Factor Deficiencies, Uncommon

 

Clinical Background

Inherited deficiencies of factors II, V, VII, X, XI, XII and XIII, high molecular weight kininogen (HMWK), prekallikrein and fibrinogen deficiency are uncommon.

Epidemiology

  • Incidence
    • Factors II, V, X, XI, XII, XIII – 1/1-2,000,000
    • Factor XI deficiency is rare in general population, but more common in Ashkenazi Jewish population
    • Factor VII – 1/500,000
  • Age – may be discovered in adulthood
  • Sex – M:F, equal

Inheritance – all disorders have autosomal recessive inheritance

Pathophysiology

  • Most factor deficiencies are due to either quantitative or qualitative abnormalities in the proteins
  • Factor II (prothrombin)
    • Activated to thrombin by prothrombinase complex (factor Xa and factor Va)
    • Thrombin converts fibrinogen to fibrin and is a potent platelet activator
  • Factor V
    • Factor V is activated by thrombin
    • Activated factor V acts as a cofactor in the conversion of prothrombin (factor II) to thrombin (factor IIa) by activated factor X
  • Factor VII
    • Activated FVII binds to tissue factor and initiates the extrinsic pathway of coagulation by converting factor X to factor Xa
  • Factor X
    • Factor X is activated by either the “intrinsic tenase complex” (factor IXa and factor VIIIa) or the “extrinsic tenase complex” (factor VIIa and tissue factor)
    • Activated factor X and activated factor V (cofactor) convert prothrombin (factor II) to thrombin (factor IIa)
  • Factor XI
    • Activated by thrombin and through other mechanisms
    • Activated factor XI converts factor IX to factor IXa
  • Factor XII (Hageman factor), HMWK (Fitzgerald factor) and prekallikrein (Fletcher factor)
    • Involved in initiation of the intrinsic pathway of coagulation through contact with negatively charged or hydrophobic surfaces
    • The contact factors initiate the coagulation cascade in the partial thromboplastin time (aPTT) test, but are not necessary for coagulation in vivo (deficiency not associated with bleeding)
  • Factor XIII
    • Activated to factor XIIIa by thrombin
    • Factor XIIIa is a transglutaminase that covalently crosslinks fibrin, resulting in a clot that resists mechanical and enzymatic degradation
  • Fibrinogen
    • Fibrinogen is converted to fibrin by factor IIa (thrombin)
    • Deficiency varies from hypo- to afibrinogenemia

Clinical Presentation

  • The bleeding phenotype ranges from mild to severe, depending on the defect (a variety of different mutation types have been reported for most factor deficiencies) and whether multiple abnormalities are present
    • Combined inherited deficiencies, such as deficiency of all vitamin K-dependent factors (II, VII, IX, and X), are rare
    • Factor II
      • Extent of bleeding does not always correlate with factor II activity
      • Mild to moderate mucocutaneous and soft tissue bleeding
        • May include hemarthrosis and intracranial bleeding in patients with very low activity
    • Factor V
      • May be associated with combined inherited deficiency of factor V and factor VIII
      • Mild, moderate, and severe forms exist
        • Patients with severe deficiency present in childhood with umbilical stump bleeding, easy bruising, and epistaxis
    • Factor VII
      • May be associated with combined inherited deficiency of factor VII and factor X
      • Poor correlation between extent of bleeding and factor VII activity
      • Severe bleeding in patients with very low activity may resemble bleeding seen in hemophilia A or B
    • Factor X
      • May be associated with combined inherited deficiency of factor X and factor VII
      • Bleeding may be mild, moderate, or severe, depending on the mutation
        • Severe bleeding in patients with very low activity may resemble bleeding seen in hemophilia A or B
    • Factor XI
      • Extent of bleeding does not always correlate with factor XI activity
      • Symptoms are generally milder than in patients with hemophilia A or B
      • Some patients are asymptomatic
      • Can be associated with excessive bleeding, usually related to surgical procedures or trauma (tooth extraction, tonsillectomy, nasal surgery)
    • Factor XII, HMWK, and prekalikrein
      • Asymptomatic; deficient individuals have no bleeding tendency despite markedly prolonged partial thromboplastin times (often >100 seconds)
    • Factor XIII
      • Umbilical stump bleeding at birth, delayed post-surgical or post-traumatic bleeding, intracranial hemorrhage, poor wound healing, and recurrent abortion
    • Fibrinogen
      • Afibrinogenemia usually presents in childhood and is associated with bleeding of variable severity (often severe)
      • Hypofibrinogenemia is associated with bleeding of variable severity