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 microg of heparin per 10(7) cells (apparent Kd, 30 nM). The loss of anticoagulant activity was less marked in the presence of low molecular weight forms of heparin. Binding to the cell blocked acceleration of the thrombin:antithrombin interaction by heparin. Neutralisation of heparin activity was also shown to occur in the presence of 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 were identified as histone and ribosomal proteins that will become exposed during 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 idiopathic thromboembolism often associated with cancer (Trousseau's syndrome). The findings also suggest a reason for the reported advantage of LMWH over UFH in treating venous thromboembolism in cancer patients and in improving patient survival.
Morita
S
S
Thrombosis Research Institute, London, UK.
Gebska
M A
MA
Kakkar
A K
AK
Scully
M F
MF
D000327:Adsorption; D000990:Antithrombin III / Q000187:drug effects; D005434:Flow Cytometry; D006493:Heparin / Q000378:metabolism / Q000493:pharmacokinetics*; D006495:Heparin, Low-Molecular-Weight / Q000378:metabolism / Q000493:pharmacokinetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D009336:Necrosis; D009369:Neoplasms / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D010447:Peptide Hydrolases / Q000097:blood / Q000187:drug effects; D011485:Protein Binding; D012269:Ribosomal Proteins / Q000378:metabolism; D013923:Thromboembolism / Q000209:etiology; D014407:Tumor Cells, Cultured
D006495:Heparin, Low-Molecular-Weight; D006657:Histones; D012269:Ribosomal Proteins; C046193:antithrombin III-protease complex; D000990:Antithrombin III; D006493:Heparin; D010447:Peptide Hydrolases