`Hemorrhagic Diatheses

Excessive bleeding can result from (1) increased fragility of vessels, (2) platelet deficiency or
dysfunction, and () derangement of coagulation, alone or in combination!
1. Bleeding Disorders Caused By Vessel Wall Abnormalities
Disorders "ithin this category, sometimes called nonthrombocytopenic purpuras, are
relatively common but do not usually cause serious bleeding problems! #ost often, they induce
small hemorrhages (petechiae and purpura) in the s$in or mucous membranes, particularly the
gingivae! %n occasion, ho"ever, more significant hemorrhages can occur into &oints, muscles,
and subperiosteal locations, or ta$e the form of menorrhagia, nosebleeds, gastrointestinal
bleeding, or hematuria! The platelet count, the bleeding time, and tests of coagulation (PT, PTT)
usually yield normal results!
'he varied clinical conditions in "hich abnormalities in the vessel "all cause bleeding include
the follo"ing(
#any infections induce petechial and purpuric hemorrhages, particularly
meningococcemia, other forms of septicemia, infective endocarditis, and several of the
ric$ettsioses! 'he involved mechanisms include microbial damage to the
microvasculature (vasculitis) and disseminated intravascular coagulation (D)*)! +ailure
to recogni,e meningococcemia as a cause of petechiae and purpura can be catastrophic
for the patient!
Drug reactions sometimes induce cutaneous petechiae and purpura "ithout causing
thrombocytopenia! )n many instances the vascular in&ury is mediated by the deposition of
drug-induced immune complexes in vessel "alls, "hich leads to hypersensitivity
(leu$ocytoclastic) vasculitis!
.curvy and the Ehlers-Danlos syndrome are associated "ith microvascular bleeding,
"hich results from defects in collagen that "ea$ens vessel "alls! 'he same mechanism
may account for the spontaneous purpura that are commonly seen in the elderly and the
s$in hemorrhages that are seen "ith *ushing syndrome, in "hich the protein-"asting
effects of excessive corticosteroid production cause loss of perivascular supporting tissue!
Henoch-.ch/nlein purpura is a systemic hypersensitivity disease of un$no"n cause that
is characteri,ed by a purpuric rash, colic$y abdominal pain, polyarthralgia, and acute
glomerulonephritis! 0ll these changes result from the deposition of circulating immune
complexes "ithin vessels throughout the body and "ithin the glomerular mesangial
regions!
Hereditary hemorrhagic telangiectasia (also $no"n as 1eber-%sler-2endu syndrome) is
an autosomal dominant disorder characteri,ed by dilated, tortuous blood vessels "ith thin
"alls that bleed readily! 3leeding can occur any"here, but it is most common under the
mucous membranes of the nose (epistaxis), tongue, mouth, and eyes, and throughout the
gastrointestinal tract!
4erivascular amyloidosis can "ea$en blood vessel "alls and cause bleeding! 'his
complication is most common "ith amyloid light-chain (05) amyloidosis and often
manifests as mucocutaneous petechiae!
0mong these conditions, serious bleeding is most often associated "ith hereditary
telangiectasia! 'he bleeding in each is nonspecific, and the diagnosis of these entities is based on
the recognition of other more specific associated findings!
2. Bleeding Related To Reduced Platelet Number: Trombocyto!enia
2eduction in platelet number constitutes an important cause of generali,ed bleeding! 0
count belo" 166,666 platelets785 is generally considered to constitute thrombocytopenia!
Ho"ever, spontaneous bleeding does not become evident until platelet counts fall belo" 26,666
platelets785! 4latelet counts in the range of 26,666 to 96,666 platelets785 can aggravate post-
traumatic bleeding! 3leeding resulting from thrombocytopenia is associated "ith a normal 4'
and 4''!
)t hardly needs reiteration that platelets are critical for hemostasis, since they form
temporary plugs that stop bleeding and promote $ey reactions in the coagulation cascade!
.pontaneous bleeding associated "ith thrombocytopenia most often involves small vessels!
*ommon sites for such hemorrhages are the s$in and the mucous membranes of the
gastrointestinal and genitourinary tracts! Most feared, however, is intracranial bleeding, which is
a threat to any patient with a markedly depressed platelet count!
'he many causes of thrombocytopenia can be classified into four ma&or categories!
Decreased platelet production! 'his can result from conditions that depress marro"
output generally (such as aplastic anemia and leu$emia) or affect mega$aryocytes
some"hat selectively! Examples of the latter include certain drugs and alcohol, "hich
may suppress platelet production through uncertain mechanisms "hen ta$en in large
amounts: H);, "hich may infect mega$aryocytes and inhibit platelet production: and
myelodysplastic syndromes, "hich may occasionally present "ith isolated
thrombocytopenia!
Decreased platelet survival! 'his important mechanism of thrombocytopenia can have an
immunological or nonimmunological basis! )n immune thrombocytopenia platelet
destruction is caused by antibodies to platelets or, less often, immune complexes that
deposit on platelets! 0ntibodies to platelets can recogni,e self-antigens (autoantibodies)
or non-self antigens (alloantibodies)! 0utoimmune thrombocytopenia is discussed in the
follo"ing section! 0lloantibodies can arise "hen platelets are transfused or cross the
placenta from the fetus into the pregnant mother! )n the latter case, )g< antibodies made
in the mother can cause clinically significant thrombocytopenia in the fetus! 'his is
reminiscent of hemolytic disease of the ne"born, in "hich red cells are the target! 'he
most important nonimmunological causes are disseminated intravascular coagulation
(D)*) and the thrombotic microangiopathies, in "hich unbridled, often systemic, platelet
activation reduces platelet life span! =onimmunological destruction of platelets may also
be caused by mechanical in&ury, such as in individuals "ith prosthetic heart valves!
.e>uestration! 'he spleen normally se>uesters 6? to 9? of the body@s platelets, but
this can rise to A6? to B6? "hen the spleen is enlarged, producing moderate degrees of
thrombocytopenia!
Dilution! #assive transfusions can produce a dilutional thrombocytopenia! 1ith
prolonged blood storage the number of viable platelets decreases: thus, plasma volume
and red cell mass are reconstituted by transfusion, but the number of circulating platelets
is relatively reduced!
Cronic "mmune Trombocyto!enic Pur!ura #"TP$
Chronic ITP is caused by autoantibodies to platelets! )t can occur in the setting of a
variety of predisposing conditions and exposures (secondary) or in the absence of any $no"n
ris$ factors (primary or idiopathic)! 'he contexts in "hich chronic )'4 occurs secondarily are
numerous and include individuals "ith systemic lupus erythematosus, H); infection, and 3-cell
neoplasms such as chronic lymphocytic leu$emia! 'he diagnosis of primary chronic )'4 is made
only after secondary causes are excluded!
4athogenesis!
'he autoantibodies, most often directed against platelet membrane glycoproteins ))b-)))a
or )b-)C, can be demonstrated in the plasma and bound to the platelet surface in about A6? of
patients! )n the over"helming ma&ority of cases, the antiplatelet antibodies are of the )g< class!
0s in autoimmune hemolytic anemias, antiplatelet antibodies act as opsonins that are recogni,ed
by )g< +c receptors expressed on phagocytes, leading to increased platelet destruction! 'he
thrombocytopenia is usually mar$edly improved by splenectomy, indicating that the spleen is the
ma&or site of removal of opsoni,ed platelets! 'he splenic red pulp is also rich in plasma cells, and
part of the benefit of splenectomy (a common treatment for chronic )'4) may stem from the
removal of a source of autoantibodies! )n some instances the autoantibodies may also bind to and
damage mega$aryocytes, leading to decreases in platelet production that further exacerbate the
thrombocytopenia!
*linical +eatures!
*hronic )'4 occurs most commonly in adult "omen typically under D6 years of age! 'he
female-to-male ratio is ( 1! )t is often insidious in onset and is characteri,ed by bleeding into
the s$in and mucosal surfaces! *utaneous bleeding is seen in the form of pinpoint hemorrhages
(petechiae), "hich are especially prominent in the dependent areas "here the capillary pressure
is higher! 4etechiae can become confluent, giving rise to ecchymoses! %ften there is a history of
easy bruising, nosebleeds, bleeding from the gums, and hemorrhages into soft tissues from
relatively minor trauma! 'he disease may manifest first "ith melena, hematuria, or excessive
menstrual flo"! .ubarachnoid hemorrhage and intracerebral hemorrhage are serious and
sometimes fatal complications, but fortunately they are rare in treated patients! .plenomegaly
and lymphadenopathy are uncommon in primary disease, and their presence should lead one to
consider other diagnoses, such as )'4 secondary to a 3-cell neoplasm!
'he clinical signs and symptoms are not specific but rather reflective of the
thrombocytopenia! 'he findings of a lo" platelet count, normal or increased mega$aryocytes in
the bone marro", and large platelets in the peripheral blood are ta$en as presumptive evidence of
accelerated platelet destruction! 'he 4' and 4'' are normal! 'ests for platelet autoantibodies are
not "idely available!
Acute "mmune Trombocyto!enic Pur!ura
5i$e chronic )'4, this condition is caused by autoantibodies to platelets, but its clinical
features and course are distinct! 0cute )'4 is mainly a disease of childhood occurring "ith e>ual
fre>uency in both sexes! .ymptoms appear abruptly and usually follo" a viral illness, "hich
typically occurs about 2 "ee$s before the onset of the thrombocytopenia! Enli$e chronic )'4,
acute )'4 is self-limited, usually resolving spontaneously "ithin F months! <lucocorticoids are
given only if the thrombocytopenia is severe! )n about 26? of children, usually those "ithout a
viral prodrome, thrombocytopenia persists: these less fortunate children have a childhood form
of chronic )'4 that follo"s a course similar to the adult disease!
Drug%"nduced Trombocyto!enia
Drugs can induce thrombocytopenia through direct effects on platelets and secondary to
immunologically mediated platelet destruction! 'he drugs most commonly implicated are
>uinine, >uinidine, and vancomycin, all of "hich bind platelet glycoproteins and in one "ay or
another create antigenic determinants that are recogni,ed by antibodies!
G2DH
#uch more rarely,
drugs such as gold salts induce true autoantibodies through un$no"n mechanisms!
'hrombocytopenia, "hich may be severe, is also a common conse>uence of platelet inhibitory
drugs that bind glycoprotein ))b7)))a: it is hypothesi,ed that these drugs induce conformational
changes in glycoprotein ))b7)))a and create an immunogenic epitope!
eparin!induced thrombocytopenia (IT) has a distinctive pathogenesis and is of
particular importance because of its potential for severe clinical conse"uences!
G29H
'hrombocytopenia occurs in about 9? of persons receiving heparin! #ost develop so-called type
) thrombocytopenia, "hich occurs rapidly after the onset of therapy and is of little clinical
importance, sometimes resolving despite the continuation of therapy! )t most li$ely results from a
direct platelet-aggregating effect of heparin! 'ype )) thrombocytopenia is less common but of
much greater clinical significance! )t occurs 9 to 1D days after therapy begins (or sooner if the
person has been sensiti,ed to heparin) and, paradoxically, often leads to life-threatening venous
and arterial thrombosis! 'his severe form of H)' is caused by antibodies that recogni,e
complexes of heparin and platelet factor D, "hich is a normal component of platelet granules!
#inding of antibody to these comple$es activates platelets and promotes thrombosis, even in the
setting of thrombocytopenia! Enless therapy is immediately discontinued and an alternative
nonheparin anticoagulant instituted, clots "ithin large arteries may lead to vascular insufficiency
and limb loss, and emboli from deep venous thrombosis can cause fatal pulmonary
thromboembolism! 'he ris$ of severe H)' is lo"ered, but not completely eliminated, by the use
of lo"-molecular-"eight heparin preparations! Enfortunately, once severe H)' develops even
lo"-molecular-"eight heparins exacerbate the thrombotic tendency and must be avoided!
&"V%Associated Trombocyto!enia
Thrombocytopenia is one of the most common hematologic manifestation of I%
infection! 3oth impaired platelet production and increased destruction contribute! *DD and
*C*2D, the receptor and coreceptor, respectively, for H);, are found on mega$aryocytes,
allo"ing these cells to be infected! H);-infected mega$aryocytes are prone to apoptosis and their
ability to produce platelets is impaired! H); infection also causes 3-cell hyperplasia and
dysregulation, "hich predisposes to the development of autoantibodies! )n some instances the
antibodies are directed against platelet membrane glycoprotein ))b-))) complexes! 0s in other
immune cytopenias, the autoantibodies opsonini,e platelets, promoting their destruction by
mononuclear phagocytes in the spleen and else"here! 'he deposition of immune complexes on
platelets may also contribute to the accelerated loss of platelets in some patients "ho are H);
infected!
Trombotic 'icroangio!aties: Trombotic Trombocyto!enic Pur!ura #TTP$ and
&emolytic%(remic )yndrome #&()$
'he term thrombotic microangiopathy encompasses a spectrum of clinical syndromes
that includes ''4 and HE.! 0ccording to its original description, ''4 "as defined as the pentad
of fever, thrombocytopenia, microangiopathic hemolytic anemia, transient neurologic deficits,
and renal failure! HE. is also associated "ith microangiopathic hemolytic anemia and
thrombocytopenia but is distinguished by the absence of neurologic symptoms, the prominence
of acute renal failure, and its fre>uent occurrence in children! 1ith time, experience, and
increased mechanistic insight, ho"ever, these distinctions have blurred! #any adult patients "ith
I''4J lac$ one or more of the five criteria, and some patients "ith IHE.J have fever and
neurologic dysfunction! It is now appreciated that &' and TTP are both caused by insults that
lead to the e$cessive activation of platelets, which deposit as thrombi in microcirculatory beds!
'hese intravascular thrombi cause a microangiopathic hemolytic anemia and "idespread organ
dysfunction, and the attendant consumption of platelets leads to thrombocytopenia! )t is believed
that the varied clinical manifestations of ''4 and HE. are related to differing proclivities for
thrombus formation in tissues!
TTP is usually associated with a deficiency in a plasma en(yme called )*)MT'+,, also
designated Iv1+ metalloprotease!J 0D0#'.1 normally degrades very high-molecular-"eight
multimers of von 1illebrand factor (v1+)! )n its absence, these multimers accumulate in plasma
and tend to promote platelet activation and aggregation! .uperimposition of endothelial cell
in&ury (caused by some other condition) may further promote the formation of platelet
microaggregates, thus initiating or exacerbating clinically evident ''4!
'hrombotic microangiopathies resembling HE. can also be seen follo"ing exposures to other
agents that damage endothelial cells (e!g!, certain drugs and radiation therapy)! 'he prognosis in
these settings is guarded, because the HE. is often complicated by chronic, life-threatening
conditions!
Bleeding disorders related to de*ecti+e !latelet *unction
Kualitative defects of platelet function can be inherited or ac>uired! .everal inherited
disorders characteri,ed by abnormal platelet function and normal platelet count have been
described! 0 brief discussion of these rare diseases is "arranted because they provide excellent
models for investigating the molecular mechanisms of platelet function!
Inherited disorders of platelet function can be classified into three pathogenically distinct
groups( (1) defects of adhesion, (2) defects of aggregation, and () disorders of platelet secretion
(release reaction)!
3leeding resulting from defective adhesion of platelets to subendothelial matrix is best
illustrated by the autosomal recessive disorder 3ernard-.oulier syndrome, "hich is
caused by an inherited deficiency of the platelet membrane glycoprotein complex )b-)C!
'his glycoprotein is a receptor for v1+ and is essential for normal platelet adhesion to
the subendothelial extracellular matrix!
3leeding due to defective platelet aggregation is exemplified by <lan,mann
thrombasthenia, "hich is also transmitted as an autosomal recessive trait!
'hrombasthenic platelets fail to aggregate in response to adenosine diphosphate (0D4),
collagen, epinephrine, or thrombin because of deficiency or dysfunction of glycoprotein
))b-)))a, an integrin that participates in Ibridge formationJ bet"een platelets by binding
fibrinogen!
Disorders of platelet secretion are characteri,ed by the defective release of certain
mediators of platelet activation, such as thromboxanes and granule-bound 0D4!
0mong the ac"uired defects of platelet function, t"o are clinically significant! 'he first is
caused by ingestion of aspirin and other nonsteroidal anti!inflammatory drugs! 0spirin is a
potent, irreversible inhibitor of the en,yme cyclooxygenase, "hich is re>uired for the synthesis
of thromboxane 0
2
and prostaglandins! 'hese mediators play important roles in platelet
aggregation and subse>uent release reactions! 'he antiplatelet effects of aspirin form the basis
for its use in the prophylaxis of coronary thrombosis! &remia is the second condition
exemplifying an ac>uired defect in platelet function! 'he pathogenesis of platelet dysfunction in
uremia is complex and involves defects in adhesion, granule secretion, and aggregation!
,. &emorragic Diatesis Related to Abnormalities in Clotting -actors
)nherited or ac>uired deficiencies of virtually every coagulation factor have been reported
as causes of bleeding diatheses! Enli$e the petechial bleeding seen "ith thrombocytopenia,
bleeding due to isolated coagulation factor deficiencies most commonly manifests as large post!
traumatic ecchymoses or hematomas, or prolonged bleeding after a laceration or any form of
surgical procedure! 3leeding into the gastrointestinal and urinary tracts, and particularly into
"eight-bearing &oints (hemarthrosis), is common! 'ypical stories include the patient "ho oo,es
blood for days after a tooth extraction or "ho develops a hemarthrosis after minor stress on a
$nee &oint!
ereditary deficiencies typically affect a single clotting factor! 'he most common and
important inherited deficiencies of coagulation factors affect factor ;))) (hemophilia 0), and
factor )C (hemophilia 3)! Deficiencies of v1+ (von 1illebrand disease) are also discussed here,
as this factor influences both coagulation and platelet function! 2are inherited deficiencies of
each of the other coagulation factors have also been described! 0ll cause bleeding except for
factor C)) deficiency: presumably, in vivo the extrinsic path"ay and thrombin-mediated
activation of factors C) and )C compensate for the absence of factor C))!
)c"uired deficiencies usually involve multiple coagulation factors simultaneously and
can be based on decreased protein synthesis or a shortened half!life! ;itamin L deficiency
results in the impaired synthesis of factors )), ;)), )C, and C and protein *! #any of these
factors are made in the liver and are therefore deficient in severe parenchymal liver disease!
0lternatively, in D)*, multiple coagulation factors are consumed and are therefore deficient!
0c>uired deficiencies of single factors occur, but they are rare! 'hese are usually caused by
inhibitory autoantibodies!
Vitamin . De*iciency
Deficiency in vitamin L may occur in a variety of medical and surgical settings! 4oor oral
inta$e, broad-spectrum antibiotics, and age are all ris$ factors for vitamin L deficiency! 'he
upta$e of the vitamin is intimately lin$ed to the liver, as biliary salts are re>uired for intestinal
absorption! ;itamin L deficiency can therefore be caused by anything that impairs the
metabolism of bile acids! 'his includes intra- or extrahepatic cholestasis, biliary system fistulae
or obstruction, primary biliary cirrhosis, or treatment "ith bile acid binders (ie, cholestyramine)!
'here are also nonhepatic causes of vitamin L deficiency, such as malnutrition or the
administration of broadspectrum antibiotics! +inally, the most commonly used oral
anticoagulants, coumarin derivatives such as "arfarin, act by disrupting the vitamin L cycle!
;itamin L is fat soluble and is an essential component in the production of several of the
coagulation proteins! )t "as initially named ILoagulationsvitaminJ in reference to its connection
"ith the coagulation system! )nvestigation of the underlying cause of the hemorrhagic disease
that cattle developed in the early part of the 26th century (eventually found to be due to the
ingestion of spoiled s"eet clover containing coumarols) helped to elucidate the role and
importance of this factor! ;itamin L serves as a coen,yme in the posttranslational carboxylation
of factors )), ;)), )C, and C! 'his modification creates sites on these proteins for calcium ion
coordination and thereby renders them functional!
0n alteration in the synthesis of vitamin L-dependent coagulation factors is usually
reflected by changes in specific laboratory parameters! )nitially, there is a prolongation of the
prothrombin time (4') because factor ;)), a critical component of the coagulation cascade
synthesi,ed in the liver, has a half-life of only D to M hours! 0n increase in the activated partial
thromboplastin time (4'') may occur as "ell "hen there is a substantial decline in factors )), )C,
and C, "hich have longer half-lives!
2eplacement of vitamin L may be "arranted "hen the 4' is prolonged by more than
seconds or to an )nternational =ormali,ed 2atio ()=2) of greater than 1!9! 1hen there is no
evidence of active bleeding and the )=2 is moderately prolonged, vitamin L can be administered
orally, subcutaneously, intramuscularly, or intravenously, although the intramuscular route is less
preferable in the setting of coagulopathy! Dosing regimens commonly utili,ed include 9 mg
orally or 16 mg subcutaneously once a day for to 9 consecutive days! )f there is no
improvement in the 4' after three doses, ho"ever, additional replacement usually provides no
further benefit! 0dditionally, in patients "ith severe liver disease, vitamin L supplementation
often has only a modest effect in correcting the prolonged 4'! )n this setting, inade>uate hepatic
protein synthetic function is the primary issue!
;)'0#)= L D).%2DE2.
&emorragic Disease o* te Ne/born
Hemorrhagic disease of the ne"born, because of vitamin L deficiency, develops during
the first "ee$ of life, usually bet"een days 2 and M!

*linical manifestations include bleeding in
the s$in or from mucosal surfaces, circumcision, or venipuncture sites! 2arely, internal bleeding,
including retroperitoneal or intracranial hemorrhage, is the primary manifestation of hemorrhagic
disease of the ne"born! 'hese ominous complications are the rationale for the use of vitamin L
prophylaxis in neonates!
0lmost all neonates are vitamin L deficient, presumably as a result of deficient vitamin L
nutriture in the pregnant mother during the third trimester and because of the lac$ of coloni,ation
of the colon by bacteria that produce vitamin L in the neonate! Ho"ever, this deficiency is
further aggravated in some patients by inade>uate dietary inta$e of vitamin L! 'his disorder is
more prevalent in breast-fed babies, as human mil$, in contrast to co"@s mil$, contains only 19
8g75 of vitamin L!

=eonates "ith hemorrhagic disease of the ne"born have a prolonged prothrombin time
and partial thromboplastin time (4'')! Ho"ever, it is critical to distinguish "hether the
prolongation of these times is a manifestation of the deficiency of the vitamin L-dependent
proteins because of vitamin L deficiency or to decreased synthetic capacity of the liver in
ne"borns! Elevation of the abnormal (des-N-carboxy) prothrombin (4);L0-))) antigen level is
indicative of vitamin L deficiency, as this form of prothrombin appears only "hen post-
translational modification is impaired but not "hen protein synthesis is impaired! 0dministration
of vitamin L (166 8g) corrects the deficiency state and usually does not need to be repeated in
the other"ise healthy infant!
4rophylactic vitamin L has been in use for in-hospital births for the past D9 years!
;itamin L (166 8g to 1 mg) is administered intramuscularly to the ne"born immediately after
birth! 0t these doses, vitamin L administration carries little morbidity and can prevent
hemorrhagic disease of the ne"born! .ome of these vitamin L protocols are under revision and
have been updated!
Disseminated "ntra+ascular Coagulation #D"C$
*IC is an acute, subacute, or chronic thrombohemorrhagic disorder characteri(ed by
the e$cessive activation of coagulation, which leads to the formation of thrombi in the
microvasculature of the body! )t occurs as a secondary complication of many different disorders!
.ometimes the coagulopathy is locali,ed to a specific organ or tissue! 0s a conse>uence of the
thrombotic diathesis there is consumption of platelets, fibrin, and coagulation factors and,
secondarily, activation of fibrinolysis! D)* can present "ith signs and symptoms relating to the
tissue hypoxia and infarction caused by the myriad microthrombi: "ith hemorrhage caused by
the depletion of factors re>uired for hemostasis and the activation of fibrinolytic mechanisms: or
both!
Etiology and 4athogenesis!
)t the outset, it must be emphasi(ed that *IC is not a primary disease! )t is a
coagulopathy that occurs in the course of a variety of clinical conditions! )n discussing the
general mechanisms underlying D)*, it is useful to briefly revie" the normal process of blood
coagulation and clot removal!
*lotting can be initiated by either of t"o path"ays( (1) the e$trinsic pathway, "hich is
triggered by the release of tissue factor (Itissue thromboplastinJ): and (2) the intrinsic pathway,
"hich involves the activation of factor C)) by surface contact "ith collagen or other negatively
charged substances! 3oth path"ays, through a series of intermediate steps, result in the
generation of thrombin, "hich in turn converts fibrinogen to fibrin! 0t the site of in&ury,
thrombin further augments local fibrin deposition by directly activating the intrinsic path"ay and
factors that inhibit fibrinolysis!
-nce clotting is initiated, it is critically important that it be limited to the site of in.ury!
2emar$ably, as thrombin is s"ept a"ay in the bloodstream and encounters normal vessels, it is
converted to an anticoagulant through binding to thrombomodulin, a protein found on the surface
of endothelial cells! 'he thrombin-thrombomodulin complex activates protein *, "hich is an
important inhibitor of t"o procoagulants, factor ; and factor ;)))! %ther activated coagulation
factors are removed from the circulation by the liver, and as you "ill recall, the blood also
contains several potent fibrinolytic factors, such as plasmin! 'hese and additional chec$s and
balances normally ensure that &ust enough clotting occurs at the right place and time!
+rom this brief revie" it should be clear that D)* could result from pathologic activation
of the extrinsic and7or intrinsic path"ays of coagulation or the impairment of clot-inhibiting
mechanisms! .ince the latter rarely constitute primary mechanisms of D)*, "e "ill focus on the
abnormal initiation of clotting!
Two ma.or mechanisms trigger *IC/ (+) release of tissue factor or thromboplastic
substances into the circulation, and (0) widespread in.ury to the endothelial cells!
'hromboplastic substances can be derived from a variety of sources, such as the placenta in
obstetric complications and the cytoplasmic granules of acute promyelocytic leu$emia cells!
#ucus released from certain adenocarcinomas can directly activate factor C, independent of
factor ;))!
1ndothelial in.ury can initiate D)* in several "ays! )n&uries that cause endothelial cell
necrosis expose the subendothelial matrix, leading to the activation of platelets and both arms of
the coagulation path"ay! Ho"ever, even subtle endothelial in&uries can unleash procoagulant
activity! %ne mediator of such effects is '=+, "hich is implicated in D)* occurring "ith sepsis!
'=+ induces endothelial cells to express tissue factor on their cell surfaces and to decrease the
expression of thrombomodulin, shifting the chec$s and balances that govern hemostasis to"ards
coagulation! )n addition, '=+ upregulates the expression of adhesion molecules on endothelial
cells, thereby promoting the adhesion of leu$ocytes, "hich can damage endothelial cells by
releasing reactive oxygen species and preformed proteases! 1idespread endothelial in&ury may
also be produced by deposition of antigen-antibody complexes (e!g!, systemic lupus
erythematosus), temperature extremes (e!g!, heat stro$e, burns), or microorganisms (e!g!,
meningococci, ric$ettsiae)! Even subtle endothelial in&ury can unleash procoagulant activity by
enhancing membrane expression of tissue factor!
D)* is most li$ely to be associated "ith obstetric complications, malignant neoplasms,
sepsis, and ma.or trauma! 'he triggers in these conditions are often multiple and interrelated!
+or example, in bacterial infections endoto$ins can in&ure endothelial cells and inhibit the
expression of thrombomodulin directly or through production of '=+: stimulate the release of
thromboplastins from inflammatory cells: and activate factor C))! 0ntigen-antibody complexes
formed in response to the infection can activate the classical complement path"ay, giving rise to
complement fragments that secondarily activate both platelets and granulocytes! )n massive
trauma, e$tensive surgery, and severe burns, the ma&or trigger is the release of tissue
thromboplastins! )n obstetric conditions, thromboplastins derived from the placenta, dead
retained fetus, or amniotic fluid may enter the circulation! ypo$ia, acidosis, and shock, "hich
often coexist in very ill patients, can also cause "idespread endothelial in&ury, and supervening
infections can complicate the problems further! )mong cancers, acute promyelocytic leukemia
and adenocarcinomas of the lung, pancreas, colon, and stomach are most fre>uently associated
"ith D)*!
'he possible conse>uences of D)* are t"ofold! +irstly, there is widespread deposition of
fibrin "ithin the microcirculation! 'his leads to ischemia of the more severely affected or more
vulnerable organs and a microangiopathic hemolytic anemia, "hich results from the
fragmentation of red cells as they s>uee,e through the narro"ed microvasculature! .econdly, the
consumption of platelets and clotting factors and the activation of plasminogen leads to a
hemorrhagic diathesis! 4lasmin not only cleaves fibrin, but it also digests factors ; and ;))),
thereby reducing their concentration further! )n addition, fibrin degradation products resulting
from fibrinolysis inhibit platelet aggregation, fibrin polymeri,ation, and thrombin! 0ll of these
derangements contribute to the hemostatic failure seen in D)*!
*linical +eatures!
'he onset can be fulminant, as in endotoxic shoc$ or amniotic fluid embolism, or
insidious and chronic, as in cases of carcinomatosis or retention of a dead fetus! %verall, about
96? of the affected are obstetric patients having complications of pregnancy! )n this setting the
disorder tends to be reversible "ith delivery of the fetus! 0bout ? of the affected patients have
carcinomatosis! 'he remaining cases are associated "ith the various entities previously listed!
)t is almost impossible to detail all the potential clinical presentations, but a fe" common
patterns are "orthy of description! 'hese include microangiopathic hemolytic anemia: dyspnea,
cyanosis, and respiratory failure: convulsions and coma: oliguria and acute renal failure: and
sudden or progressive circulatory failure and shoc$! )n general, acute *IC, associated with
obstetric complications or ma.or trauma, for e$ample, is dominated by a bleeding diathesis,
whereas chronic *IC, such as occurs in cancer patients, tends to present with thrombotic
complications! 'he diagnosis is based on clinical observation and laboratory studies, including
measurement of fibrinogen levels, platelets, the 4' and 4'', and fibrin degradation products!
'he prognosis is highly variable and largely depends on the underlying disorder! The
only definitive treatment is to remove or treat the inciting cause! 'he management re>uires
meticulous maneuvering bet"een the .cylla of thrombosis and the *harybdis of bleeding
diathesis! 0dministration of anticoagulants or procoagulants has been advocated in specific
settings, but not "ithout controversy!
.ource(
Hoffman, et al! 266A! Hematology( 3asic 4rinciples and 4ractice! 9th ed! 4hiladelphia( Elsevier!
2obbins and *otran! 2616! 4athologic 3asis of Disease! A
th
ed! 4hiladelphia( Elsevier!