New exciting aspect of the coagulation system

All the players in the coagulation system are known—or are they? Thrombin is a key enzyme in the system that controls clot formation; too much or too little can lead to either hemorrhage or thrombosis. At the medical plenary “Rethinking Events in the Hemostatic Process: Role of factor V and TFPI,” Rodney Camire, Philadelphia, Pennsylvania, USA, explained that extrinsic Xase, intrinsic Xase and prothrombinase are regulators of thrombin. “By dampening inhibitors you can control thrombin,” he said.

Camire shared his expertise with hundreds of attendees Monday morning. “FV is very similar to FVIII in some ways and needs to be processed at specific sites,” he said, pointing out however, that FV is a procofactor requiring proteolytic activation in the B domain. The role of the B domain is to keep the molecule active. By looking at sequences for the alignment of FV B domain, Camire and his research team experimented with how both the basic region (BR) and the acidic regions (AR) contribute to keeping the molecule active.

Camire stated that the FV BR fragment and FXa compete for FV-810 binding. There is a discrete segment of the B domain that serves an essential autoinhibitory function to maintain FV as a procofactor. “Disseminating this region is the driving force to unveil a high affinity binding site for FVa,” he explained.

He pointed out that an important step in thrombin generation is the activation of FV to FVa. Mr. Camire said that certain Australian snakes have a unique form of FV in their venom with these inhibitory sequences removed, thereby creating an active procoagulant cofactor.

Tissue factor pathway inhibitor (TFPI) naturally forms in the blood. TFPI binds FV in plasma, but shows no affinity to FVa. “There are two to three different forms of FVa that are generated during the initiation of coagulation that are sensitive to TFPI alpha (TFPIα),” said Camire.

Camire also said that there are new physiologic forms of FV. Citing research from east Texas (USA), individuals have been found that have a mutations in exon 13 of FV, which causes a spliced transcript. Thus, there are forms of FV that are B domainless, that lack the BR, but harbor in the acidic region. Known as FV short, this binds to TFPIα. These patients were shown to have 10 times the level of TFPIα. TFPIα via the BR can block FVa function. This is currently a therapeutic target for hemophilia treatment.

In summary he said blocking TFPI function will enhance coagulation. “Antibodies targeting TFPI are in clinical trials. Specific B domain sequences are key autoinhibitory elements responsible for keeping FV as a procofactor. Dismantling these sequences drives FV activation. These mutations change a weak splice site into a strong splice site.”




source: http://www.wfhcongressdaily.org/2016/07/new-exciting-aspect-of-the-coagulation-system/