Enhanced microvascular function in the cutaneous circulation with platelet inhibition is not related to alterations in blood viscoelastic properties

Abstract

Platelet inhibition with aspirin and/or clopidogrel are part of a comprehensive strategy for the primary and secondary prevention of cardiovascular disease, respectively. In the cutaneous microcirculation, treatment of clopidogrel (CLO) but not aspirin (ASA) increases cutaneous microvascular relaxation in response to reactive hyperemia. CLO is mechanistically distinct from ASA in that it works through inhibiting the platelet P2Y12 receptor and may change blood viscosity and thus the shear stimulus on the microcirculation. In this study, we sought to determine if platelet inhibition with CLO changes whole blood viscoelastic properties and is related to increased microvascular function. Nine middle‐aged healthy subjects (5 men, 4 women; 56 ± 1 yr) participated in a randomized, double blind, placebo‐controlled crossover experiment. Treatment phases included a sucrose placebo, CLO (75 mg; Bristol‐Myers Squibb), and ASA (81 mg; Bayer) for 7–10 days with a two week washout period between each treatment. On the final day of treatment, laser Doppler flux (LDF) was measured during a standardized 5 minutes reactive hyperemia protocol and area under the curve (AUC) and total hyperemic response (THR) were calculated and normalized to maximal cutaneous vascular conductance (%CVCmax: 43°C and 28 mM sodium nitroprusside). Blood viscoelasticity was measured using a Vilastic‐3 viscoelasticity analyzer at 2 Hz across a physiologically relevant shear rate range of 25 to 1000 s−1. Blood temperature was maintained at time of draw using a heat exchanger. CLO and ASA did not change hematocrit relative to the placebo control (41.6 ± 0.9, 41.9 ± 0.6, and 41.5 ± 0.7 % respectively). AUC and THR increased in the CLO trial (AUC = 3783 ± 342, THR = 2306 ± 266 %CVCmax * s; P<0.0001 vs. placebo) but there was no difference between ASA (AUC = 3101 ± 325, THR = 1695 ± 197 %CVCmax * s) and placebo (AUC = 3000 ± 283, THR = 1675 ± 170 %CVCmax * s, P>0.05) Apparent kinematic viscosity and elasticity was unchanged in either CLO or ASA treatment relative to placebo across the entire range measured when normalized to a hematocrit of 45 %. 7–10 days of CLO or ASA does not change hematocrit or blood viscoelastic properties in healthy humans and is not related to functional measures of microvascular function (p>0.05). Improvements in cutaneous microvascular function by CLO is not a result of shear‐stress induced vasodilation, further indicating that CLO may alter sensory nervous activity and/or endothelium‐derived hyperpolarizing factor mechanisms.Support or Funding InformationNIH R01 HL093238‐07