A clotting time longer than 226 s in the INTEM channel of the thromboelastometer is an independent risk factor for mortality during bleeding

Bleeding can result in complex coagulation disorders and hemostatic failure. Rotational thromboelastometry (ROTEM) is a point-of-care method using whole blood samples for the diagnosis of hemostatic disorders [1, 2].

All ROTEM analyses could be performed with single use reagents consisting of three tissue factor-activated assays, EXTEM (extrinsic pathway), FIBTEM (fibrin contribution to clot firmness), APTEM (inhibition of fibrinolysis) and two contact-activated assays INTEM (intrinsic pathway without heparin neutralization) and HEPTEM (intrinsic pathway with heparin neutralization). All assays estimate clotting time (CT), clot formation time (CFT), clot firmness and fibrinolytic processes [3].

Prolongation of clotting time in INTEM (CT_INTEM) in trauma patients was significantly associated with death [4, 5]. A CT_INTEM over 240 s was found in 11/22 nonsurvivors after severe traumatic brain injury in an analysis by Schöchl et al. [5]. A therapeutic approach for patients with CT_INTEM over 240 s is the administration of fresh frozen plasma [2, 6‐8].

Our aim was therefore to investigate the relationship between CT_INTEM, 30-day mortality and fresh frozen plasma treatment. Our primary hypothesis was that there is an independent association between CT_INTEM and 30-day mortality in patients with bleeding. Second, we hypothesized that fresh frozen plasma might be associated with 30-day mortality in patients with elevated CT_INTEM.

The study was registered in German Clinical Trials registration (registration number DRKS00026153) on September 2021 (principal investigator: PD Dr. med. Sven Oliver Schneider, Saarland University, Department of Anesthesiology, Intensive Care Medicine and Pain Medicine, Homburg/Saar, Germany). After approval by the ethics committee (Ärztekammer Saarland; number 93/20), the data were retrospectively collected. The requirement for written informed consent was waived by the ethics committee.

During the study period 2656 patients had documented index ROTEM analyses. Among these 459 patients did not meet the inclusion criteria by virtue of missing information about CT_INTEM analysis, comorbidities or outcome. The final study population includes 2197 patients.

The results of the C‑statistic showed that CT_INTEM had a discrimination for prediction of 30-day mortality (optimal threshold > 226 s, C‑statistic 0.62, sensitivity 47% and specificity 72%; Fig. 1). The number needed to screen (NNS), the positive predictive value (PPV), and the negative predictive value (NPV) were calculated for 30-day mortality using the optimal threshold of CT_INTEM > 226 s (NNS: 7, PPV: 0.29, NPV: 0.85).

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Patients with CT_INTEM > 226s had less orthopedic or general surgery and more surgery with cardiopulmonary bypass (Table 1). Interestingly, the comorbidities during hospital admission were not significantly different except for coronary heart disease. The outcome was split into the time before and after the ROTEM analysis. Patients with CT_INTEM > 226s required more blood transfusions, had more renal replacement therapy and required more coagulation factors (Table 2).

Patients with CT_INTEM > 226s had an increased 30-day mortality compared to patients with CT_INTEM ≤ 226s (29% versus 15%, p < 0.001; Table 2; Fig. 2). Even after adjustment for confounding factors CT_INTEM > 226s remained an independent risk factor for 30-day mortality. This remained true in sensitivity analyses (Table 3a). We compared survival versus nonsurvival in patients suffering from CT_INTEM over 226 s. Acute myocardial infarction, gastrointestinal bleeding, gastrointestinal ischemia, renal replacement therapy and therapy with prothrombin concentrate and fibrinogen were seen significantly more often in nonsurvivors (Appendix 2).

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Patients with CT_INTEM > 226s had more cardiothoracic and vascular surgery with cardiopulmonary bypass (Table 1). Cardiopulmonary bypass requires anticoagulation, which typically prolongs CT_INTEM. Therefore, two subgroup analyses were done in patients with and without cardiopulmonary bypass. A CT_INTEM > 226s was associated with a significantly increased 30-day mortality only in patients without cardiopulmonary bypass (adjusted HR: 2.2; 95% CI 1.7–2.9, p < 0.001; Table 3a; Fig. 2; NNS: 3, PPV: 0.47, NPV: 0.82). In contrast, a CT_INTEM > 226s in patients with cardiopulmonary bypass was not significant in the second adjusted analysis (adjusted HR: 1.5; 95% CI 0.9–2.4, p = 0.1; Table 3a; NNS: 13, PPV: 0.16, NPV: 0.92).

A therapeutic approach for patients with CT_INTEM > 226s is the administration of fresh frozen plasma. The 30-day mortality rate seems lower in patients with CT_INTEM > 226s treated with fresh frozen plasma than in patients without treatment (Fig. 3). After adjustment for confounding factors, however, the risk reduction is not significant (Table 3b).

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Patients with CT_INTEM over 226 s had a significantly increased independent risk for 30-day mortality. The overall mortality was 19%. This is consistent with previous reports in trauma patients with bleeding [9, 10]. In our study the definition of bleeding is determined at the discretion of the treating physician. The literature shows no uniform definition for major bleeding [11]. The International Society on Thrombosis and Haemostasis provides a clear definition for nonsurgical patients and a proposed definition for surgical patients, the latter being less objective and partly subjective [12, 13]. While management principles are generally similar, the underlying pathophysiology of major bleeding differs across contexts. Multiple factors contribute to the complex causes of bleeding in trauma and in surgical patients that include blood loss, hemodilution, acquired platelet dysfunction, coagulation factor consumption in extracorporeal circuits, activation of fibrinolytic, fibrinogenolytic and inflammatory pathways and hypothermia [14].

However, early mortality is caused by continued hemorrhage, hemorrhagic shock, trauma-induced coagulopathy and incomplete resuscitation. Numerous factors are known to be associated with a higher complication risk including death after bleeding. These factors include, e.g., age, acute kidney injury, acute lung injury, emergency at hospital admission, bleeding, coagulation disorders and gastrointestinal ischemia [10, 15‐19]. Moreover, in patients undergoing cardiopulmonary bypass residual heparin effect or protamine overdose can be one reason for prolongation of CT_INTEM [20]. This is consistent with our findings that CT_INTEM > 226s were associated with higher 30-day mortality only in patients without cardiopulmonary bypass. There are limited investigations regarding clotting time CT_INTEM in the context of bleeding and patient outcome; however, a prolongation of CT_INTEM has been observed in nonsurviving trauma patients [4, 5]. Interestingly, we observed the highest difference in nonsurvivors versus survivors, with the exception of a greatly increased need for coagulation factors in the presence of gastrointestinal ischemia (Appendix 2). Gastrointestinal ischemia might be a result of shock during bleeding and a result of the catecholamine treatment in hypovolemic patients and may be a sign for uncontrolled hemorrhage; however, in cardiac surgery gastrointestinal ischemia could be also a potential risk for abnormal hemostatics [21]. To avoid that gastrointestinal ischemia or any other adverse event is a confounder in our analysis, we split the outcome in the time before and after ROTEM analysis (Table 2). The occurrence of all adverse events before ROTEM analysis was adjusted in our sensitive analysis as confounders. This includes also the occurrence of gastrointestinal ischemia. Nevertheless, CT_INTEM over 226 s remained an independent risk factor for 30-day mortality (Table 3a).

We speculate that the leading cause of death in patients with CT_INTEM over 226 s is a hemostatic dysfunction in the intrinsic pathway. The intrinsic pathway begins with factor XII (Hageman factor XII), which activates factor XI. Patients deficient in factor XII do not exhibit bleeding complications, while factor XI deficient patients (hemophilia C or Rosenthal syndrome) sometimes experience bleeding, suggesting factor XI plays a role in hemostasis independent of the contact pathway [22, 23]; however, the reasons for the prolongation might be highly speculative. Different reasons resulting in a prolonged CT_INTEM are heparin and release of endogenous heparinoids from the microcirculation due to glycocalyx shedding [24], heparin-like effect (trauma, cardiopulmonary bypass and liver disease e.g. cirrhosis) [24‐28], protamine overdose (results in factor V inhibition) [29], direct oral anticoagulants [30‐32], fibrinogen deficiency, factor XII deficiency (consumption due to hyperfibrinolysis) [33], other factor deficiencies in the intrinsic pathway (VIII, IX and XI) or the common pathway (II, V and X).

This abnormal parameter during bleeding requires a differentiated treatment strategy including protamine, tranexamic acid, treatment of platelet dysfunction with desmopressin or platelet concentrates, treatment of factor XIII deficiency, and treatment of factor deficiencies of the extrinsic and intrinsic pathway [2]. Following the recommendations of Weber et al., we performed CT_EXTEM to identify and correct extrinsic pathway abnormalities using factor concentrates and fibrinogen. CT_INTEM was assessed to address intrinsic pathway deficits, with the addition of fresh frozen plasma considered as advised [2, 6‐8, 34].

The use of fresh frozen plasma is controversial. Patients without a coagulopathy, bleeding indication or need for massive transfusion have been shown to experience higher mortality when given fresh frozen plasma. Therefore, careful evaluation of the indications for the use of fresh frozen plasma is vital as inappropriate administration may increase the risk of death [35].

In Europe a coagulation disorder resulting in massive bleeding is generally managed first by the addition of coagulation factor concentrates. Studies have shown that goal-directed coagulation management is associated with a reduced incidence of massive transfusion and lower requirements for red blood cells and fresh frozen plasma [36, 37]. Studies have shown that prothrombin complex concentrate reverses coagulopathy faster and more effectively than fresh frozen plasma, achieves higher clotting factor concentrations with smaller infusion volumes [8, 11, 38, 39]. In contrast, in the USA fresh frozen plasma is often used to maintain the red blood cell-plasma ratio and to replace losses due to bleeding and even serves as a volume expander [40, 41]. Nevertheless, studies have shown a better efficacy when both prothrombin complex concentrate and fresh frozen plasma are used together [42].

This coagulation treatment supports the relevance of other coagulation factors not included in prothrombin complex concentrates and fibrinogen to treat bleeding in massive hemorrhage which might affect 4–6% of patients with trauma-induced coagulopathy [36, 37]. This is consistent with our findings and a previous study that fresh frozen plasma does not increase 30-day mortality during bleeding and coagulation deficits [43]; however, the effects of correcting abnormal clotting with fresh frozen plasma on morbidity and mortality need to be further investigated [36, 44].

The most important limitation of this study is the lack of CT_HEPTEM results as the INTEM/HEPTEM CT ratio is the key to differentiate heparin-like effects from factor deficiencies. In the absence of HEPTEM measurements, our interpretation of CT_INTEM prolongation remains uncertain as it may be influenced not only by residual heparin or heparin-like substances, but also by endogenous anticoagulants (e.g., increased antithrombin activity), impaired synthesis or consumption of clotting factors, or other coagulopathies. In addition, we did not have systematic data on other relevant laboratory values (e.g., pH, base excess, hemoglobin) or vital parameters, which limits our ability to assess whether patients with prolonged CT_INTEM suffered more from severe shock. Another limitation of our study is that although the majority of patients presented with hemorrhagic shock, we cannot fully exclude the contribution of other mechanisms, such as cardiogenic or septic shock, to the observed coagulation changes. Our dataset only included information on adverse events, as listed in Table 2. To address this, we performed a sensitivity analysis by randomly dividing the cohort into two groups to confirm our results. Therefore, while our adjusted analyses and moderate ROC-AUC suggest that CT_INTEM has some discriminatory value, the findings should be interpreted with caution and always in conjunction with other clinical information. A larger multicenter study, including HEPTEM is needed to clarify these mechanisms in a more precise population and confirm our findings.

In summary, in our study CT_INTEM over 226 s might be an independent risk factor for 30-day mortality in patients with bleeding and could be useful for decision making regarding treatment with fresh frozen plasma.