Coagulation - Factor VIII deficiency (Hemophilia A)

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Coagulation

Hereditary bleeding disorders

Factor VIII deficiency (Hemophilia A)

Reviewers: Kendall Crookston, M.D., Ph.D., University of New Mexico; Lizabeth Rosenbaum, M.D., University of New Mexico; Julie Gober-Wilcox, M.D., Resident, University of New Mexico (see Reviewers page)
Revised: 16 October 2010, last major update October 2010
Copyright: (c) 2002-2010, PathologyOutlines.com, Inc.

Definition
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● Factor VIII deficiency (hemophilia A) is the most common congenital bleeding disorder that is inherited as an X-linked recessive trait
● It is characterized by mild, moderate or severe bleeding episodes

Terminology
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● Factor VIII is also known as the anti-hemophilic factor

Epidemiology
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● Almost exclusively affects males
● 1 in every 10,000 births or 1 in 5000 male births
● Rarely affects females (see etiology)
● Female carriers are unaffected

Pathophysiology
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● Factor VIII is a plasma protein produced in the liver and by the reticuloendothelial system (Wikipedia)
● It circulates mainly bound to von Willebrand factor protein
● It functions as a cofactor along with activated factor IX to activate factor X, which in turn with its cofactor, factor Va, activates thrombin
● Normal plasma activity is 50%-150% (0.5-1.5 IU/mL)
● Biologic half life is 8-12 hours

Coagulation cascade

Sites
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● Bleeding into muscle, soft tissue or joints (hemarthrosis), GI/GU tract bleeding, easy bruising, excessive bleeding after surgery, trauma, dental procedures or circumcision; epistaxis, poor wound healing, intracranial hemorrhage, scalp hematoma, development of pseudotumors with repetitive hematoma formation, menorrhagia

Incidence of sites of bleeding:
● hemarthrosis: 70-80%
● muscle/soft tissue: 10-20%
● other major bleeds: 5-10%
● central nervous system: <5%

Incidence of bleeding into joints:
● Knee: 45%
● Elbow: 30%
● Ankle: 15%
● Shoulder: 3%
● Wrist: 3%
● Hip: 2%
● Other: 2%

Etiology
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● Inherited as an X-linked recessive trait, however 30% are due to spontaneous mutations
● The gene for factor VIII is a large gene located on a fragile region of the X chromosome
● The most common mutation involves inversion of intron 22; less common mutations include missense, large deletions, small point mutations and insertions/deletions
● Hemophilic females develop disease due to:
     - high degree of X-inactivation in carriers
     - hemizygosity of the X chromosome in females with Turner syndrome (XO karyotype)
     - homozygosity in female progeny of a hemophilia A carrier and an affected hemophilic male

Clinical features
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● Clinical severity is dependent on factor levels:
   - Mild (>5% activity; >0.05 IU/mL); occurs in 30%-40% and typically presents with bleeding after surgery or trauma
   - Moderate (1%-5% activity; 0.01-0.05 IU/mL); occurs in 10% and presents with bleeding after surgery or trauma, less commonly with spontaneous bleeding
   - Severe (<1% activity; <0.01 IU/mL); occurs in 50% and presents with spontaneous bleeding into joints, muscles and with life-threatening hemorrhage
● 30% of cases are due to spontaneous mutations, and have no family history of bleeding
● 35% of patients with severe hemophilia A will develop alloantibody inhibitors to factor VIII after replacement therapy (link)
● Formation of factor VIII alloantibodies is highest in individuals with intron 22 inversions, large deletions and nonsense mutations (Blood Coagul Fibrinolysis 2003;14 Suppl 1:S17)

Laboratory
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● Prolonged PTT with correction after mixing study (at 0 and 2 hr)
● Normal PT and bleeding time
● Measure both factor VIII and IX activity by functional plasma clot-based assay or chromogenic substrate-based assay
● Rule out vWD by vWF antigen and ristocetin cofactor activity
● Bethesda assay for quantitation of inhibitor
● Candidates for genetic testing include patients who have a diagnosis of hemophilia A or B, at-risk women who are related to an affected man (proband) who has a known mutation, and female carriers of hemophilia A or B seeking prenatal diagnosis
● First-line testing involves identification of the inversion of intron 22
● Obtain linkage analysis using restriction fragment length polymorphism (RFLP) if no inversion is detected or family members are available for testing
● Cord blood sampling for measurement of factor VIII activity in male fetus of known carrier

Prognostic factors
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● Chronic complications of hemophilia include musculoskeletal problems (e.g.chronic synovitis, arthropathy, fractures, contractures), inhibitor formation (which complicates treatment), and transfusion-related infections (e.g. HIV, HBV, HCV, etc.)

Case reports
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● Intraosseous hematoma in a newborn (AJNR Am J Neuroradiol 2000;21:308)
● Intracranial pseudotumor (Br J Neurosurg 2009;23:455))

Treatment
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● Need 80-100% of normal factor VIII levels for surgical hemostasis with major surgery or major bleeding, 30-50% postoperatively or to prevent minor bleeding
● Use plasma-derived or recombinant factor VIII concentrates (1 unit/kg raises levels in vivo by 2%):
     - Major surgery/bleeding - 40-50 units factor VIII concentrate/kg every 12 hours as necessary, usually for 7-10 days
     - Postoperatively - 15-25 units/kg every 12 hours as necessary, usually for 7-10 days
     - Minor bleeding - 15-20 units/kg every 12-24 hours as necessary
     - Mild/moderate bleeding - DDAVP (if patients respond to DAVP)
     - Prophylaxis in severe hemophilia A – 25-40 units/kg three times weekly
● Antifibrinolytic and topical agents (e.g. epsilon-aminocaproic acid, tranexamic acid, fibrin sealants) as adjuvant therapy
● Treatment of acute bleeding episodes in patients with inhibitors:
     - For low titer inhibitors: high dose factor VIII (to overwhelm inhibitor), porcine factor VIII (if no cross reactivity with inhibitor)
     - For high-titer inhibitors: factor VIII bypassing agents (prothrombin complex concentrates, FEIBA, recombinant factor VIIa)

Differential diagnosis
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● von Willebrand Disease (particularly type 2N or type 3)
● Factor IX deficiency (hemophilia B)
● Acquired hemophilia A (autoantibody against factor VIII)
● Other factor deficiencies (XI, XII)
● Familial combined factor deficiencies (typically have an autosomal recessive pattern)

Additional references
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● Hematol Oncol Clin North Am 2010;24:181, Blood 2007;110:815, World Federation of Hemophilia. Guidelines for the management of hemophilia, Consultative Hemostasis and Thrombosis: Elsevier, 2007

End of Coagulation > Hereditary bleeding disorders > Factor VIII deficiency (Hemophilia A)

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