Decreased Thrombin Generation Potential Is Associated with Increased Thrombin Generation Markers in Sepsis Associated Coagulopathy

Introduction: Sepsis associated coagulopathy (SAC) is commonly seen in patients which eventually leads to dysfunctional hemostasis and disseminated intravascular coagulation (DIC). Thrombin generation plays an important role in the overall pathophysiology of this process. Previous studies have reported an increase in thrombin generation markers such as thrombin antithrombin complex (TAT) and prothrombin fragment (F1.2). (Hoppensteadt et al. Clin Appl Thromb Hemost. 2014 Mar;20(2):129-35). Sepsis eventually results in consumption coagulopathy in which some of the clotting factors are consumed. The purpose of this study is to determine the thrombin generation potential of baseline blood samples obtained from sepsis associated coagulopathy patients and demonstrate their relevance to thrombin generation markers.

Materials and Methods: Baseline citrated blood samples were prospectively collected from 49 patients with sepsis and suspected DIC. DIC scores were determined according to the ISTH scoring system (PTINR, fibrinogen, D-dimer and platelet count). Healthy control (n=50) represented citrated plasma obtained from a commercial supplier (George King Biomediacl, Overland Park, KS). Thrombin generation studies were carried out using a commercially available florigenic substrate methods with thrombin calibrator and PPP reagent (calibrated automated thrombogram; CAT). Such parameters as peak thrombin, lag time and area under the curve were compiled. TAT and F1.2 were measured using commercially available ELISA methods (Seimens, Indianpolis, IN). Functional antithrombin levels were measured using a chromogenic substrate method. All results were calculated in terms of mean ± SD. Applicable statistical methods were used to correlate the thrombin generation parameters with thrombin generation markers and antithrombin.

Results: The peak thrombin levels were lower (82±40nM) in the SAC patients in comparison to higher levels observed in the normal plasma (133±10nM). The AUC was lower (561 ±280) in the SAC group in comparison to the normal (624±18). The SAC group showed much longer lag time (4.1±2.1) in comparison to the normal (2.1 ± 2.2). Wide variations in the results were observed in these parameters in the SAC group. The compsoite data is compiled in the table. the F1.2 levels in the DIC group were much higher (570±48 pmol) in comparison to the normal (210±25 pmol). The TAT levels also increased in the SAC group (27.9 ±5.1 ng/ml) in comparison to the normal (2.8 ±0.8 ng/ml). The functional antithrombin levels were decreased in the SAC group (64 ±11%). No correlation was observed between thrombin generation parameters and thrombin generation markers.

Conclusion: These results validate the earlier observations that thrombin generation such as F1.2 and TAT are decreased in patients with SAC. However thrombin generation parameters are significantly elevated in this group in comparison to normals. This may be due to the consumption of prothrombin due to the activation of the coagulation system. The SAC group also showed wide variations in both the thrombin generation parameters and the F1.2 and TAT. These variations may be due to the differences in the endogenous pathophysiology state in the SAC patients. The decreased functional AT levels observed in the SAC group are due to the formation of the complex between generated thrombin and antithrombin. Simultaneous profiling of thrombin generation and thrombin generation markers may be helpful in the risk stratification of these patients.

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