Factors V, VII, X, XI, XII and XIII, high molecular weight kininogen (HMWK) and prekallikrein are the most frequently occurring uncommon factor deficiencies.

Deficiency of factor XI

• Inheritance
  • Autosomal recessive
• Presentation
  • Often asymptomatic
  • Can be associated with excessive bleeding, usually related to injury (tooth extraction, tonsillectomy, nasal surgery)
• Pathophysiology
  • Factors XI, XII, HMWK and prekallikrein are referred to as contact factors
  • Factor XI is activated which then activates IX

Deficiency of factor XII

• Inheritance
  • Autosomal recessive
• Presentation
  • Asymptomatic
• Pathophysiology
  • Factor XII is activated to XIIa by protein and protein surface extractions
  • XIIa activates XI, which then activates IX

Deficiency of factor XIII

• Inheritance
  • Autosomal recessive
• Presentation
  • Most common - umbilical cord bleeding  
• Pathophysiology
  • Most significant role in tensile strength and integrity of fibrin clot

Deficiency of HMWK (Fitzgerald factor)

• Inheritance
  • Autosomal recessive
• Presentation
  • Generally asymptomatic  
• Pathophysiology
  • HMWK is involved in the activation of the intrinsic pathway, which is initiated when trauma occurs to a blood vessel (such as exposure of blood to collagen in damaged vessel wall or in vitro by contact with a syringe or test tube)
  • HMWK functions as a cofactor, binding to prekallikrein and factor XI, thus accelerating their activation by factor XIIa
  • Individuals have normal hemostasis and no excessive bleeding in spite of PTT often >100 seconds

Deficiency of prekallikrein (Fletcher factor)

• Inheritance
  • Autosomal recessive
• Presentation
  • Completely asymptomatic
• Pathophysiology
  • Hemostasis is normal and excessive bleeding absent in spite of partial thromboplastic time (PTT) often >100 seconds

Deficiency of factor V

• Inheritance
  • Rare autosomal recessive disorders
    • May rarely be found as a combined defect with factor VIII
• Presentation
  • Most common - moderate bleeding tendency with ecchymosis, epistaxis, gingival bleeding and hemorrhage following minor lacerations
• Pathophysiology
  • Activated factor V combines with activated factor X to cleave prothrombin to thrombin

Deficiency of factor VII

• Inheritance
  • Autosomal recessive
• May be associated with other factor deficiencies
• Presentation
  • May be associated with bilirubin disorders, mental retardation, microcephaly and cleft palate
  • Mucosal bleeding, but bleeding will be more severe if associated with other factor deficiencies
• Pathophysiology
  • Activated factor VII activates both factors IX and X

Deficiency of factor X

• Inheritance
  • Autosomal recessive
• Presentation
  • Most common - moderate to severe bleeding
    • Primarily of soft tissues, joints, mucous membranes, umbilical cord
• Pathophysiology
  • Activated factor X complexes with activated factor V to cleave prothrombin to thrombin

Deficiency of fibrinogen

• Inheritance
  • Autosomal recessive
• Several genetic mutations associated with the disease
  • Varies from hypo- to afibrinogenemia
• Presentation
  • Varies from asymptomatic to moderate bleeding
• Pathophysiology
  • Fibrinogen is activated to fibrin by thrombin
  • Fibrin is a stabilizing factor in the clotting sequence

Deficiency of prothrombin (factor II)

• Autosomal recessive disorder
  • Types I and II variants
• Presentation
  • Mild to moderate mucocutaneous and soft tissue bleeding
    • Significant surgical bleeding
• Pathophysiology
  • Prothrombin is activated to thrombin by factor Va and factor Xa complex
  • Thrombin is a potent platelet activator

Diagnosis

• Indications for testing
  • Excessive bleeding during procedures with otherwise normal testing for factors VIII and IX
  • Isolated elevated PTT
• Laboratory testing              
  • Elevated PTT - test for HMWK and prekallikrein deficiency
  • Other factors - base testing on family history and patient’s clinical presentation