Jacob M. Kroh

It has been estimated that about two million people a year die from thrombosis either directly or indirectly. Thrombosis is also the second leading cause of death in cancer patients. Despite all of this, the underlying mechanisms of thrombosis remain poorly understood.  There are two distinct pathways that merge into a common pathway. The first step in the common pathway is then the activation of inactive prothrombin to active thrombin. Once thrombin is activated, it converts the soluble fibrinogen into insoluble fibrin and starts clot formation. Prothrombin must be activated by proteases for coagulation to proceed. The coagulation proteases are arginine-specific serine proteases. Any disturbance in this process can lead to aberrant clot formation within the blood vessel. This condition is called thrombosis. Citrullination is a post-translational modification of arginine residues carried out by a group of enzymes known as protein arginine deiminases (PADs). PADs convert the positively charged arginine into polar uncharged citrulline. Given that arginine residues play a crucial role in thrombin activation from inactive prothrombin; it stands to reason that the citrullination of prothrombin would alter its activation and activity. However, how citrullination impacts these processes remains unclear. Our hypothesis, therefore, is that citrullination of prothrombin will have a negative effect on the activation of thrombin. This in turn would affect clot formation. Consequently, since thrombin is required to activate processes downstream, we reason that a lowered local thrombin concentration ought to result in less effective clot formation. Our work will result in a better understanding of the coagulation cascade by contributing valuable knowledge on how modified prothrombin effects clot formation