Recombinant biologics for treatment of bleeding disorders.

Bleeding disorders and haemorrhage have an enormous social, medical and financial impact worldwide. Haemostasis is the process that arrests bleeding through the concerted activities of the vasculature, platelets and the plasma coagulation factors. Bleeding disorders can result from congenital deficiencies in one or more of the key coagulation factors. For example, factor VIII (FVIII) and FIX are deficient in haemophilias A and B, respectively. Alternatively, acquired bleeding disorders arise from the loss of procoagulant function, hyperactivity of fibrinolytic pathways or the dysfunction of cellular elements such as platelets. Haemostatic disorders can require transfusions of blood, blood products and coagulation factor concentrates. These are the medical mainstay in treating uncontrolled bleeding, but carry an intrinsic risk of viral and prion disease transmission and transfusion reactions. FVIII and FIX concentrates prepared from blood made home treatment of haemophilias possible. However, these concentrates were prepared using some donors infected with hepatitis and human immunodeficiency virus, and haemophilia patients were infected. Safety concerns led to the commercial development of recombinant FVIII and FIX. Recombinant FVIIa is also now commercially available for haemophilia patients who have developed neutralizing antibodies to FVIII and FIX. Thrombin directly catalyses clot formation, and FXIII crosslinks fibrin and thereby hardens clots. Both are being developed as recombinant products for use as topical haemostatic agents, either combined or for stand-alone applications. Recombinant FXIII is currently being evaluated for treatment and prevention of bleeding arising from congenital and acquired FXIII deficiencies. Basic research is providing novel therapeutic avenues of intervention in bleeding disorders; from applied research, the future could lead to new methods of economical protein production and reduced cost to patients. Bleeding disorders and haemorrhage have an enormous social, medical and financial impact worldwide. Haemostasis is the process that arrests bleeding through the concerted activities of the vasculature, platelets and the plasma coagulation factors. Bleeding disorders can result from congenital deficiencies in one or more of the key coagulation factors. For example, factor VIII (FVIII) and FIX are deficient in haemophilias A and B, respectively. Alternatively, acquired bleeding disorders arise from the loss of procoagulant function, hyperactivity of fibrinolytic pathways or the dysfunction of cellular elements such as platelets. Haemostatic disorders can require transfusions of blood, blood products and coagulation factor concentrates. These are the medical mainstay in treating uncontrolled bleeding, but carry an intrinsic risk of viral and prion disease transmission and transfusion reactions. FVIII and FIX concentrates prepared from blood made home treatment of haemophilias possible. However, these concentrates were prepared using some donors infected with hepatitis and human immunodeficiency virus, and haemophilia patients were infected. Safety concerns led to the commercial development of recombinant FVIII and FIX. Recombinant FVIIa is also now commercially available for haemophilia patients who have developed neutralizing antibodies to FVIII and FIX. Thrombin directly catalyses clot formation, and FXIII crosslinks fibrin and thereby hardens clots. Both are being developed as recombinant products for use as topical haemostatic agents, either combined or for stand-alone applications. Recombinant FXIII is currently being evaluated for treatment and prevention of bleeding arising from congenital and acquired FXIII deficiencies. Basic research is providing novel therapeutic avenues of intervention in bleeding disorders; from applied research, the future could lead to new methods of economical protein production and reduced cost to patients.