PMID- 36277784 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20221025 IS - 2297-055X (Print) IS - 2297-055X (Electronic) IS - 2297-055X (Linking) VI - 9 DP - 2022 TI - Serial thrombin generation and exploration of alternative anticoagulants in critically ill COVID-19 patients: Observations from Maastricht Intensive Care COVID Cohort. PG - 929284 LID - 10.3389/fcvm.2022.929284 [doi] LID - 929284 AB - BACKGROUND: COVID-19 associated coagulopathy (CAC) is associated with an increase in thromboembolic events. Current guidelines recommend prophylactic heparins in the management of CAC. However, the efficacy of this strategy in the intensive care population remains uncertain. OBJECTIVE: We aimed to measure thrombin generation (TG) to assess CAC in intensive care unit (ICU) patients receiving thromboprophylaxis with low molecular weight heparin (LMWH) or unfractionated heparin (UFH). In addition, we performed statistical modeling to link TG parameters to patient characteristics and clinical parameters. Lastly, we studied the potency of different anticoagulants as an alternative to LMWH treatment in ex vivo COVID-19 plasma. PATIENTS/METHODS: We included 33 patients with confirmed COVID-19 admitted at the ICU. TG was measured at least twice over the course of 6 weeks after admission. Thrombin generation parameters peak height and endogenous thrombin potential (ETP) were compared to healthy controls. Results were subsequently correlated with a patient characteristics and laboratory measurements. In vitro spiking in TG with rivaroxaban, dabigatran, argatroban and orgaran was performed and compared to LMWH. RESULTS: Anti-Xa levels of all patients remained within the therapeutic range throughout follow-up. At baseline, the mean (SE) endogenous thrombin potential (ETP) was 1,727 (170) nM min and 1,620 (460) nM min for ellagic acid (EA) and tissue factor (TF), respectively. In line with this we found a mean (SE) peak height of 353 (45) nM and 264 (96) nM for EA and TF. Although fluctuating across the weeks of follow-up, TG parameters remained elevated despite thromboprophylaxis. In vitro comparison of LMWHs and direct thrombin inhibitors (e.g., agratroban, dabigatran) revealed a higher efficacy in reducing coagulation potential for direct thrombin inhibition in both ellagic acid (EA) and tissue factor (TF) triggered TG. CONCLUSION: In a sub-group of mechanically ventilated, critically ill COVID-19 patients, despite apparent adequate anti-coagulation doses evaluated by anti-Xa levels, thrombin generation potential remained high during ICU admission independent of age, sex, body mass index, APACHE II score, cardiovascular disease, and smoking status. These observations could, only partially, be explained by (anti)coagulation and thrombosis, inflammation, and multi-organ failure. Our in vitro data suggested that direct thrombin inhibition compared with LMWH might offer an alternate, more effective anticoagulant strategy in COVID-19. CI - Copyright (c) 2022 van de Berg, Mulder, Alnima, Nagy, van Oerle, Beckers, Hackeng, Hulshof, Sels, Henskens, van der Horst, ten Cate, Spronk, van Bussel and MaastrICCht Collaborators. FAU - van de Berg, Tom W AU - van de Berg TW AD - Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands. AD - Department of Internal Medicine, Maastricht University Medical Centre+, Maastricht, Netherlands. FAU - Mulder, Mark M G AU - Mulder MMG AD - Department of Intensive Care Medicine, Maastricht University Medical Centre+, Maastricht, Netherlands. FAU - Alnima, Teba AU - Alnima T AD - Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, Netherlands. FAU - Nagy, Magdolna AU - Nagy M AD - Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands. AD - Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands. FAU - van Oerle, Rene AU - van Oerle R AD - Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands. AD - Central Diagnostic Laboratory, Maastricht University Medical Centre+, Maastricht, Netherlands. FAU - Beckers, Erik A M AU - Beckers EAM AD - Department of Internal Medicine, Maastricht University Medical Centre+, Maastricht, Netherlands. AD - Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands. FAU - Hackeng, Tilman M AU - Hackeng TM AD - Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands. AD - Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands. FAU - Hulshof, Anne-Marije AU - Hulshof AM AD - Central Diagnostic Laboratory, Maastricht University Medical Centre+, Maastricht, Netherlands. FAU - Sels, Jan-Willem E M AU - Sels JEM AD - Department of Intensive Care Medicine, Maastricht University Medical Centre+, Maastricht, Netherlands. AD - Department of Cardiology, Maastricht University Medical Centre+, Maastricht, Netherlands. FAU - Henskens, Yvonne M C AU - Henskens YMC AD - Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands. AD - Central Diagnostic Laboratory, Maastricht University Medical Centre+, Maastricht, Netherlands. FAU - van der Horst, Iwan C C AU - van der Horst ICC AD - Department of Intensive Care Medicine, Maastricht University Medical Centre+, Maastricht, Netherlands. AD - Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands. FAU - Ten Cate, Hugo AU - Ten Cate H AD - Department of Internal Medicine, Maastricht University Medical Centre+, Maastricht, Netherlands. AD - Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands. AD - Thrombosis Expertise Centre Maastricht, Maastricht University Medical Centre+, Maastricht, Netherlands. FAU - Spronk, Henri M H AU - Spronk HMH AD - Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands. AD - Department of Internal Medicine, Maastricht University Medical Centre+, Maastricht, Netherlands. AD - Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands. FAU - van Bussel, Bas C T AU - van Bussel BCT AD - Department of Intensive Care Medicine, Maastricht University Medical Centre+, Maastricht, Netherlands. AD - Care and Public Health Research Institute, Maastricht University, Maastricht, Netherlands. CN - MaastrICCht Collaborators LA - eng PT - Journal Article DEP - 20221006 PL - Switzerland TA - Front Cardiovasc Med JT - Frontiers in cardiovascular medicine JID - 101653388 PMC - PMC9582511 OTO - NOTNLM OT - COVID OT - DOACs OT - ICU OT - anticoagulation OT - thrombin generation COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/10/25 06:00 MHDA- 2022/10/25 06:01 PMCR- 2022/10/06 CRDT- 2022/10/24 04:38 PHST- 2022/04/26 00:00 [received] PHST- 2022/09/20 00:00 [accepted] PHST- 2022/10/24 04:38 [entrez] PHST- 2022/10/25 06:00 [pubmed] PHST- 2022/10/25 06:01 [medline] PHST- 2022/10/06 00:00 [pmc-release] AID - 10.3389/fcvm.2022.929284 [doi] PST - epublish SO - Front Cardiovasc Med. 2022 Oct 6;9:929284. doi: 10.3389/fcvm.2022.929284. eCollection 2022.