Venous thromboembolism (VTE) is an important cause of vascular morbidity and mortality. Many risk factors have been identified for venous thrombosis that lead to alterations in blood flow, activate the vascular endothelium, and increase the propensity for blood coagulation. However, the precise molecular and cellular mechanisms that cause blood clots in the venous vasculature have not been fully elucidated. Patients with sickle cell disease (SCD) demonstrate all the risk factors for venous stasis, activated endothelium, and blood hypercoagulability, making them particularly vulnerable to VTE. In this review, we will discuss how mouse models have elucidated the complex vascular pathobiology of SCD. We review the dysregulated pathways of inflammation and coagulation in SCD and how the resultant hypercoagulable state can potentiate thrombosis through down-regulation of vascular anticoagulants. Studies of VTE pathogenesis using SCD mouse models may provide insight into the intersection between the cellular and molecular processes involving inflammation and coagulation and help to identify novel mechanistic pathways.
This paper describes the use of a microfluidic device comprising channels with dimensions mimicking those of the smallest capillaries found in the human microcirculation. The device structure, associated with a pair of microelectrodes, provides a tool to electrically measure the transit time of red blood cells through fine capillaries and thus generate an electrical signature for red blood cells in the context of human erythroid genetic disorders, such as sickle cell disease or hereditary spherocytosis, in which red cell elasticity is altered. Red blood cells from healthy individuals, heated or not, and red blood cells from patients with sickle cell disease or hereditary spherocytosis where characterized at a single cell level using our device. Transit time and blockade amplitude recordings were correlated with microscopic observations, and analyzed. The link between the electrical signature and the mechanical properties of the red blood cells is discussed in the paper, with greater transit time and modified blockade amplitude for heated and pathological red blood cells as compared to those from healthy individuals. Our single cell-based methodology offers a new and complementary approach to characterize red cell mechanical properties in human disorders under flow conditions mimicking the microcirculation. Red blood cells (RBCs) are the most abundant and simple type of blood cells whose main role is fulfilling the gas exchange to deliver oxygen to the tissues. Human RBCs are biconcave and flexible discs with an average diameter of 6-8 µm and a thickness of 2 µm. They lack nucleus and organelles and have a specific membrane composition and organization that enables them to deform and squeeze through the microcirculatory system 1. However, under certain pathophysiological conditions, these properties are altered triggering changes in the deformability and survival rate of circulating RBCs, as observed in several human disorders like sickle cell disease and hereditary spherocytosis 2. Sickle cell disease (SCD) is a genetic hereditary disorder caused by a single point mutation in the β-globin gene, generating an abnormal hemoglobin (HbS) that polymerizes under hypoxic conditions leading to the sickling and alteration of circulating red cells 3. The hallmarks of sickle cell disease are hemolytic anemia and painful vaso-occlusive crises because of the obstruction of fine capillaries 4,5. In SCD, RBC properties are severely altered, with increased cellular dehydration, rigidity and fragility 6,7. Hereditary spherocytosis (HS) is the most prevalent cause of hemolytic anemia due to genetic mutations in membrane or cytoskeletal proteins that disturb the structural and morphological stability of the RBC altering its biconcave shape and plasticity. HS RBCs are recognized by their spherical shape and extreme fragility, and are mainly trapped in the spleen, leading to decreased cell life span and resultant anemia 8 .
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