Abstract Number: PB1472
Meeting: ISTH 2020 Congress
Background: Acute systemic painful vaso-occlusive crisis (VOC) is the predominant clinical event requiring sickle cell disease (SCD) patients to seek emergency medical care. VOC often serves as an antecedent to acute chest syndrome (ACS), which is a type of acute lung injury and one of the leading causes of mortality in SCD. Based on clinical epidemiology, ACS is preceded by thrombocytopenia and involves pulmonary thrombosis across pulmonary artery branches in 17% of ACS patients. However, the etiological mechanism that contributes to this sub-type of ACS pathophysiology remains largely unknown. Although adenosine diphosphate (ADP) release following hemolysis is known to activate platelets by stimulating their purinergic receptors P2Y1 and P2Y12, antagonists of P2Y12 have not shown any benefit and the role of purinergic signaling in SCD remains elusive.
Aims: To elucidate the role of platelet purinergic signaling in promoting pulmonary thrombosis in SCD humanized mice in vivo.
Methods: We used a novel intravital microscopy enabled experimental model of platelet-dependent pulmonary thrombosis in transgenic, humanized SCD mice, triggered by an intravenous (IV) administration of 2.5 mg/kg ADP. This method allows real time in vivo visualization of platelet-enabled pulmonary thrombosis in the lung of live SCD mice using multi-photon-excitation based quantitative fluorescence intravital lung microscopy (qFILM).
Results: We discovered that ADP-triggered pulmonary thrombosis involves entrapment of embolic platelet aggregates in the bottle-necks located between the pulmonary arterioles and capillaries. Surprisingly, ADP triggered pulmonary thrombosis in control mice but failed to induce pulmonary thrombosis in SCD mice. Remarkably, in vivo platelet aggregation studies confirmed that SCD mouse platelets were indeed refractory to ADP induced aggregation.
Conclusions: Our preliminary findings suggest an impaired platelet response to ADP in SCD and warrant the need for further studies to understand the role of purinergic signaling in the pathogenesis of ACS of SCD.
To cite this abstract in AMA style:Brzoska T, Menchikova EV, Vats R, Kaminski TW, Tutuncuoglu E, Tofovic SP, Jackson EK, Gladwin MT, Sundd P. Platelet Purinergic Signaling Regulates Pulmonary Thrombosis in Sickle Cell Disease [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/platelet-purinergic-signaling-regulates-pulmonary-thrombosis-in-sickle-cell-disease/. Accessed March 5, 2024.
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