The significance of vasodilator-stimulated phosphoprotein for risk stratification of stent thrombosis

Summary

Low-response to the P2Y12 adenosine diphosphate (ADP)-receptor antagonist clopidogrel was suggested to correspond to a higher incidence of stent thrombosis (ST). This prospective observational study assessed the capability of two platelet function assays, e.g. direct measurement of the phosphorylation status of vasodilator-stimulated phosphoprotein (VASP) and ADP-induced platelet aggregation for definition of the individual risk to develop ST. Ninety-nine patients with an elevated high risk to develop ST were enrolled. All patients received a dual antiplatelet therapy consisting of 100 mg aspirin and 75 mg clopidogrel during an observation period of six months. Flow cytometry of VASP phosphorylation and densitometrically-determined measurement of ADP-induced platelet aggregation was performed 72–96 hours after stent implantation. These data were related to angiographically confirmed ST. Nine patients suffered from angiographically confirmed ST (9.1%). The meanVASP-platelet reactivity indices (VASP-PRI) and values for ADP-induced platelet aggregation in the ST group were significantly higher (60.8 ± 13.0 and 60.9 ± 13.1, respectively) compared to patients without ST (41.3 ± 14.0 and 50.8 ± 14.4, P<0.001 vs. 0.048, respectively). There was a fair correlation between both methods using non-linear regression analysis (r=0.332). In a multivariate analysis, VASP was the only independent predictor of ST and was superior to previously identified angiographic parameters. Receiver- operator characteristic (ROC) curve analysis revealed a cut-off value for VASP-PRI of <48% to be associated with low risk of ST. In conclusion, determination ofVASP phosphorylation is superior to conventional platelet aggregometry and angiographic parameters for assessing the risk of ST. Patients with a VASP-PRI >48% seem to have a significantly increased risk.

Keywords

Stent thrombosis - VASP phosphorylation - platelet aggregometry - clopidogrel

• References

• 1 Joner M, Finn AV, Farb A. et al. Pathology of drugeluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol 2006; 48: 193-202.
• 2 Mauri L, Hsieh WH, Massaro JM. et al. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med 2007; 356: 1020-1029.
• 3 Cutlip DE, Baim DS, Ho KK. et al. Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials. Circulation 2001; 103: 1967-1971.
• 4 Iakovou I, Schmidt T, Bonizzoni E. et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. J Am Med Assoc 2005; 293: 2126-2130.
• 5 Bavry AA, Kumbhani DJ, Helton TJ. et al. What is the risk of stent thrombosis associated with the use of paclitaxel-eluting stents for percutaneous coronary intervention?: a meta-analysis. J Am Coll Cardiol 2005; 45: 941-946.
• 6 Smit JJ, van’t Hof AW, de Boer MJ. et al. Incidence and predictors of subacute thrombosis in patients undergoing primary angioplasty for an acute myocardial infarction. Thromb Haemost 2006; 96: 190-195.
• 7 Mauri L, Hsieh WH, Massaro JM. et al. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med 2007; 356: 1020-1029.
• 8 Grossmann R, Sokolova O, Schnurr A. et al. Variable extent of clopidogrel responsiveness in patients after coronary stenting. Thromb Haemost 2004; 92: 1201-1206.
• 9 Wenaweser P, Dorffler-Melly J, Imboden K. et al. Stent thrombosis is associated with an impaired response to antiplatelet therapy. J Am Coll Cardiol 2005; 45: 1748-1752.
• 10 Geisler T, Langer H, Wydymus M. et al. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 2006; 27: 2420-2425.
• 11 Ajzenberg N, Aubry P, Huisse MG. et al. Enhanced shear-induced platelet aggregation in patients who experience subacute stent thrombosis: a case-control study. J Am Coll Cardiol 2005; 45: 1753-1756.
• 12 Gurbel PA, Bliden KP, Samara W. et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. J Am Coll Cardiol 2005; 46: 1827-1832.
• 13 Hochholzer W, Trenk D, Bestehorn HP. et al. Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J Am Coll Cardiol 2006; 48: 1742-1750.
• 14 Ozuyaman B, Godecke A, Kusters S. et al. Endothelial nitric oxide synthase plays a minor role in inhibition of arterial thrombus formation. Thromb Haemost 2005; 93: 1161-1167.
• 15 Schafer A, Fraccarollo D, Eigenthaler M. et al. Rosuvastatin reduces platelet activation in heart failure: role of NO bioavailability. Arterioscler Thromb Vasc Biol 2005; 25: 1071-1077.
• 16 Geiger J, Brich J, Honig-Liedl P. et al. Specific impairment of human platelet P2Y(AC) ADP receptormediated signaling by the antiplatelet drug clopidogrel. Arterioscler Thromb Vasc Biol 1999; 19: 2007-2011.
• 17 Schafer A, Bonz AW, Eigenthaler M. et al. Late thrombosis of a drug-eluting stent during combined anti-platelet therapy in a clopidogrel nonresponsive diabetic patient: shall we routinely test platelet function?. Thromb Haemost 2007; 97: 862-865.
• 18 Schwarz UR, Geiger J, Walter U. et al. Flow cytometry analysis of intracellular VASP phosphorylation for the assessment of activating and inhibitory signal transduction pathways in human platelets--definition and detection of ticlopidine/clopidogrel effects. Thromb Haemost 1999; 82: 1145-1152.
• 19 Geiger J, Teichmann L, Grossmann R. et al. Monitoring of clopidogrel action: comparison of methods. Clin Chem 2005; 51: 957-965.
• 20 Barragan P, Bouvier JL, Roquebert PO. et al. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Catheter Cardiovasc Interv 2003; 59: 295-302.
• 21 Lev EI, Patel RT, Maresh KJ. et al. Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance. J Am Coll Cardiol 2006; 47: 27-33.
• 22 Van der Planken MG, Claeys MJ, Vertessen FJ. et al. Comparison of turbidimetric aggregation and in vitro bleeding time (PFA-100) for monitoring the platelet inhibitory profile of antiplatelet agents in patients undergoing stent implantation. Thromb Res 2003; 111: 159-164.
• 23 Gurbel PA, Bliden KP, Hiatt BL. et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908-2913.