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Cardiovascular risk factors are important determinants of platelet-dependent thrombin generation in adult survivors of childhood cancer

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Abstract

Cardiovascular disease is the most frequent non-malignant cause of morbidity and mortality in adult survivors of childhood or adolescent cancer. Thrombin generation (TG) analysis gives insight in hypercoagulability as an important mechanism linked to cardiovascular risk factors (CVRFs). In 200 individuals, from the cardiac and vascular late sequelae in long-term survivors of childhood cancer study, TG in platelet-rich plasma (PRP) and platelet-free plasma (PFP) at 1pM tissue factor was investigated. Endogenous thrombin potential (ETP) and peak height were the analysed parameters of a TG curve. Sex-specific multivariable linear regression analysis adjusted for age and CVRFs was used to assess the clinical determinants of TG. Females presented with higher ETP and peak height compared to males, both in PRP and PFP. Hypertension (beta estimate, ß: 184.8 [90.7; 278.8]), obesity (ß: 161.9 [63.9; 259.5]), and HbA1c (ß: 715.6 [97.4; 1333.8]) were associated with higher ETP in PRP only. ETP in PRP was positively associated with obesity and HbA1c in both males and females and with dyslipidemia (ß: 253.07 [72.92; 433.22]) and systolic hypertension (ß: 436.7 [119.02; 754.39]) in females only. CVRFs showed no association with TG variables in PFP. In conclusion, this study presents an important relation between traditional CVRFs and TG in the presence of platelets only. Sex-specific differences in TG with females presenting with higher TG, particularly those with dyslipidemia and systolic hypertension, were demonstrated. These results highlight the potential of the platelet-coagulant function in identifying cancer survivors at higher risk for adverse cardiovascular events.

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Acknowledgements

We thank all former childhood cancer patients who underwent clinical examination for this study. We are very grateful to Markus Nagler for performing the statistical analysis of this study. The CVSS study is funded by the Deutsche Forschungsgemeinschaft (DFG) (SP 1381/2-1&2, FA 1038/2-1&2, WI 3881/2-1&2). The Gutenberg Health Study is funded through the government of Rhineland-Palatinate (“Stiftung Rheinland-Pfalz für Innovation”, contract AZ 961-386261/733), the research programs “Wissen schafft Zukunft” and “Center for Translational Vascular Biology (CTVB)” of the Johannes Gutenberg-University of Mainz, and its contract with Boehringer Ingelheim and PHILIPS Medical Systems, including an unrestricted grant for the Gutenberg Health Study. PS Wild is funded by the Federal Ministry of Education and Research (BMBF 01EO1503) and he received honoraria for lectures or consulting from Boehringer Ingelheim, Bayer HealthCare, Sanofi-Aventis, Bayer Vital, AstraZeneca, DiaSorin, and Evonik and he get non-financial support from DiaSorin and I.E.M.

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Author notes

  1. Jörg Faber and Philipp S. Wild contributed equally.

Authors and Affiliations

  1. Clinical Epidemiology, Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany

    Marina Panova-Noeva, Hugo ten Cate & Philipp S. Wild

  2. Pediatric Hematology/Oncology/Hemostaseology, Center for Childhood and Adolescence Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

    Marie A. Neu, Susan Eckerle & Jörg Faber

  3. Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI) at the University Medical Center Mainz, Mainz, Germany

    Claudia Spix, Astrid Schneider, Irene Schmidtmann & Hiltrud Merzenich

  4. Laboratory for Clinical Thrombosis and Hemostasis, Department of Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands

    Henri M. Spronk & Hugo ten Cate

  5. Department of Ophthalmology, University Medical Center Mainz of the Johannes Gutenberg-University Mainz, Mainz, Germany

    Norbert Pfeiffer

  6. Department of Psychosomatic Medicine and Psychotherapy, University Medical Center Mainz of the Johannes Gutenberg-University Mainz, Mainz, Germany

    Manfred Beutel

  7. Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

    Karl J. Lackner

  8. Center for Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

    Thomas Münzel

  9. Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

    Marina Panova-Noeva & Philipp S. Wild

  10. DZHK (German Center for Cardiovascular Research), Partner Site RhineMain, Mainz, Germany

    Marina Panova-Noeva, Karl J. Lackner, Thomas Münzel & Philipp S. Wild

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  1. Marina Panova-Noeva
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  2. Marie A. Neu
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Correspondence to Marina Panova-Noeva.

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Panova-Noeva, M., Neu, M.A., Eckerle, S. et al. Cardiovascular risk factors are important determinants of platelet-dependent thrombin generation in adult survivors of childhood cancer. Clin Res Cardiol 108, 438–447 (2019). https://doi.org/10.1007/s00392-018-1374-4

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