Platelets in Sepsis: An Update on Experimental Models and Clinical Data

Abstract

Beyond their important role in hemostasis, platelets play a crucial role in inflammatory diseases. This becomes apparent during sepsis, where platelet count and activation correlate with disease outcome and survival. Sepsis is caused by a dysregulated host response to infection, leading to organ dysfunction, permanent disabilities, or death. During sepsis, tissue injury results from the concomitant uncontrolled activation of the complement, coagulation, and inflammatory systems as well as platelet dysfunction. The balance between the systemic inflammatory response syndrome (SIRS) and the compensatory anti-inflammatory response (CARS) regulates sepsis outcome. Persistent thrombocytopenia is considered as an independent risk factor of mortality in sepsis, although it is still unclear whether the drop in platelet count is the cause or the consequence of sepsis severity. The role of platelets in sepsis development and progression was addressed in different experimental in vivo models, particularly in mice, that represent various aspects of human sepsis. The immunomodulatory function of platelets depends on the experimental model, time, and type of infection. Understanding the molecular mechanism of platelet regulation in inflammation could bring us one step closer to understand this important aspect of primary hemostasis which drives thrombotic as well as bleeding complications in patients with sterile and infectious inflammation. In this review, we summarize the current understanding of the contribution of platelets to sepsis severity and outcome. We highlight the differences between platelet receptors in mice and humans and discuss the potential and limitations of animal models to study platelet-related functions in sepsis.

Keywords: infection; inflammation; platelets; sepsis; thrombocytopenia.

Figure 1

The role of platelets in sepsis and receptors involved in mice and humans. Human and mouse platelets express a variety of immune receptors involved in thrombosis or/and inflammation during sepsis. Many receptors are conserved between mice and human and other receptors are species-restricted. FcαR, Fc-alpha receptor; FcεR, Fc-epsilon receptor; FcγR, Fc-gamma receptor; TLR, toll-like receptor; CLEC-2, C-type lectin-like receptor-2; DC-SIGN, dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin; NOD, nucleotide binding oligomerization domain containing 1; GP, glycoprotein; P2Y₁₂, purinergic receptor P2Y₁₂; PAR, proteinase-activated receptor.

Figure 2

Possible causes of thrombocytopenia in sepsis. Thrombocytopenia in sepsis might be either regulated by altered platelet production or hemophagocytosis, or by platelet scavenging in the circulation either due to platelet-leukocyte or platelet- pathogen interactions, vessel injury, or desialylation. Platelets can also be targeted by antibodies during sepsis or reduced due to disseminated intravascular coagulation (DIC).

Figure 3

Overview of different mouse models to study sepsis. The role of platelets was addressed using single PAMP injection, single live pathogen or polymicrobial pathogens. Platelets regulate thrombosis, inflammation, bleeding, and sepsis outcome in a receptor- and pathogen-dependent manner. PAMP, pathogen-associated molecular pattern; LPS, lipopolysaccharides; M1, streptococcal M1 protein; iv, intravenous; in, intranasal; ip, intraperitoneal; P2Y₁₂, purinergic receptor P2Y₁₂; GP, glycoprotein; TLR, toll-like receptor; CLEC-2, C-type lectin-like receptor-2; PAR, proteinase-activated receptor.