High platelet turnover and reactivity in renal transplant recipients patients

Francesca Cesari; Rossella Marcucci; Anna Maria Gori; Roberto Caporale; Alessandra Fanelli; Rita Paniccia; Maria Zanazzi; Elisabetta Bertoni; Aida Larti; Maurizio Salvadori; Gian Franco Gensini; Rosanna Abbate

doi:10.1160/TH10-02-0124

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2010; 104(04): 804-810
DOI: 10.1160/TH10-02-0124

Platelets and Blood Cells

Schattauer GmbH

High platelet turnover and reactivity in renal transplant recipients patients

Authors

Francesca Cesari

¹Department of Medical and Surgical Critical Care, Thrombosis Centre; Center for the Study at Molecular and Clinical Level of Chronic, Degenerative and Neoplastic Diseases to Develop Novel Therapies, University of Florence, Italy
Rossella Marcucci

¹Department of Medical and Surgical Critical Care, Thrombosis Centre; Center for the Study at Molecular and Clinical Level of Chronic, Degenerative and Neoplastic Diseases to Develop Novel Therapies, University of Florence, Italy
Anna Maria Gori

²Centro S. Maria agli Ulivi, Fondazione Don Carlo Gnocchi Onlus IRCCS, Impruneta, Florence, Italy
Roberto Caporale

³Central Laboratory, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
Alessandra Fanelli

³Central Laboratory, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
Rita Paniccia

¹Department of Medical and Surgical Critical Care, Thrombosis Centre; Center for the Study at Molecular and Clinical Level of Chronic, Degenerative and Neoplastic Diseases to Develop Novel Therapies, University of Florence, Italy
Maria Zanazzi

⁴Renal Unit, Careggi University Hospital, Florence, Italy
Elisabetta Bertoni

⁴Renal Unit, Careggi University Hospital, Florence, Italy
Aida Larti

⁴Renal Unit, Careggi University Hospital, Florence, Italy
Maurizio Salvadori

⁴Renal Unit, Careggi University Hospital, Florence, Italy
Gian Franco Gensini

²Centro S. Maria agli Ulivi, Fondazione Don Carlo Gnocchi Onlus IRCCS, Impruneta, Florence, Italy
Rosanna Abbate

¹Department of Medical and Surgical Critical Care, Thrombosis Centre; Center for the Study at Molecular and Clinical Level of Chronic, Degenerative and Neoplastic Diseases to Develop Novel Therapies, University of Florence, Italy

Abstract

Summary

Renal transplant recipients (RTRs) patients are at increased risk of cardiovascular morbidity and mortality. We aimed this study to assess reticulated platelets (RP), platelet reactivity and von Willebrand factor (vWF) levels in RTRs patients. In 150 RTRs patients [84 (56%) not on acetylsalicylic acid (ASA) treatment, group A; 66 (44%) on ASA 100 mg treatment, group B] and in 60 healthy control subjects, RP were measured by a Sysmex XE-2100 and were expressed as the percentage of RP of the total optical platelet count (immature platelet fraction; IPF), as the percentage of RP highly fluorescent (H-IPF) and as the absolute number of RP (IPF#). Platelet function was assessed by optical aggregometry (PA) induced by 1 mmol arachidonic acid (AA-PA), 2 and 10 μM ADP (ADP2-PA and ADP10-PA) and 2 μg/ml collagen (Coll-PA). vWF levels were measured by using a miniVidas analyser. Group A and group B showed significant higher values of RP than controls. At a multiple linear regression analysis IPF and IPF# were significantly and positively related to collagen-PA. By analysing group B according to residual platelet reactivity (RPR), we observed a significant higher number of RP among patients with RPR by collagen. Moreover at a multiple logistic regression analysis, IPF# significantly affected the risk of having a RPR by collagen. With regard to vWF, RTRs patients showed higher levels than control subjects. We documented a higher platelet turn-over in both groups of RTRs patients and increased platelet reactivity in RTRs patients not on ASA therapy than controls.

Keywords

Reticulated platelets - platelet reactivity - renal transplantation

Full Text

References

References
1 Foley RN, Parfrey PS, Samak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998; 32: 112-119.
2 Kasiske BL, Chakkera HA, Roel J. Explained and unexplained ischemic heart disease risk after renal transplantation. J Am Soc Nephrol 2000; 11: 1735-1743.
3 Raine AE. Hypertension and ischemic heart disease in renal transplant recipients. Nephrol Dial Transplant 1995; 10: 95-100.
4 Cottone S, Palermo A, Vaccaro F. et al. Inflammation and endothelial activation are linked to renal function in long-term kidney transplantation. Transplant Int 2007; 20: 82-87.
5 Marcucci R, Zanazzi M, Bertoni E. et al. Risk factors for cardiovascular disease in renal transplant recipients: new insights. Transpl Int 2000; 13S: 419-424.
6 Averna M, Barbagallo CM, Ganci A. et al. Determinants of enhanced thromboxane biosynthesis in renal transplantation. Kidney Int 2001; 59: 1574-1579.
7 Hryszko T, Malyszko J, Malyszko JS. et al. A possible role of thrombin-activatable fibrinolysis inhibitor in disturbances of fibrinolytic system in renal transplant recipients. Nephrol Dial Transplant 2001; 16: 1692-1696.
8 Malyszko J, Malyszko JS, Takada A. et al. Effects of immunosuppressive drugs on platelet aggregation in vitro. Ann Transplant 2002; 7: 55-68.
9 Tomasiak M, Rusak T, Gacko M. et al. Cyclosporine enhances platelet procoagulant activity. Nephrol Dial Transplant 2007; 22: 1750-1756.
10 Grotz W, Siebig S, Olschewski M. et al. Low-dose aspirin therapy is associated with improved allograft function and prolonged allograft survival after kidney transplantation. Transplantation 2004; 12: 1848-1853.
11 Acikel S, Yildirir A, Aydinalp A. et al. Incidence of aspirin resistance and its relationship with cardiovascular risk factors and graft function in renal transplant recipients. Transplant Proc 2008; 40: 3485-3488.
12 Briggs C, Kunka S, Hart D. et al. Assessment of an immature platelet fraction (IPF) in peripheral thrombocytopenia. Br J Haematol 2004; 126: 93-99.
13 Abe Y, Wada H, Tomatsu H. et al. A simple technique to determine thrombopoiesis level using immature platelet fraction (IPF). Thromb Res 2006; 118: 463-469.
14 Cesari F, Marcucci R, Caporale R. et al. Relationship between high platelet turnover and platelet function in high-risk patients with coronary artery disease on dual antiplatelet therapy. Thromb Haemost 2008; 99: 930-935.
15 Kasiske BL, Vazquez MA, Harmon WE. et al. Recommendations for the outpatient surveillance of renal transplant recipients American Society of Transplantation. J Am Soc Nephrol 2000; 11: S1-86.
16 Practice guidelines for primary care physicians: 2003 ESH/ESC Hypertension guidelines.. ESH/ESC hypertension guidelines committee. Hypertension 2003; 21: 1779-1786.
17 Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003; 26: 5-20.
18 Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adult (Adult Treatment Panel III) final report. Circulation 2002; 106: 3143-3421.
19 Paniccia R, Antonucci E, Maggini N. et al. Assessment of platelet function on whole blood by multiple electrode aggregometry in high-risk patients with coronary artery disease receiving antiplatelet therapy. Am J Clin Pathol 2009; 131: 834-842.
20 Gum PA, Kottke-Marchant K, Welsh PA. et al. A prospective, blinded determination of natural history of aspirin resistance among stable patients with cardiovascular disease. J Am Coll Cardiol 2003; 41: 961-965.
21 Marcucci R, Gori AM, Paniccia R. et al. Residual platelet reactivity is associated with clinical and laboratory characteristics in patients with ischemic heart disease undergoing PCI on dual antiplatelet therapy. Atherosclerosis 2007; 195: 217-223.
22 Gori AM, Marcucci R, Paniccia R. et al. Thrombotic events in high risk patients are predicted by evaluating different pathways of platelet function. Thromb Haemost 2008; 100: 1136-1145.
23 Pham PT, Pham PC, Danovitch GM. Cardiovascular disease posttransplant. Semin Nephrol 2007; 27: 430-444.
24 Marcén R. Cardiovascular risk factors in renal transplantation--current controversies. Nephrol Dial Transplant. 2006; 21: 3-8.
25 Davis SF, Yeung AC, Meredith IT. et al. Early endothelial dysfunction predicts the development of transplant coronary artery disease at 1 year posttransplant. Circulation 1996; 93: 457-462.
26 Denton MD, Davis SF, Baum MA. et al. The role of the graft endothelium in transplant rejection: evidence that endothelial activation may serve as a clinical marker for the development of chronic rejection. Pediatr Transplant 2000; 4: 252-260.
27 Labarrere CA, Lee JB, Nelson DR. et al. C-reactive protein, arterial endothelial activation, and development of transplant coronary artery disease: a prospective study. Lancet 2002; 360: 1462-1467.
28 Reul RM, Fang JC, Denton MD. et al. CD40 and CD40 ligand (CD154) are coex-pressed on microvessels in vivo in human cardiac allograft rejection. Transplantation 1997; 64: 1765-1774.
29 Moss MB, de Siqueira MA, Mann GE. et al. Platelet aggregation in arterial hyper-tension. Is there a nitric oxide-urea connection? Clin Exp Pharmacol Physiol 2010; 37: 167-172.
30 Fatini C, Sticchi E, Bolli P. et al. Platelet aggregability is modulated by eNOS locus in non-type 2 diabetic patients with acute coronary syndrome. Nutr Metab Cardiovasc Dis. 2009 doi:10.1016/j.numecd.2009.07.001.
31 Martin JF, Trowbridge EA, Salmon GL. et al. The biological significance of platelet volume: its relationship to bleeding time, platelet thromboxane B2 production and megakaryocyte nucler DNA concentration. Thromb Res 1983; 32: 443-460.
32 Jakubowski JA, Thompson CB, Vaillancourt R. et al. Arachidonic acid metabolism by platelets of differing size. Br J Haematol 1983; 53: 503-511.
33 Tschoepe D, Roesen P, Kauffmann L. et al. Evidence for abnormal platelet glyco-protein expression in diabetes mellitus. Eur J Clin Invest 1990; 20: 166-170.
34 Guthikonda S, Lev EI, Patel R. et al. Reticulated platelets and uninhibited COX-1 and COX-2 decrease the antiplatelet effects of aspirin. Journal Thromb Haemost 2007; 5: 490-496.
35 Stohlawetz PJ, Dzirlo L, Hergovich N. et al. Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans. Blood 2000; 95: 2983-2989.
36 Tàssies D, Reverter JC, Cases A. et al. Effect of recombinant human erythropoietin treatment on circulating reticulated platelets in uremic patients: association with early improvement in platelet function. Am J Hematol 1998; 59: 105-109.
37 Altun B, Usalan C, Haznedaroglu IC. et al. Thrombopoietin and thrombospondin in renal allograft recipients. Blood Coagul Fibrinolysis 1999; 10: 233-237.
38 Bonnefoy A, Hoylaerts MF. Thrombospondin-1 in von Willebrand factor function. Curr Drug Targets 2008; 9: 822-832.
39 Pimanda JE, Ganderton T, Maekawa A. et al. Role of thrombospondin-1 in control of von Willebrand factor multimer size in mice. J Biol Chem 2004; 279: 21439-21448.
40 Li J, Franco RS, Wang Y. et al. Megakaryocytic differentiation of HIMeg-1 cells induced by interferon gamma and tumour necrosis factor alpha but not by thrombopoietin. Cytokine 1998; 10: 880-889.