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 thrombosis or hemorrhage.
At the medical plenary “Rethinking Events in the Hemostatic Process: Role of Factor V and TFPI,” held during the WFH 2016 World Congress, Rodney Camire of the Children’s Hospital of Philadelphia, U.S.A., explained that a number of inhibitors acting on factor Xa generated through the intrinsic and extrinsic clotting pathways, and on prothrombinase itself, all impact the regulation of thrombin. “By dampening inhibitors you can control thrombin,” he said.
Sharing his expertise with hundreds of attendees, Camire explained, “FV is very similar to FVIII in some ways and needs to be processed at specific sites.” FV however, he elaborated, is a procofactor requiring proteolytic activation including the removal of the B domain. He pointed out that an important step in thrombin generation is the activation of FV to FVa. One role of this B domain is widely believed to be to block FV procofactor activity.
Camire and his research team investigated how two regions of the B domain, the basic region (BR) and the acidic region (AR2), contribute to keeping the molecule in this inactive state. However, they found that there is a discrete segment of the B domain that serves an essential autoinhibitory function, maintaining FV as a procofactor. “Dispensing with this region is the driving force to unveil a high affinity binding site for FXa,” he explained. Camire said that certain Australian snakes have a unique form of FV in their venom that lacks these inhibitory sequences, thereby creating an active procoagulant cofactor.
Tissue factor pathway inhibitor (TFPI) normally exists in two variant forms in the blood: TFPIα and TFPIβ. TFPI binds FV in plasma, but shows no affinity for FVa. “There are two to three different forms of FV that are generated during the initiation of coagulation that are sensitive to TFPIα,” said Camire.
Camire also said that new physiologic forms of FV have been reported. Citing research from East Texas (U.S.A.), he described a family of individuals with a moderately severe bleeding disorder that have a mutation in exon 13 of FV, which impacts the splicing of its transcript. The resulting form of FV essentially lacks the majority of the B domain, including the BR, but harbors the acidic region. Known as FV-short, this form of FV has been show to bind to TFPIα. These patients were shown to have 10 times the normal physiologic level of TFPIα. This, and other research, has given rise to the hypothesis that TFPIα alters the function of different forms of FV(a), which in turn impacts thrombin generation. This is currently a therapeutic target for hemophilia treatment.
Camire concluded that evidence suggests that blocking TFPI function and inhibition of FV activation may enhance coagulation. “Antibodies targeting TFPI are in clinical trials. Specific [FV] B domain sequences are key autoinhibitory elements responsible for keeping FV as a procofactor. Dismantling these sequences drives FV activation.”