Hemophilia A (ORPHA:98878)
A rare genetic hematological disorder characterized by spontaneous or prolonged hemorrhages due to factor VIII deficiency.
Epidemiology
Hemophilia A is the most common form of hemophilia. Prevalence is estimated at around 1 in 6,000 males. It primarily affects males, but females may also be symptomatic with a generally milder clinical picture.
Clinical description
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 factor VIII deficiency in both males and females. If the biological activity of factor VIII is below 1 IU/dL, hemophilia is severe and manifests as frequent spontaneous hemorrhages and abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction (severe hemophilia A). If the biological activity of factor VIII 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). If the biological activity of factor VIII 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). Patients may also be labeled as having mild hemophilia A if they have a FVIII >40 IU/dL and a DNA change in the F8 gene and one of the following: (i) a family member with the same DNA change and FVIII of <40 IU/dL, and the DNA change is found in <1% of the population; and (ii) the international databases list the DNA change as being associated with hemophilia A and <40 IU/dL FVIII. 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
Hemophilia A is caused by mutations in the F8 gene (Xq28) encoding coagulation factor VIII.
Diagnostic methods
Diagnosis is suspected based on prolonged coagulation times (activated partial thromboplastin time, aPTT) and can be confirmed by measuring factor VIII activity and antigen levels.
Differential diagnosis
Differential diagnosis includes von Willebrand disease (VWD), including type 2N VWD and other coagulation anomalies leading to prolonged coagulation times, in particular combined factor V and factor VIII deficiency.
Antenatal diagnosis
Prenatal diagnosis 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 a female carrier, there is a 50% risk that male offspring will be affected and a 50% risk that each 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 is the most straight forward treatment approach, using plasma-derived or recombinant factor VIII concentrates. 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. Recently, bioengineered prolonged half-life factor VIII products and non-factor therapeutics such as emicizumab (a bispecific antibody that mimics the function of factor VIIIa) were approved. Emicizumab is approved for bleeding prophylaxis in hemophilia A with and without inhibitors. Other non-factor therapies and gene therapy are under development. 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 in severe hemophilia A. 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 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