eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

Hemophilia, Overview

Author: Dimitrios P Agaliotis, MD, PhD, FACP, Consulting Staff, Department of Medicine, Baptist Health System
Coauthor(s): Robert A Zaiden, MD, Fellow in Medical Oncology, University of Florida at Jacksonville; Saduman Ozturk, PA-C, Physician Assistant, Bone Marrow Transplant Center, Florida Hospital Cancer Institute
Contributor Information and Disclosures

Updated: Jan 2, 2008

Introduction

Background

Hemophilia A (HA), which comprises approximately 80% of cases, is considered the classic form of hemophilia, and hemophilia B (HB) is termed Christmas disease. Hemophilia A is a consequence of a congenital deficiency of factor VIII (FVIII), and hemophilia B is a consequence of a congenital deficiency of factor IX (FIX). This deficiency results in insufficient generation of thrombin by FIXa and FVIIIa complex through the intrinsic pathway of the coagulation cascade. For more information on factor deficiencies, see Factor XIII and Factor IX.

The classification of the severity of hemophilia has been based on either clinical bleeding symptoms or on plasma procoagulant levels, which are the most widely used criteria. Persons with less than 1% normal factor (<0.01 IU/mL) are considered to have severe hemophilia. Persons with 1-5% normal factor (0.01-0.05 IU/mL) are considered to have moderately severe hemophilia. Persons with more than 5% but less than 40% normal factor (>0.05 to <0.40 IU/mL) are considered to have mild hemophilia. Clinical bleeding symptom criteria have been used because patients with FVIII or FIX levels less than 1% occasionally have little or no spontaneous bleeding and appear to have clinically moderate or mild hemophilia. Furthermore, the reverse is true for patients with procoagulant activities of 1-5%, who may present with symptoms of clinically severe disease.

Pathophysiology

The genes for both FVIII (ie, hemophilia A) and FIX (ie, hemophilia B) are located on the long arm of chromosome X. The gene for FVIII (F8C) located within the Xq28 region, is unusually large, representing 186 kb of the X chromosome. It comprises 26 exons and 25 introns. Mature FVIII contains 2332 amino acids. Approximately 40% of cases of severe FVIII deficiency arise from a large inversion that disrupts the FVIII gene. Deletions, insertions, and point mutations account for the remaining 50-60% of hemophilia A defects. Low FVIII levels may arise from defects outside the FVIII gene, as in type IIN von Willebrand disease, in which the molecular defect resides in the FVIII-binding domain of von Willebrand factor.

The FIX gene (F9), located within the Xq27 region, has 34 kb and composes 8 exons and 7 intervening sequences. The mature protein is composed of 415 amino acids. Point mutations and deletions in the FIX gene are the most common causes of hemophilia B.

The hallmark of hemophilia is hemorrhage into the joints. This bleeding is painful and leads to long-term inflammation and deterioration of the joint, resulting in permanent deformities, misalignment, loss of mobility, and extremities of unequal lengths. Human synovial cells synthesize high levels of tissue factor pathway inhibitor, resulting in a higher degree of factor Xa (FXa) inhibition, which predisposes hemophilic joints to bleed. This effect may also account for the dramatic response of FVIIa infusions in patients with acute hemarthroses and FVIII inhibitors. Synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage progress, with subchondral bone-cyst formation.

Approximately 30% of patients with severe hemophilia A develop alloantibody inhibitors that can neutralize FVIII. These inhibitors are typically immunoglobulin G (IgG), predominantly of the IgG4 subclass, that do not fix complements and do not result in the end-organ damage observed with circulating immune complexes. They neutralize the coagulant effects of replacement therapy. The inhibitors occur at a young age (about 50% by age 10 y), principally in patients with less than 1% FVIII. In the United States, levels of FVIII inhibitors are most often measured by using the Bethesda method. In this method, 1 Bethesda unit (BU) equals the amount of antibody that destroys one half of the FVIII in an equal mixture of normal and patient plasma in 2 hours at 37°C. FIX inhibitors can produce anaphylaxis and nephrotic syndrome in individuals with complete gene deletions.

Frequency

United States

The annual incidence of hemophilia A in Europe and North America is approximately 1 case per 5000 male births. It is the most common X-linked genetic disease, and the second most common factor deficiency after von Willebrand disease (VWD). The incidence of hemophilia B is estimated to be approximately 1 case per 30,000 male births. In the United States, the prevalence of hemophilia A is 20.6 cases per 100,000 male individuals, with 60% of those having severe disease. The prevalence of hemophilia B is 5.3 cases per 100,000 male individuals, with 44% of those having severe disease.

International

The worldwide incidence of hemophilia A is approximately 1 case per 5000 male individuals, with approximately one third of affected individuals not having a family history. Hemophilia B occurs in 1 case per 25,000 male individuals and represents one fourth to one fifth of all patients with hemophilia. The prevalence of hemophilia A varies with the reporting country, with a range of 5.4-14.5 cases per 100,000 male individuals. The prevalence of hemophilia B varies from 0.9-3.2 cases per 100,000 male individuals.

Mortality/Morbidity

Before the widespread use of replacement therapy, patients with severe hemophilia had a shortened lifespan and diminished quality of life that was greatly affected by hemophilic arthropathy. Home therapy for hemarthroses became possible with factor concentrates. Prophylactic therapies with lyophilized concentrates that eliminate bleeding episodes help prevent joint deterioration, especially when instituted early in life (ie, at age 1-2 y). Life expectancy has increased from 11 years before the 1960s for patients who were severely affected to older than 50-60 years by the early 1980s.¹

Overall, the mortality rate for patients with hemophilia is twice that of the healthy male population. For severe hemophilia, the rate is increased 4-6 times. If hepatitis and cirrhosis are excluded, the overall mortality rate of patients with severe hemophilia A is 1.2 times that of the healthy male population.^2,3

• Viral complications became a problem during the replacement era.
  • The most serious of these was HIV infection. The first deaths of people with hemophilia due to AIDS were observed in the early 1980s. Rates of seroconversion were more than 75% for severe disease, 46% for moderate disease, and 25% for mild disease. In severe hemophilia B, seroconversion was observed at a rate of 46%. More than 50% of patients with hemophilia were infected with HIV by 1983.
  • In the United States, death rates of patients with hemophilia increased from 0.4 deaths per million population in 1979-1981 to 1.2 deaths per million population in 1987-1989; AIDS accounted for 55% of all hemophilia deaths. Causes of death shifted from intracranial and other bleeding to AIDS and cirrhosis from hepatitis.
  • The most common cause of death in patients with severe hemophilia is AIDS.
• Life-threatening hemorrhage is also a significant problem.
  • Intracranial hemorrhage is a life-threatening hemorrhage with a lifetime risk of 2-8%, accounting for one third of deaths due to hemorrhage.
  • Other life-threatening hemorrhages include soft-tissue hemorrhages that obstruct airways or damage the internal organs. The life expectancy of patients with inhibitors is only slightly higher than the life expectancy of people without inhibitors. Fewer patients with inhibitors than patients without inhibitors have seroconversion for HIV.
  • Intracranial hemorrhage is the second most common cause of death and the most common cause of death related to hemorrhage. Of patients with severe hemophilia, 10% have intracranial bleeding, with a mortality rate of 30%.
• See also Complications below.

Race

Hemophilia A and hemophilia B are observed in all ethnic and racial groups.

• In general, the demographics of hemophilia follow the racial distribution in a given population with a multiracial background as observed in the United States.
• The prevalence might be observed in the Chinese population.

Sex

Both forms of hemophilia are sex-linked coagulopathies because they are inherited as X-linked traits; therefore, the disease primarily affects male individuals. Female individuals who carry the affected genes usually do not have bleeding manifestations. Lyonized females (ie, those with unequal inactivation of FVIII or FIX alleles and with hemizygosity of all or part of the X chromosome) may be symptomatic.

• Female patients may have clinical bleeding due to hemophilia if 1 of 3 conditions is present: (1) extreme lyonization, (b) homozygosity for the hemophilia gene (eg, father with hemophilia and mother who is a carrier), or (3) Turner syndrome (XO) associated with the affected hemophilia gene (on average, only the X chromosome).
• Mild hemophilia may be more common in girls than previously recognized. In 1 study, 5 of 55 patients with mild hemophilia (factor levels 5-50%) were girls.⁴

Age

See Mortality/Morbidity.

Clinical

History

• Ask about the patient's family history and bleeding symptoms.
  • Male patients with severe hemophilia present at circumcision.
  • Easy bruising may occur at the start of ambulation or primary dentition.
  • The patient may have a history of hemarthroses and prolonged bleeding with surgical procedures, trauma, dental extraction, and he or she may have spontaneous bleeding in soft tissues.
  • A traumatic challenge relatively late in life may have to occur before mild or moderate hemophilia is diagnosed. Factors that elevate FVIII levels (eg, age, ABO blood type, stress, exercise) may mask mild hemophilia. Physiologically low levels of all vitamin K–dependent procoagulant factors may complicate the early diagnosis of hemophilia B.
• The principal sites of bleeding in patients with hemophilia are as follows:
  • For joints, weight-bearing joints and other joints are affected.
  • Regarding muscles, those most commonly affected are the flexor groups of the arms and gastrocnemius of the legs. Iliopsoas bleeding is dangerous because of the large volumes of blood loss and because of compression of the femoral nerve.
  • In the genitourinary tract, gross hematuria may occur in as many as 90% of patients.
  • In the GI tract, bleeding may complicate common GI disorders.
  • Bleeding in the CNS is the leading cause of hemorrhagic death among patients with hemophilia.

Physical

• Direct the examination to identify signs related to spontaneous or, with minimal challenge, bleeding in the joints, muscles, and other soft tissues.
• Observe the patient's stature.
• Examine the weight-bearing joints, especially the knees and ankles, and, in general, the large joints for deformities or ankylosis.
• Look for jaundice, other signs of liver failure (eg, cirrhosis from viral infection), and signs of opportunistic infections in patients who are HIV seroconverted.

Causes

• Hemophilia A and hemophilia B are a consequence of a congenital deficit of FVIII and FIX, respectively.
• The defect results in the insufficient generation of thrombin by the FIXa and FVIIIa complex by means of the intrinsic pathway of the coagulation cascade.
• This mechanism, in combination with the effect of the tissue-factor pathway inhibitor, creates an extraordinary tendency for spontaneous bleeding.

• Search for CME/CE on This Topic »

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• Hemophilia Overview
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