Hereditary bleeding disorders

Factor VIII deficiency (hemophilia A)

Last author update: 1 October 2010
Last staff update: 28 February 2023

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PubMed Search: Factor VIII deficiency[title] AND Hemophilia A [title]

Kendall Crookston, M.D., Ph.D.
Julie Kim Harrington, M.D.
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Cite this page: Crookston K, Rosenbaum LS, Gober-Wilcox J. Factor VIII deficiency (hemophilia A). website. Accessed April 14th, 2024.
Definition / general
  • 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
  • Factor VIII is also known as the anti-hemophilic factor
  • 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
  • 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%
  • 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
  • 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
Diagrams / tables

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Coagulation cascade

Clinical features
  • 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 (Factor VIII inhibitor)
  • Formation of factor VIII alloantibodies is highest in individuals with intron 22 inversions, large deletions and nonsense mutations (Blood Coagul Fibrinolysis 2003;14:S17)
  • 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
  • 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
  • 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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