Researchers at Baylor College of Medicine are recommending that all COVID-19 patients admitted to the ICU undergo a thromboelastography (TEG) to test for the risk of forming blood clots.
This recommendation comes after they found that more than half of the patients tested under these same conditions developed clinically significant blood clots that went undetected using routine screenings.
The findings appear in in the latest edition of JAMA Network Open.
The main advantage of TEG testing is its potential to deliver immediate goal-oriented and individualized care to a bleeding patient:
- Global assessment of blood coagulability, including coagulation cascade, platelet function, and fibrinolysis
- Rapid real-time bedside test with a simple methodology (point-of-care testing)
- Diagnosis of coagulopathic bleeding
- Guide transfusion therapy and decrease the use of blood products
- Detect dynamic changes in blood coagulation during resuscitation
- Predict the clinical efficacy of therapeutic agents affecting blood coagulability
TEG has convincingly demonstrated its usefulness to help improve outcomes in cardiac surgery.
“As the surgical critical care team at Baylor St. Luke’s Medical Center was discussing their work in the ICU a few weeks ago, I was amazed to hear them express that one of their greatest challenges was that the central intravenous and arterial lines and the dialysis catheters kept unexpectedly clotting in COVID-19 patients in the ICU,” said Dr. Todd Rosengart, chair and professor of the Michael E. DeBakey Department of Surgery at Baylor and senior author of the paper. “I’d never seen or heard anything like this in my 30 years as a surgeon, even in our sickest patients.”
This prompted Rosengart and colleagues to look at what types of tests could be performed to identify these otherwise undetected blood clots.
Researchers observed 21 patients with confirmed COVID-19 infection admitted to the Baylor St. Luke’s Medical Center ICU between March 15 and April 9.
They found that the standard clotting profile or screening of the patients was fairly normal. They were then moved to the next level of more specific clotting tests, which included analyzing a patient’s fibrinogen and D dimer levels.
Fibrinogen is the protein that makes up the clot and D dimer levels are used to indicate the rate at which a patient’s clots are being broken down, which would usually suggest that the body is “chewing up” all of the clotting factors.
For the COVID-19 patients in the ICU, researchers found that the levels of fibrinogen were more than three times the normal range, indicating that the body was churning out this protein.
Looking at these two results together, there was no clear indication that these patients were at increased risk for forming blood clots.
At this point, the researchers looked to a third tier of tests that is not a regularly used process in most ICU patients, the thromboelastography test.
This test looks at how quickly a clot forms, its strength and stability. It is used mostly for open heart surgery patients who often have abnormal clot function and also is commonly used for trauma patients.
This test showed the researchers two things: the patients who they found were clotting their central intravenous and arterial lines and dialysis catheters had abnormally high clotting function compared to the patients who did not have clotting issues, and the clot breakdown function was significantly higher in the patients who were clotting less than others.
Among the 21 patients studied, 13 of them, or 62%, developed 46 blood clots that could only be detected through the TEG test.
For patients who are at a higher risk of blood clots as indicated by the TEG test, the researchers recommend administering additional blood thinners.
“The TEG test should be performed on all COVID-19 ICU patients immediately to find those who are at a higher risk of clotting,” Rosengart said.
“At the point where physicians discover that their central line and catheter is clotting, the horse is out of the barn.”
The researchers are now looking at whether these undetected blood clots could be related to the unexplained deaths they are seeing in COVID-19 patients.
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.
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 St. Luke’s Medical Center from March 15 to April 9, 2020, with SARS-CoV-2 infection confirmed by reverse transcription–polymerase chain reaction test of nasopharyngeal swab.
This study is reported following Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines for a cohort study.
All patients received standard deep vein thrombosis chemoprophylaxis on ICU admission and therapeutic anticoagulation (heparin infusion or enoxaparin [2 mg/kg/d]) for thrombotic complications.
All patients underwent TEG and TEG with heparinase correction on ICU admission. 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.
Results
This cohort study included 21 patients (mean [SD] age, 68 [11] years [range, 50-89 years]; 12 [57%] men). Among these patients, 20 (95%) had comorbidities, with a mean (SD) of 3 (2) comorbidities each (range, 1-7 comorbidities each). Mean (SD) follow-up was 11 (4) days.
Regrading thromboembolism risk, 4 patients (19%) had atrial fibrillation, a history of malignant tumors, or chronic kidney disease. Four patients (19%) required extracorporeal membrane oxygenation, and 18 patients (86%) required renal replacement therapy.
There were 2 mortalities (10%), both occurring as pulseless electrical activity after acute-onset pulmonary hypertension.
Cohort mean international normalized ratio (INR), partial thromboplastin, and platelet levels were within reference ranges, but fibrinogen and dimerized plasmin fragment D levels were elevated (Table 1).
A total of 19 patients (90%) demonstrated hypercoagulable TEG, including 14 patients (74%) with hypercoagulable TEG as defined by fibrinogen activity and MA criteria and 5 patients (26%) with hypercoagulable TEG as defined by MA criteria alone.
There were 13 patients (62%) who demonstrated clinical evidence of thrombotic events, with a total of 46 events recorded and a range of 1 to 8 events per patient. All but 1 of these patients presented with arterial, central venous, or dialysis catheter or filter thromboses (Table 1). These patients received therapeutic anticoagulation a mean (SD) of 6 (5) days after ICU admission (range, 1-18 days).
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).
In comparison, innate TEG MA was significantly greater for the high event rate group than the low event rate group (mean [SD], 75 [7] mm vs 61 [21] mm; P = .01). Elevated MA was observed in 10 patients (100%) in the high event rate group vs 5 patients (45%) in the low event rate group. Innate TEG MA provided 100% sensitivity and 100% negative predictive value (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.
References
1. Han H, Yang L, Liu R, et al. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection. Clin Chem Lab Med. Published online March 16, 2020;/j/cclm.ahead-of-print/cclm-2020-0188/cclm-2020-0188.xml. doi:10.1515/cclm-2020-0188
2. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094-1099. doi:10.1111/jth.14817
3. Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020;18(5):1023-1026. doi:10.1111/jth.14810
4. Geerts W. Central venous catheter-related thrombosis. Hematology Am Soc Hematol Educ Program. 2014;2014(1):306-311. doi:10.1182/asheducation-2014.1.306
5. Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020;(April):S0049-3848(20)30120-1. doi:10.1016/j.thromres.2020.04.013
6. Dolhnikoff M, Duarte-Neto AN, de Almeida Monteiro RA, et al. Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19. J Thromb Haemost. Published online April 15, 2020. doi:10.1111/jth.14844
More information: JAMA Network Open (2020). DOI: 10.1001/jamanetworkopen.2020.11192
