I marcatori di attivazione dell’emostasi: hanno un’utilità clinica? Maria Benedetta Donati

1. IV Corso Educazionale della SISET Cremona, 20-21 Febbraio 2004 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.

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

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

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

5. < 40 years 40-50 years 51-70 years >70 years Smoke Never 7.7 8.7 22.3 49.5 Present 83.9 76.8 52.3 21.0 Past 7.7 14.3 24.7 27.9 Hypercholesterolemia 28.3 27.42 24.2 15.0 Hypertension 12.2 24.2 36.2 44.3 Diabete mellitus 2.9 7.2 15.8 18.8 Previous AMI 6.4 10.9 15.2 17.4 Previous Angina 23.2 35.0 39.3 40.0 Conventional risk factors (%) in Italian patients with Myocardial Infarction at different age. (n= 12490) GISSI-2 Study, Lancet 1990

6. Fibrinogen Cellular activation:membrane receptorsadhesive moleculesproteolytic enzymes TF t-PA VWF Ox-LDL, homocysteine, O- - , shear stress,hypertension, diabetes. smoking, diet, infectious microrganisms… Inflammation THROMBOSIS

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. “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 from de Gaetano G, Thromb Haemost 2001

10. “… 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 from de Gaetano G, Thromb Haemost 2001

11. 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. de Gaetano et al., It Heart J, 2002

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

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

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

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

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

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

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

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 Interaction: Clinical Relevance 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)

25. Selectin PSGL-1 2-integrin Flowing Rolling Firm adhesion and further recruitment Hypothetical sequence of interactions between PMN leukocytes and activated platelets or injured endothelial cells Cerletti et al., Thromb Haemost 1999

26. Metanalysis of Adhesive Molecules Studies Ridker, Lancet 2001

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

29. 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). IL-6 levels and traditional risk factors Ridker PM et al., Circulation 2000

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

31. 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) * Adjusted for age and sex ** Adjusted for age sex and cholesterol *** Adjusted for age sex cholesterol and triglycerides de Gaetano-Donati K et al., AIDS 2003

32. Dwayne SG, Circulation. 2003

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

34. Relative risks of myocardial infarction by quintiles of tPA antigen in analyses controlling for known atherosclerotic risk factors Ridker PM et al., Lancet. 1993

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

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

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

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

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

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

42. Fibrinogen Cellular activation:membrane receptorsadhesive moleculesproteolytic enzymes TF t-PA VWF Ox-LDL, homocysteine, O- - , shear stress,hypertension, diabetes. smoking, diet, infectious microrganisms… Inflammation THROMBOSIS