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C H A P T E R 137

RARE COAGULATION FACTOR DEFICIENCIES

David Gailani, Allison P. Wheeler, and Anne T. Neff

INTRODUCTION (WHF, www.wfh.org) and the International Rare Bleeding Disorder
Database (RBDD, www.rbdd.org) have collected information on the
In this chapter the term rare coagulation factor deficiency is applied to worldwide prevalence of rare coagulation factor deficiencies (Fig.
disorders caused by mutations in single genes, other than those for 137.2). 1,3,4 The European Network of Rare Bleeding Disorders (EN-
von Willebrand factor, factor VIII, or factor IX, that cause reduced RBD) recently reclassified these disorders based on clinical severity
plasma activity of one or more coagulation proteins, ultimately to facilitate development of evidenced-based diagnostic and treat-
1–3
4
leading to a defect in thrombin and/or fibrin formation. The most ment strategies (Table 137.2). They noted the strongest associations
common inherited deficiencies affecting plasma coagulation are those between bleeding severity and coagulation factor activity with
for factors VIII (hemophilia A) and IX (hemophilia B), with frequen- fibrinogen, factor X, and factor XIII deficiencies, and weaker associa-
cies of 1 in 10,000 and 1 in 30,000 male births, respectively (Chapter tions with deficiencies of factor V and factor VII. The association
135). In comparison, severe deficiency of fibrinogen; one of the between factor XI levels and propensity to bleed is very weak. This
protease zymogens prothrombin, prekallikrein or factors VII, X, XI, chapter contains sections describing deficiency states for each coagu-
or XII; one of the cofactors (factor V or high-molecular-weight lation factor. The number from the Online Mendelian Inheritance
kininogen); or the transaminase factor XIII occurs in one in 500,000 in Man (OMIM) database for the deficiency is given in the section
to 2 million individuals (Table 137.1). These conditions are primarily title. Updated lists of mutations associated with the factor deficiencies
inherited as autosomal recessive conditions, implying carrier frequen- can be found at several websites such as http://www.hgmd.org and
cies of approximately 1 in 1000 persons; 10-fold higher than the http://www.clotbase.bicnirrh.res.in. Table 137.1 lists properties of
carrier frequency for the alleles causing X-linked hemophilia A or B. coagulation factors and features of their deficiency states; while Table
The rarity of these disorders, therefore, is due to their recessive nature, 137.3 contains treatment recommendations.
and not low allele frequency. This is important to keep in mind, as
partial (heterozygous) deficiencies of these proteins are relatively
common and may contribute to bleeding symptoms. As with any FIBRINOGEN DEFICIENCY(OMIM 202400)
recessive trait, incidences are up to 10-fold higher in areas where
consanguinity is common. 1,3 Fibrinogen was first purified from plasma in the late 19th century.
Fig. 137.1A shows a scheme reflecting our current understanding Fibrinogen and fibrin are designated factor I and Ia, respectively, by
of the major enzymatic reactions involved in thrombin generation the International Committee for the Nomenclature of Blood Clot-
and fibrin formation. During hemostasis, factor VIIa binds to tissue ting. Congenital absence of fibrinogen (afibrinogenemia) was first
factor in the wall of a damaged blood vessel. The factor VIIa/tissue described in 1920 and has an estimated incidence of 1 in 1 million
5,6
factor complex converts factor X to Xa, which in turn converts people (Table 137.1). Partial deficiency is called hypofibrinogenemia.
prothrombin to thrombin in the presence of factor Va. Mice lacking Fibrinogen is synthesized in hepatocytes as a 340,000-Da protein
prothrombin, or factor VII, X, or V die in utero or soon after birth, composed of two trimers, each containing an Aα, Bβ, and γ chain
demonstrating the importance of these proteins. Thrombin, among (Fig. 137.3), which are encoded by separate genes (FGA, FGB, FGG)
its many functions, converts fibrinogen to fibrin. Factor IX is also within a 50-kb region of chromosome 4. Thrombin converts fibrino-
activated by factor VIIa/tissue factor and, with factor VIIIa, sustains gen to fibrin by cleaving fibrinopeptides A and B from the Aα and
thrombin generation by activating factor X. In some situations factor Bβ chains, respectively. Fibrinogen also binds glycoprotein IIb/IIIa,
IX activation by factor XIa is required. The older model shown in facilitating platelet aggregation. Fibrinogen in platelet α-granules is
Fig. 137.1B highlights the order of reactions during coagulation in a taken up from plasma via a glycoprotein IIb/IIIa-dependent mecha-
prothrombin time (PT) or activated partial thromboplastin time nism. Between 8% and 15% of plasma fibrinogen contains at least
(aPTT) assay. Here factor XI activation requires the contact factors, one γ chain that is a product of an alternatively spliced mRNA called
factor XII, prekallikrein, and high-molecular-weight kininogen. γ′-fibrinogen. γ′-fibrinogen modulates thrombin and factor XIII
Deficiency of a contact factor does not result in abnormal bleeding activity and influences clot architecture.
indicating that other mechanisms exist for factor XI activation. For The normal plasma fibrinogen concentration is 1.5 to 4.0 g/L
example, thrombin activates factor XI (Fig. 137.1A). Finally, factor (150–400 mg/dL). Afibrinogenemic patients have levels <0.1 g/L as
XIII is activated by thrombin and cross-links fibrin monomers within determined by both clotting and immunoreactive assays, due to
a fibrin polymer, increasing the strength of the fibrin strands homozygosity or compound heterozygosity for fibrinogen gene muta-
5,6
(Fig. 137.1A). tions. Hypofibrinogenemia is a milder condition due to heterozy-
The disorders discussed in this chapter represent 3% to 5% of gosity for a mutation. The first causative mutation for fibrinogen
coagulation factor deficiencies. Their rarity, clinical heterogeneity, deficiency was reported in 1999, and over 200 fibrinogen gene dele-
and the limited availability of standardized testing present challenges tions, frameshifts, nonsense, missense, and frameshift mutations have
1–3
for establishing evidence-based treatment guidelines. Common subsequently been identified in afibrinogenemic and hypofibrinogen-
6
symptoms include hemorrhage with invasive procedures and child- emic patients (www.geht.org/databaseang/fibrinogen). The FGA
birth, and bleeding from mucosal surfaces. Bleeding involving the gene is most commonly affected. Missense mutations are more preva-
central nervous system (CNS) often accompanies severe deficiencies lent in the FGB and FGG genes and cluster in the polypeptide
of fibrinogen and factors XIII, X, or VII. Gastrointestinal (GI) bleed- C-termini affecting D-domain formation (Fig. 137.3) and interfering
6
ing is a particular problem in factor X deficiency, and umbilical cord with secretion. In afibrinogenemia, fibrinogen is not secreted due to
bleeding is most common with fibrinogen, factor XIII, or factor X lack of synthesis of one of the fibrinogen chains or the presence of a
deficiency. Hemarthroses can occur with afibrinogenemia and severe mutant chain that alters fibrinogen structure. Nonsecretable fibrino-
deficiency of factors II or X. The World Federation of Hemophilia gen polypeptides are usually degraded in the hepatocyte. Some FGG
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