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Utility of Thromboelastography and velocity curve derivative in diagnosing COVID‐19 associated coagulopathy

Abstract Background COVID‐19 associated coagulopathy (CAC) can either be localized or systemic hypercoagulable state with increased risk of thromboembolism. This study looked into the usefulness of Thromboelastography (TEG) and the velocity curve (V‐curve) derivative from TEG in diagnosing and differentiating different stages of CAC. Materials and Methods A prospective single cohort study of RT‐PCR confirmed COVID‐19 patients was carried out for 2 weeks. Severe COVID‐19 patients in the adult critical care units with a TEG report were recruited for the study. Citrated kaolin TEG was performed on the day of admission before anticoagulation. TEG parameters included were R and K time, alpha angle, maximum amplitude, clotting index, lysis at 30 min. The first‐degree velocity curve of TEG is plotted as V‐curve which extrapolates thrombus generation potential. Parameters analyzed were the maximum rate of thrombus generation as well as thrombus generated (TG). Results The study included 43 patients with an average age of 58.34 (±15.35). TEG as well as V‐curve of all the patients were hypercoagulable compared with age‐matched reference range. We had 79.06% of patients in hypercoagulable stage. The mortality rate was 32.56% and 30.23% developed thrombotic incidents. Patients who succumbed to death had prolonged PT, aPTT, MA, Ly30, with a reduced TG (p < .05). The presence of fibrinolysis was associated with thromboembolism (OR = 6.76, CI = 1.48–25.82). Repeat TEG was done randomly in 11 patients and revealed a persistent hypercoagulable stage with increasing fibrinolysis activity. Conclusion TEG is a useful tool in diagnosing and categorizing Coagulopathy associated with COVID‐19.


| INTRODUCTION
COVID-19 associated coagulopathy (CAC) is characterized by a hypercoagulable state with a predilection for thromboembolism (TE).
Inflammation on type II pneumocytes leads to extensive macrophage recruitment and activation which leads to vessel wall damage and tissue factor expression. This triggers entry of procoagulants and proinflammatory mediators into pulmonary vasculature eventually resulting in pulmonary immunethrombi formation mediated by macrophages. 1 Breakdown of these microthrombi confined in the lungs leads to an elevated D-Dimer. 2,3 Coagulopathy in COVID-19 progresses from an initial pulmonary microthrombi to a systemic hypercoagulable state with widespread activation of coagulation and then to a hypocoagulable picture seen in later phases of the disease. 4 The second stage with a systemic hypercoagulability is most commonly observed in severe cases with a high propensity to develop TE. 4 The most important findings in CAC are highly elevated D-Dimer levels, elevated fibrinogen levels, modest reduction in platelet count, a mild prolongation of Prothrombin time (PT) together with a reduced fibrinolysis activity which is different from what we observe either in sepsis induced coagulopathy (SIC) or disseminated intravascular coagulation (DIC). 4,5 COIVD-19 patients suffer from thromboembolic complications more common than other conditions requiring critical care. 6 The widespread activation of the coagulation system leading to a profound prothrombotic state was the basis of recommending anticoagulation in patients requiring hospital admission. [7][8][9] In view of the increasing number of severe COVID-19 admission to our hospital in 2021, we studied the role of Thromboelastography (TEG) in the diagnosis and monitoring of coagulation status, TEs, and patient outcome.

| RESULTS
We had 46 patients with TEG reports during the study duration and three did not meet inclusion criteria (n = 43). Average age of the T A B L E 2 Comparison of Thromboelastography parameters between stages of coagulopathy   (Figure 1). These three patients did not receive anticoagulation as they were already in a hypocoagulable stage. The different stages of CAC as seen in TEG is given in Figure S1. The mean duration of ICU stay (7.07 vs. 7) as well as platelet count were comparable between these two groups (Table S1). The platelet range was 8-470 Â 10 3 /μL and 97-512 Â 10 3 cells/μL among those who succumbed to death and survived respectively with three patients among non-survivors developing severe thrombocytopenia (<50 000/μL). Levels of D-Dimer were also comparable among these two groups while prolonged PT and aPTT was observed among nonsurvivors (Table S1).
During the ICU stay, 13 (30.23%) developed TEs while they were on heparin, but no hemorrhagic events reported. The events in decreasing order of incidence were acute coronary syndrome (n = 10), deep venous thrombosis (DVT) with pulmonary thromboembolism (PTE) (n = 2) and middle cerebral artery (MCA) infarction (n = 1). One patient with PTE and another patient with MCA infarct was discharged after recovery while all others had succumbed to death (11/13). The TEG parameters did not show any difference between patients who developed TEs and those who did not (Table S2)  and an increased endogenous thrombin generation potential early in the disease which later get reduced in the ICUs. [13][14][15][16] Based on the severity of the disease, decrease in the levels of protein C and antithrombin was found in severe COVID-19 (SOFA>10). 17 We observed a general shift toward a prothrombotic state in our study group (Table 1) which was evident in clot initiation, clot dynamics, clot strength, and resolution ( Figure S1). An Australian critical care team evaluated coagulation status in COVID-19 patients in the ICU using TEG and V-curve and they had observed a similar hypercoagulable picture in the clot initiation, amplification, and propagation. 17  As the severity of COVID-19 increases, a hypocoagulable picture appear which is similar to other consumptive coagulopathies. 4,22 ).
Lower thrombus generation has been seen in patients admitted to ICU during the later stages of the disease implying as the disease progresses, patients develop an overt coagulopathy which might be associated with septic shock. 22 Sepsis with a refractory septic shock and severe metabolic acidosis tend to reduce the thrombin generation potential in the ICU. 23 We have observed a mortality rate of 32.55% among the study population. Mortality correlated with MA, LY 30 and TG among TEG parameters ( Table 3). The laboratory profile comparison revealed that non-survivors had a prolonged PT/aPTT at admission and it could be due to the fact that 50% of them (7/14) already were in septic shock (Table S1). Abnormal coagulation parameters have been associated with a poor outcome in COVID-19 cases as disease progresses into an irreversible stage with cellular shut down. 24 CAC is associated with a hypercoagulable condition which puts the patients at risk of TEs. The cumulative incidence of TE in COVID-19 patients admitted to ICU is around 30% and systemic anticoagulation has been recommended to patients requiring ICU admission. 7,8 Even while on anticoagulation patients develop TEs. 25,26 We have observed that 79% of our patients had a hypercoagulable TEG tracing at the time of admission and 30.23% (13/43) had a documented TE during ICU stay even when they were on therapeutic doses of anticoagulants. The high incidence of TE in CAC might be due to the widespread inflammation and severity of the infection which in turn causes widespread clot formation. 6,27 Majority of them had arterial thrombosis and two patients developed PTE following DVT.
Among the 34 hypercoagulable tracings, 13 had secondary fibrinolysis activity ( Figure 1) and six of them had physiological lysis activity. Fibrinolysis activity plays a crucial part in the lungs where pulmonary microthrombi breakdown early in the disease phase is supposed to cause the elevated D-Dimer levels seen in COVID- 19. 2,5,11,21 The high prevalence of TE even while on anticoagulation is believed to be due to the hypercoagulable state with a reduced fibrinolysis activity, however, this particular feature is not proven yet. 21 We had repeated TEG in 11/46 patients before discharging from ICU and the repeat TEG ( Figure 2) showed that they were still having a hypercoagulable stage even after anticoagulation (median-5 days, IQR-7 days). Interestingly the fibrinolysis activity was more in the repeat TEG compared with their first report and the clinical significance of this might be worth looking into. The increase in fibrinolysis activity on the second TEG might probably be due to a result of reduction in disease severity and inflammation as compared with the day of admission. We were not able to follow up these patients once they were discharged from the hospital.
Thrombotic complications including central retinal artery occlusion (CRAO), pulmonary thromboembolisms, and mesenteric ischemia have been reported even after being discharged from hospital. [34][35][36] Coagulopathy in COVID-19 has been said to be profound and prolonged even after discharge. 29,30,37 There is still a paucity of evidence as to how long one should continue anticoagulants if they are at risk of TE following CAC.

| LIMITATIONS
The study cohort lacked platelet function, fibrinogen, and other coag-

ACKNOWLEDGEMENT
We graciously acknowledge the effort and guidance put by Dr. Jecko Thachil, MD in completing this manuscript. He had critically reviewed this article multiple times to guide us whenever we were in doubts.
We went through a lot of communications and every time, he was there to offer his knowledge and wisdom at the earliest.

CONFLICT OF INTERESTS
We declare that we do not have any conflicts of interests among ourselves.

DATA AVAILABILITY STATEMENT
Data available on request due to privacy/ethical restrictions.