Impact of P2Y(12) inhibitory effects induced by clopidogrel on platelet procoagulant activity in type 2 diabetes mellitus patients.
BACKGROUND
Type 2 diabetes mellitus (T2DM) patients have a variable response profile to the P2Y(12) receptor antagonist clopidogrel. P2Y(12) receptor signalling promotes platelet procoagulant activity. The aim of this study was to determine if T2DM patients with suboptimal clopidogrel response have greater platelet procoagulant activity compared with optimal responders and evaluate if this can be modulated by enhancing P2Y(12) receptor inhibition.


METHODS
A total of 50 T2DM patients in a steady state phase of clopidogrel therapy were studied. Suboptimal responders were randomly assigned to standard (75 mg) or high (150 mg) clopidogrel maintenance therapy for one-month. Afterwards, all patients resumed standard therapy. Platelet procoagulant activity assessed by thrombin-induced platelet-fibrin clot formation using thrombelastography (TEG) was determined at baseline, one-month post-randomization, and one-month after resuming standard therapy.


RESULTS
In the overall study population, the reaction time (R), a measure of time to initial thrombin induced platelet-fibrin clot formation, and the time to maximum rate of thrombin generation (TMRTG) values were 6.3+/-1.7 and 7.6+/-1.9 minutes, respectively. Suboptimal clopidogrel responders (n=30) had acceleration of R (p=0.002) and TMRTG (p=0.002) compared to optimal responders (n=20). Suboptimal clopidogrel responders treated with a 150 mg dose showed prolongation of R (p=0.0001) and TMRTG (p<0.0001), which returned to baseline values after resuming standard dosage. No differences were observed among patients randomized to 75 mg.


CONCLUSIONS
T2DM patients with suboptimal clopidogrel response have enhanced platelet procoagulant activity compared to patients with optimal response, which can be down-regulated by more potent platelet P2Y(12) inhibition using high clopidogrel maintenance dosing.
Angiolillo
Dominick J
DJ
Division of Cardiology, University of Florida College of Medicine Jacksonville, Jacksonville, FL 32209, USA. dominick.angiolillo@jax.ufl.edu
Capranzano
Piera
P
Desai
Bhaloo
B
Shoemaker
Steven B
SB
Charlton
Ronald
R
Zenni
Martin M
MM
Guzman
Luis A
LA
Bass
Theodore A
TA
D001779:Blood Coagulation Factors / Q000032:analysis*; D000077144:Clopidogrel; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D058919:Purinergic P2 Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*
D001779:Blood Coagulation Factors; C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; C049426:platelet procoagulant factor; D000077144:Clopidogrel; D013988:Ticlopidine