Evaluation of COVID‐19 coagulopathy; laboratory characterization using thrombin generation and nonconventional haemostasis assays

Abstract

Introduction Patients with COVID‐19 are known to have a coagulopathy with a thrombosis risk. It is unknown whether this is due to a generalized humoral prothrombotic state or endothelial factors such as inflammation and dysfunction. The aim was to further characterize thrombin generation using a novel analyser (ST Genesia, Diagnostica Stago, Asnières, France) and a panel of haematological analytes in patients with COVID‐19. Methods Platelet poor plasma of 34 patients with noncritical COVID‐19 was compared with 75 patients with critical COVID‐19 (as defined by WHO criteria) in a retrospective study by calibrated automated thrombography and ELISA. Patients were matched for baseline characteristics of age and gender. Results Critical patients had significantly increased fibrinogen, CRP, interleukin‐6 and D‐dimer compared to noncritical patients. Thrombin generation, in critical patients, was right shifted without significant differences in peak, velocity index or endogenous thrombin potential. Tissue plasminogen activator (tPA), tissue factor pathway inhibitor (TFPI) and vascular endothelial growth factor (VEGF) were significantly increased in the critical versus noncritical patients. Critically ill patients were on haemodiafiltration (31%; heparin used in the circuit) or often received escalated prophylactic low‐molecular weight heparin. Conclusion These results confirm increased fibrinogen and D‐dimer in critical COVID‐19‐infected patients. Importantly, disease severity did not increase thrombin generation (including thrombin‐antithrombin complexes and prothrombin fragment 1 + 2) when comparing both cohorts; counter‐intuitively critical patients were hypocoaguable. tPA, TFPI and VEGF were increased in critical patients, which are hypothesized to reflect endothelial dysfunction and/or contribution of heparin (which may cause endothelial TFPI/tPA release).

Thrombin generation in patients with COVID-19 with and without thromboprophylaxis

“…Our results are perfectly in line with three very recent findings by Blasi A. et al [26], Nougier C. et al [33], as well as White et al [34] who measured TG on ST Genesia ® . All these studies demonstrated normal TG profile in COVID-19 under thromboprophylaxis.…”

Prothrombotic changes in patients with COVID‐19 are associated with disease severity and mortality

“…We We confirm and extend published findings on hemostatic alterations in COVID-19 and compare hemostatic profiles between patients stratified according to level of care and according to level of respiratory support. Previous studies were either small or assessed a limited number of hemostatic tests, but in aggregate these studies are in line with our findings on changes in the VWF/ADAMTS13 axis, 18,[30][31][32][33] in vivo and ex vivo activation of coagulation, 18,19,25,[34][35][36] and in vivo and ex vivo fibrinolytic status. [18][19][20]26 We first assessed disease severity according to level of care and found, in line with existing literature, 18,19 39 We also demonstrated that hemostatic parameters became progressively more prothrombotic with increasing respiratory support, with the exception of prothrombin and antithrombin, platelet VWF plasma levels increased with increasing disease severity, which is likely related to the massive release of cytokines that has been described in severe COVID-19.…”

“…We confirm and extend published findings on hemostatic alterations in COVID‐19 and compare hemostatic profiles between patients stratified according to level of care and according to level of respiratory support. Previous studies were either small or assessed a limited number of hemostatic tests, but in aggregate these studies are in line with our findings on changes in the VWF/ADAMTS13 axis, 18,30‐33 in vivo and ex vivo activation of coagulation, 18,19,25,34‐36 and in vivo and ex vivo fibrinolytic status 18‐20,26 …”

Thrombin Generation in Patients with Coronavirus Disease 2019

“…Taken together, these and previous findings are suggestive of some degrees of coagulation exhaustion in COVID-19, at least at a stage of disease needing oxygen therapy and/or intensive care, which would hence confirm the existence of initial local and/or systemic activation of blood coagulation, followed by significant exhaustion, as earlier noted in other studies, even using different markers. [12][13][14][15] These findings are also in keeping with solid evidence of prolonged prothrombin times and decreased platelet counts in COVID-19 patients, especially those progressing to severe/critical illness, as underpinned in most recent meta-analyses. [16][17][18] It is also noteworthy that the almost unvaried evidence in thrombin generation values performed with or without TM would suggest that the protein C system may be a minor player on COVID-19 coagulopathy, while activation of platelets and the factor XII-dependent pathway may alternatively appear as major drivers.…”