Hemophilia

Hemophilias are disorders of blood clotting and consequently may lead to serious bleeding. In the majority of cases, these disorders are hereditary. There are three types of hemophilia, determined based on which clotting factor is deficient: hemophilia A (factor VIII), hemophilia B (factor IX), and hemophilia C (factor XI). All types result in impaired secondary hemostasis (plasmatic coagulation) that manifests as increased activated partial thromboplastin time (aPTT). Hemophilia presents with hemarthrosis (bleeding into joints) and muscular or soft tissue hematomas. Depending on the remaining clotting factor activity, bleeding may occur spontaneously or in response to trauma of varying severity. Repeated hemarthrosis can eventually lead to joint destruction, a serious long-term complication of hemophilia. Diagnosis is based on patient history and a mix of semiquantitative and quantitative measurements of clotting factor activity. Severe hemophilia (enzyme activity < 1%) is treated with prophylactic substitution of clotting factors, whereas mild hemophilia A, in particular, can also be treated with desmopressin, a synthetic vasopressin analog.

• Caused by an X-linked recessive defect (inherited or spontaneous mutation) or antibody production against clotting factors
• Hemophilia A (factor VIII deficiency): ∼ 80% of cases
• Hemophilia B (factor IX deficiency): ∼ 20% of cases
• Hemophilia C (factor XI deficiency): very rare (increased frequency in Ashkenazi Jews); caused by an autosomal recessive defect

Hemophilia usually affects males, as it is primarily an X-linked recessive disease.

• Spontaneous or delayed-onset bleeding (joints, muscular and soft tissue, mucosa) in response to different degrees of trauma
  • Repeated hemarthrosis (e.g., knee joint) → hemophilic arthropathy (i.e., destruction of the joint due to repeated hemarthrosis)
  • Recurrent bruising or hematoma formation
  • Oral mucosa bleeding, epistaxis, excessive bleeding following small procedures (e.g., dentist procedures)
  • Hemophilia C is usually not associated with spontaneous bleeding, hemarthosis, or deep tissue bleeding. ^[1]
• Further sites/symptoms of hemorrhage:
  • CNS (e.g., headache, neck stiffness)
  • Gastrointestinal tract (e.g., melena, hematemesis)
  • Genitourinary system (e.g., hematuria)
• Female carriers may show mild symptoms.
• The degree of bleeding and, therefore, severity of hemophilia depends on residual factor activity levels; normal reference activity is > 50%

Petechial bleeding is a common sign of platelet disorders, NOT coagulation disorders such as hemophilia.

• Patient and family history
• Genetic testing
• Screening
  • Prothrombin time: normal
  • Platelet count: normal
  • Activated partial thromboplastin time (aPTT): usually prolonged
• If aPTT prolonged → mixing study
• If mixing study is positive (or if patient/family history are strongly positive) → quantitative assessment of factor activity levels

• Differential diagnosis: see ”Classification" in hemostasis and bleeding disorders

• Substitution of clotting factors
  • Mild or moderate hemophilia: when needed (e.g., trauma or surgery)
  • Severe hemophilia: prophylactic (additional substitution may be needed in, e.g., trauma)
  • Substitution of
    • Factor VIII concentrate for hemophilia A ^[2]
    • Factor IX concentrate for hemophilia B
    • Factor XI concentrate for hemophilia C
    • Desmopressin
      • Indication: mild hemophilia A
      • Synthetic analog of vasopressin
      • Triggers the release of vWF from endothelial cells, which leads to an increase in factor VIII plasma concentration ^[3]
• Antifibrinolytic therapy (e.g., ε-Aminocaproic acid, tranexamic acid)
  • Used in addition to factor substitution (e.g., if surgery is performed in the oral cavity)
  • Inhibits the break down of clots to reduce the risk of bleeding
• Emicizumab
  • Description: a humanized monoclonal bispecific antibody that reduces the risk of bleeding events
  • Therapeutic use: hemophilia A
  • Mechanism of action: bridges activated factor IX and factor X by binding to both factors (thereby replacing the deficient factor VIII) → activation of factor X → restored clotting cascade

1. Mohammed BM, Matafonov A, Ivanov I, et al. An update on factor XI structure and function. Thromb Res. 2018; 161 : p.94-105. doi: 10.1016/j.thromres.2017.10.008 . | Open in Read by QxMD
2. Witmer C, Young G. Factor VIII inhibitors in hemophilia A: rationale and latest evidence. Therapeutic Advances in Hematology. 2012; 4 (1): p.59-72. doi: 10.1177/2040620712464509 . | Open in Read by QxMD
3. Candy V, Whitworth H, Grabell J, et al. A decreased and less sustained desmopressin response in hemophilia A carriers contributes to bleeding. Blood Advances. 2018; 2 (20): p.2629-2636. doi: 10.1182/bloodadvances.2018023713 . | Open in Read by QxMD