The polyphosphate-factor XII pathway drives coagulation in prostate cancer-associated thrombosis
2015 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 11, 1379-1389 p.Article in journal (Refereed) Published
Cancer is a leading cause of thrombosis. We identify a new procoagulant mechanism that contributes to thromboembolism in prostate cancer and allows for safe anticoagulation therapy development. Prostate cancer-mediated procoagulant activity was reduced in plasma in the absence of factor XII or its substrate of the intrinsic coagulation pathway factor XI. Prostate cancer cells and secreted prostasomes expose long chain polyphosphate on their surface that colocalized with active factor XII and initiated coagulation in a factor XII-dependent manner. Polyphosphate content correlated with the procoagulant activity of prostasomes. Inherited deficiency in factor XI or XII or high-molecular-weight kininogen, but not plasma kallikrein, protected mice from prostasome-induced lethal pulmonary embolism. Targeting polyphosphate or factor XII conferred resistance to prostate cancer-driven thrombosis in mice, without increasing bleeding. Inhibition of factor XII with recombinant 3F7 antibody reduced the increased prostasome-mediated procoagulant activity in patient plasma. The data illustrate a critical role for polyphosphate/factor XII-triggered coagulation in prostate cancer-associated thrombosis with implications for anticoagulation without therapy-associated bleeding in malignancies.
Place, publisher, year, edition, pages
2015. Vol. 126, no 11, 1379-1389 p.
Cardiac and Cardiovascular Systems Cancer and Oncology
IdentifiersURN: urn:nbn:se:uu:diva-267337DOI: 10.1182/blood-2015-01-622811ISI: 000363479500019PubMedID: 26153520OAI: oai:DiVA.org:uu-267337DiVA: diva2:873619
FunderSwedish Cancer Society, 100615Swedish Research Council, K2013-65X-21462-014-5Swedish Heart Lung Foundation, 20140741Stockholm County Council, 20140464German Research Foundation (DFG), SFB877German Research Foundation (DFG), SFB841EU, European Research Council, ERC-StG-2012-311575_F-12