Antiprothrombin Antibodies

  • Polona Žigon University Medical Centre Ljubljana, Department of Rheumatology
  • Aleš Ambrožič University Medical Centre Ljubljana, Department of Rheumatology
  • Borut Božič University of Ljubljana, Faculty of Pharmacy University Medical Centre Ljubljana, Department of Rheumatology
  • Saša Čučnik University Medical Centre Ljubljana, Department of Rheumatology
Keywords: antiphospholipid antibodies, antiphospholipid syndrome, anti-phosphatidylserine prothrombin antibodies, antiprothrombin antibodies, clinical utility, enzyme immunoassays, thrombosis,

Abstract

In patients with the antiphospholipid syndrome (APS), the presence of a group of pathogenic autoantibodies called antiphospholipid antibodies causes thrombosis and pregnancy complications. The most frequent antigenic target of antiphospholipid antibodies are phospholipid bound β2-glycoprotein 1 (β2GPI) and prothrombin. The international classification criteria for APS connect the occurrence of thrombosis and/or obstetric complications together with the persistence of lupus anticoagulant, anti-cardiolipin antibodies (aCL) and antibodies against β2GPI (anti-β2GPI) into APS. Current trends for the diagnostic evaluation of APS patients propose determination of multiple antiphospholipid antibodies, among them also anti-prothrombin antibodies, to gain a common score which estimates the risk for thrombosis in APS patients. Antiprothrombin antibodies are common in APS patients and are sometimes the only antiphospholipid antibodies being elevated. Methods for their determination differ and have not yet been standardized. Many novel studies confirmed method using phosphatidylserine/prothrombin (aPS/PT ELISA) as an antigen on solid phase encompass higher diagnostic accuracy compared to method using prothrombin alone (aPT ELISA). Our research group developed an in-house aPS/PT ELISA with increased analytical sensitivity which enables the determination of all clinically relevant antiprothrombin antibodies. aPS/PT exhibited the highest percentage of lupus anticoagulant activity compared to aCL and anti-β2GPI. aPS/PT antibodies measured with the in-house method associated with venous thrombosis and presented the strongest independent risk factor for the presence of obstetric complications among all tested antiphospholipid antibodies.

 

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References

Roubey RA. Autoantibodies to phospholipid-binding plasma proteins: a new view of lupus anticoagulants and other "antiphospholipid" autoantibodies. Blood. 1994; 84(9): 2854-67.

Galli M, Comfurius P, Maassen C, Hemker HC, de Baets MH, van Breda-Vriesman PJ, et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet. 1990; 335(8705): 1544-7.

Matsuura E, Igarashi Y, Fujimoto M, Ichikawa K, Koike T. Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease. Lancet. 1990; 336(8708): 177-8.

McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein I (apolipoprotein H). ProcNatlAcadSciUSA. 1990; 87(11): 4120-4.

Bevers EM, Galli M, Barbui T, Comfurius P, Zwaal RF. Lupus anticoagulant IgG's (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin. ThrombHaemost. 1991; 66(6): 629-32.

Hughes GR. Thrombosis, abortion, cerebral disease, and the lupus anticoagulant. BrMedJ(ClinResEd). 1983; 287(6399): 1088-9.

Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). JThrombHaemost. 2006; 4(2): 295-306.

Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum. 1999; 42(7): 1309-11.

Otomo K, Atsumi T, Amengual O, Fujieda Y, Kato M, Oku K, et al. Efficacy of the antiphospholipid score for the diagnosis of antiphospholipid syndrome and its predictive value for thrombotic events. Arthritis and rheumatism. 2012; 64(2): 504-12. Epub 2011/09/29.

Sciascia S, Sanna G, Murru V, Roccatello D, Khamashta MA, Bertolaccini ML. GAPSS: the Global Anti-Phospholipid Syndrome Score. Rheumatology (Oxford). 2013; 52(8): 1397-403. Epub 2013/01/15.

Degen SJ, Davie EW. Nucleotide sequence of the gene for human prothrombin. Biochemistry. 1987; 26(19): 6165-77.

Shapiro SS, Martinez J. Human prothrombin metabolism in normal man and in hypocoagulable subjects. The Journal of clinical investigation. 1969; 48(7): 1292-8. Epub 1969/07/01.

Mann KG, Nesheim ME, Church WR, Haley P, Krishnaswamy S. Surface-dependent reactions of the vitamin K-dependent enzyme complexes. Blood. 1990; 76(1): 1-16. Epub 1990/07/01.

Bajaj SP, Rapaport SI, Barclay S, Herbst KD. Acquired hypoprothrombinemia due to non-neutralizing antibodies to prothrombin: mechanism and management. Blood. 1985; 65(6): 1538-43.

Edson JR, Vogt JM, Hasegawa DK. Abnormal prothrombin crossed-immunoelectrophoresis in patients with lupus inhibitors. Blood. 1984; 64(4): 807-16.

Fleck RA, Rapaport SI, Rao LV. Anti-prothrombin antibodies and the lupus anticoagulant. Blood. 1988; 72(2): 512-9.

Oosting JD, Derksen RH, Bobbink IW, Hackeng TM, Bouma BN, De Groot PG. Antiphospholipid antibodies directed against a combination of phospholipids with prothrombin, protein C, or protein S: an explanation for their pathogenic mechanism? Blood. 1993; 81(10): 2618-25.

Permpikul P, Rao LV, Rapaport SI. Functional and binding studies of the roles of prothrombin and beta 2-glycoprotein I in the expression of lupus anticoagulant activity. Blood. 1994; 83(10): 2878-92. Epub 1994/05/15.

Bajaj SP, Rapaport SI, Fierer DS, Herbst KD, Schwartz DB. A mechanism for the hypoprothrombinemia of the acquired hypoprothrombinemia-lupus anticoagulant syndrome. Blood. 1983; 61(4): 684-92. Epub 1983/04/01.

Galli M, Bevers EM, Comfurius P, Barbui T, Zwaal RF. Effect of antiphospholipid antibodies on procoagulant activity of activated platelets and platelet-derived microvesicles. BrJHaematol. 1993; 83(3): 466-72.

Arvieux J, Darnige L, Caron C, Reber G, Bensa JC, Colomb MG. Development of an ELISA for autoantibodies to prothrombin showing their prevalence in patients with lupus anticoagulants. ThrombHaemost. 1995; 74(4): 1120-5.

Galli M, Barbui T. Antiprothrombin antibodies: detection and clinical significance in the antiphospholipid syndrome. Blood. 1999; 93(7): 2149-57.

Matsuura E, Igarashi Y, Yasuda T, Triplett DA, Koike T. Anticardiolipin antibodies recognize beta 2-glycoprotein I structure altered by interacting with an oxygen modified solid phase surface. JExpMed. 1994; 179(2): 457-62.

Pengo V, Biasiolo A, Fior MG. Autoimmune antiphospholipid antibodies are directed against a cryptic epitope expressed when beta 2-glycoprotein I is bound to a suitable surface. ThrombHaemost. 1995; 73(1): 29-34.

Cucnik S, Kveder T, Rozman B, Bozic B. Binding of high-avidity anti-beta2-glycoprotein I antibodies. Rheumatology (Oxford). 2004; 43(11): 1353-6. Epub 2004/07/29.

Matsuda J, Saitoh N, Gotoh M, Kawasugi K, Gohchi K, Tsukamoto M. Phosphatidyl serine-dependent antiprothrombin antibody is exclusive to patients with lupus anticoagulant. BrJRheumatol. 1996; 35(6): 589-91.

Galli M, Beretta G, Daldossi M, Bevers EM, Barbui T. Different anticoagulant and immunological properties of anti-prothrombin antibodies in patients with antiphospholipid antibodies. ThrombHaemost. 1997; 77(3): 486-91.

Atsumi T, Ieko M, Bertolaccini ML, Ichikawa K, Tsutsumi A, Matsuura E, et al. Association of autoantibodies against the phosphatidylserine-prothrombin complex with manifestations of the antiphospholipid syndrome and with the presence of lupus anticoagulant. Arthritis Rheum. 2000; 43(9): 1982-93.

Zigon P, Ambrozic A, Cucnik S, Kveder T, Rozman B, Bozic B. Modified phosphatidylserine-dependent antiprothrombin ELISA enables identification of patients negative for other antiphospholipid antibodies and also detects low avidity antibodies. Clin Chem Lab Med. 2011; 49(9): 1573.

Pierangeli SS, Goldsmith GH, Branch DW, Harris EN. Antiphospholipid antibody: functional specificity for inhibition of prothrombin activation by the prothrombinase complex. BrJHaematol. 1997; 97(4): 768-74.

Simmelink MJ, Horbach DA, Derksen RH, Meijers JC, Bevers EM, Willems GM, et al. Complexes of anti-prothrombin antibodies and prothrombin cause lupus anticoagulant activity by competing with the binding of clotting factors for catalytic phospholipid surfaces. BrJHaematol. 2001; 113(3): 621-9.

Amengual O, Atsumi T, Koike T. Specificities, properties, and clinical significance of antiprothrombin antibodies. Arthritis Rheum. 2003; 48(4): 886-95.

Horbach DA, van OE, Derksen RH, De Groot PG. The contribution of anti-prothrombin-antibodies to lupus anticoagulant activity--discrimination between functional and non-functional anti-prothrombin-antibodies. ThrombHaemost. 1998; 79(4): 790-5.

Puurunen M, Palosuo T, Lassila R, Anttila M, Vaarala O. Immunologic and hematologic properties of antibodies to prothrombin and plasminogen in a mouse model. Lupus. 2001; 10(2): 108-15. Epub 2001/03/10.

Wu JR, Lentz BR. Phospholipid-specific conformational changes in human prothrombin upon binding to procoagulant acidic lipid membranes. ThrombHaemost. 1994; 71(5): 596-604.

Cakir B, Rivadeneira AC, Hayes PM, Ortel TL, Petri M, Roubey RA. Anti-prothrombin autoantibodies: detection and characterization. Lupus. 1998; 7(2): S219-S.

Field SL, Chesterman CN, Dai YP, Hogg PJ. Lupus antibody bivalency is required to enhance prothrombin binding to phospholipid. J Immunol. 2001; 166(10): 6118-25. Epub 2001/05/09.

Zigon P, Cucnik S, Ambrozic A, Sodin Semrl S, Kveder T, Bozic B. Antibodies to phosphatidylserine/prothrombin complex as an additional diagnostic marker of APS? Lupus. 2012; 21(7): 790-2. Epub 2012/05/29.

Willems GM, Janssen MP, Comfurius P, Galli M, Zwaal RF, Bevers EM. Kinetics of prothrombin-mediated binding of lupus anticoagulant antibodies to phosphatidylserine-containing phospholipid membranes: an ellipsometric study. Biochemistry. 2002; 41(48): 14357-63.

Galli M. Anti-Prothrombin Antibodies. In: Asherson RA, Cervera R, Piette JC, Shoenfeld Y, editors. The Antiphospholipid Syndrome II: Elsevier; 2002. p. 59-70.

Rao LV, Hoang AD, Rapaport SI. Mechanism and effects of the binding of lupus anticoagulant IgG and prothrombin to surface phospholipid. Blood. 1996; 88(11): 4173-82.

Akimoto T, Akama T, Kono I, Sumida T. Relationship between clinical features and binding domains of anti-prothrombin autoantibodies in patients with systemic lupus erythematosus and antiphospholipid syndrome. Lupus. 1999; 8(9): 761-6. Epub 1999/12/22.

Pengo V, Biasiolo A, Brocco T, Tonetto S, Ruffatti A. Autoantibodies to phospholipid-binding plasma proteins in patients with thrombosis and phospholipid-reactive antibodies. Thrombosis and haemostasis. 1996; 75(5): 721-4. Epub 1996/05/01.

Rao LV, Hoang AD, Rapaport SI. Differences in the interactions of lupus anticoagulant IgG with human prothrombin and bovine prothrombin. ThrombHaemost. 1995; 73(4): 668-74.

De Groot PG, Horbach DA, Simmelink MJ, van OE, Derksen RH. Anti-prothrombin antibodies and their relation with thrombosis and lupus anticoagulant. Lupus. 1998; 7 Suppl 2: S32-S6.

Sciascia S, Sanna G, Murru V, Roccatello D, Khamashta MA, Bertolaccini ML. Anti-prothrombin (aPT) and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies and the risk of thrombosis in the antiphospholipid syndrome. A systematic review. Thrombosis and haemostasis. 2013; 111(2). Epub 2013/11/01.

Tincani A, Morozzi G, Afeltra A, Alessandri C, Allegri F, Bistoni O, et al. Antiprothrombin antibodies: a comparative analysis of homemade and commercial methods. A collaborative study by the Forum Interdisciplinare per la Ricerca nelle Malattie Autoimmuni (FIRMA). ClinExpRheumatol. 2007; 25(2): 268-74.

Bardin N, Alessi MC, Dignat-George F, Vague IJ, Sampol J, Harle JR, et al. Does the anti-prothrombin antibodies measurement provide additional information in patients with thrombosis? Immunobiology. 2007; 212(7): 557-65.

Nojima J, Iwatani Y, Suehisa E, Kuratsune H, Kanakura Y. The presence of anti-phosphatidylserine/prothrombin antibodies as risk factor for both arterial and venous thrombosis in patients with systemic lupus erythematosus. Haematologica. 2006; 91(5): 699-702.

Tsutsumi A, Hayashi T, Chino Y, Mamura M, Goto D, Matsumoto I, et al. Significance of antiprothrombin antibodies in patients with systemic lupus erythematosus: clinical evaluation of the antiprothrombin assay and the antiphosphatidylserine/prothrombin assay, and comparison with other antiphospholipid antibody assays. ModRheumatol. 2006; 16(3): 158-64.

Zigon P, Cucnik S, Ambrozic A, Kveder T, Semrl SS, Rozman B, et al. Detection of Antiphosphatidylserine/Prothrombin Antibodies and Their Potential Diagnostic Value. Clinical and Developmental Immunology. 2013; 2013: 8.

Forastiero RR, Martinuzzo ME, Cerrato GS, Kordich LC, Carreras LO. Relationship of anti beta2-glycoprotein I and anti prothrombin antibodies to thrombosis and pregnancy loss in patients with antiphospholipid antibodies. ThrombHaemost. 1997; 78(3): 1008-14.

Sater MS, Finan RR, Abu-Hijleh FM, Abu-Hijleh TM, Almawi WY. Anti-phosphatidylserine, anti-cardiolipin, anti-beta2 glycoprotein I and anti-prothrombin antibodies in recurrent miscarriage at 8-12 gestational weeks. European journal of obstetrics, gynecology, and reproductive biology. 2012; 163(2): 170-4. Epub 2012/05/05.

Sugiura-Ogasawara M, Atsumi T, Ozaki Y, Koike T, Suzumori K. Phosphatidylserine-dependent antiprothrombin antibodies are not useful markers for high-risk women with recurrent miscarriages. FertilSteril. 2004; 82(5): 1440-2.

Tsutsumi A, Atsumi T, Yamada H, Hirayama KE, Ichikawa K, Fujimoto S, et al. Anti-phosphatidylserine/prothrombin antibodies are not frequently found in patients with unexplained recurrent miscarriages. AmJ ReprodImmunol. 2001; 46(3): 242-4.

Akimoto T, Akama T, Saitoh M, Kono I, Sumida T. Antiprothrombin autoantibodies in severe preeclampsia and abortion. The American journal of medicine. 2001; 110(3): 188-91. Epub 2001/02/22.

Bertolaccini ML, Atsumi T, Koike T, Hughes GR, Khamashta MA. Antiprothrombin antibodies detected in two different assay systems. Prevalence and clinical significance in systemic lupus erythematosus. ThrombHaemost. 2005; 93(2): 289-97.

Marozio L, Curti A, Botta G, Canuto EM, Salton L, Tavella AM, et al. Anti-Prothrombin Antibodies are Associated with Adverse Pregnancy Outcome. AmJ ReprodImmunol. 2011; %20. doi: 10.1111/j.1600-0897.2011.01031.x.: 10-0897.

Vlagea A, Gil A, Cuesta MV, Arribas F, Diez J, Lavilla P, et al. Antiphosphatidylserine/prothrombin antibodies (aPS/PT) as potential markers of antiphospholipid syndrome. Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2013; 19(3): 289-96. Epub 2012/03/06.

Abou-Nassar K, Carrier M, Ramsay T, Rodger MA. The association between antiphospholipid antibodies and placenta mediated complications: a systematic review and meta-analysis. Thrombosis research. 2011; 128(1): 77-85. Epub 2011/03/23.

Giannakopoulos B, Krilis SA. The pathogenesis of the antiphospholipid syndrome. The New England journal of medicine. 2013; 368(11): 1033-44. Epub 2013/03/15.

Mehdi AA, Uthman I, Khamashta M. Antiphospholipid syndrome: pathogenesis and a window of treatment opportunities in the future. European journal of clinical investigation. 2010; 40(5): 451-64. Epub 2010/03/30.

Meroni PL, Borghi MO, Raschi E, Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nature reviews Rheumatology. 2011; 7(6): 330-9. Epub 2011/05/11.

Oku K, Amengual O, Atsumi T. Pathophysiology of thrombosis and pregnancy morbidity in the antiphospholipid syndrome. European journal of clinical investigation. 2012; 42(10): 1126-35. Epub 2012/07/13.

Fischetti F, Durigutto P, Pellis V, Debeus A, Macor P, Bulla R, et al. Thrombus formation induced by antibodies to beta2-glycoprotein I is complement dependent and requires a priming factor. Blood. 2005; 106(7): 2340-6. Epub 2005/06/16.

Arnout J. The pathogenesis of the antiphospholipid syndrome: a hypothesis based on parallelisms with heparin-induced thrombocytopenia. ThrombHaemost. 1996; 75(4): 536-41.

Bohgaki M, Atsumi T, Yamashita Y, Yasuda S, Sakai Y, Furusaki A, et al. The p38 mitogen-activated protein kinase (MAPK) pathway mediates induction of the tissue factor gene in monocytes stimulated with human monoclonal anti-beta2Glycoprotein I antibodies. IntImmunol. 2004; 16(11): 1633-41.

Lopez-Pedrera C, Buendia P, Cuadrado MJ, Siendones E, Aguirre MA, Barbarroja N, et al. Antiphospholipid antibodies from patients with the antiphospholipid syndrome induce monocyte tissue factor expression through the simultaneous activation of NF-kappaB/Rel proteins via the p38 mitogen-activated protein kinase pathway, and of the MEK-1/ERK pathway. Arthritis and rheumatism. 2006; 54(1): 301-11. Epub 2005/12/31.

Vega-Ostertag M, Casper K, Swerlick R, Ferrara D, Harris EN, Pierangeli SS. Involvement of p38 MAPK in the up-regulation of tissue factor on endothelial cells by antiphospholipid antibodies. Arthritis and rheumatism. 2005; 52(5): 1545-54. Epub 2005/05/10.

Galli M, Daldossi M, Barbui T. Anti-glycoprotein Ib/IX and IIb/IIIa antibodies in patients with antiphospholipid antibodies. ThrombHaemost. 1994; 71(5): 571-5.

Field SL, Hogg PJ, Daly EB, Dai YP, Murray B, Owens D, et al. Lupus anticoagulants form immune complexes with prothrombin and phospholipid that can augment thrombin production in flow. Blood. 1999; 94(10): 3421-31.

Roubey RA. Immunology of the antiphospholipid antibody syndrome. Arthritis Rheum. 1996; 39(9): 1444-54.

Ferro D, Quintarelli C, Valesini G, Violi F. Lupus anticoagulant and increased thrombin generation in patients with systemic lupus erythematosus. Blood. 1994; 83(1): 304.

Musial J, Swadzba J, Jankowski M, Grzywacz M, Bazan-Socha S, Szczeklik A. Thrombin generation measured ex vivo following microvascular injury is increased in SLE patients with antiphospholipid-protein antibodies. ThrombHaemost. 1997; 78(4): 1173-7.

Pierangeli SS, Girardi G, Vega-Ostertag M, Liu X, Espinola RG, Salmon J. Requirement of activation of complement C3 and C5 for antiphospholipid antibody-mediated thrombophilia. Arthritis and rheumatism. 2005; 52(7): 2120-4. Epub 2005/06/30.

Romay-Penabad Z, Liu XX, Montiel-Manzano G, Papalardo De Martinez E, Pierangeli SS. C5a receptor-deficient mice are protected from thrombophilia and endothelial cell activation induced by some antiphospholipid antibodies. Annals of the New York Academy of Sciences. 2007; 1108: 554-66. Epub 2007/09/26.

Oku K, Atsumi T, Bohgaki M, Amengual O, Kataoka H, Horita T, et al. Complement activation in patients with primary antiphospholipid syndrome. Annals of the rheumatic diseases. 2009; 68(6): 1030-5. Epub 2008/07/16.

Simmelink MJ, De Groot PG, Derksen RH. A study on associations between antiprothrombin antibodies, antiplasminogen antibodies and thrombosis. Journal of thrombosis and haemostasis : JTH. 2003; 1(4): 735-9. Epub 2003/07/23.

Bu C, Li Z, Zhang C, Gao L, Cai G. IgG antibodies to plasminogen and their relationship to IgG anti-beta(2)-glycoprotein 1 antibodies and thrombosis. Clinical rheumatology. 2008; 27(2): 171-8. Epub 2007/07/25.

Kujovich JL. Thrombophilia and thrombotic problems in renal transplant patients. Transplantation. 2004; 77(7): 959-64. Epub 2004/04/17.

Blank M, Shoenfeld Y. Antiphospholipid antibody-mediated reproductive failure in antiphospholipid syndrome. Clinical reviews in allergy & immunology. 2010; 38(2-3): 141-7. Epub 2009/06/30.

Matalon ST, Shoenfeld Y, Blank M, Yacobi S, von Landenberg P, Ornoy A. Antiphosphatidylserine antibodies affect rat yolk sacs in culture: a mechanism for fetal loss in antiphospholipid syndrome. Am J Reprod Immunol. 2004; 51(2): 144-51. Epub 2004/01/30.

Sun WY, Witte DP, Degen JL, Colbert MC, Burkart MC, Holmback K, et al. Prothrombin deficiency results in embryonic and neonatal lethality in mice. Proceedings of the National Academy of Sciences of the United States of America. 1998; 95(13): 7597-602. Epub 1998/06/24.

Rand JH, Wu XX, Quinn AS, Taatjes DJ. The annexin A5-mediated pathogenic mechanism in the antiphospholipid syndrome: role in pregnancy losses and thrombosis. Lupus. 2010; 19(4): 460-9. Epub 2010/04/01.

Cervera R, Asherson RA. Diagnostic Criteria in Autoimmune Diseases. In: Shoenfeld Y, Cervera R, Gershwin ME, editors. Antiphospholipid syndrome. Totowa: Humana Press; 2008. p. 9-14.

Alijotas-Reig J. Treatment of refractory obstetric antiphospholipid syndrome: the state of the art and new trends in the therapeutic management. Lupus. 2013; 22(1): 6-17. Epub 2012/11/16.

Yang P, Kruh JN, Foster CS. Antiphospholipid antibody syndrome. Current opinion in ophthalmology. 2012; 23(6): 528-32. Epub 2012/10/09.

Bramham K, Hunt BJ, Germain S, Calatayud I, Khamashta M, Bewley S, et al. Pregnancy outcome in different clinical phenotypes of antiphospholipid syndrome. Lupus. 2010; 19(1): 58-64. Epub 2009/11/10.

Published
2015-05-05
How to Cite
1.
Žigon P, Ambrožič A, Božič B, Čučnik S. Antiprothrombin Antibodies. ZdravVestn [Internet]. 5May2015 [cited 18Apr.2019];84(3). Available from: https://vestnik.szd.si/index.php/ZdravVest/article/view/1103
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Review