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Bleeding tendencies caused by inherited deficiencies of one or more coagulation factors are rare disorders distributed worldwide. Homozygotes or compound heterozygotes for the mutant genes responsible for these defects exhibit bleeding manifestations that are of variable severity and usually related to the extent of the decreased activity of the particular coagulation factor. Heterozygotes for the various deficiencies rarely display a bleeding tendency. Numerous mutations have been identified in genes encoding coagulation factors II, V, VII, X, XI, and XIII. For some factors, such as factors II, VII, and X, mutations giving rise to dysfunctional proteins predominate, whereas for other factors, such as factors V, XI, and XIII, true protein deficiencies usually are found. Combined deficiency of factors V and VIII, inherited as an autosomal recessive trait, results from mutations in genes encoding two proteins that transport factors V and VIII out of the endoplasmic reticulum to the Golgi compartment. The very rare combined deficiency of the vitamin K-dependent coagulation factors can be caused by mutations in the gene encoding for a carboxylase that γ-carboxylates glutamic acid residues in these proteins or in the gene encoding vitamin K epoxide reductase. Treatment of patients with the various coagulation factor deficiencies may be necessary during spontaneous bleeding episodes, during and after surgical procedures, and for prevention of intracranial hemorrhage. In most deficiency states, plasma replacement has been used, but specific concentrates of all the vitamin K-dependent factors and of factors VII, XI, and XIII are available.

Acronyms and Abbreviations

Acronyms and abbreviations that appear in this chapter include: aPTT, activated partial thromboplastin time; CRM, cross-reacting material; DIC, disseminated intravascular coagulation; ELISA, enzyme-linked immunosorbent assay; ERGIC, endoplasmic reticulum-Golgi intermediate compartment; GGCX, γ-glutamyl carboxylase; Gla, γ-carboxyglutamic acid; HK, high-molecular-weight kininogen; LMAN1, mannose-binding lectin; MCFD, multiple combined-factor deficiency; MRP, multidrug resistance protein; PAR, protease-activated receptor; PK, prekallikrein; PT, prothrombin time; TAFI, thrombin-activatable fibrinolysis inhibitor; VKDFD, vitamin K-dependent factors deficiency; VKORC1, vitamin K epoxide reductase complex.

Inherited deficiencies of the coagulation factors other than factor VIII (hemophilia A), factor IX (hemophilia B) are rare bleeding disorders that have been described in most populations. Their relative frequency varies among populations partly as a result of high frequencies of specific mutant genes in inbred populations. Several population surveys indicate that common among these bleeding disorders are factors XI and VII deficiency, less common disorders are factors V and X deficiency and afibrinogenemia, and the rarest disorders are factor II (prothrombin) deficiency, combined factor V and VIII deficiency, factor XIII deficiency, and deficiency of all the vitamin K-dependent factors (Table 125–1). The severity of bleeding manifestations in affected patients who are homozygotes or compound heterozygotes for a mutant gene is variable and usually related to the extent of the deficiency. Some patients have only mild bruising or display excessive bleeding only following trauma. Other patients, usually with less than 1 percent of normal factor VII, XIII, or X activity, can exhibit intracranial hemorrhages and hemarthroses ...

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