Role of inflammation and platelet activation in the adverse cardiovascular outcomes of patients undergoing surgery for critical limb ischaemia
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Date
05/07/2014Author
Burdess, Anne
Metadata
Abstract
Increased platelet activation and inflammation play a key role in atherothrombosis. Patients with
peripheral arterial disease are at increased risk of adverse cardiovascular events, particularly at the time
of surgery. We postulated that the increase in peri-operative cardiovascular events is mediated by
increased platelet activation and inflammation. We hypothesized that peri-operative dual anti-platelet
therapy would improve biomarkers of atherothrombosis without causing unacceptable bleeding in
patients undergoing surgery for critical limb ischaemia (CLI).
Prior to interventional study, I validated a sensitive flow cytometric technique for the reproducible
assessment of in vivo platelet activation in patients with peripheral arterial disease. Thirty patients with
stable claudication, attended on two occasions to permit within-day and between-day comparisons. A
variety of platelet activation markers were compared to the gold standard of platelet–monocyte
aggregation. Platelet-monocyte aggregation demonstrated comparable within-day (mean difference ±
co-efficient of reproducibility; 0.9±15.4%) and between-day reproducibility (2.0±12.4%). Plateletmonocyte
aggregates correlated well with other platelet activation markers (P selectin r=0.30; Platelet
CD40L r=0.41; Platelet microparticles r=0.27; P≤0.026) and monocyte activation markers (monocyte
CD40 r=0.27;monocyte CD11b r=0.47; P≤0.026).
In a cross sectional study, I demonstrated that resting in vivo platelet activation and inflammation was
increased in patients with CLI in comparison to healthy controls, patients with stable claudication and
those undergoing treatment for acute coronary syndromes. In addition, platelet activation and
inflammation throughout the peri-operative period was markedly increased in CLI patients compared
with non-vascular patients undergoing arthroplasty, and exceeded the rise attributable to the stress of
surgery itself.
In a prospective double-blind randomised controlled trial, 108 patients undergoing infra-inguinal
revascularisation or amputation for CLI were maintained on aspirin (75 mg daily) and randomised to
clopidogrel (600 mg prior to surgery, and 75 mg daily for 3 days; n=50) or matched placebo (n=58).
Peri-operative in vivo platelet activation and inflammation, cardiac-Troponin I (c-TnI) release and
bleeding outcomes were recorded. Clopidogrel reduced markers of platelet activation and inflammation
before surgery and throughout the post-operative period. Overall, there were 18 troponin-positive
events (16.7%), with half of the troponin rises (9) occurring prior to surgery. Patients with postoperative
elevations in c-Tn I had significantly greater levels of pre-operative platelet-monocyte
aggregation, monocyte CD40, IL-6 and hsCRP. However, despite reducing platelet and inflammatory
markers, clopidogrel did not have a direct effect on peri-operative c-Tn I. There was no increase in
major life-threatening or minor bleeding, although blood transfusions and wound haematomas were
significantly increased.
Using sensitive and validated methodologies, I have provided a detailed examination of in vivo platelet
activation and inflammation in high-risk vascular surgical patients. This approach has provided the first
objective assessment of the risks and benefits of intensive peri-operative anti-platelet therapy in this
patient group. Dual anti-platelet therapy reduced biomarkers of atherothrombosis without causing
unacceptable bleeding. However, large-scale clinical trials would be required to confirm whether these
reductions translate into improvements in clinical outcome.