The use of prophylaxis in the treatment of rare bleeding disorders

Rare bleeding disorders (RBDs) are a heterogeneous group of coagulation factor deficiencies that include fibrinogen, prothrombin, α₂-antiplasmin, plasminogen activator inhibitor-1, and factors II, V, V/VIII, VII, X, XI and XIII. The incidence varies based upon the disorder and typically ranges from 1 in 500,000 to 1 per million population. Symptoms vary with the disorder and residual level of the clotting factor, and can range from relatively minor such as epistaxis, to life threatening, such as intracranial hemorrhage. Rapid treatment of bleeding episodes in individuals with severe bleeding phenotypes is essential to preserve life or limb and to prevent long-term sequelae; therapeutic options depend on the deficiency and range from plasma-derived (eg, fresh frozen plasma, prothrombin complex concentrates, factor X concentrate) to highly purified and recombinant single factor concentrates. The rarity of these disorders limits the feasibility of conventional prospective clinical trials; instead, clinicians rely upon registries, published case reports/series and experience to guide treatment. In some disorders, long-term prophylactic therapy is administered in response to the bleeding phenotype in an individual patient or based on the known natural history and severity of the deficiency. Intermittent prophylaxis, surrounding surgery, pregnancy, labor, and menstruation may be required to prevent or control excessive bleeding. This review summarizes therapeutic options, guidelines, recommendations and observations from the published literature for long-term, surgical, gynecological, and obstetric prophylaxis in deficiencies of fibrinogen; prothrombin; factors II, V, V/VIII, VII, X, XI and XIII; combined vitamin-K dependent factors; α2-antiplasmin; and plasminogen activator inhibitor 1. Platelet disorders including Glanzmann's thrombasthenia and Bernard-Soulier syndrome are also addressed.