Thromboinflammatory mechanisms in sickle cell disease - challenging the hemostatic balance

Abstract

Sickle cell disease (SCD) is an inherited hemoglobinopathy that is caused by the presence of abnormal hemoglobin S (HbS) in red blood cells, leading to alterations in red cell properties and shape, as the result of HbS dexoygenation and subsequent polymerization. SCD pathophysiology is characterized by chronic inflammatory processes, triggered by hemolytic and vaso-occlusive events, which lead to the varied complications, organ damage and elevated mortality seen in individuals with the disease. In association with activation of the endothelium and leukocytes, hemostatic alterations and thrombotic events are well-documented in SCD. Here we discuss the role for inflammatory pathways in modulating coagulation and inducing platelet activation in SCD, due to tissue factor activation, adhesion molecule expression, inflammatory mediator production and the induction of innate immune responses, amongst other mechanisms. Thromboinflammatory pathways may play a significant role in some of the major complications of SCD, such as stroke, venous thromboembolism and possibly acute chest syndrome, besides exacerbating the chronic inflammation and cellular interactions that trigger vaso-occlusion, ischemia-reperfusion processes, and eventually organ damage.

Sickle Cell Disease: A Paradigm for Venous Thrombosis Pathophysiology

“…Sickle blood also exhibits increased TF-dependent procoagulant activity, and consequently increased thrombin generation, as reflected by elevated levels of thrombin anti-thrombin complexes (TAT), prothrombin fragment 1.2 (F1.2), and D-dimers [ 22 , 23 , 24 , 25 ]. Since the molecular and cellular events involved in vascular thrombosis are complex and involve many overlapping pathways, the use of murine models could provide important insight into the processes, particularly those dysregulated inflammatory and coagulation pathways in SCD [ 26 ] that are critical to VTE pathogenesis.…”

“…TLR-4-mediated activation of nuclear factor-κB transcription factor activity also upregulates endothelial cytokine generation (tumor necrosis factor-alpha (TNF-α) and interleukin1-beta (IL-1β), as well as TF expression [ 82 , 87 ]. Furthermore, heme induces assembly of the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome in endothelial cells and leukocytes, with the consequent secretion of IL-1β [ 26 , 77 , 88 , 89 ]. Finally, heme can activate complement via TLRs and P-selectin, leading to deposition of C3 on glomerular and hepatic endothelial cells and subsequent microvascular thrombosis [ 83 , 90 ].…”

The molecular basis for the prothrombotic state in sickle cell disease

“…That red cells in SCD are likely to be involved in thrombus formation is supported by the relationship between hematocrit and VTE, 24 possibly resulting from alterations in viscosity, adhesive cellular interactions, and microvascular stasis. 56,57 Studies of sickle red cells have identified numerous receptors and ligands that mediate adhesive interactions with the vessel wall, implicating their role in Prothrombotic state in sickle cell disease haematologica | 2020; 105 (10) 2371…”

“…As described above, intravascular TF expression in the setting of SCD-related endothelial damage is likely a major contributor to the hypercoagulable state of SCD; however, the role of "blood borne" TF in SCD-related thrombosis is largely unknown. [86][87][88][89] Studies have shown Prothrombotic state in sickle cell disease haematologica | 2020; 105 (10) 2373 that SCD patients have elevated blood borne TF procoagulant activity. [52][53][54][55]90 Specifically, TF + EV, which are derived from monocytes and endothelial cells, have been found to be elevated in SCD patients during acute VOC.…”

“…Studies of vascular pathobiology using in vitro and animal models of SCD have identified both insightful and discrepant findings, when compared with human SCD, as noted in the accompanying review in this issue of the Journal by Conran and De Paula. 10 Here we examine the molecular basis for the prothrombotic state and establish the scientific rationale to target dysregulated coagulation pathways in patients with SCD. For a more comprehensive overview of arterial thrombosis and/or SCD management, the reader is referred to recent publications in the literature.…”