Rotational Thromboelastometry Profile among Critically ill COVID-19 Patients

Dear Editor,

Thromboinflammation has a contributing role in Coronavirus disease 2019 (COVID-19) pneumonia pathogenesis. ¹ Rotational thromboelastometry (RT) evaluates viscoelastic changes during the coagulation process and could enable the identification of hypercoagulability, as an indirect marker of pulmonary microvascular thrombosis in real-time^2–4. Therefore, we propose to study the modifications in maximum clot firmness (MCF) and other RT parameters in critically-ill COVID-19 patients compared with healthy controls (HC).

A prospective observational cohort study was performed at a high complexity hospital in Argentina. In the COVID-19 cohort, we included adult patients admitted to ICU due to COVID-19, between August and November 2020. In the HC cohort, we included healthy non-hospitalized volunteers. Exclusion criteria were: age <18 years or >80 years, anticoagulant use, tocilizumab use, transfusion of blood products (<7 days), hereditary thrombophilia or bleeding disorders, pregnancy, and active cancer.

In ICU patients, blood samples were collected at ICU admission (T1), and 5 (T5) and 10 days (T10) after ICU admission. In RT, only NaHEPTEM assay, which evaluates blood clot formation by recalcification without activators with adjunct heparinase, and is considered more sensitive to detect hypercoagulable states, was performed. RT were performed in a ROTEM® Delta instrument (Tem Innovations GmbH, Munich, Germany). Patient demographics and comorbidities were recorded. Also, standard basic coagulation tests were performed to all participants.

We calculate a sample size to test the hypothesis that the MCF was significantly higher in COVID-19 patients than in HC. We assumed a mean MCF of 69 mm for healthy people and 75 mm for COVID-19 patients, with a standard deviation of 6 for healthy people and 7 for COVID-19 patients, based on the study of Pavoni et al. ⁵ With a power of 80% and alpha of 0.5, a ratio of COVID-19/HC of 1.2, with a two-sided test, the sample size was 23 for COVID-19 patients and 19 HC. Statistical differences between groups were evaluated by the chi–squared test. Correlation by Spearman Rank test when appropriate. A two–tailed P–value < 0.05 was considered significant. All statistical tests were performed using IBM SPSS 23.

One hundred seventeen patients were admitted to our ICU with COVID-19 during the study period. Ninety-four patients were excluded, mainly due to convalescent plasma therapy. Thus, 23 COVID-19 patients and 19 HC were included in the final analysis ( Supplemental Material )

We observed significantly higher values of MCF in COVID-19 patients at ICU admission (T1) against HC group (64 [IQR 59-68] vs 56 [IQR 52-60], p < 0.001). In the COVID-19 group the MCF also had a significant increase at T5 (69 [IQR 64-70]), compared to T1 (p = 0.011). Additionally, higher fibrinogen levels and MFC were found in COVID-19 group at any time point, (T1, T5 and T10) compared to HC (Figure 1).

Figure 1.

Evolution of medians of different parameters: D-Dimer and fibrinogen, as well as NaHEPTEM temograms parameters CFT, MaxV, A₅ and MCF, during the evaluation period (T1, T5 and T10) according to mechanical ventilation treatment or not. Green lines indicated the parameter median obtained in the healthy control group.

Comparing COVID-19 MV patients with non-MV COVID-19 patients at T1, we observed significantly higher levels of fibrinogen and higher MaxV in MV patients. Also, higher A₅, as well as shorter clotting formation time (CFT) were registered, but without reaching statistical significance. However, the presence of a CFT <25th percentile or Amplitude at 5 min (A₅) >75th percentile of the HC range in temograms at T1 was associated with mechanical ventilation (MV) requirements at T1 (75% of MV vs 25% of non-MV [p = 0.039]). At T5, we observed significantly higher MCF and fibrinogen among MV patients. Finally at T10, we found a tendency of higher A₅ and MCF in MV patients without significant difference. This shorter CFT and higher Maximum velocity of clot formation (MaxV), observed in MV COVID-19 patients only on T1, could be explained due to the clot formation velocity increasing along with days from ICU admission in all patients.

In COVID-19 patients, a CFT below the lower quartile, and an A₅ above the higher quartile of the HC values at T1, was associated with MV requirement at T5 (same values in both parameters: 90.9% of MV vs 41.7% in non-MV [p = 0.027]). We hypothesize that the increment in clot formation velocity (shorter CFT, higher MaxV, and A₅) could reveal high thrombin generation in the early ICU stage in COVID-19 MV patients, which may reflect more critical illness. Figure 2 shows the distribution RT parameters from samples taken on patients under MV or not, independently of ICU time after admission.

Figure 2.

Distribution of hemostatic parameters: D-Dimer (a) and fibrinogen (b), as well as NaHEPTEM parameters CFT(c), MaxV(d), A₅(e) and MCF (f) in all blood samples performed from ICU patients with COVID-19, according to the need of mechanical ventilation treatment. Dashed lines indicated the parameter median obtained in the healthy control group.

Our study suffers from several limitations. Firstly, we do not carry out a systematic search for deep vein thrombosis and pulmonary embolism among asymptomatic patients. Secondly, despite the sample-size calculation being adequate for testing the hypothesis, a relatively low number of patients were included for further analysis. As for strengths, we highlight the strict exclusion criteria implemented, the use of a test that is not affected by heparin presence, and the analysis of RT parameters at multiple time-points along with the study, which may reduce potential bias.

NaHEPTEM assays could detect hypercoagulation among critically ill patients with COVID-19, and also some RT parameters seem to be further altered in patients that required MV. Nevertheless, more studies are required to entirely comprehend hypercoagulation and hypoxemia relation, and test whether RT can be used in clinical settings for this purpose.

Supplemental Material

sj-docx-1-cat-10.1177_10760296221091213 - Supplemental material for Rotational Thromboelastometry Profile among Critically ill COVID-19 Patients

Supplemental material, sj-docx-1-cat-10.1177_10760296221091213 for Rotational Thromboelastometry Profile among Critically ill COVID-19 Patients by Indalecio Carboni Bisso, Iván Huespe, Eduardo Prado, Melina Garbarini, Marina Sol López, Luis Barrera, Marcos Las Heras, Jorge Sinner and Marta Martinuzzo in Clinical and Applied Thrombosis/Hemostasis

Supplemental Material

sj-docx-2-cat-10.1177_10760296221091213 - Supplemental material for Rotational Thromboelastometry Profile among Critically ill COVID-19 Patients

Supplemental material, sj-docx-2-cat-10.1177_10760296221091213 for Rotational Thromboelastometry Profile among Critically ill COVID-19 Patients by Indalecio Carboni Bisso, Iván Huespe, Eduardo Prado, Melina Garbarini, Marina Sol López, Luis Barrera, Marcos Las Heras, Jorge Sinner and Marta Martinuzzo in Clinical and Applied Thrombosis/Hemostasis