Open Access

Antiphospholipid (Hughes) syndrome: beyond pregnancy morbidity and thrombosis

Journal of Autoimmune Diseases20096:3

DOI: 10.1186/1740-2557-6-3

Received: 21 October 2008

Accepted: 19 May 2009

Published: 19 May 2009


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.


The antiphospholipid (Hughes) syndrome (APS), first described in 1983, is an autoimmune disease characterised by recurrent arterial or venous thrombosis, pregnancy morbidity and the persistence of positive antiphospholipid antibodies (aPL) [1]. Although only thrombosis and pregnancy loss are included in the revised classification criteria for APS [2], other features are also described [3]. These include heart valve disease, livedo reticularis, thrombocytopenia and neurological manifestations such as migraine and seizures. Recently a number of other features have been described in APS, which we discuss in this review.

Stenotic lesions and vasculopathy

Vascular occlusions are increasingly being recognized in patients with APS, although the exact etiology remains unclear [4]. We found a high prevalence of renal artery stenosis (RAS) in APS patients with uncontrolled hypertension compared to two control groups [5]. Other stenotic lesions such as coeliac [6] and intracerebral arterial stenosis [7] have also been reported. These stenotic lesions are smooth and well defined and are different from those seen in atherosclerotic RAS or fibromuscular dysplasia [5]. Interestingly histological examination in SLE patients with APS [8] and a case report of a resected superior mesenteric artery showed fibro-elastic thickening of the intima and thrombosis [9]. These findings suggest that thrombosis and intimal and smooth muscle hyperplasia may be responsible for the vasculopathy in APS. Preliminary reports suggest that anticoagulation with a high intensity international normalized ratio (INR) helps to control blood pressure and prevents re-stenosis in APS patients with RAS [10]. Similarly, other case reports emphasize the importance of high intensity INR in various stenotic lesions in APS patients [7, 11, 12].

Coronary artery disease

Since the description of the APS syndrome, a number of cardiac manifestations have been described including cardiac valvular abnormalities (Libman-Sacks endocarditis) [13, 14]. Coronary artery disease in young adults and coronary artery bypass graft occlusions have been reported in APS patients [15]. Although typical myocardial infarction (MI) is well described in patients with APS [16, 17], a number of reports have described MI and so called Syndrome X in the absence of atherosclerotic obstructive coronary artery lesions [1820]. Cardiac Syndrome X is defined by the presence of angina-like chest pain, a positive response to stress testing and normal coronary arteriograms. Syndrome X is seen in menopausal women [21] and so was linked to low oestrogen levels [22]. However, in APS patients, Syndrome X and MI were observed in young women who were not menopausal [23]. Histopathological findings in myocardial tissue of a patient with APS, showed a non-inflammatory micro-vasculopathy, characterized by thrombi, and further ultra-structural studies confirmed the thrombosis and demonstrated endothelial activation [24]. These findings support the hypothesis that the endothelial dysfunction and subsequent thrombosis seen in the APS patients may be responsible for Syndrome X/MI and argues against the lack of oestrogen theory. Experts in this field recommend long term anticoagulation in this group of patients [19, 20].

Cerebral manifestations

Although stroke is the only accepted neurological criterion for the diagnosis of APS, a number of other manifestations are observed in the APS. The spectrum of non- thrombotic cerebral manifestations may range from focal neurological lesions to diffuse global dysfunction. It includes severe headaches, often migranous, hemiplegic migraine, cognitive dysfunction and memory deficits, dysphasia (mixing or inappropriate words), behavioural changes and seizure disorders [25]. Extrapyramidal symptoms such as chorea have also been described in association with sub-cortical dementia in patients with APS [26]. Tektonidou et al noted a significant association between cognitive dysfunction and white matter lesions in the brain in patients with APS [27]. It is not uncommon to see white matter changes in the brain mimicking multiple sclerosis. Although a double blind cross-over trial comparing low molecular weight heparin with placebo failed to show positive results [28], clinical experience suggests that severe cognitive dysfunction and intractable headaches often respond to anticoagulation therapy in these patients [25].

Skeletal manifestations of the APS

APS may involve multiple organs such as kidney, brain, eye, ear and liver and it may also affect the skeleton. A prospective cohort study [29] together with several case reports of osteonecrosis in primary APS in the absence of osteoporosis [30, 31], have strengthened the possible association between aPL and osteonecrosis. Our own experience is that non-traumatic metatarsal fractures are more prevalent in APS/aPL positive patients [32, 33]. Interestingly most had normal DEXA scans, none had any preceding trauma and none had received high doses of steroids. To assess the true prevalence of these fractures and their relation to aPL, a prospective study is needed in both symptomatic and asymptomatic patients.

Endothelial dysfunction

Accelerated atheroma has been described as a feature of APS as in other autoimmune inflammatory conditions. APS/aPL are associated with accelerated atherosclerosis [34] by targeting some of the steps that constitute early atherogenesis from endothelial activation to oxidized LDL uptake by foam macrophages [35, 36]. The ankle-brachial index (ABI) was found to be abnormal in patients with APS with thrombosis as well as in APS patients with pregnancy morbidity without thrombosis [37, 38]. A recent study by Charakida et al of endothelial assessment in patients with APS is worth mentioning. She studied 90 age, sex and cardiovascular risk factor profile matched patients with primary APS and a control group of 90 people with negative aPL. High resolution ultrasound was used to determine carotid intima media thickness (cIMT), endothelium dependent flow mediated dilatation (FMD) and endothelium independent nitroglycerine mediated dilatation of the brachial artery. This data showed significantly reduced FMD and increased cIMT in APS patients as compared to healthy individuals [39]. This corroborates previous observations by Medina et al [40]. Similarly, observations by Ames et al of subclinical atherosclerosis using intima-medial thickness in patients with primary APS in their 4th decade are worth mentioning [41]. This data indicates that endothelial dysfunction and pre-clinical atherosclerosis is prevalent in APS/aPL patients. The increased prevalence of an abnormal ABI in patients with APS, suggests that a large vessel vasculopathy could be a contributing factor to both thrombosis and pregnancy loss in APS [37, 38].

Complications following renal biopsy in patients with APS/aPL

Although APS is by definition a hypercoaguable state, a surprising recent preliminary report by Chaib et al found an increased risk of bleeding complications following renal biopsy in patients with lupus nephritis (LN) and APS/aPL as compared to LN alone [42]. This single centre study examined > 200 patients of which 86 were APS/aPL positive. The study identified a positive lupus anticoagulant and elevated serum creatinine levels as significant risk factors for post biopsy bleeding complications.

Livedo reticularis and "Seronegative APS"

"Sero-negative" APS has remained an enigma and the concept is controversial. According to classification criteria for APS, aPL (lupus anticoagulant and anticardiolipin antibodies) and Beta 2 Glycoprotein I (B2GPI) antibodies are essential for the classification of patients with APS. Although aPL and anti-B2GPI are sensitive tests, they are not sensitive enough to pick up all patients with APS. A small group of APS patients remain persistently negative for routine assays of aPL [43, 44]. Livedo reticularis was included in the original clinical description of the APS. Frances et al reported significant associations between pathological livedo reticularis (racemosa) and cerebral or ocular ischemic arterial events, seizures, heart valve abnormalities, hypertension and Raynaud's phenomenon in patients with APS [45]. As with APS, livedo reticularis in the absence of aPL has been associated with pregnancy morbidity and abnormal ABI [46]. Livedo reticularis shares a number of features with APS such as pregnancy loss, arterial thrombosis, heart valve abnormalities and seizures [47] and indeed it is the most common cutaneous manifestation of APS [48, 49]. There is therefore increasing evidence that "seronegative" APS does exist and it may be that serological markers other than aPL and anti-B2GPI are important in these patients. Pathological livedo reticularis may therefore be a clinical marker of the "seronegative APS" [46, 50].


The spectrum of APS is not limited to thrombosis or pregnancy morbidity and clinicians should be aware of the broad range of manifestations with multi-system involvement.


Authors’ Affiliations

The Lupus Research Unit, The Rayne Institute, St Thomas' Hospital


  1. Hughes GR: Thrombosis, abortion, cerebral disease and the lupus anticoagulant. BMJ. 1983, 287: 1088-1089. 10.1136/bmj.287.6399.1088.PubMed CentralView ArticlePubMedGoogle Scholar
  2. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RH, DE Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA: International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006, 4: 295-306. 10.1111/j.1538-7836.2006.01753.x.View ArticlePubMedGoogle Scholar
  3. Khamashta MA, Cervera R, Asherson RA, Font J, Gil A, Coltart DJ, Vázquez JJ, Paré C, Ingelmo M, Oliver J, et al: Association of antibodies against phospholipids with heart valve disease in systemic lupus erythematosus. Lancet. 1990, 335: 1541-1544. 10.1016/0140-6736(90)91373-I.View ArticlePubMedGoogle Scholar
  4. Christodoulou C, Sangle S, D'Cruz DP: Vasculopathy and arterial stenotic lesions in the antiphospholipid syndrome. Rheumatology (Oxford). 2007, 46: 907-10. 10.1093/rheumatology/kem040.View ArticleGoogle Scholar
  5. Sangle SR, D'Cruz DP, Jan W, Karim MY, Khamashta MA, Abbs IC, Hughes GR: Renal artery stenosis in the antiphospholipid (Hughes) syndrome and hypertension. Ann Rheum Dis. 2003, 62: 999-1002. 10.1136/ard.62.10.999.PubMed CentralView ArticlePubMedGoogle Scholar
  6. Sangle SR, Jan W, Lau IS, Bennett AN, Hughes GRV, D'Cruz DP: Coeliac artery stenosis and antiphospholipid (Hughes) syndrome/antiphospholipid antibodies. Clin Exp Rheumatol. 2006, 24: 349-PubMedGoogle Scholar
  7. Wong M, Sangle S, Jan W, Hughes GR, D'Cruz DP: Intracerebral arterial stenosis with neurological events associated with antiphospholipid syndrome. Rheumatology (Oxford). 2005, 44: 948-9. 10.1093/rheumatology/keh645.View ArticleGoogle Scholar
  8. Sipek-Dolnicar A, Hojnik J, Bozic B, Vizjak A, Rozman B, Ferluga D: Clinical presentations and vascular histopathology in autopsied patients with systemic lupus erythematosus and anticardiolipin antibodies. Clin Exp Rheumatol. 2002, 20: 335-42.PubMedGoogle Scholar
  9. Kojima E, Naito K, Iwai M, Hirose Y, Isobe K, Takano K: Antiphospholipid syndrome complicated by thrombosis of the superior mesenteric artery, co-existence of smooth muscle hyperplasia. Intern Med. 1997, 36: 528-31. 10.2169/internalmedicine.36.528.View ArticlePubMedGoogle Scholar
  10. Sangle SR, D'Cruz DP, Abbs IC, Khamashta MA, Hughes GR: Renal artery stenosis in hypertensive patients with antiphospholipid (Hughes) syndrome: outcome following anticoagulation. Rheumatology (Oxford). 2005, 44: 372-377. 10.1093/rheumatology/keh490.View ArticleGoogle Scholar
  11. Rosenthal E, Sangle SR, Taylor P, Khamashta MA, Hughes GR, D'Cruz DP: Treatment of mesenteric angina with antiphospholipid (Hughes) syndrome and coeliac artery stenosis. Ann Rheum Dis. 2006, 65: 1398-9. 10.1136/ard.2005.050344.PubMed CentralView ArticlePubMedGoogle Scholar
  12. Remondino GI, Mysler E, Pissano MN, Furattini MC, Basta MC, Presas JL, Allievi A: A reversible bilateral renal artery stenosis in association with antiphospholipid syndrome. Lupus. 2000, 9: 65-7. 10.1177/096120330000900112.View ArticlePubMedGoogle Scholar
  13. Cervera R: Coronary and valvular syndromes and antiphospholipid antibodies. Thromb Res. 2004, 114: 501-507. 10.1016/j.thromres.2004.06.026.View ArticlePubMedGoogle Scholar
  14. Tenedios F, Erkan K, Lockshin MD: Cardiac involvement in the antiphospholipid syndrome. Lupus. 2005, 14: 691-696. 10.1191/0961203305lu2202oa.View ArticlePubMedGoogle Scholar
  15. Kaplan SD, Chartash EK, Pizzarello RA, Furie RS: Cardiac manifestations of antiphospholipid syndrome. Am Heart J. 1992, 124: 1331-1338. 10.1016/0002-8703(92)90420-Z.View ArticlePubMedGoogle Scholar
  16. Vaarala O: Antiphospholipid antibodies and myocardial infarction. Lupus. 1998, 7: S132-134. 10.1177/096120339800700229.View ArticlePubMedGoogle Scholar
  17. Hamsten A, Norberg R, Bjorkholm M, de Faire U, Holm G: Antibodies to cardiolipin in young survivors of myocardial infarctions: an association with recurrent cardiovascular events. Lancet. 1986, 18: 113-116. 10.1016/S0140-6736(86)92258-0.View ArticleGoogle Scholar
  18. Nair S, Khamashta MA, Hughes GRV: Syndrome X and Hughes syndrome. Lupus. 2002, 11: 332-10.1191/0961203302lu210xx.View ArticlePubMedGoogle Scholar
  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 report and literature review. Angiology. 2001, 52: 785-788. 10.1177/000331970105201109.View ArticlePubMedGoogle Scholar
  20. Davies JO, Hunt BJ: Myocardial infarction in young patients without coronary atherosclerosis: assume primary antiphospholipid syndrome until proved otherwise. Int J Clin Pract. 2007, 61: 379-384. 10.1111/j.1742-1241.2006.01245.x.View ArticlePubMedGoogle Scholar
  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 chest pain predicts cardiovascular events in women without obstructive coronary artery disease: results from the NIH-NHLBI sponsored Women's ischaemia Syndrome Evaluation (WISE) study. Eur Heart J. 2006, 27: 1408-1415. 10.1093/eurheartj/ehl040.View ArticlePubMedGoogle Scholar
  22. Kaski JC: Cardiac syndrome X in women: the role of oestrogen deficiency. Heart. 2006, 92: 35-39. 10.1136/hrt.2005.070318.View ArticleGoogle Scholar
  23. Sangle S, D'Cruz D: Syndrome X (angina pectoris with normal coronary arteries) and myocardial infarction in patients with anti-phospholipid (Hughes) syndrome. Lupus. 2008, 17: 83-85. 10.1177/0961203307086036.View ArticlePubMedGoogle Scholar
  24. Kattwinkel N, Villanueva AG, Labib SB, Aretz HT, Walek JW, Burns DL, Klenz JT: Myocardial infarction caused by microvasculopathy in a patient with primary antiphospholipid syndrome. Ann Int Med. 1992, 116: 974-976.View ArticlePubMedGoogle Scholar
  25. Sanna G, D'Cruz D, Cuadrado MJ: Cerebral manifestations in the antiphospholipid (Hughes) syndrome. Rheum Dis Clin North Am. 2006, 32: 465-90. 10.1016/j.rdc.2006.05.010.View ArticlePubMedGoogle Scholar
  26. Ciubotaru CR, Esfahani F, Benedict RH, Wild LM, Baer AN: Chorea and rapidly progressive subcortical dementia in antiphospholipid syndrome. J Clin Rheumatol. 2002, 8 (6): 332-339. 10.1097/00124743-200212000-00010.View ArticlePubMedGoogle Scholar
  27. Tektonidou MG, Varsou N, Kotoulas G, Antoniou A, Moutsopolous HM: Cognitive deficits in patients with antiphospholipid syndrome: association with clinical, laboratory, and brain magnetic resonance imaging findings. Arch Intern Med. 2006, 166 (20): 2278-2284. 10.1001/archinte.166.20.2278.View ArticlePubMedGoogle Scholar
  28. Cuadrado MJ, Khamashta MA, D'Cruz D, Hughes GRV: Migraine in Hughes syndrome – heparin as a therapeutic trial?. QJM. 2001, 94 (2): 114-115. 10.1093/qjmed/94.2.114.View ArticlePubMedGoogle Scholar
  29. Tektonoidou MG, Malagari K, Vlachoyiannopoulos PG, Kelekis DA, Moutsopoulos HM: Asymptomatic avascular necrosis in patients with primary antiphospholipid syndrome in the absence of corticosteroid use: a prospective study by magnetic resonance imaging. Arthritis Rheum. 2003, 48: 732-736. 10.1002/art.10835.View ArticleGoogle Scholar
  30. Seleznick MJ, Silveira LH, Espinoza LR: Avascular necrosis associated with anticardiolipin antibodies. J Rheumatol. 1991, 18: 1416-1417.PubMedGoogle Scholar
  31. Egan RM, Munn RK: Catastrophic antiphospholipid syndrome presenting with multiple thromboses and sites of avascular necrosis. J Rheumatol. 1994, 21: 2376-2379.PubMedGoogle Scholar
  32. Sangle S, D'Cruz DP, Khamashta MA, Hughes GR: Antiphospholipid antibodies, systemic lupus erythematosus, and non-traumatic metatarsal fractures. Ann Rheum Dis. 2004, 63: 1241-3. 10.1136/ard.2003.016105.PubMed CentralView ArticlePubMedGoogle Scholar
  33. Vasoo S, Sangle S, Zain M, D'Cruz D, Hughes G: Orthopaedic manifestations of the antiphospholipid (Hughes) syndrome. Lupus. 2005, 14: 339-45. 10.1191/0961203305lu2146rr.View ArticlePubMedGoogle Scholar
  34. Davies RJ, Sangle SR, Khamashta MA, D'Cruz DP: Antiphospholipid (Hughes) syndrome and atheroma. Lupus. 2006, 15: 55-58. 10.1177/0961203306071669.View ArticleGoogle Scholar
  35. Brown MS, Goldstein JL: Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis. A Rev Biochem. 1983, 52: 223-61. 10.1146/ ArticleGoogle Scholar
  36. Henriksen T, Mahoney EM, Steinburg D: Enhanced macrophage degradation of biologically modified low density lipoprotein. Arteriosclerosis. 1983, 3: 149-59.View ArticlePubMedGoogle Scholar
  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. 10.1136/ard.2003.016204.PubMed CentralView ArticlePubMedGoogle Scholar
  38. Christodoulou C, Zain M, Bertolaccini ML, Sangle S, Khamashta MA, Hughes GR, D'Cruz DP: Prevalence of an abnormal ankle-brachial index in patients with antiphospholipid syndrome with pregnancy loss but without thrombosis: a controlled study. Ann Rheum Dis. 2006, 65: 683-4. 10.1136/ard.2005.037911.PubMed CentralView ArticlePubMedGoogle Scholar
  39. Charakida M, Halcox JP, Sangle S, D'Cruz D, Donald AE, Mackworth-Young CG, Klein NJ, Hughes G, Deanfield JE: Endothelial Dysfunction and Increased Carotid Intima-Media Thickness in Primary Antiphospholipid Syndrome. Arthritis Rheum. 2006, 54 (2): 557-558. 10.1002/art.21569.View ArticleGoogle Scholar
  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 syndrome. Ann Rheum Dis. 2003, 62: 607-10. 10.1136/ard.62.7.607.PubMed CentralView ArticlePubMedGoogle Scholar
  41. Margarita A, Batuca J, Scenna G, Alves JD, Lopez L, Iannaccone L, Matsuura E, Ames PR: Subclinical atherosclerosis in primary antiphospholipid syndrome. Ann N Y Acad Sci. 2007, 1108: 475-80. 10.1196/annals.1422.050.View ArticlePubMedGoogle Scholar
  42. Chaib AI, Mellilo N, Sangle SR, Sabharwal T, Tungekar F, Abbs IC, et al: Antiphospholipid antibodies and increased bleeding complications following renal biopsy: a single centre study. Arthritis Rheum. 2007, 56 (9): S740-Google Scholar
  43. Roubey RAS, Roch B, Amengual O, Atsumi T, Khamashta MA, Hughes GRV: Antiphospholipid antibody-negative syndrome – other phospholipids. Hughes Syndrome. Antiphospholipid syndrome. Edited by: Khamashta MA. 2000, London: Springer, 253-60.View ArticleGoogle Scholar
  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. 10.1136/ard.62.6.540.PubMed CentralView ArticlePubMedGoogle Scholar
  45. Frances C, Niang S, Laffitte E, Pelletier F, Costedoat N, Piette JC: Dermatologic manifestations of the antiphospholipid syndrome: two hundred consecutive cases. Arthritis Rheum. 2005, 52: 1785-93. 10.1002/art.21041.View ArticlePubMedGoogle Scholar
  46. Sangle S, Christodoulou C, Paul S, Hughes GR, D'Cruz DP: The point prevalence of an abnormal ankle-brachial index in antiphospholipid antibody negative patients with livedo reticularis: a controlled study. Ann Rheum Dis. 2008, 67: 276-7. 10.1136/ard.2007.074567.View ArticlePubMedGoogle Scholar
  47. Frances 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: 209-19. 10.1097/00005792-199907000-00001.View ArticleGoogle Scholar
  48. Weinstein S, Piette W: Cutaneous manifestations of antiphospholipid antibody syndrome. Hematol Oncol Clin North Am. 2008, 22: 67-77. 10.1016/j.hoc.2007.10.011.View ArticlePubMedGoogle Scholar
  49. Kriseman YL, Nash JW, Hsu S: Criteria for the diagnosis of antiphospholipid syndrome in patients presenting with dermatologic symptoms. J Am Acad Dermatol. 2007, 112-5. 10.1016/j.jaad.2006.11.033.Google Scholar
  50. Hughes GRV, Khamashta MA: Seronegative antiphospholipid syndrome. Ann Rheum Dis. 2003, 62: 1127-10.1136/ard.2003.006163.PubMed CentralView ArticlePubMedGoogle Scholar


© Mialdea et al; licensee BioMed Central Ltd. 2009

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.