A Novel Marker of Coronary Artery Stent Restenosis: High Thrombin-Induced Clot Strength Identified by Thrombelastography


Rates of in-stent restenosis (ISR), a limitation of percutaneous coronary intervention (PCI), are dependent on several factors, including: lesion characteristics, procedural factors, and stent type. The efficacy of bare-metal stents (BMS) has been severely constrained by ISR, with recurrent angiographic stenosis reported in 16-44% of patients.

With the advent of drug-eluting stents (DES), ISR rates have fallen, but it still remains a concern, especially considering the increasing number of patients treated with DES each year.1 The underlying causes of DES-ISR are multifactorial. It has been suggested that local and systemic inflammation, along with stent polymer hypersensitivity are major contributors.2,3 Despite the growing use of second-generation DES that are designed to reduce local inflammatory responses,4-5 inconsistent rates of ISR are still reported, suggesting an involvement of other mechanisms.6-8

In-Stent Restenosis and Inflammation

Vascular inflammation has been proposed as a core mechanism leading to ISR.9 C-reactive protein (CRP), a marker of systemic inflammation, has been linked to clinical and angiographic outcomes in patients undergoing BMS implantation.10,11 Platelet-related periprocedural thrombotic and inflammatory processes that influence neointimal hyperplasia and angiogenesis have also been considered as key risk factors in the development of ISR.12,13 Hypercoagulability has also been shown to be associated with an increased risk for ISR of super facial femoral artery stents.14

Since hypercoagulability measured by thrombelastography (TEG) is highly influenced by the ability of thrombin to generate tensile strength of the platelet-fibrin clot, we hypothesized that analysis of thrombogenicity by TEG identifies patients with ISR. In addition, we performed conventional aggregation and lipid analysis in consecutive patients scheduled for elective angiography for suspicion of stent restenosis.

Study Results

Sixty-nine patients (41%) had ISR. Within the first year, 21% patients were identified with initial restenosis, whereas 45% and 34% of patients were identified with initial restenosis during 1-3 years and >3 years respectively. Patients with ISR and without ISR had similar demographic characteristics—except more women and patients treated with dual antiplatelet therapy were in the ISR group.

TEG revealed that patients with ISR had a higher thrombin-induced platelet-fibrin clot strength (TIP-FCS; p = 0.001), clotting index (p = 0.001), fibrinogen activity (p = 0.0001), and clot firmness (p = 0.0001), as well as a shorter clotting time (p = 0.08) and a shorter K (p = 0.01). When analyzed by TIP-FCS quartiles, 70% of patients with TIP-FCS of >69 (the highest quartile) had ISR as compared to only 5% patients with TIP-FCS of <61mm (the lowest quartile; p < 0.001).

Platelet Aggregation and Lipoprotein Cholesterol Profile
There were no differences in both maximum and final ADP-induced (5 and 20 uM) and collagen-induced (4 ug/ml) platelet aggregation between patients with and without ISR (p = NS for all comparisons). There were no significant differences in various lipid parameters evaluated except higher Apo B100/A1 ratio was observed among patients with ISR compared to patients without ISR (p = 0.0283).

Patients with Single ISR
Among 79 patients treated with prior single stent, 22.8% (n = 18) had ISR. Patients with ISR had higher TIP-FCS (p < 0.0001), ApoB 100/A1 ratio (p = 0.007), and higher prevalence of TIP-FCS >67mm (p < 0.0001) and ApoB 100/A1 ratio >7.5 (p = 0.04).

Patients with Multiple ISR
Among patients with multiple prior stents, 12% (n = 11) had single ISR and 44% (n = 40) had multiple ISR. Patients with single and multiple ISR had higher ApoB 100/A1 ratio and low HDL (<40) compared to patients with no ISR (p ≤ 0.05). Compared to patients with no ISR, patients with multiple ISR had higher TIP-FCS and higher prevalence of TIP-FCS >67 (p < 0.0001 for both).

Univariate and Multivariate Analysis
In a univariate analysis, TIP-FCS >67 was associated with a relative risk (OR) of 8.8 (95% CI 3.92-19.58; p < 0.0001) in identifying ISR. In addition, treatment with multiple stents (OR = 3.6; 95% CI 1.79-7.27; p = 0.0003), ApoB/A1 ratio >0.75 (OR = 4.0; 95% CI 1.04-5.35; p = 0.04), female gender (OR = 2.2; 95% CI 1.10-4.28; p = 0.03), and to a lesser extent, prior stroke (OR = 2.4; 95% CI 0.95-5.91; p = 0.06) were associated with higher risk for ISR.

By multivariate analysis, TIP-FCS >67 (OR = 8.1, 95% CI = 2.66-24.50, p = 0.0002), treatment with multiple stents (OR = 3.5, 95% CI = 1.17-10.32, p = 0.02) and to a lesser extent low HDL cholesterol (<40mg/dL) (OR = 3.05, 95% CI = 0.98-9.54, p = 0.054) were associated with ISR.

Our results indicate that a prothrombotic phenotype marked by increased platelet-fibrin clot strength measured by the TEG MA parameters is independently associated with ISR.

For a full discussion of results, read the November/December issue.


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Keywords: CardioSource WorldNews Interventions

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