Effect of low or high doses of low‐molecular‐weight heparin on thrombin generation and other haemostasis parameters in critically ill patients with COVID‐19

Puzzolo, Maria Cristina; Pulcinelli, Fabio M.; Foà, Robin; Albante, Alida; Alessandri, Francesco; Alvaro, Domenico; Antonelli, Guido; Araimo‐Morselli, Fabio; Auricchio, Daniela; Baldacci, Erminia; Barone, F.; Bilotta, Federico; Brisciani, Matteo; Bruno, Katia; Cappannoli, Alessandro; Cardinale, Vincenzo; Ceccarelli, Giancarlo; Celli, Paola; Chistolini, Antonio; Consolo, Stella; Claudia, Croce; Crocitti, Beatrice; Curreli, Mariaignazia; d’Ettorre, Gabriella; Daniela, De Lauri; Lazzaro, Francesco De; Luca, Maria Lucia De; Fedele, Francesco; Ferretti, Antonietta; Galardo, Gioacchino; Giannetti, Lorena; Ianni, Stefano; Imperiale, Carmela; Maestrini, Viviana; Magnanimi, Eugenia; Federica, Maldarelli; Mancone, Massimo; Martelli, Maurizio; Martelli, S.; Mastroianni, Claudio Maria; Messina, Teresa; Olivieri, Sandra; Pallotta, Agnese; Elisa, Pattelli; Filippo, Pecorari; Perrella, S.; Mario, Piazzolla; Monica, Portieri; Pugliese, Francesco; Pulcinelli, Fabio; Fabiola, Ratini; Ricci, Claudia; Ruberto, Franco; Santopietro, Pietro; Santoro, Cristina; Serrao, Alessandra; Guglielmo, Tellan; Titi, Luca; Paolo, Tordiglione; Tosi, Antonella; Fausto, Trigilia

doi:10.1111/bjh.17003

Cited by 26 publications

(27 citation statements)

References 13 publications

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“…22,23 Moreover, recent reports demonstrated significant ex vivo thrombin generation in the majority of patients with COVID-19 despite anticoagulant therapy, suggesting that before anticoagulation, patients are profoundly hypercoagulable. 18,19,24 This hypercoagulable state is also detected in rotational thromboelastography studies using the EXTEM, which contains a heparin-neutralizing agent. 25 In addition, a hypofibrinolytic state has been demonstrated using whole blood thromboelastography, tissue plasminogen activator-modified thromboelastography, and a plasma-based clot lysis test.…”

Section: Introductionmentioning

confidence: 85%

“…Several studies demonstrated a hypercoagulable profile by whole blood thromboelastography with conflicting results on the presence of characteristics of disseminated intravascular coagulation 22,23 . Moreover, recent reports demonstrated significant ex vivo thrombin generation in the majority of patients with COVID‐19 despite anticoagulant therapy, suggesting that before anticoagulation, patients are profoundly hypercoagulable 18,19,24 . This hypercoagulable state is also detected in rotational thromboelastography studies using the EXTEM, which contains a heparin‐neutralizing agent 25 .…”

Section: Introductionmentioning

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: Introductionmentioning

confidence: 85%

Section: Introductionmentioning

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

View full text Add to dashboard Cite

show abstract

“…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%

“…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. Interestingly, one study showed that a persisting thrombin burst despite anticoagulation correlated with non-survival [123], whereas another found no difference between noncritical and critically ill COVID-19 patients [124].…”

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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“…Heparin has been widely used in clinic such as thromboembolic diseases, hemodialysis, and cardiovascular surgery (Ayerst et al, 2017;Aslani et al, 2020;Yu et al, 2020). With the advancement of pharmacology and clinical medicine, the application of heparin continues to expand (Chistolini et al, 2020). The negatively charged sulfate groups of heparin can bind and release various positively charged growth factors such as transforming growth factor β (TGF-β) and vascular endothelial growth factor (VEGF) (Jo et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Heparin-Modified Amniotic Membrane Combined With Growth Factors for Promoting Corneal Wound Healing After Alkali Burn

Zhao

Zuo

Zhong

et al. 2020

Front. Bioeng. Biotechnol.

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Ocular chemical burns are potentially blinding ocular injuries and require urgent management. Amniotic membrane (AM) transplantation is an effective surgical treatment, one of the reasons is because AM is a rich source of growth factors that can promote epithelialization and wound healing. However, growth factors will be gradually lost and insufficient after preparation process and long-time storage, leading to unsatisfactory therapeutic effects. Herein, we present a modified AM (AM-HEP) for the supplement and sustained release of growth factor by surface grafting heparin for treatment of ocular chemical burns. Heparin grafting rate and stability, microstructure, physical property, and sustained release of epithelial growth factor (EGF) of AM-HEP were characterized. Biocompatibility and ability to promote corneal epithelial cell growth and migration were evaluated and compared with a biological amnion, which is available on the market in vitro. The therapeutic effects of AM-HEP combined with EGF (AM-HEP@EGF) in vivo had been evaluated in a model of mouse corneal alkali burn. The results indicated that heparin was introduced into AM and maintain stability over 3 weeks at 37°C. The modification process of AM-HEP did not affect microstructure and physical property after comparing with non-modified AM. EGF could be combined quickly and effectively with AM-HEP; the sustained release could last for more than 14 days. AM-HEP@EGF could significantly promote corneal epithelial cell growth and migration, compared with non-modified AM and control group. Faster corneal epithelialization was observed with the transplantation of AM-HEP@EGF in vivo, compared with the untreated control group. The corneas in the AM-HEP@EGF group have less inflammation and were more transparent than those in the control group. The results from in vitro and in vivo experiments demonstrated that AM-HEP@EGF could significantly enhance the therapeutic effects. Taken together, AM-HEP@EGF is exhibited to be a potent clinical application in corneal alkali burns through accelerating corneal epithelial wound healing.

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Effect of low or high doses of low‐molecular‐weight heparin on thrombin generation and other haemostasis parameters in critically ill patients with COVID‐19

Abstract: The clinical picture of the coronavirus 2 (SARS‐CoV‐2)/COVID‐19‐related acute respiratory syndrome is often associated with a coagulopathy. An elevated D‐dimer has been linked with an unfavorable prognosis in COVID‐19 patients.

Cited by 26 publications

References 13 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

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

Heparin-Modified Amniotic Membrane Combined With Growth Factors for Promoting Corneal Wound Healing After Alkali Burn

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