Aspirin and statin therapy in sepsis, a red herring?

Campbell, R; McGuire, AW; Young, L; Mackay, A

doi:10.1186/2197-425x-3-s1-a227

Cited by 9 publications

(9 citation statements)

References 4 publications

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“…Plasma levels of lactate dehydrogenase (LDH; A), blood urea nitrogen (BUN; B), and aspartate aminotransferase (ASAT; C) in cecal ligation and puncture (CLP)-and sham-operated mice, 20 h after transfusion of Tyrode's albumin buffer (buffer) without platelets, 1.4 × 10 9 wild-type (WT)washed platelets, WT-washed platelets treated with clopidogrel and acetylsalicylic acid (ASA), or platelet factor 4 (PF4)-β3 −/−washed platelets treated with clopidogrel and ASA. Results are the mean ± standard error of the mean antiplatelet therapy in sepsis and the available reports, mostly retrospective, have generated variable results with either a beneficial effect of antiplatelet drugs [22][23][24]55 or no effect [27][28][29][30] on the severity and outcome of sepsis. Ongoing randomized controlled clinical trials may be expected to provide a definitive answer as to whether antiplatelet therapy can modulate the severity of the outcome in patients with sepsis.…”

Section: Discussionmentioning

confidence: 99%

“…19 The dichotomy of platelets in their beneficial or detrimental effects in sepsis questions the potential benefit of inhibition of platelet hemostatic functions to attenuate tissue injury and improve outcomes in sepsis. Numerous clinical studies, mostly retrospective, have generated variable results with either beneficial effect of antiplatelet drugs [22][23][24][25][26] or no effect [27][28][29][30] on sepsis severity or outcome. Preclinical studies in animal models of sepsis reported conflicting results using clopidogrel with either no protective role 31,32 or a reduced sepsis-induced inflammation.…”

Section: Introductionmentioning

confidence: 99%

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Transfusion of fresh washed platelets does not prevent experimental polymicrobial‐induced septic shock in mice

Rabouel

Magnenat

Lefebvre

et al. 2022

Journal of Thrombosis and Haemostasis

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Introduction:The specific role of platelets during sepsis is not yet fully understood, probably related to the paradox of platelets being potentially beneficial but also deleterious via their thrombotic functions.Objective: To evaluate the impact of thrombocytopenia on septic shock in mice and to investigate whether transfusion of fresh washed platelets, either fully functional or with impaired hemostatic properties, might have beneficial effects.Methods: Septic shock was induced by cecal ligation and puncture (CLP). Experimental depletion of circulating platelets was induced with a rat anti-mouse GPIbα monoclonal antibody. Transfusion of either wild-type washed platelets, platelets treated with the antiplatelet drugs acetylsalicylic acid (ASA) and clopidogrel, or GPIIbIIIa-deficient washed platelets treated with ASA and clopidogrel was performed 4 h after CLP surgery.Results: Depletion of circulating platelets negatively affected septic shock, worsening systemic inflammation, coagulopathy, organ damage, and mortality, raising the question of whether a higher platelet count could be protective. Transfusion of fully functional platelets or platelets with combined treatment with ASA and clopidogrel, with or without additional GPIIbIIIa deficiency, afforded an immediate return of circulating platelet counts to their initial values before surgery. However, transfusion of each of the three types of platelets did not prevent arterial hypotension, inflammatory response, coagulopathy, and organ damage during septic shock. Conclusion:Depletion of circulating platelets negatively affects septic shock, while transfusion of washed platelets has no significant beneficial effect in mice.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transfusion of fresh washed platelets does not prevent experimental polymicrobial‐induced septic shock in mice

Rabouel

Magnenat

Lefebvre

et al. 2022

Journal of Thrombosis and Haemostasis

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“…Our findings indicating a lack of any beneficial impact of clopidogrel treatment on the pathogenesis of sepsis and septic shock in mice, question whether clopidogrel treatment might be beneficial in septic patients. Numerous clinical trials have generated variable results with either beneficial effect of antiplatelet drugs [19][20][21][22][23]49 or no effect [24][25][26][27] on sepsis severity or outcome. However, most clinical studies were retrospective, of small size and/or included patient groups that were not matched for potential confounding factors, such as comorbidity and other chronic medication.…”

Section: Discussionmentioning

confidence: 99%

“…Antiplatelet drugs such as acetylsalicylic acid (ASA) and P2Y 12 receptor targeting drugs, including the thienopyridine compounds clopidogrel and prasugrel and direct antagonists such as ticagrelor, are the cornerstone of the treatment and secondary prevention of arterial thrombosis. 17,18 However, clinical studies related to antiplatelet therapy of sepsis generated discordant results with several studies showing a survival benefit in septic patients receiving ASA [19][20][21] or antiplatelet agents (ASA and others), 22,23 while others showed no better outcome after ASA 24,25 or antiplatelet agents. 26,27 In addition, there are only few reports on the effects of antiplatelet drugs in animal models of sepsis.…”

Section: Introductionmentioning

confidence: 99%

Platelet P2Y12 Receptor Deletion or Pharmacological Inhibition does not Protect Mice from Sepsis or Septic Shock

Rabouel

Magnenat

Delabranche

et al. 2021

TH Open

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Introduction Platelets are increasingly appreciated as key effectors during sepsis, raising the question of the usefulness of antiplatelet drugs to treat patients with sepsis. Objective Evaluate the potential contribution of the platelet P2Y12 receptor in the pathogenesis of polymicrobial-induced sepsis and septic shock in mice. Methods The effects of P2Y12 inhibition using clopidogrel treatment and of platelet-specific deletion of the P2Y12 receptor in mice were examined in two severity grades of cecal ligation and puncture (CLP) leading to mild sepsis or septic shock. Results Twenty hours after induction of the high grade CLP, clopidogrel- and vehicle-treated mice displayed a similar 30% decrease in mean arterial blood pressure (MAP) characteristic of shock. Septic shock-induced thrombocytopenia was not modified by clopidogrel treatment. Plasma concentrations of inflammatory cytokines and myeloperoxidase (MPO) were similarly increased in clopidogrel- and vehicle-treated mice, indicating comparable increase in systemic inflammation. Thrombin-antithrombin (TAT) complexes and the extent of organ damage were also similar. In mild-grade CLP, clopidogrel- and vehicle-treated mice did not display a significant decrease in MAP, while thrombocytopenia and plasma concentrations of TNFα, IL6, IL10, MPO, TAT and organ damage reached similar levels in both groups, although lower than those reached in the high grade CLP. Similarly, mice with platelet-specific deletion of the P2Y12 receptor were not protected from CLP-induced sepsis or septic shock. Conclusion The platelet P2Y12 receptor does not contribute to the pathogenesis of sepsis or septic shock in mice, suggesting that P2Y12 receptor antagonists may not be beneficial in patients with sepsis or septic shock.

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“…Some of these studies point to the direction that sepsis patients on antiplatelet therapy have survival benefits [6][7][8], which are attributed to the drug's anti-inflammatory properties in addition to their antiaggregatory effects, as determined by experimental studies [9][10][11]. Other studies did not confirm benefits on severity and outcome, however, and the hypercoagulable state in sepsis remains difficult to manage [12][13][14]. One reason for limited success of antiplatelet drugs is high on-treatment platelet reactivity during sepsis.…”

Section: Introductionmentioning

confidence: 99%

Circulating MicroRNA Levels Indicate Platelet and Leukocyte Activation in Endotoxemia Despite Platelet P2Y12 Inhibition

Braza-Boïls

Barwari

Gutmann

et al. 2020

IJMS

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There is evidence for the effects of platelet inhibition on innate immune activation. Circulating microRNAs (miRNAs) have been implicated as markers of platelet and leukocyte activation. In the present study, we assessed the effects of P2Y 12 inhibitors on platelet and leukocyte miRNAs during endotoxemia. Healthy volunteers were randomly assigned to receive oral ticagrelor (n = 10), clopidogrel (n = 8) or no drug (n = 8) for one week, followed by an intravenous bolus of 2 ng/kg endotoxin. Serum was collected at baseline, after one week of antiplatelet treatment and 6 and 24 h after endotoxin administration. MiRNAs were screened using LNA-based qPCR, followed by TaqMan-qPCR validation of candidates. Clinical validation was performed in 41 sepsis patients. Platelet-enriched miR-197, miR-223 and miR-223* were decreased in volunteers following antiplatelet therapy. Endotoxin increased platelet miRNAs, whilst the opposite effect was seen for leukocyte-enriched miR-150. Neither of these endotoxin-mediated effects were altered by P2Y 12 inhibitors. Sepsis patients with fatal outcomes (n = 12) had reduced miR-150 levels compared with survivors (n = 29). In conclusion, we show that miR-150 is downregulated in experimental endotoxemia and can predict survival in sepsis but is unaffected by P2Y 12 inhibition. While P2Y 12 inhibition reduces platelet-associated miRNAs in healthy volunteers, it fails to attenuate the response of platelet miRNAs to endotoxemia.

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Aspirin and statin therapy in sepsis, a red herring?

Cited by 9 publications

References 4 publications

Transfusion of fresh washed platelets does not prevent experimental polymicrobial‐induced septic shock in mice

Transfusion of fresh washed platelets does not prevent experimental polymicrobial‐induced septic shock in mice

Platelet P2Y12 Receptor Deletion or Pharmacological Inhibition does not Protect Mice from Sepsis or Septic Shock

Circulating MicroRNA Levels Indicate Platelet and Leukocyte Activation in Endotoxemia Despite Platelet P2Y12 Inhibition

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