Since Christmas is coming up, let's talk about Hemophilia A (factor VIII deficiency) and Hemophilia B (factor IX deficiency, also known as Christmas disease)

Deficiencies in Factors VIII and IX are the most common severe inherited bleeding disorders.

Pathophysiology: 

• Factors VIII and IX are required for activation of factor X.
• In patients with Hemophilia A (factor VIII deficiency) or Hemophilia B (factor IX deficiency, also known as Christmas disease), after an injury, clot formation is delayed. 
• Inadequate thrombin generation leads to failure to form a tightly crosslinked fibrin clot to support platelet plug, which leads to easy bleeding.
• Clot that is formed may be friable and rebleeding occurs during physiologic lysis of clots or with minimal new trauma

Clinical Manifestations:

• 2% of neonates with hemophilia have intracranial hemorrhages
• 30% of male infants with hemophilia bleed with circumcision
• Continued bleeding from umbilical stump in neonate
• In absence of positive family history (hemophilia has high rate of spontaneous mutation), hemophilia may go undiagnosed in a newborn
• Easy bruising, intramuscular hematomas, and hemarthroses (hallmark for hemophilic bleeding) begin when child begins to cruise
• Bleeding from minor traumatic lacerations of the mouth (e.g. torn frenulum) can persist for hours or days
• Iliopsoas hemorrhage: patient may lose large volumes of bleed into the muscle, leading to hypovolemic shock, with only a vague complaint of area of referred pain in the groin. Hip is held in a flexed, internally rotated position, due to irritation of the iliopsoas.
  • Confirmed on CT or US
  • Clinically unable to extend hip
• Hemarthrosis rare in patients with acquired hemophilia

Lab findings and diagnosis

• Reduced levels of factor VIII or factor IX will cause higher PTT 
• PTT is usually 2-3x upper limit of normal in patients with severe hemophilia.
• Platelet count, bleeding time, prothrombin time, and thrombin time are all normal
• If PTT is not corrected after administration of factor VIII or IX, an inhibitor may be present.
  • 25-35% of patients with hemophilia who received infusions of factor VIII or factor IX, a factor specific antibody may develop (inhibitor)

Genetics

• Hemophilia occurs in 1:5000 males, with 85% having factor VIII deficiency and 10-15% having factor IX deficiency
• No apparent racial predilection, appearing in all ethnic groups

 

Classification

• Severe hemophilia: <1% activity of specific clotting factor and bleeding is often spontaneous
• Moderate hemophilia: 1-5% activity and require mild

trauma to induce bleeding

• Mild hemophilia: >5% activity and can go many years before diagnosis and usually require significant trauma to induce bleeding.

Treatment

• Ask patient or family if they brought their dosing information with them or their factor replacement with them. In many cases, they have it!
• For life-threatening or major hemorrhages, dose should aim to achieve levels of 100% activity
  • Hemophilia A: 50U/kg recombinant Factor VIII (each U/kg of factor VIII in hemophilia A increases factor by 2%)
  • Hemophilia B: 100U/kg recombinant Factor IX (each U/kg of factor VIII in hemophilia A increases factor by 1%)
  • Aim for 50% correction in moderate bleeds and 100% correction in severe bleeds
  • If you don’t have factor-specific products:
    • Hemophilia A
      • can give 1U cryoprecipitate (~80U of factor VIII) or try PCC (as it contains factors II, VII, IX, and X)
      • activated PCC (FEIBA) 75-100U/kg
    • Hemophilia B
      • FFP NO LONGER RECOMMENDED (volume of FFP required has high risk of volume overload)
      • Cryoprecipitate does NOT contain factor IX, so will not work.
• For acute bleeding in patients with mild hemophilia A:
  • Can give DDAVP: increases factor VIII by 3-5x by encouraging release of endogenous factor VIII. Recommended dose: 0.3mcg/kg/dose IV
• For mild bleeding:
  • TXA (clot stabilizer)
  • Desmopressin
  • Aminocaproic acid
• If patient has inhibitors:
  • Hemophilia A: 
    • Activated PCC (75-100U/kg) (do NOT give if on patient is on emicizumab (Hemlibra) due to risk of thrombosis)
    • Recombinant factor VII 90mcg/kg
  • Hemophilia B:
    • Recombinant factor VII 90mcg/kg

 

Summary:

• Aim for 50% correction in moderate bleeds and 100% correction in severe bleeds
• Hemophilia A: 50U/kg recombinant Factor VIII (each U/kg of factor VIII in hemophilia A increases factor by 2%)
• Hemophilia B: 100U/kg recombinant Factor IX (each U/kg of factor VIII in hemophilia A increases factor by 1%)
• Treatment if patient has no inhibitors:
  • Hemophilia A: 
    • Severe bleed: Give full dose factor XIII (50U/kg), even if the patient is on prophylaxis
    • Mild bleeds: factor XIII replacement (25U/kg), TXA, DDAVP, aminocaproic acid
  • Hemophilia B: 
    • Severe bleed: Give full dose factor IX (100U/kg), even if the patient is on prophylaxis
    • Mild bleeds: factor IV replacement (50U/kg), TXA, aminocaproic acid
• Treatment if patient has inhibitors:
  • Hemophilia A: 
    • Activated PCC (75-100U/kg) (do NOT give if on patient is on emicizumab (Hemlibra) due to risk of thrombosis)
    • Recombinant factor VII 90mcg/kg
  •  Hemophilia B:
    • Recombinant factor VII 90mcg/kg

 

References

Kliegman R, Stanton B, St. Geme JW, Schor NF, Behrman RE. Nelson Textbook of Pediatrics. Edition 20. Elsevier; 2016. Accessed December 1, 2023. https://search.ebscohost.com/login.aspx?direct=true&db=cat01362a&AN=hshs.004567758&site=eds-live