Abstract Number: PB1607
Meeting: ISTH 2020 Congress
Background: Hemostatic abnormalities and impaired platelet function have been described in patients affected by connective tissue disorders, however the mechanisms underlying platelet defects have never been investigated. Megakaryocytes, the platelet progenitors, express different extracellular matrix proteins. Mutations of genes encoding for the Collagen VI chains are responsible for a broad spectrum of diseases in humans, including Bethlem myopathy and Ullrich Congenital Muscular Dystrophy (UCMD).
Aims: We observed a mild bleeding tendency in Bethlem myopathy and UCMD patients and investigated the defects in platelet functionality whose mechanisms are unknown.
Methods: We exploited a Collagen VI-null mouse model (Col6a1-/-) by performing megakaryocyte culture and radiation chimeras using bone marrow Lineage negative cell transplantations. Further, we performed platelet function tests and megakaryocyte culture from Bethlem myopathy and UCMD patient samples.
Results: We found that megakaryocytes express Collagen VI and that platelets produced by Col6a1-/- megakaryocytes display significantly increased susceptibility to activation and intracellular calcium signaling. Consistently, Col6a1-/-megakaryocytes and platelets showed increased expression of Stromal Interaction Molecule 1 (STIM1) and ORAI1, the components of Store-Operated Calcium Entry (SOCE), and activation of the mammalian Target Of Rapamycin (mTOR) signaling pathway. Rapamycin rescued STIM1 and ORAI1 expression, calcium flows and platelet susceptibility to activation in mice in vivo.
We demonstrated that these defects are cell autonomous as transplantation of Lineage negative cells from Col6a1-/-mice in wild type lethally irradiated mice showed the same alteration in SOCE and platelet activation as compared to Col6a1-/-mice. Importantly, platelets of patients affected by Bethlem myopathy and UCMD displayed increased expression of STIM1 and ORAI1 and were more prone to activation.
Conclusions: These data indicate that the absence of Collagen VI in megakaryocytes leads to the production of platelets with altered function. Platelet function tests should be performed in the management of patients affected by Collagen VI-related diseases.
To cite this abstract in AMA style:Abbonante V, Di Buduo CA, Battiston M, Chrisam M, Sereni L, Semplicini C, Villa A, Pegoraro E, Braghetta P, De Marco L, Bonaldo P, Balduini A. The Ablation of Collagen VI Leads to the Release of Platelets with Altered Functions [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/the-ablation-of-collagen-vi-leads-to-the-release-of-platelets-with-altered-functions/. Accessed February 28, 2024.
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