Mechanisms of Thrombocytopenia During Septic Shock: A Multiplex Cluster Analysis of Endogenous Sepsis Mediators

Bedet, Alexandre; Razazi, Keyvan; Boissier, Florence; Surénaud, Mathieu; Hüe, Sophie; Giraudier, Stéphane; Brun‐Buisson, Christian; Dessap, Armand Mekontso

doi:10.1097/shk.0000000000001015

Cited by 46 publications

(44 citation statements)

References 33 publications

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“…More importantly, the innate immune responses in Rag2 KO rats, such as high serum levels of TNFa, IL-1, IL-6, and IL-10, and the development of thrombocytopenia also represent those seen in patients with sepsis (22,23). A recent study shows that innate immune response is a factor involved in thrombocytopenia pathogenesis in sepsis patients (24). Thus, this rat sepsis model could provide more insight into mechanism study of sepsis-associated thrombocytopenia.…”

Section: Discussionmentioning

confidence: 89%

Macrophage Depletion Mitigates Platelet Aggregate Formation in Splenic Marginal Zone and Alleviates LPS-Associated Thrombocytopenia in Rats

Liu

Ryan

et al. 2019

Front. Med.

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Sepsis is often accompanied with thrombocytopenia partly due to platelet sequestration in the lung and liver. The spleen can store up to one-third of circulating platelets and can also significantly affect platelet transfusion outcomes by accumulating platelets. However, in sepsis, it is not clear whether there are platelet changes in the spleen which could contribute to sepsis-associated thrombocytopenia and also influence platelet transfusion outcomes. By using confocal microscopy, we examined endogenous rat platelets and infused human platelets in the spleen of severe combined immune deficient Rag2 KO rats which were injected intraperitoneally with lipopolysaccharide (LPS). LPS-injected Rag2 KO rats developed sepsis as indicated by increased TNFa, IL-6, IL-1b, and IL-10 levels and thrombocytopenia. Large platelet aggregates were observed in the spleen with majority located in the marginal zone and closely associated with CD169+ macrophages. Depletion of macrophages by clodrosome resulted in reduction of LPS-induced cytokine generation and alleviated LPS-induced thrombocytopenia. Macrophage depletion also remarkedly diminished large platelet aggregate formation in the splenic marginal zone but had less effect on those in red pulp. Infusion of human platelets into LPS-injected rats failed to raise platelet counts in the peripheral blood. In LPS-injected rat spleen, human platelets interacted with aggregated rat platelets in the marginal zone. In contrast, human platelets infused into control rats were located outside of splenic marginal zone. This study provides morphological evidence of platelet aggregates in the splenic marginal zone in sepsis which can interact with infused platelets and thus can contribute to platelet infusion refractoriness in sepsis. It indicates that macrophages play an important role in LPS-associated thrombocytopenia. It also suggests that CD169+ macrophages support platelet aggregate formation in the splenic marginal zone.

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Section: Discussionmentioning

confidence: 89%

Macrophage Depletion Mitigates Platelet Aggregate Formation in Splenic Marginal Zone and Alleviates LPS-Associated Thrombocytopenia in Rats

Liu

Ryan

et al. 2019

Front. Med.

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“…The platelet count was correlated with thrombopoiesis growth factors, innate immunity/endothelial dysfunction, and platelet activation biomarkers. 22 Moreover, pneumococcus directly promotes platelet activation and aggregation. 4 Therefore, thrombocytopenia is usually thought to reflect infection severity associated with higher mortality, including in CAP patients.…”

Section: Discussionmentioning

confidence: 99%

<p>Platelet Count within the Normal Range at Hospital Admission is Associated with Mortality in Patients with Community-Acquired Pneumonia</p>

Moulis¹,

Christiansen²,

Darvalics³

et al. 2020

CLEP

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Background Apart from their hemostatic role, platelets are immune cells that play a role in fighting infections. The presence of thrombocytopenia and thrombocytosis at hospital admission are predictors of mortality in community-acquired pneumonia patients. We hypothesized that variations in platelet counts within the normal range also may be associated with mortality in these patients. Methods The study included all adults in the North and Central Denmark Regions with a first acute hospital admission for community-acquired pneumonia during 2006–2012. We assessed the association between the first platelet count within ± 24 hours of admission (within the normal range of 150 to 400 x 10 9 /L) and 30-day mortality using Cox models. Analyses were adjusted for age, sex, Charlson Comorbidity Index score, hemoglobin level, leukocyte count, and creatinine level at admission. Results Among the 12,905 study patients, 30-day mortality was 12.4%. The mean platelet count upon admission was 250 × 10 9 /L. Compared with the 250–275 × 10 9 /L category, platelet counts of 151–175 were associated with a lower 30-day mortality (adjusted hazard ratio [aHR]: 0.79, 95% confidence interval [CI]: 0.63–0.99), while higher platelet counts were associated with a higher 30-day mortality (351–375 × 10 9 /L, aHR: 1.34, 95% CI: 1.07–1.68; 376–400× 10 9 /L, aHR: 1.21, 95% CI: 0.94–1.56). Conclusion Platelet counts, even within the normal range, are associated with mortality in adult patients hospitalized for community-acquired pneumonia.

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“…We found that DEX blunted LPS-induced thrombocytopenia, a hallmark of sepsis and endotoxemia [45]. Platelet activation and local coagulation is a protective mechanism against endothelial dysfunction [46], and against pathogens serving their trapping and elimination [47]. However, exaggerated platelet activation is a major contributor to thrombocytopenia and may lead to disseminated intravascular coagulation, and ultimately to multiple organ failure [47].…”

Section: Discussionmentioning

confidence: 99%

Kinetics of Physiological and Behavioural Responses in Endotoxemic Pigs with or without Dexamethasone Treatment

Kanitz

Tuchscherer

et al. 2019

IJMS

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Although dexamethasone (DEX) is a widely used immunoregulatory agent, knowledge about its pharmacological properties in farm animals, especially pigs, is insufficient. Previous studies suggest that compared to other species, pigs are less sensitive to the immunosuppression conferred by DEX and more sensitive to the threat of bacterial endotoxins. However, there is a paucity of studies examining DEX immunomodulation in endotoxemia in this species. In this study, a porcine endotoxemia model was established by lipopolysaccharide (LPS) and the effect of DEX-pretreatment on the magnitude and kinetics of neuroendocrine, metabolic, hematologic, inflammatory, and behavioural responses were examined. DEX decreased cortisol, adrenocorticotropic hormone (ACTH), red blood cell, hemoglobin, hematocrit, and lymphocyte whereas glucose concentration was increased under both normal and endotoxemic conditions. By contrast, DEX decreased triglyceride, lactate, and IL-6 concentrations and increased platelet count only under an endotoxemic condition. DEX also reduced the frequency of sickness behaviour following LPS challenge. PCA showed that glucose and triglyceride metabolism together with red blood cell count mainly contributed to the separation of clusters during DEX treatment. Our study demonstrates that DEX protects pigs from inflammation and morbidity in endotoxemia, in spite of their less sensitivity to DEX. Moreover, its considerable role in the regulation of the metabolic and hematologic responses in endotoxemic pigs is revealed for the first time.

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Mechanisms of Thrombocytopenia During Septic Shock: A Multiplex Cluster Analysis of Endogenous Sepsis Mediators

Abstract: Multiple mechanisms seemed involved in thrombocytopenia during septic shock, including endothelial dysfunction/coagulopathy, hemodilution, and altered thrombopoiesis.

Cited by 46 publications

References 33 publications

Macrophage Depletion Mitigates Platelet Aggregate Formation in Splenic Marginal Zone and Alleviates LPS-Associated Thrombocytopenia in Rats

Macrophage Depletion Mitigates Platelet Aggregate Formation in Splenic Marginal Zone and Alleviates LPS-Associated Thrombocytopenia in Rats

<p>Platelet Count within the Normal Range at Hospital Admission is Associated with Mortality in Patients with Community-Acquired Pneumonia</p>

Kinetics of Physiological and Behavioural Responses in Endotoxemic Pigs with or without Dexamethasone Treatment

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