In vitro hypercoagulability and ongoing in vivo activation of coagulation and fibrinolysis in COVID‐19 patients on anticoagulation

Blasi, Annabel; Meijenfeldt, Fien A. von; Adelmeijer, Jelle; Calvo, Andrea; Ibáñez, Cristina; Perdomo, Juan; Reverter, Juan Carlos; Lisman, Ton

doi:10.1111/jth.15043

Cited by 115 publications

(194 citation statements)

References 29 publications

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“…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 …”

Section: Discussionsupporting

confidence: 90%

“…We first assessed disease severity according to level of care and found, in line with existing literature, 18,19 that patients receiving a higher level of care had increased plasma levels of markers of in vivo activation of coagulation and fibrinolysis. Ex vivo thrombin generation was higher compared to controls and similar in patients in general wards and patients in higher levels of care, despite significantly higher doses of LMWH in patients in higher levels of care, confirming our previous findings that current anticoagulant strategies might not be sufficient 18 and suggesting that patients with COVID‐19 are profoundly hypercoagulable before administration of anticoagulants. However, as bleeding complications have also been associated with (severe) COVID‐19, 37 increasing doses of anticoagulant therapy is not without risks, and further research on optimal anticoagulant strategies are warranted.…”

Section: Discussionmentioning

confidence: 99%

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

Meijenfeldt

Havervall

Adelmeijer

et al. 2021

Research and Practice in Thrombosis and Haemostasis

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Background and Aims Patients with severe coronavirus disease 2019 (COVID‐19) are at significant risk of thrombotic complications. However, their prothrombotic state is incompletely understood. Therefore, we measured in vivo activation markers of hemostasis, plasma levels of hemostatic proteins, and functional assays of coagulation and fibrinolysis in plasma from patients with COVID‐19 and determined their association with disease severity and 30‐day mortality. Methods We included 102 patients with COVID‐19 receiving various levels of respiratory support admitted to general wards, intermediate units, or intensive care units and collected plasma samples shortly after hospital admission. Results Patients with COVID‐19 with higher respiratory support had increased in vivo activation of coagulation and fibrinolysis, as reflected by higher plasma levels of d ‐dimer, thrombin‐antithrombin, and plasmin‐antiplasmin complexes as compared to patients with no to minimal respiratory support and healthy controls. Moreover, the patients with COVID‐19 with higher respiratory support exhibited substantial ex vivo thrombin generation and lower ex vivo fibrinolytic capacity, despite higher doses of anticoagulant therapy compared to less severely ill patients. Fibrinogen, factor VIII, and von Willebrand factor levels increased, and ADAMTS13 levels decreased with increasing respiratory support in patients with COVID‐19. Low platelet count; low levels of prothrombin, antithrombin, and ADAMTS13; and high levels of von Willebrand factor were associated with short‐term mortality. Conclusions Severe COVID‐19 is associated with prothrombotic changes with increased in vivo activation of coagulation and fibrinolysis, despite anticoagulant therapy.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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

Meijenfeldt

Havervall

Adelmeijer

et al. 2021

Research and Practice in Thrombosis and Haemostasis

Self Cite

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“…Although our study is specific for TTP identification/exclusion, findings may also have relevance to other situations in which rapid ADAMTS13 testing is desired. We would be foolish, for example to ignore in the COVID‐19 era, recent reports of reduced ADAMTS13 in patients with severe disease, 25‐27 and the likely preference for rapid testing in that setting. Also, clinicians may be faced with critically ill patients with TMA with mild‐moderate reductions in ADAMTS13 activity (eg, patients with pre‐eclampsia, which can be very difficult to distinguish from TTP clinically).…”

Section: Resultsmentioning

confidence: 99%

A multicenter laboratory assessment of a new automated chemiluminescent assay for ADAMTS13 activity

Favaloro

Mohammed

Chapman

et al. 2021

Journal of Thrombosis and Haemostasis

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Background Thrombotic thrombocytopenic purpura (TTP) is a rare but potentially fatal disorder caused by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency. Prompt identification/exclusion of TTP can thus be facilitated by rapid ADAMTS13 testing. The most commonly utilized (enzyme‐linked immunosorbent assay [ELISA]–based) assay takes several hours to perform and so does not generally permit rapid testing. Objectives To evaluate the utility of a new automated test for ADAMTS13 activity, the HemosIL AcuStar ADAMTS13 Activity assay, based on chemiluminescence and able to be performed on an ACL AcuStar instrument within 33 minutes. Patients/Methods This multicenter (n = 8) assessment included testing of more than 700 test samples, with similar numbers of prospective (n = 348) and retrospective (n = 385) samples. The main comparator was the Technozym ADAMTS13 Activity ELISA. We also assessed comparative performance for detection of ADAMTS13 inhibitors using a Bethesda assay. Results Overall, the chemiluminescent assay yielded similar results to the comparator ELISA, albeit with slight negative bias. ADAMTS13 inhibitor detection was also comparable, albeit with slight positive bias with the AcuStar assay. Assay precision was similar with both assays, and we also verified assay normal reference ranges. Conclusions The HemosIL AcuStar ADAMTS13 Activity assay provided results rapidly, which were largely comparable with the Technozym ADAMTS13 Activity ELISA assay, albeit lower on average. Conversely, inhibitor levels tended to be identified at a higher level on average. Thus, the HemosIL AcuStar ADAMTS13 Activity assay provides a fast and accurate means to quantitate plasma levels of ADAMTS13 for TTP/ADAMTS13 identification/exclusion, and potentially also for other applications.

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“…Escher et al [66, 68] reported elevated vWF antigen and function, together with increased FVIII clotting activity in COVID-19 patients, likely reflecting the combined effect of the greater release of Weibel-Palade bodies from endothelial cells and the acute-phase reaction that raises the FVIII level. ADAMTS13 activity is mild-to-moderately reduced in COVID-19 patients [68-70].…”

Section: Endothelium Von Willebrand Factor and Abo Blood Groupmentioning

confidence: 99%

The Impact of COVID-19 Disease on Platelets and Coagulation

2020

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Coronavirus disease 2019 (COVID-19) causes a spectrum of disease; some patients develop a severe proinflammatory state which can be associated with a unique coagulopathy and procoagulant endothelial phenotype. Initially, COVID-19 infection produces a prominent elevation of fibrinogen and D-dimer/fibrin(ogen) degradation products. This is associated with systemic hypercoagulability and frequent venous thromboembolic events. The degree of D-dimer elevation positively correlates with mortality in COVID-19 patients. COVID-19 also leads to arterial thrombotic events (including strokes and ischemic limbs) as well as microvascular thrombotic disorders (as frequently documented at autopsy in the pulmonary vascular beds). COVID-19 patients often have mild thrombocytopenia and appear to have increased platelet consumption, together with a corresponding increase in platelet production. Disseminated intravascular coagulopathy (DIC) and severe bleeding events are uncommon in COVID-19 patients. Here, we review the current state of knowledge of COVID-19 and hemostasis.

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In vitro hypercoagulability and ongoing in vivo activation of coagulation and fibrinolysis in COVID‐19 patients on anticoagulation

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 115 publications

References 29 publications

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

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

A multicenter laboratory assessment of a new automated chemiluminescent assay for ADAMTS13 activity

The Impact of COVID-19 Disease on Platelets and Coagulation

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