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Intravascular hemolysis triggers ADP-mediated generation of platelet-rich thrombi in precapillary pulmonary arterioles
Tomasz Brzoska, … , Mark T. Gladwin, Prithu Sundd
Tomasz Brzoska, … , Mark T. Gladwin, Prithu Sundd
Published June 16, 2020
Citation Information: JCI Insight. 2020;5(14):e139437. https://doi.org/10.1172/jci.insight.139437.
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Research Article Pulmonology Vascular biology

Intravascular hemolysis triggers ADP-mediated generation of platelet-rich thrombi in precapillary pulmonary arterioles

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Abstract

Patients with hereditary or acquired hemolytic anemias have a high risk of developing in situ thrombosis of the pulmonary vasculature. While pulmonary thrombosis is a major morbidity associated with hemolytic disorders, the etiological mechanism underlying hemolysis-induced pulmonary thrombosis remains largely unknown. Here, we use intravital lung microscopy in mice to assess the pathogenesis of pulmonary thrombosis following deionized water–induced acute intravascular hemolysis. Acute hemolysis triggered the development of αIIbβ3-dependent platelet-rich thrombi in precapillary pulmonary arterioles, which led to the transient impairment of pulmonary blood flow. The hemolysis-induced pulmonary thrombosis was phenocopied with intravascular ADP- but not thrombin-triggered pulmonary thrombosis. Consistent with a mechanism involving ADP release from hemolyzing erythrocytes, the inhibition of platelet P2Y12 purinergic receptor signaling attenuated pulmonary thrombosis and rescued blood flow in the pulmonary arterioles of mice following intravascular hemolysis. These findings are the first in vivo studies to our knowledge to suggest that acute intravascular hemolysis promotes ADP-dependent platelet activation, leading to thrombosis in the precapillary pulmonary arterioles, and that thrombin generation most likely does not play a significant role in the pathogenesis of acute hemolysis–triggered pulmonary thrombosis.

Authors

Tomasz Brzoska, Ravi Vats, Margaret F. Bennewitz, Egemen Tutuncuoglu, Simon C. Watkins, Margaret V. Ragni, Matthew D. Neal, Mark T. Gladwin, Prithu Sundd

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Figure 1

Intravascular hemolysis triggers acute pulmonary thrombosis in mice.

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Intravascular hemolysis triggers acute pulmonary thrombosis in mice.
WT ...
WT mice were intravascularly (IV) administered with 150 μL dH2O (n = 7 mice) to induce acute hemolysis and pulmonary circulation was imaged using quantitative fluorescence intravital lung microscopy (qFILM). (A) qFILM images of the same field of view (FOV) at 7 different time points are shown. t = 0 seconds (s) corresponds to time point before IV dH2O administration and other displayed time points are relative to IV dH2O. Pulmonary thrombosis was absent at t = 0 s. Following 150 μL dH2O, platelet-rich thrombi (white arrowheads) sequestered in the pulmonary arteriole (t = 10 s). By t = 15 s, the thrombi were trapped in the arteriolar bottlenecks causing local impairments in blood flow. Pulmonary thrombosis started to resolve by t = 23 s and completely resolved by t = 2 minutes. Data are representative of 7 independent experiments. Platelets are shown in green and pulmonary microcirculation in purple. Asterisks denote alveoli. Dotted ellipses denote arteriolar bottlenecks. White arrow mark the direction of blood flow within the feeding arteriole. The diameter of the shown arteriole is 29 μm. Scale bar: 50 μm. Complete qFILM time series corresponding to A is shown in Supplemental Video 2. (B) Pulmonary thrombi area plotted as a function of time showing changes in the total area of platelet-rich thrombi following 150 μL IV dH2O. Red arrow indicates pulmonary thrombi max area.
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