The polyphosphate-factor XII pathway drives coagulation in prostate cancer-associated thrombosis
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The polyphosphate-factor XII pathway drives coagulation in prostate cancer-associated thrombosis. / Nickel, Katrin F; Ronquist, Göran; Langer, Florian; Labberton, Linda; Fuchs, Tobias A; Bokemeyer, Carsten; Sauter, Guido; Graefen, Markus; Mackman, Nigel; Stavrou, Evi X; Ronquist, Gunnar; Renné, Thomas.
In: BLOOD, Vol. 126, No. 11, 10.09.2015, p. 1379-89.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - The polyphosphate-factor XII pathway drives coagulation in prostate cancer-associated thrombosis
AU - Nickel, Katrin F
AU - Ronquist, Göran
AU - Langer, Florian
AU - Labberton, Linda
AU - Fuchs, Tobias A
AU - Bokemeyer, Carsten
AU - Sauter, Guido
AU - Graefen, Markus
AU - Mackman, Nigel
AU - Stavrou, Evi X
AU - Ronquist, Gunnar
AU - Renné, Thomas
PY - 2015/9/10
Y1 - 2015/9/10
N2 - 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.
AB - 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.
U2 - 10.1182/blood-2015-01-622811
DO - 10.1182/blood-2015-01-622811
M3 - SCORING: Journal article
C2 - 26153520
VL - 126
SP - 1379
EP - 1389
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 11
ER -
