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2140 Part XII: Hemostasis and Thrombosis Chapter 124: Inherited Deficiencies of Coagulation Factors II, V, V+VIII, VII, X, XI, and XIII 2141

are commonly observed, and is unrelated to trauma in approximately by a disulfide bond. Factor VII can be converted to factor VIIa by factor
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20 percent of cases. 117,131 Hematuria, GI, and spontaneous CNS bleeding Xa, factor IXa, factor XIIa, thrombin, and factor VIIa in the
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is less common. There is insufficient data on the incidence of bleeding presence of TF, in an autoactivation reaction. Binding of factor VII to
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during pregnancy and PPH in women with combined factor V+VIII. TF strikingly enhances these reactions. 142–146
Heterozygotes exhibit slight but significantly reduced mean lev- The initial generation of thrombin that heralds blood coagulation
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els of factors V and VIII. In a literature survey of 161 heterozygotes, occurs when blood is exposed to TF present in the subendothelium in
22 reported having significant bleeding manifestations. However, no tissues, or on the surface of stimulated monocytes or microparticles.
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correlation between the factor V or factor VIII levels and bleeding ten- The exposed TF forms a complex with circulating factor VIIa and sup-
dency was noted. 25 ports the initiation of coagulation by converting factors IX and X into
LMAN1 gene knockout mice duplicate the F5F8-deficient phe- their active forms (factor IXa and factor Xa). 147,148 Following the genera-
notype in humans, albeit with a milder presentation, resulting from a tion of trace amounts of factor VIIa there is a feedback amplification of
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lesser reduction in plasma levels of factors V and VIII. The partial the signal, as factor VII bound to TF: factor VIIa is both self-activated,
perinatal lethality observed in LMAN1-deficient mice on some genetic and activated by factor IXa and factor Xa. Hence, the TF–factor VIIa
backgrounds was unexpected and has been explained as the result of a complex has two roles: to increase the conversion of factor VII to factor
further drop in the level of LMAN1-dependent protein(s) below a criti- VIIa and to increase the proteolytic activity of factor VIIa toward its
cal threshold, or because of a strain-specific difference in another cargo substrates, factors IX and X. Factors IXa and Xa may remain associated
receptor whose function overlaps with LMAN1. with cells that display the TF, or disseminate in the blood and bind to
the surface of activated platelets, which form the initial platelet plug. 149
THERAPY GENETICS
Because of the mild-to-moderate bleeding symptoms, treatment is on The factor VII gene (F7) spans approximately 12.8 kb and is located
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demand, depending on the severity of bleeding. According to a recent on chromosome 13q34, 30,151 2.8 kb upstream from the factor X gene.
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result from the EN-RBD project, however, the level of F5F8 to ensure The gene contains a prepro leader sequence and eight exons that encode
the absence of bleeding symptoms should be greater than 40 percent. the mature protein. Promoter and silencer elements of the 5′ flanking
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The recommended therapy includes FFP, which provides factor V, and region have been characterized. 153,154 The disorder manifests in homozy-
factor VIII concentrate, which compensates for the shorter half-life of gotes or compound heterozygotes, some of which are also homozygotes
plasma factor VIII. An antifibrinolytic agent such as tranexamic acid or for polymorphisms associated with reduced factor VII levels. 155,156
ε-aminocaproic acid can be helpful in patients exhibiting menorrhagia, More than 240 mutations have been reported (see http://www.isth.
epistaxis, or gingival bleeding. DDAVP (1-deamino-8-D-arginine vaso- org/?MutationsRareBleedin and Ref. 12). The mutations are distributed
pressin, desmopressin) could be administered for less-severe bleeding. throughout the gene, and most are missense mutations (62.2 percent);
Patients with severe bleeding episodes or patients undergoing surgical other type of mutations are equally present (ranging from approximately
procedures, including dental extractions, should receive FFP as replace- 6.2 percent of mutations in 3′-5′ untranslated region [UTR] to 12.3 per-
ment for factor V and cryoprecipitate or factor VIII concentrate as a cent of deletions/insertions [del/ins]). Most mutations causing factor
source of factor VIII. DDAVP can be used to increase factor VIII level, VII deficiency have been observed in individual patients. However,
but this treatment sometimes fails. 134
one missense mutation (Ala244Val) was detected in 102 (84 percent)
of 121 independent mutant alleles discerned in 88 unrelated patients in
Israel. Most subjects were of Iranian and Moroccan-Jewish origin and
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FACTOR VII DEFICIENCY shared an identical haplotype, consistent with a founder effect. In the
general Iranian-Jewish and Moroccan-Jewish populations, the preva-
DEFINITION AND HISTORY lence of the Ala244Val allele are 0.023 and 0.025, respectively. Several
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Factor VII was first identified as serum prothrombin conversion additional clusters of patients with a specific mutation were reported:
accelerator or proconvertin and its hereditary deficiency described (1) Ala294Val, with or without a deletion of nt C, at position 11128, pre-
by Alexander and colleagues in 1951. Among the rare clotting fac- vails in patients from Poland and Germany but has also been identified
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tor deficiencies, the relative frequency of factor VII deficiency is high in other Europeans 158,159 ; (2) 12 unrelated families from Norway who
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(see Table 124–1). 101,102 A presumptive diagnosis can be easily made carry Gln100Arg ; (3) IVS75G>A, which was detected in six unre-
because, except for very rare cases of factor X deficiency only affect- lated patients from the Lazio region in Italy, all of whom bear the same
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ing the TF pathway of coagulation (see “Laboratory Diagnosis” below), haplotype, suggesting a founder effect ; and (4) Gly331Ser, which was
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factor VII deficiency is the only coagulation disorder that produces a identified in 10 Italian and four German patients on one haplotype.
prolonged PT and a normal aPTT. The widely distributed and common Arg304Gln mutation probably is a
recurrent mutation. 163
Three polymorphisms in the factor VII gene are also associated
PROTEIN with reduced plasma levels of the factor. The first polymorphism, an
Human factor VII is a single-chain glycoprotein (Mr ~50,000) that is Arg353Gln substitution, results in impaired secretion of factor VII from
secreted from the liver parenchymal cells as a zymogen. The mature cells and gives rise to a 20- to 25-percent decrease in plasma factor
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protein consists of 406 amino acids organized in three main domains: VII level in heterozygotes and a 40- to 50-percent decrease in homozy-
a Gla domain at the N-terminus containing 10 Gla residues, an epider- gotes. 165,166 The second polymorphism associated with a diminished fac-
mal growth factor (EGF) domain in the center, and a serine protease tor VII level is a decanucleotide insertion upstream from the 5′ end of
domain at the C-terminus. Factor VII zymogen circulates in blood at the gene at −323, which confers a 33 percent decrease in the promoter
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an extremely low concentration (~500 ng/mL) and has the shortest activity. A third polymorphism associated with factor VII level is a
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half-life of all coagulation factors (4 to 6 hours; see Table 124–3). Factor hypervariable region 4 polymorphism (HVR4) in intron 7. The vari-
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VII is converted to the activated form, factor VIIa, by cleavage of an able number of tandem repeats (five to eight copies of 37 bp) apparently
Arg152-Ile153 bond, resulting in a two-chain molecule held together influences the splicing efficiency. The effect of the variable repeats on

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