High affinity binding of heparin by necrotic tumour cells neutralises anticoagulant activity - Implications for cancer related thromboembolism and heparin therapy

We have observed a striking neutralisation of the anticoagulant activity of unfractionated heparin in the presence of a pancreatic carcinoma cell line (MIA PaCa-2) due to binding of around 9 mug of heparin per 10(7) cells (ap parent Kd, 30 nM). The loss of anticoagulant activity was less marked in th e presence of low molecular weight forms of hepa-rin. Binding to the cell b locked acceleration of the thrombin: antithrombin interaction by heparin. N eutralisation of heparin activity was also shown to occur in the presence o f a number of other tumour cell lines. FACS analysis demonstrated that live cells did not bind heparin and high affinity binding only occurred to dead MIA PaCa-2 cells. Heparin binding proteins accumulating in cell medium wer e identified as histone and ribosomal proteins that will become exposed dur ing necrosis. The release of these proteins from cells within the necrotic core of a tumour or from cells killed during chemotherapy may abrogate the heparan sulphate/antithrombin system and possibly contribute to the idiopat hic thromboembolism often associated with cancer (Trousseau's syndrome). Th e findings also suggest a reason for the reported advantage of LMWH over UF H in treating venous thromboembolism in cancer patients and in improving pa tient survival.