Sufficient Thrombin Generation Despite 95% Hemodilution: An In Vitro Experimental Study.

Johannes Gratz,Herbert Schöchl,Markus Honickel,Christoph J Schlimp,Oliver Grottke,Nadine Hochhausen

doi:10.3390/jcm9123805

Abstract

Guidelines for the treatment of severe bleeding comprise viscoelastic-test-guided use of coagulation factor concentrates as part of their recommendations. The aim of this study is to investigate the effects of substituting fibrinogen, prothrombin complex concentrate, and a combination of both on conventional coagulation tests, viscoelastic test results, and thrombin generation. Blood was drawn from seven healthy volunteers to obtain platelet-free plasma, which later was diluted by replacing 40%, 60%, 80%, 90%, 95%, and 99% with a crystalloid solution. The diluted samples were spiked with fibrinogen concentrate, prothrombin complex concentrate, a combination of both, or a corresponding amount of crystalloid solution. Up to a dilution level of 95%, viscoelastically determined clotting time was significantly shorter in the group substituted with fibrinogen only in comparison with the additional use of prothrombin complex concentrate. Clot firmness and endogenous thrombin potential remained at relatively stable values up to a dilution level of 95% with the substitution of fibrinogen but not prothrombin complex concentrate. Substitution of prothrombin complex concentrate led to an excessive overshoot of thrombin generation. The results of our study question currently propagated treatment algorithms for bleeding patients that include the use of prothrombin complex concentrate for patients without former intake of oral anticoagulants. Even in severely bleeding patients, thrombin generation might be sufficient to achieve adequate hemostasis.

Highlights

Hemorrhage in severely injured patients is associated with high mortality and is the leading cause of death in trauma patients [1]
The aim of this study is to investigate the effects of substituting fibrinogen, prothrombin complex concentrate, and a combination of both on conventional coagulation tests, viscoelastic test results, and thrombin generation
Fibrinogen concentrations were significantly higher at any dilution level in the groups containing fibrinogen concentrate (FC, FC+prothrombin complex concentrate (PCC)) versus those not containing fibrinogen concentrate (Figure 1)

Summary

Introduction

Hemorrhage in severely injured patients is associated with high mortality and is the leading cause of death in trauma patients [1]. Explanatory models for trauma-induced coagulopathy have focused on blood loss, dilution of coagulation factors due to volume replacement, hypothermia, and acidosis [3]. These factors might play a role in the development of trauma-induced coagulopathy, recent literature provides a more differentiated picture, characterizing it as a multifaceted process, including many more drivers such as shock-related hypoperfusion, endothelial injury with glycocalyx shedding, and platelet dysfunction [4,5]. Fibrinogen is the first single coagulation factor that drops beyond critical levels in bleeding patients [7], and low fibrinogen levels upon hospital admission have been associated with increased mortality in trauma patients [8]. Maintaining plasma fibrinogen levels ≥1.5 g/L is one of the cornerstones in hemostatic management of bleeding trauma patients [6]

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