eMedicine Specialties > Pediatrics: General Medicine > Hematology
Hemophilia A and B
Updated: Dec 2, 2008
Introduction
Background
Hemophilia A and B are inherited bleeding disorders caused by deficiencies of clotting factor VIII (FVIII) and factor IX (FIX), respectively. They account for 90-95% of severe congenital coagulation deficiencies. The 2 disorders are considered together because of their similar clinical pictures and similar patterns of inheritance.
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).
A bioassay of FVIII was introduced in 1950. Although the intimate relationship between FVIII and von Willebrand factor (vWF) is now known, it was not appreciated at the time. In 1953, decreased factor FVIII in patients with vWF deficiency was first described. Further research by Nilson and coworkers indicated the interaction between these 2 clotting factors.
In 1952, Christmas disease was described and named after the surname of the first patient who was examined in detail. This disease was distinct from hemophilia because 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.
Pathophysiology
The role of the coagulation system 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 alter clot formation and, as a consequence, result in clinical bleeding.
Frequency
United States
Hemophilia A is much more common than hemophilia B. The prevalence of hemophilia is 1 case per 5,000 males; 80-85% of these cases are hemophilia A, 14% are hemophilia B, and the remainder are various other clotting abnormalities. Approximately 17,000 persons have hemophilia in the United States. About 60% of cases are severe.
International
Hemophilia has a worldwide distribution.
Race
Hemophilia affects all racial groups.
Sex
Both hemophilia A and B are X-linked recessive disorders; therefore, they almost exclusively affect males. Reports of affected females are rare, and these cases are attributed to extreme lyonization or the presence of 2 independent mutations.
Age
Significant deficiency in FVIII or FIX may be 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.
Clinical
Physical
Approximately 30-50% of patients with severe hemophilia present with manifestations of neonatal bleeding (eg, after circumcision). Approximately 1-2% of neonates have intracranial hemorrhage. Other neonates may present with severe hematoma and prolonged bleeding from the cord or umbilical area.
After the immediate neonatal period, bleeding is uncommon in infants until they become toddlers, when trauma -related soft-tissue hemorrhage occurs. Young children may also have oral bleeding when their teeth are erupting. Bleeding from gum and tongue lacerations is often troublesome because the oozing of blood may continue for a long time despite local measures. As physical activity increases in children, hemarthrosis and hematomas occur. Chronic arthropathy is a late complication of recurrent hemarthrosis in a target joint. Traumatic intracranial hemorrhage is a serious life-threatening complication that requires urgent diagnosis and intervention.
Petechiae usually do not occur in patients with hemophilia because they are manifestations of capillary blood leaking, which is typically the result of vasculitis or abnormalities in the number or function of platelets.
Hemophilia is classified according to the clinical severity as mild, moderate, or severe. Patients with severe disease usually have less than 1% factor activity. It is characterized by spontaneous hemarthrosis and soft tissue bleeding in the absence of precipitating trauma. Patients with moderate disease have 1-5% factor activity and bleed with minimal trauma. Patients with mild hemophilia have more than 5% factor VIII (FVIII) activity and bleed only after significant trauma or surgery.
Table 1. Severity, Factor Activity, and Hemorrhage TypeOpen table in new window
Table
| Classification | Factor Activity, % | Cause of Hemorrhage |
| Mild | >5-40 | Major trauma or surgery |
| Moderate | 1-5 | Mild-to-moderate trauma |
| Severe | <1 | Spontaneous, hemarthrosis |
| Classification | Factor Activity, % | Cause of Hemorrhage |
| Mild | >5-40 | Major trauma or surgery |
| Moderate | 1-5 | Mild-to-moderate trauma |
| Severe | <1 | Spontaneous, hemarthrosis |
Causes
Both of these disorders are inherited in an X-linked recessive pattern. The genes for FVIII and factor IX (FIX) are located on the long arm of the X chromosome in bands q28 and q27, respectively. The factor VIII gene is one of the largest genes; it is 186 kilobases (kb) long and has a 9-kb coding region that contains 26 exons. The mature protein contains 2332 amino acids and has a molecular weight of 300 kD. It includes 3 A domains, 1 B domain, and 2 C domains. 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.
Numerous mutations in the gene structure have been described. Genetic abnormalities include genetic deletions of variable size, abnormalities with stop codons, and frame-shift defects. Data suggest that 45% of severe hemophilia A cases result from an inversion mutation.1 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.
More on Hemophilia A and B |
 Overview: Hemophilia A and B |
| Differential Diagnoses & Workup: Hemophilia A and B |
| Treatment & Medication: Hemophilia A and B |
| Follow-up: Hemophilia A and B |
| Multimedia: Hemophilia A and B |
| References |
| Next Page » |
References
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Further Reading
Keywords
hemophilia a, hemophilia b, factor VIII deficiency, FVIII deficiency, factor VIII hemophilia, factor IX deficiency, FIX deficiency, factor IX hemophilia, Christmas disease, angiostaxis, coagulation disorder, coagulation deficiency, bleeding disorder, hepatitis A, hepatitis B, hepatitis C, human immunodeficiency virus infection, HIV, hemarthrosis, hematomas, petechiae, vasculitis
