Coagulation Corner

The most frequent reports on coagulant proteins and cancer interactions include tissue factor; TF TF-factor VIIa, factor Xa, factor IIa (thrombin)-factor II receptors (also called proease-activated receptors (PARs), and factor XIIIa-factor Ia (fibrin). TF and factor VIIa contribute to the extrinsic cascade and possibly to the development of cancer. Other factors from the intrinsic pathway, such as factors XI and XII, have not yet been directly implicated in cancer progression. Blood coagulation cascades can be activated by different mechanisms and to different levels in cancer patients. The alterations range from subtle abnormalities in laboratory tests to clinically overt thrombosis and disseminated intravascular coagulation. Up to 50% of all cancer patients and 90% of those with metastases exhibit hemostatic abnormalities. These abnormalities may be reflected in the dominance of the tumor cell-associated procoagulant pathway, which leads to thrombin generation and hypercoagulation. Similar observations were made using in vitro ovarian cancer cells for the coagulation process. Direct activation of blood coagulation by the induction of thrombin may occur through the activity of tumor cell procoagulation, whereas indirect activation may occur through the production of tumor-associated cytokines that trigger TF production by host macrophages (MAs). The coagulation pathway components may contribute to tumor cell proliferation, invasion, and metastasis  although these alterations could also be a consequence of advanced disease.

Tissue Factor (TF) is the cell surface receptor that activates coagulation by binding the serine protease coagulation factor VIIa (VIIa). The activation of the coagulation cascade leads to thrombin generation, fibrin formation and platelet activation which together may aide tumor growth and metastasis. TF is released from tumor cells by shedding or TF comes in contact with coagulation factors when tumor cells enter the blood stream, leading to a hypercoagulable state and its clinical manifestation of spontaneous thrombosis (Trousseau's Syndrome) that occurs in several types of cancer. This provides clear evidence that TF is a frequent marker of advanced cancer. Aberrant TF expression has been detected in various human tumors, including breast cancer but is not usually found in normal tissues from these sites. Elevated expression of TF in tumors has been associated with certain unfavorable prognostic indicators, such as angiogenesis, metastasis, advanced disease stage, and multidrug resistance

Treatment:

Some chemotherapeutic agents used for cancer may induce thrombosis but their biological alterations in the hemostatic system are not well understood. The main mechanisms of thrombogenesis associated with chemotherapeutic agents are: 1) The release of procoagulantsand cytokines from tumor cells damaged by the cell-targeted treatment; 2) A toxic effect directed towards vascular endotheli- In a cooperative group study of 433 breast cancer patients treated with adjuvant chemotherapy it was also to be about a 5% incidence of thromboembolic disease. It has also been reported a 17.6% incidence of thrombosis in159 patients receiving a five-drug chemotherapy regimen for stage IV (metastatic) breast cancer. 

Heparins are the most extensively used anticoagulants in clinics. In blood coagulation, unfractionated heparin and low-molecular-weight heparins potentiate the activity of antithrombin III, thus inhibiting the activation of coagulation factors II and X. They also release TFPI, a physiologic inhibitor of the TF pathway that prevents pulmonary embolism and is used to treat deep vein thrombosis. Retrospective and meta-analytic studies of deep vein thrombosis treatment have shown longer survival among cancer patients with thrombosis who were treated with unfractionated heparin and low-molecular-weight heparins than among patients treated without heparin. Thus, the use of anticoagulants might allow them to live longer.

Coagulation factors have a profound effect on tumor cell behavior in both in vivo and in vitro studies. These factors could enhance tumor cell proliferation, invasion, angiogenesis, and metastasis. Hence, targeting activated coagulation factors might provide a viable cancer treatment strategy.

Clinical Studies: