Elsevier

Translational Research

Volume 200, October 2018, Pages 35-42
Translational Research

Response to aspirin therapy in patients with myeloproliferative neoplasms depends on the platelet count

https://doi.org/10.1016/j.trsl.2018.05.009Get rights and content

Patients with myeloproliferative neoplasms (MPN) are at an increased risk of thrombotic events even during antiplatelet therapy with aspirin. In the current study, we sought to investigate the association of the platelet count with the inhibitory potential of antiplatelet therapy in MPN. We determined arachidonic acid (AA)- and adenosine diphosphate (ADP)-inducible platelet reactivity by multiple electrode aggregometry in 93 patients with essential thrombocythemia, polycythemia vera or primary myelofibrosis. In patients without aspirin therapy (n = 44), the platelet count did not correlate with platelet aggregation. In aspirin-treated patients (n = 49), we observed a moderate correlation of residual AA-inducible platelet aggregation with the platelet count (r = 0.49; P < 0.001). Further, patients with high on-treatment residual platelet reactivity to AA (HRPR AA) had a significantly higher platelet count than patients without HRPR AA (547 × 109/L [340 – 644 × 109/L] vs 358 × 109/L [242 – 501 × 109/L], P = 0.01). Receiver-operating characteristic curve analysis revealed a platelet count of ≥317 × 109/L as best threshold to distinguish between patients without and with HRPR AA (area under the curve: 0.73). After adding the direct ADP P2Y12 inhibitor cangrelor to blood samples from all 93 patients in vitro, residual ADP-inducible platelet reactivity correlated weakly with the platelet count (r = 0.26, P = 0.01), but the platelet count did not differ significantly between patients with and without HRPR ADP (396 × 109/L [316 – 644 × 109/L] vs 340 × 109/L [241 – 489 × 109/L]; P = 0.2). In conclusion, our findings suggest that the extent of platelet inhibition by aspirin in patients with MPN at least in part depends on their individual platelet count.

Introduction

Essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) are common forms of myeloproliferative neoplasms (MPN). In the majority of affected patients janus kinase (JAK) 2 or calreticulin (CALR) mutations lead to increased proliferation of myeloid cells and therefore, they often present with thrombocytosis, leukocytosis, increased red cell counts or anemia and/or progressive splenomegaly. They may develop bleedings, most likely due to an acquired von Willebrand syndrome at high platelet counts,1, 2, 3 but are particularly prone to thromboembolism.4, 5, 6 The increased clotting activity in MPN is complex and more often affects the arterial than the venous vascular system.7 The risk of developing thrombotic complications differs from one individual to the next, mainly depending on a history of thrombosis, the JAK2/myeloproliferative leukemia virus oncogene (MPL)mutation, and the patients’ age.8 Additional risk factors for thrombosis in MPN comprise male sex and cardiovascular risk factors like tobacco use, hypertension, and diabetes.6 Further, the occurrence of thromboembolic events has been linked to high platelet counts during follow-up, particularly if the latter are combined with high leukocyte counts.9, 10, 11 Although a high platelet count itself has not been proven to be directly responsible for the risk of thromboembolism, platelets circulate in an activated state in MPN,12 and the higher the platelet count, the more platelets may contribute to thrombosis. Indeed, high platelet counts during the course of the disease have been associated with thromboembolic events.9 Consequently, lowering the platelet count by cytoreductive therapy and low-dose aspirin (75–100mg once daily) are currently recommended for both primary and secondary prevention in MPN patients at risk of thromboembolism.13, 14, 15 However, many patients with MPN develop thromboembolic events despite aspirin therapy, which may be attributed to insufficient platelet inhibition by aspirin, also known as “aspirin resistance”.16 Aspirin resistance is a rare finding in patients without hematological disorders.17, 18 In patients with MPN, aspirin resistance may result from a rare defect of the platelet population allowing arachidonic acid (AA)-inducible platelet aggregation,19 but more likely from high platelet turnover.20 Newly formed platelets entering the circulation after aspirin ingestion may not have been exposed to aspirin due to its short half-life and therefore remain non-inhibited. Thus, twice daily administration of aspirin rather than a single dose per day has been recommended to reduce the risk of thromboembolic events.20, 21 Similarly, Perrier-Cornet et al recently found twice daily aspirin or cytoreduction to overcome in vitro “aspirin resistance.”22 It should be kept in mind, however, that this regimen may also be associated with a higher risk of gastrointestinal bleedings.

Platelet function may differ from one patient to the other, and it is currently not clear if patients with MPN have normal, hyper-reactive, or impaired platelet function. Even though it is anticipated that platelet counts serve as surrogate marker for increased platelet production, it has not been studied at which platelet count a single dose of aspirin achieves effective platelet inhibition in MPN. The latter is of particular importance, if antiplatelet therapy is considered. Assessing platelet function and thus the response to antiplatelet therapy may allow tailoring of antiplatelet therapy. However, platelet function testing is not widely available in clinical routine diagnostics, so far.

Multiple studies in atherosclerotic cardiovascular disease (CVD) have shown an association of residual platelet aggregation in vitrowith the occurrence of ischemic events.23, 24 In the current study, we sought to investigate the association of the platelet count with the inhibitory potential of antiplatelet therapy in MPN. We, therefore, assessed platelet response to AA and adenosine diphosphate (ADP) in patients with ET, PV, or PMF using whole blood impedance aggregometry. Moreover, we aimed at identifying a threshold of the platelet count in MPN which is linked to poor response to antiplatelet therapy.

Section snippets

Patients

Patients with ET, PV, or PMF were consecutively recruited at the outpatient department of the Division of Hematology and Hemostaseology of the Medical University of Vienna, Austria, from November 2014 until October 2015 to investigate the association of the platelet count with response to antiplatelet therapy. The diagnoses were based on the 2008 revised WHO criteria.25 All aspirin-treated patients took 100mg aspirin once daily, and received aspirin 2–3hours prior to blood sampling. Exclusion

Results

Clinical and laboratory characteristics of the overall study population (n = 93), and of patients without (n = 44) and with aspirin therapy (n = 49) are given in TableI.

In patients without aspirin therapy, the platelet count did not correlate with AA- and TRAP-inducible platelet aggregation (AA: r = 0.01; TRAP: r = 0.29; both P > 0.05). In aspirin-treated patients, we observed a moderate correlation of residual AA-inducible platelet aggregation with the platelet count (r = 0.49, P < 0.001; Fig 1

Discussion

In the current study, we investigated the association of the platelet count with response to aspirin therapy and ADP P2Y12 receptor inhibition in patients with MPN. Residual AA-inducible platelet aggregation correlated significantly with the platelet count in aspirin-treated patients suggesting that HRPR AA can be anticipated in MPN patients with high platelet counts. Subsequently, we identified a platelet count ≥317 × 109/L as best predictor of HRPR AA. This threshold may mirror a high

Acknowledgments

Conflicts of Interest: All authors have read the journal's policy on disclosure of potential conflicts of interest and have none to declare.

All authors have read the journal´s authorship agreement and the manuscript has been reviewed and approved by all named authors.

Author contributions are as follow:

Thomas Gremmel, Heinz Gisslinger and Simon Panzer designed the study. Thomas Gremmel and Simon Panzer evaluated the data and wrote the manuscript. Bettina Gisslinger and Heinz Gisslinger were

References (38)

Cited by (0)

1

Thomas Gremmel and Bettina Gisslinger share first authorship.

2

Simon Panzer and Heinz Gisslinger share senior authorship.

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