1. I marcatori di attivazione dell’emostasi: hanno un’utilità clinica? Maria Benedetta Donati Center for High Technology and Education in Biomedical Sciences. Catholic University,Campobasso, Italy. IV Corso Educazionale della SISET Cremona, 20-21 Febbraio 2004

2. Age Sex Smoking Food Socio-economic conditions Diabetes Hypertension Dyslipidemia Others Conventional risk factors account for less than 60% of cardiovascular risk Coronary Artery Disease as multifactorial disorder

3. GISSI-2 Study, Lancet 1990 Age distribution of Italian patients with Acute Myocardial Infarction

4. GISSI-2 Study Lancet 1990 Prevalence of family history of Acute Myocardial Infarction in Italian patients with MI at different age

5. GISSI-2 Study, Lancet 1990 Conventional risk factors (%) in Italian patients with Myocardial Infarction at different age. (n= 12490) 40.039.335.023.2Previous Angina 17.415.210.96.4Previous AMI 18.815.87.22.9Diabete mellitus 44.336.224.212.2Hypertension 15.024.227.4228.3Hypercholesterolemia 27.924.714.37.7Past 21.052.376.883.9Present 49.522.38.77.7Never Smoke >70 years51-70 years40-50 years< 40 years

6. THROMBOSIS Ox-LDL, homocysteine, O - -, shear stress, hypertension, diabetes. smoking, diet, infectious microrganisms… Inflammation Cellular activation: membrane receptors adhesive molecules proteolytic enzymes Fibrinoge n TF t-PA VWF

7. Haemostatic markers of cardiovascular risk Platelet paradox Adhesive molecules / cytokines t-PA / von Willebrand Factor Factor VII Fibrinogen

8. Haemostatic markers of cardiovascular risk Platelet paradox Adhesive molecules / cytokines t-PA / von Willebrand Factor Factor VII Fibrinogen

9. from de Gaetano G, Thromb Haemost 2001 “Every time the vascular wall is damaged, the earliest phenomenon which can be observed is the accumulation of blood platelets. Among aggregated platelets a few white blood corpuscules are also captured…” Giulio Bizzozero, 1882 Two small mural thrombi which have formed within a small artery of the omentum of a guinea pig. The larger one contains, among blood platelets, a white blood corpuscule

10. from de Gaetano G, Thromb Haemost 2001 “… Therefore, fibrin is deposited on top of the platelet layers as elongated fibrillar bundles. The latter acquire the property of a foreign surface so that they are rapidly covered by increasing layers of platelets and become active as new centres for blood coagulation…” Giulio Bizzozero, 1882 Fibrin on a thread with which canine blood had been beaten during 45 s, examined in methyl-salt solution. The surface of the thread is clogged by masses consisting of blood platelets among which two white blood corpuscules can be seen

11. de Gaetano et al., It Heart J, 2002 The Platelet Paradox Despite the long-lasting observation of the role of platelets in experimental thrombosis the remarkable antithrombotic effect of antiplatelet drugs in several ischemic conditions, There is still little clinical data showing a direct relationship between platelet number (and/or any platelet function parameter) and ischemic events.

12. Antithrombotic Trialists' Collaboration, BMJ 2002 Proportional effects of antiplatelet therapy on vascular events

13. The Platelet Paradox No Platelet Marker selected by ECAT or PLAT to predict the risk of vascular events

14. Haemostatic markers of cardiovascular risk Platelet paradox Adhesive molecules / cytokines t-PA / von Willebrand Factor Factor VII Fibrinogen

15. Soluble CD40 Ligand in Acute Coronary Syndromes

16. Heeschen et al., N Engl J Med 2003 Soluble CD40 Ligand in Acute Coronary Syndromes

17. Heeschen et al., N Engl J Med 2003 Soluble CD40 Ligand in Acute Coronary Syndromes

18. Heeschen et al., N Engl J Med 2003 Soluble CD40 Ligand in Acute Coronary Syndromes

19. Heeschen et al., N Engl J Med 2003 Soluble CD40 Ligand in Acute Coronary Syndromes

20. Heeschen et al., N Engl J Med 2003 Soluble CD40 Ligand in Acute Coronary Syndromes

21. Danesh et al., JAMA 1998 Association of leukocyte count with coronary heart disease: a meta-analysis of prospective studies

22. Platelet-leukocyte Interaction: Clinical Relevance Platelet- leukocyte interaction and the subsequent leukocyte activation: new parameters to predict the risk and to monitor the severity of ischemic disease ?

23. Platelet-leukocyte Interaction: Clinical Evidence Activated leukocytes Activated leukocytes in blood of patients with unstable angina (Mehta et al, 1990) Increased monocyte and PMN expression of CD11b in unstable angina (Mazzone et al, 1993) Enhanced response to activation of PMN from patients with valve replacement (Maugeri et al, 1997)

24. Platelet-leukocyte conjugates in peripheral blood of patients with unstable angina (Ott et al, 1996) in patients with acute myocardial infarction (May et al, 1997) a predictive index of acute reocclusion following coronary angioplasty (Mickelson et al, 1996) a marker of myocardial infarction (Michelson et al, 2002) Platelet-leukocyte Interaction: Clinical Relevance

25. Cerletti et al., Thromb Haemost 1999 Hypothetical sequence of interactions between PMN leukocytes and activated platelets or injured endothelial cells

26. Ridker, Lancet 2001 Metanalysis of Adhesive Molecules Studies

28. Burzotta et al., Am J Cardiol 2001 Plasma concentrations of IL-6 according to genotype

29. Ridker PM et al., Circulation 2000 IL-6 levels and traditional risk factors Median baseline IL-6 levels according to number of traditional risk factors present (hypertension, hyperlipidemia, smoking, diabetes, age >60 years, family history, and body mass index >27.3 kg/m2).

30. Malik et al., Lancet 2001 Metanalysis of Adhesive Molecules Studies

31. de Gaetano-Donati K et al., AIDS 2003 Univariate and multivariate analysis of plasmatic levels of endothelial markers (sICAM-1, P-selectin, PAI-1 and t-PA) in HAART and naïve HIV patients (values are means ± sd) Marker (ng/ml) HAART Group Naive Group UnivariateMultivariate PP*P**P*** sICAM-1508.±184.4551.3±190.40.20.30.70.8 P-selectin145.0±72.2115.1±55.50.01<0.050.020.06 PAI-141.6±29.228.3±25.1<0.010.06 0.3 t-PA9.8±4.96.5±3.9<0.00010.001<0.01 *Adjusted for age and sex **Adjusted for age sex and cholesterol ***Adjusted for age sex cholesterol and triglycerides

32. Dwayne SG, Circulation. 2003

33. Ridker PM, Ann Intern Med. 1999 Relative risk for future myocardial infarction among apparently healthy middle-aged men in the Physicians’ Health Study

34. Ridker PM et al., Lancet. 1993 Relative risks of myocardial infarction by quintiles of tPA antigen in analyses controlling for known atherosclerotic risk factors Model Quintile of tPA antigen (range, ng/nL) 1 (<5.2) 2 (5.2-7.1) 3 (7.2-9.2) 4 (9.3-12.2) 5 (>12.2) P for trend tPA alone1.001.271.751.882.810.0008 tPA and total cholesterol 1.001.141.531.752.710.001 tPA and HDL cholesterol 1.000.941.121.351.840.03 tPA and non-lipid risk factors 1.001.121.401.682.100.04 tPA, non-lipid risk factors, total and HDL cholesterol 1.000.850.981.261.560.14

35. Haemostatic markers of cardiovascular risk Platelet paradox Adhesive molecules / cytokines t-PA / von Willebrand Factor Factor VII Fibrinogen

36. The Northwick Park Heart Study, 1986. Role of coagulant Factor VII in the risk of ischaemic heart disease

37. The Medical Research Council's General Practice Research Framework, Lancet 1998 Cumulative proportion (%) of men with ischemic heart disease, main effects

38. Iacoviello et al, N Engl J Med 1998 A Polymorphism of Factor VII Gene as an inherited protective Factor for Myocardial Infarction * adjusted for confounders Factor VII R353Q genotypes

39. Danesh et al, JAMA 1998 Prospective studies of fibrinogen and coronary heart disease

41. Danesh et al., Circulation 2001 Fibrin D-Dimer and Coronary Heart Disease

42. THROMBOSIS Ox-LDL, homocysteine, O - -, shear stress, hypertension, diabetes. smoking, diet, infectious microrganisms… Inflammation Cellular activation: membrane receptors adhesive molecules proteolytic enzymes Fibrinoge n TF t-PA VWF