Cardiovascular Disease in Antiphospholipid Syndrome

Author(s): Kali Polytarchou*, Dimitrios Varvarousis, Antonis S. Manolis

Journal Name: Current Vascular Pharmacology

Volume 18 , Issue 6 , 2020


Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by venous, arterial or microvascular thrombosis or obstetric events in the presence of persistently positive antiphospholipid antibodies and constitutes a major cause of cardiovascular events in young people. Τhis review highlights the pathophysiology of cardiovascular complications in patients with APS and possible treatment options.

Patients with APS have endothelial dysfunction, accelerated endothelial proliferation and intimal hyperplasia, atherogenesis, platelet activation, inflammatory products secretion and coagulation-fibrinolytic dysregulation. Cardiovascular complications include accelerated atherosclerosis, acute coronary syndrome, Libman-Sacks endocarditis, cardiomyopathy and venous, arterial or intracardiac thrombi. Moreover, pulmonary hypertension and peripheral microvascular dysfunction are common findings.

Management of these patients is not well documented. The role of primary thrombosis prevention remains controversial in individuals with positive antiphospholipid antibodies. Treatment of traditional cardiovascular risk factors according to current guidelines for the prevention of cardiovascular disease in the general population is recommended for primary prevention of APS. Anticoagulation therapy with unfractionated or low-molecular-weight heparin overlapped with a vitamin K antagonist remains the mainstay of the treatment for APS patients with venous thrombosis, whereas direct oral anticoagulants are not yet recommended. Data are scarce regarding the secondary arterial thrombosis prevention and it is not clear whether dual or triple antithrombotic therapy is necessary. To date, it is recommended to follow current guidelines for the management of acute coronary syndrome in the general population. New treatment targets are promising options for patients with catastrophic APS.

Keywords: Antiphospholipid syndrome, cardiovascular disease, acute coronary syndrome, acute myocardial infarction, thrombophilia, systemic lupus erythematosus, endothelial dysfunction, anticoagulation treatment.

[1]
Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4(2): 295-306.
[http://dx.doi.org/10.1111/j.1538-7836.2006.01753.x ] [PMID: 16420554]
[2]
Asherson RA, Cervera R, de Groot PG, et al. Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus 2003; 12(7): 530-4.
[http://dx.doi.org/10.1191/0961203303lu394oa ] [PMID: 12892393]
[3]
Garcia D, Erkan D. Diagnosis and Management of the Antiphospholipid Syndrome. N Engl J Med 2018; 378(21): 2010-21.
[http://dx.doi.org/10.1056/NEJMra1705454 ] [PMID: 29791828]
[4]
Oztürk MA, Haznedaroğlu IC, Turgut M, Göker H. Current debates in antiphospholipid syndrome: the acquired antibody-mediated thrombophilia. Clin Appl Thromb Hemost 2004; 10(2): 89-126.
[http://dx.doi.org/10.1177/107602960401000201 ] [PMID: 15094931]
[5]
Durcan L, Petri M. Epidemiology of the antiphospholipid syndrome. Cervera R, Espinosa, Khamashta MA (eds), Antiphospholipid syndrome in systemic autoimmune diseases, 2nd edition. Elsevier, Amsterdam 2016; pp. 17-30.
[6]
Corban MT, Duarte-Garcia A, McBane RD, Matteson EL, Lerman LO, Lerman A. Antiphospholipid syndrome: role of vascular endothelial cells and implications for risk stratification and targeted therapeutics. J Am Coll Cardiol 2017; 69(18): 2317-30.
[http://dx.doi.org/10.1016/j.jacc.2017.02.058 ] [PMID: 28473138]
[7]
Zuo Y, Barbhaiya M, Erkan D. Primary thrombosis prophylaxis in persistently antiphospholipid antibody-positive individuals: where do we stand in 2018? Curr Rheumatol Rep 2018; 20(11): 66.
[http://dx.doi.org/10.1007/s11926-018-0775-8 ] [PMID: 30203272]
[8]
Harper BE, Wills R, Pierangeli SS. Pathophysiological mechanisms in antiphospholipid syndrome. Int J Clin Rheumatol 2011; 6(2): 157-71.
[http://dx.doi.org/10.2217/ijr.11.9 ] [PMID: 23487578]
[9]
Cavazzana I, Andreoli L, Limper M, Franceschini F, Tincani A. Update on antiphospholipid syndrome: ten topics in 2017. Curr Rheumatol Rep 2018; 20(3): 15.
[http://dx.doi.org/10.1007/s11926-018-0718-4 ] [PMID: 29541874]
[10]
Cervera R. Antiphospholipid syndrome. Thromb Res 2017; 151(Suppl. 1): S43-7.
[http://dx.doi.org/10.1016/S0049-3848(17)30066-X ] [PMID: 28262233]
[11]
Kaul M, Erkan D, Sammaritano L, Lockshin MD. Assessment of the 2006 revised antiphospholipid syndrome classification criteria. Ann Rheum Dis 2007; 66(7): 927-30.
[http://dx.doi.org/10.1136/ard.2006.067314 ] [PMID: 17337473]
[12]
Kravvariti E, Konstantonis G, Tentolouris N, Sfikakis PP, Tektonidou MG. Carotid and femoral atherosclerosis in antiphospholipid syndrome: Equivalent risk with diabetes mellitus in a case-control study. Semin Arthritis Rheum 2018; 47(6): 883-9.
[http://dx.doi.org/10.1016/j.semarthrit.2017.10.015 ] [PMID: 29150207]
[13]
Caraiola S, Jurcut C, Dima A, Jurcut R, Baicus C, Baicus A. Impaired ankle-brachial index in antiphospholipid syndrome: Beyond the traditional risk factors. J Clin Lab Anal 2019; 33(1): e22617.
[http://dx.doi.org/10.1002/jcla.22617 ] [PMID: 29992646]
[14]
Di Minno MND, Scalera A, Tufano A, et al. The association of adjusted global antiphos pholipid syndrome score (aGAPSS) with cardiovascular disease in subjects with antiphospholipid antibodies. Atherosclerosis 2018; 278: 60-5.
[http://dx.doi.org/10.1016/j.atherosclerosis.2018.09.010 ] [PMID: 30253290]
[15]
Cervera R, Piette JC, Font J, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002; 46(4): 1019-27.
[http://dx.doi.org/10.1002/art.10187 ] [PMID: 11953980]
[16]
Asanuma Y, Oeser A, Shintani AK, et al. Premature coronary-artery atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003; 349(25): 2407-15.
[http://dx.doi.org/10.1056/NEJMoa035611 ] [PMID: 14681506]
[17]
Di Minno MND, Emmi G, Ambrosino P, et al. Subclinical atherosclerosis in asymptomatic carriers of persistent antiphospholipid antibodies positivity: A cross-sectional study. Int J Cardiol 2019; 274: 1-6.
[http://dx.doi.org/10.1016/j.ijcard.2018.06.010 ] [PMID: 30454720]
[18]
Tamis-Holland JE, Jneid H, Reynolds HR, et al. Contemporary diagnosis and management of patients with myocardial infarction in the absence of obstructive coronary artery disease: a scientific statement from the American heart association. Circulation 2019; 139(18): e891-908.
[http://dx.doi.org/10.1161/CIR.0000000000000670 ] [PMID: 30913893]
[19]
Manolis AS, Manolis AA, Manolis TA, Melita H. Acute coronary syndromes in patients with angiographicaly normal or near normal (non-obstructive) coronary arteries. Trends Cardiovasc Med 2018; 28(8): 541-51.
[http://dx.doi.org/10.1016/j.tcm.2018.05.006 ] [PMID: 29859655]
[20]
Geller BJ, Mega JL, Morrow DA, et al. Autoantibodies to phosphorylcholine and cardiovascular outcomes in patients with acute coronary syndromes in the ATLAS ACS-TIMI 46 trial. J Thromb Thrombolysis 2014; 37(3): 310-6.
[http://dx.doi.org/10.1007/s11239-013-0968-y ] [PMID: 23860881]
[21]
Bundhun PK, Boodhoo KD, Long MY, Chen MH. Impact of antiphospholipid syndrome and/or systemic lupus erythematosus on the long-term adverse cardiovascular outcomes in patients after percutaneous coronary intervention: a systematic review and meta-analysis. Medicine (Baltimore) 2016; 95(12): e3200.
[http://dx.doi.org/10.1097/MD.0000000000003200 ] [PMID: 27015221]
[22]
Nazir S, Tachamo N, Lohani S, Hingorani R, Poudel DR, Donato A. Acute myocardial infarction and antiphospholipid antibody syndrome: a systematic review. Coron Artery Dis 2017; 28(4): 332-5.
[http://dx.doi.org/10.1097/MCA.0000000000000476 ] [PMID: 28225386]
[23]
Watad A, Tiosano S, Grysman N, et al. The association between systemic lupus erythematosus and valvular heart disease: an extensive data analysis. Eur J Clin Invest 2017; 47(5): 366-71.
[http://dx.doi.org/10.1111/eci.12744 ] [PMID: 28295225]
[24]
Turiel M, Sarzi-Puttini P, Peretti R, et al. Five-year follow-up by transesophageal echocardiographic studies in primary antiphospholipid syndrome. Am J Cardiol 2005; 96(4): 574-9.
[http://dx.doi.org/10.1016/j.amjcard.2005.04.022 ] [PMID: 16098314]
[25]
Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC guidelines for the management of infective endocarditis: The task force for the management of infective endocarditis of the European society of cardiology (ESC). Endorsed by: European association for cardio-thoracic surgery (EACTS), the European association of nuclear medicine (EANM). Eur Heart J 2015; 36(44): 3075-128.
[http://dx.doi.org/10.1093/eurheartj/ehv319 ] [PMID: 26320109]
[26]
Galve E, Ordi J, Barquinero J, Evangelista A, Vilardell M, Soler-Soler J. Valvular heart disease in the primary antiphospholipid syndrome. Ann Intern Med 1992; 116(4): 293-8.
[http://dx.doi.org/10.7326/0003-4819-116-4-293 ] [PMID: 1733383]
[27]
Tektonidou MG, Ioannidis JP, Moyssakis I, et al. Right ventricular diastolic dysfunction in patients with anticardiolipin antibodies and antiphospholipid syndrome. Ann Rheum Dis 2001; 60(1): 43-8.
[http://dx.doi.org/10.1136/ard.60.1.43 ] [PMID: 11114281]
[28]
Pardos-Gea J, Avegliano G, Evangelista A, Vilardell M, Ordi-Ros J. Cardiac manifestations other than valvulopathy in antiphospholipid syndrome: long-time echocardiography follow-up study. Int J Rheum Dis 2015; 18(1): 76-83.
[http://dx.doi.org/10.1111/1756-185X.12191 ] [PMID: 24131635]
[29]
Kampolis C, Tektonidou M, Moyssakis I, Tzelepis GE, Moutsopoulos H, Vlachoyiannopoulos PG. Evolution of cardiac dysfunction in patients with antiphospholipid antibodies and/or antiphospholipid syndrome: a 10-year follow-up study. Semin Arthritis Rheum 2014; 43(4): 558-65.
[http://dx.doi.org/10.1016/j.semarthrit.2013.07.016 ] [PMID: 24012042]
[30]
Tufano A, Lembo M, Di Minno MN, et al. Left ventricular diastolic abnormalities other than valvular heart disease in antiphospholipid syndrome: An echocardiographic study. Int J Cardiol 2018; 271: 366-70.
[http://dx.doi.org/10.1016/j.ijcard.2018.05.040 ] [PMID: 30223375]
[31]
Mavrogeni SI, Sfikakis PP, Kitas GD, Kolovou G, Tektonidou MG. Cardiac involvement in antiphospholipid syndrome: The diagnostic role of noninvasive cardiac imaging. Semin Arthritis Rheum 2016; 45(5): 611-6.
[http://dx.doi.org/10.1016/j.semarthrit.2015.09.005 ] [PMID: 26616201]
[32]
Azeem T, Vassallo M, Samani NJ. Images in cardiology. Endomyocardial fibrosis associated with antiphospholipid syndrome. Heart 2000; 84(2): 156.
[http://dx.doi.org/10.1136/heart.84.2.156 ] [PMID: 10979722]
[33]
Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European society of cardiology (ESC) and the European respiratory society (ERS): endorsed by: association for European pediatric and congenital cardiology (AEPC), international society for heart and lung transplantation (ISHLT). Eur Heart J 2016; 37(1): 67-119.
[http://dx.doi.org/10.1093/eurheartj/ehv317 ] [PMID: 26320113]
[34]
Parthvi R, Sikachi RR, Agrawal A, et al. Pulmonary hypertension associated with antiphospholipid antibody: Call for a screening tool? Intractable Rare Dis Res 2017; 6(3): 163-71.
[http://dx.doi.org/10.5582/irdr.2017.01044 ] [PMID: 28944137]
[35]
Zuily S, Domingues V, Suty-Selton C, et al. Antiphospholipid antibodies can identify lupus patients at risk of pulmonary hypertension: A systematic review and meta-analysis. Autoimmun Rev 2017; 16(6): 576-86.
[http://dx.doi.org/10.1016/j.autrev.2017.04.003 ] [PMID: 28411166]
[36]
Merkel PA, Chang Y, Pierangeli SS, Convery K, Harris EN, Polisson RP. The prevalence and clinical associations of anticardiolipin antibodies in a large inception cohort of patients with connective tissue diseases. Am J Med 1996; 101(6): 576-83.
[http://dx.doi.org/10.1016/S0002-9343(96)00335-X ] [PMID: 9003103]
[37]
Morrisroe KB, Stevens W, Nandurkar H, et al. The association of antiphospholipid antibodies with cardiopulmonary manifestations of systemic sclerosis. Clin Exp Rheumatol 2014; 32(6)(Suppl. 86): S-133-7.
[PMID: 24564981]
[38]
D’Armini AM, Totaro P, Nicolardi S, et al. Impact of high titre of antiphospholipid antibodies on postoperative outcome following pulmonary endarterectomy. Interact Cardiovasc Thorac Surg 2010; 10(3): 418-22.
[http://dx.doi.org/10.1510/icvts.2009.221630 ] [PMID: 19934162]
[39]
Wolf M, Boyer-Neumann C, Parent F, et al. Thrombotic risk factors in pulmonary hypertension. Eur Respir J 2000; 15(2): 395-9.
[http://dx.doi.org/10.1034/j.1399-3003.2000.15b28.x ] [PMID: 10706510]
[40]
Martinuzzo ME, Pombo G, Forastiero RR, Cerrato GS, Colorio CC, Carreras LO. Lupus anticoagulant, high levels of anticardiolipin, and anti-beta2-glycoprotein I antibodies are associated with chronic thromboembolic pulmonary hypertension. J Rheumatol 1998; 25(7): 1313-9.
[PMID: 9676762]
[41]
Andreoli L, Chighizola CB, Banzato A, Pons-Estel GJ, Ramire de Jesus G, Erkan D. Estimated frequency of antiphospholipid antibodies in patients with pregnancy morbidity, stroke, myocardial infarction, and deep vein thrombosis: a critical review of the literature. Arthritis Care Res (Hoboken) 2013; 65(11): 1869-73.
[http://dx.doi.org/10.1002/acr.22066 ] [PMID: 23861221]
[42]
Schofield JR, Blitshteyn S, Shoenfeld Y, Hughes GR. Postural tachycardia syndrome (POTS) and other autonomic disorders in antiphospholipid (Hughes) syndrome (APS). Lupus 2014; 23(7): 697-702.
[http://dx.doi.org/10.1177/0961203314524468 ] [PMID: 24569396]
[43]
Egolum UO, Stover DG, Anthony R, Wasserman AM, Lenihan D, Damp JB. Intracardiac thrombus: diagnosis, complications and management. Am J Med Sci 2013; 345(5): 391-5.
[http://dx.doi.org/10.1097/MAJ.0b013e318272b0b0 ] [PMID: 23328835]
[44]
Urbanus RT, Siegerink B, Roest M, Rosendaal FR, de Groot PG, Algra A. Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young women in the RATIO study: a case-control study. Lancet Neurol 2009; 8(11): 998-1005.
[http://dx.doi.org/10.1016/S1474-4422(09)70239-X ] [PMID: 19783216]
[45]
Vaarala O, Mänttäri M, Manninen V, et al. Anti-cardiolipin antibodies and risk of myocardial infarction in a prospective cohort of middle-aged men. Circulation 1995; 91(1): 23-7.
[http://dx.doi.org/10.1161/01.CIR.91.1.23 ] [PMID: 7805207]
[46]
Tektonidou MG, Andreoli L, Limper M, Tincani A, Ward MM. Management of thrombotic and obstetric antiphospholipid syndrome: a systematic literature review informing the EULAR recommendations for the management of antiphospholipid syndrome in adults. RMD Open 2019; 5(1): e000924.
[http://dx.doi.org/10.1136/rmdopen-2019-000924 ] [PMID: 31168416]
[47]
Tektonidou MG, Andreoli L, Limper M, et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis 2019; 78(10): 1296-304.
[http://dx.doi.org/10.1136/annrheumdis-2019-215213]
[48]
Cohen H, Hunt BJ, Efthymiou M, et al. RAPS trial investigators. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol 2016; 3(9): e426-36.
[http://dx.doi.org/10.1016/S2352-3026(16)30079-5 ] [PMID: 27570089]
[49]
Pengo V, Banzato A, Bison E, Zoppellaro G, Padayattil Jose S, Denas G. Efficacy and safety of rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome: Rationale and design of the Trial on Rivaroxaban in AntiPhospholipid Syndrome (TRAPS) trial. Lupus 2016; 25(3): 301-6.
[http://dx.doi.org/10.1177/0961203315611495 ] [PMID: 26466613]
[50]
Woller SC, Stevens SM, Kaplan DA, et al. Apixaban for the secondary prevention of thrombosis among patients with antiphospholipid syndrome: study rationale and design (ASTRO-APS). Clin Appl Thromb Hemost 2016; 22(3): 239-47.
[http://dx.doi.org/10.1177/1076029615615960 ] [PMID: 26566669]
[51]
Pengo V, Denas G, Zoppellaro G, et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood 2018; 132(13): 1365-71.
[http://dx.doi.org/10.1182/blood-2018-04-848333 ] [PMID: 30002145]
[52]
Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2019; 40(2): 87-165.
[http://dx.doi.org/10.1093/eurheartj/ehy394 ] [PMID: 30165437]
[53]
Mora-Ramírez M, González-Pacheco H, Amezcua-Guerra LM. Stents coated with mammalian target of rapamycin inhibitors (mTOR) appear to be the best choice in patients with antiphospholipid syndrome and myocardial infarction. J Clin Rheumatol 2016; 22(5): 281.
[http://dx.doi.org/10.1097/RHU.0000000000000409 ] [PMID: 27464778]
[54]
Erkan D, Willis R, Murthy VL, et al. A prospective open-label pilot study of fluvastatin on proinflammatory and prothrombotic biomarkers in antiphospholipid antibody positive patients. Ann Rheum Dis 2014; 73(6): 1176-80.
[http://dx.doi.org/10.1136/annrheumdis-2013-203622 ] [PMID: 23933625]
[55]
Watanabe T, Oku K, Amengual O, et al. Effects of statins on thrombosis development in patients with systemic lupus erythematosus and antiphospholipid antibodies. Lupus 2018; 27(2): 225-34.
[http://dx.doi.org/10.1177/0961203317716787 ] [PMID: 28659045]
[56]
Kotyla PJ. Simvastatin reduces antiphospholipid antibodies formation in patients with systemic lupus erythematosus: a preliminary study. Lupus 2018; 27(9): 1572-3.
[http://dx.doi.org/10.1177/0961203318772015 ] [PMID: 29699441]
[57]
Andrade D, Tektonidou M. Emerging therapies in antiphospholipid syndrome. Curr Rheumatol Rep 2016; 18(4): 22.
[http://dx.doi.org/10.1007/s11926-016-0566-z ] [PMID: 26995745]
[58]
Schmidt-Tanguy A, Voswinkel J, Henrion D, et al. Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients. J Thromb Haemost 2013; 11(10): 1927-9.
[PMID: 23902281]
[59]
Polytarchou K, Manolis AS. Ranolazine and its antiarrhythmic actions. Cardiovasc Hematol Agents Med Chem 2015; 13(1): 31-9.
[http://dx.doi.org/10.2174/187152571301150730113903 ] [PMID: 26245658]
[60]
Nishimura M, Nii T, Trimova G, et al. The NF-κB specific inhibitor DHMEQ prevents thrombus formation in a mouse model of antiphospholipid syndrome. J Nephropathol 2013; 2(2): 114-21.
[http://dx.doi.org/10.5812/nephropathol.10112 ] [PMID: 24475437]
[61]
Yamashita C, Hayashi T, Mori T, et al. Angiotensin II receptor blocker reduces oxidative stress and attenuates hypoxia-induced left ventricular remodeling in apolipoprotein E-knockout mice. Hypertens Res 2007; 30(12): 1219-30.
[http://dx.doi.org/10.1291/hypres.30.1219 ] [PMID: 18344628]
[62]
Felau SM, Sales LP, Solis MY, et al. Omega-3 fatty acid supplementation improves endothelial function in primary antiphospholipid syndrome: a small-scale randomized double-blind placebo-controlled trial. Front Immunol 2018; 9: 336.
[http://dx.doi.org/10.3389/fimmu.2018.00336 ] [PMID: 29552010]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 18
ISSUE: 6
Year: 2020
Published on: 16 September, 2020
Page: [538 - 548]
Pages: 11
DOI: 10.2174/1570161117666190830101341
Price: $65

Article Metrics

PDF: 30
HTML: 3