Features Of Antiphospholipid Syndrome Research Articles

PS1585 ELDERLY WITH ANTIPHOSPHOLIPID SYNDROME PRESENT WITH DISTINCT CLINICAL PROFILE: A RETROSPECTIVE SINGLE CENTER STUDY

Background:Antiphospholipid syndrome (APS) is an acquired autoimmune disorder. It is characterized by venous and/or arterial thrombosis and/or pregnancy related morbidity in the presence of persistent antiphospholipid antibodies (aPL). It can occur as primary or as secondary APS in association with an autoimmune disorder (usually SLE). APS mainly affects women who are of child‐bearing age and less often elderly patients.Aims:We aimed to describe the clinical and immunological features of APS in patients diagnosed after the age of 55.Methods:The PSA (Phospholipid Syndrome Aged) study is a retrospective study of patients with suspected APS, who were referred to the Thrombosis and Haemostasis Clinic during the last decade (2009–2018). Clinical and serological data of patients with late onset APS (occurred after the age of 55) were analyzed and compared with patients presenting with early onset APS. The aPL (anticardiolipin (ACA) and anti‐b2GP‐I antibodies, IgG and IgM) were measured by ELISA (Euroimmun, Germany).Results:We evaluated 149 patients diagnosed with APS (56,4% males, median age 43,74 ± 13,4 years). Patients with late onset APS were 32 (21,5%) and consisted Group A. The other 117 patients were Group B. Median follow‐up was 62,5 months (13–147). The most common clinical manifestation was stroke (20,5%), followed by deep vein thrombosis of the lower extremities (15,4%) and pulmonary embolism (12,7%). Clinical characteristics of patients are shown in table 1. x2 test was used to assess statistical significance.All triple positive patients were in group B (10 women and one man). All patients were treated with antithrombotic treatment including antiplatelet agents (26,5%) and/or oral anticoagulants (69%). 14% of the patients received only LMWH (younger women). Male gender, LA positivity and a higher frequency of secondary APS were statistically significant in the older group.Summary/Conclusion:Elderly APS patients should not be disregarded because they represent 21,4% of an APS population. Patients aged >55 who are diagnosed with APS share a distinct disease profile. Clinicians must be aware of this situation in order to identify specific causes, to evaluate the risk of recurrence and to establish a therapeutic approach.image

Laboratory Diagnostics in Thrombophilia.

A thrombophilic disorder is a hereditary or acquired condition that increases the risk of thrombosis. The most common hereditary thrombophilias that predispose to venous thrombosis in the Caucasian population are the heterozygous forms of the factor V Leiden and prothrombin G20210A mutation that are generally detected by direct DNA genotyping. Immunologic antigen assays and chromogenic or clot-based activity assays are used to identify deficiencies in the natural coagulation inhibitors antithrombin, protein C and protein S. Because pre-analytical errors and acquired causes of low antithrombin, protein C or protein S levels are considerably more common than hereditary deficiencies, all potential conditions that may lower activity levels of the natural coagulation inhibitors (e.g. concomitant liver disease, pregnancy, anticoagulant therapy) must be considered and excluded before the diagnosis of an inhibitor deficiency can be made. To avoid misclassification, the diagnosis should not be made based on a single abnormal test result. Thus, repetitive testing when the patient is not on anticoagulant therapy is mandatory to confirm the diagnosis. Screening for antiphospholipid syndrome (APS) comprises testing for lupus anticoagulants (LAs) and the presence of IgG or IgM antibodies directed against phospholipids and phospholipid-binding proteins such as β-2-glycoprotein-I. A combination of clot-based assays has been recommended to demonstrate LA activity, whereas solid-phase immunoassays allow the detection of anti-cardiolipin and anti-β-2-glycoprotein-I antibodies. The diagnosis of APS requires the persistence of antiphospholipid antibodies for at least 12 weeks together with thrombotic and/or obstetric features of APS.

Addison's disease in antiphospholipid syndrome: a rare complication.

SummaryAddison’s disease (AD) is the most common endocrine manifestation of antiphospholipid syndrome (APS), but it remains a very rare complication of the syndrome. It is caused by adrenal venous thrombosis and consequent hemorrhagic infarction or by spontaneous (without thrombosis) adrenal hemorrhage, usually occurring after surgery or anticoagulant therapy. We present a clinical case of a 36-year-old female patient with a previous diagnosis of APS. She presented with multiple thrombotic events, including spontaneous abortions. During evaluation by the third episode of abortion, a CT imaging revealed an adrenal hematoma, but the patient was discharged without further investigation. A few weeks later, she presented in the emergency department with manifestations suggestive of adrenal insufficiency. Based on that assumption, she started therapy with glucocorticoids, with significant clinical improvement. After stabilization, additional investigation confirmed AD and excluded other etiologies; she also started mineralocorticoid replacement. This case illustrates a rare complication of APS that, if misdiagnosed, may be life threatening. A high index of suspicion is necessary for its diagnosis, and prompt treatment is crucial to reduce the morbidity and mortality potentially associated.Learning points:AD is a rare but life-threatening complication of APS.It is important to look for AD in patients with APS and a suggestive clinical scenario.APS must be excluded in patients with primary adrenal insufficiency and adrenal imaging revealing thrombosis/hemorrhage.Glucocorticoid therapy should be promptly initiated when AD is suspected.Mineralocorticoid replacement must be started when there is confirmed aldosterone deficiency.Hypertension is a common feature of APS; in patients with APS and AD, replacement therapy with glucocorticoids and mineralocorticoids may jeopardize hypertension management.

Closing the Serological Gap in the Antiphospholipid Syndrome: The Value of "Non-criteria" Antiphospholipid Antibodies.

Most clinicians use the 2006 Sydney classification criteria to evaluate patients suspected of having antiphospholipid syndrome (APS). Although sensitive and specific for APS, many patients fulfilling clinical criteria for the syndrome are persistently negative for the specific serological tests ("laboratory criteria"). These "seronegative APS" (SN-APS) patients can go undiagnosed and untreated until they experience serious clinical events. This study's objective was to describe antibody profiles of SN-APS patients using non-criteria markers, assess the clinical utility of these markers separately and in combination, and suggest incorporation into guidelines for patients suspected of APS. We categorized 175 consecutive patients suspected of APS into 2 subgroups: 107 fulfilling Sydney APS classification for seropositive APS (SP-APS) and 68 with clinical manifestations suggestive of APS but having negative serology, on 2 occasions, for criteria markers (SN-APS). On study inclusion, samples were retested for criteria and 11 non-criteria markers, including antiphosphatidylserine/prothrombin antibodies. Using 4 of 11 non-criteria tests, a cumulative 30.9% of SN-APS patients were detected. Combining results of all 11 non-criteria tests, 25 SN-APS (36.8%) and 89 SP-APS (83.2%) were positive for 1 or more non-criteria antibodies. Failure to diagnose APS can result in severe clinical consequences. Patients displaying clinical features of APS, but negative for conventional criteria markers, should undergo additional testing for non-criteria biomarkers. In our cohort, around one-third of SN-APS patients showed reactivity to 1 or more non-criteria markers. An update to the current classification criteria incorporating new serological markers should be considered to identify and stratify patients with APS for more effective treatment and management.

Refractory obstetrical antiphospholipid syndrome: Features, treatment and outcome in a European multicenter retrospective study.

To describe the consecutive pregnancy outcome and treatment in refractory obstetrical antiphospholipid syndrome (APS). Retrospective multicenter open-labelled study from December 2015 to June 2016. We analyzed the outcome of pregnancies in patients with obstetrical APS (Sydney criteria) and previous adverse obstetrical event despite low-dose aspirin and low-molecular weight heparin LMWH (LMWH) conventional treatment who experienced at least one subsequent pregnancy. Forty nine patients with median age 27years (23-32) were included from 8 European centers. Obstetrical APS was present in 71%, while 26% had obstetrical and thrombotic APS. Lupus anticoagulant was present in 76% and triple antiphospholipid antibody (APL) positivity in 45% of patients. Pregnancy loss was noted in 71% with a median age of gestation of 11 (8-21) weeks. The presence of APS non-criteria features (35% vs 17% in pregnancies without adverse obstetrical event; p=0.09), previous intrauterine death (65% vs 38%; p=0.06), of LA (90% vs 65%; p=0.05) were more frequent in pregnancies with adverse pregnancy outcome, whereas isolated recurrent miscarriage profile was more frequent in pregnancies without any adverse pregnancy outcome (15% vs 41%; p=0.04). In univariate analysis considering all pregnancies (index and subsequent ones), an history of previous intrauterine death was associated with pregnancy loss (odds-ratio 2.51 (95% CI 1.274.96); p=0.008), whereas previous history of prematurity related to APS (odds-ratio 0.13 95%CI 0.04 0.41, P=0.006), steroids use during the pregnancy (odds-ratio 0.30 95% CI 0.11-0.82, p=0.019) and anticardiolipids isolated profile (odds-ratio 0.51 95% CI 0.26-1.03, p=0.0588) were associated with favorable outcome. In multivariate analysis, only previous history of prematurity, steroids use and anticardiolipids isolated profiles were associated with live-birth pregnancy. The main features of refractory obstetrical APS were the high rates of LA and triple APL positivity. Steroids could be effective in this APS profile, but prospective studies are necessary.

Clinical performance of antibodies to prothrombin and thrombin in Chinese patients with antiphospholipid syndrome: potential interest in discriminating patients with thrombotic events and non-thrombotic events.

A hallmark feature of antiphospholipid syndrome (APS) is the presence of a wide spectrum of antiphospholipid antibodies. In this study, we evaluated the clinical relevance of antibodies to prothrombin (PT) (aPT) and thrombin (aThr) in Chinese patients with APS. A total of 229 subjects were tested, including 86 patients with APS [35 patients with primary APS (PAPS), 51 patients with APS associated with other diseases (APSAOD)], 104 patients with non-APS diseases (disease controls), and 39 healthy controls. Serum IgG/IgM/IgA aPT and aThr were determined by ELISA. The levels of both IgG/IgM/IgA aPT and IgG/IgM/IgA aThr were significantly increased in patients with PAPS and APSAOD compared with patients with non-APS thrombosis and non-APS PRM, and HC. Both IgG aPT and IgG aThr exhibited promising diagnostic potentials for APS with sensitivities and specificities of 16.3 and 95.8% (IgG aPT), and 19.8 and 99.3% (IgG aThr), respectively. Importantly, both IgG aPT (OR 4.06; 95% CI 1.49-11.05) and IgG aThr (OR 4.49; 95% CI 1.62-12.45) were significantly correlated with arterial, but not venous, thrombotic events. Our findings highlighted that IgG aPT and IgG aThr could serve as promising biomarkers to identify patients at risk of arterial thrombosis in China.

Stillbirth: the impact of antiphospholipid syndrome?

Fetal death resulting in stillbirth is generally acknowledged as a feature of antiphospholipid syndrome. Recently published studies appear to confirm the association between antiphospholipid antibodies (aPL) and stillbirth, though additional studies of better design would be welcome. Emerging evidence suggests that treatment with heparin agents and low dose aspirin to prevent fetal death is imperfect. New therapeutic approaches for patients with lupus anticoagulant or triple aPL positivity are needed.

Cognitive disorders and antiphospholipid antibodies.

Cognitive disorders have frequently been described in the field of antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). Nevertheless, the relationship between those disorders and antiphospholipid antibodies (aPL) remains unclear and seems to involve various mechanisms. Overlap with systemic lupus erythematosus, the small sample size of studies, and discrepancies in antiphospholipid antibodies and cognitive impairment determinations complicate analyses of the literature data. In this paper, we summarize current knowledge on epidemiologic, clinical data, imaging findings and treatment of cognitive dysfunction associated with aPL. We separately analyzed data on aPL-positive carriers without history of clinical feature of APS, APS patients without overlaps autoimmune disease, and SLE-associated aPL patients.

Antiphospholipid Antibody-Mediated Thrombotic Mechanisms in Antiphospholipid Syndrome: Towards Pathophysiology-Based Treatment.

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by a persistently high titer of antiphospholipid antibodies (aPLs). In addition to pregnancy morbidity, arterial and/or venous thrombosis is another clinical feature of APS. Regardless of the type of APS, the thrombi formed by the induction of aPLs can lead to deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke and gangrene. Although the concept of APS was introduced approximately 32 years ago, its thrombogenic pathophysiology is still unclear. Therefore, patients are treated with anticoagulant and/or antiplatelet regimens just as in other thrombotic disorders even though the thrombotic pathophysiology is mainly aPLs-mediated. In this review, we provided an update of the cellular, auto-immune and genetic factors known to play important roles in the generation of thrombi. Current successful regimens are also outlined along with potential emerging treatment strategies that may lead to the optimum management of thrombotic APS patients.

Clinical characterization of antiphospholipid syndrome by detection of IgG antibodies against β2 -glycoprotein i domain 1 and domain 4/5: ratio of anti-domain 1 to anti-domain 4/5 as a useful new biomarker for antiphospholipid syndrome.

It has been suggested that only antibodies against domain 1 (D1) of β2 -glycoprotein I (β2 GPI) are pathogenic and diagnostic. The role of antibodies against other β2 GPI domains is still debated. This study was undertaken to evaluate the clinical relevance of domain specificity profiling of anti-β2 GPI IgG antibodies in antiphospholipid syndrome (APS) patients and in control groups of patients with systemic autoimmune rheumatic diseases and in asymptomatic antiphospholipid antibody (aPL) carriers. We evaluated 159 subjects with persistently positive, medium or high-titer anti-β2 GPI IgG, including 56 patients with thrombotic (obstetric or nonobstetric) primary APS, 31 women with obstetric primary APS, 42 aPL-positive patients with systemic autoimmune rheumatic diseases, and 30 asymptomatic aPL carriers. One hundred healthy donors were included. Anti-β2 GPI D1 and D4/5 IgG were tested on research enzyme-linked immunosorbent assays containing recombinant β2 GPI domains. As compared to other groups, aPL carriers displayed higher frequency/titer of anti-D4/5 IgG. Unlike anti-D4/5, anti-D1 IgG antibodies were more frequent and at higher titer in triple than in single or double aPL-positive subjects. An anti-D1 to anti-D4/5 ratio of ≥1.5 was predictive of systemic autoimmunity (odds ratio 3.25 [95% confidence interval 1.45-7.49], P = 0.005). Neither anti-D1 nor anti-D4/5 antibodies were associated with APS clinical criteria. Anti-D1 IgG is the preferential specificity not only in vascular and obstetric primary APS, but also in patients with systemic autoimmune rheumatic disease with no clinical features of APS. Conversely, aPL carriers do not have a polarized profile toward D1. Combined testing for anti-β2 GPI IgG with different domain specificity allows a more accurate aPL profiling, with polarization toward anti-D1 IgG as a possible fingerprint of systemic autoimmunity.

An A1-A1 mutant with improved binding and inhibition of β2GPI/antibody complexes in antiphospholipid syndrome.

β2 glycoprotein I (β2GPI) is the most common antigen for autoimmune antibodies in antiphospholipid syndrome (APS). Thrombosis is a clinical feature of APS. We created a molecule (A1-A1) that consists of two identical β2GPI-binding modules from ApoE receptor 2 (ApoER2). A1-A1 binds to β2GPI/antibody complexes, preventing their association with ApoER2 and anionic phospholipids, and reducing thrombus size in the mouse model of APS. Here, we describe a mutant of A1-A1 (mA1-A1ND) with improved affinity for β2GPI. mA1-A1ND inhibits the binding of β2GPI to cardiolipin in the presence of anti-β2GPI antibodies, and inhibits the binding to phospholipids in plasma samples of APS patients, affecting the clotting time. Reduction of the clotting time demonstrates the presence of soluble β2GPI/antibody complexes in patients' plasma. These complexes either already exist in patients' plasma or form rapidly in the proximity to phospholipids. All members of the low-density lipoprotein receptor family bind β2GPI. Modeling studies of A1 in a complex with domain V of β2GPI (β2GPI-DV) revealed two possible modes of interaction of a ligand-binding module from lipoprotein receptors with β2GPI-DV. In both orientations, the ligand-binding module interferes with binding of β2GPI to anionic phospholipids; however, it interacts with two different but overlapping sets of lysine residues in β2GPI-DV, depending on the orientation.

Cardiac Manifestations in Antiphospholipid Syndrome--A Brief Review of the Literature

Antiphospholipid syndrome (APS) or Hughes syndrome represents a systemic autoimmune disorder characterized by arterial and/or venous thrombosis, multiple and recurrent fetal losses, accompanied by persistently elevated levels of antiphospholipid antibodies (aPL). This syndrome is considered primary if unassociated with any other connective tissue disease, or secondary if it appears in association with other autoimmune disorders, mainly systemic lupus erythematosus. Cardiac manifestations in APS are integral part of the syndrome. aPL are involved in the pathogenesis of pseudoinfective endocarditis (Libman Sacks) and other valvular manifestations presented as their thickening and dysfunction. Intracardiac thrombi and myxomas, pulmonary hypertension and left ventricular dysfunction are also distinguishing features of APS. On the other hand, accelerated atherosclerosis, proven in APS and also aPL mediated, is accountable for the development of coronary and peripheral artery disease. This leads to higher cardiovascular mortality rate in the population of patients with low incidence of the traditional atherosclerosis risk factors. Furthermore, recent studies implied that presence of certain aPL could be a risk factor for a specific cardiac manifestation. Bearing all this in mind, early diagnosis of cardiac manifestations, control and abolition of traditional risk factors, as well as close cardiac follow-up of APS patients, are crucial in reducing their cardiovascular mortality.

Immunoreactivity and avidity of IgG anti-β2-glycoprotein I antibodies from patients with autoimmune diseases to different peptide clusters of β2-glycoprotein I.

The pathogenicity of antibodies against β2-glycoprotein I (anti-β2GPI) depends on multiple factors such as subclass type, epitope binding and avidity. Due to their large heterogeneity, their impact on antiphospholipid syndrome (APS) onset is still not fully clarified. We studied the binding characteristics of IgG anti-β2GPI with known avidity from sera of 201 autoimmune patients (87 with APS, 67 with APS associated with systemic lupus erythematosus (SLE), 47 with only SLE) to six β2GPI peptides corresponding to amino acid clusters on domains I-II, II, III and III-IV by indirect ELISA and evaluated their association with clinical features of APS. Peptides A (LKTPRV; domain I-II), B (KDKATF; domain IV) and C (TLRVYK; domain III) were derived from a hexapeptide phage display library previously shown to react with pathogenic monoclonal anti-β2GPI. Peptides D (NGPANSK; domain III), E (YNPLWFV; domain II) and F (KMDGNHP; domain III-IV) represent surface amino acid clusters on β2GPI. The percentage of patients positive for peptides were observed as follows: 30.3% for peptide D, 28.90% for B, 25.9% for C, 24.9% for E, 24.4% for F and 10.0% for A. The anti-peptide antibodies in studied serum samples were predominantly of heterogeneous avidity, followed by law avidity anti-peptide antibodies, whereas only a few were of high avidity. Positive and negative correlations were found between several anti-peptide antibodies and the rate of thrombosis. Our results indicated diverse reactivity of IgG anti-β2GPI to different epitopes on β2GPI. Classification of IgG anti-β2GPI into subgroups regarding epitope specificity and avidity could represent an additional tool in understanding their pathogenicity in APS.

Both IgG and IgM anti-beta2 glycoprotein I antibodies assays are clinically useful to the antiphospholipid syndrome diagnosis

Objectives:The aim of our study was to evaluate the clinical values of anti-beta2 glycoprotein I antibodies (anti-beta2GPI) IgG and IgM comparing with lupus anticoagulant (LA), anticardiolipin antibodies (aCL) in the two clinical groups of antiphospholipid syndrome (APS), vascular thrombosis (VT) and pregnancy morbidity (PM).Methods:Eighty patients who fulfilled the APS clinical criteria, VT n = 34; PM n = 40, both VT and PM n = 6 were included. LA, aCL and three anti-beta2GPI ELISA kits were tested.Results:Sensitivities of LA, aCL and anti-beta2GPI assays were found respectively 62, 26 and 41% in VT, and 28, 28 and 30% in PM. The sensitivity for the APS diagnosis could reach to 63% using triple tests. The presence of LA (P<0·01, OR = 4·3) or anti-beta2GPI IgG alone (P<0·05, OR = 8·4) was significantly associated with VT. IgM isotype was found more frequent in PM (92%) than in VT (57%) among all positive anti-beta2GPI cases.Conclusion:Both IgG and IgM anti-beta2GPI assays were useful when clinical features of APS presented, even its standardization is ongoing. A decreased by half sensitivity of LA in PM compared with that in VT underlines the importance of adding anti-beta2GPI in PM of APS, especially IgM isotype although recent review questioned its significance.

Anesthetic management of antiphospholipid syndrome patients who underwent cardiac surgery: three cases report

Antiphospholipid syndrome (APS) is a rare disease in which patients display prolonged coagulation test results in vitro, but usually develop thrombotic symptoms in vivo. Patients with APS are at increased risk of valvular heart disease or coronary vascular disease, conditions that often necessitate cardiac surgery via bypass. The management of anticoagulation during cardiopulmonary bypass (CPB) is particularly challenging in these patients because of the unique features of APS. Patients with APS are constantly at risk of arterial and venous thrombotic events. Therefore it is very important to maintain proper anticoagulation perioperatively, especially during CPB. In this paper, we present three successful cases of APS patients who underwent cardiac surgery with CPB.

Value of Isolated IgA Anti–β2‐Glycoprotein I Positivity in the Diagnosis of the Antiphospholipid Syndrome

To examine the prevalence of isolated IgA anti-β2 -glycoprotein I (anti-β2 GPI) positivity and the association of these antibodies, and a subgroup that bind specifically to domain IV/V of β2 GPI, with clinical manifestations of the antiphospholipid syndrome (APS) in 3 patient groups and to evaluate the pathogenicity of IgA anti-β2 GPI in a mouse model of thrombosis. Patients with systemic lupus erythematosus (SLE) from a multiethnic, multicenter cohort (LUpus in MInorities, NAture versus nurture [LUMINA]) (n = 558), patients with SLE from the Hopkins Lupus Cohort (n = 215), and serum samples referred to the Antiphospholipid Standardization Laboratory (APLS) (n = 5,098) were evaluated. IgA anti-β2 GPI titers and binding to domain IV/V of β2 GPI were examined by enzyme-linked immunosorbent assay (ELISA). CD1 mice were inoculated with purified IgA anti-β2 GPI antibodies, and surgical procedures and ELISAs were performed to evaluate thrombus development and tissue factor (TF) activity. A total of 198 patients were found to be positive for IgA anti-β2 GPI isotype, and 57 patients were positive exclusively for IgA anti-β2 GPI antibodies. Of these, 13 of 23 patients (56.5%) in the LUMINA cohort, 17 of 17 patients (100%) in the Hopkins cohort, and 10 of 17 patients (58.9%) referred to APLS had at least one APS-related clinical manifestation. Fifty-four percent of all the IgA anti-β2 GPI-positive serum samples reacted with domain IV/V of anti-β2 GPI, and 77% of those had clinical features of APS. Isolated IgA anti-β2 GPI positivity was associated with an increased risk of arterial thrombosis (P < 0.001), venous thrombosis (P = 0.015), and all thrombosis (P < 0.001). The association between isolated IgA anti-β2 GPI and arterial thrombosis (P = 0.0003) and all thrombosis (P = 0.0003) remained significant after adjusting for other risk factors for thrombosis. In vivo mouse studies demonstrated that IgA anti-β2 GPI antibodies induced significantly larger thrombi and higher TF levels compared to controls. Isolated IgA anti-β2 GPI-positive titers may identify additional patients with clinical features of APS. Testing for these antibodies when other antiphospholipid tests are negative and APS is suspected is recommended. IgA anti-β2 GPI antibodies directed to domain IV/V of β2 GPI represent an important subgroup of clinically relevant antiphospholipids.

Diagnose eines primären Antiphospholipidsyndroms bei Ulcus cruris unter Marcumar-Therapie

Antiphospholipid syndrome features not only deep vessel thrombosis but also may have cutaneous manifestations such as Raynaud phenomenon, acral necrosis, livedo reticularis, subcutaneous nodules, and leg ulcers. A 72-year-old man presented with a rapidly progressing leg ulcer. He was already on anticoagulation with warfarin due to atrial fibrillation and disclosed a history of stroke with temporary paresis of the left leg. Histopathology of a biopsy of the edge of the ulcer revealed occlusive arteriosclerosis of medium-sized arteries. Serology showed autoantibodies against cardiolipin, β2- glycoprotein I, and phosphatidylserine which led to the diagnosis of antiphospholipid syndrome. Therapy with low molecular weight heparin, dexamethasone, and azathioprine in combination with stage-adjusted wound care led to complete healing of the ulcer within 5 months.

Heparin, antiphospholipid antibodies and the brain

One of the most striking observations in the clinical world of antiphospholipid syndrome (APS) is the dramatic and almost immediate improvement seen in many patients with neurological features such as headache, balance problems and memory loss, following the institution of low molecular weight (LMW) heparin treatment. From the earliest clinical descriptions of the syndrome, neurological involvement has been recognized as a common – indeed a central – feature. It was also noted that with anticoagulation treatment, many of those symptoms and signs, some of which had been present for months (for example chorea) or even years (epilepsy), rapidly improved. One of the problems facing clinicians dealing with APS patients is the limitation of treatment choices. Aspirin yes – but then what? Warfarin (Coumadin) poses a grave medical (and social) decision in a patient with worsening headache and concerns about stroke, yet with no previous thrombosis. Some lessons have been learnt from the management of APS in pregnancy. Those women on warfarin, usually changed to LMW heparin at the onset of pregnancy, are often free of cerebral symptoms for the whole eight to nine months of their pregnancy (and some assert that they are even better on LMW heparin than warfarin). Some years ago, in the absence of any more scientific guidance, we introduced a ‘heparin therapeutic trial’ for patients with increasing clinical APS problems despite anti-platelet therapy. This involved a two to three week course of LMW heparin (dalteparin/enoxaparin) with a clinical outcome defined by the patient. Placebo effects, certainly. But very often a decisive response. Such observations again focus on the pathogenesis and management of APS. Antibody mediated, undoubtedly, but is the brain pathology thrombotic, direct anti-neuronal attack, or predominantly vascular ‘sludging’? The rapid improvement in cognitive function, or in migraine severity when heparin is introduced, or on warfarin when the INR is carefully maintained at a higher level (e.g. 3.5–4) suggests that improvement in blood flow is important, though radiological and isotopic supporting evidence of this is scanty. At the present time, stroke and transverse myelitis are the two most feared neurological sequelae of antiphospholipid antibody (aPL) positivity – so much so that it remains an unfortunate fact that aPL testing is not yet routine in stroke screening. However, other non-stroke neurological features of APS are now widely recognized – balance problems, multiple sclerosis-like syndrome, deafness, anosmia, sleep disturbance. And, most prominent of all, memory loss There is little doubt that APS will become an important chapter in the broader field of neurology. Are there lessons for lupus? In lupus patients, many attempts have, over the years, been made to link particular antibodies to brain involvement – lymphocytotoxic antibodies, anti-NR2 and anti-ribosomal-P, for example. Most have proved disappointing as major diagnostic candidates. The link between brain pathology and aPL, however, appears to be more substantial, both in APS as well as in lupus. In a recent Italian multi-centre study of 959 lupus patients, the two items in the survey with the strongest link to neuropsychiatric involvement were anticardiolipin antibodies (p> 0.001) and lupus anticoagulant (p> 0.001). Thirty years ago, the pathogenesis of many nonfocal neuropsychiatric disorders in lupus was considered to involve both vascular and immune mechanisms. Much the same today. Correspondence to: GRV Hughes, London Lupus Centre, London Bridge Hospital, London SE1 2PR, UK Email: graham.hughes@hcaconsultant.co.uk Received 18 May 2012; accepted 21 May 2012

Sneddon's syndrome: case report and review of its relationship with antiphospholipid syndrome

The Sneddon's syndrome is a rare disorder characterized by the occurrence of cerebrovascular disease associated with livedo reticularis. The antiphospholipid syndrome is the most frequent type of acquired thrombophilia, defined by the occurrence of thrombosis or pregnancy morbidity in the presence of persistently positive antiphospholipid antibodies. Approximately 80% of Sneddon's syndrome patients have an antiphospholipid antibody marker. These antibodies may play a pathogenetic role in some cases of Sneddon's syndrome, and many authors consider these two syndromes as the same entity. Although clinical features of antiphospholipid syndrome and Sneddon's syndrome may overlap, there is a distinction between clinical and laboratory evidence suggesting that these two entities are different diseases. A recent finding of coagulopathies, including elevated levels of coagulation factor VII, decreased levels of protein S, and activated protein C in Sneddon's syndrome patients suggested a possible biological link between the vasculopathy and a primary coagulopathy. Moreover, the clinical course seems to be progressive in Sneddon's syndrome patients and includes increase of disability and cognitive deterioration, more arterial involvement, and the antiphospholipid syndrome shows a more benign course. Both syndromes share clinical and laboratory features, and whether Sneddon's syndrome represents a spectrum of antiphospholipid syndrome remains unclear. Sneddon's syndrome patients have a worse prognosis and may represent a subgroup of patients who demands more rigorous follow-up. It is important to recognize the Sneddon's syndrome, particularly because stroke episodes may be prevented through appropriate treatment.

CAPS Registry

Patients with catastrophic antiphospholipid syndrome (APS) have in common: a) clinical evidence of multiple organ involvement developing over a very short period of time; b) histopathological evidence of multiple small vessel occlusions, and c) laboratory confirmation of the presence of antiphospholipid antibodies (aPL), usually in high titre. Although patients with catastrophic APS represent less than 1% of all patients with APS, they are usually in a life-threatening situation. The rarity of this syndrome makes it extraordinarily difficult to study in any systematic way. In order to correlate all the published case reports as well as newly diagnosed cases from all over the world, an international registry of patients with catastrophic APS (CAPS Registry) was created in 2000 by the European Forum on aPL. Currently, it documents the clinical, laboratory and therapeutic data of more than 400 patients and can be consulted through Internet at www.med.ub.es/MIMMUN/FORUM/CAPS.HTM. The analysis of this registry has allowed the characterization of the clinical and laboratory features of the catastrophic APS as well as the establishment of preliminary criteria for its classification and guidelines for its management.