Blood clots may cause heart attacks, strokes, pulmonary emboli and venous thrombosis. They contribute to mortality and morbidity in septic shock, acute trauma injury and complications of diabetes. Our laboratory primarily studied blood clotting and its relationship to inflammation.

We sought to identify factors regulating blood clotting and determine their function. We also investigated clotting protein defects in human disease, clotting protein function in animal models of human disease, structures of clotting proteins and complexes by crystallographic and biophysical techniques, relationships between coagulation and inflammation and regulation of clotting genes.

Proteins of the protein C anticoagulant pathway protect against septic shock, and we investigated activated protein C (APC) protection from lethal effects of Escherichia coli infusion in nonhuman primates. APC blocked E. coli induced coagulation, facilitated clot lysis and limited cytokine elaboration, presenting itself as a candidate for treatment of severe sepsis. A phase III trial conducted by Eli Lilly confirmed that APC effectively treats sepsis and it is now marketed as Xigris. These results provide impetus to establish the numerous mechanisms of APC function. We identified the endothelial protein C receptor (EPCR) and are investigating its function. Blocking receptor function increases sensitivity to bacterial infusion, blood clotting, inflammation and vascular degeneration. We showed that this is partly due to EPCR’s contribution to protein C activation, as hypercoagulation correlating with septic shock lethality occurred in mice lacking the EPCR gene. Mutations to block specific EPCR-functions are in progress.

Structures of clotting proteins and complexes must be solved to fully understand clotting regulation and potential therapies. We solved the crystal structure of EPCR bound to a portion of protein C, showing a requirement for a bound lipid. EPCR deficient mice develop anti-phospholipid antibodies that inhibit activated protein C anticoagulation. We suspect that this contributes to abnormal blood clotting in patients with these antibodies.

Blood vessel injuries, such as in angioplasty, cause cell proliferation and narrowing of vessel diameter and necessitate additional procedures. We found that modulating the protein C pathway in mice decreases vascular damage, suggesting this as a therapy.

My Publications