Abstract Number: PB1613
Meeting: ISTH 2020 Congress
Background: TREM-like transcript-1 (TLT-1) is an immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor that is highly and exclusively expressed in the megakaryocyte (MK) lineage. TLT-1 is localized in α-granules, and rapidly translocates to the plasma membrane upon activation. Unlike other ITIM-containing receptors, TLT-1 acts as a positive regulator of platelet function and protects against inflammation-mediated hemorrhaging. However, its functional roles in thrombopoiesis and thrombosis remain undefined.
Aims: To determine the physiological function of TLT-1 in platelet production and function in mice, and the molecular mechanism underlying how it regulates these processes.
Methods: MK morphology, proplatelet formation and platelet function were analyzed in TLT-1 knockout (KO) and control mice by biochemical and microscopic assays.
Results: TLT-1 KO mice have a 20% reduction in platelet count and normal platelet size, and reduced proplatelet formation in vitro, despite normal megakaryopoiesis. Platelets from TLT-1-deficient mice expressed normal receptor levels, but exhibited reduced aggregation, secretion and thrombus formation to collagen under flow in vitro. Thrombus formation and stability was also reduced following laser-induced arterial injury in TLT-1 KO mice. Mechanistically, we demonstrate that TLT-1 is marginally tyrosine phosphorylated and associated with the SH2 domain-containing tyrosine phosphatases Shp1 and Shp2 in resting platelets, which increased in response to collagen in suspension. TLT-1 phosphorylation and Shp1, Shp2 interactions were also increased in fibrinogen-adhered platelets, and significantly reduced in thrombin-stimulated platelets pretreated with the alphalIbbeta3 antagonist lotrafiban. Residual TLT-1 phosphorylation and bound Shp1 and Shp2 was maintained observed in the presence of lotrafiban, suggesting this is a direct consequence of fibrinogen binding to TLT-1.
Conclusions: Findings from this study establish that TLT-1 is a positive regulator of platelet function, proplatelet formation and thrombus formation in mice, and that is signals via Shp1 and Shp2 in platelets in response to collagen and fibrinogen.
To cite this abstract in AMA style:Smith CW, Washington VA, Senis YA, Mazharian A. TREM-like Transcript-1 Is a Positive Regulator of Platelet Production and Thrombosis [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/trem-like-transcript-1-is-a-positive-regulator-of-platelet-production-and-thrombosis/. Accessed November 30, 2023.
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