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Increased thrombin generation in a mouse model of cancer cachexia is partially interleukin‐6 dependent
Author(s) -
Reddel C. J.,
Allen J. D.,
Ehteda A.,
Taylor R.,
Chen V. M. Y.,
Curnow J. L.,
Kritharides L.,
Robertson G.
Publication year - 2017
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.13612
Subject(s) - medicine , cancer , cachexia , fibrinogen , coagulation , thrombin , platelet , fibrin , cancer research , tissue factor , hemostasis , tissue factor pathway inhibitor , cancer cell , immunology , platelet activation , endocrinology
Essentials Cancer cachexia and cancer‐associated thrombosis have not previously been mechanistically linked. We assessed thrombin generation and coagulation parameters in cachectic C26 tumor‐bearing mice. C26 mice are hypercoagulable, partially corrected by blocking tumor derived interleukin‐6. Coagulability and anti‐inflammatory interventions may be clinically important in cancer cachexia.Summary Background Cancer cachexia and cancer‐associated thrombosis are potentially fatal outcomes of advanced cancer, which have not previously been mechanistically linked. The colon 26 (C26) carcinoma is a well‐established mouse model of complications of advanced cancer cachexia, partially dependent on high levels of interleukin‐6 ( IL ‐6) produced by the tumor. Objectives To assess if cancer cachexia altered the coagulation state and if this was attributable to tumor IL ‐6 production. Methods In male BALB /c* DBA 2 (F1 hybrid) mice with a C26 tumor we used modified calibrated automated thrombogram and fibrin generation (based on overall hemostatic potential) assays to assess the functional coagulation state, and also examined fibrinogen, erythrocyte sedimentation rate ( ESR ), platelet count, tissue factor pathway inhibitor ( TFPI ) and hepatic expression of coagulation factors by microarray. C26 mice were compared with non‐cachectic NC 26, pair‐fed and sham control mice. IL ‐6 expression in C26 cells was knocked down by lentiviral sh RNA constructs. Results C26 mice with significant weight loss and highly elevated IL ‐6 had elevated thrombin generation, fibrinogen, ESR , platelets and TFPI compared with all control groups. Fibrin generation was elevated compared with pair‐fed and sham controls but not compared with NC 26 tumor mice. Hepatic expression of coagulation factors and fibrinolytic inhibitors was increased. Silencing IL ‐6 in the tumor significantly, but incompletely, attenuated the increased thrombin generation, fibrinogen and TFPI . Conclusions Cachectic C26 tumor‐bearing mice are in a hypercoagulable state, which is partly attributable to IL ‐6 release by the tumor. The findings support the importance of the coagulation state in cancer cachexia and the clinical utility of anti‐inflammatory interventions.