Platelet function in diabetes

Transcription

1 Platelet function in diabetes Agneta Siegbahn, MD, PhD, FESC Professor Clinical Coagulation Science Department of Medical Sciences and Uppsala Clinical Research Center Uppsala University Disclosures: None

2 Background Individuals with type II diabetes have 2-4 fold increased risk of CAD Patients with DM without previous MI carry the same level of risk for subsequent ACSs as non-diabetes patients with previous MI Excess cardiovascular risk in DM persists despite controlling for hypertension, hypercholesterolemia, smoking and physical inactivity Platelet hyperactivity contributes to this as platelets play a pivotal role in thrombusformation within the vessels Diabetic patients on standard antiplatelet therapy for secondary prevention have significantly worse outcome compared to their non-diabetic counterparts

3 Aggregation Fibrinogen GPVI-FcRγ α 2 β 1 -integrin von Willebrand factor GPIbα GPIX GPV Adhesion Fibronectin α IIb β3-integrin ADP ADP TXA 2 TXA 2 PAR1 THROMBIN Activation

4 Fibrinogen receptor GPIIb-IIIa GPIIb- IIIa Fibrinogen Laminin receptor GPIIb-IIIa

5 Adapted from Ferroni P et al. J Thromb Haemost 2004; 2: T2DM GlyLDL, Hyperglycemia Hyperinsulinemia Impaired Ca 2+ homeostasis Effects of altered glycemic control on platelet function Inhibition of Na/K ATPase Platelet activation Ca 2+ Activation of PKC TXA 2 NO production GPIbα GPIX GPV ROS production Non-enzymatic glycation of GPs

6 Platelet activation markers in controls and patients with type 2 diabetes before and after improved metabolic control Controls (n = 32) Patients at 0 months (n = 30) Patients after 3 months (n = 30) HbA 1c (%) 10.6 ± ± 0.7 CD31 (MCF) CD49b (MCF) CD62P (MCF) CD63 (MCF) *** ** *** ** Values are expressed as median values and quartiles (Q25 - Q75) or means ± SD *p<0.05; **p<0.01; ***p<0.01 (patients at 0 months vs. controls) p<0.05; p<0,01; p<0,001 (patients after 3 months vs. patients at 0 months) Eibl N et al. Eur J Clin Invest 2004; 34(3): 205-9

7 Urinary 11-dehydro-TXB 2, plasma scd40 L and plasma sp-selectin in individuals with and without diabetes treated with low doses of aspirin DM = 82 patients on aspirin 100 mg/day Controls = 39 individuals without DM on aspirin 100 mg/day Evangelista et al. J Thromb Haemost 2007;5:

8 Relationship Between Active Metabolite (AM) Exposure and P2Y12 inhibition by VASP(PRI) Prasugrel 10 mg Clopidogrel 75 mg Plasma Concentration of AM by Diabetic Status AUC AM (µm*h) Inhibition of P2Y 12 Receptor Function Measured by VASP Assay on Addition of Clopidogrel AM by Diabetic Status Wallentin et al., & Siegbahn EHJ 2008;29:21-30 Erlinge et al. JACC 2008;52:

9 Microparticles (MPs) in hemostasis MP MP MP 0.5 µm MPs are vesicles that bud off from cells, lack a nucleus, contain a membrane skeleton; considered as ectosomes Express antigens from their parental cells on their surface Mainly constituted by proteins and lipids, may contain mrna The size is between 0.1 μm to 1 μm Circulating MPs are principally of platelet origin, also derived from red and white blood cells and endothelial cells MPs play an important role in thrombosis PDMPs may express tissue factor and integrin α IIb β 3 Image adapted from Tilley et al. Thromb Res 2008; 122: 604-9

10 Platelet microparticles in diabetic patients DM = 48, Healthy subjects = 30 Omoto et al. Nephron 1999; 81:

11 TYPE 2 DIABETES sp-selectin VLA-4 VCAM-1 svcam-1, se-selectin TF CD63 RANTES TF ICAM-1 Mac-1 EDMP CD40L PDMP MDMP CD40L Hypercoagulability Cytokines Atherosclerosis Aterotrombosis Adapted from S. Nomura, Dynamic Role of Microparticles in Type 2 Diabetes Mellitus, Current Diabetes Reviews 2009, Volume 5, Number 4

12 Conclusions platelet abnormalities in diabetes Disordered calcium homeostasis and activation of PKC affect platelet shape change, secretion and aggregation Increased TXA2 production from arachidonic acid inducing further platelet activation Increased expression of surface receptors also due to nonenzymatic glycation of the receptor proteins Reduced insulin response which affects responses to agonists Increased formation of platelet-derived microparticles Increased platelet-dependent activation of coagulation Platelets in DM are rich in proinflammatory cytokines and growth factor which contribute to inflammation and atherogenesis

13 Thank you!