Regulation of platelet production and function by ITIM-containing receptors

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Smith, Christopher William (2019). Regulation of platelet production and function by ITIM-containing receptors. University of Birmingham. Ph.D.

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Abstract

Platelets are small highly reactive anucleate cells that circulate in the blood and regulate haemostasis and thrombosis. Understanding the mechanisms regulating platelet function has implications for health and disease. Immunoreceptor tyrosine-based inhibition motif (ITIM)-receptors regulate megakaryocyte and platelet function. The aim of this thesis was to determine the role of ITIM-receptors LAIR-1 and TLT-1 in platelet production and function. LAIR-1 ablation in megakaryocytes results in enhanced SFK activity which is transferred to platelets, rendering them hyper-reactive. LAIR-1 deficient mice exhibit enhanced ferric chloride, but not laser-induced thrombosis in vivo, correlating with GPVI hyper-reactivity observed in vitro. LAIR-1/PECAM-1 double deficient (DKO) mice were mildly thrombocythemic, with platelets hyper-responsive to GPVI activation in vitro. Interestingly, DKO mice lacked the enhanced SFK activity and in vivo thrombosis phenotype of single KO mice. TLT-1 deficient mice exhibit mild thrombocytopenia, with normal aggregation responses to ITAM-receptor and GPCR activation in vitro, and haemostatic response in vivo. Reduced thrombus stability was observed following laser, but not ferric chloride injury in deficient mice, due to marked reduction in α-granule secretion. In addition, TLT-1 was described as a highly sensitive platelet activation marker in vivo, rapidly detected and present throughout core and shell of thrombi.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):