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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

factor VII level is less conspicuous than the decanucleotide insertion at deficiency, replacement therapy may not be required during labor and
the promoter region and the Arg353Gln polymorphism. delivery, while it would be required in women with low factor VII coag-
ulant activity levels or a positive bleeding history who are more likely
to be at risk of PPH. 181,183–185 A recent review of the literature noted that
CLINICAL FEATURES hemorrhage rates were equivalent in women with and without prophy-
Bleeding manifestations occur in homozygotes and in compound hete- laxis, thus concluding that use of hemostatic prophylaxis should not
rozygotes for factor VII deficiency. However, a typical feature of this dis- be considered mandatory, but as part of an individualized discussion
ease is its clinical heterogeneity: some patients do not bleed at all after taking into consideration response to previous hemostatic challenges
186
major hemostatic challenge, while others with similar levels report fre- and mode of delivery. Replacement therapy is unnecessary for minor
quent bleeding episodes. Life- or limb-endangering bleeding manifes- bleeding episodes. Local hemostasis for skin lacerations and admin-
tations are relatively rare, the most frequent symptoms being epistaxis istration of an antifibrinolytic agent for menorrhagia, epistaxis, and
and menorrhagia. However, CNS bleeding was also reported to have gingival hemorrhage usually are sufficient to arrest bleeding. Asymp-
high incidence (16 percent) in a series of 75 infants, the authors con- tomatic patients undergoing minimally invasive surgery, such as dental
168
cluding that the greatest risk factor for this development was trauma procedures, can be successfully treated with tranexamic acid given both
related to the birth process. In addition, heterozygotes who have partial orally or intravenously at the usual dosages.
factor VII deficiency may present with bleeding; a recent survey of 499
heterozygotes revealed that 19 percent reported pathologic bleeding.
155
Dental extractions, tonsillectomy, and surgical procedures involving the FACTOR X DEFICIENCY
urogenital tracts frequently are accompanied by bleeding when no prior DEFINITION AND HISTORY
therapy is instituted. Normal pregnancy is accompanied by increased
concentrations of fibrinogen and factor VII, nonetheless, cases of mis- Inherited factor X deficiency was identified by two independent groups,
carriages and PPH, albeit at relatively low rates, have been observed in each of which described a patient with a bleeding diathesis that could
patients with factor VII deficiency. 169,170 not be attributed to deficiencies in other known coagulation factors. The
Thrombotic episodes have also been reported in 3 to 4 percent of factor in both patients was subsequently named factor X. 187–189
patients with factor VII deficiency, particularly in the presence of sur-
gery and replacement treatment, but spontaneous thrombosis may also PROTEIN
occur. A survey of 514 cases with severe or partial factor VII deficiency
recorded seven patients with venous thrombosis and one patient with Factor X is mainly synthesized by the liver as a 488-amino-acid pro-
190
arterial thrombosis. Most of the cases presented with associated risk tein and circulates in plasma at a concentration of 8 to 10 mcg/mL.
171
factors, mainly surgery, prolonged immobilization, and treatment with Its primary structure is homologous to that of other vitamin K–depen-
PCCs. 172 dent proteins, such as prothrombin, factor VII, factor IX, protein C,
191
When factor VII is completely lacking, as in knockout mice, and protein S. The first 40-amino-acid residues, the prepropep-
there is no embryonic lethality; however, fatal hemorrhage occurs tide, contain the hydrophobic signal sequences targeting the protein
192
perinatally. 173,174 for secretion. The Gla domain forms the N-terminus of the mature
protein and contains 11 Gla residues that are responsible for calcium
and phospholipid binding. Adjacent to the Gla domain is a short
193
THERAPY aromatic amino acid stack of predominantly hydrophobic amino
acids, followed by the EGF domain, believed to mediate protein–
As for all the other congenital bleeding disorders, replacement therapy protein interactions. The heavily glycosylated 52-amino-acid activation
is essential in patients who present with severe hemorrhage, such as peptide of factor X separates the EGF domain from the C-terminal cat-
hemarthrosis or intracerebral bleeding, surgical hemostasis, and for indi- alytic domain. Factor X undergoes proteolytic processing in the ER so
viduals with a bleeding history. Factor replacement therapy may also be that circulating factor is a two-chain, disulfide-linked protein consisting
used for prophylaxis in children with severe factor VII deficiency. The of a 17-kDa light chain made up of the Gla and EGF domains and a
175
EN-RBD study suggests a trough factor VII activity level of 25 percent is 40-kDa heavy chain made up of the activation and catalytic domains.
194
needed for patients to remain asymptomatic ; prophylactic treatment The heavy chain contains the activation peptide (residues 143 to 195)
25
is usually recommended for patients with major bleeding episodes such and the catalytic serine protease domain, structurally homologous to
as CNS and gastrointestinal bleeding and hemarthroses. A number of that of other coagulation serine proteases containing the catalytic site
replacement therapeutic options have been administered to patients formed by residues His236, Asp282, and Ser379. The 52-residue acti-
with factor VII deficiency, including FFP, PCCs, plasma-derived fac- vation peptide is released after factor X is converted to its active form
tor VII concentrates (volume overload should be expected if plasma is factor Xa by the cleavage between residues Arg194 and Ile195. Phys-
used as the replacement material) and rFVIIa. rFVIIa has been success- iologically factor X is activated by TF/factor VIIa (extrinsic pathway)
ful in managing patients with hemarthroses and during surgery, 176,177 and factor IXa/factor VIIIa (intrinsic pathway), but it can also be
195
and is the only treatment supported by substantial literature 12,176 (see activated in vitro by Russel viper venom. In turn, factor Xa catalyses
196
Table 124–3). PCCs containing activated clotting factors can be used, thrombin formation. In presence of factor Va, Ca , and phospholipid
2+
but they confer a risk of thrombosis, while specific factor VII concen- membrane, factor Xa forms the prothrombinase complex that acceler-
175
175
trates have been used successfully in series of patients. The treatment ates to 280,000-fold thrombin formation. 197
of factor VII deficiency is sometimes challenging, because of the short
in vivo half-life of factor VII, its low recovery, and its rapid clearance,
178
which is more evident in children. Because of these features, replace- GENETICS
ment regimens require frequent dosing. A significant rise in the factor The factor X gene spans approximately 25 kb and is made up of eight
192
VII level is observed during pregnancy in women with mild/moderate exons. The factor X gene shows significant homology with the genes
forms of factor VII deficiency (heterozygotes), but not in women of other vitamin K–dependent serine proteases, which suggests all of
with severe deficiency. 179–182 Therefore, in women with mild/moderate these multidomain genes evolved from a common ancestral gene. 198

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