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Hemolysis Triggers Platelet-Dependent Pulmonary Arteriole Thrombosis

1University of Pittsburgh School of Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Pittsburgh, United States, 2University of Pittsburgh, Department of Bioengineering, Pittsburgh, United States, 3West Virginia University, Department of Chemical and Biomedical Engineering, Morgantown, United States, 4University of Pittsburgh, Center for Biologic Imaging, Pittsburgh, United States, 5University of Pittsburgh, Hemophilia Center of Western Pennsylvania, Pittsburgh, United States, 6University of Pittsburgh School of Medicine, Department of Surgery, Pittsburgh, United States, 7University of Pittsburgh School of Medicine, Division of Pulmonary Allergy and Critical Care Medicine, Pittsburgh, United States

Abstract Number: PB0127

Meeting: ISTH 2020 Congress

Theme: Coagulation and Natural Anticoagulants » Animal Models in Thrombosis and Hemostasis

Background: Intravascular hemolysis promotes platelet activation, endothelial dysfunction and sterile inflammation, leading to a chronic prothrombotic state in hemolytic disorders. Although, pulmonary thrombosis is one of the most common pulmonary complication associated with hemolytic disorders, the in vivo pathogenesis and the role of platelets in promoting this hemolysis-driven morbidity remains unclear.

Aims: To elucidate the cellular, molecular and biophysical pathways contributing to the pathogenesis of hemolysis-induced pulmonary thrombosis in mice.

Methods: C57BL/6J (WT) mice were intravascularly (IV) administered distilled water (dH2O) to trigger acute hemolysis or IV administered with pathologically relevant agonists known to be upregulated in hemolytic disorders. Mice were IV administered with fluorescent Abs against lineage markers for platelets and a fluorescent dextran. The pulmonary microcirculation was visualized using multi-photon-excitation enabled quantitative intravital fluorescence lung microscopy (qFILM).

Results: Acute hemolysis triggered transient obstruction of pulmonary arteriolar bottle-necks located at the junction of pulmonary arterioles and capillaries by platelet aggregates, resulting in loss of blood flow in the down-stream pulmonary capillaries. Identical to acute hemolysis, IV adenosine diphosphate (ADP), collagen, thrombin and thromboplastin (TF) also triggered dose-dependent pulmonary arteriole thrombosis in mice. Although heparin prevented TF-induced pulmonary arteriole thrombosis, it failed to prevent ADP-triggered pulmonary thrombosis in mice. Unlike heparin, eptifibatide completely abrogated both TF- and ADP-dependent pulmonary thrombosis.

Conclusions: We provide the first ever real-time in vivo characterization of the pathogenesis of acute hemolysis induced pulmonary thrombosis. Our data suggest that hemolysis-triggered pulmonary thrombosis involves entrapment of platelet-rich thrombi in the pre-capillary pulmonary arterioles. Our results also suggest that platelet procoagulant activity contributes to pathogenesis of hemolysis-associated pulmonary arteriole thrombosis.

To cite this abstract in AMA style:

Brzoska T, Vats R, Bennewitz MF, Tutuncuoglu E, Watkins SC, Ragni MV, Neal MD, Gladwin MT, Sundd P. Hemolysis Triggers Platelet-Dependent Pulmonary Arteriole Thrombosis [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/hemolysis-triggers-platelet-dependent-pulmonary-arteriole-thrombosis/. Accessed September 29, 2023.

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