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Recombinant biologics for treatment of bleeding disorders

Key Points

  • 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 cause considerable morbidity and mortality in the industrialized world, as shown by the more than 2 million patients who received treatment for serious blood loss in 2002. Historically, these disorders have been treated with products derived from human plasma or animal sources. With the advent of recombinant technologies, new products have been developed that are generally perceived as safer and which have well-defined specificity of action and potency. Recombinant biologics have also provided some unforeseen benefits, yielding new insights into the mechanism of haemostasis as well as novel pharmacological strategies.

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Figure 1: Estimates of patients treated for major bleeding events and haemophilia prophylaxis in the industrialized world (2002).
Figure 2: The key enzymatic and cellular events leading to clot formation.
Figure 3: Enzymatic relationships within the coagulation pathway.


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Special thanks to D. Adler, D. Irwin, K. Lewis, G. McKnight, B. Wetzel and A. Yeomans (ZymoGenetics Inc.) for their assistance with this manuscript; and A. Thompson (Puget Sound Blood Center) for his discussions on blood-blanking issues.

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P. B. is currently an employee of ZymoGenetics, which is developing recombinant thrombin and factor XIII as discussed in the text.

Related links

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Entrez Gene

α2-plasmin inhibitor









tissue factor


thrombin-activated fibrinolysis inhibitor

type-2 plasminogen-activator inhibitor


Online Mendelian Inheritance in Man

Haemophilia A

Haemophilia B



American Hemotology Association

American Association of Blood Banks

Blood Centers of the Pacific

International Society for Fibrinolysis and Proteolysis

International Fibrinogen Research Society

The International Society on Thrombosis and Haemostasis

World Blood Supply (

World Federation of Hemophilia



A collection of blood within soft tissue that results in swelling (tumour).


A disorder that prevents normal clotting of the blood.


'Iatros' means physician in Greek, and '-genic', means induced by. An iatrogenic disease is a disease that is caused by a physician.


A condition in which the patient is more prone to bleeding than normal.


Tenase is the complex of the cofactor factor VIIIa (FVIIIa) and the enzyme FIXa assembled on a membrane surface. The function of this multi-enzyme complex is to proteolytically activate FX (to FXa).


Prothrombinase is the complex of the cofactor factor Va (FVa) and the enzyme FXa assembled on a membrane surface. The function of this multi-enzyme complex is to proteolytically activate prothrombin (FII) to a-thrombin (FIIa).

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Bishop, P., Lawson, J. Recombinant biologics for treatment of bleeding disorders. Nat Rev Drug Discov 3, 684–694 (2004).

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