Mechanisms of platelet clearance and translation to improve platelet storage

Abstract

Hundreds of billions of platelets are cleared daily from circulation via efficient and highly regulated mechanisms. These mechanisms may be stimulated by exogenous reagents or environmental changes to accelerate platelet clearance, leading to thrombocytopenia. The interplay between antiapoptotic Bcl-x and proapoptotic molecules Bax and Bak sets an internal clock for the platelet lifespan, and BH3-only proteins, mitochondrial permeabilization, and phosphatidylserine (PS) exposure may also contribute to apoptosis-induced platelet clearance. Binding of plasma von Willebrand factor or antibodies to the ligand-binding domain of glycoprotein Ibα (GPIbα) on platelets can activate GPIb-IX in a shear-dependent manner by inducing unfolding of the mechanosensory domain therein, and trigger downstream signaling in the platelet including desialylation and PS exposure. Deglycosylated platelets are recognized by the Ashwell-Morell receptor and potentially other scavenger receptors, and are rapidly cleared by hepatocytes and/or macrophages. Inhibitors of platelet clearance pathways, including inhibitors of GPIbα shedding, neuraminidases, and platelet signaling, are efficacious at preserving the viability of platelets during storage and improving their recovery and survival in vivo. Overall, common mechanisms of platelet clearance have begun to emerge, suggesting potential strategies to extend the shelf-life of platelets stored at room temperature or to enable refrigerated storage.

Proteolytic processing of platelet receptors

“…Along with red cells, platelets feature as a predominant cell type in the bloodstream. Platelet numbers in a healthy individual are usually maintained at a stable level ranging from 150 to 400 × 10 6 per mL of blood . These levels of platelets vastly exceed the numbers required to mount a normal hemostatic response, and so they are consistent with the idea that the role of platelets in biology extends beyond hemostasis .…”

Genetic colocalization atlas points to common regulatory sites and genes for hematopoietic traits and hematopoietic contributions to disease phenotypes

“…Complement-mediate apoptotic cell clearance mechanisms are indeed important for regulating platelet count. 12 Notably, pathways analyses of red cell and platelet lineage-restricted colocalization QTLs were not enriched processes ascribed to hematopoiesis, erythropoiesis, or megakaryopoiesis. This suggests that genes and processes linked to terminal red cell and platelet traits are largely impacted by cellular function and reactivity, rather than developmental perturbations.…”

Heterotrimeric G-protein subunit Gα i2 contributes to agonist-sensitive apoptosis and degranulation in murine platelets

“…PS exposure in apoptotic platelets, triggered by exogenous agents or physiological changes, leads to their clearance from the circulation (Lebois and Josefsson ; Quach et al. ). G α i2 has previously been shown to participate in the apoptosis machinery of different cell types (Lopez‐Aranda et al.…”

“…Cell membrane scrambling with phosphatidylserine (PS) exposure fosters the assembly of tenase and prothrombinase complexes, and subsequently promoting factor Xa and thrombin generation (Lebois and Josefsson 2016). In platelets, unconstrained apoptosis has been implicated in thrombocytopenia, bleeding disorders, microparticle shedding as well as affecting their quality during storage (Lebois and Josefsson 2016;Quach et al 2018). PS exposure in apoptotic platelets, triggered by exogenous agents or physiological changes, leads to their clearance from the circulation (Lebois and Josefsson 2016;Quach et al 2018).…”

“…In platelets, unconstrained apoptosis has been implicated in thrombocytopenia, bleeding disorders, microparticle shedding as well as affecting their quality during storage (Lebois and Josefsson 2016;Quach et al 2018). PS exposure in apoptotic platelets, triggered by exogenous agents or physiological changes, leads to their clearance from the circulation (Lebois and Josefsson 2016;Quach et al 2018). Ga i2 has previously been shown to participate in the apoptosis machinery of different cell types (Lopez-Aranda et al 2008;Bissinger et al 2016).…”