Download PDF
Semin Thromb Hemost 2012; 38(01): 114-124
DOI: 10.1055/s-0031-1300957
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Vitamin D, Thrombosis, and Hemostasis: More than Skin Deep

Giovanni Targher
1   Section of Endocrinology, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
,
Isabella Pichiri
1   Section of Endocrinology, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
,
Giuseppe Lippi
2   Clinical Chemistry Laboratory, Department of Clinical Pathology and Laboratory Medicine, Academic Hospital, University of Parma, Italy
› Author Affiliations
Further Information

Publication History

Publication Date:
07 February 2012 (online)

    Permissions and Reprints

Abstract

Vitamin D3 deficiency is a highly prevalent condition worldwide. Clinically, vitamin D3 has a key role in calcium homeostasis and bone mineralization and has recently been implicated in the pathogenesis and/or progression of several acute and chronic illnesses, including cardiovascular disease (CVD). Accumulating evidence from observational, prospective studies suggests that low levels of serum 25-hydroxyvitamin D3 are independently associated with an increased risk of CVD events and death. The molecular mechanisms of this association remain incompletely understood. A variety of biologically plausible mechanisms may mediate a cardiovascular role for the active metabolite of vitamin D3. 1-α,25-dihydroxyvitamin D3 regulates the renin–angiotensin system, suppresses proliferation of vascular cell smooth muscle, improves insulin resistance and endothelial cell-dependent vasodilation, inhibits myocardial cell hypertrophy, exerts anticoagulant and antifibrotic activity, and modulates macrophage activity and cytokine generation. Overall, the high prevalence of vitamin D3 deficiency and the plausible biological mechanisms linking this to CVD risk suggest that the treatment of vitamin D3 deficiency to prevent CVD is a promising field to explore. Large placebo-controlled randomized clinical trials are urgently needed to determine whether vitamin D supplementation could have any potential benefit in reducing future CVD events and mortality risk.

Keywords

vitamin D deficiency - cardiovascular disease - hemostasis - thrombosis
 

  • References

  • 1 Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357 (3) 266-281
    CrossrefPubMedGoogle Scholar
  • 2 Adams JS, Hewison M. Update in vitamin D. J Clin Endocrinol Metab 2010; 95 (2) 471-478
    CrossrefPubMedGoogle Scholar
  • 3 Thacher TD, Clarke BL. Vitamin D insufficiency. Mayo Clin Proc 2011; 86 (1) 50-60
    CrossrefPubMedGoogle Scholar
  • 4 Windaus A, Linsert O, Luttringhaus A, Weidlich G. Über das krystallisierte Vitamin D 2 . Liebigs Ann Chem 1932; 492: 226-241
    PubMedGoogle Scholar
  • 5 Brockman H. Die Isolierung des antirachitischen Vitamins aus thunfischleberol. H-S Zeit. Physiol Chem 1936; 241: 104-115
    CrossrefPubMedGoogle Scholar
  • 6 U.S. Department of Agriculture, Agricultural Research Service. 2010. USDA National Nutrient Database for Standard Reference, Release 23. Available at: http://www.ars.usda.gov/nutrientdata
    PubMedGoogle Scholar
  • 7 Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC. November 30, 2010. Available at: http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx
    PubMedGoogle Scholar
  • 8 Thomas MK, Lloyd-Jones DM, Thadhani RI , et al. Hypovitaminosis D in medical inpatients. N Engl J Med 1998; 338 (12) 777-783
    CrossrefPubMedGoogle Scholar
  • 9 van der Wielen RP, Löwik MR, van den Berg H , et al. Serum vitamin D concentrations among elderly people in Europe. Lancet 1995; 346 (8969) 207-210
    CrossrefPubMedGoogle Scholar
  • 10 Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocr Rev 2001; 22 (4) 477-501
    CrossrefPubMedGoogle Scholar
  • 11 Looker AC, Pfeiffer CM, Lacher DA, Schleicher RL, Picciano MF, Yetley EA. Serum 25-hydroxyvitamin D status of the US population: 1988-1994 compared with 2000-2004. Am J Clin Nutr 2008; 88 (6) 1519-1527
    CrossrefPubMedGoogle Scholar
  • 12 Gordon CM, DePeter KC, Feldman HA, Grace E, Emans SJ. Prevalence of vitamin D deficiency among healthy adolescents. Arch Pediatr Adolesc Med 2004; 158 (6) 531-537
    CrossrefPubMedGoogle Scholar
  • 13 Gannagé-Yared MH, Chemali R, Yaacoub N, Halaby G. Hypovitaminosis D in a sunny country: relation to lifestyle and bone markers. J Bone Miner Res 2000; 15 (9) 1856-1862
    CrossrefPubMedGoogle Scholar
  • 14 Cigolini M, Miconi V, Soffiati G , et al. Hypovitaminosis D among unselected medical inpatients and outpatients in Northern Italy. Clin Endocrinol (Oxf) 2006; 64 (4) 475
    CrossrefPubMedGoogle Scholar
  • 15 Lippi G, Montagnana M, Targher G. Vitamin D deficiency among Italian children. CMAJ 2007; 177 (12) 1529-1530, author reply 1530
    PubMedGoogle Scholar
  • 16 Arabi A, El Rassi R, El-Hajj Fuleihan G. Hypovitaminosis D in developing countries-prevalence, risk factors and outcomes. Nat Rev Endocrinol 2010; 6 (10) 550-561
    CrossrefPubMedGoogle Scholar
  • 17 Somjen D, Weisman Y, Kohen F , et al. 25-hydroxyvitamin D3-1alpha-hydroxylase is expressed in human vascular smooth muscle cells and is upregulated by parathyroid hormone and estrogenic compounds. Circulation 2005; 111 (13) 1666-1671
    CrossrefPubMedGoogle Scholar
  • 18 Hewison M, Zehnder D, Chakraverty R, Adams JS. Vitamin D and barrier function: a novel role for extra-renal 1 α-hydroxylase. Mol Cell Endocrinol 2004; 215 (1-2) 31-38
    CrossrefPubMedGoogle Scholar
  • 19 Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol Renal Physiol 2005; 289 (1) F8-F28
    CrossrefPubMedGoogle Scholar
  • 20 Koyama T, Hirosawa S. Anticoagulant effects of synthetic retinoids and activated vitamin D3. Semin Thromb Hemost 1998; 24 (3) 217-226
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Koyama T, Shibakura M, Ohsawa M, Kamiyama R, Hirosawa S. Anticoagulant effects of 1alpha,25-dihydroxyvitamin D3 on human myelogenous leukemia cells and monocytes. Blood 1998; 92 (1) 160-167
    PubMedGoogle Scholar
  • 22 Ohsawa M, Koyama T, Yamamoto K, Hirosawa S, Kamei S, Kamiyama R. 1alpha,25-dihydroxyvitamin D(3) and its potent synthetic analogs downregulate tissue factor and upregulate thrombomodulin expression in monocytic cells, counteracting the effects of tumor necrosis factor and oxidized LDL. Circulation 2000; 102 (23) 2867-2872
    CrossrefPubMedGoogle Scholar
  • 23 Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 2002; 110 (2) 229-238
    CrossrefPubMedGoogle Scholar
  • 24 Sun J, Kong J, Duan Y , et al. Increased NF-kappaB activity in fibroblasts lacking the vitamin D receptor. Am J Physiol Endocrinol Metab 2006; 291 (2) E315-E322
    CrossrefPubMedGoogle Scholar
  • 25 Aihara K, Azuma H, Akaike M , et al. Disruption of nuclear vitamin D receptor gene causes enhanced thrombogenicity in mice. J Biol Chem 2004; 279 (34) 35798-35802
    CrossrefPubMedGoogle Scholar
  • 26 Wu-Wong JR, Nakane M, Ma J. Vitamin D analogs modulate the expression of plasminogen activator inhibitor-1, thrombospondin-1 and thrombomodulin in human aortic smooth muscle cells. J Vasc Res 2007; 44 (1) 11-18
    CrossrefPubMedGoogle Scholar
  • 27 Wu-Wong JR, Nakane M, Ma J, Ruan X, Kroeger PE. VDR-mediated gene expression patterns in resting human coronary artery smooth muscle cells. J Cell Biochem 2007; 100 (6) 1395-1405
    CrossrefPubMedGoogle Scholar
  • 28 Watkins RR, Yamshchikov AV, Lemonovich TL, Salata RA. The role of vitamin D deficiency in sepsis and potential therapeutic implications. J Infect 2011; 63 (5) 321-326
    CrossrefPubMedGoogle Scholar
  • 29 Takeda M, Yamashita T, Sasaki N , et al. Oral administration of an active form of vitamin D3 (calcitriol) decreases atherosclerosis in mice by inducing regulatory T cells and immature dendritic cells with tolerogenic functions. Arterioscler Thromb Vasc Biol 2010; 30 (12) 2495-2503
    CrossrefPubMedGoogle Scholar
  • 30 Wu-Wong JR. Potential for vitamin D receptor agonists in the treatment of cardiovascular disease. Br J Pharmacol 2009; 158 (2) 395-412
    CrossrefPubMedGoogle Scholar
  • 31 Hyppönen E, Berry D, Cortina-Borja M, Power C. 25-Hydroxyvitamin D and pre-clinical alterations in inflammatory and hemostatic markers: a cross sectional analysis in the 1958 British Birth Cohort. PLoS ONE 2010; 5 (5) e10801
    CrossrefPubMedGoogle Scholar
  • 32 Jorde R, Haug E, Figenschau Y, Hansen JB. Serum levels of vitamin D and haemostatic factors in healthy subjects: the Tromsø study. Acta Haematol 2007; 117 (2) 91-97
    CrossrefPubMedGoogle Scholar
  • 33 Ngo DT, Sverdlov AL, McNeil JJ, Horowitz JD. Does vitamin D modulate asymmetric dimethylarginine and C-reactive protein concentrations?. Am J Med 2010; 123 (4) 335-341
    CrossrefPubMedGoogle Scholar
  • 34 Cigolini M, Iagulli MP, Miconi V, Galiotto M, Lombardi S, Targher G. Serum 25-hydroxyvitamin D3 concentrations and prevalence of cardiovascular disease among type 2 diabetic patients. Diabetes Care 2006; 29 (3) 722-724
    CrossrefPubMedGoogle Scholar
  • 35 Shea MK, Booth SL, Massaro JM , et al. Vitamin K and vitamin D status: associations with inflammatory markers in the Framingham Offspring Study. Am J Epidemiol 2008; 167 (3) 313-320
    PubMedGoogle Scholar
  • 36 Schleithoff SS, Zittermann A, Tenderich G, Berthold HK, Stehle P, Koerfer R. Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr 2006; 83 (4) 754-759
    PubMedGoogle Scholar
  • 37 Zittermann A, Frisch S, Berthold HK , et al. Vitamin D supplementation enhances the beneficial effects of weight loss on cardiovascular disease risk markers. Am J Clin Nutr 2009; 89 (5) 1321-1327
    CrossrefPubMedGoogle Scholar
  • 38 Timms PM, Mannan N, Hitman GA , et al. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders?. QJM 2002; 95 (12) 787-796
    CrossrefPubMedGoogle Scholar
  • 39 Pittas AG, Harris SS, Stark PC, Dawson-Hughes B. The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in nondiabetic adults. Diabetes Care 2007; 30 (4) 980-986
    CrossrefPubMedGoogle Scholar
  • 40 Rostand SG. Ultraviolet light may contribute to geographic and racial blood pressure differences. Hypertension 1997; 30 (2 Pt 1) 150-156
    CrossrefPubMedGoogle Scholar
  • 41 Krause R, Bühring M, Hopfenmüller W, Holick MF, Sharma AM. Ultraviolet B and blood pressure. Lancet 1998; 352 (9129) 709-710
    PubMedGoogle Scholar
  • 42 Martins D, Wolf M, Pan D , et al. Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med 2007; 167 (11) 1159-1165
    CrossrefPubMedGoogle Scholar
  • 43 Chonchol M, Scragg R. 25-Hydroxyvitamin D, insulin resistance, and kidney function in the Third National Health and Nutrition Examination Survey. Kidney Int 2007; 71 (2) 134-139
    CrossrefPubMedGoogle Scholar
  • 44 Tarcin O, Yavuz DG, Ozben B , et al. Effect of vitamin D deficiency and replacement on endothelial function in asymptomatic subjects. J Clin Endocrinol Metab 2009; 94 (10) 4023-4030
    CrossrefPubMedGoogle Scholar
  • 45 Al Mheid I, Patel R, Murrow J , et al. Vitamin D status is associated with arterial stiffness and vascular dysfunction in healthy humans. J Am Coll Cardiol 2011; 58 (2) 186-192
    CrossrefPubMedGoogle Scholar
  • 46 Watson KE, Abrolat ML, Malone LL , et al. Active serum vitamin D levels are inversely correlated with coronary calcification. Circulation 1997; 96 (6) 1755-1760
    CrossrefPubMedGoogle Scholar
  • 47 Doherty TM, Tang W, Dascalos S , et al. Ethnic origin and serum levels of 1alpha,25-dihydroxyvitamin D3 are independent predictors of coronary calcium mass measured by electron-beam computed tomography. Circulation 1997; 96 (5) 1477-1481
    CrossrefPubMedGoogle Scholar
  • 48 de Boer IH, Kestenbaum B, Shoben AB, Michos ED, Sarnak MJ, Siscovick DS. 25-hydroxyvitamin D levels inversely associate with risk for developing coronary artery calcification. J Am Soc Nephrol 2009; 20 (8) 1805-1812
    CrossrefPubMedGoogle Scholar
  • 49 Targher G, Bertolini L, Padovani R , et al. Serum 25-hydroxyvitamin D3 concentrations and carotid artery intima-media thickness among type 2 diabetic patients. Clin Endocrinol (Oxf) 2006; 65 (5) 593-597
    CrossrefPubMedGoogle Scholar
  • 50 Kendrick J, Targher G, Smits G, Chonchol M. 25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey. Atherosclerosis 2009; 205 (1) 255-260
    CrossrefPubMedGoogle Scholar
  • 51 Melamed ML, Muntner P, Michos ED , et al. Serum 25-hydroxyvitamin D levels and the prevalence of peripheral arterial disease: results from NHANES 2001 to 2004. Arterioscler Thromb Vasc Biol 2008; 28 (6) 1179-1185
    CrossrefPubMedGoogle Scholar
  • 52 Giovannucci E, Liu Y, Hollis BW, Rimm EB. 25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med 2008; 168 (11) 1174-1180
    CrossrefPubMedGoogle Scholar
  • 53 Dobnig H, Pilz S, Scharnagl H , et al. Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Arch Intern Med 2008; 168 (12) 1340-1349
    CrossrefPubMedGoogle Scholar
  • 54 Wang TJ, Pencina MJ, Booth SL , et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation 2008; 117 (4) 503-511
    CrossrefPubMedGoogle Scholar
  • 55 Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med 2008; 168 (15) 1629-1637
    CrossrefPubMedGoogle Scholar
  • 56 Kilkkinen A, Knekt P, Aro A , et al. Vitamin D status and the risk of cardiovascular disease death. Am J Epidemiol 2009; 170 (8) 1032-1039
    CrossrefPubMedGoogle Scholar
  • 57 Pilz S, März W, Wellnitz B , et al. Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography. J Clin Endocrinol Metab 2008; 93 (10) 3927-3935
    CrossrefPubMedGoogle Scholar
  • 58 Pilz S, Dobnig H, Nijpels G , et al. Vitamin D and mortality in older men and women. Clin Endocrinol (Oxf) 2009; 71 (5) 666-672
    CrossrefPubMedGoogle Scholar
  • 59 Ginde AA, Scragg R, Schwartz RS, Camargo Jr CA. Prospective study of serum 25-hydroxyvitamin D level, cardiovascular disease mortality, and all-cause mortality in older U.S. adults. J Am Geriatr Soc 2009; 57 (9) 1595-1603
    CrossrefPubMedGoogle Scholar
  • 60 Sun Q, Shi L, Rimm EB , et al. Vitamin D intake and risk of cardiovascular disease in US men and women. Am J Clin Nutr 2011; 94 (2) 534-542
    CrossrefPubMedGoogle Scholar
  • 61 Pittas AG, Chung M, Trikalinos T , et al. Systematic review: vitamin D and cardiometabolic outcomes. Ann Intern Med 2010; 152 (5) 307-314
    CrossrefPubMedGoogle Scholar
  • 62 Grandi NC, Breitling LP, Brenner H. Vitamin D and cardiovascular disease: systematic review and meta-analysis of prospective studies. Prev Med 2010; 51 (3-4) 228-233
    CrossrefPubMedGoogle Scholar
  • 63 Chonchol M, Kendrick J, Targher G. Extra-skeletal effects of vitamin D deficiency in chronic kidney disease. Ann Med 2011; 43 (4) 273-282
    CrossrefPubMedGoogle Scholar
  • 64 Wang L, Manson JE, Song Y, Sesso HD. Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med 2010; 152 (5) 315-323
    CrossrefPubMedGoogle Scholar
  • 65 Holick MF, Binkley NC, Bischoff-Ferrari HA , et al; Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011; 96 (7) 1911-1930
    CrossrefPubMedGoogle Scholar
  • 66 Niramitmahapanya S, Harris SS, Dawson-Hughes B. Type of dietary fat is associated with the 25-hydroxyvitamin D3 increment in response to vitamin D supplementation. J Clin Endocrinol Metab 2011; 96 (10) 3170-3174
    CrossrefPubMedGoogle Scholar