Platelet aggregation and response to aspirin therapy in cardiac allograft vasculopathy

doi:10.1016/j.healun.2020.01.1344

The Journal of Heart and Lung Transplantation

Volume 39, Issue 4, April 2020, Pages 371-378

https://doi.org/10.1016/j.healun.2020.01.1344 Get rights and content

BACKGROUND

Long-term survival after heart transplantation (HTx) is compromised by cardiac allograft vasculopathy (CAV) characterized by coronary macro- and microvascular disease. The pathogenesis of CAV is unclear and may involve coronary thrombosis. We investigated whether HTx patients with CAV had higher platelet aggregation and turnover than HTx patients without CAV and healthy controls. Furthermore, we investigated the anti-platelet effect of low-dose aspirin in HTx patients.

METHODS

We included 57 patients who had undergone HTx (median 8.3 years from HTx) and 57 healthy controls. Platelet aggregation was measured on-aspirin and off-aspirin using impedance aggregometry with adenosine diphosphate (ADP) and arachidonic acid (AA). We evaluated platelet turnover by flow cytometry, CAV burden by coronary angiography and echocardiography, and microvascular function by echocardiographic coronary flow velocity reserve (CFVR).

RESULTS

Off-aspirin, HTx patients with CAV (n = 21) had higher ADP-induced platelet aggregation than healthy controls (p < 0.01) and HTx patients without CAV (n = 36) (p < 0.05). Aspirin treatment reduced AA-induced platelet aggregation in both HTx groups, but HTx patients with CAV had higher platelet aggregation on-aspirin than HTx patients without CAV (p < 0.05). Platelet turnover did not differ between HTx patients with CAV and HTx patients without CAV (p > 0.34). HTx patients with lower CFVR values had higher platelet aggregation than HTx patients with higher CFVR values (p < 0.05).

CONCLUSIONS

Off-aspirin, platelet aggregation was higher in HTx patients with CAV than in HTx patients without CAV and healthy controls. On-aspirin, platelet aggregation was higher in HTx patients with CAV than in HTx patients without CAV. Aspirin monotherapy may not provide sufficient platelet inhibition in HTx patients with CAV.

Section snippets

Study population

We included 58 HTx patients (median 8.3 [4.0‒12.1] years after HTx) from October 2016 to June 2018 at the Department of Cardiology, Aarhus University Hospital, Denmark. Patients were eligible for participation if they were >12 months from HTx, ≥18 years of age, had creatinine level ≤250 µmol/liter and platelet count ≥120 × 10⁹/liter, and if a short interruption of prescribed anti-platelet therapy was considered safe. An available dataset from an earlier study on healthy individuals off-aspirin

Demographic and biochemical data

We included 57 patients (36 patients with no CAV, 21 patients with CAV). Baseline patient characteristics and medication are shown in Table 1; biochemical data, including platelet count and turnover, are shown in Table 2; and platelet aggregation data are shown in Table 3. Patient characteristics and medication were comparable between groups. As aspirin is initiated at our institution when CAV is diagnosed, the CAV group was more likely to receive aspirin therapy. Most patients were male with a

Discussion

The main findings of this study are that (1) off-aspirin, HTx patients had significantly higher ADP-induced platelet aggregation than healthy controls; (2) on dichotomizing HTx patients, those with CAV had significantly higher ADP-induced platelet aggregation compared with healthy controls or patients without CAV; (3) on-aspirin, HTx patients with CAV had reduced effect of aspirin, indicated by significantly higher AA-induced platelet aggregation than HTx patients without CAV; (4) HTx patients

Strengths and limitations

This is a cross-sectional, single-center study with a relatively small cohort of patients. Nevertheless, the sample size was based on a sample size calculation. The patients have been examined thoroughly in a blinded fashion with appropriate methods. A strength of our study is the verification of aspirin adherence by serum thromboxane B₂. The healthy controls were gender-matched, but their mean age was lower than that of the HTx group. However, a study from our institution found no association

Disclosure statement

The authors have no conflict of interest to declare.

The authors thank the invasive cardiologists, Evald Høj Christiansen, Steen Carstensen, Michael Mæng, Christian Juhl Terkelsen, and Ashkan Efterkhari, who performed coronary angiography; Lene Lindencrone Konrad for echocardiographic assistance; the laboratory technicians, Mai Stenulm Veirup and Vivi Bo Mogensen, for performing all platelet aggregation and enzyme-linked immunosorbent assay analyses; and Aarhus University and Scandiatransplant

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The pathogenesis of CAV overlaps extensively with atherosclerosis which, in the non-transplanted heart, is affected by dysregulated platelet aggregation.15 Dysregulated platelet aggregation is exaggerated in adult HTx recipients compared to healthy controls and is most pronounced in those with CAV.16,17 It is not surprising, therefore, that ASA is an appealing therapy to potentially attenuate the development of CAV.
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View full text

Platelet aggregation and response to aspirin therapy in cardiac allograft vasculopathy

BACKGROUND

METHODS

RESULTS

CONCLUSIONS

Section snippets

Study population

Demographic and biochemical data

Discussion

Strengths and limitations

Disclosure statement

J Heart Lung Transplant

Transplant Proc

JACC Cardiovasc Imaging

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

J Heart Lung Transplant

J Thromb Haemost

Thromb Res

J Heart Lung Transplant

JACC Cardiovasc Interv

J Surg Res

Atherosclerosis

Repeated episodes of thrombosis as a potential mechanism of plaque progression in cardiac allograft vasculopathy

Eur Heart J