Elevated TFPI in malignant disease: relation to cancer type and hypercoagulation

Abstract

Summary.We have previously reported high levels of the coagulation inhibitor TFPI in the blood of patients with gastrointestinal cancer. TFPI is not an acute-phase reactant, but high levels have also been reported in patients with septicaemia and disseminated intravascular coagulation (DIC). To study its relationship with other types of malignancy, TFPI activity was first determined in plasma samples from 214 patients with various malignancies. In a second cohort of 83 patients, total and free TFPI antigen, protein C, antithrombin, fibrin monomer and D-dimer were also measured. Elevated TFPI activity and antigens were found in about half of the patients with solid tumours. In contrast, elevated TFPI was rare in haematological malignancies (12%). In the 18 patients with acute nonlymphocytic leukaemia (ANLL), elevated free TFPI was found only in patients who also had DIC. No correlation was found between TFPI levels and fibrin monomer or D-dimer levels. Only four out of 20 patients with solid tumours had normal levels of fibrin monomer and D-dimer, yet three out of these four had elevated TFPI. In conclusion, elevated TFPI in ANLL is related to the coexistence of DIC. In solid tumour disease increased TFPI may reduce protective fibrin formation, but the pathogenic mechanism is as yet unknown.

Discovery and analysis of hepatocellular carcinoma genes using cDNA microarrays

“…Stimulation of the membrane glycoprotein LAMP2 suggests that this adhesive glycoprotein may promote tumor invasion and metastasis in hepatocarcinoma patients (Sarafian et al 1998). The tissue factor pathway inhibitor TFPI, which inhibits the extrinsic coagulation system, was activated in liver cancer patients and may reduce fibrin formation (Iversen et al 1998). Inactivation or repression of one or more of these products by drug intervention may slow the progression of hepatic cancer.…”

The Thrombophilic State in Cancer Patients

“…It could be a consequence of the hypercoagulability in cancer patients, since thrombin induces a redistribution and acute release of TFPI in vitro as well as in vivo in animals [22, 23]. However, Iversen et al [24]failed to demonstrate any correlation between TFPI and the markers of activated coagulation in patients with solid tumors. For these authors the high TFPI levels would have a deleterious effect by inhibiting fibrin formation which is produced as a defense mechanism against tumor invasion.…”

Heparanase and Coagulation–New Insights

“…Concentration of TFPI in plasma is increased in patients with acute myocardial infarction 21,22. There are also reports on increased plasma levels of TFPI in relation to diabetes mellitus,23 renal diseases,24 and cancer 25,26. Recently we demonstrated that exogenous addition or over-expression of heparanase by transfected cells resulted in release of TFPI from the cell surface and its accumulation in the cell culture medium 27.…”

“…Importantly, the in vitro studies were supported by elevation of TFPI levels in the plasma of transgenic mice over-expressing heparanase. Moreover, increased levels of TFPI have been noted in the plasma of cancer patients,25,26 reflecting, possibly, induction of heparanase expression and elevation of its plasma levels revealed by ELISA assay 28. In human umbilical vein endothelial cell (HUVEC) and tumor-derived cell lines, release of TFPI from the cell surface correlated with enhanced TF-mediated coagulation.…”