Prothrombotic disturbances of hemostasis of patients with severe COVID-19: A prospective longitudinal observational study

Hardy, Michaël; Michaux, Isabelle; Lessire, Sarah; Douxfils, Jonathan; Dogné, Jean Michel; Bareille, Marion; Horlait, Geoffrey; Bulpa, Pierre; Chapelle, Céline; Laporte, Silvy; Testa, Sophie; Jacqmin, Hugues; Lecompte, T.; Dive, Alain; Mullier, François

doi:10.1016/j.thromres.2020.10.025

Cited by 37 publications

(44 citation statements)

References 10 publications

(12 reference statements)

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“…5 E, the appearance of an abnormal pattern was highest at around 2 weeks. Compared with the previous studies showing the time course and prevalence of abnormal hemostasis parameters, the appearance of an abnormal waveform pattern might be prolonged for longer durations than the elevated levels of D-dimer and PAI-1 29 and be observed more frequently than the elevation of D-dimer, although the detail information on the durations from the onset of COVID-19 was not available and the types of the subjects and the countries where researches were performed were different 30 , 31 . These potential differences between the APTT clot waveform and other hemostasis parameters might suggest the possibility that the abnormal APTT clot waveform might reflect some unique abnormalities in coagulation, which might not directly result in the abnormal routine hemostasis parameters.…”

Section: Discussioncontrasting

confidence: 56%

Clot waveform of APTT has abnormal patterns in subjects with COVID-19

Shimura

Kurano

Kanno

et al. 2021

Sci Rep

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In Coronavirus disease 2019 (COVID-19) subjects, recent evidence suggests the presence of unique coagulation abnormalities. In this study, we performed clot waveform analyses to investigate whether specific modulations are observed in COVID-19 subjects. We analyzed the second derivative of the absorbance in routine APTT tests performed using an ACL-TOP system. We observed high frequencies of abnormal patterns in APTT second-derivative curves that could be classified into an early shoulder type, a late shoulder type, or a biphasic type, high maximum first-derivative and second-derivative peak levels, and a low minimum second-derivative peak level in COVID-19 subjects. These modulations were not observed in subjects with disseminated intravascular coagulation. These abnormal patterns are also observed in patients with lupus anticoagulant, hemophilia, or factor IX deficiency. The plasma fibrinogen levels might also be involved in the abnormal APTT waveforms, especially the high maximum first-derivative and second-derivative peak levels. The abnormal patterns in the APTT second-derivative curves appear with highest frequency at around 2 weeks after the onset of COVID-19 and were not associated with the severity of COVID-19. These results suggest the possible presence of a specific abnormal coagulopathy in COVID-19.

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Section: Discussioncontrasting

confidence: 56%

Clot waveform of APTT has abnormal patterns in subjects with COVID-19

Shimura

Kurano

Kanno

et al. 2021

Sci Rep

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“…These data confirm other recent observations from COVID-19 case series of reduced ADAMTS13 activity [ 10 , [13] , [14] , [15] ] or markedly increased VWF/ADAMTS13 ratio [ 12 , 32 , 33 ]. Although in a further small case series in which comprehensive hemostasis testing was performed longitudinally in COVID-19 patients for the duration of hospital admission, reduced ADAMTS13 was an inconsistent finding [ 34 ]. It is noteworthy that low ADAMTS13 plasma levels predicted mortality in COVID-19 patients in three independent studies [ 16 , 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Recombinant ADAMTS13 reduces abnormally up-regulated von Willebrand factor in plasma from patients with severe COVID-19

Turecek

Peck

Rangarajan

et al. 2021

Thrombosis Research

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Thrombosis affecting the pulmonary and systemic vasculature is common during severe COVID-19 and causes adverse outcomes. Although thrombosis likely results from inflammatory activation of vascular cells, the mediators of thrombosis remain unconfirmed. In a cross-sectional cohort of 36 severe COVID-19 patients, we show that markedly increased plasma von Willebrand factor (VWF) levels were accompanied by a partial reduction in the VWF regulatory protease ADAMTS13. In all patients we find this VWF/ADAMTS13 imbalance to be associated with persistence of ultra-high-molecular-weight (UHMW) VWF multimers that are highly thrombogenic in some disease settings. Incubation of plasma samples from patients with severe COVID-19 with recombinant ADAMTS13 (rADAMTS13) substantially reduced the abnormally high VWF activity, reduced overall multimer size and depleted UHMW VWF multimers in a time and concentration dependent manner. Our data implicate disruption of normal VWF/ADAMTS13 homeostasis in the pathogenesis of severe COVID-19 and indicate that this can be reversed ex vivo by correction of low plasma ADAMTS13 levels. These findings suggest a potential therapeutic role for rADAMTS13 in helping restore haemostatic balance in COVID-19 patients.

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“…So far, some in vitro studies have reported that there was a heparin concentration dependent decrease in thrombin generation [120,121]. Studies showed that COVID-19 patients had a higher endogenous thrombin potential [31,39,48,66,[122][123][124][125][126][127]] than manufacturer's reference range, healthy controls or patients with sepsis, sometimes despite UFH or LMWH anticoagulation at a minimum of prophylactic dosing. Few studies found a heparin dose-dependent decrease in thrombin generation [125,127] as described in vitro.…”

Section: Impact Of Differences In Anticoagulation Regimens (Type (Ufhmentioning

confidence: 99%

Viscoelastometric Testing to Assess Hemostasis of COVID-19: A Systematic Review

Bareille

Hardy

Douxfils

et al. 2021

JCM

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Infection by SARS-CoV-2 is associated with a high risk of thrombosis. The laboratory documentation of hypercoagulability and impaired fibrinolysis remains a challenge. Our aim was to assess the potential usefulness of viscoelastometric testing (VET) to predict thrombotic events in COVID-19 patients according to the literature. We also (i) analyzed the impact of anticoagulation and the methods used to neutralize heparin, (ii) analyzed whether maximal clot mechanical strength brings more information than Clauss fibrinogen, and (iii) critically scrutinized the diagnosis of hypofibrinolysis. We performed a systematic search in PubMed and Scopus databases until December 31st, 2020. VET methods and parameters, and patients’ features and outcomes were extracted. VET was performed for 1063 patients (893 intensive care unit (ICU) and 170 non-ICU, 44 studies). There was extensive heterogeneity concerning study design, VET device used (ROTEM, TEG, Quantra and ClotPro) and reagents (with non-systematic use of heparin neutralization), timing of assay, and definition of hypercoagulable state. Notably, only 4 out of 25 studies using ROTEM reported data with heparinase (HEPTEM). The common findings were increased clot mechanical strength mainly due to excessive fibrinogen component and impaired to absent fibrinolysis, more conspicuous in the presence of an added plasminogen activator. Only 4 studies out of the 16 that addressed the point found an association of VETs with thrombotic events. So-called functional fibrinogen assessed by VETs showed a variable correlation with Clauss fibrinogen. Abnormal VET pattern, often evidenced despite standard prophylactic anticoagulation, tended to normalize after increased dosing. VET studies reported heterogeneity, and small sample sizes do not support an association between the poorly defined prothrombotic phenotype of COVID-19 and thrombotic events.

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Prothrombotic disturbances of hemostasis of patients with severe COVID-19: A prospective longitudinal observational study

Cited by 37 publications

References 10 publications

Clot waveform of APTT has abnormal patterns in subjects with COVID-19

Clot waveform of APTT has abnormal patterns in subjects with COVID-19

Recombinant ADAMTS13 reduces abnormally up-regulated von Willebrand factor in plasma from patients with severe COVID-19

Viscoelastometric Testing to Assess Hemostasis of COVID-19: A Systematic Review

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