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Thromb Haemost 2020; 120(05): 768-775
DOI: 10.1055/s-0040-1709523
Cellular Haemostasis and Platelets
Georg Thieme Verlag KG Stuttgart · New York

Platelet Integrin αIIbβ3 Activation is Associated with 25-Hydroxyvitamin D Concentrations in Healthy Adults

Floor E. Aleva
1   Department of Respiratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
2   Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
3   Radboud Centre for Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands
,
Rahajeng N. Tunjungputri
2   Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
3   Radboud Centre for Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands
,
Lisa N. van der Vorm
1   Department of Respiratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
4   Synapse Research Institute, Maastricht, The Netherlands
5   Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands
6   Department of Clinical Chemistry and Haematology, GelreZiekenhuizen, Apeldoorn, The Netherlands
,
Yang Li
7   Department of Genetics, University Medical Centre Groningen, Nijmegen, The Netherlands
,
Yvonne F. Heijdra
1   Department of Respiratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
,
Marije Oosting
2   Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
3   Radboud Centre for Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands
,
Sanne P. Smeekens
2   Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
3   Radboud Centre for Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands
,
Martin Jaeger
2   Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
3   Radboud Centre for Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands
,
Leo A.B. Joosten
2   Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
3   Radboud Centre for Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands
,
Philip G. de Groot
2   Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
3   Radboud Centre for Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands
,
Mihai G. Netea
2   Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
3   Radboud Centre for Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands
8   Department for Genomics and Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
,
Andre J.A.M. van der Ven
2   Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
3   Radboud Centre for Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands
,
Quirijn de Mast
2   Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
3   Radboud Centre for Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands
› Institutsangaben Funding F.E.A. was supported by a grant from the Lung Foundation Netherlands (Project #5.1.13.033). M.G.N. was supported by an ERC Consolidator Grant (#310372) and a Spinoza Grant of the Netherlands Organization for Scientific Research. Y.L. and M.O. were supported by a VENI grant (# 863.13.011 and 016.176.006) from the Netherlands Organization for Scientific Research (NWO).
Weitere Informationen

Publikationsverlauf

09. November 2019

24. Februar 2020

Publikationsdatum:
05. Mai 2020 (online)

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Abstract

Background Cardiovascular events are associated with low circulating vitamin D concentrations, although the underlying mechanisms are poorly understood. This study investigated associations between 25-hydroxyvitamin D concentrations, platelet function, and single-nucleotide polymorphisms (SNPs) in genes influencing vitamin D biology in the 500 Functional Genomics (500FG) cohort.

Methods In this observational study, platelet activation and function were measured by flow cytometry by binding of fibrinogen to the activated fibrinogen receptor integrin αIIbβ3 and expression of P-selectin, markers of platelet aggregation and degranulation, respectively. These parameters were correlated to serum 25-hydroxyvitamin D and genotyping was performed to investigate SNPs in genes important for vitamin D biology.

Results Circulating 25-hydroxyvitamin D concentrations correlated inversely with baseline platelet binding of fibrinogen to integrin αIIbβ3 (Pearson's r= –0.172, p = 0.002) and platelet responses to platelet agonist cross-linked collagen-related peptide (CRP-XL) (Pearson's r= –0.196,p = 0.002). This effect was due to circulating vitamin D levels ≤50nmol/L, since no differences in platelet fibrinogen binding were observed between subjects with normal 25-hydroxyvitamin D concentrations (>75nmol/L) and a 25-hydroxyvitamin D insufficiency (50–75 nmol/L). No correlations between 25-hydroxyvitamin D concentrations and platelet P-selectin expression were found. Several SNPs in the GC region of the vitamin D binding proteingene were associated with platelet responses to CRP-XL.

Conclusion Low circulating vitamin D concentrations are associated with increased platelet fibrinogen binding to integrin αIIbβ3 in unstimulated samples and after stimulation with CRP-XL. These findings may contribute to the increased incidence of cardiovascular events in vitamin D deficient adults and its seasonal variation. Further studies are needed to investigate causality.

Keywords

platelets - vitamin D - inflammation - hemostasis - fibrinogen

Supplementary Material

 

  • References

  • 1 Lozano R, Naghavi M, Foreman K. , et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380 (9859): 2095-2128
    CrossrefPubMedGoogle Scholar
  • 2 Hong JS, Kang HC. Seasonal variation in case fatality rate in Korean patients with acute myocardial infarction using the 1997-2006 Korean National Health Insurance Claims Database. Acta Cardiol 2014; 69 (05) 513-521
    CrossrefPubMedGoogle Scholar
  • 3 Hopstock LA, Wilsgaard T, Njølstad I. , et al. Seasonal variation in incidence of acute myocardial infarction in a sub-Arctic population: the Tromsø Study 1974-2004. Eur J Cardiovasc Prev Rehabil 2011; 18 (02) 320-325
    CrossrefPubMedGoogle Scholar
  • 4 Loughnan ME, Nicholls N, Tapper NJ. Demographic, seasonal, and spatial differences in acute myocardial infarction admissions to hospital in Melbourne Australia. Int J Health Geogr 2008; 7: 42
    CrossrefPubMedGoogle Scholar
  • 5 Patel NJ, Pant S, Deshmukh AJ. , et al. Seasonal variation of acute myocardial infarction related hospitalizations in the United States: perspective over the last decade. Int J Cardiol 2014; 172 (03) e441-e442
    CrossrefPubMedGoogle Scholar
  • 6 Norman AW. Sunlight, season, skin pigmentation, vitamin D, and 25-hydroxyvitamin D: integral components of the vitamin D endocrine system. Am J ClinNutr 1998; 67 (06) 1108-1110
    PubMedGoogle Scholar
  • 7 Sokol SI, Tsang P, Aggarwal V, Melamed ML, Srinivas VS. Vitamin D status and risk of cardiovascular events: lessons learned via systematic review and meta-analysis. Cardiol Rev 2011; 19 (04) 192-201
    CrossrefPubMedGoogle Scholar
  • 8 Vacek JL, Vanga SR, Good M, Lai SM, Lakkireddy D, Howard PA. Vitamin D deficiency and supplementation and relation to cardiovascular health. Am J Cardiol 2012; 109 (03) 359-363
    CrossrefPubMedGoogle Scholar
  • 9 Wang L, Song Y, Manson JE. , et al. Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies. CircCardiovascQual Outcomes 2012; 5 (06) 819-829
    PubMedGoogle Scholar
  • 10 Wang TJ, Zhang F, Richards JB. , et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 2010; 376 (9736): 180-188
    CrossrefPubMedGoogle Scholar
  • 11 Ng LL, Sandhu JK, Squire IB, Davies JE, Jones DJ. Vitamin D and prognosis in acute myocardial infarction. Int J Cardiol 2013; 168 (03) 2341-2346
    CrossrefPubMedGoogle Scholar
  • 12 Lee JH, Gadi R, Spertus JA, Tang F, O'Keefe JH. Prevalence of vitamin D deficiency in patients with acute myocardial infarction. Am J Cardiol 2011; 107 (11) 1636-1638
    CrossrefPubMedGoogle Scholar
  • 13 Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357 (03) 266-281
    CrossrefPubMedGoogle Scholar
  • 14 Khoo AL, Chai L, Koenen H, Joosten I, Netea M, van der Ven A. Translating the role of vitamin D3 in infectious diseases. Crit Rev Microbiol 2012; 38 (02) 122-135
    CrossrefPubMedGoogle Scholar
  • 15 Kongsbak M, Levring TB, Geisler C, von Essen MR. The vitamin Dreceptor and T cell function. Front Immunol 2013; 4: 148
    PubMedGoogle Scholar
  • 16 Foley JH, Conway EM. Cross talk pathways between coagulation and inflammation. Circ Res 2016; 118 (09) 1392-1408
    CrossrefPubMedGoogle Scholar
  • 17 Donaldson GC, Hurst JR, Smith CJ, Hubbard RB, Wedzicha JA. Increased risk of myocardial infarction and stroke following exacerbation of COPD. Chest 2010; 137 (05) 1091-1097
    CrossrefPubMedGoogle Scholar
  • 18 Davì G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007; 357 (24) 2482-2494
    CrossrefPubMedGoogle Scholar
  • 19 Silvagno F, De Vivo E, Attanasio A, Gallo V, Mazzucco G, Pescarmona G. Mitochondrial localization of vitamin D receptor in human platelets and differentiated megakaryocytes. PLoS One 2010; 5 (01) e8670
    CrossrefPubMedGoogle Scholar
  • 20 Ahn J, Yu K, Stolzenberg-Solomon R. , et al. Genome-wide association study of circulating vitamin D levels. Hum Mol Genet 2010; 19 (13) 2739-2745
    CrossrefPubMedGoogle Scholar
  • 21 Voipio AJ, Pahkala KA, Viikari JS. , et al. Determinants of serum 25(OH)D concentration in young and middle-aged adults. The Cardiovascular Risk in Young Finns Study. Ann Med 2015; 47 (03) 253-262
    CrossrefPubMedGoogle Scholar
  • 22 Ferrarezi DA, Bellili-Muñoz N, Dubois-Laforgue D. , et al. Allelic variations of the vitamin D receptor (VDR) gene are associated with increased risk of coronary artery disease in type 2 diabetics: the DIABHYCAR prospective study. Diabetes Metab 2013; 39 (03) 263-270
    CrossrefPubMedGoogle Scholar
  • 23 García-Bailo B, Jamnik J, Da Costa LA, Badawi A, El-Sohemy A. Genetic variation in the vitamin D receptor, plasma 25-hydroxyvitamin D, and biomarkers of cardiometabolic disease in Caucasian young adults. J Nutrigenet Nutrigenomics 2013; 6 (4-5): 256-267
    CrossrefPubMedGoogle Scholar
  • 24 Levin GP, Robinson-Cohen C, de Boer IH. , et al. Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes. JAMA 2012; 308 (18) 1898-1905
    CrossrefPubMedGoogle Scholar
  • 25 Ter Horst R, Jaeger M, Smeekens SP. , et al. Host and environmental factors influencing individual human cytokine responses. Cell 2016; 167 (04) 1111-1124 e1113
    CrossrefPubMedGoogle Scholar
  • 26 Tunjungputri RN, Li Y, de Groot PG. , et al. The inter-relationship of platelets with interleukin-1β-mediated inflammation in humans. ThrombHaemost 2018; 118 (12) 2112-2125
    PubMedGoogle Scholar
  • 27 Li Y, Oosting M, Deelen P. , et al. Inter-individual variability and genetic influences on cytokine responses to bacteria and fungi. Nat Med 2016; 22 (08) 952-960
    CrossrefPubMedGoogle Scholar
  • 28 Bu FX, Armas L, Lappe J. , et al. Comprehensive association analysis of nine candidate genes with serum 25-hydroxy vitamin D levels among healthy Caucasian subjects. Hum Genet 2010; 128 (05) 549-556
    CrossrefPubMedGoogle Scholar
  • 29 Jorde R, Schirmer H, Wilsgaard T. , et al. Polymorphisms related to the serum 25-hydroxyvitamin D level and risk of myocardial infarction, diabetes, cancer and mortality. The Tromsø Study. PLoS One 2012; 7 (05) e37295
    CrossrefPubMedGoogle Scholar
  • 30 Kühn T, Kaaks R, Teucher B. , et al. Plasma 25-hydroxyvitamin D and its genetic determinants in relation to incident myocardial infarction and stroke in the European prospective investigation into cancer and nutrition (EPIC)-Germany study. PLoS One 2013; 8 (07) e69080
    CrossrefPubMedGoogle Scholar
  • 31 Li Y, Tesson BM, Churchill GA, Jansen RC. Critical reasoning on causal inference in genome-wide linkage and association studies. Trends Genet 2010; 26 (12) 493-498
    CrossrefPubMedGoogle Scholar
  • 32 Millstein J, Zhang B, Zhu J, Schadt EE. Disentangling molecular relationships with a causal inference test. BMC Genet 2009; 10: 23
    PubMedGoogle Scholar
  • 33 Mortality GBD. ; GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015; 385 (9963): 117-171
    CrossrefPubMedGoogle Scholar
  • 34 Badimon L, Vilahur G. Thrombosis formation on atherosclerotic lesions and plaque rupture. J Intern Med 2014; 276 (06) 618-632
    CrossrefPubMedGoogle Scholar
  • 35 Verdoia M, Pergolini P, Rolla R. , et al; Novara Atherosclerosis Study Group (NAS). Vitamin D levels and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor. Platelets 2016; 27 (06) 576-582
    CrossrefPubMedGoogle Scholar
  • 36 Cumhur Cure M, Cure E, Yuce S, Yazici T, Karakoyun I, Efe H. Mean platelet volume and vitamin D level. Ann Lab Med 2014; 34 (02) 98-103
    CrossrefPubMedGoogle Scholar
  • 37 Verouti SN, Tsoupras AB, Alevizopoulou F, Demopoulos CA, Iatrou C. Paricalcitol effects on activities and metabolism of platelet activating factor and on inflammatory cytokines in hemodialysis patients. Int J Artif Organs 2013; 36 (02) 87-96
    CrossrefPubMedGoogle Scholar
  • 38 Verdoia M, Pergolini P, Nardin M. , et al; Novara Atherosclerosis Study Group (NAS). Vitamin D levels and platelet reactivity in diabetic patients receiving dual antiplatelet therapy. Vascul Pharmacol 2019; 120: 106564
    CrossrefPubMedGoogle Scholar
  • 39 Park YC, Kim J, Seo MS, Hong SW, Cho ES, Kim JK. Inverse relationship between vitamin D levels and platelet indices in Korean adults. Hematology 2017; 22 (10) 623-629
    CrossrefPubMedGoogle Scholar
  • 40 Lu BC, Shi XJ, Liang L, Dong N, Liu ZZ. Platelet surface CD62p and serum vitamin D levels are associated with clopidogrel resistance in Chinese patients with ischemic stroke. J Stroke Cerebrovasc Dis 2019; 28 (05) 1323-1328
    CrossrefPubMedGoogle Scholar
  • 41 Zhou Z, Gushiken FC, Bolgiano D. , et al. Signal transducer and activator of transcription 3 (STAT3) regulates collagen-induced platelet aggregation independently of its transcription factor activity. Circulation 2013; 127 (04) 476-485
    CrossrefPubMedGoogle Scholar
  • 42 Lange CM, Gouttenoire J, Duong FH, Morikawa K, Heim MH, Moradpour D. Vitamin D receptor and Jak-STAT signaling crosstalk results in calcitriol-mediated increase of hepatocellular response to IFN-α. J Immunol 2014; 192 (12) 6037-6044
    CrossrefPubMedGoogle Scholar
  • 43 Olson KC, Kulling PM, Olson TL. , et al. Vitamin D decreases STAT phosphorylation and inflammatory cytokine output in T-LGL leukemia. Cancer Biol Ther 2017; 18 (05) 290-303
    CrossrefPubMedGoogle Scholar
  • 44 López-Farré AJ, Mateos-Cáceres PJ, Sacristán D. , et al. Relationship between vitamin D binding protein and aspirin resistance in coronary ischemic patients: a proteomic study. J Proteome Res 2007; 6 (07) 2481-2487
    CrossrefPubMedGoogle Scholar
  • 45 Verdoia M, Daffara V, Pergolini P. , et al; Novara Atherosclerosis Study Group (NAS). Vitamin D binding protein rs7041 polymorphism and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor. VasculPharmacol 2017; 93-95: 42-47
    PubMedGoogle Scholar
  • 46 Chari R, Getz T, Nagy Jr B. , et al. Protein kinase C[delta] differentially regulates platelet functional responses. Arterioscler Thromb Vasc Biol 2009; 29 (05) 699-705
    CrossrefPubMedGoogle Scholar
  • 47 Ford JA, MacLennan GS, Avenell A, Bolland M, Grey A, Witham M. ; RECORD Trial Group. Cardiovascular disease and vitamin D supplementation: trial analysis, systematic review, and meta-analysis. Am J Clin Nutr 2014; 100 (03) 746-755
    CrossrefPubMedGoogle Scholar
  • 48 Elamin MB, Abu Elnour NO, Elamin KB. , et al. Vitamin D and cardiovascular outcomes: a systematic review and meta-analysis. J Clin Endocrinol Metab 2011; 96 (07) 1931-1942
    CrossrefPubMedGoogle Scholar
  • 49 Pittas AG, Chung M, Trikalinos T. , et al. Systematic review: vitamin D and cardiometabolic outcomes. Ann Intern Med 2010; 152 (05) 307-314
    PubMedGoogle Scholar
  • 50 Rafiq R, Aleva FE, Schrumpf JA. , et al. Prevention of exacerbations in patients with COPD and vitamin D deficiency through vitamin D supplementation (PRECOVID): a study protocol. BMC Pulm Med 2015; 15: 106
    CrossrefPubMedGoogle Scholar
  • 51 Verdoia M, Schaffer A, Barbieri L. , et al; Novara Atherosclerosis Study Group (NAS). Impact of gender difference on vitamin D status and its relationship with the extent of coronary artery disease. Nutr Metab Cardiovasc Dis 2015; 25 (05) 464-470
    CrossrefPubMedGoogle Scholar