Thrombin Biology in the 21st Century

In September of 2005, some of the world's leading experts on thrombin biology met to discuss and broaden the current information available on thrombin and its role in hemostasis, inflammation, aberrations in coagulation, and cancer. One of the reasons for convening the symposium is that there is a real need to think about thrombin in a much broader context than merely as a local topical hemostat, and the articles in this supplement provide a platform from which to do this.

The program was divided into three segments: the biochemistry of thrombin, the role of thrombin in inflammation and cancer, and the role of thrombin in the treatment of coagulopathies. Dr. Earl Davie, from the University of Washington (Seattle, WA), presented the overview of thrombin structure and function. Thrombin is the central enzyme in vertebrate biology involved in blood coagulation and platelet aggregation. It has been known to stimulate the secretion of mitogens in a variety of cell types. Exosites, in addition to the catalytic site in the thrombin molecule, act specifically with substrates and cofactors, distinguishing it from relatively nonspecific serine proteases such as trypsin. Dr. Wolfram Bode, from the Max Planck Institute of Biochemistry, Martinsried, Germany, described the extended recognition sites on thrombin's surface, which reflect its versatility and multifunctional specificity. He illustrated the presentation with a large number of crystal structures of thrombin bound to synthetic and protein inhibitors, substrate fragments, cofactors, and carbohydrates. Dr. Harold Roberts, from the University of North Carolina (Chapel Hill, NC), discussed a cell-based model he developed to generate thrombin using activated monocytes as a source of tissue factor and the activated platelet surface to anchor coagulation proteins.

The second part of the symposium, dealing with the role of thrombin in inflammation and cancer, was opened by Dr. Nigel Bunnett, from the University of California (San Francisco, CA). Dr. Bunnett focused on protease-activated receptors that are often generated and secreted during injury and inflammation. These receptors orchestrate tissue responses to insults, including hemostasis, inflammation, nociception, and repair mechanisms on binding to serine proteases such as thrombin. Dr. Charles T. Esmon, from the Oklahoma Medical Research Foundation (Oklahoma City, OK), focused on the activated protein C anticoagulant pathway in inflammation. This pathway is critical to both regulation of blood coagulation and control of the innate inflammatory response. Dr. Wolfram Ruf, from the Scripps Research Institute and the La Jolla Institute for Molecular Medicine (San Diego, CA), addressed hypercoagulable states triggered by tissue factor and the role of thrombin in cancer. Thrombin generation leading to fibrin generation and platelet deposition is initiated by tissue factor. It is critical for metastasis and signaling by thrombin-dependent protease-activated receptor-1. Dr. Thomas Möller, from the University of Washington (Seattle, WA), discussed the activation of microglial cells by thrombin. Dr. Möller showed that pure thrombin preparations produce a limited profile of microglia activation, triggering only intracellular calcium signals and small changes in surface antigen expression, contrary to previously published reports.

The final portion of the symposium dealt with the biology of thrombin in the treatment of coagulopathies. Dr. Ulla Hedner, from Lund University (Malmo, Sweden), and Novo Nordisk (Denmark), began this session with a discussion of the mechanism of factor VIIa (FVIIa) in the treatment of bleeding in patients with hemophilia. These patients have inhibitors against FVIII or FIX. Dr. Hedner introduced the use of pharmacologic doses of rFVIIa to induce hemostasis not only in hemophilia patients, but also in patients with thrombocytopenia, platelet defects, and with profuse bleeding triggered by extensive surgery or trauma. Dr. Paul Bishop from Zymogenetics, Inc. (Seattle, WA), the sponsor of this symposium, discussed the synthesis of recombinant human thrombin and compared it with plasma-derived thrombin in terms of its composition, primary, secondary, and tertiary structure, enzymatic activity, and in vivo pharmacology. Dr. Jeffrey Lawson, from Duke University (Durham, NC), concluded the session with a discussion of the clinical use of thrombin in surgery. Its ease of use and effectiveness have made it routine for topical hemostasis in nearly all types of surgical procedures. The use of bovine thrombin, the only preparation currently approved for clinical use, however, causes an array of adverse clinical events resulting from the development of antibodies against thrombin, prothrombin, FV, and cardiolipin.

It has been our pleasure to participate in this conference and serve as guest editors of this publication. We believe the knowledge, experience, and expertise with thrombin brought to light by the prominent faculty at this symposium will help bring a safer thrombin to the medical community.