Although once primarily recognized for its roles in hemostasis and thrombosis, the platelet has been increasingly recognized as a multipurpose cell. Indeed, circulating platelets have the ability to influence a wide range of seemingly unrelated pathophysiologic events. Here, we highlight some of the notable observations that link platelets to inflammation, reinforcing the platelet’s origin from a lower vertebrate cell type with both hemostatic and immunologic roles. In addition, we consider the relevance of platelets in cancer biology by focusing on the hallmarks of cancer and the ways platelets can influence multistep development of tumors. Beyond its traditional role in hemostasis and thrombosis, the platelet’s involvement in the interplay between hemostasis, thrombosis, inflammation, and cancer is likely complex, yet extremely important in each disease process. The existence of animal models of platelet dysfunction and currently used antiplatelet therapies provide a framework for understanding mechanistic insights into a wide range of pathophysiologic events. Thus, the basic scientist studying platelet function can think beyond the traditional hemostasis and thrombosis paradigms, while the practicing hematologist must appreciate platelet relevance in a wide range of disease processes.

Objective The platelet glycoprotein (GP) Ib-IX receptor is a well characterized adhesion receptor supporting hemostasis and thrombosis via interactions with von Willebrand factor (VWF). We examine the GPIb-IX/VWF axis in murine polymicrobial sepsis, as modeled by cecal ligation and puncture (CLP). Approach and Results Genetic absence of the GPIb-IX ligand, VWF, prolongs survival following CLP, but absence of the receptor, GP Ib-IX, does not. Since absence of either VWF or GP Ib-IX significantly impairs hemostasis and thrombosis we sought to define additional GP Ib-IX-dependent pathways impacting survival in the CLP model. We document the absence of GPIb-IX leads to reduced platelet-neutrophil and platelet-monocyte interactions. Twenty four hours following CLP, absence of GP Ib-IX coincides with an alteration in cytokine levels, such as TNFα secreted by monocytes, and increased Mac-1 expression by neutrophils. Conclusions In contrast, to the well-characterized pro-inflammatory properties of platelets, we describe in the CLP model an anti-inflammatory property associated with platelet GP Ib-IX. Thus, a single platelet receptor displays a dual modulatory role in both the thrombotic and inflammatory pathways associated with polymicrobial sepsis. In sharing leucine rich motifs with toll-like receptors, platelet GPIb-IX can be considered a multi-functional participant in hemostasis, thrombosis, and the inflammatory cascade. The results highlight a dynamic role for platelets in systemic inflammation and add to the complex pathophysiologic events that occur during the dysregulated coagulation and inflammation associated with sepsis.

Purpose of review The platelet paradigm that is well established in hemostasis and thrombosis can be extended to other disease states. A consideration for some major health issues, such as inflammation, cancer, infection, and neuroscience and how platelet function impacts the pathophysiology of each clinical situation is provided. Recent findings Decades of research and knowledge of platelet function exists and the same is true for inflammation and cancer. The literature is full of platelet biology overlapping into other, non-thrombotic, disease states. However, major gaps exist that prevent a complete mechanistic understanding of platelet function in these other diseases. While much of the overlap provides antidotal relationships, future studies will likely uncover novel pathophysiological pathways that are highly relevant to human diseases. Summary Recent findings in four major disease areas, inflammation, cancer, infection and neuroscience are described with current literature linking the disease to platelet function. The availability of anti-platelet therapies, such as aspirin, exist and future consideration can be given as to whether anti-platelet therapy is potentially beneficial or harmful as mechanisms of platelet involvement are better defined.

Objective Poor prognosis of sepsis is associated with bacterial lipopolysaccharide (LPS)-induced intravascular inflammation, microvascular thrombosis, thrombocytopenia, and disseminated intravascular coagulation. Platelets are critical for thrombosis, and there have been increasing evidence of the importance of platelets in endotoxemia. The platelet adhesion receptor, the glycoprotein Ib-IX complex (GPIb-IX), mediates platelet adhesion to inflammatory vascular endothelium and exposed subendothelium. Thus, we have investigated the role of GPIb-IX in LPS-induced platelet adhesion, thrombosis and thrombocytopenia. Approach and Results LPS-induced mortality is significantly decreased in mice expressing a functionally deficient mutant of GPIbα. Furthermore, we have developed a micellar peptide inhibitor, MPαC, which selectively inhibits the VWF-binding function of GPIb-IX and GPIb-IX-mediated platelet adhesion under flow without affecting GPIb-IX-independent platelet activation. MPαC inhibits platelet adhesion to LPS-stimulated endothelial cells in vitro and alleviates LPS-induced thrombosis in glomeruli in mice. Importantly, MPαC reduces mortality in LPS-challenged mice, suggesting a protective effect of this inhibitor during endotoxemia. Interestingly, MPαC, but not the integrin antagonist, Integrilin, alleviated LPS-induced thrombocytopenia. Conclusion These data indicate an important role for the platelet adhesion receptor GPIb-IX in LPS-induced thrombosis and thrombocytopenia, and suggest the potential of targeting GPIb as an anti-platelet strategy in managing endotoxemia.