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The antiphospholipid syndrome is an autoimmune disease characterised by recurrent arterial or venous thrombosis, pregnancy morbidity and the persistence of positive antiphospholipid antibodies. Many other clinical manifestations may occur including heart valve disease, livedo reticularis, thrombocytopenia and neurological manifestations such as migraine and seizures. We review a number of other manfestations including stenotic lesions, coronary artery disease and accelerated atherosclerosis, skeletal disorders and the concept of seronegative antiphospholipid syndrome. Introduction sis  have also been reported. These stenotic lesions are The antiphospholipid (Hughes) syndrome (APS), first smooth and well defined and are different from those described in 1983, is an autoimmune disease character- seen in atherosclerotic RAS or fibromuscular dysplasia . ised by recurrent arterial or venous thrombosis, pregnancy Interestingly histological examination in SLE patients morbidity and the persistence of positive antiphospholi- with APS  and a case report of a resected superior pid antibodies (aPL) . Although only thrombosis and mesenteric artery showed fibro-elastic thickening of the pregnancy loss are included in the revised classification intima and thrombosis . These findings suggest that criteria for APS , other features are also described . thrombosis and intimal and smooth muscle hyperplasia These include heart valve disease, livedo reticularis, may be responsible for the vasculopathy in APS. Prelimi- thrombocytopenia and neurological manifestations such nary reports suggest that anticoagulation with a high as migraine and seizures. Recently a number of other fea- intensity international normalized ratio (INR) helps to tures have been described in APS, which we discuss in this control blood pressure and prevents re-stenosis in APS review. patients with RAS . Similarly, other case reports emphasize the importance of high intensity INR in vari- ous stenotic lesions in APS patients [7,11,12]. Stenotic lesions and vasculopathy Vascular occlusions are increasingly being recognized in patients with APS, although the exact etiology remains Coronary artery disease unclear . We found a high prevalence of renal artery ste- Since the description of the APS syndrome, a number of nosis (RAS) in APS patients with uncontrolled hyperten- cardiac manifestations have been described including car- sion compared to two control groups . Other stenotic diac valvular abnormalities (Libman-Sacks endocarditis) lesions such as coeliac  and intracerebral arterial steno- [13,14]. Coronary artery disease in young adults and cor- Page 1 of 4 (page number not for citation purposes) Journal of Autoimmune Diseases 2009, 6:3 http://www.jautoimdis.com/content/6/1/3 onary artery bypass graft occlusions have been reported in Interestingly most had normal DEXA scans, none had any APS patients . Although typical myocardial infarction preceding trauma and none had received high doses of (MI) is well described in patients with APS [16,17], a steroids. To assess the true prevalence of these fractures number of reports have described MI and so called Syn- and their relation to aPL, a prospective study is needed in drome X in the absence of atherosclerotic obstructive cor- both symptomatic and asymptomatic patients. onary artery lesions [18-20]. Cardiac Syndrome X is defined by the presence of angina-like chest pain, a posi- Endothelial dysfunction tive response to stress testing and normal coronary arteri- Accelerated atheroma has been described as a feature of ograms. Syndrome X is seen in menopausal women  APS as in other autoimmune inflammatory conditions. and so was linked to low oestrogen levels . However, APS/aPL are associated with accelerated atherosclerosis in APS patients, Syndrome X and MI were observed in  by targeting some of the steps that constitute early young women who were not menopausal . His- atherogenesis from endothelial activation to oxidized topathological findings in myocardial tissue of a patient LDL uptake by foam macrophages [35,36]. The ankle-bra- with APS, showed a non-inflammatory micro-vasculopa- chial index (ABI) was found to be abnormal in patients thy, characterized by thrombi, and further ultra-structural with APS with thrombosis as well as in APS patients with studies confirmed the thrombosis and demonstrated pregnancy morbidity without thrombosis [37,38]. A endothelial activation . These findings support the recent study by Charakida et al of endothelial assessment hypothesis that the endothelial dysfunction and subse- in patients with APS is worth mentioning. She studied 90 quent thrombosis seen in the APS patients may be respon- age, sex and cardiovascular risk factor profile matched sible for Syndrome X/MI and argues against the lack of patients with primary APS and a control group of 90 peo- oestrogen theory. Experts in this field recommend long ple with negative aPL. High resolution ultrasound was term anticoagulation in this group of patients [19,20]. used to determine carotid intima media thickness (cIMT), endothelium dependent flow mediated dilatation (FMD) and endothelium independent nitroglycerine mediated Cerebral manifestations Although stroke is the only accepted neurological crite- dilatation of the brachial artery. This data showed signifi- rion for the diagnosis of APS, a number of other manifes- cantly reduced FMD and increased cIMT in APS patients as tations are observed in the APS. The spectrum of non- compared to healthy individuals . This corroborates thrombotic cerebral manifestations may range from focal previous observations by Medina et al . Similarly, neurological lesions to diffuse global dysfunction. It observations by Ames et al of subclinical atherosclerosis includes severe headaches, often migranous, hemiplegic using intima-medial thickness in patients with primary th migraine, cognitive dysfunction and memory deficits, dys- APS in their 4 decade are worth mentioning . This phasia (mixing or inappropriate words), behavioural data indicates that endothelial dysfunction and pre-clini- changes and seizure disorders . Extrapyramidal symp- cal atherosclerosis is prevalent in APS/aPL patients. The toms such as chorea have also been described in associa- increased prevalence of an abnormal ABI in patients with tion with sub-cortical dementia in patients with APS . APS, suggests that a large vessel vasculopathy could be a Tektonidou et al noted a significant association between contributing factor to both thrombosis and pregnancy cognitive dysfunction and white matter lesions in the loss in APS [37,38]. brain in patients with APS . It is not uncommon to see white matter changes in the brain mimicking multiple Complications following renal biopsy in patients sclerosis. Although a double blind cross-over trial com- with APS/aPL paring low molecular weight heparin with placebo failed Although APS is by definition a hypercoaguable state, a to show positive results , clinical experience suggests surprising recent preliminary report by Chaib et al found that severe cognitive dysfunction and intractable head- an increased risk of bleeding complications following aches often respond to anticoagulation therapy in these renal biopsy in patients with lupus nephritis (LN) and patients . APS/aPL as compared to LN alone . This single centre study examined > 200 patients of which 86 were APS/aPL Skeletal manifestations of the APS positive. The study identified a positive lupus anticoagu- APS may involve multiple organs such as kidney, brain, lant and elevated serum creatinine levels as significant risk eye, ear and liver and it may also affect the skeleton. A pro- factors for post biopsy bleeding complications. spective cohort study  together with several case reports of osteonecrosis in primary APS in the absence of Livedo reticularis and "Seronegative APS" osteoporosis [30,31], have strengthened the possible "Sero-negative" APS has remained an enigma and the con- association between aPL and osteonecrosis. Our own cept is controversial. According to classification criteria for experience is that non-traumatic metatarsal fractures are APS, aPL (lupus anticoagulant and anticardiolipin anti- more prevalent in APS/aPL positive patients [32,33]. bodies) and Beta 2 Glycoprotein I (B2GPI) antibodies are Page 2 of 4 (page number not for citation purposes) Journal of Autoimmune Diseases 2009, 6:3 http://www.jautoimdis.com/content/6/1/3 7. Wong M, Sangle S, Jan W, Hughes GR, D'Cruz DP: Intracerebral essential for the classification of patients with APS. arterial stenosis with neurological events associated with Although aPL and anti-B2GPI are sensitive tests, they are antiphospholipid syndrome. Rheumatology (Oxford) 2005, not sensitive enough to pick up all patients with APS. A 44:948-9. 8. Sipek-Dolnicar A, Hojnik J, Bozic B, Vizjak A, Rozman B, Ferluga D: small group of APS patients remain persistently negative Clinical presentations and vascular histopathology in autop- for routine assays of aPL [43,44]. Livedo reticularis was sied patients with systemic lupus erythematosus and anticar- diolipin antibodies. Clin Exp Rheumatol 2002, 20:335-42. included in the original clinical description of the APS. 9. Kojima E, Naito K, Iwai M, Hirose Y, Isobe K, Takano K: Antiphos- Frances et al reported significant associations between pholipid syndrome complicated by thrombosis of the supe- pathological livedo reticularis (racemosa) and cerebral or rior mesenteric artery, co-existence of smooth muscle hyperplasia. Intern Med 1997, 36:528-31. ocular ischemic arterial events, seizures, heart valve 10. Sangle SR, D'Cruz DP, Abbs IC, Khamashta MA, Hughes GR: Renal abnormalities, hypertension and Raynaud's phenomenon artery stenosis in hypertensive patients with antiphospholi- in patients with APS . As with APS, livedo reticularis pid (Hughes) syndrome: outcome following anticoagulation. Rheumatology (Oxford) 2005, 44:372-377. in the absence of aPL has been associated with pregnancy 11. Rosenthal E, Sangle SR, Taylor P, Khamashta MA, Hughes GR, D'Cruz morbidity and abnormal ABI . Livedo reticularis DP: Treatment of mesenteric angina with antiphospholipid (Hughes) syndrome and coeliac artery stenosis. Ann Rheum shares a number of features with APS such as pregnancy Dis 2006, 65:1398-9. loss, arterial thrombosis, heart valve abnormalities and 12. Remondino GI, Mysler E, Pissano MN, Furattini MC, Basta MC, Presas seizures  and indeed it is the most common cutaneous JL, Allievi A: A reversible bilateral renal artery stenosis in asso- ciation with antiphospholipid syndrome. Lupus 2000, 9:65-7. manifestation of APS [48,49]. There is therefore increas- 13. Cervera R: Coronary and valvular syndromes and antiphos- ing evidence that "seronegative" APS does exist and it may pholipid antibodies. Thromb Res 2004, 114:501-507. 14. Tenedios F, Erkan K, Lockshin MD: Cardiac involvement in the be that serological markers other than aPL and anti-B2GPI antiphospholipid syndrome. Lupus 2005, 14:691-696. are important in these patients. Pathological livedo retic- 15. Kaplan SD, Chartash EK, Pizzarello RA, Furie RS: Cardiac manifes- ularis may therefore be a clinical marker of the "seronega- tations of antiphospholipid syndrome. Am Heart J 1992, 124:1331-1338. tive APS" [46,50]. 16. Vaarala O: Antiphospholipid antibodies and myocardial infarc- tion. Lupus 1998, 7:S132-134. Conclusion 17. Hamsten A, Norberg R, Bjorkholm M, de Faire U, Holm G: Antibod- ies to cardiolipin in young survivors of myocardial infarc- The spectrum of APS is not limited to thrombosis or preg- tions: an association with recurrent cardiovascular events. nancy morbidity and clinicians should be aware of the Lancet 1986, 18:113-116. 18. Nair S, Khamashta MA, Hughes GRV: Syndrome X and Hughes broad range of manifestations with multi-system involve- syndrome. Lupus 2002, 11:332. ment. 19. Lagana B, Baratta L, Tubani L, Golluscio V, Delfino M, Rossi Fanelli F: Myocardial infarction with normal coronary arteries in a patient with primary antiphospholipid syndrome. Case Competing interests report and literature review. Angiology 2001, 52:785-788. The authors declare that they have no competing interests. 20. Davies JO, Hunt BJ: Myocardial infarction in young patients without coronary atherosclerosis: assume primary antiphos- pholipid syndrome until proved otherwise. Int J Clin Pract 2007, Authors' contributions 61:379-384. MM has written the manuscript, SRS has conceived and 21. Johnson BD, Shaw LJ, Pepine CJ, Reis SE, Kelsey SF, Sopko G, Rogers WJ, Mankad S, Sharaf BL, Bittner V, Bairey Merz CN: Persistent compiled the material and helped to write the manuscript chest pain predicts cardiovascular events in women without and DPD has supervised the drafting of the manuscript. obstructive coronary artery disease: results from the NIH- All authors have read and approved the final manuscript. NHLBI sponsored Women's ischaemia Syndrome Evalua- tion (WISE) study. Eur Heart J 2006, 27:1408-1415. 22. Kaski JC: Cardiac syndrome X in women: the role of oestro- References gen deficiency. Heart 2006, 92:35-39. 1. Hughes GR: Thrombosis, abortion, cerebral disease and the 23. Sangle S, D'Cruz D: Syndrome X (angina pectoris with normal lupus anticoagulant. BMJ 1983, 287:1088-1089. coronary arteries) and myocardial infarction in patients with 2. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, anti-phospholipid (Hughes) syndrome. Lupus 2008, 17:83-85. Derksen RH, DE Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld 24. Kattwinkel N, Villanueva AG, Labib SB, Aretz HT, Walek JW, Burns Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA: International con- DL, Klenz JT: Myocardial infarction caused by microvasculop- sensus statement on an update of the classification criteria athy in a patient with primary antiphospholipid syndrome. for definite antiphospholipid syndrome (APS). J Thromb Hae- Ann Int Med 1992, 116:974-976. most 2006, 4:295-306. 25. Sanna G, D'Cruz D, Cuadrado MJ: Cerebral manifestations in the 3. Khamashta MA, Cervera R, Asherson RA, Font J, Gil A, Coltart DJ, antiphospholipid (Hughes) syndrome. Rheum Dis Clin North Am Vázquez JJ, Paré C, Ingelmo M, Oliver J, et al.: Association of anti- 2006, 32:465-90. bodies against phospholipids with heart valve disease in sys- 26. Ciubotaru CR, Esfahani F, Benedict RH, Wild LM, Baer AN: Chorea temic lupus erythematosus. Lancet 1990, 335:1541-1544. and rapidly progressive subcortical dementia in antiphos- 4. Christodoulou C, Sangle S, D'Cruz DP: Vasculopathy and arterial pholipid syndrome. J Clin Rheumatol. 2002, 8(6):332-339. stenotic lesions in the antiphospholipid syndrome. Rheumatol- 27. Tektonidou MG, Varsou N, Kotoulas G, Antoniou A, Moutsopolous ogy (Oxford) 2007, 46:907-10. HM: Cognitive deficits in patients with antiphospholipid syn- 5. Sangle SR, D'Cruz DP, Jan W, Karim MY, Khamashta MA, Abbs IC, drome: association with clinical, laboratory, and brain mag- Hughes GR: Renal artery stenosis in the antiphospholipid netic resonance imaging findings. Arch Intern Med. 2006, (Hughes) syndrome and hypertension. Ann Rheum Dis 2003, 166(20):2278-2284. 62:999-1002. 28. Cuadrado MJ, Khamashta MA, D'Cruz D, Hughes GRV: Migraine in 6. Sangle SR, Jan W, Lau IS, Bennett AN, Hughes GRV, D'Cruz DP: Coe- Hughes syndrome – heparin as a therapeutic trial? QJM. 2001, liac artery stenosis and antiphospholipid (Hughes) syn- 94(2):114-115. drome/antiphospholipid antibodies. Clin Exp Rheumatol 2006, 24:349. Page 3 of 4 (page number not for citation purposes) Journal of Autoimmune Diseases 2009, 6:3 http://www.jautoimdis.com/content/6/1/3 29. Tektonoidou MG, Malagari K, Vlachoyiannopoulos PG, Kelekis DA, 50. Hughes GRV, Khamashta MA: Seronegative antiphospholipid Moutsopoulos HM: Asymptomatic avascular necrosis in syndrome. Ann Rheum Dis 2003, 62:1127. patients with primary antiphospholipid syndrome in the absence of corticosteroid use: a prospective study by mag- netic resonance imaging. Arthritis Rheum 2003, 48:732-736. 30. Seleznick MJ, Silveira LH, Espinoza LR: Avascular necrosis associ- ated with anticardiolipin antibodies. J Rheumatol 1991, 18:1416-1417. 31. Egan RM, Munn RK: Catastrophic antiphospholipid syndrome presenting with multiple thromboses and sites of avascular necrosis. J Rheumatol 1994, 21:2376-2379. 32. Sangle S, D'Cruz DP, Khamashta MA, Hughes GR: Antiphospholi- pid antibodies, systemic lupus erythematosus, and non-trau- matic metatarsal fractures. Ann Rheum Dis 2004, 63:1241-3. 33. Vasoo S, Sangle S, Zain M, D'Cruz D, Hughes G: Orthopaedic man- ifestations of the antiphospholipid (Hughes) syndrome. Lupus 2005, 14:339-45. 34. Davies RJ, Sangle SR, Khamashta MA, D'Cruz DP: Antiphospholipid (Hughes) syndrome and atheroma. Lupus 2006, 15:55-58. 35. Brown MS, Goldstein JL: Lipoprotein metabolism in the macro- phage: implications for cholesterol deposition in atheroscle- rosis. A Rev Biochem 1983, 52:223-61. 36. Henriksen T, Mahoney EM, Steinburg D: Enhanced macrophage degradation of biologically modified low density lipoprotein. Arteriosclerosis 1983, 3:149-59. 37. Barón MA, Khamashta MA, Hughes GR, D'Cruz DP: Prevalence of an abnormal ankle-brachial index in patients with primary antiphospholipid syndrome: preliminary data. Ann Rheum Dis 2005, 64:144-6. 38. Christodoulou C, Zain M, Bertolaccini ML, Sangle S, Khamashta MA, Hughes GR, D'Cruz DP: Prevalence of an abnormal ankle-bra- chial index in patients with antiphospholipid syndrome with pregnancy loss but without thrombosis: a controlled study. Ann Rheum Dis 2006, 65:683-4. 39. Charakida M, Halcox JP, Sangle S, D'Cruz D, Donald AE, Mackworth- Young CG, Klein NJ, Hughes G, Deanfield JE: Endothelial Dysfunc- tion and Increased Carotid Intima-Media Thickness in Pri- mary Antiphospholipid Syndrome. Arthritis Rheum 2006, 54(2):557-558. 40. Medina G, Casaos D, Jara LJ, Vera-Lastra O, Fuentes M, Barile L, Salas M: Increased carotid artery intima-media thickness may be associated with stroke in primary antiphospholipid syn- drome. Ann Rheum Dis 2003, 62:607-10. 41. Margarita A, Batuca J, Scenna G, Alves JD, Lopez L, Iannaccone L, Mat- suura E, Ames PR: Subclinical atherosclerosis in primary antiphospholipid syndrome. Ann N Y Acad Sci 2007, 1108:475-80. 42. Chaib AI, Mellilo N, Sangle SR, Sabharwal T, Tungekar F, Abbs IC, et al.: Antiphospholipid antibodies and increased bleeding com- plications following renal biopsy: a single centre study. Arthri- tis Rheum 2007, 56(9):S740. 43. Roubey RAS, Roch B, Amengual O, Atsumi T, Khamashta MA, Hughes GRV: Antiphospholipid antibody-negative syndrome – other phospholipids. In Hughes Syndrome. Antiphospholipid syndrome Edited by: Khamashta MA. London: Springer; 2000:253-60. 44. Carmo-Pereira S, Bertolaccini ML, Escudero-Conteras A, Khamashta MA, Hughes GR: Value of IgA anticardiolipin and anti-beta2- glycoprotein I antibody testing in patients with pregnancy morbidity. Ann Rheum Dis 2003, 62:540-3. 45. Frances C, Niang S, Laffitte E, Pelletier F, Costedoat N, Piette JC: Dermatologic manifestations of the antiphospholipid syn- drome: two hundred consecutive cases. Arthritis Rheum 2005, Publish with Bio Med Central and every 52:1785-93. scientist can read your work free of charge 46. Sangle S, Christodoulou C, Paul S, Hughes GR, D'Cruz DP: The point prevalence of an abnormal ankle-brachial index in "BioMed Central will be the most significant development for antiphospholipid antibody negative patients with livedo disseminating the results of biomedical researc h in our lifetime." reticularis: a controlled study. Ann Rheum Dis 2008, 67:276-7. Sir Paul Nurse, Cancer Research UK 47. Frances C, Papo T, Wechsler B, Laporte JL, Biousse V, Piette JC: Sneddon Syndrome with or without antiphospholipid anti- Your research papers will be: bodies, A comparative study in 46 patients. Medicine (Baltimore) available free of charge to the entire biomedical community 1999, 78:209-19. 48. Weinstein S, Piette W: Cutaneous manifestations of antiphos- peer reviewed and published immediately upon acceptance pholipid antibody syndrome. Hematol Oncol Clin North Am 2008, cited in PubMed and archived on PubMed Central 22:67-77. 49. Kriseman YL, Nash JW, Hsu S: Criteria for the diagnosis of yours — you keep the copyright antiphospholipid syndrome in patients presenting with der- BioMedcentral matologic symptoms. J Am Acad Dermatol 2007:112-5. Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 4 of 4 (page number not for citation purposes)
Journal of Autoimmune Diseases – Springer Journals
Published: May 19, 2009
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