Platelets in Wiskott-Aldrich syndrome: Victims or executioners?

Abstract

Microthrombocytopenia is the clinical hallmark of WAS, a rare X-linked immunodeficiency that is characterized by eczema, autoimmunity, and cancer susceptibility. This disease is caused by mutations in the WAS gene, which is expressed in hematopoietic cells and regulates actin cytoskeleton remodeling thereby modulating various cellular functions, including motility, immunologic synapse assembly, and signaling. Despite extensive studies that have provided great insight into the relevance of this molecule to innate and cellular immunity, the exact mechanisms of microthrombocytopenia in WAS are still unknown. This review focuses on the recent progress made in dissecting the pathogenesis of platelet defects in patients with WAS and their murine counterparts. In parallel, we will provide an overview of the state-of-the art platelets as immune modulators at the interface between hemostasis and the immune system, which suggests that these cells may have a direct role in the pathogenesis of immune dysregulation in WAS.

Vascular surveillance by haptotactic blood platelets in inflammation and infection

“…Arp2/3 in platelets is activated by NPFs of the WAVE and WASp families, as well as cortactin and HS1 31 , 44 , 62 . Patients with loss-of-function mutations of WASp present with immunodeficiency and bleeding complications, known as Wiskott–Aldrich syndrome 63 . Consequently, it was tempting to speculate whether impaired platelet migration and haptotaxis contribute to the clinical symptoms of WAS patients.…”

Clonal hematopoietic mutations linked to platelet traits and the risk of thrombosis or bleeding

“…In Was-deficient mice, platelet turnover was shortened, with proteomic evidence for alterations in proteins of metabolic and proteasomal pathways. 77 Furthermore, in both the mutant mice and patients, there is evidence for a hyperactivation status of the platelets, thus explaining the higher elimination rate. Several groups reported on alterations in integrin activation in the patient's platelets.…”

Lentiviral gene therapy corrects platelet phenotype and function in patients with Wiskott-Aldrich syndrome

“…Several studies have been conducted to elucidate the pathogenesis of thrombocytopenia in patients with WAS. Defective platelet production by megakaryocytes and accelerated peripheral elimination have been proposed as the underlying cause, highlighting an unsolved dichotomy 21 . Megakaryocytes have been described to fail both in the maturation step and in proplatelet production 21 .…”

“…Defective platelet production by megakaryocytes and accelerated peripheral elimination have been proposed as the underlying cause, highlighting an unsolved dichotomy 21 . Megakaryocytes have been described to fail both in the maturation step and in proplatelet production 21 . Conversely, several articles showed that after normal thrombopoiesis, platelets in the periphery are the target of both innate and adaptive immunity 21 .…”