Features of nervous system damage in antiphospholipid syndrome

Antiphospholipid syndrome (APS) is an autoimmune process that increases the risk of arterial and venous thrombosis. The mechanism of damage to the central nervous system (CNS) can be not only due to thrombosis, but also antiphospholipid antibodies (APA) circulating in the peripheral blood. The latter can damage the cerebral vascular endothelium, alter the resistance of the blood-brain barrier and penetrate into the central nervous system, exerting a damaging effect on astroglia and neurons, as evidenced by the release of neurospecific proteins into the peripheral bloodstream. The role of APS in developing cerebral ischemia, migraine, epilepsy, chorea, transverse myelitis, multiple sclerosis, cognitive impairment and mental disorders, as well as the peripheral nervous system is described. It should also be noted about a role of APS for emerging neurological disorders in COVID-19, enabled apart from thrombogenesis due to APA via 2 potential mechanisms - molecular mimicry and neoepitope formation. Further study of the APS pathogenesis and interdisciplinary interaction are necessary to develop effective methods for patient management.

1. Gris J.-C., Makatsariya A.D., Bitsadze V.O. et al. Antiphospholipid syndrome and pregnancy. [Antifosfolipidnyj sindrom i beremennost']. Akusherstvo i ginekologiya. 2018;(10):5-11. (In Russ.). https://doi.org/10.18565/aig.2018.10.5-11.

2. Vila P., Hernandez M.C., Lopez-Fernandez M.F., Batlle J. Prevalence, follow-up and clinical significance of the anticardiolipin antibodies in normal subjects. Thromb Haemost. 1994;72(2):209-13.

3. Makatsariya A.D., Bitsadze V.O., Khizroeva J.Kh. et al. Pathogenetic significance of antiphospholipid antibodies. [Patogeneticheskoe znachenie antifosfolipidnyh antitel]. Prakticheskaya medicina. 2012;(5):9-21. (In Russ.).

4. Fleetwood T., Cantello R., Comi C. Antiphospholipid syndrome and the neurologist: from pathogenesis to therapy. Front Neurol. 2018;9:1001.

5. Gris J.-C., Nobile B., Bouvier S. Neuropsychiatric presentations of antiphospholipid antibodies. Thrombs Res. 2015;135(Suppl 1):S56-9. https://doi.org/10.1016/S0049-3848(15)50445-3.

6. Katzav A., Pick C.G., Korczyn A.D. et al. Hyperactivity in a mouse model of the antiphospholipid syndrome. Lupus. 2001;10(7):496-9. https://doi.org/10.1191/096120301678416060.

7. Chapman J., Cohen-Armon M., Shoenfeld Y., Korczyn A.D. Antiphospholipid antibodies permeabilize and depolarize brain synaptoneurosomes. Lupus. 1999;8(2):127-33. https://doi.org/10.1191/096120399678847524.

8. Blinov D.V. Current concepts of the role of altered blood-brain barrier resistance in the pathogenesis of CNS diseases. Part 1: structure and formation of the blood-brain barrier. [Sovremennye predstavleniya o roli narusheniya rezistentnosti gematoencefalicheskogo bar'era v patogeneze zabolevanij CNS. Chast' 1: stroenie i formirovanie gematoencefalicheskogo bar'era]. Epilepsy and paroxysmal conditions. 2013;5(3):65-75. (In Russ.).

9. Blinov D.V. Current concepts of the role of altered blood-brain barrier resistance in the pathogenesis of CNS diseases. Part 2: functions and mechanisms of the blood-brain barrier damage. [Sovremennye predstavleniya o roli narusheniya rezistentnosti gematoencefalicheskogo bar'era v patogeneze zabolevanij CNS. Chast' 2: funkcii i mekhanizmy povrezhdeniya gematoencefalicheskogo bar'era]. Epilepsy and paroxysmal conditions. 2014;6(1):70-84. (In Russ.).

10. Blinov D.V. Patients with neurological diseases: rationale for a pharmacoeconomic evaluation of cost optimization for management with neuron-specific proteins assessment as markers of increased blood-brain barrier permeability. [Pacienty s nevrologicheskimi rasstrojstvami: obosnovanie neobhodimosti farmakoekonomicheskoj ocenki optimizacii zatrat na vedenie s ispol'zovaniem nejrospecificheskih belkov v kachestve markerov povysheniya pronicaemosti gematoencefalicheskogo bar'era]. FARMAKOEKONOMIKA. Modern Pharmacoeconomic and Pharmacoepidemiology. 2014;7(1):40-5. (In Russ.).

11. Madjidova Y.N., Rakhimbaeva G.S., Azizova R.B. Neuroimmunopathogenetic mechanisms of epilepsy. [Nejroimmunopatogeneticheskie mekhanizmy epilepsii]. Epilepsy and paroxysmal conditions. 2014;6(1):15-8. (In Russ.).

12. Huseynova S., Mukhtarova S., Alasgarova S. AO-40. Acute brain injury of very low birthweight infants born to mothers with autoimmune disorders in pregnancy. Early Human Development. 2010;86:S16. https://doi.org/10.1016/j.earlhumdev.2010.09.048.

13. Frauenknecht K., Katzav A., Grimm C. et al. Neurological impairment in experimental antiphospholipid syndrome is associated with increased ligand binding to hippocampal and cortical serotonergic 5-HT1A receptors. Immunobiology. 2013;218(4):517-26. https://doi.org/10.1016/j.imbio.2012.06.011.

14. Yaremchuk O.Z., Posokhova K.A., Tokarskyi O.S. The influence of L-arginine on the level of synthesis of nitric oxide and the content of glial fibrillary acidic protein in brain during experimental antiphospholipid syndrome. Scientific Issue Ternopil Volodymyr Hnatiuk National Pedagogical University. Series: Biology. 2019;77(3):39-45. https://doi.org/10.25128/2078-2357.19.3.5.

15. Yaremchuk O., Soroka Yu., Kulitska M. et al. Neuroprotective effect of aminoguanidine in experimental obstetric antiphospholipid syndrome. Georgian Med News. 2020;(301):159-65.

16. Rajput P.S., Lyden P.D., Chen B. et al. Protease activated receptor-1 mediates cytotoxicity during ischemia using in vivo and in vitro models. Neuroscience. 2014;281;229-40. https://doi.org/10.1016/j.neuroscience.2014.09.038.

17. Cervera R., Boffa M.C., Khamashta M.A., Hughes G.R. The EuroPhospholipid project: epidemiology of the antiphospholipid syndrome in Europe. Lupus. 2009;18(10):889-93. https://doi.org/10.1177/0961203309106832.

18. Kenet G., Sadetzki S., Murad H. et al. Leiden and antiphopholipid antibodies are significant risk factors for ischemic stroke in children. Stroke. 2000;31(6):1283-8. https://doi.org/10.1161/01.str.31.6.1283.

19. Sciascia S., Sanna G., Khamashta M.A. et al. The estimated frequency of antiphospholipid antibodies in young adults with cerebrovascular events: a systematic review. Ann Rheumat Dis. 2015;74(11):2028-33. https://doi.org/10.1136/annrheumdis-2014-205663.

20. Kalashnikova L.A. Neurology of antiphospholipid syndrome. The medicine. [Nevrologiya antifosfolipidnogo sindroma. Medicina]. Moscow: Medicina, 2003. 256 p. (In Russ.).

21. Khamashta M.A., Cervera R., Asherson R.A. et al. Association of antibodies against phospholipids with valvular heart disease in patients with systemic lupus erythematosus. Lancet. 1990;335(8705):1541-4. https://doi.org/10.1016/0140-6736(90)91373-i.

22. Provenzale J.M., Barboriak D.P., Allen N.B., Ortel T.L. Patients with antiphospholipid antibodies: CT and MR findings of the brain. AJR Am J Roentgenol. 1996;167(6):1573-8. https://doi.org/10.2214/ajr.167.6.8956600.

23. Tukhfatullina S.I., Gaynetdinova D.D. Ischemic and nonischemic manifestations of antiphospholipid syndrome. [Ishemicheskie i neishemicheskie proyavleniya pri antifosfolipidnom syndrome]. Kazanskij medicinskijzhurnal. 2015;96(1):61-9. (In Russ.). https://doi.org/10.17750/KMJ2015-061.

24. Bedenko A.S. Vertigo caused by vestibular migraine: current problems of pathogenesis, diagnostics and therapy. [Vestibulyarnaya migren' kak prichina golovokruzheniya: aktual'nye problemy patogeneza, diagnostiki i terapii]. Epilepsy and paroxysmal conditions. 2020;12(3):177—81. (In Russ.). https://doi.org/10.17749/2077-8333/epi.par.con.2020.032.

25. Kalashnikova L.A. Non-ischemic neurological manifestations in patients with primary antiphospholipid syndrome. [Neishemicheskie nevrologicheskie proyavleniya u bol'nyh pervichnym antifosfolipidnym sindromom]. Zhurnal nevrologii i psihiatrii imeni S.S. Korsakova. 2005;105(2):18-23. (In Russ.).

26. Hughes G.R.V. Migraine, memory loss, and “multiple sclerosis”. Neurological features of the antiphospholipid (Hughes') syndrome. Postgrad Med J. 2003;79(928):81-3. https://doi.org/10.1136/pmj.79.928.81.

27. Tabeeva G.R. Migraine and cerebrovascular pathology. [Migren' i cerebrovaskulyarnaya patologiya]. Spravochnik poliklinicheskogo vracha. 2014;(3):45.

28. Karlov V.A. Russian League Against Epilepsy: the challenge of time. [Rossijskaya Protivoepilepticheskaya Liga segodnya: vyzov vremeni]. Epilepsy and paroxysmal conditions. 2020;12(1):5. (In Russ.).

29. What has been achieved and what has not been achieved in 2020. [Chto udalos' i chego ne udalos' dostich' v 2020 godu]. Epilepsy and paroxysmal conditions. 2021;13(1):5. (In Russ.).

30. Karlov V.A. Russian League Against Epilepcy: the answer to the present challenge. Epilepsy and paroxysmal conditions. 2021;13(1S):88-90. (In Russ.). https://doi.org/10.17749/2077-8333/epi.par.con.2021.085.

31. Mikhalovska-Karlova E.P. Bioethical management of patients with epilepsy: sex and age-related aspects. Epilepsy and paroxysmal conditions. 2020;12(2):117—21. (In Russ.). https://doi.org/10.17749/2077-8333/epi.par.con.2020.039.

32. Noureldine M.H., Harifi G., Berjawi A. et al. Hughes syndrome and epilepsy: when to test for antiphospholipid antibodies? Lupus. 2016;25(13):1397-411. https://doi.org/10.1177/0961203316651747.

33. de Carvalho J.F., Pasoto S.G., Appenzeller S. Seizures in primary antiphospholipid syndrome: the relevance of smoking to stroke. Clin Dev Immunol. 2012;2012:981519. https://doi.org/10.1155/2012/98151.

34. Carecchio M, Cantello R, Comi C. Revisiting the molecular mechanism of neurological manifestations in antiphospholipid syndrome: beyond vascular damage. J Immunol Res. 2014;2014:239398. https://doi.org/10.1155/2014/239398.

35. Rodrigues C.E., de Carvalho J.F. Clinical, radiologic, and therapeutic analysis of 14 patients with transverse myelitis associated with antiphospholipid syndrome: report of 4 cases and review of the literature. Semin Arthritis Rheum. 2011;40(4):349-57. https://doi.org/10.1016/j.semarthrit.2010.05.004.

36. Brey R.L., Muscal E., Chapman J. Antiphospholipid antibodies and the brain: a consensus report. Lupus. 2011;20(20):153-7. https://doi.org/10.1177/0961203310396748.

37. Cervera R., Piette J.C., 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. https://doi.org/10.1002/art.10187.

38. Sanna G., Bertolaccini M.L., Cuadrado M.J. et al. Central nervous system involvement in the antiphopholipid (Hughes) syndrome. Rheumatology (Oxford). 2003;42(2):200-13. https://doi.org/10.1093/rheumatology/keg080.

39. Santos M.S., de Carvalho J.F., Brotto M. et al. Peripheral neuropathy in patients with primary antiphospholipid (Hughes') syndrome. Lupus. 2010;19(5):583-90. https://doi.org/10.1177/0961203309354541.

40. Ruiz-Irastorza G., Crowther M., Branch W., Khamashta M. Antiphospholipid syndrome. Lancet. 2010;376(9751):1498-509. https://doi.org/10.1016/S0140-6736(10)60709-X.

41. Arachchillage D.J., Cohen H. Use of new oral anticoagulants in antiphospholipid syndrome. Curr Rheumatol Rep. 2013;15(6):331. https://doi.org/10.1007/s11926-013-0331-5.

42. Satybaldyeva M.A., Reshetnyak T.M. New oral anticoagulants in the therapy of antiphospholipid syndrome. [Novye oral'nye antikoagulyanty v terapii antifosfolipidnogo sindroma]. Nauchno-prakticheskaya revmatologiya. 2016;54(2):219-26. (In Russ.). https://doi.org/10.14412/1995-4484-2016-219-226.

43. Tamm M.V. COVID-19 in Moscow: prognoses and scenarios. [Koronavirusnaya infekciya v Moskve: prognozy i scenarii]. FARMAKOEKONOMIKA. Modern Pharmacoeconomic and Pharmacoepidemiology. 2020;13(1):43-51. (In Russ.). https://doi.org/10.17749/2070-4909.2020.13.1.43-51.

44. Fedorova E.A., Afanasyev D.O., Sokolov A.V., Lazarev M.P. Impact of disease information (Ebola and COVID-19) on the pharmaceutical sector in Russia and USA. [Vliyanie informacii o zabolevaniyah (lihoradka Ebola i COVID-19) na farmacevticheskij sektor Rossii i SShA]. FARMAKOEKONOMIKA. Modern Pharmacoeconomic and Pharmacoepidemiology. 2021;14(2):213-24. (In Russ.). https://doi.org/10.17749/2070-4909/farmakoekonomika.2021.054.

45. Di Renzo D.K., Makatsariya A.D., Tsibizova V.I. et al. Obstetric and perinatal care units functioning during the COVID-19 pandemic. [O principah raboty perinatal'nogo stacionara v usloviyah pandemii koronavirusa]. Vestnik RAMN. 2020;75(1):83-92. (In Russ.). https://doi.org/10.15690/vramn1324.

46. Bitsadze V.O., Sukontseva T.A., Akinshina S.V. et al. Septic shock. [Septicheskij shok]. Obstetrics, Gynecology and Reproduction. 2020;14(3):314-26. (In Russ.). https://doi.org/10.17749/2313-7347/ob.gyn.rep.2020.169.

47. Yupatov E.Yu., Maltseva L.I., Yusupova N.Z. et al. To the question on vaccination of pregnant women during COVID-19 pandemic. [K voprosu o vakcinacii beremennyh zhenshchin v kontekste pandemii COVID-19]. Obstetrics, Gynecology and Reproduction. 2020;14(5):656-66. (In Russ.). https://doi.org/10.17749/2313-7347/ob.gyn.rep.2020.170.

48. Khizroeva J.Kh., Makatsariya A.D., Bitsadze V.O. et al. Laboratory monitoring of COVID-19 patients and importance of coagulopathy markers. [Laboratornyj monitoring COVID-19 i znachenie opredeleniya markerov koagulopatii]. Obstetrics, Gynecology and Reproduction. 2020;14(2):132-47. (In Russ.). https://doi.org/10.17749/2313-7347.141.

49. Grigorieva K.N., Bitsadze V.O., Khizroeva J.Kh. et al. Macrophage activation syndrome in COVID-19. [Sindrom aktivacii makrofagov pri COVID-19]. Obstetrics, Gynecology and Reproduction. 2021;15(3):313-20. (In Russ.). https://doi.org/10.17749/2313-7347/ob.gyn.rep.2021.217.

50. Mehra M., Desai S.S., Kuy S.R. et al. Cardiovascular disease, drug therapy, and mortality in Covid-19. N Engl J Med. 2020;382(25):e102. https://doi.org/10.1056/NEJMoa2007621.

51. Wichmann D., Sperhake J-P., Lutgehetmann M. et al. Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study. Ann Intern Med. 2020;173(4):268-77. https://doi.org/10.7326/M20-2003.

52. Solomon I.H., Normandin E., Bhattacharyya S. et al. Neuropathological features of Covid-19. N Engl J Med. 2020;383(10):989-92. https://doi.org/10.1056/NEJMc2019373.

53. Zhang Y., Xiao M., Zhang S. et al. Coagulopathy and antiphospholipid antibodies in patients with Covid-19. N Engl J Med. 2020;382(17):e38. https://doi.org/10.1056/NEJMc2007575.

54. Tung M.L., Tan B., Cherian R., Chandra B. Anti-phospholipid syndrome and COVID-19 thrombosis: connecting the dots. Rheumatol Adv Pract. 2021;5(1):rkaa081. https://doi.org/10.1093/rap/rkaa081.

55. Delgado-Roche L., Mesta F. Oxidative stress as key player in severe acute respiratory syndrome coronavirus (SARS-CoV) infection. Arch Med Res. 2020;51(5):384-7. https://doi.org/10.1016/j.arcmed.2020.04.019.

56. Lopez-Pedrera C., Barbarroja N., Jimenez-Gomez Y. et al. Oxidative stress in the pathogenesis of atherothrombosis associated with antiphospholipid syndrome and systemic lupus erythematosus: new therapeutic approaches. Rheumatology (Oxford). 2016;55(12):2096-108. https://doi.org/10.1093/rheumatology/kew054.

57. Escher R., Breakey N., Lammle B. Severe COVID-19 infection associated with endothelial activation. Thromb Res. 2020;190:62. https://doi.org/10.1016/j.thromres.2020.04.014.

58. Zachariah U., Nair S.C., Goel A. et al. Targeting raised von Willebrand factor levels and macrophage activation in severe COVID-19: Consider low volume plasma exchange and low dose steroid. Thromb Res. 2020;192:2. https://doi.org/10.1016/j.thromres.2020.05.001.