Page 2163 - Williams Hematology ( PDFDrive )

2138 Part XII: Hemostasis and Thrombosis Chapter 124: Inherited Deficiencies of Coagulation Factors II, V, V+VIII, VII, X, XI, and XIII 2139

the binding sites for membrane phospholipids, prothrombin, and with homozygotes at greater risk than heterozygotes. The trans associ-
activated protein C; both light and heavy chains probably are nec- ation of factor V Leiden and a mutation in factor V that causes factor
essary for factor Xa binding. Assembly of factors Va and Xa on the V deficiency results in a prothrombotic state comparable to factor V
phospholipid membrane of platelets in the presence of calcium ions Leiden homozygosity. This is sometimes termed “pseudohomozygous”
forms the prothrombinase complex, which catalyzes the conversion activated protein C resistance and does not cause bleeding despite low
of prothrombin to thrombin. The contribution of factor Xa in the factor V antigen levels. Among several polymorphisms detected in
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absence of factor Va to overall thrombin generation is relatively minor. the factor V gene, His1299Arg in exon 13 is particularly interesting
Importantly, incorporation of the cofactor into the macromolecular because it is associated with a reduced plasma factor V level and mild
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enzyme complex enhances prothrombin activation by several orders activated protein C resistance. His1299Arg co-segregates with several
of magnitude. 78 other polymorphisms encoding several amino acid changes, together
In addition to hepatocytes, the primary site of factor V secretion, named R2 haplotype. In two heterozygotes for factor V Arg506Gln
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approximately 20 percent of the protein in whole blood is localized in mutation who presented with venous thrombosis, reduced factor V
the α granules of platelets, where it is complexed with an extremely activity resulting from the His1299Arg polymorphism harbored by
large protein, multimerin. Megakaryocytes do not synthesize factor V; the non-Leiden chromosome, imparted a pseudohomozygous pheno-
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rather, endocytosis of plasma-derived factor V accounts for the platelet type for activated protein C resistance. Additional polymorphisms or
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factor V pool. Following endocytosis factor V is modified intracellu- mutations in the factor V gene have been observed to increase the risk
larly; these changes to platelet factor V appear to provide the cofactor of venous thrombosis. 98
with unique physical and functional characteristics, which render it In addition, there are at least two examples in which platelet fac-
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more procoagulant compared with its plasma counterpart. Platelet tor V is reduced. In the Quebec platelet disorder, initially described as
degranulation and release of platelet factor V at the site of vascular injury an autosomal dominant disorder with severe bleeding manifestations,
is thought to be a critical contributor to the local factor V concentration. platelet factor V levels are reduced because of enhanced proteolysis
Furthermore, there is some evidence that, because platelet factor V is resulting from overexpression of urokinase-type plasminogen activa-
locally released in high concentrations, it is less susceptible to inhibition tor, as they are in factor V New York. 100
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and may function normally in hemostasis. Factor Va is inactivated by
activated protein C through limited proteolysis at Arg506, Arg306, and
Arg679 in the presence of protein S, calcium ions, and either platelet CLINICAL MANIFESTATIONS
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or endothelial cell membrane phospholipids. Partial protection from Factor V deficiency is inherited as an autosomal recessive trait. Het-
this cleavage is provided by factor Xa when bound to factor Va on the erozygotes, whose plasma factor V activity ranges between 25 and 60
surface of platelets. 83 percent of normal, usually are asymptomatic, although an American
registry recorded mild bleeding in 50 percent of the cases. Accord-
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ing to a recent classification by the SSC of the ISTH, factor V defi-
GENETICS ciency may be classified as severe, moderate, and mild when factor V
The factor V gene maps to chromosome 1q21–25. It is greater than levels are undetectable, less than 10 percent, and 10 percent or greater,
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80 kb in length and the coding sequence is divided into 25 exons, rang- respectively. 24
ing in size from 72 to 2820 base pairs (bp), and 24 introns, varying Common manifestations include ecchymoses, epistaxis, gin-
between 0.4 kb and 11 kb. The sequence encoding the large B domain gival bleeding, hemorrhage following minor lacerations, and men-
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is contained within exon 13. orrhagia. 101–103 Severe deficiency typically presents at birth or in early
A total of 132 distinct mutations of the factor V gene have been childhood, but depending on factor levels some patients remain asymp-
identified, of which 64 are missense, 36 are insertions/deletions, 17 tomatic. Bleeding from other sites is less common, but instances of
are nonsense, 15 are splice site mutations, and one is a deletion of hemarthroses unrelated to trauma and intracerebral hemorrhage have
the whole gene (see http://www.isth.org/?MutationsRareBleedin and been reported. Trauma, dental extractions, and surgery confer a high
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Ref. 10). Most mutations cause truncations and are localized through- risk of excessive bleeding.
out the gene. Several mutations have interesting features. One, a PPH occurs in more than 50 percent of pregnancies in women
Tyr1702Cys transition, was identified in eight unrelated families, of with factor V deficiency, 104,105 especially those with low factor V activity
whom six were Italian. The frequency of this mutant allele in Italy is levels. Venous and arterial thromboses have been described in patients
0.002. Another mutation, an Ala221Val (New Brunswick) alteration, with factor V levels ranging between 2 and 14 percent of normal.
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characterized in the homozygous state by activity and antigen levels of Factor V deficiency deprives activated protein C of one of its essen-
29 and 39 percent of normal, respectively displays decreased stability tial substrates, thereby downregulating the inhibitory function of the
of the expressed protein and was the first genetic defect reported to protein C system.
be associated with type II deficiency. Additional mutations exhibit Development of a functional factor V inhibitor after receiving
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decreased secretion of the protein from producing cells. 88,89 Remark- plasma transfusions was reported in only two patients with hereditary
ably, the Gln773ter and Arg1133ter mutations and a 4-bp deletion deficiency; the inhibitor disappeared in one patient, but a low titer of the
mutation, all present in exon 13 and predicted to result in partial inhibitor persisted in the other patient. 107,108 Factor V is indispensable
truncation of the B-domain and complete truncation of the A3-, C1-, for life, as was demonstrated by experimental knockout mice lacking
and C2-domains, cause no bleeding or only a mild bleeding tendency the factor V gene, which die either in utero at embryonic day 9 or 10
in affected patients having factor V antigen and activity levels 1 per- because of defects in yolk-sac vasculature and somite formation; the
cent of normal. 90–92 remaining half develop to term but die of massive hemorrhage within
Factor V Leiden (Arg506Gln) is a highly prevalent (up to 5 percent hours of birth. The expression of a minimal factor V activity because
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in some populations) polymorphism in the factor V gene that decreases of the introduction of a liver-specific transgene, below the sensitivity
the efficiency of factor Va inactivation by activated protein C. Patients threshold of the detection assay (<0.1 percent), leads to the survival of
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with factor V Leiden are at increased risk of unprovoked thrombosis, mice. 110

Kaushansky_chapter 124_p2133-2150.indd 2138 17/09/15 3:40 pm