Hemophilia B 

Hemophilia B is an inherited, X-linked, recessive disorder resulting in deficiency of functional plasma coagulation factor IX. Spontaneous mutation and acquired immunologic processes can result in this disorder as well. Hemophilia B comprises approximately 20% of hemophilia cases, approximately 50% of whom have factor IX levels of greater than 1%.

Morbidity and death are primarily the result of hemorrhage, although infectious diseases (eg, HIV, hepatitis) became prominent, particularly in patients who received blood products prior to 1985.

Laboratory studies for suspected hemophilia B include a complete blood cell count, coagulation studies, and a factor IX assay (see Workup). The treatment of hemophilia may involve management of hemostasis, management of bleeding episodes, use of factor replacement products and medications, treatment of patients with factor inhibitors, and treatment and rehabilitation of patients with hemophilia synovitis (see Treatment).

For related information, see Hemophilia A, Acquired Hemophilia, and Hemophilia C.

Historical background

Hemophilia is one of the oldest described genetic diseases. An inherited bleeding disorder in males was recognized in Talmudic records of the second century. The modern history of hemophilia began in 1803 with the description of hemophilic kindred by John Otto, followed by the first review of hemophilia by Nasse in 1820. Wright demonstrated evidence of laboratory defects in blood clotting in 1893; however, FVIII was not identified until 1937 when Patek and Taylor isolated a clotting factor from the blood, which they called antihemophilia factor (AHF).

In 1952, Christmas disease was described and named after the surname of the first patient who was examined in detail. Mixing plasma from a patient with "true hemophilia" and with plasma from a patient with Christmas disease corrected the clotting time; thus, hemophilia A and B were differentiated.

In the early 1960s, cryoprecipitate was the first concentrate available for the treatment of patients with hemophilia. In the 1970s, lyophilized intermediate-purity concentrates were obtained from a large pool of blood donors. The introduction of concentrated lyophilized products that are easy to store and transport has dramatically improved the quality of life of patients with hemophilia and facilitated their preparation for surgery and home care.

In the 1980s, the risk of transmitting viral contaminants in commercial FVIII concentrates became increasingly recognized. By the mid 1980s, most patients with severe hemophilia had been exposed to hepatitis A, hepatitis B, and hepatitis C viruses and human immunodeficiency virus (HIV). New viricidal techniques have been effective in eliminating new HIV transmissions and virtually eliminating hepatitis B and hepatitis C exposures. The present standard of using recombinant products, especially those without exposure to animal proteins, in the treatment of hemophilia virtually eliminates the risk of viral exposure.

Severity classification

The classification of the severity of hemophilia has been based on either clinical bleeding symptoms or plasma procoagulant levels; the latter 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 FIX levels of 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. The coexistence of thrombophilic states such as factor V Leiden mutation, protein C or protein S deficiency, or prothrombin G20210A mutations may be seen in a minority of patients, in which they counterbalance bleeding tendencies and therefore have lessened or delayed symptoms.

Factor IX deficiency, dysfunctional factor IX, or factor IX inhibitors lead to disruption of the normal intrinsic coagulation cascade, resulting in spontaneous hemorrhage and/or excessive hemorrhage in response to trauma. Hemorrhage sites include joints (eg, knee, elbow), muscles, CNS, GI system, genitourinary (GU) system, pulmonary system, and cardiovascular system. Patients who acquired HIV, hepatitis, or other viruses suffer from maladies associated with those infections.

Coagulation system

The role of the coagulation system, as depicted in the image below, is to produce a stable fibrin clot at sites of injury. The clotting mechanism has 2 pathways: intrinsic and extrinsic.

The intrinsic system is initiated when factor XII is activated by contact with damaged endothelium. The activation of factor XII can also initiate the extrinsic pathway, fibrinolysis, kinin generation, and complement activation.

In conjunction with high-molecular-weight kininogen (HMWK), factor XIIa converts prekallikrein (PK) to kallikrein and activates factor XI. Activated factor XI, in turn, activates factor IX in a calcium-dependent reaction. Factor IXa can bind phospholipids. Then, factor X is activated on the cell surface; activation of factor X involves a complex (tenase complex) of factor IXa, thrombin-activated FVIII, calcium ions, and phospholipid.

In the extrinsic system, the conversion of factor X to factor Xa involves tissue factor (TF), or thromboplastin; factor VII; and calcium ions. TF is released from the damaged cells. It is thought to be a lipoprotein complex that acts as a cell surface receptor for FVII, with its resultant activation. It also adsorbs factor X to enhance the reaction between factor VIIa, factor X, and calcium ions. Factor IXa and factor XII fragments can also activate factor VII.

In the common pathway, factor Xa (generated through the intrinsic or extrinsic pathways) forms a prothrombinase complex with phospholipids, calcium ions, and thrombin-activated factor Va. The complex cleaves prothrombin into thrombin and prothrombin fragments 1 and 2. Thrombin converts fibrinogen into fibrin and activates FVIII, factor V, and factor XIII.

Fibrinopeptides A and B, the results of the cleavage of peptides A and B by thrombin, cause fibrin monomers to form and then polymerize into a meshwork of fibrin; the resultant clot is stabilized by factor XIIIa and the cross-linking of adjacent fibrin strands. Because of the complex interactions of the intrinsic and extrinsic pathways (factor IXa activates factor VII), the existence of only one in vivo pathway with different mechanisms of activation has been suggested.

FVIII and FIX circulate in an inactive form. When activated, these 2 factors cooperate to cleave and activate factor X, a key enzyme that controls the conversion of fibrinogen to fibrin. Therefore, the lack of either of these factors may significantly impair clot formation and, as a consequence, result in clinical bleeding.

Genetics

The gene for FIX—like the gene for FVIII—is located on the long arm of chromosome X, within the Xq27 region. The FIX gene (F9) 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.

Clinical manifestations

The hallmark of hemophilia is hemorrhage into the joints. This bleeding is painful and leads to long-term inflammation and deterioration of the joint (typically the ankles in children and the ankles, knees, and elbows in adults and adolescents), 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. Synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage progress, with eventual subchondral bone-cyst formation.

Inhibitors

Approximately 3-5% of patients with severe hemophilia B develop alloantibody inhibitors that can neutralize FIX. These inhibitors are usually immunoglobulin G antibodies and appear after the first infusions of FIX concentrate.

Both genetic and environmental factors determine the frequency of inhibitor development. Specific molecular abnormalities (eg, gene deletions, stop codon mutations, frameshift mutations) and an absence or paucity of endogenous FIX (severe disease) are associated with a higher incidence of inhibitor development. In addition, inhibitors are more likely to develop in black children. In addition, purified products (some no longer marketed) have been associated with increased inhibitor development.

Hemophilia B is an X-linked recessive disease caused by an inherited or acquired mutation in the FIX gene or by an acquired factor IX inhibitor. The gene for FIX is located on the long arm of the X chromosome in band q27. FIX contains 415 amino acids and has a molecular weight of 57,000 d. The gene that encodes this protein is 33 kb and contains 8 exons and 7 introns.

Several hundred mutations with different amino acid substitutes have been described in hemophilia B. These mutations include partial and total deletions, missense mutations, and others that result in the decreased or absent production of FIX or the production of an abnormal protein. Evaluation and knowledge of the specific gene defect in families with severe hemophilia enables accurate gene tracking, carrier analysis, and prenatal diagnosis.

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.

Hemophilia has a worldwide distribution. The incidence of hemophilia B is estimated to be approximately 1 case per 25,000-30,000 male births. The prevalence of hemophilia B is 5.3 cases per 100,000 male individuals, with 44% of those having severe disease.

Hemophilia B is much less common than hemophilia A. Of all hemophilia cases, 80-85% are hemophilia A, 14% are hemophilia B, and the remainder are various other clotting abnormalities.

Racial, sexual, and age-related differences in incidence

Hemophilia B occurs in all races and ethnic groups. In general, the demographics of hemophilia follow the racial distribution in a given population; for example, rates of hemophilia among whites, African Americans, and Hispanic males in the US are similar.

Because hemophilia is an X-linked, recessive condition, it occurs predominantly in males. Females usually are asymptomatic carriers. However, mild hemophilia may be more common in carriers than previously recognized. In 1 study, 5 of 55 patients with mild hemophilia (factor levels 5-50%) were girls.^[1]

Females may have clinical bleeding due to hemophilia if 1 of 3 conditions is present: (1) extreme lyonization (ie, inactivation of the normal FIX allele in one of the X chromosomes), (b) homozygosity for the hemophilia gene (ie, father with hemophilia and mother who is a carrier, two independent mutations, or some combination of inheritance and new mutations), or (3) Turner syndrome (XO) associated with the affected hemophilia gene.

Significant deficiency in FVIII may be evident in the neonatal period. It continues through the life of the affected individual. The absence of hemorrhagic manifestations at birth does not exclude hemophilia. Excessive bleeding after normal trauma encountered during ambulation at the toddler stage may be the first indication of hemophilia.

Significant deficiency in FIX may become evident in the neonatal period and continue through the life of the affected individual. The absence of hemorrhagic manifestations at birth does not exclude hemophilia. Excessive bleeding after normal trauma encountered during ambulation at the toddler stage may be the first indication of hemophilia.

The Leyden phenotype of hemophilia B manifests as severe childhood disease, which subsequently improves at the onset of puberty, likely due to androgen effect.

With appropriate education and treatment, patients with hemophilia can live full and productive lives. Prophylaxis and early treatment with factor concentrate that is safe from viral contamination have dramatically improved the prognosis of patients regarding morbidity and mortality due to severe hemophilia. Nevertheless, approximately one quarter of patients with severe hemophilia age d 6-18 years have below-normal motor skills and academic performance and have more emotional and behavioral problems than others.^[2]

Factor concentrates have made home-replacement therapy possible, improving patients' quality of life. In addition, dramatic gains in life expectancy occurred during the era of replacement therapy. The life expectancy rose from 11 years or less for patients with severe hemophilia before the 1960s to almost 60 years prior to HIV epidemic in the 1980s.^{[3, 4]}

Viral infection from contaminated factor concentrate became a problem during the replacement era. Most patients with hemophilia who received plasma-derived products that were not treated to eliminate potential contaminating viruses became infected with HIV or hepatitis A, hepatitis B, or hepatitis C viruses.

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 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. AIDS remains the most common cause of death in patients with severe hemophilia.^[4] Indeed, HIV-infected individuals are likely to die of that disease rather than from hemophilia.

With improved screening of donors, new methods of factor concentrate purification, and recombinant concentrates, infectious complications now mostly of historical importance. However, even with these methods, some viruses (eg, parvovirus B19) cannot be removed and may be transmitted through plasma-derived products. Other potential infectious agents include those that cause Creutzfeldt-Jakob disease. With the development of animal protein–free products, the risk of contamination with these agents may be decreased.

Intracranial hemorrhage and hemorrhages into the soft tissue around vital areas, such as the airway or internal organs, remain the most important life-threatening complications. The lifetime risk of intracranial bleeding is 2-8% and accounts for one third of deaths due to hemorrhage, even in the era of factor replacement. 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%.

Chronic debilitating joint disease results from repeated hemarthrosis; synovial membrane inflammation; hypertrophy; and, eventually, destructive arthritis. Early replacement of coagulation factors by means of infusion is essential to prevent functional disability. Thus, prophylactic therapy administered 2-3 times weekly, starting when patients are young, is considered the standard of care in most developed countries.

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).

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

Starting in infancy, regular dental evaluation is recommended, along with instruction regarding proper oral hygiene, dental care, and adequate fluoridation.

Encourage the patient to engage in appropriate exercise. Advise the patient against participating in contact and collision sports.

Patient and family education about early recognition of hemorrhage signs and symptoms is important for instituting or increasing the intensity of replacement therapy. This treatment helps prevent the acute and chronic complications of the disease that may vary from life-threatening events to quality-of-life–impairing events.

In addition, educating patients or family members about factor replacement administration at home has greatly enhanced the quality of life of patients with severe hemophilia.

For patient education information, see the Blood and Lymphatic System Center, as well as Hemophilia.