Page 2338 - Hematology_ Basic Principles and Practice ( PDFDrive )

2080 Part XII Hemostasis and Thrombosis

Arg 506 Gln mutation at one of the APC cleavage sites on factor Va. levels in healthy individuals precludes the use of this phenotype to
This mutation, which is designated factor V Leiden , endows activated identify carriers.
factor V Leiden with a 10-fold longer half-life in the presence of APC
than its wild-type counterpart. Elevated Levels of Procoagulant Proteins
The factor V Leiden mutation is responsible for most cases of APCR. Elevated levels of factor VIII and other coagulation factors, including
Other causes are mutations at Arg 306, another APC cleavage site. factors XI, IX, and VII, have been implicated as independent risk
Arg 306 is replaced by a Gly residue in factor V Hong Kong and by a Thr factors for thrombosis. Although the molecular bases for the high
residue in factor V Cambridge . Neither of these mutations is strongly levels of these coagulation factors have yet to be identified, genetic
associated with thrombosis. mechanisms are likely responsible because the hereditability of these
The factor V Leiden mutation is inherited in an autosomal-dominant quantitative abnormalities is high.
fashion. The prevalence of the mutation ranges from 2% to 5% in
whites, but it is rare in Asians and Africans. This racial difference Other Hereditary Disorders
likely reflects a founder effect with the mutation arising 20,000 to The dysfibrinogenemias represent a heterogeneous group of disorders
30,000 years ago, after the divergence of non-Africans from Africans characterized by abnormal fibrinogen structure and are diagnosed by
and Caucasoids from Mongoloid subpopulations. The prevalence of low functional and/or immunologic levels of fibrinogen, in associa-
factor V Leiden homozygosity is about 1 in 2500. The risk for throm- tion with prolonged thrombin and reptilase times. Acquired causes
botic complications is lower with factor V Leiden than it is with deficien- of dysfibrinogenemia, such as liver disease, must be excluded in the
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cies of antithrombin, protein C, or protein S, and in the heterozygous diagnostic work-up. Most congenital dysfibrinogenemias are asymp-
state, does not appear to be a strong risk factor for recurrent venous tomatic, and are often identified as an incidental finding when coagu-
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thrombosis. The risk for thrombosis is higher in homozygotes than lation testing is performed for other reasons. Up to 40% of the known
in heterozygotes. Acquired APC resistance may be caused by hor- dysfibrinogenemias are associated with a bleeding diathesis. Approxi-
monal changes during pregnancy or by the administration of estro- mately 15 variant fibrinogens, which represent less than 10% of
gens, such as oral contraceptive pills or hormone replacement therapy. known dysfibrinogenemias, have been reported to be associated with
A diagnosis of APCR is established using a functional assay based thrombotic complications, including fibrinogen Marburg, Caracas V,
on the ratio of the aPTT after APC addition divided by that deter- Chapel Hill III, Hannover II, Nijmegen, New York I, Christchurch
mined before APC addition. Second-generation tests, which add II and III, and Milano III. The exact mechanism by which these
dilute patient plasma to factor V–deficient plasma, are more specific dysfibrinogenemias increase the risk for thrombosis depends on the
for factor V Leiden . A normal functional test excludes factor V Leiden ; a nature of the fibrinogen defect. Most affect the C-terminal domain
positive functional test for APCR should be confirmed with a genetic of the Aα chains or the thrombin cleavage site on the Bβ chains.
test for the factor V Leiden mutation. Some laboratories only use the Some biochemical defects have been further characterized, such as
genetic test for diagnosis of factor V Leiden . defects in the release of fibrinopeptides A or B by thrombin, impaired
binding of thrombin or tissue plasminogen activator to fibrin, or
FII G20210A Mutation resistance to lysis by plasmin. It is likely that acquired and/or other
After extensive screening of 28 families with unexplained venous hereditary factors contribute to thrombosis that occurs in patients
thromboembolism, Poort and colleagues identified a heterozygous G with dysfibrinogenemia.
to A nucleotide transition at position 20210 in the 3′-untranslated Polymorphisms in the gene encoding EPCR have been associated
region of the prothrombin gene in five of the probands. This muta- with thrombosis. An EPCR polymorphism associated with high levels
tion, FII G20210A, results in elevated levels of prothrombin. Elevated of soluble EPCR has been identified. By binding circulating protein
levels of prothrombin, in turn, may increase the risk for thrombosis C and APC, soluble EPCR competes with cell surface EPCR for
by enhancing thrombin generation or by inhibiting factor Va inacti- protein C and prevents circulating APC from functioning as an
vation by APC. anticoagulant.
The mechanism by which the FII G20210A mutation causes
increased prothrombin levels appears to vary. Enhanced protein
synthesis may result from more efficient 3′-end formation, increased ACQUIRED HYPERCOAGULABLE STATES
messenger RNA stability, increased translation efficiency, or some
combination of these mechanisms. An intronic FII gene polymor- Acquired hypercoagulable states include antiphospholipid antibody
phism, A19911G, which influences splicing efficiency, may modulate syndrome and cancer, as well as pregnancy and estrogen therapy (oral
the effect of the FII G20210A mutation such that heterozygous contraception or hormone replacement therapy). These disorders can
carriers of both mutations have a greater risk for thrombosis than occur in isolation or can be superimposed on hereditary hypercoagu-
those with only the FII G20210A mutation. lable states. Heparin-induced thrombocytopenia is an immune-
Like the factor V Leiden mutation, the prevalence of the FII G20210A mediated adverse drug reaction, and is a strong, independent risk
mutation is higher in whites and low in Asians, American Indians, factor for arterial and venous thrombosis.
and African Americans. A founder effect likely explains the higher
prevalence in whites. The mutation may have provided a survival
advantage based on a protective effect with childbirth or severe sepsis. Lupus Anticoagulants and the
FII G20210A is found in 1% to 6% of whites. The mutation is Antiphospholipid Syndrome
more common in southern Europe than in northern Europe, a gradi-
ent opposite to that of factor V Leiden . Rare individuals homozygous First described in a study by Wasserman and colleagues in 1906
for the FII G20210A mutation have been identified. In the Leiden among patients with positive serologic tests for syphilis, antiphospho-
Thrombophilia Study, 6.2% of venous thrombosis patients and 2.3% lipid antibodies are a heterogeneous group of autoantibodies directed
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of healthy matched controls had the FII G20210A mutation. The against proteins that bind phospholipid. Antibodies can be categorized
mutation independently confers a 2.8-fold increased risk for venous into those that prolong phospholipid-dependent coagulation assays,
thrombosis, with no gender bias; a risk lower than that with anti- known as the lupus anticoagulant (LA), or anticardiolipin antibodies
thrombin, protein C, or protein S deficiency. The abnormality (ACLs), which target cardiolipin. A subset of ACL recognizes other
confers a weaker increased risk of venous thrombosis than protein C, phospholipid-bound proteins, particularly β 2 -glycoprotein I.
protein S or antithrombin deficiencies. Patients who have thrombosis in association with an LA and/or
Laboratory diagnosis of FIIG 20210A depends on genetic screen- ACL (antibodies of the immunoglobulin [Ig]G or IgM subclass
ing after PCR amplification of the 3′-untranslated region of the FII directed against cardiolipin or β 2-glycoprotein 1) are diagnosed with
gene. Although FII G20210A heterozygotes have 30% higher levels antiphospholipid syndrome (APS). The criteria for diagnosis of APS
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of prothrombin than non-carriers, the wide range of prothrombin were updated in 2006. APS is considered primary when it occurs