Hemophilia A

Epidemiology

Hemophilia A is typically an X-linked recessive genetic disorder that most often affects males, with an incidence of approximately 1 in 5,000 male births.^1,2 Between 2012 and 2018, there were an estimated 20,000 to 33,000 males with Hemophilia A living in the U.S.

Children can inherit Hemophilia A from a father with Hemophilia A, or from a mother who is a carrier.^1,2,3 Around one-third of people with Hemophilia A have no prior family history (spontaneous). Females with hemophilia are rare, but may result in females with both X chromosomes affected or when one X chromosome is inactive — females account for 3% of people with Hemophilia A.

Acquired Hemophilia A (AHA), a rare autoimmune form of Hemophilia A in which an individual develops autoantibodies to FVIII, has an estimated incidence of 1.5 to 2 cases per million per year.^4,5,6,7 It is more common in the elderly, with a median age of 73.9 at diagnosis, and can affect men and women equally.

Diagnosis

In some cases, infant boys with genetic risk factors are tested shortly after birth.² In other cases, testing is done after clinical suspicion of hemophilia due to symptoms.

Due to a variety of chromosomal abnormalities, the symptoms of hemophilia can vary greatly from one patient to another and they correlate to plasma FVIII levels.¹ Severe Hemophilia A is typically diagnosed at a very young age due to joint bleeds or intramuscular bleeding, bleeding associated with a minor medical procedure (venipuncture, circumcision, central line placement, or heel prick), mucocutaneous bleeding, or extracranial bleeding.^1,2

Individuals with mild Hemophilia A may rarely experience spontaneous bleeding, but can experience major bleeding with trauma or surgery.¹ Individuals with moderate Hemophilia A may experience occasional spontaneous bleeding, and are at risk for prolonged bleeding with minor trauma or surgery. When including mild and moderate cases, 36% of Hemophilia A cases were expected to be undiagnosed in the U.S. based on data from 2016.⁸

Pathophysiology

FVIII is a glycoprotein synthesized mainly in hepatocytes.^9,10,11,12 Von Willebrand Factor (VWF) stabilizes FVIII, protects it from premature proteolysis, and transfers it to the site of endothelial injuries. 

In primary hemostasis, which involves the formation of a platelet plug after endothelial injury, VWF:FVIII complex is critical for the recruitment and activation of platelets, and binding to collagen.^10,11,13 In this process, FVIII is freed from VWF, which activates FVIII. Activated FVIII plays a role in secondary hemostasis, which is the process of forming a stable fibrin clot.¹⁴

FVIII deficiencies, which can result from a variety of mutations to the FVIII gene, lead to varying degrees of inability to form a stable fibrin clot and thus stop bleeding.^1,14

Navigating Hemophilia A

Even a single bleed in an individual with Hemophilia A may be life-threatening or lead to debilitating joint disease^.1,15,16 Therefore, prevention of all bleeds is the goal of optimal hemophilia patient care.^17,18

One of the most serious complications of factor treatment is neutralizing antibodies to FVIII (FVIII inhibitors).^1,2 Testing for inhibitors is required in any individual with hemophilia in the following circumstances:¹

• When clinical or laboratory response to concentrate is suboptimal;
• Before and after a switch of treatment;
• Before elective invasive procedures; and 
• Within 4 weeks after intensive treatment (≥5 consecutive days of clotting factor administration) or before surgery