Obstetric Antiphospholipid Syndrome Research Articles

Protection by hydroxychloroquine prevents placental injury in obstetric antiphospholipid syndrome.

Obstetric antiphospholipid syndrome (OAPS) is mediated by antiphospholipid antibodies (aPLs, and anti‐β2 glycoprotein I antibody is the main pathogenic antibody), and recurrent abortion, preeclampsia, foetal growth restriction and other placental diseases are the main clinical characteristics of placental pathological pregnancy. It is a disease that seriously threatens the health of pregnant women. Hydroxychloroquine (HCQ) was originally used as an anti‐malaria drug and has now shown benefit in refractory OAPS where conventional treatment has failed, with the expectation of providing protective clinical benefits for both the mother and foetus. However, its efficacy and mechanism of action are still unclear. After clinical data were collected to determine the therapeutic effect, human trophoblast cells in early pregnancy were prepared and treated with aPL. After the addition of HCQ, the proliferation, invasion, migration and tubule formation of the trophoblast cells were observed so that the therapeutic mechanism of HCQ on trophoblast cells could be determined. By establishing an obstetric APS mouse model similar to the clinical situation, we were able to detect the therapeutic effect of HCQ on pathological pregnancy. The normal function of trophoblast cells is affected by aPL. Antibodies reduce the ability of trophoblast cells to invade and migrate and can impair tubule formation, which are closely related to placental insufficiency. HCQ can partially reverse these side effects. In the OAPS mouse model, we found that HCQ prevented foetal death and reduced the incidence of pathological pregnancy. Therefore, HCQ can improve pregnancy outcomes and reverse the aPL inhibition of trophoblast disease. In OAPS, the use of HCQ needs to be seriously considered.

Analysis of Serbian Primary Antiphospholipid Syndrome Patients Confirmed a Strong Association Between Livedo Reticularis and Arterial Thrombosis: A National Cross-Sectional Cohort Study.

Antiphospholipid syndrome (APS) is characterized by antiphospholipid antibodies (aPLs) associated with thrombosis (arterial and/or venous) and/or obstetrical manifestations. However, various manifestations, which are considered to be noncriteria manifestations, are frequently found in APS. The purpose of this study was to evaluate whether noncriteria manifestations may be found more frequently in subjects with thrombotic and/or obstetrical APS ("criteria" manifestations) in a population of patients with primary APS (PAPS). This study presents the results from our national cohort. This is a cross-sectional study of 360 PAPS patients. Data regarding the presence of thrombocytopenia, livedo reticularis, chorea, and valvulopathy were analyzed. The aPL analysis included the detection of anticardiolipin antibodies (aCLs: immunoglobulin G [IgG]/IgM), anti-β 2 glycoprotein I (IgG/IgM), and lupus anticoagulant positivity. In our cohort, livedo reticularis was significantly related to arterial thromboses in the same way as valvular manifestations (valvular vegetations and valvular thickening and dysfunction not related to age) ( p = 0.0001, p = 0.013, respectively). Age was strongly related to all the noncriteria manifestations analyzed. Thrombocytopenia was significantly related to β 2 glycoprotein I IgG and lupus anticoagulant positivity ( p = 0.043, p = 0.030, respectively), as well as to double and triple aPL positivity ( p = 0.041, p = 0.013 respectively). Moreover, in a multivariate model, livedo reticularis was strongly and independently related to arterial thrombosis in our cohort (odds ratio, 2.010; confidence interval, 1.229-3.288; p = 0.005). This cross-sectional analysis of a large cohort of Serbian PAPS patients confirmed a strong relationship between livedo reticularis and arterial thrombosis, suggesting a more cautious approach regarding the presence of noncriteria manifestations, especially livedo reticularis, in APS.

SERPINA1 and plasminogen as novel biomarkers in obstetric antiphospholipid syndrome patients.

To explore the potential biomarkers and mechanisms in obstetric antiphospholipid syndrome (OAPS) patients by placental proteomics. Among 212 follow-up pregnancy patients based on the Chinese Rheumatism Data Center database (CRDC), we continuously recruited 30 pregnancy patients at the late stage of pregnancy for proteomics study. Fresh placental tissues were collected and 4D label-free technologies were used to analyse the placental proteome in patients. Bioinformatic analysis was applied to identify differentially expressed proteins (DEPs) and crucial pathways. Placental tissues were also stained with haematoxylin and eosin (H & E) for histological analysis. We collected 7 OAPS patients (33.85±1.57 years), 4 SAPS patients (34.25 ± 3.86 years), 8 SLE patients (30.38±2.56 years), and 11 healthy controls (31.45±3.01 years). All patients in the SAPS and OAPS group had adverse pregnancy history. A total of 7040 proteins containing at least one unique peptide were identified. There were 214 DEPs between the healthy group and the OAPS group, of which 82 proteins were upregulated and 132 proteins were downregulated in the OAPS group based on fold change ≥1.5 and p-values ≤0.05. We found that the complement and coagulation pathway played a significant role in OAPS patients. Several key proteins (C1Q, C4b, SERPINA1, plasminogen) highly expressed in placental tissues, that may serve as biomarkers for OAPS patients. The complement and coagulation pathway and related DEPs (SERPINA1 and plasminogen) were of crucial importance in OAPS patients.

Long Term Follow up of Patients With Primary Obstetric Antiphospholipid Syndrome.

Introduction: Primary obstetric antiphospholipid syndrome (OAPS) is defined by specific morbidities and/or losses of pregnancy in the presence of persistent antiphospholipid antibodies (aPL). This variant of APS is usually treated during pregnancy and the post-partum period. Data on occurrence of thrombotic event during long term follow-up of OAPS patients is limited. Methods: A multi-centre retrospectively cohort of female patients with primary APS (pAPS) was assembled during 2004–2019. Patients were grouped according to disease presentation as pure OAPS or thrombotic APS (tAPS) for those presenting with thrombosis. Clinical and serological data were compared between groups. Results: Of 219 pAPS female patients 67 (30.6%) were diagnosed with OAPS and 152 (69.4%) with tAPS. During >10 years of follow-up 24/67 (35.8%) OAPS and 71/152 (50%) tAPS suffered a new thrombotic event (p = 0.06), while obstetric morbidity was more likely in the OAPS group (31.3 vs. 10.5%, p < 0.001) respectively. Among patients with OAPS at presentation heart valve disease and the presence of ANA were related to thrombosis following diagnosis (25 vs. 4.7%, p = 0.02; and 45.8 vs. 20.8%, p = 0.04 respectively). Conclusion: Thrombotic event following diagnosis were common among female patients with pAPS regardless of disease presentation. Heart valve disease and ANA positivity may be risk factors for thrombosis during follow-up of patients presenting with pure OAPS.

Treatment with low-dose prednisone in refractory obstetric antiphospholipid syndrome: A retrospective cohort study and meta-analysis.

Glucocorticoids have been suggested as a potential therapy in refractory obstetric antiphospholipid syndrome (oAPS). Our aims were to describe a cohort of patients with oAPS treated with low-dose glucocorticoids and to perform a systematic review and meta-analysis evaluating the effects of additional glucocorticoids on the pregnancy outcomes in oAPS patients. Retrospective study that included 11 women diagnosed with primary antiphospholipid syndrome. The meta-analysis was conducted by fitting random effects models and was checked for heterogeneity. All women had suffered from early pregnancy losses and two also had a history of fetal deaths. We studied 47 pregnancies that resulted in 32 abortions (68.1%) and 3 fetal deaths (6.4%). Twenty-six pregnancies were under treatment, mainly LDA and LMWH. Low-dose glucocorticoids were indicated in 13 pregnancies (always in association with LDA and LMWH). There was a decrease in pregnancy loss in those patients treated with LDA and LMWH. Treatment with glucocorticoids significantly increased the rate of successful pregnancy (38.5% abortions in treated vs 85.3% abortions in non-treated pregnancies; p=0.003). After multivariate GEE analysis, only glucocorticoids remained inversely associated with pregnancy loss (OR=0.157, (CI 0.025-0.968, p=0.046)). The meta-analysis showed that glucocorticoids tended to improve the frequency of successful pregnancy (OR= 0.509 (0.252-1.028), p=0.06). Three cases of gestational diabetes and one of preeclampsia were observed in our cohort. The meta-analysis, which mostly included studies using high-dose steroids, showed that glucocorticoids increased not only the frequency of preeclampsia and gestational diabetes, but also the rate of pre-term birth. The efficacy of low-dose glucocorticoids in addition to the standard therapy in patients with refractory oAPS should be confirmed in well-designed clinical trials. However, high doses of steroids significantly increase the frequency of maternal and fetal morbidities, making their use strongly inadvisable.

Clinical and therapeutic value of the adjusted Global Antiphospholipid Syndrome Score in primary obstetric antiphospholipid syndrome.

(1) To assess the clinical utility of the adjusted global antiphospholipid syndrome score (aGAPSS) to predict new obstetric events during follow-up in primary obstetric antiphospholipid syndrome (POAPS) patients under standard-of-care treatment (SC) based on the use of low-dose aspirin (LDA) + heparin and (2) to study the risk of a first thrombotic event and to evaluate whether stratification according to this score could help to identify POAPS patients who would benefit from long-term thromboprophylaxis. This is a retrospective, multicentre study. 169 women with POAPS were evaluated for the presence of a new obstetric event and/or a first thrombotic event during follow-up [time period: 2008-2020, median: 7years (6-12years)]. The outcomes of 107 pregnancies from these POAPS patients with SC were studied to evaluate relapses. Simple and multivariable logistic regression analyses were performed. Regarding obstetric morbidity, only triple positivity for antiphospholipid antibodies (aPLs) [OR = 8.462 (95% CI: 2.732-26.210); p < 0.0001] was found to be a strong risk factor independently associated with treatment failure. On the other hand, triple positivity for aPLs [OR=10.44 (95% CI: 2.161-50.469), p = 0.004] and an aGAPSS ≥7 [OR = 1.621 (95% CI: 1.198-2.193), p = 0.002] were independent risk factors associated with a first thrombotic event. LDA was marginally associated with a decrease in the risk of thrombosis only in patients with aGAPSS ≥ 7 (p = 0.048). aGAPSS appears to be useful in predicting the occurrence of a first thrombotic event in POAPS patients, and these stratification of patients could be helpful in selecting patients who would benefit from thromboprophylaxis with LDA.

Pathogenesis, Diagnosis and Management of Obstetric Antiphospholipid Syndrome: A Comprehensive Review.

Antiphospholipid syndrome is an autoimmune disorder characterized by vascular thrombosis and/or pregnancy morbidity associated with persistent antiphospholipid antibody positivity. Cases fulfilling the Sydney criteria for obstetric morbidity with no previous thrombosis are known as obstetric antiphospholipid syndrome (OAPS). OAPS is the most identified cause of recurrent pregnancy loss and late-pregnancy morbidity related to placental injury. Cases with incomplete clinical or laboratory data are classified as obstetric morbidity APS (OMAPS) and non-criteria OAPS (NC-OAPS), respectively. Inflammatory and thrombotic mechanisms are involved in the pathophysiology of OAPS. Trophoblasts, endothelium, platelets and innate immune cells are key cellular players. Complement activation plays a crucial pathogenic role. Secondary placental thrombosis appears by clot formation in response to tissue factor activation. New risk assessment tools could improve the prediction of obstetric complication recurrences or thromboses. The standard-of-care treatment consists of low-dose aspirin and prophylactic low molecular weight heparin. In refractory cases, the addition of hydroxychloroquine, low-dose prednisone or IVIG improve pregnancy outcomes. Statins and eculizumab are currently being tested for treating selected OAPS women. Finally, we revisited recent insights and concerns about the pathophysiology, diagnosis and management of OAPS.

Characteristics of Patients With Antiphospholipid Antibody Positivity in the APS ACTION International Clinical Database and Repository.

To describe the baseline characteristics of patients with positivity for antiphospholipid antibodies (aPLs) who were enrolled in an international registry, the Antiphospholipid Syndrome (APS) Alliance for Clinical Trials and International Networking (APS ACTION) clinical database and repository, overall and by clinical and laboratory subtypes. The APS ACTION registry includes adults who persistently had positivity for aPLs. We evaluated baseline sociodemographic and aPL-related (APS classification criteria and "non-criteria") characteristics of patients overall and in subgroups (aPL-positive without APS, APS overall, thrombotic APS only, obstetric APS only, and both thrombotic APS/obstetric APS). We assessed baseline characteristics of patients tested for the presence of three aPLs (lupus anticoagulant [LAC] test, anticardiolipin antibody [aCL], and anti-β2 -glycoprotein I [anti-β2 GPI]) antibodies by aPL profiles (LAC only, single, double, and triple aPL positivity). The 804 aPL-positive patients assessed in the present study had a mean age of 45 ± 13 years, were 74% female, and 68% White; additionally, 36% had other systemic autoimmune diseases. Of these 804 aPL-positive patients, 80% were classified as having APS (with 55% having thrombotic APS, 9% obstetric APS, and 15% thrombotic APS/obstetric APS). In the overall cohort, 71% had vascular thrombosis, 50% with a history of pregnancy had obstetric morbidity, and 56% had experienced at least one non-criteria manifestation. Among those with three aPLs tested (n=660), 42% were triple aPL-positive. While single-, double-, and triple aPL-positive subgroups had similar frequencies of vascular, obstetric, and non-criteria events, these events were lowest in the single aPL subgroup, which consisted of aCLs or anti-β2 GPI only. Our study demonstrates the heterogeneity of aPL-related clinical manifestations and laboratory profiles in a multicenter international cohort. Within single aPL positivity, LAC may be a major contributor to clinical events. Future prospective analyses, using standardized core laboratory aPL tests, will help clarify aPL risk profiles and improve risk stratification.

Antiphospholipid antibodies in the obstetric antiphospholipid syndrome: Detection and antibodies profile at the Maternity and Neonatal Medicine Center of Monastir, Tunisia.

This study aimed to implement lupus anticoagulant (LAC) detection techniques according to the International Society on Thrombosis and Hemostasis (ISTH) recommendations, in the Biological Laboratory of the Maternity and Neonatal Medicine Center (Monastir, Tunisia) and to evaluate the profile and the prevalence of antiphospholipid antibodies (aPL) in the obstetric antiphospholipid syndrome (OAPS). We collected two groups: a "case group" (53 women who presented one or more obstetrical criteria of APS) and a "control group." LAC was detected following the four steps recommended by ISTH 2009. Anticardiolipin (aCL) and antibeta-2-glycoprotein I (aβ2GPI) antibodies testing were performed by enzyme-linked immunosorbent assay (ELISA). aPL were found in five patients: three patients with isolated LAC, one patient with isolated IgG aCL, and one patient with triple positivity (LAC, aCL IgM, aβ2GPI IgM). Concerning LAC, 13 (24.52%) of 53 patients had a screening step with at least one positive test. The mixing step was positive in four patients and then confirmed in the confirmatory test. Thus, the prevalence of LAC in our study group is 7.54%. Surprisingly, among these positive patients, one patient had an associated combined factor V (FV) and factor VIII (FVIII) deficiency. There is no single test and no algorithm that can detect all types of LAC. It seems that the recent 2020 ISTH algorithm allows a better detection of low activity LAC than the 2009 algorithm. In our study, the most frequently identified antiphospholipid antibodies were LAC more than aCL and aβ2GPI.

Obstetric Antiphospholipid Syndrome From the Perspective of a Rheumatologist.

Antiphospholipid syndrome (APS) is an autoimmune disease that can lead to thrombotic or obstetric complications. Recent histopathological studies have shown the absence of placental thrombosis, leading to the consideration of other pathophysiological pathways such as inflammation and complement activation. Due to this, various clinical studies are being carried out with different drug agents in order to avoid their complications. The combination of prophylactic heparin treatment and low doses of aspirin today result in successful pregnancies in most cases. Despite this, a minority of patients require alternative therapies to avoid recurrent miscarriage and decrease obstetric morbidity. Thanks to the better understanding of its pathophysiology, other treatments such as low doses of glucocorticoids, hydroxychloroquine (HCQ), immunoglobulin, pravastatin, and plasmapheresis have been considered in refractory cases, achieving favorable results. Despite the great advances regarding its treatment, unfortunately, there are no treatments with a good level of evidence to reduce late obstetric complications. The evaluation of preconception risk factors, as well as the antiphospholipid antibody profile, is necessary to establish individual risk and thus anticipate possible complications.

Natural killer cells in obstetric antiphospholipid syndrome.

Natural killer cells in obstetric antiphospholipid syndrome.

The Pathophysiology of The Antiphospholipid Syndrome: A Perspective From The Blood Coagulation System.

The antiphospholipid syndrome (APS), a systemic autoimmune disease characterized by a hypercoagulability associated to vascular thrombosis and/or obstetric morbidity, is caused by the presence of antiphospholipid antibodies such as lupus anticoagulant, anti-β-2-glycoprotein 1, and/or anticardiolipin antibodies. In the obstetrical APS, antiphospholipid antibodies induce the production of proinflammatory cytokines and tissue factor by placental tissues and recruited neutrophils. Moreover, antiphospholipid antibodies activate the complement system which, in turn, induces a positive feedback leading to recruitment of neutrophils as well as activation of the placenta. Activation of these cells triggers myometrial contractions and cervical ripening provoking the induction of labor. In thrombotic and obstetrical APS, antiphospholipid antibodies activate endothelial cells, platelets, and neutrophils and they may alter the multimeric pattern and concentration of von Willebrand factor, increase the concentration of thrombospondin 1, reduce the inactivation of factor XI by antithrombin, increase the activation of factor XII, and reduce the activity of tissue plasminogen activator with the subsequent production of plasmin. All these effects result in less permeable clots, denser, thinner, and with more branched fibrin fibers which are more difficult to lysate. As a consequence, thrombosis, the defining clinical criterion of APS, complicates the clinical course of the patient.

An Update on Antiphospholipid Syndrome.

To review the recent available evidence on epidemiology, pathogenesis, clinical phenotypes, and management of antiphospholipid syndrome (APS) and summarize potential future research perspectives. Accumulating evidence has further expanded our understanding of the disease, including new data about the incidence and prevalence of APS, novel pathways supporting the role of thrombo-inflammation in APS including platelet, monocyte and endothelial cell activation, pro-inflammatory cytokine and chemokine production, complement activation, neutrophil extracellular trap release, and type I interferon gene expression that could yield to new potential treatment targets, better identification of criteria and non-criteria clinical phenotypes, antiphospholipid antibody profiles and their associations with clinical outcomes, prognostic tools, and treatment strategies based on recent evidence-based recommendations for patients with thrombotic and obstetric APS, with or without systemic lupus erythematosus. Ongoing research efforts and international collaborations enhance our knowledge of this rare and often devastating syndrome and help improve patient care and health outcomes.

Role of Direct Oral Anticoagulation Agents as Thromboprophylaxis in Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) is an autoimmune disorder that causes venous, arterial and small-vessel thrombosis, pregnancy loss, and premature birth. Cardiac valvular disease, renal thrombotic microangiopathy, thrombocytopenia, hemolytic anemia, and cognitive impairment are some of its other clinical symptoms. Antiphospholipid antibodies cause endothelial cells, monocytes, and platelets to become activated, as well as an increase in tissue factor and thromboxane A2. Complement activation might play a key function in pathogenesis.Long-term oral anticoagulation is used to treat thrombosis, and individuals having arterial episodes should be treated quickly. Patients with systemic lupus erythematosus (SLE), as well as those with solely obstetric antiphospholipid syndrome, should get primary thromboprophylaxis. Obstetric care is based on a combination of medical and obstetric high-risk management, as well as aspirin and heparin therapy. Possible supplementary therapy for this condition is hydroxychloroquine. Statins, rituximab, and novel anticoagulant medicines are all potential future treatments for non-pregnant individuals with antiphospholipid syndrome. We aim to review the role of direct-acting oral anticoagulants (DOACs) as thromboprophylactic drugs in the treatment of APS in this article.The treatment of venous thromboembolism has been transformed by a new class of DOACs. These drugs, such as rivaroxaban, function by inhibiting factor Xa directly. Not only do they have known anticoagulant actions, but they also obviate the need for dosage monitoring and modification, in contrast to warfarin.We conducted an exhaustive literature search of PubMed/MEDLINE and Google Scholar Indexes using the keywords “Antiphospholipid syndrome,” “thromboprophylaxis,” and “oral anticoagulants” up to September 2021. We found that DOACs have been shown to be non-inferior to warfarin in a variety of anticoagulation situations in a number of high-powered clinical studies. In many hypercoagulable conditions such as APS, DOACs are quickly establishing themselves as first-line therapy. This article is focused on comprehensively reviewing the mechanism of action of DOACs, their role as thromboprophylactic drugs, risks and complications of DOACs, and comparing their efficacy with the standard treatment protocol and warfarin.

O22 Pregnancy planning in non-criteria antiphospholipid syndrome

Case report - IntroductionAntiphospholipid Syndrome (APS) is an autoimmune condition manifested by vascular thrombosis with or without pregnancy related morbidities. APS classification criteria require detection of persistent antibodies: Anti-Cardiolipin Antibody (aCL), Anti-Beta Glycoprotein I (ab2GPI) and circulating Lupus Anticoagulant (LAC).Criteria for the diagnosis of obstetric antiphospholipid syndrome allow for optimal treatment planning in pregnancy and reduction of foetal and maternal morbidity. There are, however, several “non-criteria” features of APS, including late pre-eclampsia, which may also infer adverse obstetric outcomes.We highlight a treatment dilemma in a young female with lupus and APS with history of previous pregnancy that was complicated by pre-eclampsia.Case report - Case descriptionWe describe a case of a 26-year-old female with systemic lupus erythematosus (SLE), “triple positive” APS markers (aPL) and non-criteria APS obstetric morbidity.During her first pregnancy she presented at 22 weeks with severe and frequent migraine episodes. She had no other active clinical manifestations of SLE. There was no prior history of pregnancy and therefore no previous obstetric morbidity nor had she had any vascular thrombotic episodes. She had been commenced on low-dose aspirin (LDA) at the start of her pregnancy and was already taking hydroxychloroquine (HCQ). The dose of HCQ was increased to 400mg daily leading to improvement in the headaches. She had persistent strong ACL antibodies, positive LAC and ab2GPI antibodies. ANA was positive with hypocomplementemia and neutropenia but normal range double-stranded DNA antibodies.After discussion with a tertiary centre, it was recommended to continue HCQ and LDA. Low molecular weight heparin (LMWH) was not proposed as she did not fulfil criteria for obstetric APS. Her pregnancy was subsequently complicated by pre-eclampsia and post-partum sepsis.Two years later she sought advice to plan her second pregnancy, raising important questions as to whether the same treatment strategy should be followed or if alternative approaches should be considered, given the history of pre-eclampsia and its association with APS. Again, she did not meet the international consensus (revised Sapporo) criteria for diagnosis of obstetric APS.After further discussion with the tertiary centre, she commenced high-dose aspirin 150mg/day alone. Uterine artery dopplers were recommended and LMWH proposed if bilateral notching was noted. Dopplers were normal.Her blood pressure (BP) fluctuates between 130-145mmHg systolic. She has occasional crops of mouth ulcers but no other SLE features. Migraines continue every 2—3 weeks although severe attacks are infrequent. C4 is persistently low with normal Ds DNA and urine protein/creatinine ratio.Case report - DiscussionOur case raises questions on how pregnancy should be safely managed in patients without a prior history of APS-related pregnancy complications but who nevertheless have risk factors, in the form of APS antibody positivity and non-criteria obstetric manifestations of APS. Her previous pregnancy was treated with LDA and HCQ which had proved insufficient in avoiding the outcome of pre-eclampsia.The objective of prophylactic treatments is to prevent adverse outcomes such as miscarriage, which carry significant maternal morbidity including psychological manifestations such as depression and anxiety. In first pregnancies, mothers have no existing obstetric history, such that current treatment guidance provides few recommendations for preventative interventions, even where other risk factors are apparent. Furthermore, non-criteria manifestations of obstetric APS are now well recognised, which may further highlight potential risk for obstetric morbidity but fail to trigger interventions as they are not included within the current international criteria. These manifestations include late pre-eclampsia, placental abruption and late pregnancy loss, unexplained in vitro fertilisation failures, two unexplained miscarriages and three non-consecutive miscarriages. Low positive antibody titres and intermittent aPL are also included.Studies suggest that women with non-criteria APS may benefit from standard treatment for obstetric APS which includes LMWH in addition to aspirin, with good pregnancy outcomes.HCQ has a dose-dependent effect in preventing thrombosis through inhibition of platelet aggregation and aPL Ab-related thrombosis. However, pregnancy itself is a prothrombotic condition and in the presence of persistent triple positive aPL is a risk factor for adverse pregnancy outcomes.Further studies are needed to define the risk of non-criteria APS on pregnancy outcomes and define optimal treatment strategies.Case report - Key learning pointsObstetric APS carries significant risk for maternal foetal morbidity including miscarriage and pre-term birth.Significant maternal psychological effects are recognised even following a single miscarriage.The international consensus (revised Sapporo) criteria for diagnosis of obstetric antiphospholipid syndrome exclude certain non-criteria clinical and laboratory manifestations that may confer adverse pregnancy outcomes.First pregnancies are challenging to risk stratify in patients with identified aPL as there will be no prior pregnancy history to reference.Ultrasound doppler velocimetry is a useful non-invasive tool to diagnose poor placental perfusion, a predictor of obstetric complications, hence identifying high-risk pregnancies.Further research is required to establish the diagnostic validity, predictive value, and treatment implications of non-criteria manifestations of obstetric APS.

Clinical characteristics and pregnancy outcomes of non-criteria obstetric antiphospholipid syndrome

Objective: To study clinical characteristics and pregnancy outcomes under anti-coagulation therapy of non-criteria obstetric antiphospholipid syndrome. Methods: Patients suspected of obstetric antiphospholipid syndrome(OAPS) were recruited through Chinese Rheumatism Data Center from 2015 to 2019 consecutively. Patients fulfilling 2006 Sydney revised antiphospholipid syndrome criteria were classified as OAPS. Patients fulfilling definition of non-criteria OAPS(NCOAPS) by expert consensus on diagnosis and management of obstetric antiphospholipid syndrome of China were classified as NCOAPS. Clinical characteristics and laboratory results of two groups were compared. Live birth rates and pregnancy outcomes under anti-coagulation therapy were studied. Results: A total of 88 patients were enrolled, including 56 patients (63.6%) as OAPS, 32(36.4%) as NCOAPS. Live births were only reached in 16.1% (9/56) in OAPS patients and 12.5%(4/32) in NCOAPS. Fetal losses after 10 weeks of gestation and pre-eclampsia before 34 weeks were more common in OAPS group compared to NCOAPS group [78.6%(44/56) vs. 18.8%(6/32), P<0.001; 25.0%(14/56) vs. 3.1%(1/32), P=0.020, respectively]. After enrollment, 15 pregnancies were recorded in OAPS, 10 in NCOAPS, all of whom were treated with low-dose aspirin (LDA) combined with low-molecular weight heparin (LMWH). Live birth rates saw dramatic improvements compared to baseline levels in OAPS [16.1% (9/56) vs. 11/15] along with NCOAPS [12.5% (4/32) vs. 7/10]. Conclusion: Though NCOAPS and OAPS patients differ in antiphospholipid antibody spectrum and pattern of pregnancy morbidities, both groups benefit from LDA combined with LWMH treatment, as live birth rates improve. Non-criteria OAPS patients are recommended to receive anti-coagulation therapy during pregnancy.

Urine Proteomics Differentiate Primary Thrombotic Antiphospholipid Syndrome From Obstetric Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) is a multisystem disorder characterized by thrombosis and/or recurrent fetal loss. This clinical phenotype heterogeneity may result in differences in response to treatment and prognosis. In this study, we aimed to identify primary thrombotic APS (TAPS) from primary obstetric APS (OAPS) using urine proteomics as a non-invasive method. Only patients with primary APS were enrolled in this study from 2016 to 2018 at a single clinical center in Shanghai. Urine samples from 15 patients with TAPS, 9 patients with OAPS, and 15 healthy controls (HCs) were collected and analyzed using isobaric tags for relative and absolute quantification (iTRAQ) labeling combined with liquid chromatography-tandem mass spectrometry analysis to identify differentially expressed proteins. Cluster analysis of urine proteomics identified differentiated proteins among the TAPS, OAPS, and HC groups. Urinary proteins were enriched in cytokine and cytokine receptor pathways. Representative secreted cytokines screened out (fold change >1.20, or <0.83, p<0.05) in these differentiated proteins were measured by enzyme-linked immunosorbent assay in a validation cohort. The results showed that the levels of C-X-C motif chemokine ligand 12 (CXCL12) were higher in the urine of patients with TAPS than in those with OAPS (p=0.035), while the levels of platelet-derived growth factor subunit B (PDGFB) were lower in patients with TAPS than in those with OAPS (p=0.041). In addition, correlation analysis showed that CXCL12 levels were positively correlated with immunoglobulin G anti-β2-glycoprotein I antibody (r=0.617, p=0.016). Our results demonstrated that urinary CXCL12 and PDGFB might serve as potential non-invasive markers to differentiate primary TAPS from primary OAPS.

The impact of hydroxychloroquine on obstetric outcomes in refractory obstetric antiphospholipid syndrome

BackgroundThe use of low-dose aspirin (LDA) and heparin has improved pregnancy outcomes in women with antiphospholipid syndrome (APS). However, 20–30% still have adverse outcomes despite treatment. Recent retrospective studies showed a beneficial effect of hydroxychloroquine (HCQ) in APS due to its anti-inflammatory, immunomodulatory and antithrombotic properties. Data in refractory obstetric APS (OAPS) remain scarce and include heterogeneous populations with various concomitant treatments. ObjectiveThe objective of this study was to assess the impact on the obstetric outcomes of adding HCQ to classical treatments for women with refractory primary obstetric APS. MethodsIn a retrospective single-centre cohort study, we compared pregnancy outcomes in women with refractory primary OAPS (2004–2019) who received two different treatments in subsequent pregnancies. Group A received 400 mg HCQ + 60 mg enoxaparin + LDA, while Group B received 60 mg enoxaparin + LDA. The main outcome was live birth rates, while pregnancy complications (early and late pregnancy losses and placental-mediated complications) were the secondary outcome. ResultsA total of 101 pregnancies in 87 refractory primary OAPS patients were included. The rate of live-born babies in Group A (HCQ) was 97.1% (67/69) vs. 62.5% (20/32) in Group B (RR: 1.55 [95% CI, 1.19–2.1]; p < 0.001). Pregnancy complications in Group A were 8.7% (6/69) vs. 37.5% (12/32) in Group B (RR 0.22 [95% CI, 0.15–0.30]; p < 0.001). ConclusionHydroxychloroquine was associated with a higher rate of live births and a lower prevalence of pregnancy complications in refractory primary obstetric APS. The addition of HCQ to classical treatment may present a promising approach that needs to be confirmed with prospective studies.

Risk Factors for the Development of the Disease in Antiphospholipid Antibodies Carriers: A Long-term Follow-up Study

The natural history of antiphospholipid antibodies (aPL) carriers is not well-established. The objectives of the present study were (a) to study the probability of developing clinical criteria of antiphospholipid syndrome (APS), (b) to identify potential risk factors for developing thrombosis and/or obstetric complications, (c) to study the association between the antibody profile and development of APS, and (d) to determine the efficacy of primary prophylaxis. We retrospectively analyzed 138 subjects with positive aPL who did not fulfill clinical criteria for APS. The mean follow-up time was 138 ± 63.0 months. Thirteen patients (9.4%) developed thrombosis after an average period of 73.0 ± 48.0 months. Independent risk factors for thrombosis were smoking, hypertension, thrombocytopenia, and triple aPL positivity. Low-dose acetyl salicylic acid did not prevent thrombotic events. A total of 28 obstetric complications were detected in 92 pregnancies. During the follow-up, only two women developed obstetric APS. Prophylactic treatment in pregnant women was associated with a better outcome in the prevention of early abortions. The thrombosis rate in patients with positive aPL who do not meet diagnostic criteria for APS is 0.82/100 patients-year. Smoking, hypertension, thrombocytopenia, and the aPL profile are independent risk factors for the development of thrombosis in aPL carriers. Although the incidence of obstetric complications in this population is high (31.6%), only a few of them meet APS criteria. In these women, prophylactic treatment might be effective in preventing early abortions.

Coexistent antiphospholipid syndrome and myeloproliferative neoplasm

Antiphospholipid syndrome (APS) and myeloproliferative neoplasms (MPN) are associated with an increased risk of thrombosis. The optimal management of patients with coexistent APS and MPN has not been defined. A single centre and systematic literature review of patients with coexistent APS and MPN was performed. Cases were divided into two groups based on whether they met international consensus criteria for APS. Of the 12 studies identified, eight were excluded (leaving five of a total 54 patients), as although antiphospholipid antibodies (aPL) were documented, the diagnosis of APS was not conclusively demonstrated. Another ten patients with definite APS were identified at our centre. Fifteen patients (ten females, five males) were therefore included in this analysis (eleven definite APS and four highly likely), median age 44 (range: 13-71) years. Nine had polycythaemia vera and six, essential thrombocythaemia. Thirteen of the 15 patients (86.7%) had thrombotic APS (seven with initial venous events and six arterial) and two (13.3%) had obstetric APS. Nine patients were single-positive, and six double-positive for aPL. None were triple aPL-positive. Four patients at our centre had recurrent thrombotic/obstetric events, including while on anticoagulation/antiplatelet treatment.