key: cord-0745539-etibcspx
authors: Wright, Franklin L.; Vogler, Thomas O.; Moore, Ernest E.; Moore, Hunter B.; Wohlauer, Max V.; Urban, Shane; Nydam, Trevor L.; Moore, Peter K.; McIntyre, Robert C.
title: Fibrinolysis Shutdown Correlates to Thromboembolic Events in Severe COVID-19 Infection
date: 2020-05-15
journal: J Am Coll Surg
DOI: 10.1016/j.jamcollsurg.2020.05.007
sha: 71480d51449adc0ef61429a8f5350e460835dd39
doc_id: 745539
cord_uid: etibcspx

BACKGROUND: Coronavirus disease 2019 (COVID-19) predisposes patients to a prothrombotic state with demonstrated microvascular involvement. The degree of hypercoagulability appears to correlate with outcomes, however optimal criteria to assess for the highest risk patients for thrombotic events remain unclear; we hypothesized that deranged thromboelastography (TEG) measurements of coagulation would correlate with thromboembolic events. METHODS: Patients admitted to an intensive care unit with COVID-19 diagnoses that had TEG analyses performed were studied. Conventional coagulation assays, D-dimer levels, and viscoelastic parameters were analyzed using a receiver operating characteristic curve to predict thromboembolic outcomes and new onset renal failure. RESULTS: Forty-four patients with COVID-19 were included in the analysis. Derangements in coagulation laboratory values including elevated D-Dimer, fibrinogen, PT, and PTT were confirmed; viscoelastic parameters showed an elevated maximum amplitude and low lysis at 30 minutes. A complete lack of lysis of clot at 30 minutes was seen in 57% of patients and predicted VTE with an AUROC of .742 (p=0.021). A D-Dimer cutoff of 2600 ng/ml predicted need for dialysis with an AUROC of .779 (p=0.005). Overall, patients with no lysis of clot at 30 minutes and a D-Dimer of greater than 2600 ng/ml had a rate of VTE of 50% compared to 0% for patients with neither risk factor (p=0.008) and had a hemodialysis rate of 80% compared to 14% (p=0.004). CONCLUSIONS: Fibrinolysis shutdown, as evidenced by elevated D-Dimer and complete failure of clot lysis at 30 minutes on thromboelastography, predicts thromboembolic events and need for hemodialysis in critically ill patients with COVID-19. Further clinical trials are required to ascertain the need for early therapeutic anticoagulation or fibrinolytic therapy to address this state of fibrinolysis shutdown.

The novel coronavirus known as severe acute respiratory distress syndrome coronavirus2 (SARS-CoV-2), leading to Coronavirus disease 2019 (COVID- 19) , emerged in Wuhan, China in late 2019 and has become a worldwide pandemic. More than 2.7 million cases have been confirmed worldwide causing more than 190,000 deaths, with these numbers growing exponentially 1 . A subset of patients infected with COVID-19 progress to acute respiratory distress syndrome (ARDS), with 70% of critically ill patients requiring intubation and mechanical ventilation 2 .

Viral infection associated inflammation clearly predisposes patients to prothrombotic states 3 Initial studies in Wuhan that utilized multivariate regression analyses suggested a higher mortality based on age, SOFA score, and D-Dimer levels 5 . Furthermore, previous work during the H1N1 viral pneumonia outbreak demonstrated that elevations in D-Dimer levels suggest an increased thrombosis risk 6 . Specific coagulation pathway product analysis demonstrated decreased survival in patients presenting with COVID-19 and elevations in the prothrombin time, D-dimer, and fibrin degradation products 7 .

Broad evidence exists for using thromboelastography or the thromboelastogram (TEG) to predict thromboembolic rates in other disease processes. Across trauma, surgical, and mixed intensive care unit populations, hypercoagulability as demonstrated by TEG, especially an elevated maximum amplitude (MA), has reliably predicted thromboembolic events (see discussion for references). The initial study of TEG usage in 24 COVID-19 patients in Italy demonstrated that the TEG-MA and angle were elevated and the TEG-R and K values were decreased, however these findings were not correlated with outcome measures such as rates of thrombotic events 8 .

Based on prior data we hypothesize that abnormalities in TEG parameters would correlate with thromboembolic risk. The aim of this study was to develop an improved screening tool to suggest the highest risk of thromboembolic complications including renal failure.

All (2%) scored a 5 (high flow oxygen), and 2 patients (5%) scored a 4 (oxygen by mask). All patients with VTE had a score of 7 other than one patient who died; likewise, all patients with arterial thrombus had a score of 7 other than one patient who died.

The patients' conventional coagulation parameters are listed in table 2 (platelet counts, PT, PTT, D-Dimer and Fibrinogen). Pertinent abnormalities include an elevated D-dimer level, elevated fibrinogen, with normal platelet counts in the majority of patients and mildly elevated PT and aPTT with median values at or slightly above the upper limits of normal. The median ISTH DIC score was 0 (0-2), with no patients having a score higher that 4. TEG variables were consistent with a hypercoagulable state with an elevated MA and low LY30 ( Table 2) .

The receiver operating characteristic curve for VTE was only significant for TEG LY30 and VTE with an area under the curve of .742 (p=0.021 Figure 1a ). The Youden Index for VTE was identified at 0. In this patient cohort, 57% had this extreme lack of fibrinolytic activity. These patients were categorized as fibrinolysis shutdown based on the presence of elevated D-Dimer and low fibrinolytic activity; fibrinolysis shutdown has previously been described as LY30 of less than 0.8% but the more complete shutdown seen in these patients results in an LY30 of 0% as a diagnostic cutoff based on the Youden Index for maximizing sensitivity and specificity. Descriptive variables of patient with fibrinolysis shutdown versus those without shutdown are listed in table 3. The only significant differences appreciated between groups were patients with fibrinolytic shutdown had a lower incidence of a history of hyperlipidemia and a lower TEG angle, even though fibrinogen levels were similar. Patients with fibrinolysis shutdown had a 40% rate of VTE compared to 5% in patients without shutdown (p=0.013).

The time to VTE was significantly shorter in patients with fibrinolysis shutdown (Figure 2 , Log Rank p=0.001). Overall, 24 of the 44 patients with severe COVID-19 infection in the ICU were placed on full therapeutic anticoagulation, despite only 14 of these patients having documented VTE or arterial thrombotic events; 10 additional patients received therapeutic anticoagulation empirically based on physician concern for occult thrombotic events or bedside evidence of extreme hypercoagulability such as frequent clotting of central venous access or hemodialysis filters.

The receiver operating characteristic curve for new onset need for dialysis was only significant for D- 

Patients were grouped into coagulation cohorts using both LY30 and D-Dimer inflection points. Patients with neither risk factor for hypercoagulability were present in 32% of the patient population, one coagulation risk factor represented 45% of the patient population, and 23% of patients had both. The number of patients with VTE increased from 0 to 50% for patients with 0 to 2 coagulation risk factors respectively (p=0.008 Figure 4) . Similarly, the need for dialysis increased from 14% to 80% (p=0.004 Figure 4 ). While not significant, thrombotic stroke rate was also increased from 7% to 30% (p=0.274 In the trauma population, hypercoagulable TEG parameters predict venous thromboembolism (VTE) 2.4 -6.7 fold higher based on higher maximum amplitude (MA) parameters despite appropriate prophylactic anticoagulation [16] [17] [18] [19] . In a broad surgical patient population, patients with a TEG MA greater than 68 were 6 times more likely to have thrombotic events including VTE, myocardial infarction, and cerebrovascular accident 20 . In a mixed medical-surgical ICU population with baseline abnormal coagulation parameters, a TEG-MA of greater than 72 predicted thromboembolic events more effectively than conventional coagulation parameters such as INR, PTT, fibrinogen, or platelet count 21 .

In a more recent study, a low LY30 suggestive of fibrinolysis shutdown was associated with an increased risk of thrombotic complications as early as 12 hours from injury 18 . Medical inhibition of fibrinolysis with tranexamic acid has also been associated with an increased risk of thrombotic complications in trauma patients 22 . TEG MA in this COVID-19 population was universally elevated regardless whether the patient developed thrombotic complications or not, but LY30 strongly differentiated those patients with and without VTE. The first publication to utilize TEG in the ICU with COVID-19 patients drew similar conclusions that viscoelastic testing demonstrated hypercoagulability in this patient population 8 ;

however, this study of 24 patients from Italy was descriptive and did not include any outcomes associated with TEG indices. Our results suggest an that TEG LY30 serves as a prognostic marker that this patient population is at risk for thrombotic complications, and may have a better performance at identifying these at-risk patients than other coagulation measurements.

Elevated D-dimer levels were also associated with potential micro-thrombotic disease leading to Recently, acute fibrinolysis shutdown has been demonstrated in early sepsis and found to correlate to increased morbidity and mortality 32 . Fibrinolysis shutdown and organ failure has historically been associated with DIC 33 , however the ISTH score of 4 or greater to define overt DIC 9 The need for more aggressive anticoagulation or fibrinolytic therapy remains unclear, and there exist scant data to guide more aggressive therapies to mitigate the hypercoagulable state. Microvascular thrombosis may contribute to acute respiratory distress syndrome, acute renal failure, and liver function test elevations frequently observed in these patients. It is unclear but biologically plausible that treatment of the hyperthrombotic state of these patients with COVID-19 could prevent or decrease the extent of renal injury seen.

There are inherent limitations to this retrospective descriptive study. First there was variability in the laboratory testing patterns based on intensivist preference. In addition, the TEG and other coagulation parameters were drawn at variable times of the patient disease processes. Studies done to evaluate for thromboembolic events were performed for clinical suspicion rather than routine screening and therefore some VTE or arterial emboli were likely not captured or had delays in diagnosis. Clotting of central lines and iHD/CRRT circuits was commonly noted in these critically ill patients with COVID-19

but was not reliably captured in our data set, again potentially leading to an underestimation of hypercoagulable outcomes. Due to the sudden influx of patients with a COVID-19 diagnosis, outcome data are inherently limited since many patients still remain hospitalized and there are logistical hurdles to effective diagnosis of VTE. In addition, less common outcomes such as stroke and mortality would require a large cohort of patients to obtain adequate power to determine if the coagulation parameters we identified that were associated with VTE and renal failure are also associated with these adverse events.

COVID-19 causes not only hypercoagulability but also fibrinolysis shutdown which is associated with VTE, stroke, and renal failure. Defining the optimum predictive test for micro-or macro-thromboses requires further study, however the TEG in conjunction with the D-dimer appear to be a sensitive marker for severity of disease which will need to be studied in a prospective fashion. A TEG LY30 of 0% and a D-dimer of greater than 2600 ng/ml together suggest complete fibrinolysis shutdown and markedly elevated risk of renal failure, VTE, and thrombotic events. The optimum medical therapy to address this hypercoagulable and fibrinolytic state is still unknown, however these results suggest the need to consider therapeutic anticoagulation and potentially tPA therapy to directly addresses the failure in the coagulation cascade of this high-risk group of patients. 

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