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Title: Hemophilia

Category: Pediatrics

Posted: 12/1/2023 by To-Lam Nguyen, MD

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