Thrombosis Prevention without Anticoagulation.

Abstract

The ultimate goal for hematologists, cardiologists, and vascular medicine physicians is to find agents that prevent thrombosis without creating defects in hemostasis (the cessation of bleeding). To a great extent, this notion was considered an impossible dream. However, recent advances in understanding of the plasma contact activation, kallikrein/kinin, renin angiotensin, and other vasoregulatory systems make these dreams seem feasible. Presently, all anticoagulants prevent thrombosis by interfering with hemostasis. Physicians in clinical medicine are presently excited with the recent approvals by national regulatory agencies of several target-specific oral anticoagulants (TSOACs). These agents make the lives of patients who need anticoagulants much easier. However, the targets of the TSOACs, factors IIa and Xa, still increase bleeding risk. In fact, some of these agents are associated with specific organ sensitivity to bleeding not seen with warfarin or heparin-derived agents. Furthermore, although in late development, antidotes to these agents are not present and bleeding such as into the brain can be catastrophic. We can do better than the current array of agents in practice and about to be approved for clinical practice for thrombosis protection. In recent years, investigators have learned that many proteins influence thrombosis risk without altering the hemostatic system. For example, proteins like heme oxygenase, C-reactive protein, glutathione peroxidase-3 deficiency, peptidylarginine deiminase 4, and myeloid-related protein-14 (S100A9) alter arterial or venous thrombosis propensity in mice without influence on hemostasis (1–5). Additionally, there are several targets in the contact activation (CAS), kallikrein/kinin (KKS), and renin angiotensin (RAS) systems that influence thrombosis without causing bleeding. Better understanding of the mechanism(s) by which these proteins influence venous and arterial thrombosis may very well allow for additional targets to be recognized for the development of safer therapies. The next frontier in drug development to prevent or treat thrombosis is to translate the mechanistic observations on proteins that alter thrombosis risk without bleeding into therapeutic agents.