Diminished Renal Pathology in a Mouse Model of Sickle Cell Anemia in Which Fibrinogen Binding to Mac-1 Is Inhibited

Sickle cell anemia (SCA) is caused by a point mutation in the beta-globin gene. SCA has potentially devastating consequences including chronic hemolytic anemia, episodic vascular occlusion, inflammation and oxidative stress, and cumulative multi-organ damage resulting in early mortality. In fact, with reduction of childhood mortality due to early diagnosis and infection prophylaxis, end-organ damage is the major cause of death in SCA. SCA patients show hyper coagulative state in the absence of vascular occlusion. Recently, our group has shown that reduction of circulating major clotting factor, thrombin, in SCA mice significantly improves survival, reduces inflammation, results in reduced multi-organ damage and prolongs survival (Arumugam 2015). However, the mechanism(s) by which thrombin contributes to the pathophysiology of SCA remains undefined. While fibrinogen functions primarily to occlude blood vessels after cleavage by thrombin into fibrin, and thereby prevents excessive bleeding, it also plays an important role in the pathologic inflammatory disease processes through mitogenic, chemotactic, and immune-regulatory activities by interacting with neutrophils/ macrophages via the Mac-1 receptor. To test the hypothesis that leukocyte engagement of fibrinogen via Mac-1 and secondary inflammation are drivers of SCA-associated organ pathologies, hematopoietic stem cells (HSC) from the well-characterized humanized murine model of SCA, Berkeley sickle mice (HbS or SS) were tran...
Source: Blood - Category: Hematology Authors: Tags: 113. Hemoglobinopathies, Excluding Thalassemia-Basic and Translational Science: Sickle Cell Disease-Role of Coagulation and Inflammation in Pathophysiology Source Type: research