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.
Highlights
Hemolysis is one of the major pathophysiological events associated with inherited and acquired disorders such as sickle cell disease (SCD) [1,2,3], thalassemia [1, 4], paroxysmal nocturnal hemoglobinuria (PNH) [5, 6], thrombotic thrombocytopenic purpura (TTP) [7, 8], hemolytic-uremic syndrome (HUS) [7, 9], sepsis [10, 11], and malaria [12]
These findings indicate that pulmonary arteriole thrombosis triggered by acute intravascular hemolysis is predominantly dependent on platelet activation and subsequent aggregation
We found that acute intravascular hemolysis led to transient nonlethal pulmonary arteriole thrombosis in mice, which was dependent on αIIbβ3-mediated platelet aggregation
Summary
Hemolysis is one of the major pathophysiological events associated with inherited and acquired disorders such as sickle cell disease (SCD) [1,2,3], thalassemia [1, 4], paroxysmal nocturnal hemoglobinuria (PNH) [5, 6], thrombotic thrombocytopenic purpura (TTP) [7, 8], hemolytic-uremic syndrome (HUS) [7, 9], sepsis [10, 11], and malaria [12]. Thrombocytopenia, which is suggestive of intravascular platelet sequestration, is a risk factor for acute systemic and pulmonary complications of hemolytic disorders [8, 32,33,34]. Autopsy and CT studies have identified platelet-rich thrombi occluding pulmonary artery branches and arterioles in patients with diverse hemolytic disorders [19, 20, 25, 35, 36].
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