What is the genetic inheritance pattern of Factor 13 deficiency and pseudo von Willebrand's disease (Platelet Type von Willebrand disease), are they autosomal dominant or recessive?

Genetic Inheritance Patterns of Factor XIII Deficiency and Platelet-Type von Willebrand Disease

Factor XIII deficiency is inherited in an autosomal recessive pattern, while platelet-type von Willebrand disease (PT-VWD) is inherited in an autosomal dominant pattern. 1

Factor XIII Deficiency

Inheritance Pattern

• Factor XIII deficiency follows an autosomal recessive inheritance pattern 1
• This means:
  • Both parents must be carriers (heterozygous) for the child to develop the disease
  • Each child has a 25% chance of inheriting the disorder when both parents are carriers
  • The disease affects males and females equally

Epidemiology and Clinical Significance

• Extremely rare bleeding disorder with prevalence of approximately 1 in 2 million people 1
• Characterized by:
  • High risk (33%) of intracranial hemorrhage
  • Delayed bleeding after trauma or surgery
  • Poor wound healing
  • Recurrent miscarriages in affected women 1
  • Normal PT and aPTT results despite severe bleeding tendency 2

Molecular Basis

• Most patients with inherited Factor XIII deficiency show:
  • No Factor XIII activity
  • Absence of 'a' subunit protein in plasma, platelets, and monocytes
  • Defect is typically not a major gene rearrangement or deletion, but likely a single point mutation that may differ between families 2

Platelet-Type von Willebrand Disease (PT-VWD)

Inheritance Pattern

• PT-VWD is inherited in an autosomal dominant pattern 1, 3
• This means:
  • Only one parent needs to have the mutation for a child to inherit the disease
  • Each child has a 50% chance of inheriting the disorder when one parent is affected
  • The disease affects males and females equally

Epidemiology and Clinical Features

• PT-VWD is a rare qualitative variant of von Willebrand disease
• Characterized by:
  • Enhanced binding of normal von Willebrand factor (VWF) to platelets
  • Thrombocytopenia due to clearance of platelets bound to VWF
  • Mucocutaneous bleeding similar to other forms of VWD 4, 1

Molecular Basis

• PT-VWD results from gain-of-function mutations in the platelet GP1BA gene
• This gene encodes the alpha subunit of the platelet glycoprotein Ib/IX/V complex, which serves as the receptor for VWF 4

Diagnostic Approach

Factor XIII Deficiency

• Specific Factor XIII activity assays are required for diagnosis 1
• Standard coagulation tests (PT, aPTT) are typically normal 2
• Clot solubility tests may be used as screening but are only positive in severe deficiency

Platelet-Type VWD

• Diagnosis requires specialized testing to differentiate from Type 2B VWD, which has similar laboratory findings but different genetic basis 4, 1
• Key diagnostic tests include:
  • Enhanced ristocetin-induced platelet aggregation at low ristocetin concentrations
  • Normal VWF multimer pattern
  • Genetic testing to identify mutations in the GP1BA gene 4

Clinical Implications of Inheritance Patterns

• For Factor XIII deficiency (autosomal recessive):

  • Genetic counseling should emphasize that both parents must be carriers
  • Siblings have a 25% chance of being affected, 50% chance of being carriers
  • Prophylactic treatment is often recommended due to risk of life-threatening bleeds 1, 2

• For PT-VWD (autosomal dominant):

  • Genetic counseling should emphasize 50% risk of transmission to offspring
  • Family screening is important as other family members may be affected
  • Treatment approaches differ from other forms of VWD 1

Pitfalls and Caveats

• Factor XIII deficiency may be missed with routine coagulation testing (PT, aPTT) as these are typically normal despite severe bleeding tendency 2
• PT-VWD can be misdiagnosed as immune thrombocytopenia or Type 2B VWD, leading to inappropriate treatment 4
• Genetic testing is essential for definitive diagnosis and family counseling in both disorders
• Treatment approaches differ significantly between these disorders, making accurate diagnosis critical 1