Thromboelastographic Results and Hypercoagulability Syndrome in Patients With Coronavirus Disease 2019 Who Are Critically Ill

Severe acute respiratory syndrome coronavirus 2 (SAR-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) pandemic that has caused approximately 300 000 deaths globally. Disseminated intravascular coagulopathy and other COVID-19–associated coagulopathies occur among patients with severe SARS-CoV-2 infections.1 Potentially lethal hypercoagulability is an unusual, poorly defined COVID-19–associated coagulopathy presentation.2,3 We found that more than half of patients admitted to the intensive care unit (ICU) of Baylor St Luke’s Medical Center developed clinically significant thromboses that were associated with hypercoagulable thromboelastographic (TEG) parameters alone.


Introduction
Severe acute respiratory syndrome coronavirus 2 (SAR-CoV-2) is responsible for the coronavirus disease 2019  pandemic that has caused approximately 300 000 deaths globally.
Disseminated intravascular coagulopathy and other COVID-19-associated coagulopathies occur among patients with severe SARS-CoV-2 infections. 1 Potentially lethal hypercoagulability is an unusual, poorly defined COVID-19-associated coagulopathy presentation. 2,3 We found that more than half of patients admitted to the intensive care unit (ICU) of Baylor St Luke's Medical Center developed clinically significant thromboses that were associated with hypercoagulable thromboelastographic (TEG) parameters alone.

Methods
This cohort study was approved by the Baylor College of Medicine institutional review board with a waiver of informed consent granted because this was a retrospective electronic health record review of data collected for clinical purposes. The cohort included all patients admitted to the ICU of Baylor Hypercoagulability was defined as elevated fibrinogen activity greater than a 73°angle or maximum amplitude (MA) more than 65 mm on TEG with heparinase correction.
Group differences were analyzed using Fisher exact test. Analyses were conducted using SAS statistical software version 9.4 (SAS Institute). P values were 2-sided, and statistical significance was set at .05. Data were analyzed from March 21 to April 14, 2020.    (Table 1). These patients received therapeutic anticoagulation a mean (SD) of 6 (5) days after ICU admission (range, 1-18 days).

JAMA Network Open | Infectious Diseases
There were no statistically significant differences in prothrombin time, INR, partial thromboplastin time, or platelet levels between 10 patients with at least 2 thrombotic events vs 11 patients with fewer than 2 events (  (Table 2).

Discussion
This cohort study found that higher thromboses rates were associated with TEG results outside reference ranges among patients with COVID-19 who were critically ill. Risk associated with TEG results outside reference ranges manifested as a 62% thrombosis event rate, 2-fold the thrombosis event rates that have been previously reported, despite our use of recommended deep vein thrombosis prophylaxis. 4,5 Underdiagnosis or undertreatment of hypercoagulation may explain the high incidence of unexplained COVID-19 mortalities. These may be associated with potentially preventable microvascular and macrovascular thromboses and consequent cardiovascular complications, including myocardial injury and infarction. 5,6 Accordingly, our institution and other health care systems have adopted immediate full heparinization in patients with high-acuity COVID-19.
Hypercoagulation associated with COVID-19 may be due to increased angiotensin II expression secondary to angiotensin-converting enzyme 2 receptor binding and consequently increased plasminogen activator inhibitor C-1 expression, which is consistent with our observation of reduced fibrinolysis in our high thrombotic event rate group. 5,6 Similarly, angiotensin II-mediated pulmonary vasoconstriction can lead to stasis and hypercoagulability, as can COVID-19 induction of antiphospholipid antibodies and complement during cytokine storms, causing vasculitis and microthromboses.
Our finding of INR, partial thromboplastin time, and platelet levels within or close to reference ranges but elevated fibrinogen and dimerized plasmin fragment D levels reflect a complex inflammatory and hematologic profile distinct from the disseminated intravascular coagulopathy associated with COVID-19. In this context, TEG may be critical in accurately identifying patients at increased thrombosis risk and thereby avoiding unnecessary anticoagulation in patients with low thrombosis risk. Specifically, a hypercoagulable innate TEG MA yielded 100% sensitivity and 100% negative predictive value for the occurrence of multiple thromboses.
One study limitation is whether this retrospective study reflects differences in our anticoagulation practices vs other institutions or their underreporting of thrombotic events, as recently suggested. 4-6 Our findings suggest that alterations of diagnostic and prophylactic treatment guidelines may be critical for the successful treatment of coagulopathies associated with COVID-19.