Alternative Complement Pathway Activation Provokes a Hypercoagulable State with Diminished Fibrinolysis.

Jason M Samuels, Julia R Coleman, Ernest E Moore, Matt Bartley, Navin Vigneshwar, Mitchell Cohen, Christopher C Silliman, Angela Sauaia, Anirban Banerjee

Shock (Augusta, Ga.) 2020 May

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Several disease processes trigger prolonged activation of the alternative complement pathway. Crosslinks between complement activation and physiologic changes in platelets and neutrophils have been identified, but how this interplay alters the hemostatic potential in humans remains undefined. We hypothesize that activation of the alternative pathway triggers a hypercoagulable state. C3/C5 convertase Cobra Venom Factor (CVF, 10 Units/mL) was employed to activate the alternative complement pathway in whole blood. Complement inhibition was completed with inhibitors for C3/C3b (Compstatin, 25 and 50 μM), C3a receptor (SB290157, 300 nM, C3aR), and C5a receptor (W54011, 6 nM, C5aR). Coagulation was assessed using native thrombelastography which produces the following: reaction time (R time); angle; maximum amplitude (MA); percent fibrinolysis at 30-min post-MA (LY30). Inhibition with C3aR and C5aR inhibitors did not alter clot formation (R time, 11.2 vs 11.6 min, P = 0.36), clot strength (MA, 52.0 vs 52.3 mm, P = 0.43), or fibrinolysis (LY30, 1.6 vs 4.0%, P = 0.19). Compstatin did not influence clot formation or clot strength but did induce a dose-dependent increase in fibrinolysis (control LY30 3.0 vs 7.8% and 12.4% for 25 and 50 μM respectively, P = 0.0002). CVF increased MA (58.0 vs 62.8 mm, P < 0.0001), decreased LY30 (2.3 vs 1.4%, P = 0.004), and increased R time (8.4 vs 9.9 min, P = 0.008). Compstatin reversed the effects of CVF, while C5a reversed only the change in LY30. C3 contributes to fibrinolysis, as inhibition with Compstatin enhanced fibrinolysis, and CVF cleavage of C3 decreased fibrinolysis. CVF also induced a hypercoagulable state with increased clot strength.

Citation

Jason M Samuels, Julia R Coleman, Ernest E Moore, Matt Bartley, Navin Vigneshwar, Mitchell Cohen, Christopher C Silliman, Angela Sauaia, Anirban Banerjee. Alternative Complement Pathway Activation Provokes a Hypercoagulable State with Diminished Fibrinolysis. Shock (Augusta, Ga.). 2020 May;53(5):560-565