Growing evidences are supporting towards the involvement of antiphospholipid antibodies [aPLs e.g., lupus anticoagulant (LA), anticardiolipin (aCL) and anti-β2-glycoprotein I (anti-β2-GPI) antibodies] in various neurological manifestations including migraine, epilepsy and dementia in the presence or absence of autoimmune diseases such as antiphospholipid syndrome or systemic lupus erythematosus. The aim of this systematic review and meta-analysis was to assess the presence of aPLs in dementia patients without a diagnosis of any autoimmune disease. Electronic databases (e.g., PubMed, Web of Science, Scopus, ScienceDirect and Google Scholar) were searched without any year or language restrictions and based on the inclusion criteria, nine prospective case-control studies assessing only aCL were included involving 372 dementia patients and 337 healthy controls. No studies were found to assess the presence of both LA or anti-β2-GPI. The study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random-effects model. We observed the prevalence of aCL in dementia was higher (32.80%) than that of controls (9.50%) e.g., 3.45 times higher risk of presenting with dementia than the controls, and significant presence of aCL antibodies was detected in dementia patients compared to controls (OR: 4.94, 95% CI: 2.66 - 9.16, p < 0.00001; I2 = 32%, p = 0.16). Publication bias was not observed from Egger's (p = 0.081) and Begg's tests (p = 0.180). Based on the study quality assessment using modified Newcastle-Ottawa Scale for case-control studies, seven of nine studies were of high methodological quality scoring ≥ 7 (median value). In summary, aCL antibodies were significantly present in dementia patients suggesting that aCL antibodies are generated due to the autoimmune-derived effects of dementia or there might be a potential causative role of this autoantibody in dementia pathogenesis.
INTRODUCTION: Antiphospholipid antibodies (aPL) are autoantibodies that attack phospholipid through anti-beta 2-glycoprotein 1. The actions of aPL are associated with events leading to thrombosis and morbidity in pregnancy. Antiphospholipid syndrome (APS) is diagnosed when a patient is persistently positive for aPL and also has recognised clinical manifestations such as recurrent pregnancy losses, arterial or venous thrombosis and in a catastrophic case, can result in death. Unfortunately, the pathogenesis of APS is still not well established. Recently, microRNA expressed in many types of diseased tissues were claimed to be involved in the pathological progression of diseases and has become a useful biomarker to indicate diseases, including APS.
OBJECTIVE: This systematic review aims to search for research papers that are focussing on microRNA expression profiles in APS.
METHOD: Three search engines (Ebcohost, ProQuest and Ovid) were used to identify papers related to expression of specific microRNA in antiphospholipid syndrome.
RESULTS AND DISCUSSION: A total of 357 papers were found and screened, out of which only one study fulfilled the requirement. In this particular study blood samples from APS patients were tested. The microRNAs found to be related to APS were miR-19b and miR-20a. No data was found on specific microRNA being expressed in obstetric antiphospholipid syndrome. Analysis on the microRNA target genes revealed that most genes targeted by miR-19b and miR-20a involve in TGF-Beta Signalling and VEGF, hypoxia and angiogenesis pathways.
CONCLUSION: In view of the limited data on the expressions of microRNA in APS we recommend further research into this field. Characterization of microRNA profile in blood as well as in placenta tissue of patients with APS could be useful in identifying microRNAs involved in obstetric APS.
BACKGROUND: Antiphospholipid syndrome (APS) is an autoimmune disorder characterised by thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies (aPLs) based on the Sydney criteria. We aimed to explore the clinico-laboratory features and treatment strategies of APS patients retrospectively.
METHODOLOGY: The medical records of APS patients registered under Hospital Universiti Sains Malaysia (Kelantan state) between 2000 and 2015 were reviewed.
RESULTS: A total of 17 APS subjects (age 40.7 ± 12.8 years) including 11 primary (64.7%) and six secondary APS (35.3%) patients were identified. The follow-up period was 9.5 ± 6.7 years with male:female ratio of 1.0:4.7. Pregnancy morbidity was the most common clinical manifestation (11/14; 78.6%) followed by recurrent venous thrombosis (10/17; 58.8%). For other clinical features, menorrhagia was the most frequently observed manifestation (4/14; 28.6%) followed by aPLs-associated thrombocytopenia (4/17; 23.5%) and ovarian cyst (3/14; 21.4%). LA and aCL were positive in 94.1% (16/17) and 81.8% (9/11) of the patients, respectively. APTT value (76.7 ± 17.0 sec) was significantly high (p < 0.05). Low intensity warfarin alone was successful to maintain target INR (2.0 - 3.0) and prevent recurrence of thrombosis.
CONCLUSION: The tendency of pregnancy morbidity in this cohort of Malaysian Kelantanese APS patients was high compared to other previously reported APS cohorts. Low intensity warfarin was successful in preventing recurrence of thrombosis, however, APS women receiving long-term anticoagulants should be monitored for possible occurrence of menorrhagia and ovarian cysts.
We performed a cross-sectional study of all antiphospholipid syndrome (APS) patients during an 8-year period (2006-2013) to describe the clinical features, serology profiles, treatment regimes, and outcomes in our center. There were a total of 59 patients in our study with the female to male ratio of 9:1. They have a mean age of 41.6 ± 12.1 years and a mean duration of illness of 38.4 ± 68.5 months. The majority of patients presented with vascular thrombosis (69.5 %) with equal arterial and venous involvements. Twenty-six patients (44.1 %) presented with obstetric complications with recurrent abortions (32.2 %) as the main manifestation. Most patients were on daily warfarin doses of 2-6 mg (91.0 %) with target INR of 2-3. There was neither recurrent thrombosis nor bleeding complications documented. There were 80 % live births following treatment in our patients.
MicroRNAs (miRNAs) are single-stranded, endogenous RNA molecules that play a significant role in the regulation of gene expression as well as cell development, differentiation, and function. Recent data suggest that these small molecules are responsible for the regulation of immune responses. Therefore, they may act as potent modulators of the immune system and play an important role in the development of several autoimmune diseases. Antiphospholipid syndrome (APS) is an autoimmune systemic disease characterized by venous and/or arterial thromboses and/or recurrent fetal losses in the presence of antiphospholipid antibodies (aPLs). Several lines of evidence suggest that like other autoimmune disorders, miRNAs are deeply involved in the pathogenesis of APS, interacting with the function of innate and adaptive immune responses. In this review, we characterize miRNAs in the light of having a functional role in the immune system and autoimmune responses focusing on APS. In addition, we also discuss miRNAs as potential biomarkers and target molecules in treating APS.
BACKGROUND: Antiphospholipid Syndrome (APS) is an autoimmune multifactorial disorder. Genetics is believed to play a contributory role in the pathogenesis of APS, especially in thrombosis development and pregnancy morbidity. In the last 20 years, extensive research on genetic contribution on APS indicates that APS is a polygenic disorder, where a number of genes are involved in the development of its clinical manifestations.
AIMS: The aim of this systematic review is to evaluate the genetic risk factors in thrombotic primary APS. Additionally, to assess the common molecular functions, biological processes, pathways, interrelations with the gene encoded proteins and RNA-Seq-derived expression patterns over different organs of the associated genes via bioinformatic analyses.
METHODS: Without restricting the year, a systematic search of English articles was conducted (up to 4th September 2017) using Web of Science, PubMed, Scopus, ScienceDirect and Google Scholar databases. Eligible studies were selected based on the inclusion criteria. Two researchers independently extracted the data from the included studies. Quality assessment of the included studies was carried out using a modified New-Castle Ottawa scale (NOS).
RESULTS: From an initial search result of 2673 articles, 22 studies were included (1268 primary APS patients and 1649 healthy controls). Twenty-two genes were identified in which 16 were significantly associated with thrombosis in primary APS whereas six genes showed no significant association with thrombosis. Based on the NOS, 14 studies were of high quality while 6 were low quality studies. From the bioinformatic analyses, thrombin-activated receptor activity (q = 6.77 × 10-7), blood coagulation (q = 2.63 × 10-15), formation of fibrin clot (q = 9.76 × 10-10) were the top hit for molecular function, biological process and pathway categories, respectively. With the highest confidence interaction score of 0.900, all of the thrombosis-associated gene encoded proteins of APS were found to be interconnected except for two. Based on the pathway analysis, cumulatively all the genes affect haemostasis [false discovery rate (FDR) = 1.01 × 10-8] and the immune system [FDR = 9.93 × 10-2]. Gene expression analysis from RNA-Seq data revealed that almost all the genes were expressed in 32 different tissues in the human body.
CONCLUSION: According to our systematic review, 16 genes contribute significantly in patients with thrombotic primary APS when compared with controls. Bioinformatic analyses of these genes revealed their molecular interconnectivity in protein levels largely by affecting blood coagulation and immune system. These genes are expressed in 32 different organs and may pose higher risk of developing thrombosis anywhere in the body of primary APS patients.
Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombosis and/or pregnancy morbidity with persistent levels of antiphospholipid antibodies (aPLs). The development of thrombosis in APS is mediated by aPLs and contributes to the high mortality rate in APS patients. However, although APS has been reported for more than 30 years, there has been no optimal regimen for its prevention or for the management of thrombosis, mainly because the mainstay treatment strategies for managing APS are not targeted towards aPL-mediated thrombotic pathophysiology. Instead, the treatments commonly used are aimed at general thrombotic disorders. Warfarin is the most commonly used vitamin K antagonist (VKA), in addition to anti-platelet medications, such as aspirin and clopidogrel. Over the last decade, novel non-VKA oral anticoagulants, including rivaroxaban, apixaban and dabigatran, as well as immunomodulatory agents, such as rituximab, eculizumab, hydroxychloroquine, statins and sirolimus, have also been used. In this review, we discuss the current treatment strategies and future treatment outlook for thrombotic APS.
Tako Tsubo cardiomyopathy is rare, stress related and indistinguishable from acute myocardial infarction clinically. Proper diagnosis is essential to avoid unnecessary thrombolysis and life long management of coronary artery disease.
Here we present a case report of three familial primary antiphospholipid syndrome (PAPS) patients from Malaysia. The three familial patients comprised two females and one male with a mean age of 26.3 years. The first diagnosis was made between 2005 and 2009, and all patients demonstrated deep vein thrombosis, high levels of IgM and IgG anticardiolipin antibodies, and received warfarin treatment international normalized ratio (INR) 2.0-3.0. The patients ceased to show clinical symptoms after treatment. Recently (August 2014), we investigated whether the levels of antiphospholipid antibodies remained elevated, and we found that seronegativity occurred in the patients. We suspect that prolonged anticoagulant treatment might be one of the causes of reduced levels of antiphospholipid antibodies in these familial PAPS patients.
A 35-year-old Jordanian gentleman presented with worsening right iliac fossa pain of three-day durations with vomiting, loose stool and intermittent fever. He later underwent laparoscopic surgery, which was subsequently converted to open laparotomy. Intraoperatively, there was thickened bowel with multiple mesenteric lymph nodes, and also thrombosis of the small bowel vein supplying the affected bowel lesion, the diagnosis which was later confi rmed with the histopathological report. Resection with end-to-end anastomosis was done during the surgery. Within one-week post laparotomy, he developed another progressive abdominal pain and distension, vomiting and no bowel opening. He was sent for another exploratory laparotomy. Intraoperatively, there was a gangrenous small bowel segment measuring 130 cm, with an intact large bowel and previous anastomotic site. Resection of 150 cm of the small bowel was subsequently done.
BACKGROUND: Antiphospholipid syndrome (APS) is a multisystem disease that may present as venous or arterial thrombosis and/or pregnancy complications with the presence of antiphospholipid antibodies. Until today, heterogeneity of pathogenic mechanism fits well with various clinical manifestations. Moreover, previous studies have indicated that genes are differentially expressed between normal and in the disease state. Hence, this study systematically searched the literature on human gene expression that was differentially expressed in Obstetric APS.
METHODOLOGY: Electronic search was performed until 31st March 2015 through PubMed and Embase databases; where the following Medical Subject Heading (MeSH) terms were used and they had been specified as the primary focus of the articles; gene, antiphospholipid, obstetric, and pregnancy in the title or abstract. From 502 studies retrieved from the search, only original publications that had performed gene expression analyses of human placental tissue that reported on differentially expressed gene in pregnancies with Obstetric APS were included. Two reviewers independently scrutinized the titles and the abstracts before examining the eligibility of studies that met the inclusion criteria. For each study; diagnostic criteria for APS, method for analysis, and the gene signature were extracted independently by two reviewers. The genes listed were further analysed with the DAVID and the KEGG pathways.
RESULTS: Three eligible gene expression studies involving obstetric APS, comprising the datasets on gene expression, were identified. All three studies showed a reduction in transcript expression on PRL, STAT5, TF, DAF, ABCA1, and HBEGF in Obstetric APS. The high enrichment score for functionality in DAVID had been positive regulation of cell proliferation. Meanwhile, pertaining to the KEGG pathway, two pathways were associated with some of the listed genes, which were ErBb signalling pathway and JAK-STAT signalling pathway.
CONCLUSION: Ultimately, studies on a genetic level have the potential to provide new insights into the regulation and to widen the basis for identification of changes in the mechanism of Obstetric APS.
We report a case of a 21-year-old university student with underlying lupus nephritis who presented with recurrent symptoms of fever, haemoptysis, and pleuritic chest pain. CT pulmonary angiogram confirmed pulmonary embolism in the right subsegmental pulmonary arteries. One week later, she developed left renal vein and left common iliac vein thromboses, with new emboli in the left subsegmental pulmonary arteries. We hereforth discuss the diagnostic issues of a patient with systemic lupus erythematosus (SLE) on corticosteroids therapy, and also treatment of the antiphospholipid syndrome.
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.
Over the past year, many reports have been published on a variety of clinical manifestations related to antiphospholipid antibodies. The low prevalence of anticardiolipin antibodies with the rare occurrence of thrombosis and a low rate of fetal loss in studies in Malaysia and China showed a potential role for local factors. A study of cross-reactive idiotype of the anticardiolipin antibody suggested that anticardiolipin antibodies are derived from a set of natural autoreactive clones. Regarding the pathogenic role of the antiphospholipid antibody, evidence has been presented that the epitopes formed between cardiolipin and beta 2 glycoprotein I are the targets of the antiphospholipid antibody. Complement activation, abnormalities of natural anticoagulants such as protein S deficiency, and genetic association with DR4, DR7, and DRw53 have also been studied.
Antiphospholipid antibodies (aPLs) are autoantibodies with laboratory significance in developing thrombosis and pregnancy morbidity in antiphospholipid syndrome (APS). High prevalence of aPLs namely - anticardiolipin, anti-β2-glycoprotein I, lupus anticoagulant, antiphosphatidylcholine, antiphosphatidylserine, antiphosphatidylinositol, antiphosphatidylethanolamine and antiprothrombin antibodies have been observed in patients with different types of haematological malignancies and solid tumours. Although cancer patients have high risk of developing thrombosis, the risk becomes even higher in aPLs carriers. Although the relationship between aPLs and cancer has to be further investigated, however, the presence of aPLs in neoplastic patients can possibly increase the risk of developing thrombosis. As the pathogenic role of aPLs in cancer is still a matter of debate, more researches should be conducted on the association between the aPLs and malignancies towards the potential impact on understanding the pathogenicity and treatment when cancer and APS coexists.
Neurological manifestations or disorders associated with the central nervous system are among the most common and important clinical characteristics of antiphospholipid syndrome (APS). Although in the most recently updated (2006) APS classification criteria, the neurological manifestations encompass only transient ischemic attack and stroke, diverse 'non-criteria' neurological disorders or manifestations (i.e., headache, migraine, bipolar disorder, transverse myelitis, dementia, chorea, epileptic seizures, multiple sclerosis, psychosis, cognitive impairment, Tourette's syndrome, parkinsonism, dystonia, transient global amnesia, obsessive compulsive disorder and leukoencephalopathy) have been observed in APS patients. To date, the underlying mechanisms responsible for these abnormal neurological manifestations in APS remain unclear. In vivo experiments and human observational studies indicate the involvement of thrombotic events and/or high titers of antiphospholipid antibodies in the neuro-pathogenic cascade of APS. Although different types of neurologic manifestations in APS patients have successfully been treated with therapies involving anti-thrombotic regimens (i.e., anticoagulants and/or platelet antiaggregants), antineuralgic drugs (i.e., antidepressants, antipsychotics and antiepileptics) and immunosuppressive drugs alone or in combination, evidence-based guidelines for the management of the neurologic manifestations of APS remain unavailable. Therefore, further experimental, clinical and retrospective studies with larger patient cohorts are warranted to elucidate the pathogenic linkage between APS and the central nervous system in addition to randomized controlled trials to facilitate the discovery of appropriate medications for the 'non-criteria' neurologic manifestations of APS.
OBJECTIVES: Ethnic differences in systemic lupus erythematosus (SLE) have been previously described in the multiethnic Malaysian population. However, there have since been many demographic and socioeconomic changes in the country. The aim of this study is to re-examine the clinical and immunological profiles of Malaysian SLE patients of different ethnic backgrounds.
METHODS: Consecutive follow-up patients at the University Malaya Medical Centre (UMMC) from July 2010 until March 2011 were included in the study.
RESULTS: The most common clinical manifestations were malar rash (61.3%), arthritis (52.3%), haematological disease (51.6%), oral ulcers (51%) and renal disease (40.6%). Ethnic Indians had fewer malar and discoid rashes but were at higher risk of arthritis, serositis, renal and neuropsychiatric disease compared to Malays and Chinese Malaysians. Antiphospholipid syndrome (APS) was less common in Chinese. A longer duration of SLE correlated with a lower SLEDAI score.
CONCLUSION: Overall, the spectrum disease expression was similar to the earlier Malaysian study but the frequency of the more severe disease manifestations, viz. renal, haematological, neuropsychiatric involvements and serositis, were lower. This study further emphasises differences primarily between ethnic Indians and the other races in Malaysia.
KEYWORDS: Indians; Malaysia; Systemic lupus erythematosus; clinical manifestations; ethnicity
A pregnant woman with antiphospholipid syndrome presented with repeated venous thromboembolism (VTE) in the first and second trimesters of pregnancy despite receiving combination therapy with low-molecular-weight heparin and aspirin. The addition of hydroxychloroquine prevented further VTE recurrence, thus demonstrating its potential antithrombotic effects.
BACKGROUND: Antiphospholipid antibodies (aPLs) namely anticardiolipin (aCL) antibody, anti-β2-glycoprotein I (β2GPI) antibody and lupus anticoagulant (LA) are autoantibodies produced against anionic phospholipids and proteins on plasma membranes. Migraine is a primary headache disorder which has growing evidences of autoimmune-mediated pathogenesis and previous studies suggested the presence of aPLs in migraine patients.
AIMS: The aim of this study was to evaluate the comorbid association between aPLs (aCL, anti-β2GPI and LA) and migraine compared to healthy controls.
METHODS: Studies were searched through PubMed, ISI Web of Science and Google Scholar databases without restricting the languages and year (up to October 2016) and were selected based on the inclusion criteria. Two authors independently extracted data from the included studies. All analyses were conducted by using random effects model to calculate the odds ratio (OR) and 95% confidence interval (CI). Quality assessment was carried out by using the modified Newcastle-Ottawa Scale (NOS). Publication bias was evaluated via visualization of funnel plots, Begg's and Egger's tests.
RESULTS: The database searches produced 1995 articles, 13 of which were selected (912 migraineurs and 822 healthy controls). 8.59%, 15.21% and 4.11% of the migraineurs exhibited aCL, anti-β2GPI and LA which was 4.83, 1.63 and 3.03 times higher, respectively, than healthy controls. A significant presence of aCL (OR: 3.55, 95% CI: 1.59-7.95; p=0.002) or anti-β2GPI antibodies (OR: 2.02, 95% CI: 1.20-3.42; p=0.008) was observed in migraine patients, however, LA was not significantly associated (OR: 2.02, 95% CI: 0.50-8.37; p=0.320). Majority of the studies (n=10 of 13) demonstrated NOS score of 7 or above and no significant publication bias was observed.
CONCLUSION: Migraine might be an autoimmune-associated neurologic disorder. The presence of aCL or anti-β2GPI antibodies was significant in migraine patients compared to healthy controls, suggesting an involvement of these autoantibodies in migraine attack.