Hemophilia: Drug Therapy

Therapeutic target

Prevention of hemorrhage or sequelae.

Therapy recommendations

The following forms of substitution therapy or therapy are distinguished:

  • On demand (= as-needed therapy; “on-demand substitution”):
    • Substitution is always based on symptomatology.
    • Multiple doses are often required in cases of threatening bleeding.
  • Bleeding prevention continuous therapy:
    • Children with severe hemophilia; initiation no later than after one hemorrhage.
    • Adults with recurrent (recurring) joint bleeding at risk of irreversible damage; physical/psychological stress; rehabilitation measures; postoperative healing processes
  • Bleeding prevention acute therapy
    • Prior to major surgery, factor activity should be increased to 100%
    • Before small operations, raising the factors to 50% is sufficient
  • Therapy of inhibitory hemophilia:
    • Symptomatic therapy of hemorrhage
    • Causal: elimination of inhibitory bodies by immunotolerance (immunotolerance induction).

One hour after substitution, a measurement of factor activity should be made. 100% activity (or 1 I.U.) is the activity contained in one milliliter of normal plasma.

Duration of infusion

  • Initial dose – 3-4 I.U./kg bw/hour.
  • Maintenance dose – 1.5-3 I.U./kg bw/hour

Continuous infusion may lead to a reduction in the total dose, but also to the formation of inhibitors.

Basic instructions

  • Children usually require higher doses
  • The size of the wound area determines the dose level, as does the progress of wound healing
  • Caution. Acetylsalicylic acid (ASA) is contraindicated in patients with hemophilia.
  • See also under “Further Therapy.”

Possible side effects of factor concentrates:

  • Allergic reactions
  • Rarely, thromboembolic side effects (mostly local)
  • Risk of infection (v.a. Hepatitis A, B, C, HIV) almost excluded.

Further notes

  • The European Commission has approved AFSTYLA (also known as rVIII-SingleChain), this is a recombinant single-chain factor VIII, for the treatment and prophylaxis of bleeding in hemophilia A.
  • After several years of substitution therapy with factor VIII, about 30% of patients with hemophilia A develop neutralizing antibodies. These patients could be protected from bleeding by the bispecific antibody emicizumab, which replaces the function of the missing coagulation factor VIII by binding coagulation factors IX and X. The antibody was found to be effective in preventing bleeding. This was a phase III trial.
    • Emicizumab became available on the German drug market on April 1, 2018.
    • HAVEN 3 study:Emicizumab significantly optimized bleeding control compared with standard factor VIII prophylaxis in patients 12 years of age and older with severe hemophilia A without inhibitors against factor VIII.Dosing: weekly prophylaxis with emicizumab (1.5 mg per kilogram body weight) by subcutaneous injection.
  • For the first time, gene therapy has been shown to be effective over an extended period of time (phase I/II study). It was achieved permanently high FIX activity of more than 30 percent on average, so that no more spontaneous bleeding occurred.
    • A single treatment using an adenovirus that deposits the correct version of the F8 gene in liver cells prevented patients from severe bleeding over the course of three years; prophylactic factor-8 infusions were largely avoided; antibody formation has not been observed to date; and no severe liver damage has occurred.