Platelets primarily mediate hemostasis and thrombosis, whereas leukocytes are responsible for immune responses. Since platelets interact with leukocytes at the site of vascular injury, thrombosis and vascular inflammation are closely intertwined and occur consecutively. Recent studies using real-time imaging technology demonstrated that platelet–neutrophil interactions on the activated endothelium are an important determinant of microvascular occlusion during thromboinflammatory disease in which inflammation is coupled to thrombosis. Although the major receptors and counter receptors have been identified, it remains poorly understood how heterotypic platelet–neutrophil interactions are regulated under disease conditions. This review discusses our current understanding of the regulatory mechanisms of platelet– neutrophil interactions in thromboinflammatory disease.

Key Points• Coadministration of HU and an AKT2 inhibitor has beneficial effects on acute vaso-occlusive events and survival in SCD mice.Heterotypic cell-cell adhesion and aggregation mediate vaso-occlusive events in patients with sickle cell disease (SCD). Although hydroxyurea (HU), an inducer of fetal hemoglobin, is the main therapy for treatment of SCD, it is unclear whether it has immediate benefits in acute vaso-occlusive events in SCD patients. Using real-time fluorescence intravital microscopy, we demonstrated that short-term coadministration of HU and Akti XII, an AKT2 inhibitor, efficiently reduced neutrophil adhesion and platelet-neutrophil aggregation in venules of Berkeley (SCD) mice challenged with tumor necrosis factor a (TNF-a) or hypoxia/reoxygenation. Importantly, compared with HU or Akti XII treatment alone, short-term treatment with both agents significantly improved survival in those mice. We found that the level of plasma nitric oxide species was elevated by HU but not Akti XII, AKT2 phosphorylation levels in activated neutrophils and platelets were reduced by Akti XII but not HU, and the expression of endothelial E-selectin and intercellular adhesion molecule 1 was decreased by either agent. Our results suggest that short-term coadministration of HU and Akti XII has immediate benefits for acute vaso-occlusive events and survival in SCD mice exceeding those seen for single therapy. (Blood. 2015;126(22):2511-2517 IntroductionSickle cell disease (SCD), an inherited blood disorder, results from a homozygous mutation at the 6th position (Glu6Val) of the b-globin chain (hemoglobin S [HbS]) or from compound heterozygous forms such as HbSC and HbS-b-thalassemia.1 HbS tends to polymerize in the deoxygenated state, and this leads to the sickling and hemolysis of red blood cells.2,3 Importantly, decreased nitric oxide (NO) bioavailability and increased oxidative stress contribute to the pathophysiology of SCD, including activation of endothelial cells (ECs), inflammation, and organ damage. 4 Recurrent vaso-occlusive events, the hallmark of SCD, are mediated by adhesion and aggregation of red blood cells, leukocytes, and platelets on activated ECs 5,6 and cause pain crises in SCD patients. 7 Hydroxyurea (HU), the only drug approved by the US Food and Drug Administration for treatment of SCD, stimulates HbF production,8 serves as an NO donor, 9,10 and inhibits tissue factor expression in leukocytes.11 Although the mechanism by which HU acts is still not fully understood, previous studies showed that treatment of SCD patients with HU is associated with the production of NO and increases HbF levels in an NO-dependent manner. 9,10 Studies that use a humanized SCD (Berkeley) mouse model have consistently shown that short-term treatment with HU can have immediate benefits in vaso-occlusive events, independently of HbF production. 12The authors further demonstrated that combination therapy of HU and a phosphodiesterase 9 inhibitor efficiently inhibits acute vasoocclusion in SCD mice. 12Intravital microscopic ...

Interaction of activated platelets and leukocytes (mainly neutrophils) on the activated endothelium mediates thrombosis and vascular inflammation.

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