Renal Involvement in the Antiphospholipid Syndrome (APS)—APS Nephropathy

Although the kidney represents a major target organ in antiphospholipid syndrome (APS), renal involvement in APS was poorly recognized until recently. The most well-recognized renal manifestations of APS are the renal artery thrombosis/stenosis, renal infarction, hypertension, renal vein thrombosis, end-stage renal disease, increased allograft vascular thrombosis, some types of glomerular disease, and a small-vessel vaso-occlusive nephropathy, recently defined as APS nephropathy. APS nephropathy was first described in primary APS patients, characterized by acute thrombotic lesions in glomeruli and/or arterioles (thrombotic microangiopathy) and chronic vascular lesions such as fibrous intimal hyperplasia of arterioles and interlobular arteries, organized thrombi with or without recanalization, and fibrous arterial and arteriolar occlusions or focal cortical atrophy. APS nephropathy was also detected in further studies including patients with systemic lupus erythematosus (SLE)-related APS and SLE/non-APS patients with positive antiphospholipid antibodies, independently of lupus nephritis. The same histologic lesions, especially thrombotic mictroangiopathy, were also observed in patients with catastrophic APS. The most frequent clinical and laboratory characteristics of APS nephropathy in all the above groups of patients are hypertension (often severe), proteinuria (ranging from mild to nephrotic range), hematuria, and acute or chronic renal insufficiency.     

Thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome

OBJECTIVE: To evaluate the usefulness and feasibility of measuring plasma von Willebrand factor (vWF)-cleaving metalloprotease activity (ADAMTS 13) in the differential diagnosis of thrombotic thrombocytopenic purpura (TTP), the hemolytic uremic syndrome, and other thrombotic microangiopathies. DATA SOURCES: Articles published in the medical literature. DATA EXTRACTION AND SYNTHESIS: In TTP, a multimeric form of vWF that is larger than that ordinarily found in the plasma may cause systemic platelet aggregation under the high-shear conditions of the microcirculation. ADAMTS 13 is a divalent cation-activated, vWF-cleaving metalloprotease that converts unusually large vWF multimers derived from endothelial cells into smaller vWF forms in normal plasma. ADAMTS 13 is severely reduced or absent in most patients with TTP. The vWF-cleaving metalloprotease is present in fresh-frozen plasma, cryoprecipitate-depleted plasma (cryosupernatant), and in plasma that has been treated with solvent and detergent. The enzyme is defective in children with chronic relapsing TTP. Infusion of any of the plasma products that contain the vWF-cleaving metalloprotease stops or prevents (for about 3 weeks) TTP episodes in these patients. An immunoglobulin (Ig) G autoantibody to the vWF-cleaving metalloprotease is found transiently in many adult patients with acquired acute idiopathic, recurrent, and ticlopidine/clopidogrel-associated TTP. Patients with acquired TTP require plasma exchange, that is, both infusion of a plasma product containing vWF-cleaving metalloprotease and removal of autoantibody and/or unusually large vWF multimers by plasmapheresis. The pathophysiology of platelet aggregation in bone marrow transplantation/chemotherapy-associated thrombotic microangiopathy, as well as in hemolytic uremic syndrome, is not established. In neither condition is there a severe decrease in plasma vWF-cleaving metalloprotease activity, as there is in TTP. CONCLUSIONS: The presently available lengthy and complicated procedure for estimation of plasma vWF-cleaving metalloprotease activity is not yet practical for rapid diagnostic use. This test has supplanted the equally lengthy and difficult, less specific analysis of plasma vWF multimeric pattern. If the clinical distinction between TTP and hemolytic uremic syndrome is uncertain, it is appropriate to acquire (before therapy) a citrate-plasma sample for the ultimate determination of vWF-cleaving metalloprotease activity.     

Thrombotic thrombocytopenic purpura: proposal of a new pathogenic mechanism involving Helicobacter pylori infection

Thrombotic thrombocytopenic purpura (TTP) is a severe, occlusive, thrombotic microangiopathy characterized by a systemic platelet aggregation, organ ischemia, profound thrombocytopenia and erythrocyte fragmentation. Recent observations have documented that a deficiency of a von Willebrand factor (VWF)-cleaving protease, termed ADAMTS13, that normally cleaves hyper-reactive unusually large VWF multimers into smaller and less adhesive VWF forms, may be responsible for many cases of TTP. Multiple mutations of the ADAMTS13 gene can result in ADAMTS13 deficiency and cause congenital TTP, while autoantibodies neutralizing ADAMTS13 protease activity have been associated with acquired TTP. However, in spite of the recent progresses in the pathophysiology of TTP, many aspects of this disease remain still controversial. In this study, basing on the laboratory results of a group of eight patients with an acquired form of TTP, an alternative pathogenic mechanism for TTP involving Helicobacter pylori infection is proposed. In fact, Helicobacter pylori, which has been recently implied in the pathogenesis of idiopathic thrombocytopenic purpura (ITP), could function as a triggering factor in TTP by inducing platelet aggregation through an interaction with VWF.     

Thrombotic thrombocytopenic purpura: a case report

We report a case of thrombotic thrombocytopenic purpura (TTP) in a 60 years-old woman with Sjogren's syndrome. Symptomatology on admission leads to evoke the diagnosis of TTP. Biological results allow to set the diagnosis. Actually, association of haemolytic anaemia, schizocytes and thrombocytopenia are in favour of TTP. Undetectable ADAMTS 13 activity (below 5%) confirms the diagnosis. In congenital TTP, plasma ADAMTS 13 is absent or severely reduced as a consequence of mutations in the two ADAMTS 13 gene. In acquired TTP, circulating antibodies inhibit plasma ADAMTS 13 activity. In those cases, further biological studies are needed to find a cause of TTP. Follow-up implies standard laboratory tests. Plasma exchanges are progressively tapered after normalization of platelets count.     

New subsets of the antiphospholipid syndrome in 2006: "PRE-APS" (probable APS) and microangiopathic antiphospholipid syndromes ("MAPS")

The concept of "probable" antiphospholipid syndrome (APS) is almost identical with several conditions which may presage the development of the APS with its major complications of large vessel thromboses resulting in deep vein occlusions in the lower limbs (DVT) particularly and strokes. These conditions comprising livedo reticularis, chorea, thrombocytopenia, fetal loss and valve lesions. These conditions, comprising livedo reticularis, chorea, thrombocytopenia, fetal loss and valve lesions may be followed, often years later by diagnosable APS. The issue whether these patients should be more aggressively treated on presentation in order to prevent the thrombotic complications. A new subset of the APS is proposed viz. microangiopathic antiphospholipid syndrome ("MAPS") comprising those patients presenting with thrombotic microangiopathy and demonstrable antiphospholipid antibodies who may share common although not identical provoking factors (e.g. infections, drugs), clinical manifestations and haematological manifestations (severe thrombocytopenia, hemolytic anaemia) and treatments viz. plasma exchange. Patients without large vessel occlusions may be included in the MAPS subset. These conditions include thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), and the HELLP syndrome. Patients with catastrophic antiphospholipid syndrome (CAPS) who do not demonstrate large vessel occlusions also fall into this group. Disseminated intravascular coagulation (DIC) has also been reported with demonstrable antiphospholipid antibodies and also manifests severe thrombocytopenia and small vessel occlusions. It may cause problems in differential diagnosis.     

Development and application of a new ADAMTS13 assay for TTP diagnosis

A plasma glycoprotein, von Willebrand factor (VWF), is essential for normal platelet aggregation. In healthy individuals, the homo-multimeric forms (VWF multimers) are partially cleaved by a plasma metalloprotease, ADAMTS13. Congenital or acquired deficiency of ADAMTS13 activity leads to the accumulation of hyperactive large VWF multimers, inducing a life-threatening disease, thrombotic thrombocytopenic purpura (TTP). As measuring ADAMTS13 activity is important in TTP diagnosis, a number of assay methods have been developed in the past few years. However, the time and skill required for these methods prohibited the progress of clinical usage. Recently, we have developed a fluorescence resonance energy transfer (FRET) assay for ADAMTS13 activity. A synthetic 73-amino-acid peptide, FRETS-VWF73, which is now commercially available, is used as a substrate. Cleavage of this peptide between two modified residues relieves the fluorescence quenching in the intact form. Incubation of FRETS-VWF73 with normal plasma quantitatively increased fluorescence over time, while TTP-patient plasma had little or no effect. The measurement can be achieved within a one-hour period using a 96-well format in commercial plate readers with common filters. The FRET assay will be useful not only for TTP diagnosis but also characterization of thrombotic microangiopathies.     

Clinical Thrombotic Manifestations in SLE Patients With and Without Antiphospholipid Antibodies: A 5-year Follow-up

Objective To analyze the association of antiphospholipid antibodies (aPL) with the development of clinical thrombotic manifestations and to characterize the efficacy of anti-thrombotic therapies used. Methods 272 systemic lupus erythematosus (SLE) patients participated in the study. Patient files and a cumulative database were used to collect patients’ medical histories. Anti-cardiolipin (aCL), anti-beta2-glycoprotein I (aβ2GPI) antibodies, and lupus anticoagulant (LAC) were measured according to international recommendations. New thrombotic events were registered during follow-up. Results The patients were prospectively studied for 5 years, of whom 107 were aPL negative (aPL− group). Criteria for antiphospholipid syndrome (APS) were fulfilled by 84 of 165 aPL-positive patients (APS+ group) indicating that SLE patients with aPL have around 50% risk to develop thrombotic complications. The aPL+ group (n = 81) consisted of aPL+ but APS− patients. LAC was the most common aPL (n = 27, 32.1%) in patients with APS. The cumulative presence of aPL further increased the prevalence of thrombotic events. During the follow-up period, aPL developed in 8 of 107 patients (7.5%) from the aPL− group, of whom 3 (2.8%) presented with thrombotic complications. Other types of aPL developed in 7 of 165 (4.2%) aPL+ patients within 5 years. New thrombotic events occurred in 3.7% of aPL+ (n = 3) and 8.3% (n = 7) of the APS group. During follow-up, 52 of 81 aPL+ patients received primary prophylaxis, and 1 (1.9%) had transient ischemic attack (TIA). In the non-treatment group, 2 (6.9%) had stroke. Seventy-nine of 84 of the APS patients received secondary prophylaxis, and myocardial infarction occurred in 2 patients (on cumarine therapy maintaining an international normalized ratio around 2.5–3.0), and 5 suffered a stroke/TIA (1 on aspirin and 4 on aspirin + cumarine). Conclusion The findings emphasize the importance of determining both aCL and aβ2GPI antibodies and LAC in SLE patients and the need for adequate anticoagulant therapy.     

Antiphospholipid syndrome--primary or secondary? Therapeutic problem

A 44-year old woman hospitalized because of chest pain, pleuropneumonic lesions and high temperature is described. Disease of connective tissue was suspected because of symptoms (fever, chest pain) aggravated despite antibioticotherapy. During diagnostic procedures hypoxemia was observed and thrombotic lesions were discovered in the right popliteal vein and in numerous pulmonary arteries. Pulmonary thrombosis was recognised and patient was admitted to the Intensive Care Unit. Anti-ds.-DNA antibodies were not found but anticardiolipin (aCL) antibodies and lupus anticoagulant (LA) were present in high concentrations in serum. We didn't find all symptoms required for SLE diagnosis. Anticoagulant treatment was effective and we recognised primary antiphospholipid syndrome (APS). It is a less frequent syndrome than "secondary APS" connected with systemic lupus erythematosus. Patient should be treated with anticoagulant drugs and observed whether symptoms of SLE would appear.     

A case of thrombotic thrombocytopenic purpura with systemic lupus erythematosus]

We described a case of thrombotic thrombocytopenic purpura (TTP) with systemic lupus erythematosus (SLE). A-60-year old woman was admitted to our hospital because of fever, disconsciousness, and general fatigue. 32 years ago, she was diagnosed as SLE with Raynaud's phenomenon, rash, photosensitivity, arthritis, lymphocytopenia, and ANA. Her SLE was well controlled with 10 mg predonisolone as a maintance dose until several weeks ago. On admission, severe thrombocytopenia (0.7x10(4)/microl) and other laboratory data revealed microangiopathic hemolytic anemia and renal dysfunction, Immediately after diagnosed as TTP, plasma exchange and corticosteroid therapy started. In spite of the treatment, disconsciousness progressed and systemic convulsion occurred and died 4 days after admission. Autopsied examination revealed diffuse microvascular hyalinized thrombi in heart, kidney, liver, spleen, and pancreas. Some microvascular thrombi were detected in lymph nodes, bone marrow, intestine. Pathological diagnosis of TTP was made on microvascular hyalinized platelet thrombi in organs. Von Willebrand factor-cleaving protease (VWF-CP) activity in plasma on set is less than 0.5 percent of normal and inhibitor for VWF-CP was detected. We here report a valuable case for analysis of pathogenesis in SLE-TTP.     

The 'primary' antiphospholipid syndrome: antiphospholipid antibody pattern and clinical features of a series of 23 patients.

Twenty-three patients with the 'primary' antiphospholipid syndrome were studied over 2-6 years. Twenty-two (96%) had antiphospholipid antibodies detected by ELISA (87% had antibodies to thromboplastin and 70% to cardiolipin), and 18 out of the 21 tested patients (86%) had lupus anticoagulant activity by coagulative assays. Mean age of the cohort was 29.9 years and the sex ratio (female:male) 4.75:1. Eleven patients presented 18 venous and/or arterial thrombosis and 13 had 25 foetal losses (84% occurred during the second and third trimester). Other clinical features were migraine, livedo reticularis, and epilepsy. Three patients had relatives with systemic lupus erythematosus. Thrombocytopaenia was seen in 33%, antinuclear antibodies in low or moderate titre in 30%, and haemolytic anaemia in 13%. During the follow-up, two patients presented recurrent thrombosis despite anticoagulant therapy, one of them dying because of recurrent pulmonary thromboembolism. Four patients achieved successful term pregnancies after treatment with aspirin and a further patient after treatment with aspirin and low dose prednisolone. No patient developed systemic lupus erythematosus or any other definable connective tissue disease. The 'primary' antiphospholipid syndrome may exist as a distinct clinical entity and all younger patients presenting with thrombotic events, foetal losses and/or thrombocytopaenia, without any evidence of a well defined disease, should be tested for antiphospholipid antibodies in order to rule out this syndrome.     

Antiphospholipid syndrome

Antiphospholipid syndrome (APS) is a disease characterized by venous and arterial thromboses or spontaneous abortions and the repeated detection of antiphospholipid antibodies (aPL). APS may be associated with another autoimmune disease (secondary APS), particularly systemic lupus erythematosus (SLE), or unrelated to an underlying disease (primary APS). APS affects almost all organs. In addition to the clinical criteria, lupus anticoagulant testing and immunological aPL determinations are required to establish the diagnosis of APS.     

Managing pregnancy-associated clinical emergencies in systemic lupus erythematosus: a case-based approach

ABSTRACT

Introduction: Systemic lupus erythematosus (SLE)-related thrombocytopenia during pregnancy and the postpartum period have been associated with adverse pregnancy outcomes and perinatal complications. In this case report, we present two SLE patients with thrombocytopenia emergencies secondary to HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome and thrombotic thrombocytopenic purpura (TTP).

Areas covered: The first case involved a 26-year-old woman, G1P0 at 26 weeks gestation (GA), with high-titer antiphospholipid antibodies (aPL) (positive lupus anticoagulant, anti-beta 2 glycoprotein-1 (aβ2GP1), anti-cardiolipin) and non-criteria aPL to phosphatidylserine/prothrombin complex and anti-domain 1 β2GP1. This case highlights the risks associated with aPL in pregnancy, considers management issues relating to anticoagulation during pregnancy and highlights the importance of maintaining a high index of suspicion for diagnosis of HELLP in SLE patients. The second case was a 36-year-old female, G3P2 at 32 weeks GA, with class III lupus nephritis (LN) who developed severe pre-eclampsia, which included mild thrombocytopenia. This case illustrates the challenges in identifying and differentiating between three pregnancy emergencies that can be seen in SLE patients (pre-eclampsia, LN, and TTP) and presents the management of TTP in peripartum SLE.

Expert opinion: These two cases remind us of the importance of timely diagnosis and management of thrombocytopenia in this population.     

Antiphospholipid Antibodies and Atherosclerosis: Insights from Systemic Lupus Erythematosus and Primary Antiphospholipid Syndrome

The issue of atherosclerosis in the antiphospholipid syndrome (APS) is receiving considerable attention within and without the autoimmune settting. Measurement of arterial intima media thickness (IMT) of is an easy and surrogate means of detecting subclinical atherosclerosis. This technique has been applied to patients with systemic lupus erythematosus (SLE) nand primary APS in the attempt to unravel a possible association between antiphospholipid antibodies and premature atherosclerosis. The available data is reviewed in the light of the most recent atherogenic pathways that may differentially account for premature vascular disease in SLE and primary APS.     

Anti-Beta 2-glycoprotein I antibody isotype and IgG subclass in antiphospholipid syndrome patients

Beta 2-glycoprotein I (beta2-GPI) is an antigenic target recognised by antiphospholipid antibodies found in association with the antiphospholipid syndrome (APS). In this study, the prevalence of Immunoglobulin M (IgM) and IgA anti-beta2-GPI antibodies was examined in APS patients and compared with IgG antibodies. In addition the value of measuring antibody isotypes and IgG subclass was investigated in the laboratory diagnosis of APS. A solid phase enzyme linked immunosorbent assay was established to measure IgG, IgM and IgA and IgG subclass antibodies to beta2-GPI in patients with APS and a variety of other thrombotic and non-thrombotic disorders. Raised levels of IgM anti-beta2-GPI antibodies were observed in 65% of patients with APS, 21% with systemic lupus erythematosus (SLE), 23% with rheumatoid factor, 4% with stroke, 5% carotid artery stenosis (CAS), 17% with a biological false positive serology for syphilis, 43% with infectious mononucleosis (IM) and 27% with human immunodeficiency virus (HIV). The median value for IgM antibodies to beta2-GPI for all these groups ranged from 2 to 7 arbitrary units (AU). Elevated levels of IgA antibodies to beta2-GPI were found in patients with APS (47%), SLE (13%), rheumatoid factor (26%), CAS (48%), stroke (25%), VDRL false positive serology for syphilis (33%), IM (47%) and HIV (7%). The median value of IgA antibodies to beta2-GPI in all of these groups ranged from 2 to 4 AU. Conversely the median value for IgG anti-beta2-GPI in APS patients was 112 AU compared to 1-4 AU in the other conditions examined. The presence of IgM and IgA antibodies to beta2-GPI was much less specific and sensitive for APS than IgG, with raised levels of these isotypes seen in a variety of thrombotic and non-thrombotic disorders. Elevated levels of IgG1, IgG2, IgG3 and IgG4 antibodies to beta2-GPI were detected in APS patients. While all four IgG anti-beta2-GPI antibody subclasses were represented in APS patients there appeared to be a significant overall skewing towards to the IgG2 subclass.     

The association of thrombocytopenia with systemic manifestations in the antiphospholipid syndrome

Thrombocytopenia is frequently found in patients with the antiphospholipid syndrome (APS), yet data concerning clinical associations of thrombocytopenia in patients with APS are still scarce. We evaluated possible associations between thrombocytopenia and various APS-related manifestations in a large group of APS patients. Three hundred and seven APS patients were retrospectively evaluated, 259 women and 48 men. Most patients had primary APS (PAPS) (n=173, 56.1%). APS was associated with systemic lupus erythematosus (SLE) in 104 patients (33.9%). All patients underwent detailed medical interview and routine physical examination. Further data were obtained from patients' medical files regarding the expression of various clinical manifestations of the disease. There were 90 patients with thrombocytopenia (29.3%), the rate was significantly higher in SLE compared to PAPS patients (41.9% vs. 23.1%, p=0.001). Similar rates of thrombocytopenia were found in male (29.2%) and female (29.3%) patients. Significant associations were found between thrombocytopenia and cardiac valves thickening and dysfunction, epilepsy, chorea, arthritis, livedo reticularis and skin ulcerations. In contrast, the rates of thrombotic episodes as well as obstetric complications were similar in patients with and without thrombocytopenia. Our data suggest the presence of thrombocytopenia may be a risk factor for cardiac, neurological, articular and cutaneous complications in APS.     

Childhood-onset systemic lupus erythematosus

OBJECTIVES: To describe the initial clinicolaboratory manifestations and short-term outcome in a series of Nigerian children with systemic lupus erythematosus (SLE). METHODS: A nonrandomized prospective study of consecutive cases of childhood-onset SLE. Baseline and follow-up clinicolaboratory data were collected and analyzed. Each patient was followed up for 12 months. RESULTS: Eleven children were studied. There were seven girls (F:M, 1.75). Mean ages at lupus onset and diagnosis were 10.0 +/- 2.53 years and 11.2 +/- 2.53 years, respectively. Mean time at onset of renal disease following SLE symptoms onset was 1.22 +/- 0.93 years. All cases were misdiagnosed prior to presentation; diagnosis was delayed in nine patients. Lupus activity was mild, moderate and severe in two, five and four patients, respectively. Hypertension (n = 5), nephrotic syndrome (n = 6), microerythrocyturia (n = 6) and acute renal failure (n = 7) were associated morbidities. Of the 27 presenting clinical features, 17 were nondiagnostic, while 10 were diagnostic. Fever (n = 9) was a major nondiagnostic symptom; major diagnostic manifestations were lupus nephritis (n = 11), arthritis (n = 10) and serositis (n = 7). Catastrophic antiphospholipid syndrome was diagnosed in three. The glomerular lesions were nonproliferative (n = 1), focal (n = 3) and diffuse (n = 7) proliferative lupus nephritis. Complete remission rate at end-point was 71.4%. Fourteen percent of the patients relapsed. Renal survival and mortality rates were 86.0% and 30.0%, respectively. CONCLUSION: In this study, severe renal and extrarenal comorbidities were common; mortality rate was also high. High frequency of misdiagnosis and delayed diagnosis were probably responsible for these.     

Presence of autoantibodies to apolipoprotein A-1 in patients with acute coronary syndrome further links autoimmunity to cardiovascular disease

Anti-apolipoprotein A-1 (Apo A-1) autoantibodies were described in autoimmune disorders such as systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) and might be involved in the genesis of arterial and venous thrombotic events. To investigate the presence of these autoantibodies in patients with acute coronary syndrome (ACS) without other features of autoimmunity, we set up an enzyme-linked immunosorbent assay (ELISA) for anti-Apo A-1 antibodies. We used it to investigate their prevalence in ACS as compared to SLE and APS and correlated them to plasma Apo A-1 and serum amyloid A protein (SAA) concentrations. The prevalence of anti-Apo A-1 autoantibodies in the healthy control group was 1% (1/92), but was significantly higher in other groups: 21% (11/53) in ACS group (P=0.001), 13% (12/92) in SLE and/or APS group (P=0.005). Multiple linear regression revealed a significant correlation between plasma Apo A-1 (r=-0.72, P=0.013), plasma SAA concentration (r=0.76, P=0.0066) and anti-Apo A-1 IgG titre in ACS patients. The presence of anti-Apo A-1 autoantibodies in patients with ACS highlights an additional link between autoimmunity, inflammation and atherosclerosis.     

Thrombotic Thrombocytopenic Purpura and atypical Haemolytic-Uremic Syndrome: current management issues

Thrombotic hromocyopenic purpura(TTP) is a life-threatening thrombotic disorder in which platelet/von Willebrand factor deposits occur in the microcirculation of many organs including the brain, kidney, heart and abdominal viscera. A related thrombotic microangiopathy, atypical Hemolytic-Uremic Syndrome(aHUS), is characterized by platelet/fibrin deposition predominantly in the kidneys, with acute renal failure as the major presenting clinical manifestation. Key advances in understanding the pathophysiology of these disorders now allow a better classification, with ADAMTS13 deficiency associated with TTP and defects in complement regulating proteins or complement factors identified in aHUS. Therapeutic plasma exchange has markedly improved mortality in TTP from more than 90% in the past to 10% to 20% currently. Immunosuppressive therapy with corticosteroids and the anti-CD20 monoclonal antibody rituximab has assumed even greater importance in the management of TTP patients with autoantibodies to ADAMTS13. Although plasma exchange is also useful in aHUS, the advent of the anti-C5 complement pathway inhibitor eculizumab promises to further improve clinical outcomes in these patients.     

Laboratory evaluation of the antiphospholipid syndrome

The antiphospholipid syndrome (APS) was first described in 1986. The original association of this hypercoagulable state with anticardiolipin antibodies (aCL) resulted from the synthesis of evidence stemming from laboratory findings in systemic lupus erythematosus (SLE), ie, the frequent occurrence of false-positive VDRL tests and the paradoxical observation of the so-called "lupus anticoagulant" (LA), an increase in phospholipid (PL)-dependent clotting times. By the early 1990s, it was clear that a co-factor was involved in the reaction of antibodies to PL (aPL) in SLE patients with secondary APS and that this was a hitherto-obscure protein, beta-2 glycoprotein I (beta2GPI). In the intervening years, it has been established that beta2GPI and other PL-binding proteins such as prothrombin (PT) are relevant antigens in APS and assays for these antigens have been developed, standardized, and applied to subjects with both primary and secondary APS. Measurement and confirmation of LA activity is based on a stepwise approach and should follow the recommendations of the International Society of Thrombosis and Haemostasis. Although antibodies to various PL-binding proteins have been suggested as diagnostic targets for APS, the current (2006) consensus guidelines recognize only LA, aCL, and anti-beta2GPI for the classification of APS.     

Validation of Autoantibody Assays in Type 1 Diabetes: Workshop Programme

Antiphospholipid syndrome (APS) was firstly described in systemic lupus erythematosus (SLE), but it was recognized also as a primary APS (PAPS) form. These forms are not always distinguishable, since they show some common clinical/serological manifestations. We actually may deal with: (1) patients initially classified as PAPS gradually developing SLE; (2) patients with SLE and associated APS, whose complications generally affect morbidity and mortality; (3) patients with SLE and positive antiphospholipid antibodies without APS manifestations; the relevant issue in such patients is to provide effective prophylaxis. The close relationship between PAPS and SLE is also supported by: (i) nuclear autoimmunity and (ii) complement activation at least in animal models of APS. Future studies on the genetic background and/or on regulatory suppressive mechanisms may clarify how and why PAPS can evolve into SLE.