Basic Clinician Training Module 7

1. Basic Clinician TrainingModule 7 PlateletMapping™ PlateletMapping™ Assays

2. PlateletMapping™What is it? • Special TEG assay to measure effects of anti-platelet drug therapy on platelet function • Measure reduction in platelet function (MA) due to anti-platelet drugs • Provides individual’s potential total platelet function as a reference point • Identifies resistance or subtherapeutic response to drug therapy

3. PlateletMapping™What drugs are monitored? • ADP receptor inhibitors such as clopidogrel and ticlopidine • Arachadonic acid pathway inhibitors such as aspirin • GPIIb/IIIa inhibitors such as abciximab, tirofiban, eptifibatide

4. Why PlateletMapping?Personalized platelet therapy • Individual response to anti-platelet drugs determine clinical outcome • Knowing percent platelet inhibition is insufficient to determine therapeutic efficacy • Also require knowledge of total or potential platelet function as a reference point

5. Why PlateletMapping?Personalized platelet therapy • Patient A: 50% platelet inhibition is insufficient to completely reduce the risk of a thrombotic or ischemic event • Patient B: 50% platelet inhibition provides anti-thombotic protection • Patient C: 50% platelet inhibition increases risk of bleeding

6. The hemostatic process • The end result of hemostasis is a 3-D network of fibrin and platelets linked by fibrinogen via the GPIIb/IIIa receptor • The integrity of the fibrin-platelet network is expressed as the MA on the TEG analyzer.

7. The hemostatic process • Hemostasis is a tightly regulated process consisting of three separate, but interrelated, steps: • Platelet plug formation = primary hemostasis • Fibrin clot formation • Fibrinolysis • Interruption of platelet plug formation is a common therapeutic strategy to reduce risk of ischemic events (arterial thrombosis)

9. Anti-thrombotic strategiesInhibit platelet aggregation response • Inhibit platelet activation – ADP receptor inhibitors (e.g. clopidogrel) • Inhibit platelet secretion – block synthesis and secretion of TxA2, a potent platelet activator (e.g. aspirin) • Inhibit platelet aggregation – inhibit GPIIb/IIIa receptors (e.g. abciximab, tirofiban, eptifibatide)

10. PlateletMappingHow it works - platelets ADP and TxA2 both mediate activation/expression of GPIIb/IIIa receptors  aggregation

11. PlateletMappingHow it works - platelets • Activation/expression of GPIIb/IIIa receptors on platelet surface  platelet aggregation via interaction with fibrinogen • Inhibited by abciximab, tirofiban, eptifibatide

12. PlateletMappingHow it works - platelets • ADP & TxA2 sites can be activated, but if the GPIIb/IIIa receptor is inhibited, platelet aggregation will not take place

13. PlateletMappingHow it works - thrombin • Most potent platelet agonist – overrides inhibition at other platelet activation pathways • Maximally activates platelets • Provides total platelet function during TEG analysis (MA) • Cleaves fibrinogen to fibrin • Converts Factor XIII to Factor XIIIa for fibrin cross linking

14. PlateletMappingHow it works – the assay • Channel 1: Thrombin-activated platelet function provides total platelet function (MAthrombin), even in presence of anti-platelet agents • Channels 2-4: Performed in presence of heparin to inhibit thrombin activity • Channel 2: Measures contribution of fibrin(ogen) to MA(MAfibrin) by addition of ActivitorF which converts fibrinogen to fibrin and FXIII to FXIIIa • Channels 3 and 4: ADP or AA (arachadonic acid) + Activator F to measure platelet function and fibrin contribution to MA (MAADP or MAAA) • Only non-inhibited platelets will be activated by ADP or AA • Measures the reduction in platelet function due to anti-platelet agents

15. PlateletMapping assayAt a glance

16. PlateletMapping assayCalculation of platelet inhibition % inhibition = [100 – (MApi-MAf)/(MAt-MAf)] * 100 Where: MApi = MAADP or MAAA MAf= MAfibrin MAt = MAthrombin or MAKH

17. PlateletMapping assayTEG analysis - MA %Inhibition = 83.5

18. PlateletMapping assayTEG analysis – Clopidogrel resistance %Inhibition = 8.4

19. PlateletMapping assayTEG analysis – aspirin resistance MAAA MATHROMBIN MAFIBRIN %Inhibition = 0.0

20. Summary • PlateletMapping measures platelet inhibition along with total platelet function as a reference point • Monitors platelet inhibition at GPIIb/IIIa, ADP, and TxA2 receptors • Detects drug resistance as well as efficacy (i.e. inhibition) • Provides for anti-platelet drug therapy personalized to patient’s hemostatic state.

21. Overview exercises PlateletMapping assay PlateletMapping results

22. #1 The MA parameter of TEG analysis demonstrates clot strength due to the contributions of ________ and ________. Answer Next

23. #2 Which of the following component of the PlateletMapping Assay allows for personalized anti-platelet therapy? • Demonstrates percent platelet inhibition due to inhibitors of platelet activation • Demonstrates percent platelet inhibition due to inhibitors of platelet aggregration • Demonstrates total platelet function as a reference point Answer Next

24. B MAfibrin MAthrombin MAADP MAAA #3 Match all the applicable descriptions in Column A to the appropriate PlateletMapping parameters in Column B A • Demonstrates total platelet function • Demonstrates contribution of platelets and fibrin not inhibited by aspirin • Demonstrates contribution of fibrin • Demonstrates contribution of platelets and fibrin not inhibited by clopidogrel or ticlopidine: • Demonstrates contribution of platelets and fibrin not inhibited by GPIIb/IIIa inhibitors • Also known as MAKH Answer Next

25. #4 • Although a 50% inhibition of platelet function was achieved with • administration of an anti-platelet agent in each patient: • Which patient is still at risk for an thromboembolic event? A, B or C? • Which patient received optimal anti-platelet therapy? A, B, or C? Answer Next

26. #5 Each of the following patients were administered a standard dose of clopidogrel in the catherization laboratory. Based on the results of the PlateletMapping assay, which patient likely demonstrates resistance to the drug? A or B? B A Answer Next

27. #6 The following PlateletMapping assay was performed on a patient prior to cardiac surgery (on pump, CABG) and 5 days after discontinuation of clopidogrel therapy. Is this patient at high or low risk for bleeding after surgery? Answer Next

28. End of Module 7

30. #1 The MA parameter of TEG analysis provides demonstrates clot strength due to the contributions of platelets and fibrin or fibrinogen. Next

31. #2 Which of the following component of the PlateletMapping Assay allows for personalized anti-platelet therapy? • Demonstrates percent platelet inhibition due to inhibitors of platelet activation • Demonstrates percent platelet inhibition due to inhibitors of platelet aggregration • Demonstrates total platelet function as a reference point Next

32. B MAfibrin MAthrombin MAADP MAAA #3 Match all the applicable descriptions in Column A to the appropriate PlateletMapping parameters in Column B A • Demonstrates total platelet function: b (MAthrombin) • Demonstrates contribution of platelets and fibrin not inhibited by aspirin: d (MAAA) • Demonstrates contribution of fibrin: a (MAfibrin) • Demonstrates contribution of platelets and fibrin not inhibited by clopidogrel or ticlopidine: c (MAADP) • Demonstrates contribution of platelets and fibrin not inhibited by GPIIb/IIIa inhibitors: c,d (MAADP, MAAA) • Also known as MAKH: b (MAthrombin) Next

33. #4 • Although a 50% inhibition of platelet function was achieved with • administration of an anti-platelet agent in each patient: • Which patient is still at risk for an thromboembolic event? A, B or C? • Which patient received optimal anti-platelet therapy? A, B, or C? Next

34. #5 Both of the following patients were administered a standard dose of clopidogrel in the catherization laboratory. Based on the results of the PlateletMapping assay, which patient likely demonstrates resistance to the drug? A or B? B A Next

35. #6 The following PlateletMapping assay was performed on a patient prior to cardiac surgery (on pump, CABG) and 5 days after discontinuation of clopidogrel therapy. Is this patient at high or low risk for bleeding after surgery? HIGH risk for bleeding due to a high level of platelet inhibition even after a 5 day period of not taking clopidogrel. Next