Abstract:
: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.
journal_name
Bloodjournal_title
Bloodauthors
Nickel KF,Ronquist G,Langer F,Labberton L,Fuchs TA,Bokemeyer C,Sauter G,Graefen M,Mackman N,Stavrou EX,Ronquist G,Renné Tdoi
10.1182/blood-2015-01-622811subject
Has Abstractpub_date
2015-09-10 00:00:00pages
1379-89issue
11eissn
0006-4971issn
1528-0020pii
blood-2015-01-622811journal_volume
126pub_type
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