1 Hemophilia A and B

Revision by: Fariba Baghaei (Gothenburg), Eva Funding (Copenhagen), Anna-Elina Lehtinen (Helsinki)

Hemophilia A and B are caused by deficiency of coagulation factor VIII (FVIII) or IX (FIX), respectively. The blood clotting is impaired, with risk of serious and life-threatening bleeding.

Hemophilia A and B are inherited in an X-linked recessive manner and primarily affect males. Female carriers can have reduced factor levels and mild hemophilia, while severe phenotype is rare.

The clinical severity of hemophilia A and B closely correlates with the level of FVIII or FIX. In severe hemophilia, factor levels are less than 1% of normal; in moderate hemophilia 1-5% of normal, and in mild hemophilia over 5% and less than 40% of normal.

Severe hemophilia inevitably causes spontaneous painful bleeding into joints and soft tissues. Iron deposition in the cartilage will lead to inflammation, hemophilic arthropathy and severe disability. Intracranial hemorrhage can cause paralysis and death. In mild hemophilia abnormal bleeding occurs following surgical procedures or trauma, whereas the clinical severity of moderate hemophilia varies from mild to severe.

A family history of hemophilia is often the reason for referral, but 30-50% of new cases have no prior family history. Severe hemophilia can present with intracranial bleeding in infancy, bleeding from the umbilical stump or following circumcision and unusual bruises or hematomas in infant boys, sometimes leading to wrongful suspicion of child abuse. When the boy begins to crawl and walk limping may occur due to hemarthrosis.

Hemophilia is currently treated with replacement of the missing coagulation factor or the newly introduced non-replacement therapies. With modern prophylactic treatment from toddler age, young adult men with severe hemophilia are healthy with no or minimal consequences of bleeding. The overall goal of hemophilia treatment in the Nordic countries is zero bleeds and healthy joints.

Upon starting treatment around 30-40% of hemophilia A patients develop inhibitory antibodies against the replacement factor. Novel non-factor treatment options are emerging as alternatives, enabling prophylactic treatment and prevention of disability even in patients with inhibitors. Gene therapy could provide potential for the cure.