Summary
An ancillary analysis to the SepsiCoag multicentric prospective observational study on patients entering an intensive care unit with septic shock evaluated the prognostic potential of fibrin ...generation markers (FGMs) tested at inclusion in the study, on survival at day 30. After centralization of samples, three automated FGMs were compared: D‐dimers (DDi), fibrin/fibrinogen degradation products (FDP) and fibrin monomers (FM). FM was the single FGM that was significantly higher in non‐surviving patients, area under the receiver‐operator characteristic curve (AUCROC): 0·617, P < 0·0001. Significantly higher International Society on Thrombosis and Haemostasis Disseminated Intravascular Coagulation (ISTH DIC) scores were calculated in non‐survivors using each of the three FGMs. A dose‐effect relationship was observed between ISTH DIC scores and non‐survival, with highest significance obtained using FM as the FGM. An overt DIC diagnosis using the ISTH DIC score calculated using FM was a predictor of non‐survival at day 30, independently from overt DIC diagnosis based on scores calculated using FDP or DDi. The AUCROC values testing the ability of the ISTH DIC score to predict non‐survival were 0·650, 0·624 and 0·602 using FM, DDi and FDP, respectively, as the FGM. In patients with septic shock, among the commercially‐available automated assays, automated FM is the FGM best related with late prognosis.
Background
The antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity with the persistent presence of lupus anticoagulant (LAC), anti‐cardiolipin (aCL) and/or ...anti‐β2glycoprotein I (aβ2GPI) antibodies of the immunoglobulin G/immunoglobulin M (IgG/IgM) isotype. However, the role of aCL and aβ2GPI IgM as a serologic marker in APS is debated.
Objectives
We aimed to assess the diagnostic and clinical value of IgM antiphospholipid antibodies (aPL) in APS within the classification criteria.
Patients/Methods
Our multicenter study comprised 1008 patients, including APS patients and controls. Anti‐CL and aβ2GPI IgG and IgM antibodies were detected with four commercially available solid phase assays.
Results
Positivity for aCL and/or aβ2GPI antibodies was significantly correlated with thrombosis and pregnancy morbidity, independent of the isotype and solid phase assay. Higher odds ratios were obtained for IgG compared to IgM positivity. Isolated IgM was rare in thrombotic APS, but more frequent in obstetric APS, ranging from 3.5% to 5.4% and 5.7% to 12.3%, respectively, dependent on the solid phase assay. In a multivariate logistic regression analysis of aPL, IgM positivity was found to be associated with pregnancy morbidity. However, detection of IgM was not independently associated with thrombosis. Combined positivity for LAC, IgG, and IgM was highly associated with thrombosis and pregnancy morbidity.
Conclusions
Our data support testing for aCL and aβ2GPI IgM in women suspected of obstetric APS. However, no added value was found for testing IgM in patients suspected of thrombotic APS. Still, IgM aPL might be useful as a second‐line test to improve thrombotic risk stratification.
Background
Antiβ2glycoprotein I (aβ2GPI) and anticardiolipin (aCL) IgG/IgM show differences in positive/negative agreement and titers between solid phase platforms. Method‐specific semiquantitative ...categorization of titers could improve and harmonize the interpretation across platforms.
Aim
To evaluate the traditional 40/80‐unit thresholds used for aCL and aβ2GPI for categorization into moderate/high positivity with different analytical systems, and to compare with alternative thresholds.
Material and methods
aCL and aβ2GPI thresholds were calculated for two automated systems (chemiluminescent immunoassay CLIA and multiplex flow immunoassay MFI) by receiver operating characteristic curve analysis on 1108 patient samples, including patients with and without antiphospholipid syndrome (APS), and confirmed on a second population (n = 279). Alternatively, regression analysis on diluted standard material was applied to identify thresholds. Thresholds were compared to 40/80 threshold measured by an enzyme‐linked immunosorbent assay (ELISA). Additionally, likelihood ratios (LR) were calculated.
Results
Threshold levels of 40/80 units show poor agreement between ELISA and automated platforms for classification into low/moderate/high positivity, especially for aCL/aβ2GPI IgG. Agreement for semiquantitative interpretation of antiphospholipid antibodies (aPL) IgG between ELISA and CLIA/MFI improves with alternative thresholds. LR for aPL IgG increase for thrombotic and obstetric APS based on 40/80 thresholds for ELISA and adapted thresholds for the other systems, but not for IgM.
Conclusion
Use of 40/80 units as medium/high thresholds is acceptable for aCL/aβ2GPI IgG ELISA, but not for CLIA and MFI. Alternative semiquantitative thresholds for non‐ELISA platforms can be determined by a clinical approach or by using monoclonal antibodies. Semiquantitative reporting of aPL IgM has less impact on increasing probability for APS.
Background
Placenta‐mediated pregnancy complications generate short‐ and long‐term adverse medical outcomes for both the mother and the fetus. Nucleosomes and free DNA (fDNA) have been described in ...patients suffering from a wide range of inflammatory conditions.
Objective
The objective of our study was to compare nucleosomes and fDNA circulating levels during pregnancy and particularly in women developing a placenta‐mediated complication according to the subtype (preeclampsia or intrauterine growth restriction) (NCT 01736826).
Patients/Methods
A total of 115 women were prospectively included in the study across three groups: 30 healthy non‐pregnant women, 50 with normal pregnancy, and 35 with a complicated pregnancy. Blood samples were taken up to every 4 weeks for several women with normal pregnancy and nucleosomes and fDNA were quantified using enzyme‐linked immunosorbent assay and quantitative polymerase chain reaction, respectively.
Results
We show that nucleosomes and fDNA concentrations significantly increase during normal pregnancy, with concentrations at delivery differing between the two groups. Interestingly, we show that concentrations differ according to the type of placenta‐mediated complications, with higher levels in preeclampsia compared to intrauterine growth restriction.
Conclusions
These data suggest that nucleosomes and fDNA may be additional actors participating in placenta‐mediated pregnancy complications.
Background
Classification of the antiphospholipid syndrome (APS) relies predominantly on detecting antiphospholipid antibodies (aPLs). Antibodies against a domain I (DI) epitope of ...anti‐β2glycoprotein I (β2GPI) proved to be pathogenic, but are not included in the current classification criteria.
Objectives
Investigate the clinical value of detecting anti‐DI IgG in APS.
Patients/Methods
From eight European centers 1005 patients were enrolled. Anti‐cardiolipin (CL) and anti‐β2GPI were detected by four commercially available solid phase assays; anti‐DI IgG by the QUANTA Flash® β2GPI domain I assay.
Results
Odds ratios (ORs) of anti‐DI IgG for thrombosis and pregnancy morbidity proved to be higher than those of the conventional assays. Upon restriction to patients positive for anti‐β2GPI IgG, anti‐DI IgG positivity still resulted in significant ORs. When anti‐DI IgG was added to the criteria aPLs or used as a substitute for anti‐β2GPI IgG/anti‐CL IgG, ORs for clinical symptoms hardly improved. Upon removing anti‐DI positive patients, lupus anticoagulant remained significantly correlated with clinical complications. Anti‐DI IgG are mainly present in high‐risk triple positive patients, showing higher levels. Combined anti‐DI and triple positivity confers a higher risk for clinical symptoms compared to only triple positivity.
Conclusions
Detection of anti‐DI IgG resulted in higher ORs for clinical manifestations than the current APS classification criteria. Regardless of the platform used to detect anti‐β2GPI/anti‐CL, addition of anti‐DI IgG measured by QUANTA Flash® did not improve the clinical associations, possibly due to reduced exposure of the pathogenic epitope of DI. Our results demonstrate that anti‐DI IgG potentially helps in identifying high‐risk patients.
Summary
Haemostatic and vascular biology mechanisms appear to play an important role in the pathogenesis of placenta‐mediated pregnancy complications. Although low‐dose aspirin (LDA) has a modest ...effect in preventing preeclampsia, antithrombotic interventions, LDA and low molecular weight heparin (LMWH) have not definitively proven their effectiveness in women with placenta‐mediated pregnancy complications selected by previous pregnancy outcome alone. Given the heterogeneous aetiology of placenta‐mediated pregnancy complications, it is critical to stratify patients according to maternal and fetal characteristics and disease mechanisms rather than simply by pregnancy outcome, such as miscarriage. Such stratification could identify those who could benefit from antithrombotic interventions in pregnancy. We lack data on genome‐wide association studies, biomarkers and trials of interventions applied to specific homogeneous populations. Future studies should focus on elaborating different disease mechanisms and examining antithrombotic interventions in specific and more homogeneous groups, such as thrombophilic women with well‐characterized placenta‐mediated pregnancy complications, stratified by disease severity and pathological findings. Because of fetal safety concerns with new anticoagulants, the intervention should focus on heparins alone or in combination with LDA. Thus, placenta‐mediated pregnancy complications deserve precision medicine, defining disease by mechanism rather than outcome with interventions focused on a more personalized approach.
During pregnancy, maternal vitamin D insufficiency could increase the risk of preeclampsia. Aim of the study was to evaluate the relationship between vitamin D status and the occurrence of ...placenta-mediated complications (PMCs) in a population at high risk. A prospective multicenter cohort study of 200 pregnant patients was conducted. The vitamin D level of patients with placenta-mediated complications was lower at 32 weeks compared to uncomplicated pregnancies (P = 0.001). At 32 weeks, the risk of occurrence of PMCs was five times higher in patients with vitamin D deficiency (RR: 5.14 95% CI (1.50-17.55)) compared to patients with normal vitamin D levels. There was a strong, inverse relationship between serum 25(OH)D levels at 32 weeks and the subsequent risk of PMCs (P = 0.001). At 32 weeks, the vitamin D level of patients with late-onset PMCs was lower than the one of patients with early-onset PMCs and of patients without PMCs (P < 0.0001). These results suggest a role of vitamin D in the maintenance of placental performance and therefore in the prevention of the onset of late PMC.
PDF
