Hemophilia (ORPHA:448)
A rare hematological disorder characterized by spontaneous hemorrhage or prolonged bleeding due to factor VIII or IX deficiency.
Epidemiology
Prevalence in the general population is estimated at 1/12,000. Prevalence at birth is estimated at 1/5,000 in males.
Clinical description
Hemophilia primarily affects males, but female carriers of disease-causing mutations may also manifest generally milder forms of the disease. In general, onset of bleeding anomalies occurs when affected infants start to learn to walk. However, newborns with hemophilia are at risk of intra- or extracranial hemorrhage and other bleeding complications. The severity of clinical manifestations depends on the extent of the coagulation factor deficiency. If the biological activity of the coagulation factor is below 1 IU/dL, hemophilia is severe and manifests as frequent spontaneous hemorrhage and abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction (severe hemophilia A and B). If the biological activity of the coagulation factor is between 1 and 5 IU/dL, hemophilia is moderately severe with abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction but spontaneous hemorrhage is rare (moderately severe hemophilia A and B). If the biological activity of the coagulation factor is between 5 and 40 IU/dL, hemophilia is mild with abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction but spontaneous hemorrhage does not occur (mild hemophilia A and B). In patients with severe hemophilia, bleeding most often occurs in joints (hemarthroses) and muscles (hematomas), but any site may be involved following trauma or injury. Spontaneous hematuria is a frequent and highly characteristic sign of the disorder.
Etiology
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.
Diagnostic methods
Diagnosis is made on the basis of coagulation tests revealing prolonged coagulation times (activated partial thromboplastin time, aPTT). Type and severity of hemophilia are determined through specific measurements of factor VIII and IX activity and antigen levels.
Differential diagnosis
Differential diagnosis includes von Willebrand disease, combined factor VIII and factor V deficiency and other coagulation anomalies leading to prolonged coagulation times.
Antenatal diagnosis
Prenatal diagnosis performed on chorionic villi or amniocytes is rapid and informative when the familial, causative mutation is known. Knowing the familial mutation status in the fetus allows for preparation of delivery and early newborn medical management.
Genetic counseling
Inheritance is X-linked recessive and genetic counseling is recommended for affected families. For female carriers, there is a 50% risk that male offspring will be affected and a 50% risk that female offspring will be carriers. Overall, there is a 25% risk for each pregnancy that the baby will be a male offspring with hemophilia and a 25% risk that the baby will be a heterozygous female offspring.
Management and treatment
Management is provided by multidisciplinary comprehensive hemophilia care centers. Replacement therapy consisting of administration of the missing factor VIII (hemophilia A) or factor IX (hemophilia B) is the most straightforward treatment approach. Plasma-derived and recombinant factor VIII and factor IX concentrates are available. Non-factor therapies also exist for hemophilia A and new therapeutical approaches including gene therapy are under development. Treatment may be administered after a hemorrhage or prophylactically, to prevent bleeding. 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.
Prognosis
Left untreated, the disease course is severe and, in severe hemophilia, is generally fatal. Insufficient or incorrect treatment of recurrent hemarthroses and hematomas leads to physical impairment with severe disability associated with stiffness, joint deformation and physical disability. However, current treatment approaches (early prophylaxis) prevent these complications and the prognosis is favorable. Hemorrhage, HIV and HCV infections, and hepatic disease are the leading causes of death.

                            Last update: 
                            March 2022


                            - Expert reviewer(s): 
                            Pr Yesim DARGAUD | EuroBloodNet* - Dr Anne LIENHART | EuroBloodNet*


                                * European Reference Network