Seronegative Antiphospholipid Syndrome Research Articles

A case of repeated in-stent restenosis of coronary artery as a primary manifestation of seronegative antiphospholipid antibody syndrome

BackgroundAntiphospholipid antibody syndrome (APS) is a multisystemic autoimmune disorder which affects many organs or systems; however, coronary artery is relatively less frequently involved.Case presentationA 65-year-old female with effort chest pain was hospitalized for unstable angina in Janurary, 2015. Coronary angiography revealed sub-total occlusion of proximal left anterior descending (LAD) coronary artery, where a drug-eluting stent was successfully deployed. The patient experienced multiple in-stent stenosis at LAD coronary artery and coronary artery bypass graft (CABG) surgery was advised. Subsequently, severe stenosis of left circumflex (LCX) coronary artery emerged, and the patient suffered persistent in-stent restenosis. Eventually, the patient was diagnosed with seronegative antiphospholipid antibody syndrome and salvaged by immunosuppressants.ConclusionsRepeated in-stent restenosis could be a primary manifestation of seronegative antiphospholipid antibody syndrome, and suppression of autoimmune activity and inflammation other than purely coronary revascularization might be a better option.

Surviving Multiple Cardiac Arrests Secondary to Catastrophic Sero-Negative Antiphospholipid Syndrome: A Case Report

Antiphospholipid syndrome (APS) is an autoimmune disorder which predisposes to venous and arterial thrombosis due to the autoantibodies targeting phospholipids in cell membranes contributing to a pro-thrombotic state. The appropriately named catastrophic anti-phospholipid syndrome (CAPS) is distinguished from classical APS by the rapid involvement of 3+ organs, evidence of areas of small vessel occlusions, and significantly elevated anti-phospholipid titers (Cervera, 2018). To further complicate the matter, there is a growing body of evidence of the existence of sero-negative APS (SNAPS) that are negative for the classical lupus anticoagulant, anticardiolipin antibody (aCL), and anti-beta2 glycoprotein-I but may be positive for non-criteria APS antibodies. Presented below is a patient with SNAPS who responded to the therapy for CAPS despite negative classical autoantibodies. A 34 year old man with a past medical history of chronic alcohol use presented to the ED with a two day history of worsening shortness of breath. The patient was found to have an spO2 of 45-50% on room air and was quickly transitioned to a non-rebreather and subsequently BIPAP. Initial CBC was significant for WBC 22.1, Hg 19.3, Hct 58.5, MCV 100.8, and platelets of 166 consistent with neutrophilic leukocytosis and macrocytic polycythemia. D-dimer >20 was suggestive recent/on-going coagulation and/or fibrinolysis. Due to worsening respiratory failure, he was intubated and admitted to the ICU. While on 3 vasopressors he became bradycardic and a code blue was called for pulseless electrical activity (PEA). After 3 rounds of CPR he achieved return of spontaneous circulation (ROSC) and was taken for urgent CT imaging. After arriving in the radiology department he went into cardiac arrest for two rounds of CPR before achieving ROSC and being scanned and returning to the ICU. Polycythemia tests were drawn which revealed elevated erythropoietin of 52.1 (2.6-18.5) and ultimately negative JAK2. Chest CTA was significant for a PE with a heavy clot burden involving the entire right lung and the left upper and lower lobes. CT C/A/P showed findings of bilateral lower lobe pneumonia, severe gastritis, pancolitis, proctitis, pancreatitis with a 4.6cm pseudocyst, and fatty liver with congestive enhancement. Tissue-type plasminogen activator (tPA) bolus and infusion was initiated based on the imaging findings with the third cardiac arrest occurring 7 minutes later early in the morning. Repeat CBC revealed an Hgb/Hct of 22.2 g/dL and 71.5%, respectively, with a significant drop in platelets down to 103 with occasional large platelets consistent with peripheral destruction of platelets was noted on peripheral blood smear (PBS). Therapeutic phlebotomy of 300mL was subsequently performed with two additional cardiac arrests within 2 hours of each other before vascular surgery was able to perform thrombectomies of the involved pulmonary arteries and initiate catheter-directed thrombolysis. Platelet count dropped while on heparin to 25,000 so a HIT panel was ordered and he was transitioned to argatroban. At this point hematology was consulted who was concerned for CAPS and ordered aPL (anti-phospholipid) tests along with an appropriate panel of labs to rule out alternative causes. Peripheral blood smear did not reveal fragmentation of RBC to suspect TTP. Tests for ACL IgG/IgM and anti-beta2GPI IgG/IgM antibodies, COVID, HIV, ADAMTS deficiency, hereditary thrombophilia, and ANA were negative. High-dose steroids and daily plasma exchanges via vascath was initiated and within 12 hours there was significant improvement. He was extubated and off pressors in 24 hours with improved platelets. Lupus anticoagulant test results were reported after discharge with dVVT mix and PTT LA mix both being prolonged, however, repeat lupus anticoagulant 3 months later was negative. Given the potentially catastrophic effects of a missed CAPS diagnosis, a high level of clinical suspicion is needed as plasma exchange can quickly alleviate an otherwise disastrous condition. Further research into non-criteria APS autoantibodies (IgA)may be able to help guide future SNAPS diagnoses.

Contribution of anti-β2 glycoprotein1 IgA testing in the diagnosis of seronegative-APS for patients with cerebral thrombosis

Seronegative antiphospholipid syndrome has been suggested for patients with clinical manifestations highly suggestive of APS but persistently negative criteria-aPLs. Evidence gathered over the last years of research in thrombosis reported the pathogenic significance of non-criteria aPLs, among them IgA isotype. However, their role in the occurrence of neurological thrombosis, has not yet been studied. In this article, we aim to: (1) determine the prevalence of aβ2GP1 IgA in cerebral thrombosis, (2) study the association and (3) assess the diagnostic value of aβ2GP1. This study enrolled 70 patients with cerebral thrombosis without underlying autoimmune disease referred for thrombophilia assessment and 165 healthy controls. In addition to a coagulation screen and inherited thrombophilia testing, patients and controls were tested for criteria (LA; aβ2GP1; aCL IgM/IgG) and non-criteria aPLs (aβ2GP1 IgA; aCL IgA; aPS-PT; IgM/IgG). The overall aβ2GP1 IgA prevalence in patients was 61.4 % (43/70) mostly isolated in 50 % (35/70) while 50 % were positive for criteria-aPLs. aβ2GP1 IgA were the most prevalent aPLs in cerebral venous thrombosis compared with stroke (92.3 % vs 54.4 %). A significative relationship between aβ2GP1 IgA and the occurrence of CVT and stroke has been established (x2 = 6.9, p = 0.008; x2 = 4.03, p = 0.045). There was a high specificity of aβ2GP1 IgA testing for stroke (79 %) and CVT (100 %) despite a lower sensitivity (73 %; 52 %, respectively). The aβ2GP1 IgA testing improved considerably (50 %) the diagnosis of patients with cerebral thrombosis and negative criteria-aPLs, who may benefit from an adapted therapeutic care. Laboratory consensus criteria might consider aβ2GP1 IgA and set up a sequential approach improving APS diagnosis.

Early systemic lupus erythematos: onset with thrombosis

Systemic lupus erythematosus (SLE) is a global pathology that can affect people of any age, with an average age of onset between 15 and 44 years. The female/male ratio is 13:1, while in children and the elderly it is only 2:1 [2, 5]. SLE can affect any organ and presents a wide spectrum of clinical and immunological manifestations, being one of the conditions with the highest mortality rates among systemic diseases [10]. This article presents the clinical case of patient X, aged 19 years, with subacute SLE, with involvement of the skin, vessels, mucous membranes, kidneys, muscles, hematopoietic system, immune system and secondary seronegative antiphospholipid syndrome. The diagnosis was established based on clinical and immunological SLICC criteria, laboratory tests, ECG, EcoCG, chest X-ray, ultrasonography of internal organs, Doppler ultrasonography of lower limb vessels and brain MRI. Against the background of immunosuppressive, anticoagulant, antiplatelet treatment, the patient’s condition improved and she was discharged with the recommendation to continue the basic and symptomatic treatment.

Vitreous hemorrhage in a pregnant woman with a history of simultaneous pancreas and kidney transplantation: A case report

Pregnancy after simultaneous pancreas and kidney transplantation (SPKT) carries a high risk of maternal and fetal complications. We report the case of a 39-year-old woman with three consecutive pregnancies with favorable outcomes after SPKT. Within the first year of SPKT, the patient had a spontaneous pregnancy. At 32weeks of gestation, she underwent an emergency cesarean section (CS) due to severe preeclampsia and HELLP syndrome. The infant was of average birth weight and was transferred to the neonatal intensive care unit for further management. A second unplanned pregnancy occurred almost nine months after the first. The antenatal assessments for fetal growth, blood glucose, and blood pressure were normal throughout follow-up. Early in her pregnancy, the patient developed an uneventful retinopathy of the left eye. At 37weeks of gestation, she underwent an elective CS due to a short inter-pregnancy interval and delivered a healthy baby with an average birth weight. At the age of 39years, the patient had a third unplanned pregnancy. She was diagnosed with seronegative antiphospholipid syndrome. She suffered from bilateral vitreous hemorrhage and was managed successfully with a minimally invasive laser treatment combined with an intravitreal injection of anti-vascular endothelial growth factor during her third trimester. At 35weeks of gestation, the patient presented with labor pain and underwent an emergency CS and delivered a healthy baby with an average birth weight. Pregnancy after SPKT requires a multidisciplinary approach with a careful workup.

Non-criteria antiphospholipid antibodies in antiphospholipid syndrome: Diagnostic value added.

Non-criteria antiphospholipid antibodies (aPLs) increase the diagnostic value for antiphospholipid syndrome (APS) and contribute to better recognition of seronegative APS (SNAPS). However, the clinical utility and the diagnostic value of non-criteria aPLs are inconsistent. This study aimed to investigate the prevalence and clinical significance of 7 non-criteria aPLs in a large APS cohort. Seven non-criteria aPLs, including anti-phosphatidylserine/prothrombin (aPS/PT) antibodies IgG/IgA/IgM, anti-phosphatidylethanolamine antibodies (aPE) IgG/IgA/IgM, anti-Annexin V antibodies (aAnnexinV) IgG/IgA/IgM, anti-phosphatidylserine antibodies (aPS) IgM, aPS IgG, antibodies directed againsta mixture of phospholipids(APhL) IgG, and APhL IgM were tested among 175 patients with APS, 122 patients with other autoimmune diseases (as disease controls), and 50 healthy controls. In the present study, the highest prevalence of non-criteria aPLs was seen in aAnnexinV (58.86%). APhL IgG and aPS IgM showed the highest specificity (95.35%) and aPS/PT showed the highest Youden index (0.3991) for the diagnostic value of APS. The aAnnexinV also showed the highest prevalence in SNAPS (43.3%), followed by APhL IgM (21.7%), aPE (16.7%) and aPS/PT (16.7%). APhL IgG, aPS/PT, and aPS IgG showed positive association with thrombotic events in APS patients [APhL IgG: odds ratio (OR) = 2.26, 95% confidence interval (CI) 1.18-4.34, p = 0.013; aPS/PT: OR = 2.48, 95% CI: 1.32-4.69, p = 0.004; aPS IgG: OR = 1.90, 95% CI 1.01-3.60, p = 0.046; respectively). The inclusion of the non-criteria aPLs increased the accuracy of APS diagnosis from 65.7% to 87.4%. Our data provide evidence that adding the non-criteria aPLs can improve the diagnostic accuracy in APS. APhL IgG, aPS/PT, and aPS IgG may be potential biomarkers to predict the risk of thrombosis in APS.

The presence of non-criteria manifestations negatively affects the prognosis of seronegative antiphospholipid syndrome patients: a multicenter study

BackgroundSeronegative antiphospholipid syndrome (SN-APS) is often defined as the presence of APS criteria manifestations, negative antiphospholipid antibodies (aPL), and coexistence of APS non-criteria manifestations. Nevertheless, the impact of these non-criteria features is still unclear. On a different note, the relevance of one single aPL positive determination in patients with APS manifestations is another domain with limited evidence. We aim to compare the course of SN-APS and single-positive aPL (SP-aPL) patients with that of individuals with APS manifestations without non-criteria features/aPL positivity (controls).MethodsRetrospective analysis of patients with thrombosis/obstetric morbidity assessed in two European hospitals between 2005 and 2020. Patients were divided into SN-APS, SP-aPL, and control groups. Clinical characteristics, comorbidities, and therapies were compared.ResultsA total of 82 patients were included in the SN-APS group, 88 in the SP-aPL group, and 185 in the control group. In Cox regression model, SN-APS displayed more thrombosis recurrence than controls (HR 3.8, 95% CI 2.2–6.5, p < 0.001) even when adjusting for the presence of hereditary thrombophilia, systemic lupus erythematosus, or contraceptive hormonal treatment. In SP-aPL, the difference in thrombosis recurrence did not reach statistical significance (p = 0.078). Indefinite anticoagulation (p < 0.001 and p = 0.008, respectively) and vitamin K antagonist (VKA) use (p < 0.001 in both cases) were more common in SN-APS/SP-aPL.ConclusionSN-APS displayed more thrombosis recurrence, indefinite anticoagulation, and VKA use than controls without non-criteria manifestations. The presence of such features in patients with thrombosis and negative aPL may negatively impact their clinical course.

Hydroxychloroquine therapy in women with autoimmune recurrent pregnancy loss, refractory to low dose aspirin and heparin: a randomized controlled trial

Hydroxychloroquine (HCQ) is a novel medication for women suffering from autoimmune-related recurrent pregnancy loss. Many autoimmune disorders have been related to poor obstetric outcomes; anti-phospholipid syndrome (APS) is the only autoimmune disorder in which pregnancy loss is a diagnostic requirement. The goal of this study is to see how beneficial it is to provide hydroxychloroquine (HCQ) in addition to low-molecular-weight heparin (LMWH) and low-dose aspirin (LDA) to females having a record of autoimmune-related recurrent pregnancy loss and refractoriness to low-dose aspirin and LMWH in previous pregnancies, both during preconception and gestation. Patients and methods. Between January 2019 and January 2021, 120 females with a history of autoimmune recurrent pregnancy loss at Ain Shams University Maternity Hospital were examined. Participants were divided into two classes using computer-based randomization procedures. During preconception and gestation, class A (60 cases) received hydroxychloroquine (HCQ), while class B (60 cases) received a placebo. Also, they received LDA and LMWH. The primary outcome measure in this study was the rate of live births. Secondary outcomes included gestational age at delivery, birth weight, mode of delivery, Apgar score at 5 minutes, neonatal morbidity, rate of neonatal intensive care unit (NICU) admission, and postneonatal mortality rate. Results. The live birth rate was 66% in class A and 42.3 % in class B. So, it was significantly higher in class A than in class B (p-value = 0.016). Additionally, gestational age at delivery was substantially greater in class A than in class B. In terms of live births, C-section was slightly less common in class A than in class B (p-value = 0.015). Notably, the mean birth weight was 2.509 kg in class A and 1.972 kg in class B, indicating that neonatal birth weight was substantially greater in class A than in class B (p-value = 0.003). Finally, NICU admission was significantly less common in class A than in class B (p-value = 0.044). Conclusion. HCQ is a potent, safe, and cost-effective medication used to prevent adverse obstetric outcomes in females with a history of autoimmune-related recurrent pregnancy loss with refractoriness to LDA and LMWH in previous pregnancies. This randomized controlled trial (RCT) provided additional evidence to support previous studies (non-criteria or seronegative APS), in which the diagnosis of APS is made solely based on the medical history, regardless of laboratory findings for antiphospholipid antibodies (aPL). Trial registration: Pan African Clinical Trial registration number is: PACTR2021104858485905. Key words: hydroxychloroquine; anti-phospholipid syndrome; heparin; low dose aspirin; autoimmune recurrent pregnancy loss

A catastrophic seronegative anti-phospholipid syndrome: case and literature review

BackgroundAntiphospholipid Syndrome (APS) is a multisystemic autoimmune disease characterized by arterial and venous thrombosis and / or obstetric morbidity in the presence of at least one circulating anti-phospholipid antibody. The spectrum of vascular events varies from deep venous thrombosis to catastrophic APS, a rare form characterized by acute multiorgan thrombosis and high mortality.Case reportWe present the case of a 32-week pregnant woman arriving in the hospital emergency room with bilateral acute lower limb ischemia. In the obstetric evaluation, fetal death was declared. Computerized Tomography angiography showed pulmonary embolism of both pulmonary arteries, areas of splenic and right renal infarction and multiple arterial and venous thrombosis. The patient underwent urgent caesarean section and axillary-bifemoral bypass. No events registered. In the postoperative period, in an intensive care unit, treatment with rituximab and plasmapheresis were added to anticoagulant therapy. The laboratorial investigation was negative for thrombophilia and autoimmune diseases.ConclusionCatastrophic APS develops quickly, with multiorgan involvement and high mortality rate. The presented case poses a multidisciplinary challenge, with the surgical approach of extra-anatomical revascularization being less invasive and guaranteeing immediate perfusion of the lower limbs. Although the serological tests were negative for anti-phospholipid antibodies, this case hardly fits into another diagnosis. Therefore, it was treated as a catastrophic APS, having shown a favorable evolution.

P1‐88: Persistent bilateral unprovoked pulmonary embolism ‐ A case of chronic thromboembolic pulmonary hypertension in a young lady with seronegative antiphospholipid syndrome

P1‐88: Persistent bilateral unprovoked pulmonary embolism ‐ A case of chronic thromboembolic pulmonary hypertension in a young lady with seronegative antiphospholipid syndrome

A Healthy Young Lady with ‘Unprovoked’ Persistent Bilateral Pulmonary Embolism - Why?

Pulmonary embolism (PE) was reported in about 9% patients with antiphospholipid syndrome (APS). Seronegative APS is an entity which demonstrates clinical manifestations highly suggestive of APS but persistently negative APS antibodies. A 31-year-old lady presented with a two-month history of exertional dyspnoea. She had two consecutive miscarriages at 12 and 14 weeks, previously. Physical examination revealed a thin lady who was tachycardic, tachypneic, hypoxic but normotensive. There was a loud P2 without signs of heart failure. Investigations revealed a type 1 respiratory failure, sinus tachycardia with right ventricular strain pattern, cardiomegaly with normal lung fields, and dilated right atrium and right ventricle with increased in pulmonary arterial pressure of 70mmHg from echocardiography. CT pulmonary angiography (CTPA) confirmed the presence of PE over bilateral pulmonary arteries. She continued to have exertional dyspnoea and was readmitted 9 months later with worsening dyspnoea. APS antibodies performed during both admissions were negative. Seronegative APS was diagnosed. Interestingly, two CTPAs performed at 6 months and 9 months after initial presentation revealed persistent bilateral pulmonary embolism. The provoking factors for PE should be sought because ‘unprovoked’ PE especially in young individuals need further attention. APS, including seronegative APS, should be considered. Persistence of symptoms of PE also warrants further attention as chronic thromboembolic pulmonary hypertension (CTEPH) may be the cause. Currently, there are available medical and surgical treatment of CTEPH, therefore establishing its diagnosis is important and it is best performed in pulmonary hypertension expert centre.International Journal of Human and Health Sciences Supplementary Issue-2: 2021 Page: S25

'Non-criteria antiphospholipid antibodies': bridging the gap between seropositive and seronegative antiphospholipid syndrome.

We aimed to analyse the prevalence of non-criteria anti-phospholipid (aPL) antibodies and their role in the diagnosis, treatment and prognosis in a cohort of patients with clinical features consistent with a diagnosis of antiphospholipid syndrome (APS), but persistently negative for criteria aPL - anti-cardiolipin antibodies (aCL), anti-β2-glycoprotein I antibodies (aβ2-GPI) and lupus anticoagulant (LA) - named seronegative APS (SN-APS). Sera from SN-APS patients were tested for aCL by TLC-immunostaining, anti-vimentin/cardiolipin (aVim/CL) and anti-phosphatidylserine/prothrombin (anti-PS/PT) by ELISA. Control groups of our study were APS patients and healthy controls. We enrolled 114 consecutive SN-APS patients, 69 (60.5%) resulted positive for at least one non-criteria test in two occasions 12 weeks apart. Among the persistently positive patients to these tests, 97% resulted positive for aCL by TLC-immunostaining, 52.3% for aVim/CL and 17.4% for aPS/PT. SN-APS patients with double positivity (aCL by TLC-immunostaining and aVim/CL) showed a likelihood positive ratio of 8 to present mixed thrombotic and obstetrical features. Among SN-APS patients tested positive, after the therapeutic changes, three cases of recurrent thrombosis were observed [median follow-up 41 months (IQR 39.5)]. Twenty pregnancies were recorded in 17 SN-APS patients after the detection of unconventional aPL and 12 of them (60%) experienced a good outcome under conventional treatment for APS. This is the largest monocentric study demonstrating that aCL tested by TLC-immunostaining and aVim/CL can detect aPL positivity in SN-APS. It may encourage clinicians to monitor and provide adequate targeted therapy, which improve SN-APS prognosis.

Low prevalence of antiannexin A5 antibodies in unprovoked venous thrombosis.

The antiphospholipid syndrome (APS) is characterized by thrombosis or pregnancy morbidity, and the detection in the blood of at least one of three antiphospholipid antibodies (lupus anticoagulant, or anticardiolipin or anti-β2 -glycoprotein I antibodies). Diagnosing APS is important so that secondary prophylaxis may be administered to reduce risk of recurrent thrombosis and/or pregnancy morbidity. In addition to APS-defining antibodies, there may be additional autoantibodies that have a role in thrombosis and/or pregnancy morbidity. Furthermore, some patients have clinical manifestations highly suggestive of APS but are persistently negative for the APS-defining antibodies ("seronegative APS") and instead, have other autoantibodies. Antiannexin A5 (aANXA5) autoantibodies have been associated with increased risk of thrombosis and pregnancy morbidity; levels are also reportedly higher in patients with venous thrombosis compared with healthy controls. The prevalence of aANXA5 among patients with unprovoked venous thrombosis is not well-documented and determination of the frequency of aANXA5 is the objective of this study. We analysed sera from 148 patients with unprovoked venous thrombosis who had undergone routine laboratory testing for the present APS-defining antibodies. aANXA5 IgG and IgM were present in 6% and 1%, respectively. Prevalence of these antibodies in unprovoked venous thrombosis is comparable with frequencies reported in healthy individuals and is far lower than the prevalence in women with pregnancy morbidity. This may indicate lack of association with venous thrombosis, however, adequately powered case-control studies will be required to resolve this and prevalence data from this study will assist in the design of such studies.

Current Promising Biomarkers and Methods in the Diagnostics of Antiphospholipid Syndrome: A Review.

Antiphospholipid syndrome (APS) is a hypercoagulation condition associated with the incidence of heterogenic antiphospholipid antibodies (aPLs), which non-specifically affect hemostasis processes. APS is clinically manifested by recurrent arterial and venous thromboses and reproduction losses. The aPL antibodies, which may induce clinical manifestations of APS, include criteria antibodies anti-cardiolipin, anti-β2-glycoprotein-I, and lupus anticoagulant, but also non-criteria antibodies, for example anti-β2-glycoprotein-I domain I, anti-phosphatidylserine/prothrombin, anti-annexin V, and many others. APS occurs mostly in patients of younger and middle age, most frequently in females. Laboratory diagnostics of APS are quite difficult, as they include a wide spectrum of examining methods, which are based on various principles of detection and are performed using various laboratory techniques. The objective of the review is to describe the current state of potentially examined biomarkers and methods in APS diagnostics. The aforementioned biomarkers are lupus anticoagulant, anti-β2-glycoprotein-I, anti-cardiolipin, anti-β2-glycoprotein-I domain I, anti-phosphatidylserine/prothrombin, anti-β2-glycoprotein-I IgA, anti-cardiolipin IgA, anti-annexin V and II, anti-prothrombin, anti-cardiolipin/vimentin, anti-protein S/protein C, and antibodies against phospholipid antigens for whose diagnostics we may use some of the methods established for a long time and some of the modern methods—the coagulation method for the determination of lupus anticoagulant (LA), enzyme-linked imunosorbent assay (ELISA), chemiluminescence analysis (CLIA), multiplex fluorescence flow immunoassay (MFFIA), fluorescence enzyme immunoassay (EliA), line immunoassay (LIA), multiline dot assay (MLDA), and thin-layer chromatography (TLC). Conclusion: Antibodies against phosphatidylethanolamine, phosphatidic acid, phosphatidylserine, phosphatidylinositol, cardiolipin/vimentin complex, and annexin V are currently the most studied new markers. However, these assays have not been standardized until now, both from the laboratory and clinical point of view. In this review we summarize the evidence of the most studied aPL markers and their potential clinical significance in seronegative APS (SN-APS).

The Weight of IgA Anti-β2glycoprotein I in the Antiphospholipid Syndrome Pathogenesis: Closing the Gap of Seronegative Antiphospholipid Syndrome

The specific value of IgA Anti-β2glycoprotein I antibodies (aB2GP1) in the diagnosis and management of antiphospholipid syndrome (APS) is still controversial and a matter of active debate. The relevance of the IgA aB2GP1 isotype in the pathophysiology of APS has been increasingly studied in the last years. There is well know that subjects with multiple positive APS tests are at increased risk of thrombosis and/or miscarriage. However, these antibodies are not included in the 2006 APS classification criteria. Since 2010 the task force of the Galveston International Congress on APS recommends testing IgA aB2GP1 isotype in patients with APS clinical criteria in the absence of criteria antibodies. In this review, we summarize the molecular and clinical “state of the art” of the IgA aB2GP in the context of APS. We also discuss some of the characteristics that may help to evaluate the real value of the IgA aB2GP1 determination in basic research and clinical practice. The scientific community should be aware of the importance of clarifying the role of IgA aB2GP1 in the APS diagnosis.

Molecular Mechanisms of "Antiphospholipid Antibodies" and Their Paradoxical Role in the Pathogenesis of "Seronegative APS".

Antiphospholipid Syndrome (APS) is an autoimmune disease characterized by arterial and/or venous thrombosis and/or pregnancy morbidity, associated with circulating antiphospholipid antibodies (aPL). In some cases, patients with a clinical profile indicative of APS (thrombosis, recurrent miscarriages or fetal loss), who are persistently negative for conventional laboratory diagnostic criteria, are classified as “seronegative” APS patients (SN-APS). Several findings suggest that aPL, which target phospholipids and/or phospholipid binding proteins, mainly β-glycoprotein I (β-GPI), may contribute to thrombotic diathesis by interfering with hemostasis. Despite the strong association between aPL and thrombosis, the exact pathogenic mechanisms underlying thrombotic events and pregnancy morbidity in APS have not yet been fully elucidated and multiple mechanisms may be involved. Furthermore, in many SN-APS patients, it is possible to demonstrate the presence of unconventional aPL (“non-criteria” aPL) or to detect aPL with alternative laboratory methods. These findings allowed the scientists to study the pathogenic mechanism of SN-APS. This review is focused on the evidence showing that these antibodies may play a functional role in the signal transduction pathway(s) leading to thrombosis and pregnancy morbidity in SN-APS. A better comprehension of the molecular mechanisms triggered by aPL may drive development of potential therapeutic strategies in APS patients.

"Non-criteria" antiphospholipid syndrome: A nomenclature proposal.

The classification criteria for antiphospholipid syndrome (APS) generate discussion, with a growing impression that certain patients not fulfilling these criteria might be inadequately excluded from the classification. Nonetheless, these "non-criteria" patients are heterogeneously defined across different publications. We reviewed the "non-criteria" APS subgroups depicted in the literature and attempted to organize these subsets in a nomenclature proposal that could be used for research purposes. We established four potential patient profiles, grouped under the broad term "non-criteria APS": (A) "Seronegative APS": patients fulfilling clinical criteria, plus "non-criteria" manifestations, with persistently negative antiphospholipid antibodies (aPL); (B) "Clinical non-criteria APS": patients with "non-criteria" manifestations, plus aPL positivity fulfilling the classification criteria; (C) "Incomplete laboratory APS": patients fulfilling clinical criteria, plus positive aPL, but not fulfilling the classification criteria (low titer aPL); and (D) "Laboratory non-criteria APS": patients fulfilling clinical criteria, with negative or low titer criteria aPL, plus positive "non-criteria" aPL. This categorization could allow for a more homogeneous research approach to APS, enabling more sustained and universal conclusions.

\u201cNon-criteria\u201d antiphospholipid antibodies add value to antiphospholipid syndrome diagnoses in a large Chinese cohort

BackgroundDespite expansion in the 2006 Sydney antiphospholipid syndrome (APS) classification criteria to include IgG/IgM anti-β2-glycoprotein (aβ2GPI) antibodies in addition to IgG/IgM anti-cardiolipin antibodies (aCL) and lupus anticoagulant (LAC), some individuals with clinical features of APS remain seronegative (seronegative APS or SNAPS) and are at risk of recurrent thrombosis and pregnancy morbidities. Our aim was to assess the value of “non-criteria” aPL antibodies to detect these SNAPS patients.MethodsOne hundred ninety-two APS patients, 90 SNAPS patients, 193 autoimmune disease controls, and 120 healthy controls were evaluated. Ten antiphospholipid antibodies (aPLs) were tested using commercial kits, including 5 non-criteria aPLs: anti-phosphatidylserine/prothrombin antibodies (aPS/PT) IgG/IgM, aCL IgA, aβ2GPI IgA, and anti-β2GPI Domain 1 (aβ2GPI-D1) IgG.ResultsUp to 60.9% of the SNAPS and 93.5% of APS patients were detected by at least one non-criteria aPL. aPS/PT IgG had the highest Youden index in classifying APS and SNAPS from controls. aPS/PT IgG and aβ2GPI Domain 1 IgG seem to be the most significant risk factors for thrombotic events and pregnancy morbidity, respectively. aPS/PT IgG/IgM and aβ2GPI-D1 IgG were detected in some SNAPS patients, while IgA isotypes of aCL/aβ2GPI tended to appear together with other biomarkers. The combined analysis showed enhanced diagnostic performance with the inclusion of non-criteria aPLs.ConclusionsRecognition of SNAPS patients is critical for clinical management and prevention of potential thrombotic and obstetric adverse events. The non-criteria antiphospholipid antibodies help to identify a considerable portion (60.9%) of these patients who otherwise may remain untreated and at clinical risk.

Seronegative antiphospholipid syndrome: refining the value of "non-criteria" antibodies for diagnosis and clinical management.

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by arterial and venous thrombotic manifestations and/or pregnancy-related complications in patients with persistently high antiphospholipid antibodies (aPL), the most common being represented by anticardiolipin antibodies (aCL), anti-beta 2 glycoprotein-I (aβ2GPI), and lupus anticoagulant (LAC). A growing number of studies have showed that, in some cases, patients may present with clinical features of APS but with temporary positive or persistently negative titers of aPL. For these patients, the definition of seronegative APS (SN-APS) has been proposed. Nevertheless, the negativity to classic aPL criteria does not imply that other antibodies may be present or involved in the onset of thrombosis. The diagnosis of SN-APS is usually made by exclusion, but its recognition is important to adopt the most appropriate anti-thrombotic strategy to reduce the rate of recurrences. This research is in continuous development as the clinical relevance of these antibodies is far from being completely clarified. The most studied antibodies are those against phosphatidylethanolamine, phosphatidic acid, phosphatidylserine, phosphatidylinositol, vimentin/cardiolipin complex, and annexin A5. Moreover, the assays to measure the levels of these antibodies have not yet been standardized. In this review, we will summarize the evidence on the most studied non-criteria aPL, their potential clinical relevance, and the antithrombotic therapeutic strategies available in the setting of APS and SN-APS.

Annexin-A5 resistance and non-criteria antibodies for the diagnosis of seronegative antiphospholipid syndrome.

In this study, we aimed to analyze the value of annexin-A5 anticoagulant ratio (A5R) and non-criteria antibodies for the diagnosis of APS in patients with clinicalseronegative APS. Three groups were defined, including 21 seronegative APS patients with unexplained obstetrical adverse events or thrombosis history, 15 confirmed APS patients with triple aPL positivity, and a control group of 20 healthy patients without any history of thrombosis or pregnancy complications. Seronegative APS patients have similar levels of A5R in comparison to healthy controls (202% [171%-238%] versus 191% [178%-221%]; p = 0.65), whereas triple-positive APS patients have significantly more reduced A5R in comparison to both seronegative and healthy patients (149% [138%-158%] versus 202% [171%-238%] and 191% [178%-221%], respectively, p < 0.001). The non-criteria aPL were found in 24% of seronegative APS: anti-PE IgM in 3 cases (14%) and anti-PS/PT IgG and anti-PS/PT IgM in 1 (5%) case each. The frequency of non-criteria APL was significantly more frequent in comparison to healthy controls (p = 0.048). All triple-positive APS patients have at least one non-criteria aPL, and the non-criteria aPL were significantly more frequent in these patients compared to seronegative APS and healthy controls (p < 0.001). Whereas A5R levels do not allow to discriminate seronegative APS from healthy controls, our results demonstrate that non-criteria aPL can helpto APS diagnosis in clinicalseronegative APS.Key points• Annexin-A5 resistance testing does not help for the diagnosis of seronegative APS.• The non-criteria antiphospholipid antibodies can contribute to APS diagnosis in patients without conventional antibodies.