Hereditary

Overview of Hereditary Coagulation Factor Deficiencies

Definition: A group of rare, inherited bleeding disorders caused by genetic mutations that result in a deficiency or dysfunction of one or more coagulation factors
Inheritance: Typically inherited in an X-linked recessive or autosomal recessive pattern
Clinical Features:
- Bleeding Tendency: The primary symptom, with severity varying depending on the specific factor involved and the degree of deficiency
- Common Manifestations:
  - Easy bruising
  - Prolonged bleeding after cuts, dental procedures, or surgery
  - Nosebleeds (epistaxis)
  - Gum bleeding
  - Menorrhagia (heavy menstrual bleeding) in women
  - Hemarthrosis (bleeding into joints)
  - Intracranial hemorrhage (rare but life-threatening)
Diagnosis:
- Based on clinical history, bleeding symptoms, family history, and laboratory testing (coagulation assays)
- Specific diagnosis requires factor assays to measure the activity of individual coagulation factors

Specific Hereditary Coagulation Factor Deficiencies

X-Linked Recessive Disorders
- Hemophilia A (Factor VIII Deficiency):
  - Definition: The most common inherited bleeding disorder; caused by mutations in the F8 gene, which encodes Factor VIII (FVIII)
  - Pathophysiology: Deficiency of FVIII impairs the intrinsic pathway of coagulation, leading to decreased thrombin generation and impaired clot formation
  - Severity: Classified based on the level of FVIII activity:
    - Severe Hemophilia A: FVIII < 1% of normal
    - Moderate Hemophilia A: FVIII 1-5% of normal
    - Mild Hemophilia A: FVIII 5-40% of normal
  - Clinical Features:
    - Severity of bleeding is correlated with the level of FVIII activity
    - Severe Hemophilia:
      - Spontaneous bleeding into joints (hemarthrosis) and muscles
      - Prolonged bleeding after minor trauma or surgery
      - Intracranial hemorrhage
    - Moderate and Mild Hemophilia:
      - Bleeding typically occurs after trauma or surgery
      - Spontaneous bleeding is less common
  - Laboratory Findings:
    - CBC: Normal platelet count
    - Prothrombin Time (PT): Normal
    - Activated Partial Thromboplastin Time (aPTT): Prolonged
    - Mixing Study: aPTT corrects with mixing with normal plasma
    - Factor VIII Assay: Decreased FVIII activity level
    - Factor Inhibitor Assay: To rule out acquired FVIII inhibitors
  - Treatment:
    - Replacement Therapy: Infusion of FVIII concentrates
      - Recombinant FVIII products are preferred to minimize the risk of viral transmission
      - Prophylactic therapy: Regular infusions of FVIII to prevent bleeding
      - On-demand therapy: FVIII infusions to treat acute bleeding episodes
    - Desmopressin (DDAVP):
      - May be effective in mild hemophilia A to stimulate the release of FVIII from endothelial cells
    - Emicizumab:
      - A bispecific antibody that mimics the cofactor function of FVIII, bridging Factors IXa and X to restore coagulation
      - Used for prophylaxis in patients with hemophilia A with or without FVIII inhibitors
    - Gene Therapy:
      - Emerging therapeutic approach to correct the F8 gene mutation and restore FVIII production
- Hemophilia B (Factor IX Deficiency, Christmas Disease):
  - Definition: A less common X-linked recessive bleeding disorder caused by mutations in the F9 gene, which encodes Factor IX (FIX)
  - Pathophysiology: Deficiency of FIX impairs the intrinsic pathway of coagulation, leading to decreased thrombin generation and impaired clot formation
  - Clinical Features and Laboratory Findings: Similar to hemophilia A, but FVIII levels are normal and FIX levels are decreased.
  - Treatment:
    - Replacement Therapy: Infusion of FIX concentrates
    - Gene Therapy: Emerging therapeutic approach to correct the F9 gene mutation and restore FIX production
Autosomal Recessive Disorders
- Factor XI Deficiency (Hemophilia C):
  - Definition: Autosomal recessive bleeding disorder caused by mutations in the F11 gene, which encodes Factor XI (FXI)
  - Prevalence: More common in individuals of Ashkenazi Jewish descent
  - Pathophysiology: Deficiency of FXI impairs the intrinsic pathway of coagulation
  - Clinical Features:
    - Variable bleeding symptoms
    - Bleeding often occurs after surgery or trauma
    - Spontaneous bleeding is less common
  - Laboratory Findings:
    - CBC: Normal platelet count
    - PT: Normal
    - aPTT: Prolonged
    - Mixing Study: aPTT corrects with mixing with normal plasma
    - Factor XI Assay: Decreased FXI activity level
  - Treatment:
    - Plasma-Derived FXI Concentrates:
    - Fresh Frozen Plasma (FFP):
    - Antifibrinolytic Agents: Tranexamic acid or aminocaproic acid
- Factor XIII Deficiency:
  - Definition: A rare autosomal recessive bleeding disorder caused by mutations in the F13A1 or F13B genes, which encode the A and B subunits of Factor XIII (FXIII)
  - Pathophysiology: Deficiency of FXIII impairs the cross-linking of fibrin, leading to unstable clot formation
  - Clinical Features:
    - Severe bleeding tendency
    - Umbilical cord bleeding at birth
    - Delayed bleeding after trauma or surgery
    - Recurrent miscarriages in women
    - Intracranial hemorrhage
  - Laboratory Findings:
    - CBC: Normal
    - PT and aPTT: Normal (these tests do not detect FXIII deficiency)
    - Fibrinogen Level: Normal
    - Clot Solubility Test: Abnormal
    - Factor XIII Assay: Decreased FXIII activity level
  - Treatment:
    - Prophylactic FXIII Concentrate Infusions:
    - Cryoprecipitate: Historically used, but less safe due to the risk of viral transmission
- Factor V Deficiency (Parahemophilia):
  - Definition: A rare autosomal recessive bleeding disorder caused by mutations in the F5 gene, which encodes Factor V (FV)
  - Pathophysiology: Deficiency of FV impairs both the intrinsic and extrinsic pathways of coagulation
  - Clinical Features:
    - Variable bleeding symptoms
    - Easy bruising
    - Nosebleeds
    - Menorrhagia in women
    - Prolonged bleeding after surgery or trauma
  - Laboratory Findings:
    - CBC: Normal platelet count
    - PT: Prolonged
    - aPTT: Prolonged
    - Mixing Study: PT and aPTT correct with mixing with normal plasma
    - Factor V Assay: Decreased FV activity level
  - Treatment:
    - Fresh Frozen Plasma (FFP):
    - Prothrombin Complex Concentrates (PCCs):
  - Note: Factor V Leiden is a common genetic variant that causes resistance to activated protein C, leading to a hypercoagulable state (increased risk of thrombosis), not a bleeding disorder. The name similarity can cause confusion.
- Factor VII Deficiency:
  - Definition: A rare autosomal recessive bleeding disorder caused by mutations in the F7 gene, which encodes Factor VII (FVII)
  - Pathophysiology: Deficiency of FVII impairs the extrinsic pathway of coagulation
  - Clinical Features:
    - Variable bleeding symptoms
    - May range from asymptomatic to severe bleeding
  - Laboratory Findings:
    - CBC: Normal platelet count
    - PT: Prolonged
    - aPTT: Normal or slightly prolonged
    - Mixing Study: PT corrects with mixing with normal plasma
    - Factor VII Assay: Decreased FVII activity level
  - Treatment:
    - Prothrombin Complex Concentrates (PCCs):
    - Recombinant Factor VIIa (rFVIIa):
    - Fresh Frozen Plasma (FFP):
- Factor X Deficiency (Stuart-Prower Factor Deficiency):
  - Definition: A rare autosomal recessive bleeding disorder caused by mutations in the F10 gene, which encodes Factor X (FX)
  - Pathophysiology: Deficiency of FX impairs both the intrinsic and extrinsic pathways of coagulation
  - Clinical Features:
    - Variable bleeding symptoms
    - Easy bruising
    - Nosebleeds
    - Hemarthrosis (bleeding into joints)
    - Intracranial hemorrhage (rare)
  - Laboratory Findings:
    - CBC: Normal platelet count
    - PT: Prolonged
    - aPTT: Prolonged
    - Mixing Study: PT and aPTT correct with mixing with normal plasma
    - Factor X Assay: Decreased FX activity level
  - Treatment:
    - Prothrombin Complex Concentrates (PCCs):
    - Fresh Frozen Plasma (FFP):

Treatment Strategies for Hereditary Coagulation Factor Deficiencies

Replacement Therapy: Infusion of the deficient coagulation factor
- Plasma-derived or recombinant products
- Prophylactic (regular) or on-demand (treatment of bleeding episodes)
Bypassing Agents: Used to promote thrombin generation independently of the deficient factor
Adjunctive Therapies:
- Antifibrinolytic Agents: Used to prevent or treat mucosal bleeding
- Local Hemostatic Measures: Topical thrombin, fibrin sealants, pressure dressings
Gene Therapy
- For Hemophilia A and Hemophilia B, there are now options for gene therapy to be curative for the disease.
- This treatment is an option if there are high factor levels
- This test is used after to monitor production of factor.

Key Laboratory Tests for Hereditary Coagulation Factor Deficiencies

Complete Blood Count (CBC): Usually normal
Prothrombin Time (PT): May be prolonged, depending on the specific factor deficiency
Activated Partial Thromboplastin Time (aPTT): May be prolonged, depending on the specific factor deficiency
Mixing Studies: To differentiate factor deficiencies from factor inhibitors
Individual Factor Assays: To measure the activity of specific coagulation factors (definitive test)

Key Terms

Coagulation Factor: A protein involved in the coagulation cascade
Hemophilia A: Factor VIII deficiency
Hemophilia B: Factor IX deficiency
Autosomal Recessive: Inheritance pattern where two copies of an abnormal gene must be present for the disease to develop
X-Linked Recessive: Inheritance pattern where the gene is located on the X chromosome (males are more commonly affected)
Factor Assay: A laboratory test to measure the activity of a specific coagulation factor
Inhibitor: An antibody that interferes with the function of a coagulation factor
Replacement Therapy: Infusion of a deficient coagulation factor

Factor Deficiencies

Acquired