key: cord-0902945-n1gracze authors: Sehgal, Tushar; Aggarwal, Mukul; Baitha, Upendra; Gupta, Gaurav; Prakash, Bindu; Gupta, Anu; Kumar, Ganesh; Biswas, Ashutosh; Khan, Maroof; Shalimar, title: Thromboelastography determined dynamics of blood coagulation and its correlation with complications and outcomes in patients with coronavirus disease 2019 date: 2022-01-15 journal: Res Pract Thromb Haemost DOI: 10.1002/rth2.12645 sha: e8819c1abb97f59a6fd65ded796a789c00369de0 doc_id: 902945 cord_uid: n1gracze BACKGROUND: Coronavirus disease 2019 (COVID‐19) causes abnormalities in the hemostatic system, collectively known as COVID‐associated coagulopathy. The dynamics of clot formation are best discerned by whole‐blood viscoelastic tests, such as thromboelastography (TEG). We aimed to assess the various abnormalities seen on TEG and explored the predictors of outcomes in these patients. METHODS: Thromboelastography was performed for 28 patients with COVID‐19 using an automated thromboelastogram. The hemostatic condition was categorized as hypercoagulable in 17 (63%), hypocoagulable in 2 (7%), and normal in 8 (30%) based on TEG variables, such as reaction time , time until clot reaches a fixed strength, alpha angle, maximum amplitude, and clotting index. Laboratory parameters and clinical outcomes were compared between hypercoagulable and normal groups. RESULTS: Twenty‐seven patients with a median age of 50 years (interquartile range, 40‐60 years), male‐to‐female ratio of 0.9:1, median C‐reactive protein of 25.7 (10.9‐108.8) mg/L, serum ferritin of 693 (317‐1031) µg/L, and albumin 2.9 (2.6‐3.3) g/dL were included. The median prothrombin time/international normalized ratio and activated partial thromboplastin time were within normal range in the hypercoagulable and normal groups. The severity of COVID‐19 was mild in 6 (22.2%), moderate in 2 (7.4%), and severe in 19 (70.4%) patients. Twenty‐eight‐day mortality among patients with hypocoagulable and hypercoagulable states was higher than normal coagulation status. (log‐rank test, P = .002). CONCLUSIONS: Hypercoagulable state, together with a severe inflammatory state, is common in patients with COVID‐19, despite thromboprophylaxis. TEG assesses coagulation status better than conventional coagulation tests. Coagulation abnormalities are associated with poor outcomes. • Coronavirus disease 2019 (COVID-19) is frequently associated with blood-clotting abnormalities and inflammation. • Thromboelastography assesses coagulati`on abnormalities better than conventional tests. • Excessive blood clot formation is common despite treatment with heparin (anticoagulant). • Patients with COVID-19 with clotting abnormalities are less likely to survive than those without clotting abnormalities. facilitating early initiation of effective therapies. 4 In contrast, in DIC, the laboratory abnormalities listed in decreasing order of frequency are thrombocytopenia, elevated D-dimer, prolonged PT and aPTT, and low fibrinogen. In early DIC, the platelet count and fibrinogen levels may remain within the normal range, albeit reduced from the baseline levels. 5 Thromboelastography (TEG) assesses the global coagulation cascade. Existing studies on TEG in COVID-19 have reported early clot initiation, increased clot strength (due to increased fibrinogen component), and reduced fibrinolysis. [6] [7] [8] These changes suggest an underlying hypercoagulable state in patients with This is distinct from the consumptive coagulopathy seen with DIC. The CAC changes are dynamic and may be affected by multiple factors, including ongoing inflammation, sepsis, anticoagulation, renal failure, and so on. We aimed to assess the abnormalities seen on TEG and derived coagulation index (CI) in admitted patients with COVID- 19 . In addition, we explored the predictors of outcomes in these patients. The study was conducted at the COVID care facility at a tertiary care academic center in India between May 2021 and June 2021. and 65 years of age with mild/moderate/severe COVID-19 infection admitted to the hospital and who underwent TEG assessment anytime were included. Patients with prior vascular thrombosis, pregnancy, malignancy, and those on any prior antiplatelet drugs like aspirin, clopidogrel, or anticoagulant therapy for non-COVIDrelated disorders were excluded. Patients with chronic liver disease or chronic kidney disease (estimated glomerular filtration rate [eGFR] <15 mL/min or dialysis dependent) or those who expired within 24 hours of admission were also excluded. Healthy individuals were not included in the study. The criteria for acute kidney injury (AKI) included an increase in serum creatinine by ≥0.3 mg/dL (>26.5 μmol/L) observed within 48 hours; or an increase in serum creatinine to ≥1.5 times baseline, which is known or presumed to have occurred within the past 7 days; or urine volume <0.5 mL/kg/h for 6 hours. 10 The severity of COVID-19 was graded as per the Ministry of Health and Family Welfare, India guidelines. 11 Asymptomatic patients or those with only upper respiratory tract symptoms and normal oxygen saturation on room air were defined as having a mild disease. Those with lower respiratory tract involvement such as pneumonia and saturation between 90% and 94% at room air and/or respiratory rate (RR) between 24 and 30/min were defined as moderate COVID-19. Patients having saturation <90% on room air and/or a RR >30/min or severe acute respiratory illness were classified as a severe disease. 12 We followed uniform protocol management for all admitted patients. 12 Prophylactic anticoagulation (low-molecular-weight increased R-time, increased K-time, decreased alpha angle, and/or decreased MA; 13 and hypercoagulable if two or more of the following parameters were observed: decreased R-time, decreased K-time, increased alpha angle, and/or increased MA. 13 CI, which combines all TEG variables, was used to define the hypercoagulable (CI >3) and hypocoagulable (CI < −3) status. LY30 measures percent lysis 30 minutes after MA and was used to diagnose either primary or secondary fibrinolysis. Primary fibrinolysis was defined when LY30 was higher than the upper limit of the normal reference range, with CI below the lower limit of the normal reference range. 14 Secondary fibrinolysis was defined when LY30 and CI were higher than the upper limit of the normal reference range. 14 All patients were followed up for the entire duration of the hospital stay. After discharge from the hospital, patients were followed up telephonically every week for 4 weeks. In case the patient died, the date and cause of death was documented. The following data of patients were collected: clinical details including comorbidities, COVID severity, and laboratory parameters. The characteristics of the cohort are presented in Table 1 were hypercoagulable, and 2 (20%) were hypocoagulable, while 1 (10%) was normal on TEG analysis (P = .20). The laboratory results (all values in median) of the cohort are presented in Table 2 . Among the inflammatory parameters, WBC was 9.5 × 10 9 /L (7.3-15.6), C-reactive protein (CRP) was 25.7 (10.9-108.8) mg/L, ferritin was 693 (317-1031) µg/L, and albumin was 2.9 (2.6-3.3) g/dL. Hemoglobin was 10.7 (7.9-11.9) g/dL, and platelet count was 160 (124-262) × 10 9 /L. Among the renal function tests, urea was 39 (29-60) mg/dL, and serum creatinine was 0.8 (0.4- The coagulation profile, including the TEG analysis of the cohort, is shown in The association between anticoagulant status, platelet count, coagulation markers, and TEG parameters is shown in Table 4 . Twenty-one (78%) patients in the moderate and severe COVID-19 category received anticoagulation in the form of LMWH, while 6 (22%) patients in the mild COVID-19 category did not receive anticoagulation. There was no statistically significant difference between anticoagulant status, platelet count, coagulation, and TEG parameters. The phenomenon of the fibrinolytic shutdown was observed in four (15%) patients. They were reported as hypercoagulable on TEG analysis. All four patients had high D-dimer levels and LY30 of 0%, with decreased K-time and either increased alpha angle or increased MA. No clinically evident thrombosis was seen in these patients. The univariate age-adjusted hazard ratios for mortality of various parameters are shown in Table 5 . Those who died compared to those who survived were older, had higher inflammatory markers such as WBC (P < .01), fibrinogen (P = .31), and serum ferritin (P = .48). The laboratory parameters such as AST (P = .08), ALT (P = .08), ALP (P = .12) and serum urea (P = .01) were higher in those who died. TEG parameters among those who died included an increased MA (P = .31) and increased CI (P = . 19 ). There were no statistically significant differences between the two groups in the R-time, K-time, alpha angle, MA, LY30, CI, and other biochemical parameters. The agulable states was higher than normal coagulation status (log-rank test, P = .002; Figure 2 ). At a median follow-up of 21 days (IQR, 2-30), 10 patients (37%) died. All patients died due to ARDS and refractory septic shock due to COVID-19 disease. No patient had clinically evident thrombosis. Mortality occurred at a median of 3.5 days after their TEG test was done. The mortality of the patients in the normal and hypercoagulable groups were 1 of 10 (10%) versus 7 of 10 (70%), respectively (P = .20; Table 1 ). In the current study, distinct coagulation abnormalities in patients with COVID-19 were seen. The hypercoagulable state was most common, seen in two-thirds of patients characterized by reduced R-time and reduced K-time and increased alpha angle, increased MA, and increased CI. Patients with abnormal coagulation parameters on TEG had higher mortality compared to those with normal coagulation status. The proposed theories for CAC center around severe immune dysregulation, impairment of the fibrinolytic system, and/or upreg- Wright et al. 20 reported that fibrinolysis shutdown (elevated Ddimer and LY30 of 0%) predicted VTE events; however, we did not observe any VTE events in our study. The markedly elevated levels of D-dimer in patients with fibrinolysis shutdown might represent local thrombosis in the microvasculature (eg, pulmonary and renal) that are not consistently captured on whole-blood assays. 25 The hy- abnormalities at day 7 despite full anticoagulation and at discharge. 21 We did not perform a sequential TEG analysis in our patients. Maatman et al. 16 found that 50% of their 12 intensive care unit Limitations of our study include a small sample size that may limit the widespread applicability of the results. Details regarding body mass index and race/ethnicity were not collected from the patients. We could not perform TEG at a defined interval due to logistic issues. Also, sequential TEG analysis on our patients could have provided an in-depth analysis and understanding of coagulation status in these patients. Role of functional fibrinogen, a quantifier of fibrinogen contribution to clot, was not performed by TEG. In conclusion, the results of this study support hypercoagulability together with a severe inflammatory state, also called thromboinflammatory state, in patients with COVID-19. Our data show that TEG could better identify and assess hypercoagulability in patients with COVID-19 than conventional coagulation tests such as PT and aPTT. The authors thank Dilshad, Hemant, and Amar Negi for coordination and data maintenance. The authors have no conflict of interest or financial disclosures. All authors contributed substantially to the concept and design, analysis and interpretation of data. TS, MA, and Shalimar contributed to critical writing and revising intellectual content. All authors gave final approval of the version to be published. 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