Molecular Haemostasis

Introduction

Blood coagulation is an important host defense mechanism to prevent bleeding after injury. However, this system is also involved in obstruction of vessels with a clot: thrombosis. In our group, we investigate the blood coagulation mechanism to better understand the events that lead to bleeding or thrombosis, and to identify (novel) agents that can be used for pro-hemostatic or anti-thrombotic therapy.


The contact system, by Joost Meijers, Sanquin

Fig.1 The contact system is a direct link between inflammation and coagulation. Activation of factor XII induces factor XI activation and this will ultimately lead to thrombin formation. Factor XII can be activated via negatively charged substances like polyphosphates, RNA and neutrophil extracellular traps (NETs). Activated factor XII can also cleave plasma prekallikrein (PK) into kallikrein (Kal), which on its turn releases several vasoactive substances like bradykinin. At the same time, plasma kallikrein produces additional factor XIIa. Prekallikrein and factor XI are both bound to high molecular weight kininogen (HK) in plasma. Indicated alongside of the coagulation factors are the various types of inhibitor (antisense oligonucleotides, antibodies, small molecule inhibitors and naturally occurring inhibitors).

In our research, we have identified the components of the intrinsic pathway and especially the contact system as optimal targets for antithrombotic therapy. With the use of antibodies and antisense technology, we could show effective anticoagulation without the bleeding risk that accompanies currently used anticoagulants. These studies are currently expanded to determine if this strategy is also effective and safe in thrombosis on atherosclerotic vessels.

Medical needs:

Bleeding and Hemostasis

Funding:

  • Co-development/Contract Research
  • Okklo: procoagulant cyclodextrins
  • PPOP, internal funding (in competition)
  • PPOC, internal funding (in competition)

Our research