The conversion of fibrinogen to fibrin: A brief history of some key events.

The conversion of fibrinogen to fibrin is a process that has long fascinated an army of researchers. In this brief review some early break-through observations are noted and a few later unexpected results described.

Taking the thrombin "fork".

The proverb that probably best exemplifies my career in research is attributable to Yogi Berra (http://www.yogiberra.com/), ie, "when you come to a fork in the road ... take it." My career is a consequence of chance interactions with great mentors and talented students and the opportunities provided by a succession of ground-breaking improvements in technology.

Bovine thrombin: history, use, and risk in the surgical patient.

Thrombin is a common hemostatic drug used in surgical practice for over 100 years because of its simplicity and efficacy. Thrombin converts fibrinogen to fibrin, activates platelets, and induces vascular contraction. It is available in multiple forms, including human thrombin, bovine thrombin, and, most recently, human recombinant thrombin. Over 100 case reports of adverse reactions to bovine thrombin include hemorrhage, thrombosis, and substantial immune reaction when used on cardiovascular surgery patients. Approximately 30% of patients exposed to bovine thrombin develop cross-reacting antibodies. Thirty percent of patients with anticlotting factor antibodies develop abnormal coagulation that can be detected by prothrombin time, partial thromboplastin time, or thrombin time, which makes anticoagulation monitoring difficult. Patients with multiple elevated antibodies prior to surgery are also more likely to sustain adverse events. Animal studies confirm these immunological responses seen in humans. With the available clinical and laboratory data, a less immunogenic yet biologically effective thrombin should be available for use in our surgical patients.

Recollections on thrombin generation.

Against an autobiographic background, a historical sketch is given of the development of the technique of thrombin generation, from subsampling to duly calibrated continuous measurement with fluorogenic substrates. Its application to various problems in the pathophysiology of hemostasis and thrombosis is discussed.

Historical perspective of the development of thrombin inhibitors.

Progress in molecular biology has stimulated interest in the structure and function of thrombin. It has improved our understanding of its central role in thrombogenesis and has clarified the molecular events of inhibitor binding. This development has resulted in the production of recombinant hirudins and hirudin analogues. It has also allowed the molecular design of synthetic antithrombins, and encouraged the development of these products for clinical use. All pharmacological aspects speak in favor of the use of direct thrombin inhibitors as antithrombotic agents, especially in the potential indications where thrombin plays a crucial pathogenetic role. If their apparent advantages compared with heparin can be definitely demonstrated, the direct thrombin inhibitors may become the drug of choice for certain indications.