, etiology, clinical manifestations,
diagnosis, and differential diagnosis of aplastic anemia [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/3-5\">",
" 3-5",
" </a>",
" ]. Prognosis and therapy are discussed separately. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?29/14/29930?
source=see_link\">",
" \"Aplastic anemia: Prognosis and treatment\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?17/50/18217?
source=see_link\">",
" \"Hematopoietic cell transplantation in aplastic anemia\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H2\">",
" <span class=\"h1\">",
" THE PLURIPOTENT STEM CELL",
" </span>",
" &nbsp;&mdash;&nbsp;Following the atomic bombings in World War II, there was
great interest in the effects of radiation. Lethally irradiated mice frequently
died as a consequence of neutropenic infections and thrombocytopenic hemorrhage.
Their marrow was found to be \"aplastic.\" That is, the myeloid and erythroid
precursors were absent, as were lymphocytes and megakaryocytes, leaving only fat
cells, stromal elements, and blood vessels. Two striking observations in this model
led to the discovery of the pluripotent hematopoietic stem cell, which could
reconstitute all of hematopoiesis and lymphopoiesis:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" The animals did not die if the spleen was exteriorized and shielded from
irradiation [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/6\">",
" 6",
" </a>",
" ]. Injection of a suspension of spleen cells could also minimize the
pancytopenia and prevent death in lethally irradiated mice [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/7\">",
" 7",
" </a>",
" ].",
" </li>",
" <li>",
" Injections of dilute suspensions of syngeneic bone marrow cells into
lethally irradiated mice provided protection; in addition, microscopically visible
colonies were present in the spleen (CFU-S) at 10 to 14 days [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/8\">",
" 8",
" </a>",
" ]. Most of the colonies appeared to be purely erythroid or myeloid, although
some were mixed. Injection of suspensions of \"pure\" differentiated colonies into
lethally irradiated mice led to protection and reconstitution of hematopoiesis,
with macroscopic spleen colonies showing the usual mix of \"pure\" and mixed
lineages [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/9\">",
" 9",
" </a>",
" ]. Experiments using karyotypic markers showed that each spleen colony was a
clone (ie, derived from a single cell).",
" </li>",
" </ul>",
" </p>",
" <p>",
" These colony forming units-spleen (CFU-S) could be studied, and were found in
murine spleen, marrow, and some lymph nodes. They had the following
characteristics:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" They were usually in mitotic phase G(0).",
" </li>",
" <li>",
" They could travel through the peripheral blood, \"home\" to marrow, and
repopulate it.",
" </li>",
" <li>",
" They were capable of two sorts of cell division under the influence of
marrow stromal elements and cytokines, one of which leads to self renewal of the
stem cell, and the other to commitment to differentiation along one of the
lineages, accompanied by loss of pluripotency. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?24/34/25129?
source=see_link\">",
" \"Overview of hematopoiesis and stem cell function\"",
" </a>",
" .)",
" </li>",
" </ul>",
" </p>",
" <p>",
" While CFU-S assays are not available in humans, pluripotent stem cells with
very similar properties (CFU-GEMM) have been cultured in vitro and described [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/10\">",
" 10",
" </a>",
" ]. These cells have substantial capacity for self-renewal and lineage-specific
differentiation [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/10\">",
" 10",
" </a>",
" ]. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?24/34/25129?
source=see_link&amp;anchor=H5#H5\">",
" \"Overview of hematopoiesis and stem cell function\", section on
'Identification of stem and progenitor cells'",
" </a>",
" .)",
" </p>",
" <p>",
" When the pluripotent stem cell pool falls below a critical mass, for reasons
that will be described below, the conflicting pulls of self-renewal and
differentiation cannot be maintained. This leads to stem cell or bone marrow
failure and the clinical condition known as aplastic anemia.",
" </p>",
" <p class=\"headingAnchor\" id=\"H3\">",
" <span class=\"h1\">",
" CAUSES AND MECHANISMS OF STEM CELL FAILURE",
" </span>",
" &nbsp;&mdash;&nbsp;Aplastic anemia is a specific disease entity reflecting a
deficiency of hematopoietic stem cells, resulting in peripheral pancytopenia and
bone marrow aplasia (",
" <a class=\"graphic graphic_table graphicRef70072 \" href=\"UTD.htm?
7/49/7964\">",
" table 1",
" </a>",
" ). In contrast, bone marrow failure is a more encompassing term that describes
pancytopenia from a variety of different mechanisms. Examples include bone marrow
replacement by tumor or fibrosis, and myelodysplasia, in which the stem cells are
malignant, may be present in increased numbers, but do not mature normally (",
" <a class=\"graphic graphic_table graphicRef52354 \" href=\"UTD.htm?
16/15/16635\">",
" table 2",
" </a>",
" ).",
" </p>",
" <p class=\"headingAnchor\" id=\"H4\">",
" <span class=\"h2\">",
" Overview",
" </span>",
" &nbsp;&mdash;&nbsp;Stem cell failure can be congenital (eg, Fanconi anemia)
or, much more often, acquired. The major causes of acquired aplastic anemia are
exposure to a wide variety of drugs and chemicals, ionizing radiation, and some
viruses. It may also rarely complicate orthotopic liver transplantation; aplastic
anemia in this setting has a very poor outcome except in those patients who develop
the disorder in the context of fulminant hepatic failure (see",
" <a class=\"local\" href=\"#H9\">",
" 'Viral infection'",
" </a>",
" below) [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/11\">",
" 11",
" </a>",
" ].",
" </p>",
" <p>",
" Aplastic anemia has also occurred in patients with other immune disorders and
occasionally in pregnancy [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/12,13\">",
" 12,13",
" </a>",
" ]. The aplasia associated with pregnancy is frequently self-limited, ending
with delivery [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/13\">",
" 13",
" </a>",
" ]. However, it is uncertain whether or not pregnancy is causally related to
the development of aplasia in these patients [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/14\">",
" 14",
" </a>",
" ]. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?29/14/29930?
source=see_link&amp;anchor=H33#H33\">",
" \"Aplastic anemia: Prognosis and treatment\", section on 'Pregnancy following
treatment'",
" </a>",
" .)",
" </p>",
" <p>",
" Bone marrow aplasia, often with gelatinous degeneration and serous fat
atrophy, has been described in patients with anorexia nervosa. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?37/62/38890?
source=see_link&amp;anchor=H31379427#H31379427\">",
" \"Anorexia nervosa in adults and adolescents: Medical complications and their
management\", section on 'Hematologic'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H6\">",
" <span class=\"h2\">",
" Direct stem cell destruction",
" </span>",
" &nbsp;&mdash;&nbsp;Exposure to large doses of external radiation in humans as
well as mice produces dose-dependent acute hematopoietic failure [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/1,15\">",
" 1,15",
" </a>",
" ]. The presumed mechanism is direct radiation injury to the stem cells.
Similarly, cytotoxic drugs used in the treatment of malignancy kill cells by a
variety of mechanisms and can kill stem cells as well as tumor cells. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?4/0/4106?
source=see_link&amp;anchor=H7#H7\">",
" \"Biology and clinical features of radiation injury in adults\", section on
'Lethal dose of radiation'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H7\">",
" <span class=\"h3\">",
" Drugs",
" </span>",
" &nbsp;&mdash;&nbsp;Many drugs, such as certain nonsteroidal antiinflammatory
drugs (particularly phenylbutazone, which is now rarely used),",
" <a class=\"drug drug_general\" href=\"UTD.htm?1/54/1897?source=see_link\">",
" chloramphenicol",
" </a>",
" , gold, sulfonamides, antiepileptic drugs (eg,",
" <a class=\"drug drug_general\" href=\"UTD.htm?24/31/25079?source=see_link\">",
" felbamate",
" </a>",
" ,",
" <a class=\"drug drug_general\" href=\"UTD.htm?25/10/25770?source=see_link\">",
" carbamazepine",
" </a>",
" , valproic acid,",
" <a class=\"drug drug_general\" href=\"UTD.htm?34/48/35594?source=see_link\">",
" phenytoin",
" </a>",
" ) and",
" <a class=\"drug drug_general\" href=\"UTD.htm?12/5/12377?source=see_link\">",
" nifedipine",
" </a>",
" have been associated with aplastic anemia (",
" <a class=\"graphic graphic_table graphicRef70072 \" href=\"UTD.htm?
7/49/7964\">",
" table 1",
" </a>",
" ) [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/1,2,16-19\">",
" 1,2,16-19",
" </a>",
" ]. Aplasia due to phenylbutazone usually occurs after prolonged treatment [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/2\">",
" 2",
" </a>",
" ]. Similarly, gold-induced aplasia typically occurs in patients who have
received a total dose of 200 to 450 mg; it is usually severe and often irreversible
[",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/16\">",
" 16",
" </a>",
" ]. Felbamate, an antiepileptic medication, has been associated with a number
of cases of aplastic anemia [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/17\">",
" 17",
" </a>",
" ].",
" </p>",
" <p>",
" <a class=\"drug drug_general\" href=\"UTD.htm?1/54/1897?source=see_link\">",
" Chloramphenicol",
" </a>",
" was a common cause of aplasia when it was widely prescribed in the United
States between 1948 and 1967. It causes bone marrow suppression by two mechanisms
[",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/2\">",
" 2",
" </a>",
" ]:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" <a class=\"drug drug_general\" href=\"UTD.htm?1/54/1897?source=see_link\">",
" Chloramphenicol",
" </a>",
" has a direct toxic effect on erythroid precursors in the bone marrow, which
can be morphologically identified by vacuoles forming a ring about the
proerythroblast nucleus. This occurs in virtually all patients and is dose-related.
Because iron is no longer being utilized for hemoglobin synthesis, there is a rise
in the serum iron concentration with a concomitant increase in the ratio of serum
iron to total iron-binding capacity. These changes are usually reversible with
cessation of chloramphenicol therapy.",
" </li>",
" <li>",
" Bone marrow aplasia occurs as an idiosyncratic reaction to treatment with",
" <a class=\"drug drug_general\" href=\"UTD.htm?1/54/1897?source=see_link\">",
" chloramphenicol",
" </a>",
" , with a sudden onset after several months of therapy. It occurs in one of
every 20,000 patients exposed to the drug and is usually irreversible.",
" </li>",
" </ul>",
" </p>",
" <p>",
" The vast majority of patients exposed to the above drugs do not develop
aplastic anemia and the reason for idiosyncratic reactions is unknown. P-
glycoprotein (P-gp), the MDR-1 gene product and the multidrug resistance-associated
protein, are energy-dependent transmembrane efflux pumps for a variety of
lipophilic drugs. Overexpression confers the multidrug resistance phenotype (MDR)
to cancer cells. Underexpression in normal cells might allow cytoplasmic
accumulation of drugs and enhance their toxic effects.",
" </p>",
" <p>",
" One study found that P-gp activity was decreased in peripheral blood
lymphocytes and bone marrow CD34+ cells in patients with aplastic anemia; levels
were lowest in the subgroup with drug-induced aplastic anemia [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/20,21\">",
" 20,21",
" </a>",
" ]. These observations suggest that diminished P-gp activity was present prior
to development of aplasia and may have played a role in some cases by increasing
susceptibility to drug-induced injury.",
" </p>",
" <p class=\"headingAnchor\" id=\"H8\">",
" <span class=\"h3\">",
" Other",
" </span>",
" &nbsp;&mdash;&nbsp;An interview-based case-control study from the UK
identified",
" <span class=\"nowrap\">",
" solvents/degreasing",
" </span>",
" agents, pesticides, and radiation as being significant risk factors for
development of severe aplastic anemia [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/22\">",
" 22",
" </a>",
" ]. Industrial chemicals [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/23,24\">",
" 23,24",
" </a>",
" ] and insecticides (eg, benzene hexachloride (",
" <a class=\"drug drug_general\" href=\"UTD.htm?36/34/37412?source=see_link\">",
" lindane",
" </a>",
" ) [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/25\">",
" 25",
" </a>",
" ]) have long been associated with aplastic anemia. Prolonged exposure to
benzene is particularly notorious in this regard; in the past, this primarily
occurred in poorly ventilated rubber factories and shoe repair shops [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/23\">",
" 23",
" </a>",
" ].",
" </p>",
" <p>",
" Similar observations concerning toxic exposures were made in an epidemiologic
study in Thailand [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/26\">",
" 26",
" </a>",
" ]. There was a significant association between aplastic anemia and use of
nonbottled water, exposure to animals, agricultural pesticides, and animal
fertilizers.",
" </p>",
" <p>",
" A reduced ability to detoxify environmental toxins may play a role in the
genesis of aplastic anemia. In one study, the incidence of gene deletions for
glutathione S-transferase, an enzyme involved in detoxifying potentially mutagenic
electrophilic compounds, was significantly higher in patients with acquired
aplastic anemia than in healthy controls (odds ratio 3.1) [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/27\">",
" 27",
" </a>",
" ]. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?5/17/5399?
source=see_link&amp;anchor=H8#H8\">",
" \"Related disorders of the hexose monophosphate shunt and glutathione
metabolism\", section on 'Glutathione S-transferase deficiency'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H9\">",
" <span class=\"h2\">",
" Viral infection",
" </span>",
" &nbsp;&mdash;&nbsp;Certain viruses can damage stem cells and cause aplasia [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/16\">",
" 16",
" </a>",
" ]. The best documented is parvovirus B19. This agent more commonly attacks
proerythroblasts and causes transient red cell aplasia, as seen in patients with
chronic hemolytic anemia. However, pancytopenia can occur, particularly in patients
who are immunocompromised. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?17/1/17433?
source=see_link&amp;anchor=H2#H2\">",
" \"Acquired pure red cell aplasia\", section on 'Etiology and pathogenesis'",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?21/54/22377?
source=see_link\">",
" \"Clinical manifestations and pathogenesis of human parvovirus B19
infection\"",
" </a>",
" .)",
" </p>",
" <p>",
" Hepatitis viruses and HIV can also cause severe aplasia [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/28,29\">",
" 28,29",
" </a>",
" ]. The mechanism may involve T cell activation with release of cytokines (see
below) [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/30\">",
" 30",
" </a>",
" ]. Hepatitis-associated disease most often affects boys and young men, with
aplasia developing two to three months after an episode of acute hepatitis [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/29,31\">",
" 29,31",
" </a>",
" ]. Hepatitis may account for 2 to 5 percent of cases of aplastic anemia in
Western countries [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/29,31,32\">",
" 29,31,32",
" </a>",
" ]. The responsible virus has not been identified; neither hepatitis A, B, C,
nor G appears to be involved [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/29\">",
" 29",
" </a>",
" ]. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?3/41/3738?
source=see_link&amp;anchor=H6#H6\">",
" \"Acquired aplastic anemia in children and young adults\", section on
'Infectious agents'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H10\">",
" <span class=\"h2\">",
" Idiopathic aplastic anemia",
" </span>",
" &nbsp;&mdash;&nbsp;The cause remains obscure in most patients with acquired
aplastic anemia. Several observations are consistent with destruction or
suppression of the stem cell by autoimmune mechanisms [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/1,33-35\">",
" 1,33-35",
" </a>",
" ]:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Many of these patients respond to immunosuppressive therapy.",
" </li>",
" <li>",
" There is an association of aplastic anemia with the rare immunologic disease
eosinophilic fasciitis [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/36,37\">",
" 36,37",
" </a>",
" ].",
" </li>",
" <li>",
" Aplasia can occur in the context of graft-versus-host disease following
allogeneic hematopoietic cell transplantation [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/1\">",
" 1",
" </a>",
" ].",
" </li>",
" <li>",
" Bone marrow lymphocytes of patients with aplastic anemia can inhibit
hematopoiesis when cocultured with patient or normal marrow.",
" </li>",
" <li>",
" Oligoclonal or monoclonal expansions of CD8+ T cells have been found in
patients with idiopathic aplastic anemia, as well as in the closely related
disorder paroxysmal nocturnal hemoglobinuria [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/38,39\">",
" 38,39",
" </a>",
" ].",
" </li>",
" <li>",
" In a small study, T-cell receptor zeta chain expression was decreased in the
majority of patients with aplastic anemia, comparable to that seen in other
autoimmune diseases; expression was decreased regardless of disease activity or
treatment status [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/40\">",
" 40",
" </a>",
" ].",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H11\">",
" <span class=\"h3\">",
" Interferon gamma",
" </span>",
" &nbsp;&mdash;&nbsp;Bone marrow inhibition may be mediated by the release of
interferon gamma (IFN-gamma), a marrow suppressing cytokine, perhaps under the
influence of the transcription factor T-bet",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" cytokines such as TNF-alpha and various interleukins [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/41,42\">",
" 41,42",
" </a>",
" ]. IFN-gamma gene expression is specifically prevalent in the bone marrow of
patients with acquired aplastic anemia, and disappears with response to
immunosuppression [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/43\">",
" 43",
" </a>",
" ].",
" </p>",
" <p>",
" In one report, 27 of 28 patients with IFN-gamma containing T-cells
subsequently responded to immunosuppressive therapy [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/44\">",
" 44",
" </a>",
" ]. In contrast, only 11 of 32 patients lacking IFN-gamma-containing peripheral
blood lymphocytes improved to transfusion independence. Further, of patients
assessed during relapse, 12 of 13 subjects in whom IFN-gamma was present responded
to reinstitution of immunosuppressive agents. If confirmed, these results suggest
that the presence of intracellular IFN-gamma may predict for response to
immunosuppression as well as the onset of relapse.",
" </p>",
" <p class=\"headingAnchor\" id=\"H12\">",
" <span class=\"h3\">",
" Immune hypothesis",
" </span>",
" &nbsp;&mdash;&nbsp;The above observations have led to a hypothesis for immune
suppression as the underlying cause in at least some patients with idiopathic
aplastic anemia. It has been postulated that damage induced by chemicals, drugs,
viruses, or antigens leads to lymphocyte activation. Unregulated lymphocyte
activation, perhaps akin to that seen with mutations of perforin in hemophagocytic
lymphohistiocytosis [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/45\">",
" 45",
" </a>",
" ], or an autoimmune state due to impaired numbers",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" function of",
" <span class=\"nowrap\">",
" CD4+/CD25+/FOXP3+",
" </span>",
" T regulatory cells, perhaps secondary to the actions of Th17 cells (see
below), results in a hematopoietic inhibitory response [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/46-49\">",
" 46-49",
" </a>",
" ]. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?3/57/3992?
source=see_link&amp;anchor=H11#H11\">",
" \"Overview of autoimmunity\", section on 'Pathogenetic mechanisms'",
" </a>",
" .)",
" </p>",
" <p>",
" This inhibition may be mediated by IFN-gamma or the cytokine cascade released
by IFN-gamma [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/50,51\">",
" 50,51",
" </a>",
" ], ultimately leading to apoptotic death of hematopoietic stem cells in the
bone marrow [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/52-56\">",
" 52-56",
" </a>",
" ]. IFN-gamma may also lead to increased expression of the Fas receptor and
antigen [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/57\">",
" 57",
" </a>",
" ]. This receptor is involved in induction of apoptosis and in T-cell mediated
killing. Indeed, Fas antigen is found in increased concentration in CD34+ bone
marrow cells in patients with aplastic anemia [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/50,52\">",
" 50,52",
" </a>",
" ].",
" </p>",
" <p>",
" Further indirect evidence for immune suppression in aplastic anemia
includes:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Finding of a reduction of natural killer T (NKT) cells in the bone marrow of
patients with aplastic anemia as well as those with hypocellular myelodysplastic
syndrome [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/58\">",
" 58",
" </a>",
" ]. NKT cells are believed to play a regulatory role in the immune system and
many human autoimmune conditions are associated with NKT cell deficiency.",
" </li>",
" <li>",
" It has been postulated that NKG2D (natural killer group 2, member D)-
mediated immunity, which drives NK, NKT, and T cell activation, is critically
involved, at least in part, in the pathogenesis of PNH and PNH-related marrow
failure syndromes [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/59\">",
" 59",
" </a>",
" ].",
" </li>",
" <li>",
" The presence of autoantibodies to cellular antigens in some patients with AA
(eg, kinectin, anti-postmeiotic segregation increased 1 (PMS1), diazepam-binding
inhibitor-related protein-1 (DRS-1), moesin) [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/55,56,60-62\">",
" 55,56,60-62",
" </a>",
" ]. Autoantibodies to moesin have also been detected in patients with
rheumatoid arthritis [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/63\">",
" 63",
" </a>",
" ], although their pathophysiologic significance is unclear at this time.",
" </li>",
" <li>",
" IL-17 is a Th1 cell derived cytokine that exhibits many of the same
activities as IL-1 and TNF-alpha. T cells that produce IL-17 (Th17 cells) have been
implicated in the cell-mediated cytotoxicity of some autoimmune diseases, including
rheumatoid arthritis. Expression of this cytokine in mononuclear cells from the
bone marrow and peripheral blood, as well as plasma levels have been found to be
significantly increased in patients with aplastic anemia [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/47,64\">",
" 47,64",
" </a>",
" ]. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?30/23/31098?
source=see_link&amp;anchor=H1232221#H1232221\">",
" \"Normal B and T lymphocyte development\", section on 'Th17 cells'",
" </a>",
" .)",
" </li>",
" </ul>",
" </p>",
" <p>",
" In support of these observations is an early study showing that the gene
expression profile of CD34+",
" <span class=\"nowrap\">",
" stem/progenitor",
" </span>",
" cells from patients with newly diagnosed aplastic anemia is consistent with a
stressed, dying, and immunologically activated target cell population [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/65\">",
" 65",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H13\">",
" <span class=\"h2\">",
" Clonal and genetic disorders",
" </span>",
" </p>",
" <p class=\"headingAnchor\" id=\"H13878766\">",
" <span class=\"h3\">",
" Paroxysmal nocturnal hemoglobinuria",
" </span>",
" &nbsp;&mdash;&nbsp;There is a close relationship between aplastic anemia and
the clonal multilineage hematopoietic disorder paroxysmal nocturnal hemoglobinuria
(PNH). The latter disorder is especially common in patients with aplastic anemia
who have received treatment with immunosuppressive agents. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?13/17/13593?
source=see_link&amp;anchor=H10#H10\">",
" \"Pathogenesis of paroxysmal nocturnal hemoglobinuria: Missing cell
proteins\", section on 'Hematopoietic progenitors'",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?29/14/29930?
source=see_link&amp;anchor=H28#H28\">",
" \"Aplastic anemia: Prognosis and treatment\", section on 'Occurrence of
clonal disorders'",
" </a>",
" .)",
" </p>",
" <p>",
" Utilizing ultrasensitive detection methods, the PNH defect has been found to
varying degrees in both red cells and neutrophils in patients with untreated
aplastic anemia as well as in those with the refractory anemia variant of the
myelodysplastic syndrome [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/66-68\">",
" 66-68",
" </a>",
" ]. These and other observations suggest that clonality is an early event in
the evolution of aplastic anemia [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/69\">",
" 69",
" </a>",
" ].",
" </p>",
" <p>",
" An interesting, but unexplained, observation links the immune hypothesis of
aplastic anemia with the observation of cells with the PNH defect [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/70,71\">",
" 70,71",
" </a>",
" ]. In one study, flow cytometry detected a population of PNH-type cells
(range: 0.005 to 23 percent) in 68 percent of 122 patients with newly-diagnosed
aplastic anemia [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/71\">",
" 71",
" </a>",
" ]. Response to immunosuppressive treatment with ATG and",
" <a class=\"drug drug_general\" href=\"UTD.htm?31/39/32368?source=see_link\">",
" cyclosporine",
" </a>",
" was noted in 91 versus 48 percent of those with or without this PNH-type cell
population, respectively. A similar observation has been made in patients with the
myelodysplastic syndrome and a hypoplastic bone marrow. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?30/30/31210?
source=see_link&amp;anchor=H2447560#H2447560\">",
" \"Treatment of intermediate, low, or very low risk myelodysplastic
syndromes\", section on 'Immunosuppressive therapy'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H13878708\">",
" <span class=\"h3\">",
" Fanconi anemia",
" </span>",
" &nbsp;&mdash;&nbsp;There are several forms of congenital aplastic anemia. The
most common is Fanconi anemia, a familial condition characterized by pancytopenia,
macrocytic anemia, and congenital malformations. The vast majority of patients are
diagnosed before the age of 16, but occasional adults may not be diagnosed until
later in life [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/72\">",
" 72",
" </a>",
" ]. Multiple genes appear to be responsible for this illness, since at least 13
complementation groups (FA-A to FA-H) have been reported. It has been suggested
that these genes act through a final common pathway involved with DNA repair
mechanisms. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?26/13/26842?
source=see_link&amp;anchor=H4#H4\">",
" \"Inherited aplastic anemia in children\", section on 'Fanconi anemia'",
" </a>",
" .)",
" </p>",
" <p>",
" An interferon-inducible gene, MxA, is highly upregulated in these groups,
suggesting an abnormality in the interferon signaling mechanism, which may lead to
enhanced apoptosis [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/73\">",
" 73",
" </a>",
" ]. One possible mediator is interferon-gamma, which is thought to play an
important role in idiopathic aplastic anemia and perhaps some other forms as well
(see",
" <a class=\"local\" href=\"#H10\">",
" 'Idiopathic aplastic anemia'",
" </a>",
" above).",
" </p>",
" <p class=\"headingAnchor\" id=\"H14\">",
" <span class=\"h3\">",
" Telomerase mutations and telomere length",
" </span>",
" &nbsp;&mdash;&nbsp;Mutations in TERC, the gene encoding for the RNA component
of telomerase, have been seen in a small number of patients with either congenital
or acquired aplastic anemia [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/74-76\">",
" 74-76",
" </a>",
" ]. Similarly, mutations in TERT, the gene encoding telomerase reverse
transcriptase, appear to be genetic risk factors for the development of marrow
failure, possibly by making carriers with TERT mutations especially vulnerable to
environmental insults (eg, drugs, viruses) to replicating stem cells (see",
" <a class=\"local\" href=\"#H12\">",
" 'Immune hypothesis'",
" </a>",
" above) [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/77,78\">",
" 77,78",
" </a>",
" ], or by otherwise compromising telomerase activity [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/79,80\">",
" 79,80",
" </a>",
" ].",
" </p>",
" <p>",
" In a retrospective study of 183 patients with severe aplastic anemia receiving
immunosuppressive therapy at a single institution, a relationship was found between
variations in telomere length within the normal range and clinical outcomes in
patients who lacked known genetic explanations for shorter telomeres [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/81\">",
" 81",
" </a>",
" ]. In this group, shorter age-adjusted telomere length was unrelated to
response to treatment but was associated with an increased risk of relapse and
clonal evolution, and reduced overall survival.",
" </p>",
" <p>",
" Discussions of the importance of telomeres in cellular division can be found
elsewhere in UpToDate. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?26/13/26842?
source=see_link&amp;anchor=H13#H13\">",
" \"Inherited aplastic anemia in children\", section on 'Dyskeratosis
congenita'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H13878780\">",
" <span class=\"h3\">",
" Absent or abnormal thrombopoietin receptor",
" </span>",
" &nbsp;&mdash;&nbsp;Two inherited conditions associated with the development of
aplastic anemia have been described with abnormalities of MPL, the thrombopoietin
receptor:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Congenital amegakaryocytic thrombocytopenia &mdash; some subjects with this
disorder are homozygous for mutations that produce an inactive thrombopoietin
receptor and may ultimately develop bone marrow aplasia. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?26/13/26842?
source=see_link&amp;anchor=H18#H18\">",
" \"Inherited aplastic anemia in children\", section on 'Amegakaryocytic
thrombocytopenia'",
" </a>",
" .)",
" </li>",
" <li>",
" Familial aplastic anemia &mdash; Two affected children with familial
aplastic anemia from a consanguineous family were found to have homozygous nonsense
mutations of MPL [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/82\">",
" 82",
" </a>",
" ]. Of importance, these investigators identified a homozygous MPL mutation
in one subject in a screen of 33 patients with &ldquo;idiopathic&rdquo; aplastic
anemia.",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H15\">",
" <span class=\"h1\">",
" CLINICAL MANIFESTATIONS",
" </span>",
" &nbsp;&mdash;&nbsp;The patient with aplastic anemia occasionally comes to
medical attention because of fatigue and cardiopulmonary compromise associated with
progressive anemia. More common presentations include recurrent infections due to
profound neutropenia or mucosal hemorrhage due to thrombocytopenia. Increased
menstrual flow is a common complaint in premenopausal women.",
" </p>",
" <p>",
" Infections are typically bacterial, including sepsis, pneumonia, and urinary
tract infection. Invasive fungal infection is a common cause of death, especially
in subjects with prolonged and severe neutropenia [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/83\">",
" 83",
" </a>",
" ]. This was illustrated in a review of the records of 174 patients with SAA
unresponsive to initial treatment with immunosuppressive therapy (IST). In
multivariate analysis, younger age, absolute neutrophil count",
" <span class=\"nowrap\">",
" &gt;200/microL",
" </span>",
" before IST, absence of invasive fungal infection, and use of",
" <a class=\"drug drug_general\" href=\"UTD.htm?16/38/17002?source=see_link\">",
" voriconazole",
" </a>",
" were all independently predictive of better survival [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/84\">",
" 84",
" </a>",
" ].",
" </p>",
" <p>",
" The physical examination is generally not helpful. Pallor and petechiae are
the most common findings. The liver, spleen, and lymph nodes are not enlarged.",
" </p>",
" <p class=\"headingAnchor\" id=\"H16\">",
" <span class=\"h1\">",
" DIAGNOSIS",
" </span>",
" </p>",
" <p class=\"headingAnchor\" id=\"H17\">",
" <span class=\"h2\">",
" Complete blood count",
" </span>",
" &nbsp;&mdash;&nbsp;The diagnosis of aplastic anemia is suggested by the
complete blood count, which reveals pancytopenia (ie, the simultaneous presence of
neutropenia, thrombocytopenia, and anemia) along with a reduction in the absolute
number of reticulocytes.",
" </p>",
" <p>",
" Examination of the peripheral blood smear shows that the red blood cells are
normocytic but occasionally may be macrocytic (ie, mean cell volume &gt;100 fL).
Polychromatophilic red cells (ie, reticulocytes) are markedly reduced or absent.
The remaining cellular elements, while reduced in number, are morphologically
normal. Abnormal cells (eg, myeloblasts, atypical lymphoid cells) are not present.
(See",
" <a class=\"medical medical_review\" href=\"UTD.htm?28/46/29418?
source=see_link\">",
" \"Approach to the adult patient with anemia\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H18\">",
" <span class=\"h2\">",
" Bone marrow examination",
" </span>",
" &nbsp;&mdash;&nbsp;Aspiration and, of paramount importance, an adequate",
" <strong>",
" biopsy",
" </strong>",
" of the bone marrow from a site that has not suffered prior direct damage (eg,
radiation, trauma, infection), along with cytogenetic analysis, usually provide
sufficient information to establish the diagnosis of aplastic anemia. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?5/22/5482?
source=see_link&amp;anchor=H6#H6\">",
" \"Bone marrow aspiration and biopsy: Indications and technique\", section on
'Choice of aspiration or biopsy site'",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?13/23/13689?
source=see_link&amp;anchor=H3#H3\">",
" \"Evaluation of bone marrow aspirate smears\", section on 'Sample
preparation'",
" </a>",
" .)",
" </p>",
" <p>",
" The following constellation of findings is typically present:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" The bone marrow is profoundly hypocellular with a decrease in all elements;
the marrow space is composed mostly of fat cells and marrow stroma (",
" <a class=\"graphic graphic_picture graphicRef63867 \" href=\"UTD.htm?
34/43/35513\">",
" picture 1",
" </a>",
" ).",
" </li>",
" <li>",
" Infiltration of the bone marrow with malignant cells or fibrosis is not
present.",
" </li>",
" <li>",
" Residual hematopoietic cells are morphologically normal and hematopoiesis is
not megaloblastic.",
" </li>",
" </ul>",
" </p>",
" <p>",
" Other tests or findings can confirm other potential diagnoses:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" If PNH is a consideration because of coincident hemolysis or venous
thromboembolism, measurement of red cell membrane or neutrophil CD59 by flow
cytometry is indicated. There is also an important association between PNH and
aplastic anemia after immunotherapy, as 15 to 33 percent of patients develop signs
of PNH as the aplasia resolves. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?16/43/17082?
source=see_link\">",
" \"Diagnosis and treatment of paroxysmal nocturnal hemoglobinuria\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?29/14/29930?
source=see_link\">",
" \"Aplastic anemia: Prognosis and treatment\"",
" </a>",
" .)",
" </li>",
" <li>",
" The viral hemophagocytic syndrome, which may also present with pancytopenia,
is characterized by the presence of bone marrow macrophages engorged with
hematopoietic cells (",
" <a class=\"graphic graphic_picture graphicRef81067 \" href=\"UTD.htm?
17/30/17890\">",
" picture 2",
" </a>",
" ). (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?40/5/41050?
source=see_link\">",
" \"Hemophagocytic lymphohistiocytosis\"",
" </a>",
" .)",
" </li>",
" <li>",
" Cytogenetic analysis, if normal, helps to rule out hypoplastic
myelodysplastic syndrome; however, this disorder may be impossible to exclude.
(See",
" <a class=\"medical medical_review\" href=\"UTD.htm?40/57/41882?
source=see_link&amp;anchor=H47639590#H47639590\">",
" \"Clinical manifestations and diagnosis of the myelodysplastic syndromes\",
section on 'Bone marrow aspirate and biopsy'",
" </a>",
" .)",
" </li>",
" <li>",
" The diagnosis of Fanconi anemia is made by the presence of increased
chromosomal breakage in lymphocytes cultured in the presence of DNA cross-linking
agents. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?26/13/26842?
source=see_link&amp;anchor=H4#H4\">",
" \"Inherited aplastic anemia in children\", section on 'Fanconi anemia'",
" </a>",
" .)",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H19\">",
" <span class=\"h2\">",
" Diagnostic criteria",
" </span>",
" </p>",
" <p class=\"headingAnchor\" id=\"H20\">",
" <span class=\"h3\">",
" Moderate aplastic anemia",
" </span>",
" &nbsp;&mdash;&nbsp;The criteria for moderate AA include:",
" </p>",
" <p>",
" <ul class=\"bulletCompact-block\">",
" <li>",
" Bone marrow cellularity &lt;30 percent",
" </li>",
" <li>",
" Absence of severe pancytopenia",
" </li>",
" <li>",
" Depression of at least two of three blood elements below normal",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H21\">",
" <span class=\"h3\">",
" Severe aplastic anemia",
" </span>",
" &nbsp;&mdash;&nbsp;The criteria for severe aplastic anemia (SAA) are [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/85\">",
" 85",
" </a>",
" ]:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" A bone marrow biopsy showing &lt;25 percent of normal cellularity,",
" <strong>",
" or",
" </strong>",
" </li>",
" <li>",
" A bone marrow biopsy showing &lt;50 percent normal cellularity in which
fewer than 30 percent of the cells are hematopoietic and at least two of the
following are present: absolute reticulocyte count",
" <span class=\"nowrap\">",
" &lt;40,000/microliter;",
" </span>",
" absolute neutrophil count (ANC)",
" <span class=\"nowrap\">",
" &lt;500/microliter",
" </span>",
" (",
" <a class=\"calc calc_professional\" href=\"UTD.htm?12/1/12305?
source=see_link\">",
" calculator 1",
" </a>",
" ); or platelet count",
" <span class=\"nowrap\">",
" &lt;20,000/microliter.",
" </span>",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H22\">",
" <span class=\"h3\">",
" Very severe aplastic anemia",
" </span>",
" &nbsp;&mdash;&nbsp;The patient is considered to have very severe aplastic
anemia (vSAA) if the criteria for severe aplastic anemia are met and the ANC is",
" <span class=\"nowrap\">",
" &lt;200/microliter",
" </span>",
" (",
" <a class=\"calc calc_professional\" href=\"UTD.htm?12/1/12305?
source=see_link\">",
" calculator 1",
" </a>",
" ).",
" </p>",
" <p class=\"headingAnchor\" id=\"H23\">",
" <span class=\"h1\">",
" DIFFERENTIAL DIAGNOSIS",
" </span>",
" &nbsp;&mdash;&nbsp;The differential diagnosis of pancytopenia without
prominent splenomegaly includes other congenital and acquired causes of bone marrow
failure, including the acute leukemias, large granular lymphocyte leukemia, the
myelodysplastic syndromes (MDS, especially the hypocellular variant), marrow
replacement by fibrosis or tumor, severe megaloblastic anemia, paroxysmal nocturnal
hemoglobinuria (PNH), and overwhelming infection due to HIV or the viral
hemophagocytic syndrome (",
" <a class=\"graphic graphic_table graphicRef52354 \" href=\"UTD.htm?
16/15/16635\">",
" table 2",
" </a>",
" ) [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/5\">",
" 5",
" </a>",
" ]. These are easily distinguishable from aplastic anemia on evaluation of the
peripheral blood smear and bone marrow aspirate and biopsy, with some exceptions
[",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/4\">",
" 4",
" </a>",
" ]:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" It may be difficult to distinguish aplastic anemia from the hypocellular
variant of MDS. The presence of abnormal megakaryocytes and cytogenetic
abnormalities is more typical of MDS. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?40/57/41882?
source=see_link&amp;anchor=H47639590#H47639590\">",
" \"Clinical manifestations and diagnosis of the myelodysplastic syndromes\",
section on 'Bone marrow aspirate and biopsy'",
" </a>",
" .)",
" </li>",
" <li>",
" Aplastic anemia and PNH may coexist. The presence of a clone of PNH cells
can be evaluated using flow cytometry methods. However, this finding does not alter
management of the aplastic anemia. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?16/43/17082?
source=see_link&amp;anchor=H4#H4\">",
" \"Diagnosis and treatment of paroxysmal nocturnal hemoglobinuria\", section
on 'Expression of GPI anchored proteins'",
" </a>",
" .)",
" </li>",
" <li>",
" While most patients with Fanconi anemia present during childhood, a few may
present later in life. This diagnosis can be made using provocative in vitro tests
demonstrating increased chromosomal breakage [",
" <a class=\"abstract\" href=\"UTD.htm?0/36/586/abstract/86\">",
" 86",
" </a>",
" ]. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?26/13/26842?
source=see_link&amp;anchor=H8#H8\">",
" \"Inherited aplastic anemia in children\", section on 'Diagnosis'",
" </a>",
" .)",
" </li>",
" <li>",
" Patients with aplastic anemia may suffer from disorders affecting telomerase
function (eg, dyskeratosis congenita and its variants). Some, but not all, will
have characteristic physical findings and a positive family history for aplastic
anemia, isolated cytopenias, leukemia, pulmonary fibrosis, or cirrhosis. Methods
exist for determination of blood leukocyte telomere length. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?26/13/26842?
source=see_link&amp;anchor=H14#H14\">",
" \"Inherited aplastic anemia in children\", section on 'Genetic basis'",
" </a>",
" .)",
" </li>",
" </ul>",
" </p>",
" <p>",
" In patients with prominent splenomegaly from any one of a large number of
causes, mild to moderate degrees of pancytopenia can be present, secondary to
splenic trapping (hypersplenism) of all circulating elements. Unlike aplastic
anemia, their bone marrow aspirates and biopsies are generally normo- or
hypercellular. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?8/62/9194?
source=see_link&amp;anchor=H29#H29\">",
" \"Extrinsic nonimmune hemolytic anemia due to mechanical damage:
Fragmentation hemolysis and hypersplenism\", section on 'Splenomegaly'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"PATIENT_INFORMATION\">",
" <span class=\"h1\">",
" INFORMATION FOR PATIENTS",
" </span>",
" &nbsp;&mdash;&nbsp;UpToDate offers two types of patient education materials,
&ldquo;The Basics&rdquo; and &ldquo;Beyond the Basics.&rdquo; The Basics patient
education pieces are written in plain language, at the 5",
" ^{",
" th",
"}",
" to 6",
" ^{",
" th",
"}",
" grade reading level, and they answer the four or five key questions a patient
might have about a given condition. These articles are best for patients who want a
general overview and who prefer short, easy-to-read materials. Beyond the Basics
patient education pieces are longer, more sophisticated, and more detailed. These
articles are written at the 10",
" ^{",
" th",
"}",
" to 12",
" ^{",
" th",
"}",
" grade reading level and are best for patients who want in-depth information
and are comfortable with some medical jargon.",
" </p>",
" <p>",
" Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also
locate patient education articles on a variety of subjects by searching on
&ldquo;patient info&rdquo; and the keyword(s) of interest.)",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Basics topics (see",
" <a class=\"medical medical_basics\" href=\"UTD.htm?30/4/30785?
source=see_link\">",
" \"Patient information: Aplastic anemia (The Basics)\"",
" </a>",
" )",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H24\">",
" <span class=\"h1\">",
" SUMMARY",
" </span>",
" &nbsp;&mdash;&nbsp;Aplastic anemia (AA) is characterized by diminished or
absent hematopoietic precursors in the bone marrow, most often due to injury to the
pluripotent stem cell (",
" <a class=\"graphic graphic_table graphicRef70072 \" href=\"UTD.htm?
7/49/7964\">",
" table 1",
" </a>",
" ). (See",
" <a class=\"local\" href=\"#H3\">",
" 'Causes and mechanisms of stem cell failure'",
" </a>",
" above.)",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" The diagnosis of AA should be considered in every patient presenting with
pancytopenia (ie, the simultaneous presence of anemia, thrombocytopenia, and
neutropenia).",
" </li>",
" <li>",
" Examination of the peripheral blood smear reveals normocytic or macrocytic
red cells with a marked reduction in polychromatophilia (reticulocytes).
Neutrophils and platelets are decreased in number. Abnormal circulating white blood
cells are not present. (See",
" <a class=\"local\" href=\"#H17\">",
" 'Complete blood count'",
" </a>",
" above.)",
" </li>",
" <li>",
" The bone marrow BIOPSY is profoundly hypocellular with a decrease in all
elements; the marrow space is composed mostly of fat cells and marrow stroma.
Residual hematopoietic cells are morphologically normal, and infiltration with
malignant cells or fibrosis is not present. (See",
" <a class=\"local\" href=\"#H18\">",
" 'Bone marrow examination'",
" </a>",
" above.)",
" </li>",
" <li>",
" The differential diagnosis includes other causes of bone marrow failure (",
" <a class=\"graphic graphic_table graphicRef52354 \" href=\"UTD.htm?
16/15/16635\">",
" table 2",
" </a>",
" ).",
" </li>",
" </ul>",
" </p>",
" </div>",
" <div id=\"topicAgreement\">",
" Use of UpToDate is subject to the",
" <a class=\"licenseLink\" href=\"./license\" id=\"sla_in_page\"
target=\"_blank\">",
" Subscription and License Agreement",
" </a>",
" .",
" </div>",
" <div class=\"headingAnchor\" id=\"references\">",
" <h1>",
" REFERENCES",
" </h1>",
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Blood 2004; 103:325.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/586/abstract/66\">",
" Mukhina GL, Buckley JT, Barber JP, et al. Multilineage
glycosylphosphatidylinositol anchor-deficient haematopoiesis in untreated aplastic
anaemia. Br J Haematol 2001; 115:476.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/586/abstract/67\">",
" Maciejewski JP, Rivera C, Kook H, et al. Relationship between bone marrow
failure syndromes and the presence of glycophosphatidyl inositol-anchored protein-
deficient clones. Br J Haematol 2001; 115:1015.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/586/abstract/68\">",
" Sugimori C, Mochizuki K, Qi Z, et al. Origin and fate of blood cells
deficient in glycosylphosphatidylinositol-anchored protein among patients with bone
marrow failure. Br J Haematol 2009; 147:102.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/586/abstract/69\">",
" Wlodarski MW, Gondek LP, Nearman ZP, et al. Molecular strategies for
detection and quantitation of clonal cytotoxic T-cell responses in aplastic anemia
and myelodysplastic syndrome. Blood 2006; 108:2632.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/586/abstract/70\">",
" Maciejewski JP, Follmann D, Nakamura R, et al. Increased frequency of HLA-
DR2 in patients with paroxysmal nocturnal hemoglobinuria and the PNH/aplastic
anemia syndrome. Blood 2001; 98:3513.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/586/abstract/71\">",
" Sugimori C, Chuhjo T, Feng X, et al. Minor population of CD55-CD59- blood
cells predicts response to immunosuppressive therapy and prognosis in patients with
aplastic anemia. Blood 2006; 107:1308.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/586/abstract/72\">",
" Huck K, Hanenberg H, Gudowius S, et al. Delayed diagnosis and complications
of Fanconi anaemia at advanced age--a paradigm. Br J Haematol 2006; 133:188.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/586/abstract/73\">",
" Li Y, Youssoufian H. MxA overexpression reveals a common genetic link in
four Fanconi anemia complementation groups. J Clin Invest 1997; 100:2873.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/586/abstract/74\">",
" Vulliamy T, Marrone A, Dokal I, Mason PJ. Association between aplastic
anaemia and mutations in telomerase RNA. Lancet 2002; 359:2168.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/586/abstract/75\">",
" Marrone A, Stevens D, Vulliamy T, et al. Heterozygous telomerase RNA
mutations found in dyskeratosis congenita and aplastic anemia reduce telomerase
activity via haploinsufficiency. Blood 2004; 104:3936.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/586/abstract/76\">",
" Ly H, Calado RT, Allard P, et al. Functional characterization of telomerase
RNA variants found in patients with hematologic disorders. Blood 2005; 105:2332.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/586/abstract/77\">",
" Yamaguchi H, Calado RT, Ly H, et al. Mutations in TERT, the gene for
telomerase reverse transcriptase, in aplastic anemia. N Engl J Med 2005;
352:1413.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/586/abstract/78\">",
" Fibbe WE. Telomerase mutations in aplastic anemia. N Engl J Med 2005;
352:1481.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/586/abstract/79\">",
" Xin ZT, Beauchamp AD, Calado RT, et al. Functional characterization of
natural telomerase mutations found in patients with hematologic disorders. Blood
2007; 109:524.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/586/abstract/80\">",
" Calado RT, Young NS. Telomere maintenance and human bone marrow failure.
Blood 2008; 111:4446.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/586/abstract/81\">",
" Scheinberg P, Cooper JN, Sloand EM, et al. Association of telomere length of
peripheral blood leukocytes with hematopoietic relapse, malignant transformation,
and survival in severe aplastic anemia. JAMA 2010; 304:1358.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/586/abstract/82\">",
" Walne AJ, Dokal A, Plagnol V, et al. Exome sequencing identifies MPL as a
causative gene in familial aplastic anemia. Haematologica 2012; 97:524.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/586/abstract/83\">",
" Torres HA, Bodey GP, Rolston KV, et al. Infections in patients with aplastic
anemia: experience at a tertiary care cancer center. Cancer 2003; 98:86.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/586/abstract/84\">",
" Valdez JM, Scheinberg P, Nunez O, et al. Decreased infection-related
mortality and improved survival in severe aplastic anemia in the past two decades.
Clin Infect Dis 2011; 52:726.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/586/abstract/85\">",
" Rozman C, Mar&iacute;n P, Nomdedeu B, Montserrat E. Criteria for severe
aplastic anaemia. Lancet 1987; 2:955.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/36/586/abstract/86\">",
" Yoshimi A, Niemeyer C, Baumann I, et al. High incidence of Fanconi anaemia
in patients with a morphological picture consistent with refractory cytopenia of
childhood. Br J Haematol 2013; 160:109.",
" </a>",
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" INTRODUCTION",
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" THE PLURIPOTENT STEM CELL",
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" CAUSES AND MECHANISMS OF STEM CELL FAILURE",
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" Idiopathic aplastic anemia",
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" - Paroxysmal nocturnal hemoglobinuria",
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" - Fanconi anemia",
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" <a class=\"outlineLink\" href=\"#H14\">",
" - Telomerase mutations and telomere length",
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" <a class=\"outlineLink\" href=\"#H13878780\">",
" - Absent or abnormal thrombopoietin receptor",
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" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H15\">",
" CLINICAL MANIFESTATIONS",
" </a>",
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" DIAGNOSIS",
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" Complete blood count",
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" Bone marrow examination",
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" Diagnostic criteria",
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" - Moderate aplastic anemia",
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" - Severe aplastic anemia",
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" - Very severe aplastic anemia",
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" DIFFERENTIAL DIAGNOSIS",
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" <a class=\"outlineLink\" href=\"#PATIENT_INFORMATION\">",
" INFORMATION FOR PATIENTS",
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" SUMMARY",
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" REFERENCES",
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title=\"picture 1\">",
" Aplastic anemia bone marrow",
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" Causes acquired aplastic anemia",
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" Causes of bone marrow failure",
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" Treatment of intermediate, low, or very low risk myelodysplastic syndromes",
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prebiotics (unflavored and vanilla)",
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" </td>",
" <td>",
" 2R/2R, 2R/3R or 3R/3R",
" </td>",
" <td>",
" High",
" </td>",
" <td>",
" 7 times increase in risk of 5-FU toxicity",
" </td>",
" <td>",
" Positive result for clinically significant variation in DPYD",
" </td>",
" </tr>",
" <tr>",
" <td>",
" No mutation detected",
" </td>",
" <td>",
" 2R/2R",
" </td>",
" <td>",
" Moderate",
" </td>",
" <td>",
" 1.4 to 2.5 times increase in risk of 5-FU toxicity",
" </td>",
" <td>",
" Positive result for clinically significant variation in TYMS",
" </td>",
" </tr>",
" <tr>",
" <td>",
" No mutation",
" </td>",
" <td>",
" 2R/3R or 3R/3R",
" </td>",
" <td>",
" Low",
" </td>",
" <td>",
" No increase in risk of 5-FU toxicity",
" </td>",
" <td>",
" No mutation detected",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Variant of uncertain significance",
" </td>",
" <td>",
" 2R/3R or 3R/3R variant",
" </td>",
" <td>",
" Indeterminate",
" </td>",
" <td>",
" Unknown",
" </td>",
" <td>",
" Variant of uncertain significance detected",
" </td>",
" </tr>",
" </tbody>",
" </table>",
" </div>",
" <div class=\"lgnd\">",
" <div class=\"footnotes\">",
" 5-FU: 5-fluorouracil; DPYD: dihydropyrimidine dehydrogenase; TYMS:
thymidylate synthetase.",
" </div>",
" <div class=\"reference\">",
" Reproduced from: Keiser LW. The role of pharmacogenetics in the management of
fluorouracil-based toxicity. Community Oncology 2008; 5 (Suppl 12):1. Illustration
used with the permission of Elsevier Inc. All rights reserved.",
" </div>",
" </div>",
" </div>",
" </div>",
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" <div class=\"lgnd\">",
" Urinary excretion of leukotriene E4 (LTE4) in normal subjects and patients
with acute asthma. Approximately two-thirds of asthmatics have increased LTE4
excretion during an acute episode.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Data from Drazen, JM, O'Brien, J, Sparrow, D, et al, Am Rev Respir Dis 1992;
146:104.",
" </div>",
" </div>",
" </div>",
" </div>",
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var title_f0_36_590="Contents: Pediatric medical emergencies";
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" Adult and Pediatric Emergency Medicine",
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" Contents:",
" Pediatric medical emergencies",
" </h1>",
" </tds>",
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" <trs>",
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" Acute viral encephalitis in children and adolescents: Clinical
manifestations and diagnosis",
" </a>",
" </li>",
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" <a class=\"tocItem\" href=\"UTD.htm?23/18/23848\">",
" Acute viral encephalitis in children and adolescents: Treatment and
prevention",
" </a>",
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" <a class=\"tocItem\" href=\"UTD.htm?28/17/28951\">",
" Definition and etiology of fever in neonates and infants (less than
three months of age)",
" </a>",
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" <a class=\"tocItem\" href=\"UTD.htm?43/37/44633\">",
" Elevated intracranial pressure in children",
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" Emergency complications of Hirschsprung disease",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?4/45/4826\">",
" Epiglottitis (supraglottitis): Clinical features and diagnosis",
" </a>",
" </li>",
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" Epiglottitis (supraglottitis): Treatment and prevention",
" </a>",
" </li>",
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" <a class=\"tocItem\" href=\"UTD.htm?27/26/28074\">",
" Evaluation and management of fever in the neonate and young infant
(less than three months of age)",
" </a>",
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" Adult and Pediatric Emergency Medicine",
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" <trs>",
" <tds>",
" <h1>",
" Contents:",
" Pediatric orthopedics",
" </h1>",
" </tds>",
" </trs>",
" <trs>",
" <tds>",
" </tds>",
" </trs>",
" <trs>",
" <tds valign=\"top\">",
" <div class=\"toctable\" border=\"0\" cellpadding=\"0\" cellspacing=\"0\"
width=\"100%\">",
" <trs>",
" <tds>",
" <strong>",
" Ankle",
" </strong>",
" <ul>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?30/20/31050\">",
" Clinical features and management of ankle pain in the young athlete",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?14/23/14711\">",
" Evaluation of foot and ankle pain in the young athlete",
" </a>",
" </li>",
" </ul>",
" <strong>",
" Back",
" </strong>",
" <ul>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?18/45/19162\">",
" Back pain in children and adolescents: Overview of causes",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?32/62/33770\">",
" Clinical features; evaluation; and diagnosis of adolescent idiopathic
scoliosis",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?2/39/2679\">",
" Evaluation of the child with back pain",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?36/12/37065\">",
" Treatment and prognosis of adolescent idiopathic scoliosis",
" </a>",
" </li>",
" </ul>",
" <strong>",
" Child abuse",
" </strong>",
" <ul>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?11/23/11641\">",
" Differential diagnosis of the orthopedic manifestations of child
abuse",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?13/30/13802\">",
" Orthopedic aspects of child abuse",
" </a>",
" </li>",
" </ul>",
" <strong>",
" Elbow",
" </strong>",
" <ul>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?22/25/22937\">",
" Elbow injuries in the young athlete",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?37/40/38532\">",
" Radial head subluxation (nursemaid's elbow)",
" </a>",
" </li>",
" </ul>",
" <strong>",
" General topics",
" </strong>",
" <ul>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?41/4/42057\">",
" Approach to the child with a limp",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?13/37/13913\">",
" Clinical manifestations and diagnosis of osteochondritis dissecans
(OCD)",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?13/46/14057\">",
" Evaluation of the child with joint pain or swelling",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?20/26/20902\">",
" Growing pains",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?18/36/19014\">",
" Management of osteochondritis dissecans (OCD)",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?23/60/24522\">",
" Overview of benign bone tumors in children and adolescents",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?23/9/23706\">",
" Overview of the causes of limp in children",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?14/54/15208\">",
" Splinting of musculoskeletal injuries",
" </a>",
" </li>",
" </ul>",
" <strong>",
" Genetic diseases",
" </strong>",
" <ul>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?26/15/26874\">",
" Clinical features and diagnosis of Down syndrome",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?7/6/7274\">",
" Clinical features and diagnosis of the mucopolysaccharidoses",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?34/16/35082\">",
" Complications and management of the mucopolysaccharidoses",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?20/3/20538\">",
" Genetics, clinical features, and diagnosis of Marfan syndrome and
related disorders",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?12/58/13224\">",
" Management of Down syndrome",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?5/51/5945\">",
" Management of Marfan syndrome and related disorders",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?35/50/36650\">",
" Neurofibromatosis type 1 (von Recklinghausen's disease)",
" </a>",
" </li>",
" </ul>",
" <strong>",
" Heel and foot",
" </strong>",
" <ul>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?41/17/42264\">",
" Approach to the child with in-toeing",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?30/6/30823\">",
" Approach to the child with out-toeing",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?28/6/28775\">",
" Clinical features and management of heel pain in the young athlete",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?14/23/14711\">",
" Evaluation of foot and ankle pain in the young athlete",
" </a>",
" </li>",
" </ul>",
" <strong>",
" Hip",
" </strong>",
" <ul>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?41/17/42264\">",
" Approach to the child with in-toeing",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?26/30/27113\">",
" Clinical features and diagnosis of developmental dysplasia of the hip",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?0/12/199\">",
" Epidemiology and pathogenesis of developmental dysplasia of the hip",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?16/21/16729\">",
" Overview of hip pain in childhood",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?24/32/25097\">",
" Radiologic evaluation of the hip in infants, children, and
adolescents",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?22/42/23209\">",
" Slipped capital femoral epiphysis (SCFE)",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?20/48/21254\">",
" Treatment and outcome of developmental dysplasia of the hip",
" </a>",
" </li>",
" </ul>",
" <strong>",
" Knee",
" </strong>",
" <ul>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?26/55/27511\">",
" Approach to the child with bow-legs",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?6/3/6199\">",
" Approach to the child with knock-knees",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?5/9/5273\">",
" Approach to the young athlete with acute knee pain or injury",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?28/34/29223\">",
" Approach to the young athlete with chronic knee pain or injury",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?12/6/12392\">",
" Osgood-Schlatter disease (tibial tuberosity avulsion)",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?24/0/24581\">",
" Patellar dislocations in children and adolescents",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?1/45/1752\">",
" Plica syndrome",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?27/50/28455\">",
" Traumatic causes of acute knee pain and injury in the young athlete",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?3/61/4056\">",
" Treatment of knee injuries in the young athlete",
" </a>",
" </li>",
" </ul>",
" <strong>",
" Neck",
" </strong>",
" <ul>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?8/26/8616\">",
" Acquired torticollis in children",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?40/25/41368\">",
" Approach to the young athlete with neck pain or injury",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?42/49/43798\">",
" Congenital muscular torticollis",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?15/28/15815\">",
" Field care and evaluation of the young athlete with acute neck injury",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?23/8/23689\">",
" Overview of cervical spinal cord and cervical peripheral nerve injuries
in the young athlete",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?10/49/11033\">",
" Overview of musculoskeletal neck injuries in the young athlete",
" </a>",
" </li>",
" </ul>",
" <strong>",
" Osteoarticular infections",
" </strong>",
" <ul>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?14/30/14826\">",
" Bacterial arthritis: Clinical features and diagnosis in infants and
children",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?39/30/40423\">",
" Bacterial arthritis: Epidemiology, pathogenesis, and microbiology in
infants and children",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?27/33/28186\">",
" Bacterial arthritis: Treatment and outcome in infants and children",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?19/39/20087\">",
" Clinical features of hematogenous osteomyelitis in children",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?17/0/17416\">",
" Epidemiology, pathogenesis, and microbiology of hematogenous
osteomyelitis in children",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?32/32/33289\">",
" Evaluation and diagnosis of hematogenous osteomyelitis in children",
" </a>",
" </li>",
" <li>",
" <a class=\"tocItem\" href=\"UTD.htm?24/9/24730\">",
" Treatment of hematogenous osteomyelitis in children",
" </a>",
" </li>",
" </ul>",
" </tds>",
" </trs>",
" </div>",
" </tds>",
" </trs>",
" <trs>",
" <tds>",
" <img height=\"10\" src=\"./../images/spacer.myextg\" width=\"1\"/>",
" </tds>",
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