Haemophilia: Blood Coagulation Pathways

Haemophilia

• Inherited coagulation factor defect, affecting 1 in 5,000 to 1 in 10,000 males
• Three types: Haemophilia A (factor 8), Haemophilia B (factor 9), Haemophilia C (factor 11)
• Von Willebrand disease (VWF) is also an inherited bleeding disorder

Inheritance of Haemophilia

• X-linked recessive disease, affecting males
• 1/3 of cases develop post-new mutations, with no family history
• Haemophilia A is the most common, with Haemophilia B accounting for 20% of cases

Clinical Presentation

• Petechiae, purpura, hematoma, joint bleeding, mucocutaneous bleeding, intracranial hemorrhage, post-tooth extraction bleeding, post-operative bleeding, trauma
• Advanced joint and muscle bleeding

Laboratory Investigation

• Normal platelet count and function
• Normal PT, PC, INR
• Prolonged APTT
• Factor assay (8, 9, 11, VWF)

Treatment

• "On-demand" or prophylaxis
• Aimed at treating and preventing bleeding episodes and related complications
• Regular prophylaxis started at an early age can reduce physical impairment from hemophilic arthropathy

Complications of Haemophilia

• Arthropathy, deformity
• Muscle atrophy, nerve compression, limb ischemia
• Fatal ICH bleeding
• Pseudotumor (subperiosteal bleeding, new bone formation)
• Infection (HCV, HBV, HIV) due to plasma product

Factor XI Deficiency

• Ashkenazi Jews, affects both sexes
• Bleeding risk shows incomplete correlation to severity of deficiency
• Treatment: fibrinolytic inhibitor (tranexamic acid), factor XI concentrate, or fresh frozen plasma

Von Willebrand Disease

• VWF carries factor 8, platelets adhere to vascular collagen
• Most common inherited bleeding disorder
• Autosomal dominant inheritance
• Affects females, presenting with mucocutaneous bleeding
• Menorrhagia, epistaxis, rare hemarthrosis, and muscle bleeding

Laboratory Diagnosis

• Normal CBC, normal PT, normal TT
• Prolonged APTT
• VWF antigen, activity
• Factor 8 level (type III VWD)
• Platelet function test abnormal adhesion

Treatment

• Supportive: avoid antiplatelets (aspirin), anticoagulants (warfarin), fibrinolytic inhibitor (tranexamic acid)
• Cryoprecipitate, plasma, vasopressin (type 1 VWD)
• VWF/factor 8 concentrate

Acquired Coagulation Factors

• Disseminated intravascular coagulation
• Widespread inappropriate intravascular deposition of fibrin with consumption of coagulation factors and platelets
• Associated with many disorders, e.g., leukemia, trauma, obstetric complications

Clinical Presentation

• Bleeding, thrombotic lesions, organ dysfunction
• 5-10% of patients manifest thrombotic lesions

Laboratory Investigation

• Low platelet count
• Low fibrinogen concentration
• Prolonged thrombin time
• High levels of fibrin degradation products (D-dimers) in serum and urine
• Prolonged PT and APTT

Treatment

• Bleeding: supportive therapy with fresh frozen plasma and platelet concentrates
• Thrombosis: heparin or antiplatelet drugs to inhibit coagulation process

Thrombophilia

• Inherited: anti-thrombin III, protein C deficiency, protein S deficiency, factor V Leiden
• Acquired: dyslipidemia, malignancy, nephrotic syndrome, Behcet's syndrome, antiphospholipid antibody syndrome, pregnancy, COC, PNH, myeloproliferative disorder, leukemia

Clinical Picture and Investigation

• Recurrent venous thrombosis, abnormal site, young age
• Arterial thrombosis, absence of arterial atherosclerosis
• Recurrent abortion
• Thrombophlebitis
• Investigation: prolonged APTT, anticardiolipin antibody, lupus anticoagulant, level of protein S, C, anti-thrombin III, factor V Leiden

Treatment

• Anticoagulant: oral warfarin (vitamin K antagonist), parenteral heparin (subcutaneous, intravenous, unfractionated, low molecular weight)
• Side effects: heparin-induced thrombocytopenia, osteoporosis