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Inherited bleeding disorders are a heterogeneous group of conditions that lead to excessive hemorrhage. The disorders have distinct inheritance patterns, clinical bleeding symptoms, and laboratory abnormalities. Therefore, the history and physical examination are key to guiding appropriate laboratory testing and diagnosis.

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Hemophilia A, or classical hemophilia, results from congenital deficiency or absence of circulating factor VIII (FVIII). It is an X-linked recessive disorder with an incidence of approximately 1:5000 male births.1 Hemophilia B is also known as Christmas disease after Stephen Christmas who was the first child described with the disorder.2 It results from a congenital deficiency or absence of factor IX (FIX). It is an X-linked recessive disorder with an incidence of approximately 1:25,000 male births.1 Hemophilia C is an autosomal recessive disorder resulting in decreased amounts of circulating factor XI. It affects 1 in 100,000 people.

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Factor Structure and Function

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Factor VIII is a plasma glycoproteinconsisting of 6 domains, A1-A2-B-A3-C1-C2 (eFig. 436.1) .3 The encoding gene is found on the long arm of the X chromosome (Xq28).The mature protein is a heterodimer with a light chain consisting of domains A3-C1-C2 and a heavy chain composed of the domains A1-A2-B. The majority of FVIII is thought to be synthesized in liver endothelial cells. Upon release into the circulation, it is immediately noncovalently linked to von Willebrand factor (vWF). This prevents enzymatic degradation of FVIII until it is needed during coagulation. As illustrated in eFigure 436.2, during coagulation tissue factor combines with FVIIa at the site of injury. This complex activates FX and FIX, leading to conversion of prothrombin to thrombin. The initial thrombin cleavage of the FVIII light chain causes FVIII to be released into the circulation and then activated to FVIIIa by further thrombin-mediated proteolysis. FVIIIa and FIXa then act as cofactors on a phospholipid surface (typically a platelet) during activation of factor X, V, and ultimately, thrombin (eFig. 436.2).4 Many molecular defects have been described in the pathology of hemophilia A. These include gross gene rearrangements of the DNA sequence, single gene rearrangements, deletions of some or all of the gene sequence, and DNA insertions. A continually updated list of mutations leading to hemophilia A can be found at http://europium.csc.mrc.ac.uk.

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eFigure 436.1.
Graphic Jump Location

Domain structure of factor VIII. Factor VIII consists of 3 A domains, 1 B domain, and 2 C domains that are linked by an activation peptide (ap).

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Factor IX is a vitamin K–dependent serine protease believed to be synthesized in the liver and released into the circulation in its inactive form. The gene is 33 kilobases long on the end of the X chromosome (Xq27).3 During coagulation, tissue factor and FVII ...

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