Hemophilia A overview

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Fahd Yunus, M.D. [2]

Overview

Hemophilia A is a blood clotting disorder caused by a mutation of the factor VIII gene, leading to a deficiency in Factor VIII. It is the most common hemophilia. Inheritance is X-linked recessive; hence, males are affected while females are carriers or very rarely display a mild phenotype. 1 in 5,000 males are affected.

Historical Perspective

Hemophilia is sometimes referred to as “The Royal Disease”, as it affected many members of the English, German, Russian and Spanish monarchies in the 19th and 20th centuries.

Classification

Hemophilia A may be classified according to the amount of Factor VIII present, resulting in either a mild, moderate, or severe form of the disease.

Pathophysiology

The pathogenesis of hemophilia A is characterized by genetic deficiency in Factor VIII.

Causes

Hemophilia A is caused by an inherited X-linked recessive trait, with the defective gene located on the X chromosome.

Differentiating [Disease] from Other Diseases

Hemophilia A must be differentiated from other diseases that cause abnormal or excessive bleeding

The most important differential diagnosis is that of hemophilia B (also known as Christmas disease) or von Willebrand disease. The former is usually considered if factor VIII levels are normal in a person with a haemophilia phenotype. The latter is excluded on routine testing for that condition.

Epidemiology and Demographics

The incidence of Hemophilia A is approximately 1 per 5,000 to 10,000 males worldwide. In 2016, it was estimated that 20,000 males in the United States were living with Hemophilia A

Risk Factors

Risk factors for development of hemophilia A include being of male sex and having a positive family history of the disease.

Screening

Screening for hemophilia A revolves around obtaining a thorough family history of bleeding.

Natural History, Complications, and Prognosis

• Hemophilia A presentation varies depending on the stage of the disease:
  • People with mild hemophilia (5-40% of factor VIII activity in the blood) generally present with excessive bleeding following surgery (such as a dental procedure) or trauma. They may remain asymptomatic otherwise for long period of time, even into late adulthood
  • People with moderate hemophilia (1-5% of factor VIII activity in the blood) have presentation ranging between mild and severe forms. They present earlier than patients with mild hemophilia, and may bleed following minor trauma
  • People with severe hemophilia (less than 1% of factor VIII in blood) present sooner in life with abnormal bleeding episodes, usually in the first year of life. They are also at risk for spontaneous hemorrhages, i.e. unprovoked bleeding episodes, frequently in the joints and muscles

Natural History

Clinical features are usually related to abnormal or spontaneous bleeding, and can be separated into internal bleeds and external bleeds

Complications

Many of the long-term sequelae of hemophilia A are either related to the morbidity of severe bleeds, or from side effects of frequent transfusions

Prognosis

With appropriate assistance and education, patients with Hemophilia can live productive lives, both in terms of longevity and quality of life. The prognosis of these patients is helped greatly with the availability of replacement therapy.

Diagnosis

Diagnostic Criteria

The diagnosis may be suspected as coagulation testing reveals an increased PTT in the context of a normal PT and bleeding time. The diagnosis is made in the presence of very low (<10 IU) levels of factor VIII.

History and Symptoms

Hemophilia leads to a severely increased risk of bleeding from common injuries. Mild hemophilia is usually asymptomatic, unless the patient experiences an injury or undergoes surgery. Bleeding into large joints or muscles is the most common site of bleeding in hemophilia. Though uncommon, spontaneous or traumatic intracranial hemorrhages are the most catastrophic complication of hemophilia.

Physical Examination

Physical exam findings are in Hemophilia A are usually related to the site of bleeding.

Laboratory Findings

The typical coagulation profile of a patient with hemophilia A usually presents as the following:

• Prolonged partial thromboplastin time (PTT)
• Normal prothrombin time
• Normal bleeding time
• Normal fibrinogen level
• Low factor VIII

Other laboratory findings consistent with the diagnosis of hemophilia A include correction of the PTT with a 1:1 mixing study (i.e. factor VIII from the normal blood mixed with the hemophiliac blood is able to correct for the coagulation deficit)

Imaging Findings

There are no imaging findings classically associated with hemophilia

Other Diagnostic Studies

Genetic testing appears to be a promising means of determining an individual's risk of attaining or passing on Hemophilia.

Treatment

There is no definitive treatment for hemophilia A, the mainstay of therapy is supportive and preventative care. It is recommended that patients diagnosed with hemophilia be referred to hemophilia treatment centers (HTC), which provide coordinated care between physicians (usually hematologists), nurses, social workers and other staff who specialize in bleeding disorders.

Medical Therapy

Most haemophilia patients require regular supplementation with intravenous recombinant factor VIII, also known as replacement therapy. Apart from "routine" supplementation, extra factor concentrate is given around surgical procedures and after trauma, as well as emergently during any bleeding episode.

Other therapeutic options include cryoprecipitate, fresh frozen plazma (FFP), desmopressin (DDAVP), and anti-fibrinoltytic agents.

References

1. History of Bleeding Disorders | National Hemophilia Foundation. Available at . Accessed on July 30, 2016
2. How is Hemophilia Diagnosed? – NHLBI, NIH. Available at . Accessed on July 30, 2016
3. Severity of Hemophilia – World Federation of Hemophilia. Available at . Accessed on July 30,2016
4. Facts | Hemophilia | NCBDDD | CDC. Available at . Accessed on July 30,2016
5. Data & Statistics | Hemophilia | NCBDDD | CDC. Available at Accessed on July 30,2016
6. Handbook of Genetic Counseling/Hemophilia and Von Willebrand Disease – Wikibooks, open books for an open world. Available at Accessed on July 30,2016
7. Konkle BA, Josephson NC, Nakaya Fletcher S. Hemophilia A. 2000 Sep 21 [Updated 2014 Jun 5]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from:http://www-ncbi-nlm-nih-gov.laneproxy.stanford.edu/books/NBK1404/