Clinical laboratory testing for the antiphospholipid syndrome

The first aCL test was developed in 1983 and subsequently standardized. Although in the last 6 to 7 years, new and more specific tests have become available, the aCL ELISA and the LA tests are still the first choice to be used in diagnosis of APS. While there is now doubt that the anticardiolipin test is useful in the diagnosis of APS, limitations of the assay have caused uncertainty and misinterpretation of the value of the test. Utilization of validated ELISA kits with well-tested calibrators and an "in-house standard" may enable more reproducible measurements. Reporting results semiquantitatively preserves the clinical utilize of the test without the misinterpretation of a quantitative result that may lack precision. The development of newer tests such as the beta2GPI ELISA and the APhL ELISA Kit, utilizing the phospholipid mixture, give promise to a more specific and reliable diagnosis of APS, while retaining good sensitivity. Other tests such as ELISA for prothrombin antibodies and annexin V antibodies are still under development and will require standardization and extensive evaluation. The aCL test should continue to be done and included in the Sapporo criteria. The aCL test is not as specific as the anti-beta2GPI test, but it is very sensitive and together with the LA test should capture the majority of the APS patients. IgA aCL and anti-beta2GPI positivity alone is rare but occasionally found and shown to be associated with major clinical manifestations of APS. Therefore, it is now recommended to include both tests, IgA aCL and IgG, IgM and IgA anti-beta2GPI to confirm diagnosis of APS.     

High-sensitivity C-reactive protein: discriminator between patients with primary and secondary antiphospholipid syndrome

Objective

It is not clear whether primary (PAPS) or secondary (SAPS) antiphospholipid syndrome represent distinct clinical entities or whether they are the same syndrome seen against different background. Therefore we examined whether hsCRP, C3, C4 and anti-oxLDL antibodies could discriminate between PAPS and SAPS patients.

Design and methods

This study included: 44 patients with PAPS and 20 patients with SAPS associated with SLE and 37 control subjects. Antibody levels were estimated by ELISA, while C3, C4 and hsCRP were determined by immunonephelometric method.

Results

SAPS patients had significantly elevated hsCRP (mg/L) concentrations in comparison to PAPS patients (8.00 (7.00–15.00) vs. 2.27 (0.68–6.89), Mann–Whitney, p = 0.000).

Conclusion

Measurement of hsCRP should be mandatory in the follow-up of SAPS patients in order to identify a subset with a high cardiovascular risk and in PAPS in order to identify patients with a risk of evolving to SLE.     

抗磷脂综合征发病机制及诊治进展

抗磷脂综合征(antiphospholipid syndrome,APS)主要表现为血栓形成或病态妊娠,实验室检测抗磷脂抗体(an-tiphospholipid antibody,APL)阳性,如抗心磷脂抗体(anticardiolipin antibody,ACA)、抗β2-糖蛋白1(β2-glycoprotein l,β2-GP1)抗体及狼疮抗凝物(lupus anticoagulant,LAC)。β2-GP1及其抗体在APS发病机理中的作用日益受到人们的重视。APS累及全身多个系统,治疗上除肝素、华法林和阿司匹林外,还可试用免疫抑制剂、大剂量丙种球蛋白等,其他与发病机制相关的免疫治疗仍在进一步研究中。     

Antibodies to beta2-glycoprotein-I: relation of anticardiolipin antibodies with clinical and laboratory parameters in patients with systemic lupus erythematosus

OBJECTIVES: There are controversial reports on the frequency of antiphospholipid antibodies (aPL) in patients with systemic lupus erythematosus (SLE). Thus, we aimed to determine the frequency and clinical importance of aPL isotypes in Turkish patients with SLE. DESIGN AND METHODS: Fifty-nine patients with SLE and 41 healthy controls were included. Serum aPL levels were measured both in patients and healthy subjects by ELISA. RESULTS: Fifteen of the patients with SLE had the antiphospholipid syndrome (APS) (25.4%). The percentage of anticardiolipin antibody (aCL)-positive SLE patients among all patients was 56%. At least one isotype of anti-beta(2)-glycoprotein I (beta(2)-GPI) antibody was positive in 83% of patients. The positivity rates of aCL and anti-beta(2)-GPI antibodies in patients with or without APS were higher than the healthy controls. There were positive correlations between isotypes of IgM aCL, IgG and IgM anti-beta(2)-GPI and manifestations of APS. CONCLUSION: It seems that the isotypes of IgM aCL, IgG and IgM anti-beta(2)-GPI are correlated with manifestations of APS. They may play a role in pathogenesis and may be helpful in establishing the diagnosis.     

Anti-phospholipid syndrome: Current opinion on mechanisms involved,laboratory characterization and diagnostic aspects

Anti-phospholipid syndrome is a complex and severe clinical situation, associated with symptoms such as recurrent thrombosis, arterial or venous, at any site, pregnancy loss, and other related syndromes. These clinical burdens, are highly variable from patient to patient, and are associated with biological abnormalities, such as the presence of the Lupus Anticoagulant or phospholipid dependent antibodies, confirmed on two occasions at least 12 weeks apart. From the diagnosis standpoint, both, functional (clotting) or immunological assays, are difficult to standardize and to optimize, due to the absence of reference material, or a characteristic clinical group, and international reference preparations. Large cohort studies are necessary for defining the usefulness of each assay, in terms of specificity, sensitivity, accuracy and for following-up the disease evolution. Clotting assays are based on Activated Partial Thromboplastin Time (APTT) and diluted Russell Viper Venom Time (dRVVT), performed at low and high phospholipid concentration, or on 1:1 mixtures of tested sample and a normal plasma pool. They allow evaluation of the paradoxal effects of LAs, which are pro-thrombotic in vivo, and anticoagulant in vivo. Use of synthetic phospholipids improves assay specificities and sensitivities, especially in patients treated with anticoagulants. Immunoassays can also be used for testing phospholipid dependent antibodies, first identified and measured as anti-cardiolipin antibodies, but now characterized as targeted to phospholipid cofactor proteins: mainly β2GP1 (which exposes cryptic epitopes upon binding to phospholipids), and in some cases prothrombin, and more rarely Protein S, Factor XIII, Protein Z or Annexin V. Use of optimized assays designed with well-characterized anionic phospholipids, then complexed with highly purified phospholipid cofactor protein (mainly β2GP1), offers a better link between reactivity and clinical associations, than the former assays which were empirically designed with cardiolipin. Standardization also remains complicated due to the absence of international standards and harmonized quantitation units. Validation on large cohorts of negative and positive patients remains the key approach for defining assay performance and clinical usefulness. Laboratory practice for all these methods is now greatly facilitated thanks to the use of automated instruments and dedicated software. Along with clinical criteria, laboratory assays are of great usefulness for identification and confirmation of the anti-phospholipid syndrome and they allow disease follow-up when appropriate patient management is in place.     

Coffin-siris综合征1例并文献复习

目的 探讨Coffin-siris综合征(CSS)患儿的临床特征和基因特点.方法 收集2018年2月至2019年2月在中山大学附属第六医院儿科确诊的1例CSS患儿的临床表现、实验室检查及基因检测等临床资料,并以"Coffin-siris综合征"、"ARID1B"、"Coffin-siris syndrome"为关键词,...     

Antiphospholipid antibodies in critically ill patients with cancer: A prospective cohort study

Purpose

The purpose of this study is to evaluate the prevalence and the prognostic impact of antiphospholipid antibodies (aPL) in critically ill cancer patients.

Methods

This is a prospective cohort study in adult patients admitted to the intensive care unit for more than 48 hours at a cancer center. Clinical and laboratory data including coagulation parameters were obtained. Cox proportional hazard models were used to identify predictors of 6-month mortality.

Results

Ninety-five (solid tumor, 79%; hematologic malignancies, 21%) patients were included, and aPL were identified in 74% of them. Median Simplified Acute Physiology Score 3 and Sequential Organ Failure Assessment scores were 51 (37-65) and 5 (2-8) points, respectively. The most frequent aPL were lupus anticoagulant (61%) and anti-β2 glicoprotein I (32%). Vascular complications occurred in 18% of patients and were comparable between aPL + and aPL − patients. Sepsis and need for renal replacement therapy were more frequent in aPL + patients. Hospital and 6-month mortality rates were 44% and 56%, respectively. Higher Sequential Organ Failure Assessment scores (each point) (hazard ratios [HR] = 2.83 [95% confidence interval, 1.59-5.00]), medical admissions (HR = 2.66 [1.34-5.27]), and d-dimer more than 500 ng/dL (HR = 1.89 (1.04-3.44]) were independently associated with mortality. After adjusting for these covariates, aPL status was not associated with outcomes (HR = 1.22 [0.60-2.47]).

Conclusions

Lupus anticoagulants were frequent in critically ill cancer patients. However, they were not associated with medium-term survival in these patients.     

Severe digital ischemia coexists with thrombocytopenia in malignancy-associated antiphospholipid syndrome: A case report and review of literature

BACKGROUNDParaneoplastic syndromes are characterized by atypical clinical manifestations. Several reports of hepatocellular carcinoma (HCC) paraneoplastic phenomena have been reported. They usually manifest as one type in an individual, but it is not common for the two clinical manifestations to occur simultaneously.CASE SUMMARYA 52-year-old female patient was admitted to hospital with pale skin and numbness of the second to fifth fingers in the left hand, which rapidly developed into severe digital ischemia. Computed tomography angiography revealed uneven thickness of the left ulnar artery with severe local luminal stenosis. Blood analysis during hospitalization showed persistent mild to medium thrombocytopenia and insensitive to hormonal therapy. Antiphospholipid antibody testing showed high titer of IgG anticardiolipin antibodies (aCLs), IgA aCLs, IgG anti-β2-glycoprotein-I (anti-β2 GPI), and IgA anti-β2 GPI. The exact diagnosis was HCC when the high a-fetoprotein levels, computed tomography findings, and the history of chronic hepatitis B came together. This was a rare case of coexisting manifestations as presenting symptoms of malignancy-associated antiphospholipid syndrome. The patient underwent several operations, antithrombotic treatments and hormonal therapy. However, the patient refused chemotherapy and died 8 wk after diagnosis.CONCLUSIONThis report highlights the importance of atypical clinical changes that could alert the physicians to vigilance for a concomitant underlying malignancy.     

Therapeutic plasma exchange for anticoagulant-refractory antiphospholipid syndrome with severe ischemic and necrotic skin lesions: A case series

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by clinical findings including thrombosis and/or obstetric complication and laboratory findings, e.g. ≥1 positive antiphospholipid antibodies (aPL) (lupus anticoagulant, anticardiolipin IgG/IgM and/or anti-β2-glycoprotein IgG/IgM). A rare APS clinical entity is severe necrosis which is difficult to treat and often does not respond to anticoagulant therapy. Three consecutive patients with primary or secondary APS who presented with necrotic skin lesions secondary to APS were treated with therapeutic plasma exchange (TPE), glucocorticoids and low-molecular-weight heparin. All patients had a rapid-onset, either full or significant recovery of their APS-related necrotic lesions.Upon treatment, one patients showed resolution of lupus anticoagulant. Two patients had a decrease of at least 88 % in aPL titers after the initial treatment, and were kept on TPE maintenance every 5–6 weeks. None of the patients experienced significant side effects of the TPE. This is the first case series showing the clinical benefits of TPE in patients with ischemic and necrotic skin lesions due to severe anticoagulant-refractory vascular APS.     

Antiphospholipid syndrome with renal and splenic infarction after blunt trauma: A case report

BACKGROUNDIn trauma patients, bleeding is an immediate major concern. At the same time, there are few cases of acute vascular occlusion after blunt trauma, and it is unclear what assessment and diagnosis should be considered for these cases. Herein, we describe a patient diagnosed with antiphospholipid syndrome after a hypercoagulable workup for acute renal and splenic vascular occlusion due to blunt trauma.CASE SUMMARYA 20-year-old man was admitted to the emergency department with abdominal pain after hitting a tree while riding a sled 10 h ago. He had no medical history. Radiological investigations revealed occlusion of the left renal artery with global infarction of the left kidney and occlusion of branches of the splenic artery with infarction of the central portion of the spleen. Attempted revascularization of the left renal artery occlusion through percutaneous transluminal angioplasty failed due to difficulty in passing the wire through the total occlusion. Considering the presence of acute multivascular occlusions in a young man with low cardiovascular risk, additional laboratory tests were performed to evaluate hypercoagulability. The results suggested a high possibility of antiphospholipid syndrome. Treatment with a subcutaneous injection of enoxaparin was started and changed to oral warfarin after two weeks. The diagnosis was confirmed, and he continued to visit the rheumatology outpatient clinic while taking warfarin.CONCLUSIONA hypercoagulable workup can be considered in trauma patients with acute multivascular occlusion, especially in young patients with low cardiovascular risk.     

Markers of cardiovascular risk in patients with antiphospholipid syndrome: A meta-analysis of literature studies

Abstract

Several studies reported on the association between antiphospholipid syndrome (APS) and venous thrombosis. In contrast, little is known about cardiovascular (CV) risk in APS. We performed a meta-analysis on the impact of APS on major markers of CV risk.

Studies on the relationship between APS and common carotid artery intima-media thickness (CCA-IMT), internal carotid artery IMT (ICA-IMT), carotid bifurcation IMT (BIF-IMT), prevalence of carotid plaques, flow-mediated dilation (FMD), nitrate-mediated dilation (NMD), and ankle-brachial index (ABI) were systematically searched in PubMed, Web of Science, Scopus, and EMBASE databases. Twenty case-control studies (668 cases, 678 controls) were included. Compared to controls, APS patients showed a higher CCA-IMT (mean difference [MD] 0.11 mm; 95% CI 0.07, 0.14), ICA-IMT (MD 0.08 mm; 95% CI 0.05, 0.11), BIF-IMT (MD 0.09 mm; 95% CI 0.06, 0.12) and a higher frequency of carotid plaques (OR 3.87; 95% CI 1.61, 9.31). Moreover, a lower FMD was found in APS subjects than in controls (MD –4.49%; 95% CI –6.20, –2.78), with no differences in NMD (MD –1.80%; 95% CI –4.01, 0.42). Finally, an increased prevalence of pathological ABI was found in APS patients compared to controls (OR 7.26; 95% CI 1.77, 29.71).

Despite heterogeneity among studies, APS appears significantly associated with markers of subclinical atherosclerosis and CV risk. These findings can be useful to plan adequate prevention strategies and therapeutic approaches.     

Gitelman综合征1例及文献复习

<正>Gitelman综合征(GS)是一种常染色体隐性遗传的失盐性肾小管疾病,以"五低一高"和代谢性碱中毒,即低血钾、低血镁、低血氯、低尿钙、偏低血压和肾素-血管紧张素-醛固酮系统(RAAS系统)活性增高为典型临床表现[1]。临床上该病较为少见,易漏诊、误诊。现报道南京医科大学第二附属医院诊治的1例GS。1 病历资料患者,女,50岁,已婚,汉族,江苏高邮人,因"反复乏力、头晕1年"于2019年2月11日入院。患者1年前因急性胃肠炎腹泻     

Hemostatic alterations during human immunodeficiency virus infection: A review

Summary Human immunodeficiency virus (HIV) infection is associated to different clinical and laboratory hemostatic alterations. The most important is thrombocytopenia, which very often leads to a picture indistinguishable from idiopathic thrombocytopenic purpura with poor clinical relevance but with possible important problems of differential diagnosis. Thrombotic thrombocytopenic purpura is sometimes associated to HIV infections, although only few reports there exist. Finally, the high incidence of lupus anticoagulant in some phases of HIV infection has not a clinical relevance, but is essentially a laboratory finding which is to be known because it can cause a prolonged partial thromboplastin time.     

The use of convalescent plasma for pediatric patients with SARS-CoV-2: A systematic literature review

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19), a severe illness leading to pneumonia, multiorgan failure, and death. With this study, we performed a systematic review of the literature and ongoing clinical trials on convalescent plasma therapy in pediatric patients with COVID-19. The electronic databases Medline PubMed, Scopus, and Web Of Science were searched. Also, clinical trials registries were searched for potentially eligible studies. A total of 90 records were retrieved after duplicate removal. Eight studies were case reports of children treated with convalescent plasma therapy (14 children, age range, 9 weeks to 18 years); 5 children had a chronic disease. During the hospital stay, 5 received drugs (e.g., remdesivir) in addition to convalescent plasma therapy. No convalescent plasma therapy-related adverse events were reported in 5 studies and 3 made no mention of adverse events. Seven studies concluded that convalescent plasma therapy is or could be a useful therapeutic option; one study made no claims. Only 3 of the 13 retrieved trials underway were planned exclusively for children. This is the first systematic review of the literature regarding convalescent plasma therapy for COVID-19 in children. We found insufficient clinical information on the safety and efficacy of convalescent plasma therapy in children. Nevertheless, the positive outcomes of the few case reports published to date suggest that convalescent plasma therapy may be of potential benefit. Further research with well-designed and powered clinical trials is needed.     

Topiramate in the prevention of pediatric migraine: literature review

Pediatric migraine is a disabling condition, which can cause a significant impact on quality of life. Currently, no drugs have been approved by the FDA for its preventive treatment. Our aim was to review the medical literature concerning the efficacy and tolerability of topiramate in the prophylactic treatment of migraine in children and adolescents. A total of five papers were reviewed: two randomized controlled trials (RCTs), a post-hoc subset analysis of adolescents who had been included in three RCTs carried out on adults and two open studies. Topiramate has been proven to reduce headache frequency and the accompanying disability. The frequency of side effects varied considerably among studies, the most frequent being weight loss, anorexia, abdominal pain, difficulties in concentrating, sedation and paresthesia. Since these adverse events, although often transitory, may be distressing for the child, we strongly recommend to assess the disability caused by the migraine episodes before deciding to initiate a prophylactic treatment. Nevertheless, dropout rates due to side effects in the studies were very low.     

The digestive system involvement of antiphospholipid syndrome: pathophysiology,clinical characteristics,and treatment strategies

Antiphospholipid syndrome (APS) is an autoimmune disease mainly characterised by vascular thrombosis and pregnancy morbidity. APS has broad spectrum of clinical manifestations. The digestive system involvement of antiphospholipid syndrome is a critical but under-recognised condition. Digestive system involvement may be the result of direct (autoimmune-mediated) or indirect (thrombotic) mechanisms. Liver is the most commonly involved organ, followed by intestines, oesophagus, stomach, pancreas and spleen. This review describes possible digestive system manifestations in APS patients, and illustrates the epidemiology and possible pathophysiology of APS. The role of different treatment strategies in the management of digestive system manifestations of APS were also discussed.

Key messages

• Antiphospholipid syndrome is a multi-organ, multi-system disease and its clinical manifestation spectrum is gradually expanding. Since the first diagnosis of APS, the clinical manifestations of digestive system have been reported successively. This narrative review describes the major digestive system manifestations of APS and illustrates the epidemiology, pathophysiology and the role of therapeutic strategies of these patients.