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Hemolytic anemia
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Hemolytic anemia
Classification and external resources
ICD-10 D55-D59
ICD-9 282, 283, 773
DiseasesDB 5534
MedlinePlus 000571
eMedicine med/979
MeSH D000743
Hemolytic anemia (or haemolytic anaemia) is a form of anemia due to hemolysis, the
abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular
hemolysis) or elsewhere in the human body (extravascular). It has numerous possible causes,
ranging from relatively harmless to life-threatening. The general classification of hemolytic
anemia is either inherited or acquired. Treatment depends on the cause and nature of the
breakdown.
Symptoms of hemolytic anemia are similar to other forms of anemia (fatigue and shortness of
breath), but in addition, the breakdown of red cells leads to jaundice and increases the risk of
particular long-term complications, such as gallstones and pulmonary hypertension.
Contents
1 Basic features
2 Signs and symptoms
3 Causes
o 3.1 Intrinsic causes
o 3.2 Extrinsic causes
4 Pathophysiology
5 Diagnosis
6 Treatment
7 Veterinary cases
8 References
Basic features
Hemolytic anemia involves the following:
1. Abnormal and accelerated destruction of red cells and, in some anemias, their
precursors
2. Increased breakdown of hemoglobin, which may result in:
1. increased bilirubin level (mainly indirect-reacting) with jaundice
2. increased fecal and urinary urobilinogen
3. Hemoglobinanemia, methemalbuminemia, hemoglobinuria and
hemosiderinuria (where there is significant intravascular hemolysis).
3. Bone marrow compensatory reaction:
1. Erythroid hyperplasia with accelerated production of red cells, reflected by
reticulocytosis, and slight macrocytosis in peripheral blood
2. Expansion of bone marrow in infants and children with severe chronic
hemolysis - changes in bone configuration visible on X-ray
4. The balance between red cell destruction and marrow compensation determines the
severity of anemias.
Signs and symptoms
In general, signs of anemia (pallor, fatigue, shortness of breath, and potential for heart failure)
are present. In small children, failure to thrive may occur in any form of anemia. Certain
aspects of the medical history can suggest a cause for hemolysis, such as drugs, consumption
of fava beans, the presence of prosthetic heart valve, or other medical illness.
Chronic hemolysis leads to an increased excretion of bilirubin into the biliary tract, which in
turn may lead to gallstones. The continuous release of free hemoglobin has been linked with
the development of pulmonary hypertension (increased pressure over the pulmonary artery);
this, in turn, leads to episodes of syncope (fainting), chest pain, and progressive
breathlessness. Pulmonary hypertension eventually causes right ventricular heart failure, the
symptoms of which are peripheral edema (fluid accumulation in the skin of the legs) and
ascites (fluid accumulation in the abdominal cavity).
Causes
Main articles: Congenital hemolytic anemia and Acquired hemolytic anemia
They may be classified according to the means of hemolysis, being either intrinsic in cases
where the cause is related to the red blood cell (RBC) itself, or extrinsic in cases where
factors external to the RBC dominate.
[1]
Intrinsic effects may include problems with RBC
proteins or oxidative stress handling, whereas external factors include immune attack and
microvascular angiopathies (RBCs are mechanically damaged in circulation).
Intrinsic causes
Hereditary (inherited) hemolytic anemia can be due to membrane defects:
Defects of red blood cell membrane production (as in hereditary spherocytosis and
hereditary elliptocytosis)
Hereditary (inherited) hemolytic anemia can be due to defects in hemoglobin :
Defects in hemoglobin production (as in thalassemia, sickle-cell disease and
congenital dyserythropoietic anemia)
Hereditary (inherited) hemolytic anemia can be due to enzyme defects:
Defective red cell metabolism (as in glucose-6-phosphate dehydrogenase deficiency
and pyruvate kinase deficiency)
Acquired due to paroxysmal nocturnal hemoglobinuria:
Paroxysmal nocturnal hemoglobinuria (PNH), sometimes referred to as Marchiafava-
Micheli syndrome, is a rare, acquired, potentially life-threatening disease of the blood
characterized by complement-induced intravascular hemolytic anemia
Extrinsic causes
Acquired hemolytic anemia may be caused by immune-mediated causes, drugs and other
miscellaneous causes.
Immune-mediated causes could include transient factors as in Mycoplasma
pneumoniae infection (cold agglutinin disease) or permanent factors as in
autoimmune diseases like autoimmune hemolytic anemia (itself more common in
diseases such as systemic lupus erythematosus and chronic lymphocytic leukemia)
Any of the causes of hypersplenism (increased activity of the spleen) such as portal
hypertension
Acquired hemolytic anemia is also encountered in burns and as a result of certain
infections.
Lead poisoning resulting from the environment causes non-immune hemolytic
anemia.
Runners can suffer hemolytic anemia due to "footstrike hemolysis", owing to the
destruction of red blood cells in feet at foot impact.
[2][3]

Low-grade hemolytic anemia occurs in 70% of prosthetic heart valve recipients, and
severe hemolytic anemia occurs in 3%
[4]

March hemoglobinuria
Pathophysiology
In a healthy person, a red blood cell survives 90 to 120 days in the circulation, so about 1% of
human red blood cells break down each day. The spleen (part of the reticulo-endothelial
system) is the main organ that removes old and damaged RBCs from the circulation. In
healthy individuals, the breakdown and removal of RBCs from the circulation is matched by
the production of new RBCs in the bone marrow.
In conditions where the rate of RBC breakdown is increased, the body initially compensates
by producing more RBCs; however, breakdown of RBCs can exceed the rate that the body
can make RBCs, and so anemia can develop. Bilirubin, a breakdown product of hemoglobin,
can accumulate in the blood, causing jaundice, and be excreted in the urine causing the urine
to become a dark brown color.
In general, hemolytic anemia occurs as a modification of the RBC life cycle. That is, instead
of being collected at the end of its useful life and disposed of normally, the RBC disintegrates
in a manner allowing free iron-containing molecules to reach the blood. It is perhaps then
helpful to understand the physiology of the RBC and things that can go wrong to cause it to
"die" prematurely. With their complete lack of mitochondria, RBCs rely on glycolysis for the
materials needed to reduce oxidative damage. Any limitations of glycolysis can result in more
susceptibility to oxidative damage and a short or abnormal lifecycle. If the cell is unable to
signal to the reticuloendothelial phagocytes by externalizing phosphatidylserine, it is likely to
lyse through uncontrolled means.
[5][6][7]
Dogs and cats differ slightly from humans in some
details of their RBC composition and have altered susceptibility to damage, notably,
increased susceptibility to oxidative damage from onion or garlic.
[8][9][10][11][12][13][14][15][16][17]

The distinguishing feature of intravascular hemolysis is the release of RBC contents into the
blood stream. The metabolism and elimination of these products, largely iron-containing
compounds capable of doing damage through Fenton reactions, is an important part of the
condition. Several reference texts exist on the elimination pathways, for example.
[18][19]
Free
hemoglobin can bind to haptoglobin, or it may oxidize and release the heme group that is able
to bind to either albumin or hemopexin. The heme is ultimately converted to bilirubin and
removed in stool and urine.
[18]
Hemoglobin may be cleared directly by the kidneys resulting
in fast clearance of free hemoglobin but causing the continued loss of hemosiderin loaded
renal tubular cells for many days.
Additional effects of free hemoglobin seem to be due to specific reactions with NO.
[20]

Diagnosis

This section requires expansion. (March 2010)
Peripheral blood smear microscopy:
o fragments of the red blood cells ("schistocytes") can be present
o some red blood cells may appear smaller and rounder than usual (spherocytes)
o Reticulocytes are present in elevated numbers. This may be overlooked if a
special stain is not used.
The level of unconjugated bilirubin in the blood is elevated. This may lead to
jaundice.
The level of lactate dehydrogenase (LDH) in the blood is elevated
Haptoglobin levels are decreased
If the direct Coombs test is positive, hemolysis is caused by an immune process.
Hemosiderin in the urine indicates chronic intravascular hemolysis. There is also
urobilinogen in the urine.
Treatment

This section requires expansion. (March 2010)
Definitive therapy depends on the cause:
Symptomatic treatment can be given by blood transfusion, if there is marked anemia.
In severe immune-related hemolytic anemia, steroid therapy is sometimes necessary.
Sometimes splenectomy can be helpful where extravascular hemolysis is predominant
(i.e. most of the red blood cells are being removed by the spleen).
Veterinary cases
Hemolytic anemia may affect non human species as well. It has been found in a number of
animal species to result from specific triggers.
[21]

Some notable cases include hemolytic anemia found in black rhinos kept in captivity, with
the disease affecting 20% of the animals in one instance.
[22][23][24]
The disease is also found in
wild rhinos.
[25]

References
1. ^ Current Medical Diagnosis and Treatment 2009 By Stephen J. McPhee, Maxine A.
Papadakis page 436
http://books.google.com/books?id=zQlH4mXSziYC&pg=PT454&dq=hemoglobin+h
emosiderin+hemolysis+bilirubin&ei=Z2P_SuzwA6D2ygT9vOz3Dg#v=onepage&q=
hemoglobin%20hemosiderin%20hemolysis%20bilirubin&f=false
2. ^ Telford RD, Sly GJ, Hahn AG, Cunningham RB, Bryant C, Smith JA (January
2003). "Footstrike is the major cause of hemolysis during running". J. Appl. Physiol.
94 (1): 3842. doi:10.1152/japplphysiol.00631.2001. PMID 12391035.
3. ^ Lippi G, Schena F, Salvagno GL, Aloe R, Banfi G, Guidi GC (July 2012). "Foot-
strike haemolysis after a 60-km ultramarathon". Blood Transfus: 377383.
PMC 3417738/.
4. ^ Wise, Donald Lee (2000). Biomaterials Engineering and Devices: Orthopedic,
dental, and bone graft applications. ISBN 978-0-89603-859-2.
5. ^ Kolb S, Vranckx R, Huisse MG, Michel JB, Meilhac O (July 2007). "The
phosphatidylserine receptor mediates phagocytosis by vascular smooth muscle cells".
The Journal of Pathology 212 (3): 24959. doi:10.1002/path.2190. PMID 17534843.
6. ^ Bosman GJ, Willekens FL, Werre JM (2005). "Erythrocyte aging: a more than
superficial resemblance to apoptosis?". Cellular Physiology and Biochemistry 16 (1
3): 18. doi:10.1159/000087725. PMID 16121027.
7. ^ Bratosin D, Mazurier J, Tissier JP, et al. (February 1998). "Cellular and molecular
mechanisms of senescent erythrocyte phagocytosis by macrophages. A review".
Biochimie 80 (2): 17395. doi:10.1016/S0300-9084(98)80024-2. PMID 9587675.
8. ^ Chang HS, Yamato O, Sakai Y, Yamasaki M, Maede Y (January 2004).
"Acceleration of superoxide generation in polymorphonuclear leukocytes and
inhibition of platelet aggregation by alk(en)yl thiosulfates derived from onion and
garlic in dogs and humans". Prostaglandins, Leukotrienes, and Essential Fatty Acids
70 (1): 7783. doi:10.1016/j.plefa.2003.08.006. PMID 14643182.
9. ^ Yamato O, Hayashi M, Kasai E, Tajima M, Yamasaki M, Maede Y (April 1999).
"Reduced glutathione accelerates the oxidative damage produced by sodium n-
propylthiosulfate, one of the causative agents of onion-induced hemolytic anemia in
dogs". Biochimica et Biophysica Acta 1427 (2): 17582. doi:10.1016/S0304-
4165(99)00023-9. PMID 10216234.
10. ^ Yamato O, Hayashi M, Yamasaki M, Maede Y (February 1998). "Induction of
onion-induced haemolytic anemia in dogs with sodium n-propylthiosulphate". The
Veterinary Record 142 (9): 2169. doi:10.1136/vr.142.9.216. PMID 9533293.
11. ^ Yamoto O, Maede Y (January 1992). "Susceptibility to onion-induced hemolysis in
dogs with hereditary high erythrocyte reduced glutathione and potassium
concentrations". American Journal of Veterinary Research 53 (1): 1347.
PMID 1539905.
12. ^ Murase T, Maede Y (April 1990). "Increased erythrophagocytic activity of
macrophages in dogs with Babesia gibsoni infection". Nippon Juigaku Zasshi 52 (2):
3217. doi:10.1292/jvms1939.52.321. PMID 2348598.
13. ^ Ogawa E, Shinoki T, Akahori F, Masaoka T (August 1986). "Effect of onion
ingestion on anti-oxidizing agents in dog erythrocytes". Nippon Juigaku Zasshi 48
(4): 68591. doi:10.1292/jvms1939.48.685. PMID 3761777.
14. ^ Harvey JW, Rackear D (July 1985). "Experimental onion-induced hemolytic
anemia in dogs". Veterinary Pathology 22 (4): 38792. PMID 4035943.
15. ^ van Schouwenburg S (September 1982). "[Hemolytic anemia in a miniature
dashshund caused by eating large amounts of onion (Allium cepa)]" (in Afrikaans).
Journal of the South African Veterinary Association 53 (3): 212. PMID 7175912.
16. ^ Stallbaumer M (June 1981). "Onion poisoning in a dog". The Veterinary Record
108 (24): 5234. doi:10.1136/vr.108.24.523. PMID 7257143.
17. ^ Spice RN (July 1976). "Hemolytic anemia associated with ingestion of onions in a
dog". The Canadian Veterinary Journal. La Revue Vtrinaire Canadienne 17 (7):
1813. PMC 1697286. PMID 949673.
18. ^
a

b
Hematology in clinical practice: a guide to diagnosis and management By Robert
S. Hillman, Kenneth A. Ault, Henry M. Rinder page 136-139
http://books.google.com/books?id=NJs1VpA8SEoC&pg=PA138&dq=hemoglobin+h
emosiderin+hemolysis+bilirubin&ei=Z2P_SuzwA6D2ygT9vOz3Dg#v=onepage&q=
hemoglobin%20hemosiderin%20hemolysis%20bilirubin&f=false
19. ^ Wintrobe's Clinical Hematology, Volume 1 By John P. Greer
http://books.google.com/books?id=68enzUD7BVgC&pg=PA161&dq=hemoglobin+h
emosiderin+hemolysis+bilirubin&ei=Z2P_SuzwA6D2ygT9vOz3Dg#v=onepage&q=
hemoglobin%20hemosiderin%20hemolysis%20bilirubin&f=false page 160
20. ^ Boretti FS, Buehler PW, D'Agnillo F, et al. (August 2009). "Sequestration of
extracellular hemoglobin within a haptoglobin complex decreases its hypertensive and
oxidative effects in dogs and guinea pigs". The Journal of Clinical Investigation 119
(8): 227180. doi:10.1172/JCI39115. PMC 2719941. PMID 19620788.
21. ^ Mary Anna Thrall, Dale C. Baker, E. Duane Lassen, Veterinary hematology and
clinical chemistry, ISBN 0-7817-6850-0, 2004.
22. ^ Edward F. Gibbons, Barbara Susan Durrant, Jack Demarest, Conservation of
endangered species in captivity: an interdisciplinary approach, page 324, 2005, ISBN
0-7914-1911-8
23. ^ Oliver A. Ryder, Zoological Society of San Diego, Rhinoceros biology and
conservation, Zoological Society of San Diego, 1993, page 312, 335.
24. ^ Texas Monthly, Oct 1992, Vol. 20, No. 10, ISSN 0148-7736, page 98-100.
25. ^ Jutta Meister, ed. Catharine E. Bell, Encyclopedia of the world's zoos, Volume 3,
page 1008, ISBN 1-57958-174-9, 2001.
[hide]
v
t
e
Pathology: hematology, hematologic diseases of RBCs and megakaryocytes /
MEP (D50-69,74, 280-287)

Red
blood cells

Poly-
cythemia
Polycythemia vera



Anemia
Nutritional
Micro-: Iron deficiency anemia
o Plummer-Vinson syndrome
Macro-: Megaloblastic anemia
o Pernicious anemia


Hemolytic
(mostly
Normo-)
Hereditary
enzymopathy: G6PD
glycolysis
o PK
o TI
o HK
hemoglobinopathy: Thalassemia
o alpha
o beta
o delta
Sickle-cell disease/trait
HPFH
membrane: Hereditary
spherocytosis
o Minkowski-Chauffard
syndrome
Hereditary elliptocytosis
o Southeast Asian
ovalocytosis
Hereditary stomatocytosis


Acquired
Autoimmune
o WAHA
o CAD
o PCH
membrane
o PNH
MAHA
TM
o HUS
Drug-induced autoimmune
Drug-induced nonautoimmune
Hemolytic disease of the newborn



Aplastic
(mostly
Normo-)
Hereditary: Fanconi anemia
DiamondBlackfan anemia
Acquired: PRCA
Sideroblastic anemia
Myelophthisic


Blood tests
MCV
o Normocytic
o Microcytic
o Macrocytic
MCHC
o Normochromic
o Hypochromic



Other
Methemoglobinemia
Sulfhemoglobinemia
Reticulocytopenia



Coagulation/
coagulopathy

Hyper-
coagulability
primary: Antithrombin III deficiency
Protein C deficiency/Activated protein C
resistance/Protein S deficiency/Factor V Leiden
Prothrombin G20210A
acquired:Thrombocytosis
o essential
DIC
o Congenital afibrinogenemia
o Purpura fulminans
autoimmune
o Antiphospholipid




Hypo-
coagulability
Thrombocytopenia
Thrombocytopenic purpura: ITP
o Evans syndrome
TM
o TTP
Heparin-induced
thrombocytopenia
May-Hegglin anomaly


Platelet function
adhesion
o BernardSoulier
syndrome
aggregation
o Glanzmann's
thrombasthenia
platelet storage pool deficiency
o HermanskyPudlak
syndrome
o Gray platelet syndrome


Clotting factor
Hemophilia
o A/VIII
o B/IX
o C/XI
von Willebrand disease
Hypoprothrombinemia/II
XIII
Dysfibrinogenemia



M: MYL cell/phys (coag, heme,
immu, gran), csfs
rbmg/mogr/tumr/hist,
sysi/epon, btst
drug (B1/2/3+5+6),
btst, trns

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