To measure or not to measure: Platelet function testing in cardiac surgery

Daniel BolligerDepartment of Anesthesiology, University Hospital Basel

email: daniel.bolliger@usb.ch

Indications for Antiplatelet Therapy

• Primary or secondary prophylaxis in CHD, PAD, CVD

• Dual platelet inhibtion therapy (DPIT) after coronary

stenting

• DPIT after TAVI, mitral clip etc.

Platelet Functions

adhesion → activation → «Shape change» → aggregation

The Platelet

Important Platelet Receptors

Receptor Activator Function Drugs

TRAP-1/4 Thrombin Strongest PlateletActivation

----

P2Y12 ADP Important for plateletactivation

Clopidogrel, Prasu-grel, Ticagrelor

TP-alpha/beta Thromboxan A2 Platelet activation ASA, Aspirin,NSAID

GPIIa/IIIa -- Fibrinogen-Platelet-Interaction

Tirofibran,Abciximab

Collagen-Receptor

Collagen Strong activator, important for adhesion

----

GPIb/IX von Willebrand factor

Important for adhesion ----

Platelets can still be activated(especially at injury site) but thrombus isunstable.

«Selective» Inhibition

Inner Core vs. Outer Shell

Differences between Platelet Inhibitors

• Target (receptor)

• Dosing

• Duration (plasma half lives, «platelet inhibition» half lives)

• Bio availability

• CYP metabolism

• Reversible vs. irreversible platelet inhibition

• Degree of platelet inhibtion

P2Y12 AntagonistsClopidogrel and Prasugrel:- Irreversible binding and

inhibition of P2Y12receptor

- Prodrugs, activation byCYP

- Two-steps for clopidogrel, one-step for prasugrel

Ticagrelor:- Pharmacologically

reversible binding andconformation change ofthe P2Y12 receptor

- No prodrug, direct activesubstance

Increased Risk of Bleeding

0

1

2

3

4

5

6

no clopidogrel

n=165

clopidogrel

n=59

reo

pe

rati

on

fo

r b

lee

din

g (

%)

p=0.018

8x

0

2

4

6

8

10

noantiplatelet aspirin aspirin +

clopidogrel

reo

pe

rati

on

fo

r b

lee

din

g (

%)

4.2x

p=0.002

0

5

10

15

20

25

clopidogrel

n=6716

prasugrel

n=6741

fata

l b

lee

din

g

Hongo et al. JACC 2002, Yende et al. CritCare Med 2001, TRITON-TIMI NEJM 2007

Strategies to Reduce Bleeding

• Stopping before surgery

• Platelet transfusion

• Tranexamic Acid

• DDAVP

• Platelet function testing

Suggested Stopping Interval

Drug Stopping Interval

Aspirin no stopping

Clopidogrel 5 (-7) days

Prasugrel 7 days

Ticagrelor 3 days

Bridging: Heparin, GPIIb/IIIa inhibitor,

Cangrelor (iv P2Y12 receptor antagonist)

Preop changing from Prasugrel to Clopidogrel ?

Continued Aspirin Therapy

Hastings et al. BJA 2016

• Less thromboembolic events• No/minimal effect on postoperative bleeding• No increased number of allogeneic blood products• Early starting after CABG recommended

TARGET CABG Study

Mahla et al. Circulation 2012

• 94 clopidogrel-naive patients, 86 patients withclopidogrel

• Waiting time adjusted toTEG PlateletMapping results

Study Results:• No differences in postoperative

bleeding volumes• No difference in transfused blood

products

Platelet Transfusion

Platelet count

- <100’000 x 103/µl- < 50’000 x 103/µl (?)

Platelet dysfunction

- Induced by CPB- ASA- P2Y12 receptor

antagonists

Evidence for benefits of PT based on any number in platelet count or platelet dysfunction is extremely low.

Common Transfusion Triggers

Kumar et al. Transfusion 2015, Kaufman et al. Ann Int Med 2015

Cardiac Patients with PLT Inhibitors

– Chronic therapy vs. «loading dose»– Time point of last intake/loading (plasma half times 6-10 hrs)

– Potential rule:• ASA: 0-1 platelet conc.• Clopidogrel: 0-1 platelet conc.• Prasugrel/Ticagrelor (stable): 1-2 platelet conc.• Prasugrel/Ticagrelor (loading): up to 4 platelet conc.

– Cave: · (arterial) thrombosis· potentially no additional affect if used more than4 platelet conc.

?

Platelet Transfusion

Teng et al. J Thromb Haemost 2016

44 healthy patients, single dose ofticagrelor or clopidogrel with/withoutplatelet transfusion (after 24/48 hours)

PT did not reverse antiplatelet effectof ticagrelor, minimal impact on clopidogrel

Conclusions: PT is unlikely toimprove platelet function in patientswith ticagrelor and benefits areunknown in patients with clopidogrel

Conclusion: …. support the use of TXA to partially revers e platelet

aggregation dysfunction due to antiplatelet therapy.

Weber et al. EJA 2010

TXA in Patients with Platelet Inhibitors

20 patients withoutaspirin/clopidogrel

20 patients withaspirin/clopidogrel

In vitro effect of TXA on Platelet Function Testing (Multiplate):

Myles et al. NEJM 2016, Shi et al. JAMA Surgery 2013

Shi

et a

l. 20

13M

yles

et a

l. 20

16TXA in Patients with Platelet Inhibitors

Postop BlutverlustMean difference: -294 ml (95% CI -353 to -234)

Postop BlutverlustMean difference: -278 ml (95% CI -380 to -176)

General blood product sparing effect orspecific effect on platelet function?

TXA in Patients with Platelet Inhibitors

Aprotinin vs. TXA

«Clot stabilization» effect byantifibrinolytics?

Deloge et al. Eur J Anaesthesiol 2017

Limitations: - 10 studies with 596 patients- 5 of 10 studies >20 years old- only 1 study with dual antiplatelet therapy, most with aspirin

- no massive bleeding, no emergency surgery

Desborough et al. J Thromb Haemost 2017

Conclusion:DDAVP might reducepostop bleeding andtransfusion after cardiacsurgery in patients withplatelet dysfunction.

DDAVP in Cardiac Surgery

DDAVP in Cardiac Surgery

• Desmopressin (DDAVP)• tPA release• Clincial effect questionable• Might be ineffective due to

maximal release of vWF

• Von Willebrand factor(Factor VIII concentrates)

• Clinical effect not proven

Platelet Function Testing

PFA-100®

• Mimics bleeding time

• Measures time to closure of microporeaperture under high shear stress

• Sensitive to vWF deficiency and aspirintherapy

• No predictive value for bleeding after cardiac surgery

Fattorutto et al. BJA 2003

Studies with Multiplate®

Ranucci et al. BJA 2014:361 patients under P2Y12 inhibitors undergoing cardiac surgery

ADP <22 U/TRAP <75 U: PPV of 20-23% for bleeding

ADP >22 U/TRAP > 75 U: NPV of 94-95% for bleeding

ADP <22 U and TRAP <75 U: no severe bleeding

Rahe-Meyer et al. A&A 2008:100 patients undergoing cardiac surgery, 23 of them with ASA intake within 5 days before surgery

ASPI <51 U: Higher risk for platelet transfusion after surgery

ASPI <51 U: Better predictor of risk for platelet transfusion than self-reporting

TEG PlateletMapping®

Reduced platelet activation can be shown in reference to kaolin-activated TEG, and lesser increases in maximum amplitude relative to fibrin formation by reptilase and activated FXIII.

VerifyNow®

ONSET/OFFSET study

Gurbel et al. Circulation 2009

VerifyNow® was used to assess platelet activity after starting und stoppingclopidogrel and ticagrelor in stable CAD patients

Ticagrelor ispharmacologicallyreversible but not clinically!

Conclusions

• Different «platelet functions»• Different receptors are important at different times

• Different designs of platelet function tests• No platelet function testing will evaluate «all platelet

functions»

• Platelet function test to determine the need forplatelet concentrate transfusions is not yet validatedin large series of patients, and their reliability suffe rsfrom the lack of well-defined cut-off values .

Discussion