Hemostasis without clot formation: how platelets guard the vasculature in inflammation, infection, and malignancy

Abstract

Platelets are key vascular effectors in hemostasis, with activation signals leading to fast recruitment, aggregation, and clot formation. The canonical process of hemostasis is well characterized and shares many similarities with pathological thrombus formation. However, platelets are also crucially involved in the maintenance of vascular integrity under both steady state and inflammatory conditions by ensuring blood vessel homeostasis and preventing microbleeds. In these settings, platelets use distinct receptors, signaling pathways and ensuing effector functions to carry out their deeds: Instead of simply forming clots, they mainly act as individual sentinels that swiftly adapt their behavior to the local microenvironment. In this Review, we summarize previously recognized and more recent studies that have elucidated how anucleate, small platelets manage to maintain vascular integrity when faced with challenges of infection, sterile inflammation and even malignancy. We dissect how platelets are recruited to the vascular wall, how they identify sites of injury, and how they prevent hemorrhage as single cells. Further, we discuss mechanisms and consequences of platelets interacting with leukocytes and endothelial cells, the relevance of adhesion as well as signaling receptors, in particular ITAM receptors, and crosstalk with the coagulation system. Finally, we outline how recent insights into inflammatory hemostasis and vascular integrity may aid in the development of novel therapeutic strategies to prevent hemorrhagic events and vascular dysfunction in critically ill patients.

A role of platelet C-type lectin-like receptor-2 and its ligand podoplanin in vascular biology

“…4d) [42]. A more detailed explanation is provided in a recently published review by Kaiser et al [43 ▪ ].…”

Glanzmann Thrombasthenia 10 Years Later: Progress Made and Future Directions

“…Leukocyte migration through the endothelium in inflamed tissue is helped by platelets that also migrate autonomously in a αIIbβ3 and mechanosensitive manner, first shown by their capacity to bundle bacteria. [96][97][98][99] In this way, platelet sentinels survey the endothelium for injured sites perhaps recognizing endoglin at perturbed junctions to which αIIbβ3 can attach and by a process termed haptotaxis, and then control inflammation-dependent bleeding by plugging pores created by the migrating white blood cells. 99 Encounters with collagen in the subendothelium also cause the arrest of single platelets and initiate a procoagulant response induced in part by αIIbβ3 through Gα13-mediated outside-in signaling which when combined with GPVI signaling causes a Ca 2þ burst.…”

“…98 Fibrin is generated that favors the formation of microthrombi. 99 So do GT patients have exacerbated inflammatory bleeding? This remains unknown territory.…”

The Ways of the Virus: Interactions of Platelets and Red Blood Cells with SARS-CoV-2, and Their Potential Pathophysiological Significance in COVID-19

“…This process occurs under conditions of high flow rates and requires the formation of a hemostatic plug [50]. Second, they support the homeostasis of the endothelium and the tightness of intercellular contacts, which is achieved by single platelets without the formation of a hemostatic plug [51]. This function may be especially relevant during coronavirus infection.…”