Anti-FXa Activity with Intermediate-Dose Thromboprophylaxis in COVID-19

Rappaport, Stephen; Clark, Jenna; Delibert, Samantha; Maynard, Kaylee; Prasad, Paritosh; Kaufman, David; Pietropaoli, Anthony P.; Quill, Caroline M.; Groth, Christine M.

doi:10.1164/rccm.202006-2511le

Cited by 5 publications

(8 citation statements)

References 11 publications

(10 reference statements)

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“…The rationale for this approach is that both the therapeutic and intermediate doses provide superior anticoagulant effect compared to the standard dose. 15 Preprint (not peer-reviewed) status was not considered as exclusion criteria. In line with other meta-analysis related to COVID-19 treatment, we considered this strategy acceptable because of the urgency for timely evidence regarding effective treatment of COVID-19 patients.…”

Section: Search Strategy and Selection Criteriamentioning

confidence: 99%

Safety and efficacy of different prophylactic anticoagulation dosing regimens in critically and non-critically ill patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials

Ortega‐Paz

Galli

Capodanno

et al. 2021

European Heart Journal - Cardiovascular Pharmacotherapy

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Background The clinical impact of different prophylactic anticoagulation regimens among hospitalized patients with COVID-19 remains unclear. We pooled evidence from available randomized controlled trials (RCTs) to provide insights on this topic. Methods and results We searched for RCTs comparing treatment with an escalated-dose (intermediate-dose or therapeutic-dose) versus a standard-dose prophylactic anticoagulation regimen in critically and non-critically-ill COVID-19 patients requiring hospitalization and without a formal indication for anticoagulation. The primary efficacy endpoint was all-cause death, and the primary safety endpoint was major bleeding. Seven RCTs were identified, including 5,154 patients followed on average of 33 days. Compared to standard-dose prophylactic anticoagulation, escalated-dose prophylactic anticoagulation was not associated with a reduction of all-cause death (17.8% vs. 18.6%; Risk Ratio [RR] 0.96, 95% Confidence Interval [CI] 0.78–1.18) but was associated with an increase in major bleeding (2.4% vs. 1.4%; RR 1.73, 95%CI 1.15–2.60). Compared to prophylactic anticoagulation used at a standard-dose, an escalated-dose was associated with lower rates of venous thromboembolism (2.5% vs. 4.7%; RR 0.55, 95%CI 0.41–0.74) without a significant effect on myocardial infarction (RR 0.80, 95%CI 0.47–1.36), stroke (RR 0.94, 95%CI 0.43–2.09), or systemic arterial embolism (RR 1.20, 95%CI 0.29–4.95). There were no significant interactions in the subgroup analysis for critically and non-critically-ill patients. Conclusions Our findings provide comprehensive and high-quality evidence for the use of standard-dose prophylactic anticoagulation over an escalated-dose regimen as routine standard of care for hospitalized patients with COVID-19 who do not have an indication for therapeutic anticoagulation, irrespective of disease severity. Study registration This study is registered in PROSPERO (CRD42021257203).

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Section: Search Strategy and Selection Criteriamentioning

confidence: 99%

Safety and efficacy of different prophylactic anticoagulation dosing regimens in critically and non-critically ill patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials

Ortega‐Paz

Galli

Capodanno

et al. 2021

European Heart Journal - Cardiovascular Pharmacotherapy

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“…However, the contact phase pathway may play an important role in thrombosis development when contact surfaces are exposed in scenarios such as trauma injury or bacterial and viral infections 29,30 . Indeed, numerous in vivo studies have confirmed a critical function of FXII in thrombus growth and stabilization under the mentioned conditions and provided the rationale for the development of new FXIIa inhibitors, which ensure thrombo-protection in patients without causing a bleeding complications 29,31,32 .…”

Section: Introductionmentioning

confidence: 98%

Altered fibrin clot structure contributes to thrombosis risk in severe COVID-19

Wygrecka

Birnhuber

Seeliger

et al. 2021

Preprint

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The high incidence of thrombotic events suggests a possible role of the contact system pathway in COVID-19 pathology. Here, we demonstrate altered levels of factor XII (FXII) and its activation products in two independent cohorts of critically ill COVID-19 patients in comparison to patients suffering from severe acute respiratory distress syndrome due to influenza virus (ARDS-influenza). Compatible with this data, we report rapid consumption of FXII in COVID-19, but not in ARDS-influenza, plasma. Interestingly, the kaolin clotting time was not prolonged in COVID-19 as compared to ARDS-influenza. Using confocal and electron microscopy, we show that increased FXII activation rate, in conjunction with elevated fibrinogen levels, triggers formation of fibrinolysis-resistant, compact clots with thin fibers and small pores in COVID-19. Accordingly, we observed clot lysis in 30% of COVID-19 patients and 84% of ARDS influenza subjects. Analysis of lung tissue sections revealed wide-spread extra- and intra-vascular compact fibrin deposits in COVID-19. Together, our results indicate that elevated fibrinogen levels and increased FXII activation rate promote thrombosis and thrombolysis resistance via enhanced thrombus formation and stability in COVID-19.

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“…Plasma anti-FXa activity was measured 24–36 h after ICU admission and 4 h after enoxaparin injection. Based on previous studies investigating the efficacy of anti-FXa in non-COVID-19 patients, the target range of enoxaparin for VTE prophylaxis was considered 0.2–0.5 unit/mL [ 5 ].…”

Section: Methodsmentioning

confidence: 99%

“…A prophylactic dose of LMWH is often used, while some studies suggest higher thromboprophylaxis dosing such as enoxaparin 40 mg twice daily versus 40 mg once daily for intensive therapy unit (ITU) patients [ 4 ]. Monitoring for prophylaxis is not routinely used; however, authors advised that anticoagulant treatment should be guided by anti-factor Xa (anti-FXa) activity [ 5 ]. The appropriate target anti-FXa level for the prophylactic dose of enoxaparin has been suggested as between 0.2 and 0.4/0.5 IU/mL [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…Monitoring for prophylaxis is not routinely used; however, authors advised that anticoagulant treatment should be guided by anti-factor Xa (anti-FXa) activity [ 5 ]. The appropriate target anti-FXa level for the prophylactic dose of enoxaparin has been suggested as between 0.2 and 0.4/0.5 IU/mL [ 5 ]. Middeldorp and colleagues reviewed anti-FXa activity in COVID-19-infected patients admitted to the hospital, all receiving thromboprophylaxis enoxaparin (40 mg once daily), and compared 4-h anti-FXa activity levels.…”

Section: Introductionmentioning

confidence: 99%

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The Effectiveness of the Intermediate and Therapeutic Doses of Enoxaparin in COVID-19 Patients: A Comparative Study of Factor Xa Inhibition

Mansour¹,

Azadikhah²,

Zand³

et al. 2022

Acta Haematol

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Background: Management of anticoagulant therapy in COVID-19 patients is a critical role. Low Molecular Weight Heparin (LMWH) thromboprophylaxis is already recommended and anti-Factor Xa (anti-FXa) monitoring has been used to titrate LMWH doses. Methods: Through a cross-sectional study, we evaluated anti-FXa activity in patients admitted to ICU, receiving intermediate dose (30, 40, 50mg, subcutaneously (SC), twice daily) or therapeutic dose (1 mg/kg, SC, Q12h) of enoxaparin to find whether the patients of these two groups achieve anti-FXa levels in the accepted thromboprophylaxis range. Results: The occurrence of DVT was 26% in the therapeutic dose and 17% in the intermediate-dose group. D-dimer values were nearly 3.5-fold higher in those who received a therapeutic-dose of anticoagulants than in those who received intermediate dose thromboprophylaxis. Patients in the therapeutic dose group had significantly higher IL-6 levels (p≤0.001). More than one-third of the patients in the therapeutic dose group (n = 8; 42.18%) and approximately half of the patients in the intermediate-dose group (n = 12; 52.2%) achieved the target range level of anti-FXa. Patients who received therapeutic doses were more likely to have anti-FXa levels above the expected range (47.4 Vs 13% in the intermediate dose group. P<0.05). Conclusion: Therapeutic dose of enoxaparin in critically ill COVID-19 infected patients didn’t reduce the incidence of thromboembolic events and on the other hand may predispose these patients to increased risk of bleeding by increased anti-FXa activity above the desired level. Administration of intermediate-dose thromboprophylaxis is suggested to achieve anti-FXa levels in the accepted thromboprophylaxis range.

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Anti-FXa Activity with Intermediate-Dose Thromboprophylaxis in COVID-19

Cited by 5 publications

References 11 publications

Safety and efficacy of different prophylactic anticoagulation dosing regimens in critically and non-critically ill patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials

Safety and efficacy of different prophylactic anticoagulation dosing regimens in critically and non-critically ill patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials

Altered fibrin clot structure contributes to thrombosis risk in severe COVID-19

The Effectiveness of the Intermediate and Therapeutic Doses of Enoxaparin in COVID-19 Patients: A Comparative Study of Factor Xa Inhibition

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