A patient in whom hemophilia A, also known as classic hemophilia, is suspected should consult a hematologist or visit a hemophilia treatment center (HTC) for testing and diagnosis. Affected individuals have a deficiency of clotting factor VIII (FVIII), so their blood does not clot successfully. Hemophilia A is a hereditary disease, and males are more likely to be affected because it is an X chromosome-linked condition. In the United States, almost 400 babies are born with hemophilia A (1 in 5000 male births) annually. It is estimated that almost 20,000 persons in the United States currently have hemophilia A, and 400,000 worldwide. Most people with hemophilia A who receive factor replacement therapy can lead a normal life and have a normal life expectancy.¹
Role of Factor VIII in Blood Coagulation
Factor V and factor VIII, which are protein cofactors, are involved in a series of sequential enzymatic reactions. The concentration of factor VIII in plasma is low, equivalent to 0.2 μg/mL. A reduction of more than 80% in the activity of plasma factor VIII can lead to a bleeding disorder. Factor VIII circulates in the plasma as a noncovalent complex with Von Willebrand factor, which enhances factor VIII synthesis. It protects sites of active hemostasis and prevents proteolysis.²
Classification of Hemophilia A
Hemophilia A is classified on the basis of plasma procoagulant levels and clinical symptoms of bleeding as follows: A plasma factor VIII level below 0.01 IU/mL (<1% of normal) is considered severe disease. A plasma factor VIII level between 0.01 and 0.05 IU/mL (1% to 5% of normal) is classified as moderate disease. A plasma factor VIII level above 0.05 IU/mL and below 0.40 IU/mL (>5% to <40%) is considered mild disease. According to the current World Health Organization (WHO) standards, a factor VIII level of 1 IU/mL (100%) is normal. The Scientific Subcommittee on Factor VIII and Factor IX of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis recommends that plasma procoagulant levels, rather than clinical symptoms of bleeding, be used preferentially for the classification of hemophilia.³
Sites of Bleeding and Principles of Care
Bleeding in hemophilia A is classified as serious or life-threatening according to the site of bleeding. Deep compartments (eg, calf, forearm, iliopsoas muscle, mucous membranes of the genitourinary tract, gums, mouth and nose, and joint cavities) are considered “serious” sites of bleeding. The gastrointestinal tract, neck or throat, and intracranial tissues are considered life-threatening sites of bleeding. The frequency of bleeding can vary depending on the site. For example, fewer than 5% of instances of bleeding are from the central nervous system, 10% to 20% are from the muscles, and 70% to 80% are from the joint cavities (hemarthrosis). Some of the joints in which bleeding occurs most frequently are the knees, elbows, and ankles. Less commonly affected multiaxial joints are the wrists, hips, and shoulders.
Patients with a diagnosis of hemophilia A require comprehensive care. It is important to prevent bleeding and treat the clotting factor deficiency, so treatment with a specific factor concentrate is necessary. It is recommended that acute bleeds be treated within 2 hours. Published studies have found a relationship between clotting factor level and severity of bleeding. If the site of bleeding is categorized as “severe” and the clotting factor level is less than 1% of normal, spontaneous bleeding, predominantly from joints or muscles, may occur in the absence of an identifiable hemostatic challenge. If the site of bleeding is categorized as “moderate” and the clotting factor level is 1% to 5% of normal, spontaneous bleeding will occur occasionally. Bleeding may also be caused by minor trauma or surgery. In “mild” cases of hemophilia, in which clotting factor levels are 5% to less than 40% of normal, spontaneous bleeding is rare. Episodes of bleeding may be caused by major trauma or surgery.⁴
Identification of Hemophilia Cases
It is essential to collect data from hemophilia cases. They can be gathered from regional hemophilia organizations, hemophilia treatment centers, patient advocacy groups, hematologists, infectious disease specialists, and other physicians. Other potential sources of disease-specific data are clinical laboratories that test for clotting disorders, home care organizations, Medicaid claims databases, and blood bank databases.⁵
The prevalence of hemophilia A in the general population is 6 per 100,000 males. The deficiency of the coagulation protein factor VIII is inherited; the gene that codes for FVIII, F8, is located on chromosome X928. Hemophilia A is classified as a rare disease. According to the results of clinical studies, the bispecific monoclonal antibody emicizumab (HemlibraⓇ) has the potential to mimic FVIII activity because it promotes thrombin formation. It is administered subcutaneously and has a long half-life in plasma. The dosing interval is every week or every 2 weeks. Emicizumab acts as a prophylactic to prevent bleeding in pediatric and adult patients. It is licensed in the United States, Europe, and Japan and can be used with or without FVIII inhibitors.⁶
Results of Clinical Studies
Two clinical studies, HAVEN 1 and HAVEN 2, were conducted in patients with a hemophilia disorder: HAVEN 1 in adults and adolescents and HAVEN 2 in pediatric patients younger than 12 years of age. In HAVEN 2, the proportion of patients with no bleeding events ranged from 63% to 90% when the medication was given every 2 weeks at a dose of 3 mg/kg of body weight.⁶
- Hemophilia Federation of America. Hemophilia A. Accessed July 23, 2021
- Hoyer LW. Hemophilia A. N Engl J Med. 1994;330(1):38-47. doi:10:1056/NEJM199401063300108
- White GC, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J. Definitions in hemophilia. Thromb Haemost. 2001;85(03):560. doi:10:1055/s-0037-1615621
- Srivastava A, Brewer AK, Mauser‐Bunschoten EP, et al. Guidelines for the management of hemophilia. Haemophilia. 2013;19(1):e1-47. doi:10:1111/j.1365-2516.2012.02909.x
- Soucie JM, Evatt B, Jackson D, the Hemophilia Surveillance System Project Investigators. Occurrence of hemophilia in the United States. Am J Hematol. 1998;59(4):288-294.
- Mannucci PM. Hemophilia therapy: the future has begun. Haematologica. 2020;105(3):545-553. doi:10:3324/haematol.2019.232132
Reviewed by Harshi Dhingra, MD, on 8/10/2021.