|Year : 2010 | Volume
| Issue : 2 | Page : 116-124
Antiphospholipid syndrome in dermatology: An update
Reena Rai, C Shanmuga Sekar, M Kumaresan
Dept. of Dermatology, PSG Hospitals, Peelamedu, Coimbatore - 641 004, India
|Date of Web Publication||10-Mar-2010|
Dept. of Dermatology, PSG Hospitals, Peelamedu, Coimbatore - 641 004, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Antiphospholipid syndrome (APS) is characterized by the presence of antiphospholipid antibodies, recurrent thrombosis, and fetal loss. Antiphospholipid antibodies are a family of autoantibodies that recognize various combinations of phospholipids, phospholipid-binding proteins, or both. APS can occur in the absence of underlying or associated disease (primary APS) or in combination with other diseases (secondary APS). The exact pathogenic mechanism by which these antibodies cause thrombosis is not known; however, several hypotheses, such as activation of platelet and endothelial cells and interference with the coagulation system, have been proposed. Diagnosis is based on the presence of at least one clinical and laboratory criterion each, according to International Consensus Statement on preliminary classification criteria. However, APS can be diagnosed in individuals even in the absence of some of the classification criteria. Clinical manifestations involve different organs and systems such as the blood vessels, central nervous system, skin, kidneys, gastrointestinal tract, heart, and placenta. The unifying mechanism of all these manifestations is thrombosis, either arterial or venous. Skin manifestations are varied and although not included in the diagnostic criteria, may be the presenting feature of this syndrome. Therefore all dermatologists should investigate the possibility of APS when cutaneous findings are related to venous or arterial thrombosis. The risk of thrombosis cannot be predicted, and therefore treatment is not initiated until a thrombotic event occurs. Indefinite anticoagulation is prescribed once a thrombotic event occurs. Prognosis depends on the severity of the clinical manifestations and so, knowledge of the presentation of this disease is important for early detection and prompt treatment to prevent life-threatening consequences of this catastrophic disease process.
Keywords: Antiphospholipid syndrome, antiphospholipid antibodies, recurrent thrombosis, fetal loss
|How to cite this article:|
Rai R, Sekar C S, Kumaresan M. Antiphospholipid syndrome in dermatology: An update. Indian J Dermatol Venereol Leprol 2010;76:116-24
|How to cite this URL:|
Rai R, Sekar C S, Kumaresan M. Antiphospholipid syndrome in dermatology: An update. Indian J Dermatol Venereol Leprol [serial online] 2010 [cited 2018 Jun 21];76:116-24. Available from: http://www.ijdvl.com/text.asp?2010/76/2/116/60541
| Introduction|| |
Antiphospholipid antibodies (aPL) constitute a heterogeneous group of autoantibodies that share the ability to bind phospholipid alone, protein-phospholipid complexes, or phospholipid binding proteins. Antiphospholipid Syndrome (APS) is the association of aPL with hypercoagulability resulting in arterial and/or venous thrombosis, and pregnancy morbidity/obstetric complications. These antibodies include lupus anticoagulant antibodies, anticardiolpin antibodies (aCL), antibodies against -β2-glycoprotein I antibodies (anti-2GPI). The lupus anticoagulant antibodies are responsible for prolongation of the activated partial thromboplastin time in vitro but a hypercoagulable state in vivo.
This syndrome is termed as primary (primary APS) when it occurs in the absence of underlying or associated diseases; Secondary APS is associated with autoimmune diseases such as systemic lupus erythematosus (SLE). A wide variety of conditions associated with aPL are listed in [Table 1].
Antiphospholipid antibodies can also occur incidentally in healthy individuals and as a result, aPLs are considered clinically significant only when present in APS. Clinical features can vary widely and can involve any organ system but the features for both primary and secondary APS are identical. In primary APS, dermatological manifestations are probably the most common and 40% of the patients may have cutaneous features as the major complaint. Skin manifestations may be the first clue to this syndrome and it is important to be aware and investigate the possibility of APS when facing cutaneous findings related to venous or arterial thrombosis or microthrombosis.
| History|| |
The first aPL, a complement fixing antibody that reacted with extracts from bovine hearts, was detected in patients with syphilis in 1906. The relevant antigen was later identified as cardiolipin, a mitochondrial phospholipid. This observation became the basis for the Venereal Disease Research Laboratory (VDRL) test for syphilis, which is currently used. It was later established that many patients with SLE had positive test for VDRL without any other evidence for syphilis.?
In 1983, Harris and co-workers described a radioimmunoassay for the estimation of anticardiolipin antibodies (aCL), and two years later they developed the first enzyme-linked immunosorbent assay (ELISA) for the quantitative detection of anticardiolipin antibodies. These developments led to a renewed interest in aPL, which in turn led to the description, by Hughes and his colleagues in 1986, of the anticardiolipin syndrome. A year later, Harris et al. coined the term "antiphospholipid syndrome". Although Hughes et al. had recognized the features of APS in "non-lupus" patients, it was Asherson who introduced the term "primary Anti Phospholipid Syndrome" to describe patients with APS without an underlying disorder, as opposed to secondary APS, which occurs in the context of another autoimmune disorder.
In the early 1990s, two groups discovered that some aCL require the presence of the plasma phospholipids-binding protein b2-glycoprotein I (b2GPI) to bind to cardiolipin., This requirement is a feature of aCL from patients with SLE or the APS but not from patient with syphilis or other infectious diseases.?,, The demonstration that aCL are directed against a phospholipid-binding protein rather than phospholipids led to the discovery that some autoantibodies bind directly to b2GPI in the absence of phospholipids.?, This has resulted in a change of focus from phospholipids to phospholipids binding proteins.
| Pathogenesis|| |
Phospholipids are a class of polar lipids composed of a phosphate moiety and one or more fatty acid molecules produced in all types of cell in the body. Phospholipids found in the tissues are either anionic (phosphotidyl serine, phosphotidyl ionositol, phosphatidic acid and cardiolipin) or neutral (phosphotidyl choline and phosphotidyl ethanolamine).
Antiphospholipid antibodies were initially thought to target anionic phospholipids. But various evidences suggest aPLs are directed against a variety of phospholipid-binding proteins such as b 2GPI, prothrombin, protein C, and protein S immobilized on anionic phospholipid membranes. The link between aPL, APS and thrombosis has not been conclusively elucidated. Several hypotheses have been proposed to explain the cellular and molecular mechanisms by which antiphospholipid antibodies promote thrombosis.
Interference with coagulation cascade
Phospholipids are critical at several points in the extrinsic, intrinsic, and common pathways of the coagulation cascade [Figure 1]. Phospholipids are necessary for activation of factor X in the intrinsic pathway, activation of factors IX and X in the extrinsic pathway and conversion of prothrombin to thrombin in the final or common pathway. The aPL interfere with or modulate the function of phospholipid-binding proteins involved in the regulation of coagulation leading to hypercoagulable state by the following mechanisms:
- The interaction of aCL with 2GPI bound to phospholipid inhibits protein C, protein S, which are natural anticoagulants.
- Antiphospholipid antibodies bind to thrombin activated platelets, inhibiting thrombin-mediated endothelial cell prostacyclin release or inhibiting protein C activation.
- Autoantibodies to a variety of endothelial cell surface proteins including thrombomodulin, heparin sulfate, and heparin sulfate proteoglycan have been described. IgG aPLs that react with heparin sulfate have been shown to inhibit the formation of anti-thrombin III complexes that could contribute to vascular thrombosis.
- Finally, antibodies against platelet-activating factor in patients with autoimmune diseases and APS have been identified.
Activation of endothelial cells
Antiphospholipid antibodies recognize b2GPI bound to resting endothelial cells, although the basis for the interaction of b2GPI with viable endothelial cells remain unclear. Binding of antiphospholipid antibodies induces activation of endothelial cells, as assessed by up-regulation of the expression of adhesion molecules, the secretion of cytokines and the metabolism of prostacyclins resulting in hypercoagulation.
A second theory focuses on oxidant-mediated injury of the vascular endothelium. Oxidized low-density lipoprotein (LDL), a major contributor to atherosclerosis, is taken up by macrophages, leading to macrophage activation and subsequent damage to endothelial cells.? Autoantibodies to oxidized LDL occur in association with aCL, and some anticardiolipin antibodies cross-react with oxidized LDL. Moreover, anticardiolipin antibodies bind to oxidized cardiolipin, suggesting that anticardiolipin antibodies recognize oxidized phospholipids, phospholipid-binding proteins, or both, thus contributing to hypercoagulation.
| Detection Of Antiphospholipid Antibodies|| |
The most commonly detected subgroups of aPL are lupus anticoagulant antibodies, aCL and anti-b2GPI.
Division into these subgroups is broadly based on the method of detection. Lupus anticoagulant antibodies are identified by coagulation assays in which they prolong clotting times. In contrast, aCL and anti-b2GPI are detected by immunoassays that measure immunologic reactivity to phospholipids or phospholipids-binding protein (cardiolipin and b2GPI, respectively) as described in [Table 2]. In general, lupus anticoagulant antibodies are more specific for APS and aCLs are more sensitive. The specificity of aCL for APS increases with titer and is higher for IgG than IgM isotope.
| Classification Criteria For Detection Of Antiphospolipid Syndrome|| |
In 1999 an International Workshop issued the first Consensus Statement on preliminary classification criteria for definite APS. The classification criteria were revised in 2006 at the Eleventh International Congress on aPLs in Sydney, Australia. The clinical and laboratory criteria for APS were updated  and definite APS was the presence of at least one of the clinical and one of the laboratory criteria as outlined in [Table 3].
| Genetic Predisposition|| |
There is a familial association and relatives of persons with known APS are more likely to have aPL antibodies. Various studies suggest a familial occurrence of aCL and Lupus anticoagulant, with or without clinical evidence of APS. This familial tendency could be genetically determined, because APS, aCL, and lupus anticoagulant occur in families carrying haplotypes which contain HLA-DR4, -DR7, and -DRw53. . HLA-DR4 seems to be more important in Anglo-Saxons, whereas DR7 in populations of Latin origin.
| Epidemiology|| |
Several studies have been conducted to establish the prevalence of aPL in cohorts of healthy subjects. The rationale behind these studies is that knowing the prevalence of aPL in healthy persons is necessary to establish associations between aPL and different clinical manifestations: most of the studies report a frequency of elevated aPL between 1% and 5%. Most aPL in apparently healthy individuals are low titer and transient. The presence of aPL in pregnant women has been associated with pregnancy morbidity and the prevalence of aPL in healthy pregnant women has been reported to be as high as 5.3%.
The elderly have many autoantibodies which increase with age and most studies report a higher prevalence of aPL in the elderly than in younger adults.
Among patients with SLE, the prevalence of aPL is much higher, ranging from 12 to 30% for aCL, and 15 to 34% for lupus anticoagulant antibodies. In contrast, the APS may develop in 50 to 70 % of patients with both SLE and aPL after 20 years of follow-up.
| Clinical Manifestations Of Antiphospolipid Syndrome|| |
The clinical manifestations of APS involve different organs and systems, such as blood vessels, central nervous system, skin, kidneys, gastrointestinal tract, heart and placenta. The unifying mechanism of all these manifestations is thrombosis, either arterial or venous.
The spectrum of clinical manifestations that are associated with aPL is extensive. Those included in the classification criteria are outlined in [Table 3]. However, some clinical manifestations, such as heart valve disease, livedo reticularis, thrombocytopenia, APS nephropathy and neurological manifestations, have not been included in the criteria.
The literature on the clinical manifestations of APS is vast and includes a number of case reports, but there are two reports on large series of patients with APS, which provide reliable information as to the relative frequency of the different clinical manifestations of this syndrome., In a multicenter study, 53.1% of patients had primary APS, while 36.2% had SLE with secondary APS. The most frequently presenting manifestations of APS are deep vein thrombosis (31.7% of patients), thrombocytopenia (21.9%), livedo reticularis (20.4%), and stroke (13.1%). Less frequent manifestations include superficial thrombophlebitis (9.1%), pulmonary embolism (9%), transient ischemic attacks (7%), and hemolytic anemia (6.6%). Fetal loss is the presenting manifestation in 14% of female patients. Although the clinical profiles of primary APS and SLE associated APS are similar, some features such as hemolytic anemia,neutropenia, lymphopenia and heart valve disease are significantly more frequent in the latter group of patients.
| Cutaneous Manifestations Of Antiphospolipid Syndrome|| |
Dermatological manifestations may be the presenting feature in primary APS and it can be the first clue in the diagnosis of this disease. So it is important to investigate patients who present with cutaneous manifestation related to venous or arterial thrombosis or microthrombosis.
The cutaneous manifestations of APS are listed in [Table 4].
Various studies have shown the frequency of dermatological manifestations with APS.
Weinstein et al. report that livedo reticularis or racemosa is commonly seen in APS, but is one of the least specific findings and APS should be considered in patients who have idiopathic livedo reticularis with cerebrovascular accidents (Sneddon's syndrome), atrophie blanche, livedoid vasculitis, malignant atrophic papulosis, or anetoderma. Retiform (branching, stellate) purpura or necrosis is the most characteristic cutaneous lesion of many different cutaneous microvascular occlusion syndromes, including APS.
Diogenes et al. report 40 cases in which the most common dermatological manifestation was dermographism followed by acrocyanosis, urticaria, diffuse alopecia, livedo reticularis, ulcers and necrosis, nodules, Raynaud's phenomenon, purpura, pterygium unguium and subungual hemorrhage.
According to a study by Diallo et al. the most common presentation is necrosis of the extremities followed by purpuric lesions, cutaneous ulcers, acrocyanosis, livedo and subungual splinter hemorrhage.
Toubi et al. report that livedo reticularis is a marker for predicting multi-system thrombosis in antiphospholipid syndrome.
| Management Of Antiphospolipid Syndrome|| |
The management of antiphospolipid syndrome involves primary thromboprophylaxis and secondary management of thromboembolic events.
| Primary Thromboprophylaxis|| |
Primary thromboprophylaxis with low dose aspirin is instituted in patients with aPL and no thrombotic events. Wahl et al. have shown that low dose aspirin can be used in the primary thromboprophylaxis but a recent study by Erkan et al. and the Physician health study shows that aspirin is not useful in preventing thrombus formation. The controversy over thromboprophylaxis requirement in patients who are asymptomatic with aPL remains unsolved. Rand et al. proved that hydroxychloroquine reduces the formation of aPL--b2GPI complexes to phospholipid bilayers and can be used in thromboprophylaxis in APS.
Cessation of oral contraceptive,treatment of hypertension and hyperlipidemia and avoidance of smoking are additional measures to reduce the thromboembolic events.
| Secondary Thromboprophylaxis|| |
Secondary thromboprophylaxis refers to the treatment initiated after the occurrence of thrombotic events to prevent further attacks. Low molecular weight heparin has been used in the initial phase followed by warfarin in the management of APS.
The current recommendation for secondary thromboprophylaxis is life long warfarin. When using oral anticoagulation with warfarin, most clinicians favor keeping the international normalized ratio (INR) between 2.0 and 3.0 to avoid hemorrhagic complications. Every 1-point rise in INR increases the risk for major bleeding by 42% and high-intensity anticoagulation carries an increased risk of bleeding.?
A recent prospective randomized controlled trial on the efficacy and safety of high-intensity warfarin treatment (target INR, 3.0-4.0) versus standard-intensity treatment (target INR, 2.0-3.0) in 114 patients with aPLs and thrombosis showed that there was no difference in the rates of recurrent thrombosis and bleeding between the two groups.
Low-molecular-weight heparin is used instead of warfarin for treatment during pregnancy. Noble et al. have compared low molecular weight heparin and unfractionated heparin along with low dose aspirin in the treatment of APS-associated recurrent pregnancy loss and concluded that low-molecular-weight heparin is as safe as unfractionated heparin for the prevention of recurrent pregnancy loss.
Antiplatelet agents such as dipyridamole, aspirin with dipyridamole, ticlopidine or clopidogrel bisulfate have been used for secondary prevention after non-cardioembolic strokes or TIA. Intravenous immunoglobulin (IVIg) has also been used in the treatment of thrombotic events in APS.
Recently, rituximab, a monoclonal antibody that selectively depletes CD20 + B cells, has been successfully employed to treat thrombocytopenia in a small number of patients with resistant APS.
| Conclusion|| |
Antiphospholipid antibodies have long been recognized. However, it was only recently discovered that the antigenic targets of these antibodies were, in fact, plasma proteins or complexes of these proteins with phospholipids. This led to expansion of the scope of research on aPL. It has now been established that aPLs, through multiple mechanisms, act on the coagulation system, the fibrinolytic system, platelets and endothelial cells. Laboratory detection of aPL has also changed radically with the recognition of their antigenic targets. APS can affect any organ or system and although dermatological manifestations are not included in the classification criteria, they may be the presenting feature of this syndrome.
Prognosis primarily depends on the severity of the clinical manifestations and, therefore, knowledge of the presentation and manifestations of this disease is critical in early detection and prompt treatment to prevent life-threatening consequences of this disease process.
| References|| |
|1.|| Myones BL, McCurdy D. The antiphospholipid syndrome: Immunologic and clinical aspects. Clinical spectrum and treatment. J Rheumatol 2000;58: 20-8. |
|2.||2. Pierangeli SS, Gharavi AE, Harris EN. Testing for antiphospholipid antibodies: problems and solutions. Clin Obstet Gynecol 2004;44:48-57. |
|3.||3. Diógenes MJ, Diógenes PC, de Morais Carneiro RM, Neto CC, Duarte FB, Holanda RR. Cutaneous manifestations associated with antiphospholipid antibodies. Int J Dermatol 2004;43:632-7. |
|4.||4. Wassermann A, Neisser A, Bruck C. Eline serodiagnostiche Reaktion bei Syphilis. Dtsch Med Wochenschr 1906;32:745-6. |
|5.||5. Pangborn MC. A new serologically active phospholipid from beef heart. Proc Soc Exp Biol Med 1941;48:484-6. |
|6.||6. Haserick JR, Long R. Systemic Lupus erythematous preceded by false-positive serologic tests for syphilis; presentation of five cases. Ann Intern Med 1952;37:559-65. |
|7.||7. Harris EN, Gharavi AE, Boey ML, Patel BM, Mackworth-Young CG, Loizou S, et al. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet 1983;2:1211-4. |
|8.||8. Loizou S, McCrea JD, Rudge AC, Reynolds R, Boyle CC, Harris EN. Measurement of anti-cardiolipin antibodies by an enzyme-linked immunosorbent assay (ELISA): standardization and quantitation of results. Clin Exp Immunol 1985;62:738-45. |
|9.||9. Hughes GR, Harris NN, Gharavi AE. The anticardiolipin syndrome. J Rheumatol 1986;13:486-9. |
|10.||10. Harris EN, Baguley E, Asherson RA, Hughes GRV. Clinical and serological features of the antiphospholipid syndrome. J Rheumatol 1987;26:19. |
|11.||11. Asherson RA. A "primary" antiphospholipid syndrome? J Rheumatol 1988;15:1742-6. |
|12.||12. Galli M, Comfurius P, Maassen C, Hemker HC, de Baets MH, van Breda-Vriesman PJ, et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990;335:1544-7. |
|13.||13. McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: b2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci U S A 1990;87:4120-4. |
|14.||14. Hunt JE, McNeil HP, Morgan GJ, Crameri RM, Krilis SA. A phospholipid-beta 2-glycoprotein I complex is an antigen for anticardiolipin antibodies occurring in autoimmune disease but not with infection. Lupus 1992;1:75-81. |
|15.||15. Arvieux J, Roussel B, Jacob MC, Colomb MG. Measurement of antiphospholipid antibodies by ELISA using beta 2-glycoprotein I as an antigen. J Immunol Methods 1991;143:223-9. |
|16.||16. Roubey RA. Immunology of the antiphospholipid antibody syndrome. Arthritis Rheum 1996;39:1444-54. |
|17.||17. Lehninger AL. Lipid and membranes. In: Anderson S, Fox J, editors. Principles of biochemistry. New York: Worth Publishers; 1982. p. 303-29. |
|18.||18. Hanly JG, Hong C, James H, Mansour M, Jones JV. Requirement of beta 2-glycoprotein 1 as cofactor in the binding of IgM and IgA anticardiolipin antibodies. J Rhematol 1995;22:1091-6. |
|19.||19. Rao LVM, Permpikul P, Rapaport SI. Studies of the binding of lupus anticoagulant IgG to prothrombin, beta 2-glycoprotein 1 and phosphatidylserine. Blood 1993;82:405. |
|20.||20. Oosting JD, Derksen RH, Bobbink IW, Hackeng TM, Bouma BN, de Groot PG. Antiphospholipid antibodies directed against a combination of phospholipids with prothrombin, protein C or protein S: An explanation for their pathogenic mechanism? Blood 1993;81:2618-25. |
|21.||21. Oosting JD, Preissner KT, Derksen RH, de Groot PG. Autoantibodies directed against the epidermal growth factor-like domains of thrombomodulin inhibit protein C activation in vitro. Br J Haematol 1993; 85:761-8. |
|22.||22. Fillit H, Lahita R. Antibodies to vascular heparin sulfate proteoglycan in patients with systemic lupus erythematosus. Autoimmunity 1991;9:159-64. |
|23.||23. Shibata S, Harpel PC, Gharavi A, Rand J, Fillit H. Auto antibodies to heparin from patients with antiphospholipid antibody syndrome inhibit formation of anti-thrombin III complexes. Blood 1994;83:2532-40. |
|24.||24. Barquinero J, Ordi-Ros J, Selva A, Perez-Peman P, Vilardell M, Khamashta M. Antibodies against platelet-activating factor in patients with antiphospholipid antibodies. Lupus 1994;3:55-8. |
|25.||25. Meroni PL, Del Papa N, Raschi E, Panzeri P, Borghi MO, Tincani A, et al. 2-Glycoprotein I as a `cofactor' for anti- phospholipid reactivity with endothelial cells. Lupus 1998;7:S44-7. |
|26.||26. Meroni PL, Raschi E, Camera M, Testoni C, Nicoletti F, Tincani A, et al. Endothelial activation by aPL: a potential pathogenetic mechanism for the clinical manifestations of the syndrome. J Autoimmun 2000;15:237-40. |
|27.||27. Ames PR. Antiphospholipid antibodies, thrombosis and atherosclerosis in systemic lupus erythematosus: a unifying membrane stress syndrome hypothesis. Lupus 1994;3:371-7. |
|28.||28. Vaarala O, Alfthan G, Jauhiainen M, Leirisalo-Repo M, Aho K, Palosuo T. Crossreaction between antibodies to oxidised low-density lipoprotein and to cardiolipin in systemic lupus erythematosus. Lancet 1993;341:923-5. |
|29.||29. Hörkkö S, Miller E, Dudl E, Reaven P, Curtiss LK, Zvaifler NJ, et al. Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids: recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein. J Clin Invest 1996;98:815-25. |
|30.||30. Vlachoyiannopoulos PG, Samarkos M, Sikara M, Tsiligros P. Antiphospholipid antibodies: Laboratory and Pathogenetic Aspects. Crit Rev Clin Lab Sci 2007;44:271-338. |
|31.||31. de Groot PG, Derksen RH. Specificity and clinical relevance of lupus anticoagulant. Vessels 1995;1:22-6. |
|32.||32. Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999;42:1309-11. |
|33.||33. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemos 2006;4:295-306. |
|34.||34. Sebastiani GD, Galeazzi M, Morozzi G, Marcolongo R. The immunogenetics of the antiphospholipid syndrome, anticardiolipin antibodies and lupus anticoagulant. Semin Arthritis Rheum 1996;25:414-20. |
|35.||35. Petri M. Epidemiology of the antiphospholipid antibody syndrome. J Autoimmun 2000;15:145-51. |
|36.||36 Kutteh WH. Antiphospholipid antibodies and reproduction. J Reprod Immunol 1997;35:151-71. |
|37.||37. Richaud-Patin Y, Cabiedes J, Jakez-Ocampo J, Vidaller A, Llorente L. High prevalence of protein-dependent and protein-independent antiphospholipid and other autoantibodies in healthy elders. Thromb Res 2000;99:129-33. |
|38.||38. 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 disease. Am J Med 1996;101:576-83. |
|39.||39. Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, et al. Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1,000 patients. Medicine (Baltimore) 1993;72:113-24. |
|40.||40. Alarcón-Segovia D. Clinical manifestations of the antiphospholipid syndrome. J Rheumatol 1992;19:1778-81. |
|41.||41. Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002;46:1019-27. |
|42.||42. Vianna JL, Khamashta MA, Ordi-Ros J, Font J, Cervera R, Lopez-Soto A, et al. Comparison of the primary and secondary antiphospholipid syndrome: a European Multicenter Study of 114 patients. Am J Med 1994;96:3-9. |
|43.||43. Weinstein S, Piette W. Cutaneous manifestations of antiphospholipid antibody syndrome. Hematol Oncol Clin North Am 2008;22:67-77. |
|44.||44. Diallo M, Niang SO, Kane A, Dieng MT, Ndiaye B. Antiphospholipid antibodies syndrome in dermatology in Dakar: 11 case report. Dakar Med 2007;52:41-5. |
|45.||45. Asherson RA, Francès C, Iaccarino L, Khamashta MA, Malacarne F, Piette JC, et al. The antiphospholipid antibody syndrome: diagnosis, skin manifestations and current therapy. Clin Exp Rheumatol 2006;24:S46-51. |
|46.||46. Kacalak-Rzepka A, Zaluga E, Maleszka R, Królicki A, Klimowicz A. Bullous systemic lupus erythematosus with antiphospholipid syndrome. J Eur Acad Dermatol Venereol 2004;18:490-4. |
|47.||47. Elkayam O, Yaron M, Brazowski E, Caspi D. Rheumatoid nodules in a patient with primary antiphospholipid (Hughes) syndrome. Lupus 1998;7:488-91. |
|48.||48. Kuroda K, Mizoguchi M. Subcutaneous Granuloma pyogenicum in Patients with Antiphospholipid Antibodies. Dermatology 2004;208:331-4. |
|49.||49. Lee HW, Chang SE, Lee MW, Choi JH, Moon KC, Koh JK. Interstitial granulomatous dermatitis with plaques associated with antiphospholipid syndrome Br J Dermatol 2005;152:814-6. |
|50.||50. Echigo T, Hasegawa M, Inaoki M, Yamazaki M, Sato S, Takehara K. Antiphospholipid antibodies in patients with autoimmune blistering disease. J Am Acad Dermatol 2007;57:397-400. |
|51.||51. Toubi E, Krause I, Fraser A, Lev S, Stojanovich L, Rovensky J, et al. Livedo reticularis is a marker for predicting multi-system thrombosis in antiphospholipid syndrome. Clin Exp Rheumatol 2005;23:499-504. |
|52.||52. Wahl DG, Bounameaux H, de Moerloose P, Sarasin FP. Prophylactic antithrombotic therapy for patients with systemic lupus erythematosus with or without antiphospholipid antibodies: do the benefits outweigh the risks? A decision analysis. Arch Intern Med 2000;160:2042-8. |
|53.||53. Erkan D, Harrison MJ, Levy R, Peterson M, Petri M, Sammaritano L, et al. Aspirin for primary thrombosis prevention in the antiphospholipid syndrome: a randomized, double-blind, placebo-controlled trial in asymptomatic antiphospholipid antibody-positive individuals. Arthritis Rheum 2007;56:2382-91. |
|54.||54. Ginsburg KS, Liang MH, Newcomer L, Goldhaber SZ, Schur PH, Hennekens CH, et al. Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis. Ann Intern Med 1992;117:997-1002. |
|55.||55. Rand JH, Wu XX, Quinn AS, Chen PP, Hathcock JJ, Taatjes DJ. Hydroxychloroquine directly reduces the binding of antiphospholipid antibody-beta2-glycoprotein I complexes to phospholipid bilayers. Blood 2008;112:1687-95. |
|56.||56. Glasnoviæ M, Bosnjak I, Vcev A, Soldo I, Bedekoviæ D, Milakoviæ S, et al. Vascular thrombosis associated with antiphospholipide syndrome. Coll Antropol 2008;32:103-7. |
|57.||57. Erkan D, Lockshin MD. New approaches for managing antiphospholipidsyndrome. Nat Clin Pract Rheumatol 2009;5:160-70. |
|58.||58. van der Meer FJ, Rosendaal FR, Vandenbroucke JP, Briët E. Bleeding complications in oral anticoagulant therapy. An analysis of risk factors. Arch Intern Med 1993;153:1557-62. |
|59.||59. al-Sayegh FA, Ensworth S, Huang S, Stein HB, Klinkhoff AV. Hemorrhagic complications of long-term anticoagulant therapy in 7 patients with systemic lupus erythematosus and antiphospholipid syndrome. J Rheumatol 1997;24:1716-8. |
|60.||60. Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis 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;349:1133-8. |
|61.||61. Dresang LT, Fontaine P, Leeman L, King VJ. Venous thromboembolism during pregnancy. Am Fam Physician 2008;77:1709-16. |
|62.||62. Noble LS, Kutteh WH, Lashey N, Franklin RD, Herrada J. Antiphospholipid antibodies associated with recurrent pregnancy loss: prospective, multicenter, controlled pilot study comparing treatment with low-molecular-weight heparin versus unfractionated heparin. Fertil Steril 2005;83:684-90. |
|63.||63 Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest 2001;119:300S-20 |
|64.||64. Horn HC, Grau K, Junker P. IVIG treatment for progressive stroke in the primary antiphospholipid antibody syndrome. Lupus 2004;13:478-80. |
|65.||65 Rubenstein E, Arkfeld DG, Metyas S, Shinada S, Ehresmann S, Liebman HA. Rituximab treatment for resistant antiphospholipid syndrome. J Rheumatol 2006;33:355-7. |
[Table 1], [Table 2], [Table 3], [Table 4]
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