The thrombocytopenia of WAS: a familial form of ITP?

Abstract

In the first report of the concurrent immunodeficiency, thrombocytopenia, and eczema that we now call the Wiskott-Aldrich Syndrome (WAS), Alfred Wiskott asked whether it could be a familial form of Werlhof's disease (now called ITP). This review summarizes what is known about platelet production, consumption, and function in clinical and murine WAS. Both platelet production and consumption are affected by WASP deficiency. Likely molecular mechanisms have been identified for the former process, but remain problematic for the latter. Recent data in a murine model suggest that WASP deficiency could increase both the incidence of antiplatelet antibodies and susceptibility to their enhancement of platelet consumption. Wiskott's original speculation about the relationship between WAS and ITP may need to be reconsidered.

Current and emerging treatment options for Wiskott–Aldrich syndrome

“…Autoimmune thrombocytopenia and antiplatelet antibodies have been recognized in WAS patients [52,53] but due to the underlying thrombocytopenia and poor sensitivity and specificity of antiplatelet autoantibodies, this can be difficult to definitely diagnose. Mahlaoui et al described the development of severe refractory thrombocytopenia in WAS patients under 2 years of age, who had a particularly severe clinical course [4].…”

Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome

“…11 Despite intensive research, the mechanisms underlying WASPrelated thrombocytopenia and hemorrhages are not completely understood. Megakaryocyte numbers have been reported to be normal in the majority of WAS patients, [12][13][14] whereas proplatelet formation depending on actin polymerization and formation of branching structures is conserved when tested in in vitro and ex vivo cultures. 12 Peripheral destruction of platelets in the spleen is thought to play an important role in thrombocytopenia because a substantial correction of the platelet count and size after splenectomy has been reported.…”

“…12 Peripheral destruction of platelets in the spleen is thought to play an important role in thrombocytopenia because a substantial correction of the platelet count and size after splenectomy has been reported. 15 The accelerated destruction could be caused by an intrinsic defect of WASP-deficient platelets, showing an increased surface exposure of phosphatidylserine, or could be mediated by autoimmune reaction because of the presence of antiplatelet antibodies reported in patients and in the murine knockout model, 13 although the latter hypothesis is still a matter of controversy in the field. Finally, defects in filopodia and podosomes could play an additional role in migration of megakaryocytes from the endosteal to the perivascular niche within the bone marrow and during proplatelet formation.…”

Loss of the F-BAR protein CIP4 reduces platelet production by impairing membrane-cytoskeleton remodeling

“…1 Important components for cytoskeletal reorganization are the RhoGTPase Cdc42, actin nucleator Wiskott-Aldrich Syndrome Protein (WASP), and actin-associated Arp2/3 complex. 2 Wiskott-Aldrich Syndrome is characterized by microthrombocytopenia, the mechanism of which is only partially known and may include both autoimmunity 3 and dysregulated platelet production. 4,5 The molecular machinery required for membrane remodeling in megakaryocytes that generate proplatelet protrusions is also mysterious.…”