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Hemophilia is a genetic disorder characterized by spontaneous hemorrhage or prolonged bleeding due to factor VIII or IX deficiency.
ORPHA:448Classification level: Group of disorders
- Synonym(s): -
- Prevalence: 1-9 / 100 000
- Inheritance: X-linked recessive
- Age of onset: Infancy
- ICD-10: -
- OMIM: -
- UMLS: C0684275
- MeSH: -
- GARD: 10418
- MedDRA: 10061992
Annual incidence is estimated at 1/5,000 male births and the prevalence is estimated at 1/12,000.
Hemophilia primarily affects males, but female carriers of the disease-causing mutations may also manifest generally milder forms of the disease (symptomatic forms of hemophilia A and B in female carriers; see these terms). In general, onset of the bleeding anomalies occurs when affected infants start to learn to walk. The severity of the clinical manifestations depends on the extent of the coagulation factor deficiency. If the biological activity of the coagulation factor is below 1%, the hemophilia is severe and manifests as frequent spontaneous hemorrhage and abnormal bleeding as a result of minor injuries, or following surgery or tooth extraction (severe hemophilia A and B; see these terms). If the biological activity of the coagulation factor is between 1% and 5%, the hemophilia is moderately severe with abnormal bleeding as a result of minor injuries, or following surgery or tooth extraction but spontaneous hemorrhage is rare (moderately severe hemophilia A and B; see these terms). If the biological activity of the coagulation factor is between 5 and 40%, the hemophilia is mild with abnormal bleeding as a result of minor injuries, or following surgery or tooth extraction but spontaneous hemorrhage does not occur (mild hemophilia A and B; see these terms). Bleeding most often occurs around the joints (hemarthroses) and in the muscles (hematomas), but any site may be involved following trauma or injury. Spontaneous hematuria is a fairly frequent and highly characteristic sign of the disorder.
The disorder is caused by mutations in the F8 gene (Xq28) encoding coagulation factor VIII, or in the F9 gene (Xq27) encoding coagulation factor IX, which are implicated in hemophilia types A and B, respectively (see these terms).
Diagnosis is made on the basis of coagulation tests revealing prolonged blood coagulation times. The type and severity of the hemophilia are determined through specific measurements of factor VIII and IX levels.
The differential diagnosis should include von Willebrand disease (see this term) and other coagulation anomalies leading to prolonged blood coagulation times.
Prenatal diagnosis is feasible through molecular analysis of chorionic villus samples. Coagulation factor assays can also be carried out on venous and umbilical cord blood samples.
Hemophilia is transmitted in an X-linked recessive manner and around 70% of hemophiliacs have a positive family history of the disease.
Management and treatment
Treatment revolves around substitution therapy with plasma derivatives or genetically engineered recombinant alternatives. Treatment may be administered after a hemorrhage or to prevent bleeding (as a prophylactic treatment). The most frequent complication is the production of inhibitory antibodies against the administered coagulation factor. Surgical interventions, most notably orthopedic surgery, may be carried out but should be conducted in specialized centers.
Historically, the disease course is severe and, left untreated, severe hemophilia is generally fatal during childhood or adolescence. Insufficient or incorrect treatment of recurrent hemarthroses and hematomas leads to motor impairment with severe disability associated with stiffness, joint deformation and paralysis. However, current treatment approaches now allow these complications to be prevented and the prognosis is favorable: the earlier the substitutive therapy is received and the more adapted the treatment is to the clinical status of the patient, the better the prognosis.