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): ∼ 80% of cases
• Hemophilia B (factor IX): ∼ 20% of cases
• Hemophilia C (factor XI): very rare (increased frequency in Ashkenazi Jews); caused by an autosomal recessive defect

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

References:^[1][2][3]

• Spontaneous or delayed onset bleeding (joints, muscular and soft tissue, mucosa) in response to different degrees of trauma (see the table below)
  • Repeated hemarthrosis → joint destruction
• Further sites/symptoms of hemorrhage:
  • CNS (e.g., headache, neck stiffness)
  • Gastrointestinal tract (e.g., melena, hematemesis)
  • Genitourinary system (e.g., hematuria)
  • Oral mucosa bleeding, epistaxis, excessive bleeding following small procedures (e.g., dentist procedures)
• Female carriers may show mild symptoms.

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

Severity	Clinical signs	Factor VIII or IX activity
Physiologic condition	None	≥ 50%
Mild hemophilia	Hematomas following severe trauma	> 5% to < 50%
Moderate hemophilia	Hematomas following mild trauma	≥ 1% to 5%
Severe hemophilia	Spontaneous hematomas	< 1%

• 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
  • Insufficient activity of factors VIII/IX: hemophilia A⁺/B⁺
  • Total absence of factors VIII/IX: hemophilia A^-/B^-
• Differential diagnosis: see ”Classification" in Hemostasis and bleeding disorders

References:^[4]

• 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)
• Desmopressin
  • Indication: mild hemophilia A
  • Synthetic analog of vasopressin
• 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)

References:^[5][6]