Prothrombotic aspects of sickle cell disease

Abstract

Summary Sickle cell disease (SCD) is a hematologic disorder caused by a well‐characterized point mutation in the β‐globin gene. Abnormal polymerization of hemoglobin tetramers results in the formation of sickle red blood cells that leads to vascular occlusions, hemolytic anemia, vascular inflammation and cumulative, multiple organ damage. Ongoing activation of coagulation is another hallmark of SCD. Recent studies strongly suggested that hypercoagulation in SCD is not just a secondary event but contributes directly to the disease pathophysiology. In this article we summarize mechanisms leading to the activation of coagulation, review data indicating direct contribution of coagulation to the pathology of SCD and, we discuss the anticoagulation as a possible treatment strategy to attenuate the disease progression

Tissue factor at the crossroad of coagulation and cell signaling

“…The previously underappreciated expression of TF by endothelial cells plays a major role in sickle cell disease (SCD) pathology. In this context, myeloid cell TF is responsible for coagulation activation in mouse models of SCD, but endothelial cell TF primarily contributes to PAR2 signaling‐dependent vascular inflammation .…”

“…Although endothelial cell expression of TF has long been considered of little importance for pathological processes, the inflamed pulmonary vein endothelium in SCD expresses TF dependent on direct effects of hemolysis and leukocyte crosstalk . The TF pathway is crucial for both coagulation abnormalities and chronic vascular inflammation in SCD, but endothelial cell‐specific deletion of TF in a mouse model of SCD prevents selectively the upregulation of IL6, without changing markers of intravascular coagulation . Blocking TF and anticoagulation with the thrombin inhibitor dabigatran or the FXa inhibitor rivaroxaban effectively reduces lung leukocyte infiltration.…”

Factor VIIa‐induced interaction with integrin controls the release of tissue factor on extracellular vesicles from endothelial cells

“…TF activated by thiol–disulfide exchange‐dependent complement activation or cell injury‐derived ATP is frequently released on highly procoagulant extracellular vesicles (EVs) that carry specific integrin β 1 heterodimers . Although the pathological roles of endothelial cell‐expressed TF were thought to be limited to neovascularization , endothelial TF, through protease‐activated receptor (PAR) 2 signaling, contributes to vascular inflammation associated with sickle cell disease . In addition, endothelial TF can cause a prothrombotic state because of impaired control of reactive oxygen species production and possibly of TF pathway inhibitor, which is an established regulator of intravascular thrombosis and endothelial cell TF signaling .…”

“…Although the pathological roles of endothelial cell-expressed TF were thought to be limited to neovascularization [9][10][11], endothelial TF, through protease-activated receptor (PAR) 2 signaling, contributes to vascular inflammation associated with sickle cell disease [12,13]. In addition, endothelial TF can cause a prothrombotic state [14] because of impaired control of reactive oxygen species production and possibly of TF pathway inhibitor, which is an established regulator of intravascular thrombosis [15] and endothelial cell TF signaling [16].…”

A dose‐ranging study of ticagrelor in children aged 3‐17 years with sickle cell disease: A 2‐part phase 2 study

“…Current understanding of sickle cell disease (SCD) includes pathophysiology beyond the red blood cell, for example, inflammation, oxidant stress, vasoregulation, endothelial dysfunction, and thrombosis . Platelet activation is at the cross‐roads of most of these pathophysiologic pathways, both acute and chronic.…”