Neurovascular complications of antiphospholipid syndrome: a narrative review

Abstract

Background Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by thrombosis, pregnancy complications, and other nonthrombotic manifestations in the presence of antiphospholipid antibodies. Neurovascular complications, including ischemic stroke, cerebral venous thrombosis and cognitive impairment, pose significant challenges in management.

Objective To comprehensively review relevant and updated clinical aspects of neurovascular manifestations of APS.

Methods We conducted a narrative review using the PubMed, EMBASE, and Cochrane Library databases with medical terms related to APS and its neurovascular manifestations. English-language studies, published between January 1, 2015, and March 2024, were included. Key publications outside this timeframe were also considered. Studies with higher levels of evidence, such as randomized controlled trials and meta-analyses, were prioritized for inclusion.

Results Stroke is a prevalent complication in APS, with arterial thrombosis being a predominant mechanism. Despite recent trials, direct oral anticoagulants (DOACs) have not shown superiority over vitamin K antagonists (VKAs) for secondary prevention in this population. Cerebral venous thrombosis (CVT), although rare, can also occur in APS, and while DOACs have shown promise as a treatment in a general population, caution is warranted due to potential harm. Cognitive impairment affects a considerable proportion of APS patients, with thrombotic and nonthrombotic mechanisms contributing to its pathophysiology. Future research should focus on optimal management strategies for cognitive impairment and the efficacy of anticoagulation and immunosuppression.

Conclusion Understanding the complex interplay of neurovascular manifestations in APS is essential for guiding clinical decisions and improving patient outcomes. Despite advancements, some challenges remain in establishing effective preventive and treatment measures, highlighting the need for further research in this field.

Resumo

Antecedentes A síndrome antifosfolipídeo (SAF) é uma doença autoimune sistêmica caracterizada por trombose, complicações na gravidez e outras manifestações não trombóticas na presença de anticorpos antifosfolipídicos. Complicações neurovasculares, incluindo acidente vascular cerebral isquêmico, trombose venosa cerebral (TVC) e comprometimento cognitivo, representam desafios significativos no manejo.

Objetivo Revisar de forma abrangente e atualizada os aspectos clínicos relevantes das manifestações neurovasculares da SAF.

Métodos Foi realizada uma busca nas bases de dados PubMed, EMBASE e Cochrane, utilizando termos médicos relacionados à SAF e suas manifestações neurovasculares. Estudos em inglês publicados entre 1° de janeiro de 2015 e março de 2024 foram incluídos. Publicações relevantes fora deste período também foram consideradas. Estudos com níveis mais elevados de evidência, como ensaios clínicos randomizados e metanálises, foram priorizados para inclusão.

Resultados O acidente vascular cerebral é uma complicação prevalente na SAF, com a trombose arterial sendo um mecanismo predominante. Apesar de ensaios recentes, os anticoagulantes orais diretos (ACODs) não demonstraram superioridade sobre os antagonistas da vitamina K (AVKs) para a prevenção secundária nesse grupo. A trombose venosa cerebral (TVC), embora rara, também pode ocorrer na SAF, e embora os ACODs tenham mostrado promessa em seu tratamento na população geral, deve-se ter cautela devido ao possível dano. O comprometimento cognitivo afeta uma proporção considerável dos pacientes com SAF, com mecanismos trombóticos e não trombóticos contribuindo para sua fisiopatologia. Pesquisas futuras devem se concentrar em melhores estratégias de manejo para o comprometimento cognitivo e na eficácia da anticoagulação e imunossupressão.

Conclusão Compreender a complexa interação das manifestações neurovasculares na SAF é essencial para orientar decisões clínicas e melhorar os resultados dos pacientes. Apesar dos avanços, alguns desafios permanecem no estabelecimento de medidas preventivas e terapêuticas eficazes, destacando a necessidade de mais pesquisas nesse campo.

Keywords

Antiphospholipid Syndrome - Stroke - Cognition - Venous Thrombosis - Complications

Palavras-chave

Síndrome Antifosfolipídica - Acidente Vascular Cerebral - Cognição - Trombose Venosa - Complicações

Authors' Contributions

GNMM: conceptualization, investigation, visualization, and writing – original draft; ABCGM: project administration, visualization, and writing – review & editing; LCC, GJ, AYP, and FHS: writing – review and editing; JBCA: conceptualization, methodology, supervision, and writing – review & editing.

Editor-in-Chief

Ayrton Roberto Massaro.

Associate Editor

Octavio Marques Pontes Neto.

Publication History

Received: 02 April 2024

Accepted: 18 August 2024

Article published online:
10 December 2024

• References

• 1 Barbhaiya M. et al. The 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria. Arthritis Rheumatol, v. 75, n. 10, p. 1687–1702, Oct 2023. ISSN 2326–5205. Disponível em: <  https://www.ncbi.nlm.nih.gov/pubmed/37635643 >
• 2 Bertoletti L. et al. Direct oral anticoagulant use in patients with thrombophilia, antiphospholipid syndrome or venous thrombosis of unusual sites: A narrative review. Blood Rev, v. 32, n. 4, p. 272–279, Jul 2018. ISSN 1532–1681. Disponível em: <  https://www.ncbi.nlm.nih.gov/pubmed/29402471 >
• 3 Litvinova E. et al. Prevalence and Significance of Non-conventional Antiphospholipid Antibodies in Patients With Clinical APS Criteria. Frontiers in Immunology, v. 9, 2018–12–14 2018. ISSN 1664–3224. Acesso em: 2024–02–03T04:32:03.
• 4 Arreola-Diaz R. et al. The Pathophysiology of The Antiphospholipid Syndrome: A Perspective From The Blood Coagulation System. Clinical and Applied Thrombosis/Hemostasis, v. 28, p. 107602962210885, 2022–01–01 2022. ISSN 1076–0296. Acesso em: 2024–06–09T00:28:53.
• 5 Leal Rato M. et al. Neurologic Manifestations of the Antiphospholipid Syndrome—an Update. Current Neurology and Neuroscience Reports, v. 21, n. 8, 2021–08–01 2021. ISSN 1528–4042. Acesso em: 2024–02–02T23:37:30.
• 6 Barbhaiya M, Zuily S, Naden R. et al; ACR/EULAR APS Classification Criteria Collaborators. The 2023 ACR/EULAR antiphospholipid syndrome classification criteria. Arthritis Rheumatol 2023; 75 (10) 1687-1702 Available from https://www.ncbi.nlm.nih.gov/pubmed/37635643
• 7 Bertoletti L, Benhamou Y, Béjot Y. et al. Direct oral anticoagulant use in patients with thrombophilia, antiphospholipid syndrome or venous thrombosis of unusual sites: A narrative review. Blood Rev 2018; 32 (04) 272-279 Available from https://www.ncbi.nlm.nih.gov/pubmed/29402471
• 8 Litvinova E, Darnige L, Kirilovsky A, Burnel Y, de Luna G, Dragon-Durey MA. Prevalence and significance of non-conventional antiphospholipid antibodies in patients with clinical APS criteria. Front Immunol 2018; 9: 2971
• 9 Arreola-Diaz R, Majluf-Cruz A, Sanchez-Torres LE, Hernandez-Juarez J. The pathophysiology of the antiphospholipid syndrome: A perspective from the blood coagulation system. Clin Appl Thromb Hemost 2022; 28: 10 760296221088576
• 10 Leal Rato M, Bandeira M, Romão VC, Aguiar de Sousa D. Neurologic manifestations of the antiphospholipid syndrome—an update. Curr Neurol Neurosci Rep 2021; 21 (08) 41
• 11 Cervera R, Serrano R, Pons-Estel GJ. et al; Euro-Phospholipid Project Group (European Forum on Antiphospholipid Antibodies). Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis 2015; 74 (06) 1011-1018 Available from http://diposit.ub.edu/dspace/bitstream/2445/119677/1/663784.pdf
• 12 Radin M, Schreiber K, Cecchi I, Roccatello D, Cuadrado MJ, Sciascia S. The risk of ischaemic stroke in primary antiphospholipid syndrome patients: a prospective study. Eur J Neurol 2018; 25 (02) 320-325 Available from https://www.ncbi.nlm.nih.gov/pubmed/29082583
• 13 Fan Y, Xu Y, Zhang S. et al. Stroke and risk factors in antiphospholipid syndrome. J Pers Med 2023; 14 (01) 24
• 14 Fleetwood T, Cantello R, Comi C. Antiphospholipid syndrome and the neurologist: from pathogenesis to therapy. Front Neurol 2018; 9: 1001
• 15 Gašperšič N, Zaletel M, Kobal J. et al. Stroke and antiphospholipid syndrome-antiphospholipid antibodies are a risk factor for an ischemic cerebrovascular event. Clin Rheumatol 2019; 38 (02) 379-384 Available from https://www.ncbi.nlm.nih.gov/pubmed/30088114
• 16 Bu X, Peng H, Zhong C. et al. Antiphosphatidylserine antibodies and clinical outcomes in patients with acute ischemic stroke. Stroke 2016; 47 (11) 2742-2748
• 17 Mittal P, Quattrocchi G, Tohidi-Esfahani I, Sayar Z, Chandratheva A, Cohen H. Antiphospholipid syndrome, antiphospholipid antibodies, and stroke. Int J Stroke 2023; 18 (04) 383-391 https://www.ncbi.nlm.nih.gov/pubmed/36571450
• 18 Al-Banaa K, Alshaikhli A, Al-Hareeri A, Abdelhalim M, Al-Hillan A, Joshi T. Arterial dissection in antiphospholipid syndrome patients: two case reports and a literature review. Eur J Case Rep Intern Med 2021; 8 (05) 002610 https://www.ncbi.nlm.nih.gov/pubmed/34123952
• 19 Knight JS, Kanthi Y. Mechanisms of immunothrombosis and vasculopathy in antiphospholipid syndrome. Semin Immunopathol 2022; 44 (03) 347-362 https://www.ncbi.nlm.nih.gov/pubmed/35122116
• 20 Miesbach W, Gilzinger A, Gökpinar B, Claus D, Scharrer I. Prevalence of antiphospholipid antibodies in patients with neurological symptoms. Clin Neurol Neurosurg 2006; 108 (02) 135-142 https://www.ncbi.nlm.nih.gov/pubmed/16412834
• 21 Ricarte IF, Dutra LA, Abrantes FF. et al. Neurologic manifestations of antiphospholipid syndrome. Lupus 2018; 27 (09) 1404-1414 https://www.ncbi.nlm.nih.gov/pubmed/29768970
• 22 Provenzale JM, Barboriak DP, Allen NB, Ortel TL. Antiphospholipid antibodies: findings at arteriography. AJNR Am J Neuroradiol 1998; 19 (04) 611-616 https://www.ncbi.nlm.nih.gov/pubmed/9576644
• 23 Julkunen H, Hedman C, Kauppi M. Thrombolysis for acute ischemic stroke in the primary antiphospholipid syndrome. J Rheumatol 1997; 24 (01) 181-183 https://www.ncbi.nlm.nih.gov/pubmed/9002032
• 24 Neoh KK, Tang ASN, Looi I, Anita BM. Ischemic stroke in a young patient with nephrotic syndrome and antiphospholipid syndrome. Case Rep Nephrol 2020; 2020: 8828864 https://www.ncbi.nlm.nih.gov/pubmed/33332738
• 25 Camara-Lemarroy CR, Infante-Valenzuela A, Andrade-Vazquez CJ, Enriquez-Noyola RV, Garcia-Valadez EA, Gongora-Rivera F. Successful intravenous thrombolysis in a patient with antiphospholipid syndrome, acute ischemic stroke and severe thrombocytopenia. Blood Coagul Fibrinolysis 2016; 27 (03) 354-356 https://www.ncbi.nlm.nih.gov/pubmed/26575492
• 26 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 (09) e426-e436 https://www.ncbi.nlm.nih.gov/pubmed/27570089
• 27 Pengo V, Denas G, Zoppellaro G. et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood 2018; 132 (13) 1365-1371
• 28 Ordi-Ros J, Sáez-Comet L, Pérez-Conesa M. et al. Rivaroxaban versus vitamin K antagonist in antiphospholipid syndrome: a randomized noninferiority trial. Ann Intern Med 2019; 171 (10) 685-694 https://www.ncbi.nlm.nih.gov/pubmed/31610549
• 29 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 (03) 239-247 https://www.ncbi.nlm.nih.gov/pubmed/26566669
• 30 Woller SC, Stevens SM, Kaplan D. et al. Apixaban compared with warfarin to prevent thrombosis in thrombotic antiphospholipid syndrome: a randomized trial. Blood Adv 2022; 6 (06) 1661-1670
• 31 Bala MM, Celinska-Lowenhoff M, Szot W. et al. Antiplatelet and anticoagulant agents for secondary prevention of stroke and other thromboembolic events in people with antiphospholipid syndrome. Cochrane Database Syst Rev 2017; 10 (10) CD012169
• 32 Crowther MA, Ginsberg JS, Julian J. et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 2003; 349 (12) 1133-1138
• 33 Finazzi G, Marchioli R, Brancaccio V. et al. A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost 2005; 3 (05) 848-853 https://www.ncbi.nlm.nih.gov/pubmed/15869575
• 34 Bala MM, Celinska-Lowenhoff M, Szot W. et al. Antiplatelet and anticoagulant agents for secondary prevention of stroke and other thromboembolic events in people with antiphospholipid syndrome. Cochrane Database Syst Rev 2020; 10 (10) CD012169
• 35 Arachchillage DJ, Laffan M, Pericleous C. Hydroxychloroquine as an immunomodulatory and antithrombotic treatment in antiphospholipid syndrome. Int J Mol Sci 2023; 24 (02) 1331
• 36 Jorge A, McCormick N, Lu N. et al. Hydroxychloroquine and mortality among patients with systemic lupus erythematosus in the general population. Arthritis Care Res (Hoboken) 2021; 73 (08) 1219-1223 https://www.ncbi.nlm.nih.gov/pubmed/32407570
• 37 Scott RM, Smith ER. Moyamoya disease and moyamoya syndrome. N Engl J Med 2009; 360 (12) 1226-1237 https://www.ncbi.nlm.nih.gov/pubmed/19297575
• 38 Guevara-Rodriguez N, Marmanillo-Mendoza G, Castelar J, Ciobanu C, Fulger I. Unusual presentation of acquired thrombotic thrombocytopenic purpura (TTP) versus catastrophic antiphospholipid syndrome in a patient with Moya-Moya disease, case report, and literature review. Clin Case Rep 2023; 11 (05) e7317
• 39 Wang Z, Fu Z, Wang J, Cui H, Zhang Z, Zhang B. Moyamoya syndrome with antiphospholipid antibodies: a case report and literature review. Lupus 2014; 23 (11) 1204-1206 https://www.ncbi.nlm.nih.gov/pubmed/24939972
• 40 Kuroda S, Yamamoto S, Funaki T. et al; AMORE Study Group. Five-year stroke risk and its predictors in asymptomatic moyamoya disease: Asymptomatic Moyamoya Registry (AMORE). Stroke 2023; 54 (06) 1494-1504
• 41 Jerez-Lienas A, Mathian A, Aboab J. et al. Cerebral vein thrombosis in the antiphospholipid syndrome: analysis of a series of 27 patients and review of the literature. Brain Sci 2021; 11 (12) 1641
• 42 Shu L, Bakradze E, Omran SS. et al. Predictors of recurrent venous thrombosis after cerebral venous thrombosis. Neurology 2022; 99 (21) e2368-e2377
• 43 Ferro JM, Coutinho JM, Dentali F. et al; RE-SPECT CVT Study Group. Safety and efficacy of dabigatran etexilate vs dose-adjusted warfarin in patients with cerebral venous thrombosis. JAMA Neurol 2019; 76 (12) 1457-1465 https://jamanetwork.com/journals/jamaneurology/articlepdf/2749167/jamaneurology_ferro_2019_oi_190070.pdf
• 44 Field TS, Dizonno V, Almekhlafi MA. et al; SECRET Investigators. Study of rivaroxaban for cerebral venous thrombosis: A randomized controlled feasibility trial comparing anticoagulation with rivaroxaban to standard-of-care in symptomatic cerebral venous thrombosis. Stroke 2023; 54 (11) 2724-2736
• 45 Yaghi S, Shu L, Bakradze E. et al. Direct oral anticoagulants versus warfarin in the treatment of cerebral venous thrombosis (ACTION-CVT): A multicenter international study. Stroke 2022; 53 (03) 728-738
• 46 Field TS, Lindsay MP, Wein T. et al; Canadian Stroke Best Practice Recommendations Advisory Committee, in collaboration with the Canadian Stroke Consortium. Canadian stroke best practice recommendations, 7^th Cerebral venous thrombosis. Can J Neurol Sci 2024; 51 (02) 1-17
• 47 Saposnik G, Bushnell C, Coutinho JM. et al; American Heart Association Stroke Council; Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Cardiovascular and Stroke Nursing; and Council on Hypertension. Diagnosis and management of cerebral venous thrombosis: A scientific statement from the American Heart Association. Stroke 2024; 55 (03) e77-e90
• 48 Donnellan C, Cohen H, Werring DJ. Cognitive dysfunction and associated neuroimaging biomarkers in antiphospholipid syndrome: a systematic review. Rheumatology (Oxford) 2021; 61 (01) 24-41
• 49 Hassan F, Naffaa ME, Saab A, Putterman C. Cognitive impairment in anti-phospholipid syndrome and anti-phospholipid antibody carriers. Brain Sci 2022; 12 (02) 222
• 50 Coín MA, Vilar-López R, Peralta-Ramírez I. et al. The role of antiphospholipid autoantibodies in the cognitive deficits of patients with systemic lupus erythematosus. Lupus 2015; 24 (08) 875-879 https://www.ncbi.nlm.nih.gov/pubmed/25697771
• 51 Man YL, Sanna G. Neuropsychiatric manifestations of antiphospholipid syndrome—A narrative review. Brain Sci 2022; 12 (01) 91
• 52 Zhu DS, Fu J, Zhang Y. et al. Neurological antiphospholipid syndrome: Clinical, neuroimaging, and pathological characteristics. J Neurol Sci 2014; 346 (1-2): 138-144 https://www.ncbi.nlm.nih.gov/pubmed/25173939
• 53 Erkan D, Kozora E, Lockshin MD. Cognitive dysfunction and white matter abnormalities in antiphospholipid syndrome. Pathophysiology 2011; 18 (01) 93-102 https://www.ncbi.nlm.nih.gov/pubmed/20472406
• 54 Dutra LA, Braga-Neto P, Pedroso JL, Barsottini OG. Sneddon's syndrome: case report and review of its relationship with antiphospholipid syndrome. Einstein (Sao Paulo) 2012; 10 (02) 230-232
• 55 Marinho JL, Piovesan EJ, Leite Neto MP. et al. Clinical, neurovascular and neuropathological features in Sneddon's syndrome. Arq Neuropsiquiatr 2007; 65 (2B, 2b) 390-395
• 56 Samanta D, Cobb S, Arya K. Sneddon syndrome: A comprehensive overview. J Stroke Cerebrovasc Dis 2019; 28 (08) 2098-2108
• 57 Francès C, Papo T, Wechsler B, Laporte JL, Biousse V, Piette JC. Sneddon syndrome with or without antiphospholipid antibodies. A comparative study in 46 patients. Medicine (Baltimore) 1999; 78 (04) 209-219 https://www.ncbi.nlm.nih.gov/pubmed/10424203