Abstract
Vitamin K antagonist oral anticoagulants (VKAs) have been proven over 50 years to
be highly effective and acceptably safe in many settings and are still used by millions
of people worldwide.
The main concern about the safety of VKAs regards the risk of bleeding, but there
is accumulation evidence of their potentially negative effects beyond hemostasis.
Indeed, VKAs impair the action of several Vitamin-K Dependent Proteins (VKDP), such
as Bone Gla protein, Matrix Gla protein, Gas6 Protein, Periostin and Gla-Ric Protein,
involved in bone and vascular metabolism, thus exerting a detrimental effect on bone
and vascular health.
Indeed, although the evidence regarding this issue is not compelling, it has been
shown that VKAs use decreases bone mass density, increases the risk of bone fractures
and accelerates the process of vascular and valvular calcification.
Vascular calcification is a major concern in Chronic Kidney Disease (CKD) patients,
also in absence of VKAs, because of mineral metabolism derangement, chronic inflammation
and oxidative stress.
Direct Oral AntiCoagulants (DOACs) do not affect VKDP involved in vascular and valvular
calcification, and do not induce calcific valve degeneration in animal models, being
a possible alternative to AVK for CKD patients. However, the efficacy and safety of
DOACs in this population, suggested by some recent observations, requires confirmation
by dedicated, randomized study.
We reviewed here the effects of VKAs in bone and vascular health as compared to DOACs,
in order to provide the physicians with some data useful to wisely choose the most
suitable anticoagulant for every patient.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to European Journal of Internal MedicineAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Fifty years of research on antithrombotic therapy: achievements and disappointments.Eur J Intern Med. 2019; 70 (Epub 2019 Nov 1): 1-7https://doi.org/10.1016/j.ejim.2019.10.023
- Oral anticoagulant therapy. antithrombotic therapy and prevention of thrombosis, 9th ed: american college of chest physicians evidence-based clinical practice guidelines.Chest. 2012; 141 (e44S–e88S)
- Anticoagulant Utilization and direct oral anticoagulant prescribing in patients with nonvalvular atrial fibrillation.Can J Hosp Pharm. 2019; 72: 428-434
- Direct oral anticoagulants versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with chronic kidney disease.Cochrane Database Syst Rev. 2017; 11CD011373
- Role of direct oral anticoagulants in patients with kidney disease.Kidney Int. 2019; ([Epub ahead of print])
- Safety and efficacy of direct oral anticoagulants versus warfarin in patients with chronic kidney disease and atrial fibrillation.Am J Cardiol. 2020; 125: 210-214
- Vitamin K effects in human health: new insights beyond bone and cardiovascular health.J Nephrol. 2019; https://doi.org/10.1007/s40620-019-00685-0
- Vitamin K-dependent proteins involved in bone and cardiovascular health (Review).Mol Med Rep. 2018; 18: 3-15
- The effect of Gla-containing proteins on the precipitation of insoluble salts.Biochem Biophys Res Commun. 1987; 142: 113-119
- Increased bone formation in osteocalcin deficient mice.Nature. 1996; 382: 448-452
- Origin of the bone gamma-carboxyglutamic acid-containing protein found in plasma and its clearance by kidney and bone.J Biol Chem. 1981; 256: 12760-12766
- Development of arterial calcification in adiponectin-deficient mice: adiponectin regulates arterial calcification.J Bone Miner Res. 2009; 2: 1461-1468
- Matrix Gla protein: the calcification inhibitor in need of vitamin K.Thromb Haemost. 2008; 100: 593-603
- Vascular calcification, vitamin k and warfarin therapy – possible or plausible connection?.Basic Clin Pharmacol Toxicol. 2018; 122: 19-24
- CM. Smooth muscle cells give rise to osteochondrogenic precursors and chondrocytes in calcifying arteries.Circ Res. 2009; 104: 733-741
- Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein.Nature. 1997; 386: 78-81
- Mutations in the gene encoding the human matrix Gla protein cause Keutel syndrome.Nat Genet. 1999; 21: 142-144
- Unexpected role of matrix Gla protein in osteoclasts: inhibiting osteoclast differentiation and bone resorption.Mol Cell Biol. 2019; (pii: e00012-19): 39
- Congenital malformations associated with the administration of oral anticoagulants during pregnancy.J Pediatr. 1975; 86: 459-462
- Fetotoxicity of warfarin anticoagulation.Arch Gynecol Obstet. 2010; 282: 335-337
- Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves.Arterioscler. Thromb. Vasc. Biol. 1998; 18: 1400-1407
- Warfarin induces cardiovascular damage in mice.Arterioscler. Thromb. Vasc. Biol. 2013; 33: 2618-2624
- Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats.Blood. 2007; 109: 2823-2831
- The protein encoded by a growth arrest specific gene (gas6) is a new member of the vitamin K-dependent proteins related to protein S, a negative coregulator in the blood coagulation cascade.Mol Cell Biol. 1993; 13: 4976-4985
- Structural basis for Gas6-Axl signalling.EMBO J. 2006; 25: 80-87
- Molecular insights of Gas6/TAM in cancer development and therapy.Cell Death Dis. 2017; 8: e2700
- Axl and growth arrest-specific gene 6 are frequently overexpressed in human gliomas and predict poor prognosis in patients with glioblastoma multiforme.Clin Cancer Res. 2008; 14: 130-138
- Gas6/Axl mediates tumor cell apoptosis, migration and invasion and predicts the clinical outcome of osteosarcoma patients.Biochem Biophys Res Commun. 2013; 435: 493-500
- Statins protect human aortic smooth muscle cells from inorganic phosphate-induced calcification by restoring Gas6-Axl survival pathway.Circ Res. 2006; 98: 1024-1031
- Periostin regulates collagen fibrillogenesis and the biomechanical properties of connective tissues.J Cell Biochem. 2007; 101: 695-711
- The many facets of the matricelluar protein periostin during cardiac development, remodeling, and pathophysiology.J Cell Commun Signal. 2009; 3: 275-286
- Expression of periostin in patients with non-small cell lung cancer: correlation with angiogenesis and lymphangiogenesis.Int J Biol Mark. 2008; 23: 182-186
- Prognostic value of periostin in early-stage breast cancer treated with conserving surgery and radiotherapy.Oncol Lett. 2018; 15: 8072-8078
- Gla-rich protein is a novel vitamin K-dependent protein present in serum that accumulates at sites of pathological calcifications.Am J Pathol. 2009; 175: 2288-2298
- Gla-rich protein (GRP) acts as a calcification inhibitor in the human cardiovascular system.Arterioscler Thromb Vasc Biol. 2015; 35: 399-408
- Insights into the association of Gla-rich protein and osteoarthritis, novel splice variants and γ-carboxylation status.Mol Nutr Food Res. 2014; 58: 1636-1646
- Gla-rich protein is involved in the cross-talk between calcification and inflammation.Cell Mol Life Sci. 2016; 73: 1051-1065
- Oral anticoagulant drugs and the risk of osteoporosis: new anticoagulants better than old?.Semin. Thromb. Hemost. 2015; 41: 382-388
- Therapeutic warfarin use and the extrahepatic functions of vitamin K-dependent proteins.Br J Biomed Sci. 2017; 74: 163-169
- Effects of warfarin on biological processes other than haemostasis: a review.Food Chem Toxicol. 2018; 113: 19-32
- Anticoagulants and osteoporosis.Int J Mol Sci. 2019; 20: 5275
- Study of osteoporotic fractures research group. Warfarin use and risk for osteoporosis in elderly women.Ann Intern Med. 1998; 128: 829-832
- Long-term use of oral anticoagulants and the risk of fracture.Arch Intern Med. 1999; 159: 1750-1756
- Changes in bone density after exposure to oral anticoagulants: a meta-analysis.Osteoporos Int. 1999; 9: 441-448
- Oral anticoagulants and the risk of osteoporotic fractures among elderly.Pharmacoepidemiol Drug Saf. 2004; 13: 289-294
- Reduced bone density in children on long-term warfarin.Pediatr Res. 2005; 57: 578-581
- Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2.Arch Intern Med. 2006; 166: 241-246
- Single-point assessment of warfarin use and risk of osteoporosis in elderly men.J Am Geriatr Soc. 2008; 56: 1171-1176
- Aronis S assessment of bone mineral density and markers of bone turnover in children under long-term oral anticoagulant therapy.J Pediatr Hematol Oncol. 2008; 30: 592-597https://doi.org/10.1097/MPH.0b013e31817541a8
- Reduced bone density in patients on long-term warfarin.Int J Rheum Dis. 2009; 12: 130-135
- Vitamin K antagonists’ use and fracture risk: results from a systematic review and meta-analysis.J Thromb Haemost. 2015; 13: 1665-1675
- Edoxaban versus warfarin in atrial fibrillation patients at risk of falling: ENGAGE AF-TIMI 48 Analysis.J Am Coll Cardiol. 2016; 68: 1169-1178
- Association between dabigatran vs warfarin and risk of osteoporotic fractures among patients with nonvalvular atrial fibrillation.JAMA. 2017; 317: 1151-1158
- Non-vitamin K antagonist oral anticoagulants vs. Warfarin at risk of fractures: a systematic review and meta-analysis of randomized controlled trials.Front Pharmacol. 2018; 9: 348
- Osteoporotic fractures in patients with atrial fibrillation treated with conventional versus direct anticoagulants.J Am Coll Cardiol. 2019; 74 (2150–8. Adv Chronic Kidney Dis. 2019; 26:437-444)
- Association of anticoagulant therapy with risk of fracture among patients with atrial fibrillation.JAMA Intern Med. 2019; https://doi.org/10.1001/jamainternmed.2019.5679
- Risk of osteoporosis in patients with atrial fibrillation using non–vitamin k antagonist oral anticoagulants or warfarin.J Am Heart Assoc. 2020; 9e013845
- Fracture risks among patients with atrial fibrillation receiving different oral anticoagulants: a real-world nationwide cohort study.Eur Heart J. 2020; 41: 1100-1108
- Vitamin K antagonists and osteoporotic fractures: insights from comparisons with the NOACs.Eur Heart J. 2020; 41: 1109-1110
- Vascular calcification: the price to pay for anticoagulation therapy with vitamin K-antagonists.Blood Rev. 2012; 26: 155-166
- Warfarin and vascular calcification.Am J Med. 2016; 129 (e1-635.e4): 635
- The role of vitamin K in vascular calcification.Adv Chronic Kidney Dis. 2019; 26: 437-444
- Oral anticoagulant treatment: friend or foe in cardiovascular disease?.Blood. 2004; 104: 3231-3232
- Relation of oral anticoagulation to cardiac valvular and coronary calcium assessed by multislice spiral computed tomography.Am J Cardiol. 2005; 96: 747-749
- Warfarin and aortic valve calcification in hemodialysis patients.J Nephrol. 2007; 20: 417-422
- Relation of circulating Matrix Gla-Protein and anticoagulation status in patients with aortic valve calcification.Thromb Haemost. 2009; 101: 706-713
- Warfarin use and the risk of valvular calcification.J Thromb Haemost. 2009; 7: 2023-2027
- Does prolonged warfarin exposure potentiate coronary calcification in humans? Results of the Warfarin and Coronary Calcification Study.Calcif Tissue Int. 2009; 85: 494-500
- Chronic coumarin treatment is associated with increased extracoronary arterial calcification in humans.Blood. 2010; 115: 5121-5123
- Patients using vitamin K antagonists show increased levels of coronary calcification: an observational study in low-risk atrial fibrillation patients.Eur Heart J. 2011; 32: 2555-2562
- Effects of vitamin K antagonist on aortic valve degeneration in non-valvular atrial fibrillation patients: prospective 4-year observational study.Thrombosis Research. 2017; 160: 69-75
- Apixaban versus warfarin in evaluation of progression of atherosclerotic and calcified plaques (prospective randomized trial).Am Heart J. 2019; 212: 129-133
- Cardiac valve calcification and use of anticoagulants: preliminary observation of a potentially modifiable risk factor.Int J Cardiol. 2019; 278: 243-249
- On behalf of the SAM group. Intracranial calcifications under vitamin K antagonists or direct oral anticoagulants: results from the French VIKING study in older adults.Maturitas. 2020; 132: 35-39
- Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients.Kidney Int. 2007; 71: 438-441
- Interaction of vascular and bone disease in patients with normal renal function and patients undergoing dialysis.Nat Clin Pract Cardiovasc Med. 2007; 4: 26-33
- Cardiovascular calcification: the emerging role of micronutrients.Atherosclerosis. 2018; 273: 119-121
- Calciphylaxis in man. A syndrome of tissue necrosis and vascular calcification in 11 patients with chronic renal failure.Arch Intern Med. 1976; 136: 1273-1280
- Calciphylaxis: a still unmet challenge.J Nephrol. 2011; 24: 142-148
- Risk factors and mortality associated with calciphylaxis in end-stage renal disease.Kidney Int. 2001; 60: 324-332
- Calciphylaxis from nonuremic causes: a systematic review.Clin J Am Soc Nephrol. 2008; 3: 1139-1143
- Non-uremic Calciphylaxis: a rare and late adverse reaction of warfarin.Curr Drug Saf. 2019; 14: 246-248
- Warfarin, but not rivaroxaban, promotes the calcification of the aortic valve in ApoE-/- mice.Cardiovasc Ther. 2018; 36: e12438
- Roles of coagulation proteases and PARs (Protease-Activated Receptors) in mouse models of inflammatory diseases.Arterioscler Thromb Vasc Biol. 2019; 39: 13-24
- Clinical practice guideline for the evaluation and management of chronic kidney disease.Kidney Int. Suppl. 2012; 3 (2013): 19-62
- Direct oral anticoagulants versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with chronic kidney disease.Cochrane Database Syst Rev. 2017; 11CD011373
- Safety outcomes of apixaban compared with warfarin in patients with end-stage renal disease.Ann Pharmacother. 2017; 51: 445-450
- Comparison of the safety and effectiveness of apixaban versus warfarin in patients with severe renal impairment.Pharmacotherapy. 2017; 37: 412-419
- Outcomes associated with apixaban use in patients with end-stage kidney disease and atrial fibrillation in the United States.Circulation. 2018; 138: 1519-1529
- Safety and efficacy of apixaban versus warfarin in patients with advanced chronic kidney disease.Ann Pharmacother. 2018; 52: 1078-1084
- Rivaroxaban versus warfarin in patients with nonvalvular atrial fibrillation and severe kidney disease or undergoing hemodialysis.Am J Med. 2019; 132: 1078-1083
- Oral anticoagulation for patients with atrial fibrillation on long-term hemodialysis.J Am Coll Cardiol. 2020; 75: 273-285
- Efficacy and safety of oral anticoagulants in patients with atrial fibrillation and stages 4 or 5 chronic kidney disease.Am J Med. 2019; 132: 1335-1343
- Safety and efficacy of direct oral anticoagulants versus warfarin in patients with chronic kidney disease and atrial fibrillation.Am J Cardiol. 2020; 125: 210-214https://doi.org/10.1016/j.amjcard.2019.10.033
- Apixaban versus warfarin in patients with atrial fibrillation and advanced chronic kidney disease.Circulation. 2020; ([Epub ahead of print])https://doi.org/10.1161/CIRCULATIONAHA.119.044059
Article info
Publication history
Published online: June 15, 2020
Accepted:
May 21,
2020
Received in revised form:
May 1,
2020
Received:
April 1,
2020
Identification
Copyright
© 2020 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
