Postinjury fibrinolysis shutdown: Rationale for selective tranexamic acid

Abstract

Postinjury systemic fibrinolysis has been recognized as a biologic process for more than 200 years, but the specific mechanisms of regulation and their clinical implications remain to be elucidated. By the 1950s, the plasminogen-plasmin-antiplasmin system was established as critical in preserving microvascular patency during blood clotting to maintain hemostasis. The challenges in modulating systemic fibrinolysis became evident soon thereafter. In the 1960s systemic fibrinolysis was identified by thrombelastography (TEG) during the anhepatic phase of liver transplantation, prompting the recommendation for intraoperative antifibrinolytics. But the administration of antifibrinolytic was associated with fatal postoperative pulmonary emboli. During the same period, there was experimental evidence that antifibrinolytics prevented irreversible hemorrhagic shock. More recently, a randomized trial indicated that plasmin inhibition during coronary artery bypass grafting was associated with increased mortality. The interest in antifibrinolytic therapy for trauma induced coagulopathy (TIC) is a relatively recent event, largely driven by the increasing use of viscoelastic hemostatic assays. The CRASH-2 trial, published in 2010, stimulated worldwide enthusiasm for tranexamic acid (TXA). However, the limitations of this study were soon acknowledged, raising concern for the unbridled use of TXA. Most recently, the documentation of fibrinolysis shutdown soon after injury has highlighted the potential adverse effects due to the untimely administration of TXA. A recent retrospective analysis in severely injured patients supports this hypothesis. But final clarity of this volatile topic awaits the completion of the current ongoing randomized clinical trials throughout the world.

Figures

Figure 1. Blood Product Transfusions between Systemic Fibrinolysis Phenotypes

The blood component transfusion among the systemic fibrinolysis phenotypes summarized; Y axis represents the number of units within the first six hours postinjury. RBC and plasma transfusions were higher in the systemic hyperfibrinolysis phenotype. RBC= Red blood cell; Cyro = Cryoprecipitate; * p

Figure 2. U Shaped Distribution of Mortality Related to Systemic Fibrinolysis Phenotype

The mortality among the systemic fibrinolysis phenotypes was U-shaped; Y axis represents mortality by phenotype L30 = % lysis at 30 minutes by TEG Shutdown = Fibrinolysis shutdown; Physiologic = Physiologic fibrinolysis; Hyper= Hyperfibrinolysis; Ly30 = the percent fibrinolysis 30 minutes after reaching maximum amplitude measured by thombelastography. Y axis represents the percent mortality per phenotype. There is a U shaped distribution of mortality with a nadir in mortality identified in the physiologic group (Ly30 between 0.9 and 2.8%). Ly30% above and below this range had statistical increases in mortality. Reproduced from Moore et al with permission of Lippincott Williams & Wilkins.

Figure 3. Distribution of Mortality According to Systemic Fibrinolysis Phenotype

The distribution of mortality among the systemic fibrinolysis phenotypes was substantially different; Y axis represents % of total mortality per systemic fibrinolysis phenotype. The systemic hyperfibrinolysis phenotype died primarily due to hemorrhage; whereas the systemic fibrinolysis shutdown phenotype succumbed to multiple organ failure. TBI= Traumatic brain injury; Hyper = hyperfibrinolysis; Shutdown= fibrinolysis shutdown; * p

Figure 4. Regulation of Postinjury Systemic Fibrinolysis

The control of systemic fibrinolysis driven by tPA is controlled at multiple levels, including the direct inhibition of tPA, the direct inhibition of plasmin, and the inhibition at the fibrin cross-linking stage.