oa Implication of Protein-C in Thrombophilic State and Metastatic Dissemination

The coagulation/fibrinolytic system controls the intravascular fibrin homeostasis; in addition to participating in a wide variety of physio-pathological processes. The components of the system have an influence on tumor metastasis, growth and invasion. This is a result of their involvement in tumor matrix construction, angiogenesis and cell migration.

Thrombosis of unexplained etiology among healthy and cancer patients; is a major cause of death. Several homeostatic markers are currently used to predict the advent of thrombosis. However, none of these markers directly indicate the course and progression of the disease; thus thrombosis remains unexplained.

Endothelial Protein C Receptor EPCR gene carries 13 single nucleotide polymorphisms, which define 3 haplotypes: A1, A2 and A3. One of these, A3, encodes a protein, which is more sensitive than the other two in shedding enzymes. High levels of protein C are determined by PROCR haplotype 3. A3 haplotype reflects a high soluble Endothelial Protein C Receptor (sEPCR) level. Therfore, it is a candidate risk factor for venous thrombosis. We observed that the plasma concentration of sEPCR in cancer patients was much higher than that observed in controls. We suggest that sEPCR released from malignant cells could serve as a “trap” for protein C, preventing it's binding to EPCR on the surface of endothelial cells and induced thrombotic state.

We developed a method, based on activated Partial Thromboplastin Time, in order to analyze the ability of (EPCR) on the cancer cell membrane to trap circulating Activated Protein C (APC). This test is in conjunction with other specific tests used for assessing thrombotic state, such as the one to quantitate soluble fibrin and d-dimer.

Previous study of lung cancer patients, done by Department of Pathology, Free University Medical Center 2002, revealed a marked association between high EPCR levels; and poor survival or relapse in patients with stage I lung adenocarcinoma. The aim of our study is to investigate the role of sEPCR as a cause of thrombotic disorder, among cancer patients. Furthermore, to detect whether EPCR of cancer cells is haplotype 3, that affect on the level of sEPCR.