Platelet–Neutrophil Interaction and Thromboinflammation in Diabetes: Considerations for Novel Therapeutic Approaches

Abstract

Thromboinflammation has become a topic of key interest in cardiovascular disease and the prevention of diabetes complications because of the interplay between thrombosis and inflammation in diabetes. Specifically, the significant risk of vascular thrombotic disease in diabetes highlights the need for new and better therapeutic targets to help manage and prevent vascular thrombo‐occlusive disease in this condition. Similarly, the prominent role of inflammation in diabetes has sparked interest in anti‐inflammatory agents to better prevent and control vascular disease. Investigations on the effects of anticoagulation and antiplatelet interventions in patients with diabetes and cardiovascular disease show a potential role for these agents in decreasing morbidity and mortality. Neutrophils and platelets are key players in inflammation and wound‐healing response, respectively. The interaction between neutrophils and platelets is thought to be an important driver of thromboinflammation. Therefore, this review describes the mechanisms involved in platelet–neutrophil interactions that contribute to the development or exacerbation of thromboinflammation in the context of diabetes and its associated comorbidities. The effects observed by the antithrombotic/antidiabetic treatments and physical activity/dietary interventions on attenuating thromboinflammation are discussed. These data suggest that mechanisms involved in platelet–neutrophil interaction, platelet activation/aggregation, and the recruitment of neutrophils have a promising potential to become therapeutic targets to decrease thromboinflammation in patients with diabetes.

Hematological Parameters in the First Trimester and the Risk of Gestational Diabetes Mellitus — Beijing, China, 2017–2020

“…Research evidence suggests that subclinical inflammation may lead to insulin resistance by impairing β cell function and affecting insulin signaling directly (12). This may explain why classical inflammatory markers, such as WBC count and NLR, as well as the novel inflammation marker, SII, are correspondingly increased in early pregnancy among women with GDM.…”

“…This may explain why classical inflammatory markers, such as WBC count and NLR, as well as the novel inflammation marker, SII, are correspondingly increased in early pregnancy among women with GDM. Additionally, platelet aggregation and glycated platelets have been reported in diabetes, which is correlated to a setting of acute and chronic inflammation with a similar cytokine milieu as that implicated in increased WBC count ( 13 ). In terms of surrogacy for nutritional improvement, higher RBC and Hb levels are often accompanied by higher blood viscosity, which has been demonstrated to be associated with insulin resistance ( 14 ).…”

Immunothrombosis in neurovascular disease

“…Important for clinical translation, most targets of this pathway have been validated across different laboratories using different stroke models, including comorbidities and coadministration of tissue plasminogen activator. In fact, comorbidities such as hyperglycemia [ [61] , [62] , [63] ], hyperlipidemia [ 64 , 65 ], and older age [ [66] , [67] , [68] , [69] ], which are common in patients who experience stroke, have been reported to be associated with increased platelet–leukocyte interactions and an increased propensity to form NETs.

Figure 2 Platelet-dependent neutrophil extracellular trap (NET) release induces microthrombosis and neurotoxicity during ischemic stroke brain injury.

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Platelet mitochondria: the mighty few

“…Recent work linked platelet mitochondrial impairment to the dysregulation in platelet function observed in diabetes [82 ▪▪ ,83]. Mitochondrial stress tests, which calculate mitochondrial efficiency in various metabolic processes, have shown that resting platelets from diabetic patients have lower maximal respiration compared with nondiabetic patients [25,82 ▪▪ ,83]. Activation of diabetic platelets with thrombin further accentuated differences in maximal respiration, while also demonstrating a decrease in basal oxygen rate consumption (OCR) and ATP production [82 ▪▪ ].…”

“…Glucose enters platelets via the facilitative glucose transporter 1 (GLUT1) and glucose transporter 3 (GLUT3). Murine studies have demonstrated that GLUT1 and GLUT3 exhibit overlapping, as well as unique functions [25,26]. Although GLUT1 is continuously present on the plasma membrane, GLUT3 is predominantly located on a-granule membranes with only AE15% localized in the plasma membrane [20,26].…”