Changes in anticoagulant and antiplatelet drug supply at US hospitals before and during the COVID-19 pandemic (2018-2021).

PURPOSE: Antithrombotic agents have a role in coronavirus disease 2019 (COVID-19) treatment, but the pandemic disrupted medication supply. This study examined changes in the volume of oral and parenteral anticoagulant and antiplatelet medications at US hospitals during the pandemic. METHODS: IQVIA National Sales Perspective (NSP) data was used to determine the monthly volume of anticoagulants and antiplatelets purchased at US hospitals between January 2018 and February 2021. Mean monthly medication volumes, reported as extended units (EUs), and year-over-year changes in medication volume were determined. A single-group interrupted time series analysis was used to evaluate changes in the rate of growth of monthly medication volumes before (January 2019-February 2020) and during (March 2020-February 2021) the COVID-19 pandemic. RESULTS: Overall, there was a 43.4% decline in the total volume of anticoagulants and antiplatelets at US hospitals in March 2020, driven by a decrease in heparin volume. Mean monthly volumes decreased significantly (P < 0.05) for parenteral anticoagulants (-106,691,340 EU [95% CI, -200,033,910 to -13,348,780]), oral anticoagulants (-354,800 EU [95% CI, -612,180 to -97,420]), and parenteral antiplatelets (-391,880 EU [95% CI, -535,420 to -248,330]). During the pandemic, the monthly volume of oral anticoagulants, parenteral anticoagulants, and parenteral antiplatelets grew significantly more than in the prepandemic period. This growth was primarily seen in volumes of apixaban, argatroban, enoxaparin, heparin, eptifibatide, and tirofiban. Apixaban and heparin volumes continued a prepandemic uptrend, while argatroban and eptifibatide volumes reversed trend. CONCLUSION: Rapid changes in anticoagulant and antiplatelet volume at US hospitals during the COVID-19 pandemic highlight the need for institutional protocols to manage fluctuating medication volume demands.

Platelet activation and coronavirus disease 2019 mortality: Insights from coagulopathy, antiplatelet therapy and inflammation.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with an inflammatory cytokine burst and a prothrombotic coagulopathy. Platelets may contribute to microthrombosis, and constitute a therapeutic target in COVID-19 therapy. AIM: To assess if platelet activation influences mortality in COVID-19. METHODS: We explored two cohorts of patients with COVID-19. Cohort A included 208 ambulatory and hospitalized patients with varying clinical severities and non-COVID patients as controls, in whom plasma concentrations of the soluble platelet activation biomarkers CD40 ligand (sCD40L) and P-selectin (sP-sel) were quantified within the first 48hours following hospitalization. Cohort B was a multicentre cohort of 2878 patients initially admitted to a medical ward. In both cohorts, the primary outcome was in-hospital mortality. RESULTS: In cohort A, median circulating concentrations of sCD40L and sP-sel were only increased in the 89 critical patients compared with non-COVID controls: sP-sel 40,059 (interquartile range 26,876-54,678)pg/mL; sCD40L 1914 (interquartile range 1410-2367)pg/mL (P<0.001 for both). A strong association existed between sP-sel concentration and in-hospital mortality (Kaplan-Meier log-rank P=0.004). However, in a Cox model considering biomarkers of immunothrombosis, sP-sel was no longer associated with mortality, in contrast to coagulopathy evaluated with D-dimer concentration (hazard ratio 4.86, 95% confidence interval 1.64-12.50). Moreover, in cohort B, a Cox model adjusted for co-morbidities suggested that prehospitalization antiplatelet agents had no significant impact on in-hospital mortality (hazard ratio 1.05, 95% CI 0.80-1.37; P=0.73). CONCLUSIONS: Although we observed an association between excessive biomarkers of platelet activation and in-hospital mortality, our findings rather suggest that coagulopathy is more central in driving disease progression, which may explain why prehospitalization antiplatelet drugs were not a protective factor against mortality in our multicentre cohort.

Alterations in platelets during SARS-CoV-2 infection.

Coronavirus disease 2019 (COVID-19) is a pandemic syndrome caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. SARS-CoV-2 infection induces a process of inflammation and thrombosis supported by an altered platelet activation state. This platelet activation is peculiar being characterized by the formation of platelet-leukocytes rather than platelet-platelet aggregates and by an increased procoagulant potential supported by elevated levels of TF positive platelets and microvesicles.Therapeutic strategies targeting, beyond systemic inflammation (i.e. with tocilizumab, an anti interleukin-6 receptor), this state of platelet activation might therefore be beneficial. Among the antithrombotic drugs proposed as candidates to treat patients with SARS-CoV-2 infection, antiplatelet drugs, such as aspirin are showing promising results.

Platelet-leukocyte crosstalk in COVID-19: How might the reciprocal links between thrombotic events and inflammatory state affect treatment strategies and disease prognosis?

Platelet-leukocyte crosstalk is commonly manifested by reciprocal links between thrombosis and inflammation. Platelet thrombus acts as a reactive matrix that recruits leukocytes to the injury site where their massive accumulation, activation and migration promote thrombotic events while triggering inflammatory responses. As a life-threatening condition with the associations between inflammation and thrombosis, COVID-19 presents diffuse alveolar damage due to exaggerated macrophage activity and cytokine storms. These events, together with direct intracellular virus invasion lead to pulmonary vascular endothelialitis, cell membranes disruption, severe endothelial injury, and thrombosis. The developing pre-alveolar thrombus provides a hyper-reactive milieu that recruits circulating leukocytes to the injury site where their activation contributes to thrombus stabilization and thrombosis propagation, primarily through the formation of Neutrophil extracellular trap (NET). NET fragments can also circulate and deposit in further distance where they may disseminate intravascular thrombosis in severe cases of disease. Thrombi may also facilitate leukocytes migration into alveoli where their accumulation and activation exacerbate cytokine storms and tissue damage, further complicating the disease. Based on these mechanisms, whether an effective anti-inflammatory protocol can prevent thrombotic events, or on the other hand; efficient antiplatelet or anticoagulant regimens may be associated with reduced cytokine storms and tissue damage, is now of interests for several ongoing researches. Thus shedding more light on platelet-leukocyte crosstalk, the review presented here discusses the detailed mechanisms by which platelets may contribute to the pathogenesis of COVID-19, especially in severe cases where their interaction with leukocytes can intensify both inflammatory state and thrombosis in a reciprocal manner.

Impact of pre-admission antithrombotic therapy on disease severity and mortality in patients hospitalized for COVID-19.

Anticoagulant therapy is a cornerstone treatment for coronavirus disease 2019 (COVID-19) due to the high rates of thromboembolic complications associated with this disease. We hypothesized that chronic antithrombotic therapy could play a protective role in patients hospitalized for COVID-19. Retrospective, observational study of all patients admitted to our hospital for ≥ 24 h from March 1 to May 31, 2020 with SARS-CoV-2. The objective was to evaluate clinical outcomes and mortality in COVID-19 patients receiving chronic anticoagulation (AC) or antiplatelet therapy (AP) prior to hospital admission. A total of 1612 patients were evaluated. The mean (standard deviation; SD) age was 66.5 (17.1) years. Patients were divided into three groups according to the use of antithrombotic therapy prior to admission (AP, AC, or no-antithrombotic treatment). At admission, 9.6% of the patients were taking anticoagulants and 19.1% antiplatelet therapy. The overall mortality rate was 19.3%. On the multivariate analysis there were no significant differences in mortality between the antithrombotic groups (AC or AP) and the no-antithrombotic group (control group). Patients on AC had lower ICU admission rates than the control group (OR: 0.41, 95% CI, 0.18-0.93). Anticoagulation therapy prior to hospitalization for COVID-19 was associated with lower ICU admission rates. However, there were no significant differences in mortality between the patients receiving chronic antithrombotic therapy and patients not taking antithrombotic medications. These findings suggest that chronic anticoagulation therapy at the time of COVID-19 infection may reduce disease severity and thus the need for ICU admission.

Platelet and Endothelial Activation as Potential Mechanisms Behind the Thrombotic Complications of COVID-19 Patients.

The authors hypothesized that the cytokine storm described in COVID-19 patients may lead to consistent cell-based tissue factor (TF)-mediated activation of coagulation, procoagulant microvesicles (MVs) release, and massive platelet activation. COVID-19 patients have higher levels of TF+ platelets, TF+ granulocytes, and TF+ MVs than healthy subjects and coronary artery disease patients. Plasma MV-associated thrombin generation is present in prophylactic anticoagulated patients. A sustained platelet activation in terms of P-selectin expression and platelet-leukocyte aggregate formation, and altered nitric oxide/prostacyclin synthesis are also observed. COVID-19 plasma, added to the blood of healthy subjects, induces platelet activation similar to that observed in vivo. This effect was blunted by pre-incubation with tocilizumab, aspirin, or a P2Y12 inhibitor.