Bedside thromboelastography to rapidly assess the pharmacodynamic response of anticoagulants and aspirin in COVID-19: evidence of inadequate therapy in a predominantly minority population

Abstract

COVID-19 is a thromboinflammatory disease [1]. Anticoagulant prophylaxis is currently widely used to attenuate thrombotic complications, and aspirin has also been recently proposed as a potential therapeutic option [2, 3]. However, there is limited evidence of anticoagulants’ pharmacodynamic efficacy, and no study of the pharmacodynamic efficacy of aspirin is available. No published experience with bedside assays to assess anticoagulant or antiplatelet response in COVID-19 is available. Here, we report a sub-analysis of the evaluation of hemostasis in hospitalized COVID-19 patients (TARGETCOVID) study (URL: https:// www. clini caltr ials. gov; Unique identifier: NCT04493307). The study was performed in accordance with standard ethical principles and approved by the local institutional review board. All patients provided written consent. We enrolled hospitalized patients diagnosed with COVID-19 by reverse transcription-polymerase chain reaction assay (n = 120) and patients without COVID-19 but with pneumonia and an elevated D-dimer (n = 13). Using a bedside thromboelastography assay (TEG-6s, Haemonetics Corporation, Braintree, MA, USA), we measured the reaction time (R) as an indicator of anticoagulant response and platelet function with the platelet mapping assay at the time of hospital administration [4, 5]. Aspirin effect was further determined by urinary 11-dehydro-thromboxane B2 (u11-dh TxB2) with enzyme-linked immune assay (Inflammatory Markers Laboratory, Wichita, KS, USA), total thrombus formation analysis system (T-TAS) with platelet chip (Fujimori Kogyo Co, Tokyo, Japan) and whole blood aggregometry (Chronolog Corporation, Havertown, PA, USA). The majority of our COVID-19 positive patients were African Americans (67%). The difference in R (ΔR) ≥ 1 min between the kaolin and kaolin plus heparinase channels in the TEG6s indicated an anticoagulant effect [5]. Aspirin response was assessed in patients admitted on chronic aspirin therapy (≥ 14 days) and anticoagulant therapy was assessed ≥ 24 h after administration. Compared to patients on enoxaparin prophylaxis (subcutaneous enoxaparin < 80 mg BID) (n = 50), patients on heparin prophylaxis (subcutaneous unfractionated heparin ≤ 7500 units TID) (n = 21) and therapeutic anticoagulation (intravenous unfractionated heparin or subcutaneous enoxaparin ≥ 80 mg BID) (n = 17) exhibited a significantly greater ΔR (0.31 ± 0.8 versus 1.2 ± 1.7 and 1.5 ± 1.4 min, respectively, p < 0.004 for both comparisons). There was a higher incidence of poor anticoagulant response (ΔR < 1 min) with enoxaparin prophylaxis compared to heparin prophylaxis and intravenous heparin (84% versus 62% and 53%, respectively, p < 0.05 for both comparisons) (Fig. 1a). In total, 29% of patients were on aspirin therapy. With TEG-6s, 94% of COVID-19 patients demonstrated > 50% platelet aggregation induced by 1 mmol/L arachidonic acid (AA) (aspirin nonresponsiveness) (data are not shown). In patients on aspirin, u11-dh TxB2 was similar in COVID19 positive and negative patients (3760 ± 2295 versus 3051 ± 1488 pg/mg creatinine). However, the number of non-COVID-19 patients were small to draw a definitive conclusion. In COVID-19 patients, u11-dh TxB2 was lower in aspirin-treated patients than patients not on aspirin * Paul A. Gurbel [email protected]