The Dynamics of Platelet Activation during the Progression of Streptococcal Sepsis

Abstract

Platelets contribute to inflammation however, the role of platelet activation during the pathophysiological response to invasive bacterial infection and sepsis is not clear. Herein, we have investigated platelet activation in a mouse model of invasive Streptococcus pyogenes infection at 5, 12, and 18 hours post infection and correlated this to parameters of infection. The platelet population in ex-vivo blood samples showed no increased integrin activation or surface presentation of CD62P, however platelet-neutrophil complex formation and plasma levels of CD62P were increased during bacterial dissemination and the progression of sepsis, indicating that platelet activation had occurred in vivo. Platelet-neutrophil complex formation was the most discriminatory marker of platelet activation. Platelet-neutrophil complexes were increased above baseline levels during early sepsis but decreased to significantly lower levels than baseline during late sepsis. The removal of these complexes from the circulation coincided with a significant increase in organ damage and the accumulation of platelets in the liver sinusoids, suggesting that platelet activation in the circulation precedes accumulation of platelets in damaged organs. The results demonstrate that monitoring platelet activation using complementary methods may provide prognostic information during the pathogenesis of invasive S. pyogenes infection.

Platelet Depletion Impairs Host Defense to Pulmonary Infection with Pseudomonas aeruginosa in Mice

“…Here we demonstrate that infection with 1x10 6 cfu/mouse of P. aeruginosa resulted in increased BAL levels of platelet derived PF-4 and β-TG at 24 hours post infection. This supports bacterial induced platelet activation previously described in the literature [14][15][16]18,31,32]. We also observed significant increases in plasma β-TG levels, although no increases in plasma PF-4 were detected.…”

“…This provides a plausible mechanism for direct bacterial interactions with platelets which may contribute towards platelet activation. Indeed, platelet shape change, reversible states of platelet accumulation and adhesion, formation of platelet-leukocyte conjugates, elevated P-selectin expression and platelet granule release have all been detected following exposure to bacterial products or through direct interactions with bacterial pathogens, including S.aureus, Streptococcus pyogenes, Escherichia Coli and Clostidium perfringens [18,31,32].…”

Platelet‐leucocyte aggregation is augmented in cirrhosis and further increased by platelet transfusion

“…A similar pattern of enhanced complex formation occurs during the systemic pro‐inflammatory surge in sepsis and with a retraction in platelet‐leucocyte aggregation as sepsis progresses to septic shock . This may reflect immune paresis, which frequently follows immune hyper‐activation, and which may be related to deposition of platelet‐leucocyte complexes in the organs as observed in experimental models of sepsis …”

“…33 This may reflect immune paresis, which frequently follows immune hyper-activation, and which may be related to deposition of platelet-leucocyte complexes in the organs as observed in experimental models of sepsis. 34 We repeated our analyses following an elective platelet transfusion to assess the effects on the platelet-leucocyte interplay. We verified utilising thromboelastometry and plasma-based haemostasis tests, that elective transfusion of 1 or 2 pools of platelets impacts on haemostatic status in these patients.…”

Editorial: platelet transfusions in cirrhosis—do the risks outweigh the unclear benefits? Authors’ reply

“…These observations are further supported by the fact that infected patients with cirrhosis have increased amounts of circulating heparin‐like substances (heparinoids) which disappear once infection resolves. Increased production of superoxide from nitric oxide synthase in the context of systemic inflammation and sepsis favours endothelial apoptosis and necrosis as well as increased oxidant stress during which time platelets become activated and platelet‐neutrophil aggregation increases . Thrombocytopenia impairs host defences during Gram‐negative sepsis which overall demonstrates the complex interplay between the haemostatic and immunologic systems …”