Factor IX from prothrombin complex concentrate augments low dose tissue factor-triggered thrombin generation in vitro

Document Type

Journal Article

Publication Date

10-1-2018

Journal

British Journal of Anaesthesia

Volume

121

Issue

4

DOI

10.1016/j.bja.2018.05.063

Keywords

blood coagulation factors; coagulants; haemostasis; thrombin

Abstract

Background: Prothrombin complex concentrate (PCC) is increasingly used to correct acquired coagulopathy in trauma and surgery. Dosing of PCC is guided by the prothrombin time, which only reflects the onset of thrombin generation, but does not account for variations in intrinsic pathway coagulation factors, including factor IX (FIX). We hypothesised that FIX contained in PCC could strongly influence thrombin generation patterns. Methods: Pooled normal, FIX-deficient, and warfarinised plasma were used to analyse the effects of FIX contained in PCC. PCC was evaluated at final concentrations of 0.2 and 0.4 IU ml−1 in FIX-deficient and normal plasma, and at 0.6 IU ml−1 in warfarinised plasma with elevated FVIII (1.5 IU ml−1), 40% dilution with saline, or both. The effects on thrombin generation were assessed by measuring both procoagulant and inhibitory segments. Results: FIX-deficient plasma had lower peak thrombin generation [30.6 (20.5–35.8) nM vs 130.2 (107–168) nM] and endogenous thrombin potential [472 (391–532) nM vs 1096 (958–1190) nM] than normal plasma. PCC addition resulted in significant increases of peak thrombin generation [81.8 (37.3–98.3) nM] and endogenous thrombin potential [808 (472–842) nM] in FIX-deficient plasma. The combination of FVIII and PCC resulted in greater increases relative to each agent alone, restoring normal thrombin generation. After 40% dilution, adding PCC, FVIII, or both, to FIX-deficient plasma increased peak thrombin generation, and prolonged the inhibitory phase of the endogenous thrombin potential. Conclusions: FIX derived from PCC strongly enhances tissue factor-triggered thrombin generation in the presence of elevated FVIII activity. Haemodilution further enhances procoagulant effects of FIX and FVIII by slowing down inhibition of procoagulant enzymes. Dosing of PCC per prothrombin time may underestimate PCC's procoagulant potential because it does not account for intrinsic tenase or antithrombin activity.

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