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Postpartum hemorrhage (PPH) is responsible for 30% to 50% of maternal deaths. There is conflicting evidence if prepartum anemia facilitates PPH. A comprehensive analysis of studies describing their relation is missing. An extensive database search was conducted applying the terms “anemia” OR “hemoglobin” AND “postpartum hemorrhage.” We used a random-effects meta-analysis model to estimate an overall odds ratio (OR) for PPH and prepartum anemia, separating studies that were conformant and non-conformant with the World Health Organization (WHO) definitions for anemia. The search yielded 2519 studies, and 46 were appropriate for analysis. The meta-analyses of WHO-conformant (n = 22) and non-conformant (n = 24) studies showed that the risk of PPH was increased when anemia was present. The ORs were 1.45 (CL: 1.23-1.71) for WHO-conformant studies, 2.88 (CL: 1.38-6.02) for studies applying lower thresholds for anemia, and 3.28 (CL: 2.08-5.19) for undefined anemia thresholds. PPH risk appeared to increase with lower anemia thresholds. Prepartum anemia is associated with an increased risk of PPH, an observation that is important regarding improved anemia correction strategies such as iron supplementation.

Introduction: Acute respiratory illnesses from COVID19 infection are increasing globally. Reports from earlier in the pandemic suggested that patients hospitalized for COVID19 are at particularly high risk for pulmonary embolism (PE). To estimate the incidences of PE during hospitalization for COVID19, we performed a rigorous systematic review of published literature. Methods: We searched for case series, cohort studies and clinical trials from December 1, 2019 to July 13, 2020 that reported the incidence of PE among consecutive patients who were hospitalized for COVID19 in ICUs and in non-ICU hospital wards. To reflect the general population of hospitalized COVID19 patients, we excluded studies in which subject enrollment was linked to the clinical suspicion for venous thromboembolism (VTE). Results: Fifty-seven studies were included in the analysis. The combined random effects estimate of PE incidence among all hospitalized COVID19 patients was 7.1% (95% CI: 5.2%, 9.1%). Studies with larger sample sizes reported significantly lower PE incidences than smaller studies (r2 = 0.161, p = 0.036). The PE incidence among studies that included 400 or more patients was 3.0% (95% CI: 1.7%, 4.6%). Among COVID19 patients admitted to ICUs, the combined estimated PE incidence was 13.7% (95% CI: 8.0%, 20.6%). The incidence of ICU-related PE also decreased as the study sample sizes increased. The single largest COVID19 ICU study (n = 2215) disclosed a PE incidence of 2.3% (95% CI: 1.7%, 3.0%). Conclusion: PE incidences among hospitalized COVID19 patients are much lower than has been previously postulated based on smaller, often biased study reports. The incidence of “microthrombosis,” leading to occlusion of microscopic blood vessels, remains unknown.

This study aims to demonstrate the feasibility of ultrashort echo time (UTE)-based susceptibility source separation for musculoskeletal (MSK) imaging, enabling discrimination between diamagnetic and paramagnetic tissue components, with a particular focus on hemophilic arthropathy (HA). Three key techniques were integrated to achieve UTE-based susceptibility source separation: Iterative decomposition of water and fat with echo asymmetry and least-squares estimation for B0 field estimation, projection onto dipole fields for local field mapping, and χ-separation for quantitative susceptibility mapping (QSM) with source decomposition. A phantom containing varying concentrations of diamagnetic (CaCO3) and paramagnetic (Fe3O4) materials was used to validate the method. In addition, in vivo UTE-QSM scans of the knees and ankles were performed on five HA patients using a 3T clinical MRI scanner. In the phantom, conventional QSM underestimated susceptibility values due to the mixed-source cancelling the effect. In contrast, source-separated maps provided distinct diamagnetic and paramagnetic susceptibility values that correlated strongly with CaCO3 and Fe3O4 concentrations (r = −0.99 and 0.95, p < 0.05). In vivo, paramagnetic maps enabled improved visualization of hemosiderin deposits in joints of HA patients, which were poorly visualized or obscured in conventional QSM due to susceptibility cancellation by surrounding diamagnetic tissues such as bone. This study demonstrates, for the first time, the feasibility of UTE-based quantitative susceptibility source separation for MSK applications. The approach enhances the detection of paramagnetic substances like hemosiderin in HA and offers potential for improved assessment of bone and joint tissue composition.

Efanesoctocog alfa is a factor VIII fusion agent that permits weekly treatment to prevent bleeding. In this study, two thirds of treated patients had no bleeding episodes, and the annualized bleeding rate fell by 77%.

Hemophilic arthropathy from joint bleeding remains a complication with major morbidity in the increasingly aging patients with hemophilia. Prophylactic clotting factor infusions, based on pharmacokinetic dosing to reduce bleeding rates, are being explored more and more. However, there is little evidence on the benefits of pharmacokinetic dosing in direct association with bleeding events. Here, we prospectively followed a cohort of adult patients with hemophilia A and B (n = 26) and arthropathic joints on various clotting factor products over a period of 2 years with clinical and radiographic joint health assessments, frequent joint ultrasound, and pharmacokinetic studies. Joint bleeds and synovitis with synovial vascularity changes were objectively diagnosed by musculoskeletal ultrasound and power Doppler and analyzed in relation to pharmacokinetic, joint- and patient-specific parameters. Results revealed that, contrary to common beliefs, bleeding episodes were not readily explained by pharmacokinetic features, as they were not associated with more time spent below certain clotting factor thresholds. Joint bleeding was found to be associated with prominent vascularity changes, suggesting that vascular remodeling and leakiness may contribute to joint bleeding that cannot be prevented by clotting factor replacement alone.

Participants with hemophilia A received B-domain–deleted factor VIII gene therapy delivered in an AAV5 vector. A decrease in annualized bleeding rates was maintained for 2 years despite declining factor VIII levels.

Antibodies confer humoral immunity but can also be harmful when they target an autoantigen, alloantigen, allergen, or biotherapeutic. New strategies are needed for antigen-specific suppression of undesired antibody responses, particularly to T cell-dependent protein antigens, because they elicit T cell help. Here we show that liposomal nanoparticles, displaying both antigen and glycan ligands of the inhibitory coreceptor CD22, induce a tolerogenic program that selectively causes apoptosis in mouse and human B cells. These SIGLEC-engaging tolerance-inducing antigenic liposomes (STALs, where SIGLEC is defined as sialic acid-binding Ig-like lectin) induced robust antigen-specific tolerance to protein antigens in mice, preventing subsequent immune response to challenge with the same antigen. Since development of inhibitory antibodies to FVIII is a serious problem in treatment of hemophilia A patients, we investigated the potential of this approach for inducing tolerance to FVIII in a hemophilia mouse model. STALs prevented formation of inhibitory FVIII antibodies, allowing for effective administration of FVIII to hemophilia mice to prevent bleeding. These findings suggest that STALs could be used to eliminate or prevent harmful B cell-mediated immune responses.

To investigate if FVIII-Fc Fusion protein (FcFVIII) may modulate inflammation and immune stimulation in hemophilic synovium via the Fc-portion of immunoglobulin used for half-life extension we performed gene expression profiling in FVIII-deficient mice. Hemarthrosis was induced by sub-patellar puncture in FVIII-KO mice, + /- periprocedural recombinant human (rh)FVIII,murine (m)FcFVIII, or mIgG2a. Synovium was harvested at baseline and on days (D) 3 and 14, followed by RNA extraction and sequencing, and histological analysis. RNASeq data were processed using standard protocols followed by differential gene expression (DGE) analysis. Functional enrichment analysis generated molecular pathways (KEGG and Reactome). To distinguish between on-target and off-target (related and unrelated to injury/bleed) effects the following groups were compared: i) Baseline vs. injured-saline, ii) injured-saline vs. injured-rhFVIII, iii) injured-saline vs. injured-mFcFVIII. Knee injury in FVIII-KO mice resulted in hemarthrosis, which was prevented by peri-procedural rhFVIII and mFcFVIII treatments. Only a small proportion of genes was affected by FVIII treatment, exhibiting overlap but also distinct differences between both FVIII-preparations. Acutely (D3), mFcFVIII had unique on-target effects related to immune and inflammatory regulation, whereas rhFVIII mostly affected mRNA and protein processing. On day 14, macrophage profiling indicated a transition from M1 to M2, and only mFcFVIII uniquely influenced pathways and genes associated with tissue remodeling and repair. Some mFcFVIII DGE patterns resembled mIgG2a patterns. Synovial vascular remodeling and cartilage health were better with mFcFVIII than rhFVIII. Interestingly, both FVIII-preparations exerted off-target effects on immune system pathways, albeit with temporal differences. These observations provide proof-of-principle that the type of FVIII preparation can influence synovial processes beyond acute hemostasis control, deserving exploration in the setting of joint bleed control in hemophilia.

The goal of this study is to quantify hemosiderin deposition in the knee joint tissues of hemophilic arthropathy (HA) patients using quantitative susceptibility mapping on MRI. Knee synovial tissues from HA patients and controls without hemophilia were included. The tissues underwent ultrashort echo time quantitative susceptibility mapping (UTE-QSM) and clinical MRI. HA tissues were processed histologically with Perl’s Prussian Blue (PPB) staining to identify iron contents. Seven regions of interest were drawn in each tissue, and the susceptibility values were tested. Moreover, the association between the estimated magnetic susceptibility and the iron contents quantified by histology was investigated. Nine synovial tissues were procured from total knee arthroplasty of hemophilia patients (males, 40.8 ± 9.0 years), and three synovial tissues were harvested from cadaveric knee joints of donors without hemophilia as controls (males, 72.0 ± 12.8 years). The estimated susceptibility values (ESVs) showed significant differences between HA and control samples. Accordingly, HA tissues presented a mean ESV of 0.48 ± 1.08 ppm and control tissues of -0.13 ± 0.12 ppm ( p  < 0.05). A significant linear correlation was found between the iron level quantified by histology (PPB stain) and the ESV estimated by UTE-QSM ( R  = 0.908, p  < 0.01). There was a significant difference in the susceptibility in high load (HL) tissues compared to low load (LL) tissues (ESV = 5.57 ± 1.23 ppm for HL vs. 0.57 ± 0.85 ppm for LL, p  < 0.001). Reliable hemosiderin quantification in joint tissues of HA patients can be achieved using MRI based on quantitative susceptibility mapping.

[This corrects the article DOI: 10.1371/journal.pone.0320322.].