Except for MCF and ΔMCF, respectively, variables derived from EXTEM assays alone demonstrated significantly greater areas under the ROC curves than differences in variables between EXTEM and APTEM assays (Table 3).
Subcohort analyses demonstrated that all variables predicted very early fibrinolysis. However, CT failed to predict early and intermediate fibrinolysis and only MCF predicted late fibrinolysis.
The ROC curves analyzing the pooled data revealed that differences in the thromboelastometric variables usually obtainable in <15 minutes during thromboelastometric measurements (i.e., ΔCT, ΔCFT, ΔAA, ΔA5, and ΔA10, respectively) failed to predict fibrinolysis, as reflected by a lower 95% confidence limit of the areas under the ROC curve <0.6 (Table 4). In contrast, variables obtained later during the measurements demonstrated greater AUC values. Specifically, ΔA15 (AUC: 0.675 [0.016]) and ΔA20 (AUC: 0.719 [0.015]) demonstrated poor overall test performance, while only ΔMCF (0.812 [0.013]) demonstrated fair overall test performance for predicting fibrinolysis (Table 4).
Subcohort analyses demonstrated that differences among all variables predicted very early fibrinolysis, but only ΔA20 (AUC: 0.705 [0.031]) and ΔMCF (AUC: 0.846 [0.027]) predicted early increased fibrinolysis. Of note, all variables but ΔMCF (AUC: 0.769 [0.026]) failed to predict intermediate fibrinolysis and no difference in variables from EXTEM and APTEM assays predicted late fibrinolysis.
Our data derived from a large cohort of patients demonstrate that low early values of clot firmness in extrinsically activated assays (e.g., EXTEM A5) are associated with subsequent fibrinolysis and improve its early detection, albeit with moderate reliability. Additional thromboelastometric assays with the addition aprotinin fail to substantially improve early diagnosis of fibrinolysis compared with assays without aprotinin. The predictive power of thromboelastometric early clot firmness is best with early, but not late fibrinolysis.
Early thromboelastometric variables are increasingly being used for fast, point-of-care assessment of coagulation in surgical patients.39–41 Although viscoelastic assays like thromboelastometry are capable of detecting fibrinolysis, its diagnosis can be delayed since fibrinolysis may become evident only after 45 minutes or longer following initial clot formation (CT). Accordingly, early assessment for fibrinolysis would allow for prompt initiation of antifibrinolytic therapy to potentially prevent progressive consumption of coagulation factors and platelets and subsequent life-threatening coagulopathic bleeding. This early diagnosis could further reduce the clinical need for inappropriate prophylactic treatment with antifibrinolytic drugs, which is associated with adverse effects.18,19,25
Different approaches using viscoelastic tests have been proposed to achieve faster assessment of fibrinolysis.6,30–32 Levrat et al.,6 for example, found in a cohort of 78 trauma patients (5 with fibrinolysis) that a 7-mm greater MCF in APTEM when compared with an EXTEM assay run in parallel predicted fibrinolysis (area under the ROC curve: 0.92). Furthermore, they suggested that an MCF using the EXTEM assay of <18 mm identified patients with fibrinolysis (area under the ROC curve: 1.0). Similarly, Steib et al.33 reported that a thrombelastographic maximum amplitude <35 mm was associated with a 100% probability for developing fibrinolysis in 11 patients with fibrinolysis during liver transplantation. Our results derived from a larger cohort of mainly nontrauma patients support these finding that measurements of clot firmness can identify patients with fibrinolysis more promptly than making the diagnosis based on clot lysis metrics. However, we found that the difference in MCF between APTEM and EXTEM assays (AUC: 0.812) and a low MCF with the EXTEM assays (0.799) is less predictive of fibrinolysis than in these prior reports. This likely can be explained by the fact that the 5 trauma patients with fibrinolysis reported by Levrat et al.6 had “very early” fibrinolysis (median, interquartile range for EXTEM LI30: 36%, 0%–78%). In contrast, our pooled fibrinolysis cohort of 411 data sets included 192 data sets with very early as well as intermediate or late fibrinolysis.
Although MCF in the EXTEM assay and differences in MCF results between the EXTEM and APTEM assays provided the best prediction of fibrinolysis, there are likely clinical limitations with this method of diagnosis. First, MCF is obtained relatively late during thromboelastometric measurements and is dependent on the intrinsic ability to form thrombus not at a predefined time point. Moreover, the added benefit from MCF measurements may be tempered by the fact that fibrinolysis can be inferred by visual inspection of the ongoing thromboelastometry tracing. To overcome this limitation, others have proposed that fibrinolysis can be detected earlier by comparison of variables from 2 extrinsically activated assays with and without addition of the antifibrinolytic drug aprotinin run in parallel.30–32 Our findings, however, do not support the proposed benefit of additional APTEM assays for the early detection of fibrinolysis. In fact, using the “optimum” cut point derived from our data using ΔCT criteria, only 155 of our 411 patients (37.7%) would have been identified correctly as having fibrinolysis, while 626 of 2537 (24.8%) controls would have been falsely identified as having fibrinolysis, possibly resulting in exposure to antifibrinolytic drugs. The failure to improve early identification of fibrinolysis with additional APTEM assays may be related to the fact that aprotinin, in addition to its antifibrinolytic actions, exerts inhibitory effects on several coagulation factors that may decrease thrombin generation and prolong CTs.42,43
Our data suggest that the feasibility of thromboelastometric variables for the early detection of fibrinolysis varies widely with the onset time of fibrinolysis. Specifically, while several variables allow for the detection of very early fibrinolysis (Tables 3 and 4), only early variables of clot firmness from EXTEM assays and MCF allow for improved early detection of late fibrinolysis. This is readily explained by the fact that substantial plasmin generation, resulting in fibrinolysis, occurs only after fibrin formation. Thereafter, coagulation and fibrinolysis will proceed in parallel. However, fibrinolysis can become overt in viscoelastic tests only if the profibrinolytic potential exceeds the procoagulatory and antifibrinolytic potential or after all the procoagulatory and antifibrinolytic potential has been consumed.
Although additional APTEM assays did not improve early identification of fibrinolysis, these parallel assays have clinical value by potentially showing that only fibrinolysis hinders formation of a stable clot.44 For example, a marked increase in MCF is seen with the APTEM assay compared with the corresponding EXTEM assay in Figure 1, C and D. Furthermore, the additional use of the APTEM test allows for discrimination between fibrinolysis and platelet-mediated clot retraction or factor XIII deficiency since only fibrinolysis is eliminated in the APTEM test.45,46
A limitation of our study is the nature of the optimum cutoff values of the thromboelastometric variables, which were chosen at the Youden index. This cutoff is considered optimum based on the arbitrary assumption that consequences and costs of false-positive and false-negative tests are of the same importance. This assumption might not be true in every clinical setting. Nevertheless, their use provides an estimate of the relative risk for false-positive and false-negative test results. A higher sensitivity for detecting fibrinolysis would possibly result in higher, unnecessary exposure to antifibrinolytic drugs for patients who do not subsequently develop fibrinolysis. For instance, Davenport et al.47 demonstrated that an EXTEM A5 threshold of ≤35 mm detected 77% of the patients having acute traumatic coagulopathy (defined as a prothrombin ratio >1.2) and predicted the risk for massive transfusion (>10 U of packed red blood cells in 12 hours). Using this EXTEM A5 cutoff value instead of the optimum cutoff value of ≤25 mm derived from our data would have increased sensitivity for the detection of fibrinolysis from 74.7% to 92% (95% CI, 88.9%–95.0%) but simultaneously decreased specificity from 58.5% to 27.3% (95% CI, 27.3%–30.9%). Thus, while >90% of patients with fibrinolysis would have been detected, about 72% of the patients would have been considered to have been erroneously suspected of having fibrinolysis. Accordingly, the decision for an clinically relative cutoff value should be based on the severity of bleeding and the particular clinical setting since the impact of fibrinolysis on patient outcome is different for patients having severe trauma versus those undergoing liver transplantation.8,15–17,48
Another potential limitation may be that we cannot provide data using alternative methods to define fibrinolysis, such as results from euglobulin lysis time, tissue plasminogen activator values, or plasmin–antiplasmin complex concentration.29,49 These assays were not performed but are not considered to help clinical decision making since they are extremely time consuming and complex and hence unsuitable for point-of-care measurements.
In summary, low early values of clot firmness in extrinsically activated assays (e.g., EXTEM A5) are associated with fibrinolysis and improve its early detection, but with only moderate predictive capacity. The addition of aprotinin with APTEM test did not substantially improve the early diagnosis of fibrinolysis.
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