COAGULATION RESEARCH

Although the outer lining of LVADs is designed to mimic the natural endothelium, implantation of the device nevertheless causes activation of the body's coagulation pathways, frequently leading to serious bleeding episodes, thrombosis, and stroke. Researchers believe that immediately after bypass, the device stimulates intravascular coagulation: "Naturally protective clotting factors are rapidly consumed, and this creates an imbalance," describes Anne Marie Schmidt, MD. To date, physicians have wrestled with the question of whether to prescribe anticoagulant drugs (heparin or coumadin) to LVAD patients, weighing their presumed benefits against the risks of consumptive coagulation.

In SCCOR's coagulation project, investigators are seeking to develop an optimal anticoagulant that can both reduce thrombosis at the time of device implantation and prevent late bleeding events. Such a targeted agent would maintain intravascular anticoagulation while reducing extravascular bleeding by selectively blocking only the intrinsic pathway of the coagulation cascade.

Dr. Schmidt and colleagues have already proven that this goal can be achieved by selectively blocking Factor IX in the procoagulant pathway. The molecule they developed, Factor IXai, worked extremely well in earlier patient trials. Because Factor IXai is a large molecule, however, development as a clinical agent is too complex and expensive to permit competition with cheaper agents such as heparin. Another option had to be found.

With continued collaboration with Dr. Schmidt's laboratory, Transtech Pharma then turned to the development of a small molecule inhibitor of Factor IX. The resulting product, called 889, has proven successful in phase 1 human trials. Like the large Factor IXai molecule that preceded it, this smaller version selectively blocks Factor IX in the clotting cascade while leaving Factor X unaffected. Moreover, 889 is inexpensive to produce and is even orally bioavailable.

"In the SCCOR protocol, we will test the hypothesis that blocking Factor IX will reduce the process of consumptive coagulopathy," says Dr. Schmidt. "This will be studied first in large animals, then in humans including in patients with VADs."

Different LVADs may activate clotting to different degrees, according to Dr. Schmidt; evidence suggests that the Thoratec device may not activate clotting because of its particular endothelial-like surface. The choice of which device to employ during the study will be made based on further investigation into this issue.