Abstract
Diabetes is associated with an exaggerated platelet thrombotic response at sites of vascular injury. Biomechanical forces regulate platelet activation, although the impact of diabetes on this process remains ill-defined. Using a biomembrane force probe (BFP), we demonstrate that compressive force activates integrin αIIbβ3 on discoid diabetic platelets, increasing its association rate with immobilized fibrinogen. This compressive force-induced integrin activation is calcium and PI 3-kinase dependent, resulting in enhanced integrin affinity maturation and exaggerated shear-dependent platelet adhesion. Analysis of discoid platelet aggregation in the mesenteric circulation of mice confirmed that diabetes leads to a marked enhancement in the formation and stability of discoid platelet aggregates, via a mechanism that is not inhibited by therapeutic doses of aspirin and clopidogrel, but is eliminated by PI 3-kinase inhibition. These studies demonstrate the existence of a compression force sensing mechanism linked to αIIbβ3 adhesive function that leads to a distinct prothrombotic phenotype in diabetes.
Highlights
Diabetes is associated with an exaggerated platelet thrombotic response at sites of vascular injury
We initially investigated the impact of hyperglycemia on platelet adhesive function in vivo, using the streptozotocin (STZ)-induced mouse model of type 1 diabetes[29,30]
We investigated the impact of disturbed blood flow on the platelet aggregation response in diabetic mice using a needle in situ model of platelet thrombus formation[32,33]
Summary
Diabetes is associated with an exaggerated platelet thrombotic response at sites of vascular injury. Analysis of discoid platelet aggregation in the mesenteric circulation of mice confirmed that diabetes leads to a marked enhancement in the formation and stability of discoid platelet aggregates, via a mechanism that is not inhibited by therapeutic doses of aspirin and clopidogrel, but is eliminated by PI 3-kinase inhibition These studies demonstrate the existence of a compression force sensing mechanism linked to αIIbβ[3] adhesive function that leads to a distinct prothrombotic phenotype in diabetes. Platelets from individuals with diabetes are more reactive than platelets from non-diabetics, as evidenced by an increased response to soluble agonist stimulation[3,4,5] along with enhanced adhesion and aggregation responses on thrombogenic surfaces[6,7] They are more effective at supporting blood coagulation and thrombin generation[8]. As a consequence, developing thrombi exhibit a heterogeneous structure of platelets in various degrees of activation and stability, ranging from fully activated and degranulated platelets in the stable thrombus ‘core’, to minimally activated, weakly adherent discoid platelets in the dynamic thrombus outer ‘shell’[26,27,28]
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