© 2008 Schattauer GmbH, Stuttgart 805 Current use of biologicals in thrombosis and haemostasis Frederick A. Ofosu 1,2 , Trevor W. Barrowcliffe 3 1 Canadian Blood Services and 2 McMaster University, Hamilton, Ontario, Canada; 3 3 Boulby Bank, Whitby, UK Theme Issue Editorial Correspondence to: Prof. Frederick Ofosu, PhD Department of Pathology and Molecular Medicine McMaster University 1200 Main St W, HSC 3N26 Hamilton, Ontario, L8N 3Z5, Canada Tel.: +1 9055259140 22535, Fax: +1 905521 2613 E-mail: ofosuf@mcmaster.ca or Prof. Trevor W. Barrowcliffe, PhD 3 Boulby Bank Whitby YO22 4AN, UK Tel.: +44 1947 600963 E-mail: twbarrowcliffe@yahoo.co.uk Received March 31, 2008 Accepted March 31, 2008 Prepublished online April 9, 2008 doi:10.1160/TH08-04-0201 Thromb Haemost 2008; 99: 805–806 B iological medicines have been used to treat or prevent dis- ease for over a hundred years beginning with the develop- ment of effective vaccines, followed over time by the iso- lation of bovine and porcine insulins (1), porcine and bovine he- parins (2), large scale production of fractionated plasma prod- ucts (3), to the era of the manufacture of recombinant human pro- teins (4). Randomized control trials demonstrating the effective- ness of heparin and low-molecular-weight heparins for prevent- ing post-operative deep vein thrombosis, initiating the treatment of venous thrombosis, preventing or treating arterial thrombosis had become widespread by the late 1970s and 1980s (5–8). The 1970s and later periods also ushered in the prophylactic and therapeutic uses of manufactured plasma fractionation products approved for the effective management of haemophilia A (plas- ma-derived factor VIII concentrates of increasing purity) (9) and haemophilia B (prothrombin complex concentrates leading to the isolation of factor IX free of prothrombin, factor VII, or fac- tor X) (10), and a variety of topical haemostatic agents contain- ing human or bovine thrombin for accelerating haemostasis after some surgeries (11). Although the wide availability and clinical use of biological medicines have brought enormous benefits, severe adverse events can occur, as with any medicine. The most serious of these include bleeding and thrombocytopenia (heparin), development of product neutralizing antibodies (plasma-derived and recom- binant human factor VIII, factor IX, factor XI and other recom- binant therapeutic proteins) that can render the products thera- peutically ineffective (12–14), and the potential, however low, for pathogen transmission (by plasma products) (15, 16). A po- tentially deadly and unanticipated consequence of the wide- spread use of human plasma-derived clotting factor concentrates was their ability to infect patients with previously unknown human viruses, specifically human immunodeficiency virus (HIV) and hepatitis C in the early 1980s (15). The successful ap- plication of recombinant DNA technology to manufacture insu- lin (1) and human growth hormone (17) that had been approved for clinical use by the 1980s no doubt provided a strong stimulus for the successful development of recombinant human factor IX and factor VIII for clinical use (18). Around the same time more rigorous testing methods for plasmas destined for fractionation and new methods for pathogen reduction were implemented to reduce risk of virus transmission by plasma products (15, 16). Even more sensitive methods for detecting extremely low numbers of infectious agents in plasmas that are based on detect- ing DNA or RNA of infectious viruses of concern have since been introduced, and both plasma-derived and recombinant clot- ting factors and haemostatic agents are now subjected to addi- tional pathogen reduction steps prior to their release for clinical use (15, 16 ). The success of these pathogen reduction strategies is evident from the observation that no pathogen transmission by a manufactured plasma-derived or recombinant therapeutic pro- tein has been observed in North America since 1995 (15). The Theme Issue in this edition of Thrombosis and Haemo- stasis brings together investigators who are well versed in several aspects of the manufacture, characterization, standardization and specific clinical use of biological medicines to prevent or treat inherited or acquired disorders of haemostasis. As well as chapters on heparin (19), hirudin and its derivative bivalirudin (20, 21), plasma products (22), and recombinant clotting factors (23), we have included a chapter on recombinant haematopoietic growth factors. Although the latter are not usually considered as primary medicines for disorders of haemostasis, the salutary ex- periences with thrombopoietin illustrate some of the problems that can occur with this type of biological medicine, and we thought a general review might be of interest. The final chapter deals with a relatively common and occasionally serious side- effect of all therapeutic proteins (24), whether plasma-derived or recombinant, namely the induction of specific anti-therapeutic protein antibodies that may inactivate the therapeutic proteins. Current use of biologicals