Hemophilia A

GENERAL PRINCIPLES

Definition

Hemophilia A is an X-linked recessive coagulation disorder due to mutations in the gene encoding factor VIII.

Epidemiology

Hemophilia A affects ~1 in 5000 live male births.

DIAGNOSIS

Clinical Presentation

• Patients with severe hemophilia experience frequent spontaneous hemarthroses and hematomas, hematuria, and delayed posttraumatic and postoperative bleeding. Repeated bleeding into a “target” joint causes chronic synovitis and hemophilic arthropathy.

• Moderate hemophiliacs have fewer spontaneous bleeding episodes, and mild hemophiliacs may only bleed excessively after trauma or surgery.

Diagnostic Testing

The severity of hemophilia is based on baseline factor VIII activity: Severe (lt;1%), moderate (1%-5%), and mild (gt;5%-lt;40%). Mild hemophiliacs with factor VIII #8805;30% may not have a prolonged aPTT.

TREATMENT

Medications

FIRST LINE

• Mild-to-moderate hemophilia A with minor bleeding:

î DDAVP (0.3 #956;g#8725;kg IV infused over 30 minutes, or 150 #956;g intranasal) increases factor VIII activity three- to fivefold. Because not all patients have an expected response to DDAVP, they should undergo a DDAVP challenge to assess responsiveness before use. To avoid tachyphylaxis, no more than three consecutive doses should be given per week.

• Mild-to-moderate hemophilia A with major bleeding OR severe hemophilia A with any bleeding:

î Factor VIII replacement is the mainstay of therapy with many hemophiliac patients able to do home infusion.

î Factor VIII concentrate increases factor VIII activity by 2% for every 1 IU/kg infused, thus a 50 IU/kg IV bolus raises factor VIII activity by 100% over baseline.

î One to three doses of factor VIII concentrates targeting peak plasma activities of 30%-50% typically stop mild hemorrhages.

î Major traumas and surgery require maintenance of levels gt;80%.

î Adjust doses based on peak and trough factor VIII levels to achieve individualized targets based on bleeding risk.

î Continuous infusion of factor VIII provides a safe and effective alternative to intermittent infusion.³⁶ î Extended factor VIII concentrates extended half-lives 1.5-1.7-fold (to 15-19 hours) allow reduced frequency of factor infusion.³⁷

• Emicizumab (Hemlibra), a bispecific humanized monoclonal antibody that bridges activated factor IX and X to restore the function of missing activated factor VIII. It had been approved for treatment in patients with congenital VIII deficiency with or without inhibitors, based on the remarkable results from HAVEN 1-4 studies, showing gt;90% reduction in annual bleed rate. It is given as subcutaneous injection once a week to once every 4 weeks (in contrast to frequent intravenous infusion needed for traditional factors), which led to a major change in the treatment of hemophilia patients.