Anticoagulation as secondary prevention of massive lung thromboses in hospitalized patients with COVID-19

Sofia, Rosaria; Carbone, Mattias; Landoni, Giovanni; Zangrillo, Alberto; Dagna, Lorenzo

doi:10.1016/j.ejim.2022.04.009

Cited by 9 publications

(10 citation statements)

References 38 publications

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“…Severe forms of COVID-19 seem to be linked to the formation in situ of micro-clots caused by an abnormal activation of the immune system in the lungs [ 4 ]. It has been hypothesized that anticoagulant therapy may exert a prophylactic role against these immune-thrombotic events by preventing thrombi formation and progression and, furthermore, that this benefit may best be demonstrated early [ 7 ] because anticoagulants may have a lesser ability to act on already formed thrombi [ 8 ]. In our updated systematic review and meta-analysis of randomized controlled trials involving non-critically ill hospitalized patients, we demonstrated that thromboprophylaxis with therapeutic-dose heparins (primarily LMWH) was associated with a statistically significant reduction of all-cause mortality and thrombotic events balanced with a modest probability of increased major bleeding.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Heparin Full-Dose Anticoagulation on Survival of Hospitalized, Non-critically Ill COVID-19 Patients: A Meta-analysis of High Quality Studies

Pilia

Belletti

Fresilli

et al. 2023

Lung

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Background International COVID-19 guidelines recommend thromboprophylaxis for non-critically ill inpatients to prevent thrombotic complications. It is still debated whether full-dose thromboprophylaxis reduces all-cause mortality. The main aim of this updated systematic review and meta-analysis is to evaluate the effect of full-dose heparin-based thromboprophylaxis on survival in hospitalized non-critically ill COVID-19 patients. Methods A systematic review was performed across Pubmed/Medline, EMBASE, Cochrane Central Register of clinical trials, Clinicaltrials.gov, and medRxiv.org from inception to November 2022. We conducted a meta-analysis of randomized clinical trials (RCTs) comparing full-dose heparin-based anticoagulation to prophylactic or intermediate dose anticoagulation or standard treatment in hospitalized non-critically ill COVID-19 patients. The risk of bias was assessed using the Cochrane risk-of-bias tool for randomized trials and Grading of Recommendations Assessment, Development and Evaluation was applied. The primary outcome was all-cause mortality at the longest follow-up available. Results We identified 6 multicenter RCTs involving 3297 patients from 13 countries across 4 continents. The rate of all-cause mortality was 6.2% (103/1662) in the full-dose group vs 7.7% (126/1635) in the prophylactic or intermediate dose group (Risk Ratio [RR] = 0.76; 95% confidence interval [CI] = 0.59–0.98; P = 0.037). The probabilities of any mortality difference and of NNT ≤ 100 were estimated at 98.2% and 84.5%, respectively. The risk of bias was low for all included RCTs and the strength of the evidence was “moderate.” Conclusion Our meta-analysis of high-quality multicenter RCTs suggests that full-dose anticoagulation with heparin or low molecular weight heparin reduces all-cause mortality in hospitalized non-critically ill COVID-19 patients. Study registration : PROSPERO, review no. CRD42022348993. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s00408-023-00599-6.

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Section: Discussionmentioning

confidence: 99%

The Effect of Heparin Full-Dose Anticoagulation on Survival of Hospitalized, Non-critically Ill COVID-19 Patients: A Meta-analysis of High Quality Studies

Pilia

Belletti

Fresilli

et al. 2023

Lung

Self Cite

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“…We decided to focus our attention on non-critically ill patients in the hypothesis that full-dose anticoagulation is likely capable of being an effective prophylaxis against immunothrombotic events and in preventing their progression [ 22 ] . If COVID-19 MicroCLOTS are similar to the immune-thrombosis model, they are probably resistant to anticoagulants drugs thus heparin may stop the progression of the coagulation cascade avoiding the increase in thrombi size, but is not able to dissolve clots [ 23 ] . This aspect may be an explanation of conflicting results of other previous studies that grouped critical and non-critical patients without distinction.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of heparin full-dose anticoagulation in hospitalized non-critically ill COVID-19 patients: a meta-analysis of multicenter randomized controlled trials

Pilia

Belletti

Fresilli

et al. 2022

J Thromb Thrombolysis

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Arterial and venous thrombotic events in COVID-19 cause significant morbidity and mortality among patients. Although international guidelines agree on the need for anticoagulation, it is unclear whether full-dose heparin anticoagulation confers additional benefits over prophylactic-dose anticoagulation. This systematic review and meta-analysis aimed to investigate the efficacy and safety of heparin full-dose anticoagulation in hospitalized non-critically ill COVID-19 patients. We searched Pubmed/Medline, EMBASE, Clinicaltrials.gov, medRxiv.org and Cochrane Central Register of clinical trials dated up to April 2022. Randomized controlled trials (RCTs) comparing full-dose heparin anticoagulation to prophylactic-dose anticoagulation or standard treatment in hospitalized non-critically ill COVID-19 patients were included in our pooled analysis. The primary endpoint was the rate of major thrombotic events and the co-primary endpoint was the rate of major bleeding events. We identified 4 studies, all of them multicenter, randomizing 2926 patients. Major thrombotic events were 23/1524 (1.5%) in full-dose heparin anticoagulation versus 57/1402 (4.0%) in prophylactic-dose [relative risk (RR) 0.39; 95% confidence interval (CI) 0.25–0.62; p˂0.01; I 2 = 0%]. Clinical relevant bleeding events occurred in 1.7% (26/1524) among patients treated with heparin full anticoagulation dose compared to 1.1% (15/1403) in prophylactic-dose group (RR 1.60; 95% CI 0.85–3.03; p = 0.15; I 2 = 20%). Mortality was 6.6% (101/1524) versus 8.6% (121/1402) (RR 0.63; 95% CI 0.33–1.19; p = 0.15). In this meta-analysis of high quality multicenter randomized trials, full-dose anticoagulation with heparin was associated with lower rate of major thrombotic events without differences in bleeding risk and mortality in hospitalized non critically ill COVID-19 patients. Study registration PROSPERO, review no. CRD42022301874. Supplementary Information The online version contains supplementary material available at 10.1007/s11239-022-02681-x.

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“…As the disease progresses, anticoagulant therapeutic effect may be not satisfactory owing to the interactions of inflammation with the coagulation cascade. Full-dose anticoagulant therapy cannot reverse established disease process (thrombus formation) at the advanced stage ( 173 , 174 ). Additionally, thrombosis leads to the consumption of coagulation factors, and full-dose anticoagulant therapy conversely worsens bleeding risk.…”

Section: Treatment Strategymentioning

confidence: 99%

Pathophysiological mechanisms of thrombosis in acute and long COVID-19

Jing

Xiang

et al. 2022

Front. Immunol.

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COVID-19 patients have a high incidence of thrombosis, and thromboembolic complications are associated with severe COVID-19 and high mortality. COVID-19 disease is associated with a hyper-inflammatory response (cytokine storm) mediated by the immune system. However, the role of the inflammatory response in thrombosis remains incompletely understood. In this review, we investigate the crosstalk between inflammation and thrombosis in the context of COVID-19, focusing on the contributions of inflammation to the pathogenesis of thrombosis, and propose combined use of anti-inflammatory and anticoagulant therapeutics. Under inflammatory conditions, the interactions between neutrophils and platelets, platelet activation, monocyte tissue factor expression, microparticle release, and phosphatidylserine (PS) externalization as well as complement activation are collectively involved in immune-thrombosis. Inflammation results in the activation and apoptosis of blood cells, leading to microparticle release and PS externalization on blood cells and microparticles, which significantly enhances the catalytic efficiency of the tenase and prothrombinase complexes, and promotes thrombin-mediated fibrin generation and local blood clot formation. Given the risk of thrombosis in the COVID-19, the importance of antithrombotic therapies has been generally recognized, but certain deficiencies and treatment gaps in remain. Antiplatelet drugs are not in combination with anticoagulant treatments, thus fail to dampen platelet procoagulant activity. Current treatments also do not propose an optimal time for anticoagulation. The efficacy of anticoagulant treatments depends on the time of therapy initiation. The best time for antithrombotic therapy is as early as possible after diagnosis, ideally in the early stage of the disease. We also elaborate on the possible mechanisms of long COVID thromboembolic complications, including persistent inflammation, endothelial injury and dysfunction, and coagulation abnormalities. The above-mentioned contents provide therapeutic strategies for COVID-19 patients and further improve patient outcomes.

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Anticoagulation as secondary prevention of massive lung thromboses in hospitalized patients with COVID-19

Cited by 9 publications

References 38 publications

The Effect of Heparin Full-Dose Anticoagulation on Survival of Hospitalized, Non-critically Ill COVID-19 Patients: A Meta-analysis of High Quality Studies

The Effect of Heparin Full-Dose Anticoagulation on Survival of Hospitalized, Non-critically Ill COVID-19 Patients: A Meta-analysis of High Quality Studies

Efficacy and safety of heparin full-dose anticoagulation in hospitalized non-critically ill COVID-19 patients: a meta-analysis of multicenter randomized controlled trials

Pathophysiological mechanisms of thrombosis in acute and long COVID-19

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