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The Platelet VASP Test

A clinically practical test of clopidogrel responsiveness.

Clopidogrel is an oral antiplatelet agent of the thienopyridine group. It acts as a specific irreversible antagonist at the platelet P2Y12 ADP receptor. It is extensively metabolised by the hepatic cytochrome P450 enzymes.

It is used to prevent adverse cardiovascular events before, during and after percutaneous coronary intervention (PCI) and in the setting of recent stroke, recent myocardial infarction, unstable angina and established peripheral vascular disease.

Interindividual response to clopidogrel has, however, been well described. It is estimated that clopidogrel fails to elicit an adequate response in 4-30% of patients (depending on the method and criteria used).

Several mechanisms are thought to be involved in this variable response including variability in intestinal absorption, variability in hepatic conversion to an active metabolite, drug interactions and receptor polymorphisms.

Light transmission aggregometry (LTA) has traditionally been considered the reference assay for assessing platelet reactivity, but has some limitations (requires immediate analysis in a specialised laboratory, lacks standardisation).

The Platelet VASP test (PLT-VASP) is a new flow cytometry test that can assess the effect of the platelet P2Y12 antagonists (clopidogrel, ticlopidine, prasugrel).

This test is highly specific and has significant logistical advantages:

  • Analysis only needs to be performed within 48 hours from collection.
  • The samples are stored at room temperature.
  • Reproducible.
  • Only a single full citrate tube is required.
  • Aspirin and other medications such as GPIIb/IIIa antagonists do not interfere with the results.

In general the PLT-VASP test and light transmission aggregometry show good correlation, although not complete agreement. While the PLT-VASP test is specific to the P2Y12 antagonists, light transmission aggregometry will be affected by aspirin or GPIIb/IIIa antagonists. In light transmission aggregometry, multiple ADP pathways are assessed, while with the PLT-VASP test only the ADP pathway relating to the P2Y12 receptor is assessed. The PLT-VASP test is currently the most specific assay for measuring P2Y12 receptor blockade.

A recent study was performed to assess which platelet function test provided the best reflection of the in vivo plasma levels of the active metabolite of clopidogrel(1). The PLT-VASP assay demonstrated the highest correlation.

Care must be taken not to activate platelets during the collection process and the first few mls of blood collected must be discarded.

Based on the pharmacodynamic properties of clopidogrel, the optimal time to perform the test is generally at least 7 days after commencing maintenance therapy, or 6 hours after giving a loading dose.

The sample is analysed on a flow cytometer using a commercial kit.

A Platelet Reactivity Index (PRI) is obtained. This is a (percentage value).

A good response to clopidogrel is associated with a lower percentage value and a poor response (hyporesponsive) is associated with a higher percentage value. Normal individuals (not receiving clopidogrel) usually have a percentage value >69%.

Recent literature has shown a link between values obtained on the PLT-VASP test and clinical outcomes, especially in the setting of percutaneous coronary intervention.

There are studies showing a link between values obtained on the PLT-VASP test and stent thrombosis (2;3;4;5), and also between PLT-VASP values and recurrent ischaemic events (6;7;8).

In general, patients with a PRI < 50% (or at least<69%) appear to be protected. The studies have shown this cut-off to have a very high negative predictive value but low positive predictive value. Currently the PLT-VASP test therefore appears to be more reliable in identifying low risk patients than isolating a small group of high risk patients. It may, however, be very useful in the setting of conditions such as high risk percutaneous coronary intervention, to optimise therapy and prevent complications.

A few small studies have shown that PLT-VASP guided adjustment of clopidogrel loading doses and maintenance therapy improves clinical outcome and is safe (9;10). Larger, definitive prospective studies are needed to confirm these findings.

Another area needing further investigation, is to assess the utility of PLT-VASP for assessing bleeding risk. For further information, please contact the Flow Cytometry Laboratory - (011) 358 0721.

References:

  1. Bouman et al: Which platelet function test is suitable to monitor clopidogrel responsiveness, Journal of Thrombosis and Haemostasis 5:1630-1636.
  2. Barragan et al: Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated Phosphoprotein phosphorylation, Catheterisation and Cardiovascular Interventions 59:295- 302, 2003
  3. Gurbel et al: Clopidogrel effect on platelet reactivity in patients with stent thrombosis:results of the CREST study, J Am Coll Cardio 2005; 46; 1827-1832
  4. Blindt et al: The significance of vasodilator stimulated phosphoprotein for risk stratification of stent thrombosis, Cardiovascular Biology and Cell Signalling doi:10.1160/TH07-05-0324 2007
  5. Morel et al: Impaired platelet responsiveness to clopidogrel identified by flow cytometric VASP phosphorylation in patients with subacute stent thrombosis: Thromb Haemost 2007; 98
  6. Bonello et al: Vasodilator-stimulated phosphoprotein prior to percutaneous coronary intervention for exclusion of major adverse cardiovascular events: Journal of Thrombosis and Haemostasis 5:1630-1636
  7. Frere et al: ADP-induced platelet aggregation and platelet reactivity index VASP are good predictive markers for clinical outcomes in non-ST elevation acute coronary syndrome. Thromb Haemostasis 2007, 98
  8. Cayla et al: Flow cytometric assessment of vasodilatorstimulated phosphoprotein:prognostic value of recurrent events after acute coronary syndrome, Arch Cardiovas Dis, 2008; 101 (11-12)743-51
  9. Bonello et al: J Am Coll Cardio Apr 8:51(14)1412-4
  10. Fontana et al: Thromb Res 2007, doi:10,10116/ thromres. 2007.06.012

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