Identification and management of eating disorders in pregnancy: a multi-method study of maternity and health visiting services

Pregnant women with current and past eating disorders (ED) have heightened risk of adverse maternal and infant outcomes, so it is imperative women are identified and receive enhanced care during and after pregnancy to promote optimal outcomes. However, following recent changes to the classification of ED, it is unclear how many pregnant women have had ED and research is needed to understand the barriers to their care in maternity and health visiting services. A multi-method approach, comprising of four studies, was employed to: (1) investigate the prevalence of ED in pregnant women; and (2) explore the barriers to care from the perspectives of women, midwives and health visitors. Study one found the prevalence of ED before and during pregnancy were 8.8% and 6.7%, respectively, using a self-report questionnaire in 1,022 pregnant women. Study two estimated population prevalence for lifetime and current ED of 15.3% (95% CI, 11.80-19.71%) and 1.4% (95% CI, 0.64-3.35%), respectively, using diagnostic interviews in 543 pregnant women. Study three, which collated survey data from 103 pregnant and postnatal women, found disclosure of ED was low due to perceptions of poor awareness, stigma, lack of continuity in carer and limited capacity in maternity services. Study four, using a two-phased design with questionnaires (N = 265) and focus groups (N = 33) in midwives and health visitors, found the main barriers to identifying and caring for women with ED were insufficient training and related practice. The findings indicate a significant proportion of pregnant women will have had ED, yet women will often be poorly identified and receive inadequate care in maternity and health visiting services. Future research should aim to develop strategies that address the barriers identified in this research to improve care for pregnant and postnatal women with ED to promote optimal outcomes for mother and child

Platelet signaling: a complex interplay between inhibitory and activatory networks

The role of platelets in hemostasis and thrombosis is dependent on a complex balance of activatory and inhibitory signaling pathways. Inhibitory signals released from the healthy vasculature suppress platelet activation in the absence of platelet receptor agonists. Activatory signals present at a site of injury initiate platelet activation and thrombus formation; subsequently, endogenous negative signaling regulators dampen activatory signals to control thrombus growth. Understanding the complex interplay between activatory and inhibitory signaling networks is an emerging challenge in the study of platelet biology and necessitates a systematic approach to utilize experimental data effectively. In this review, we will explore the key points of platelet regulation and signaling that maintain platelets in a resting state, mediate activation to elicit thrombus formation or provide negative feedback. Platelet signaling will be described in terms of key signaling molecules that are common to the pathways activated by platelet agonists and can be described as regulatory nodes for both positive and negative regulators. This article is protected by copyright. All rights reserved

Cobimetinib and trametinib inhibit platelet MEK but do not cause platelet dysfunction

The MEK inhibitors cobimetinib and trametinib are used in combination with BRAF inhibitors to treat metastatic melanoma but increase rates of hemorrhage relative to BRAF inhibitors alone. Platelets express several members of the MAPK signalling cascade including MEK1 and MEK2 and ERK1 and ERK2 but their role in platelet function and haemostasis is ambiguous as previous reports have been contradictory. It is therefore unclear if MEK inhibitors might be causing platelet dysfunction and contributing to increased hemorrhage. In the present study we performed pharmacological characterisation of cobimetinib and trametinib in vitro to investigate potential for MEK inhibitors to cause platelet dysfunction. We report that whilst both cobimetinib and trametinib are potent inhibitors of platelet MEK activity, treatment with trametinib did not alter platelet function. Treatment with cobimetinib results in inhibition of platelet aggregation, integrin activation, alpha-granule secretion and adhesion but only at suprapharmacological concentrations. We identified that the inhibitory effects of high concentrations of cobimetinib are associated with off-target inhibition on Akt and PKC. Neither inhibitor caused any alteration in thrombus formation on collagen under flow conditions in vitro. Our findings demonstrate that platelets are able to function normally when MEK activity is fully inhibited, indicating MEK activity is dispensable for normal platelet function. We conclude that the MEK inhibitors cobimetinib and trametinib do not induce platelet dysfunction and are therefore unlikely to contribute to increased incidence of bleeding reported during MEK inhibitor therapy

Ibrutinib inhibits platelet integrin αIIbβ3 outside-in signaling and thrombus stability but not adhesion to collagen

OBJECTIVE: Ibrutinib is an irreversible Bruton tyrosine kinase inhibitor approved for treatment of Waldenstrom macroglobulinemia, chronic lymphocytic leukemia, and mantle cell lymphoma that increases the risk of bleeding among patients. Platelets from ibrutinib-treated patients exhibit deficiencies in collagen-evoked signaling in suspension; however, the significance of this observation and how it relates to bleeding risk is unclear, as platelets encounter immobile collagen in vivo. We sought to clarify the effects of ibrutinib on platelet function to better understand the mechanism underlying bleeding risk. APPROACH AND RESULTS: By comparing signaling in suspension and during adhesion to immobilized ligands, we found that the collagen signaling deficiency caused by ibrutinib is milder during adhesion to immobilized collagen. We also found that platelets in whole blood treated with ibrutinib adhered to collagen under arterial shear but formed unstable thrombi, suggesting that the collagen signaling deficiency caused by ibrutinib may not be the predominant cause of bleeding in vivo. However, clot retraction and signaling evoked by platelet adhesion to immobilized fibrinogen were also inhibited by ibrutinib, indicating that integrin αIIbβ3 outside-in signaling is also effected in addition to GPVI signaling. When ibrutinib was combined with the P2Y12 inhibitor, cangrelor, thrombus formation under arterial shear was inhibited additively. CONCLUSIONS: These findings suggest that (1) ibrutinib causes GPVI and integrin αIIbβ3 platelet signaling deficiencies that result in formation of unstable thrombi and may contribute toward bleeding observed in vivo and (2) combining ibrutinib with P2Y12 antagonists, which also inhibit thrombus stability, may have a detrimental effect on hemostasis

RXR ligands negatively regulate thrombosis and hemostasis

OBJECTIVE: Platelets have been found to express intracellular nuclear receptors including the Retinoid X receptors (RXRα and RXRβ). Treatment of platelets with ligands of RXR has been shown to inhibit platelet responses to ADP and thromboxane A2, however the effects on responses to other platelet agonists as well as the underlying mechanism has not been fully characterised. APPROACH AND RESULTS: The effect of 9-cis-retinoic acid (9-cis-RA), docosahexaenoic acid and synthetic ligand for RXR, methoprene acid on collagen receptor (GPVI) agonists and Thrombin stimulated platelet function; including aggregation, granule secretion, integrin activation, calcium mobilisation, integrin αIIbβ3 outside-in signalling and thrombus formation in vitro and in vivo were determined. Treatment of platelets with RXR ligands resulted in attenuation of platelet functional responses following stimulation by GPVI agonists and thrombin and inhibition of integrin αIIbβ3 outside-in signalling. Treatment with 9-cis-RA caused inhibition of thrombus formation in vitro and an impairment of thrombosis and haemostasis in vivo. Both RXR ligands stimulated protein kinase A activation, measured by VASP S157 phosphorylation, that was found to be dependent on both cAMP and NFκB activity. CONCLUSIONS: This study identifies a widespread, negative regulatory role for RXR in the regulation of platelet functional responses and thrombus formation and describes novel events that lead to the upregulation of PKA, a known negative regulator of many aspects of platelet function. This mechanism may offer a possible explanation for the cardioprotective effects described in vivo following treatment with RXR ligands

The metabolites of the dietary flavonoid quercetin possess potent antithrombotic activity, and interact with aspirin to enhance antiplatelet effects

Quercetin, a dietary flavonoid, has been reported to possess antiplatelet activity. However, its extensive metabolism following ingestion has resulted in difficulty elucidating precise mechanisms of action. In this study, we aimed to characterize the antiplatelet mechanisms of two methylated metabolites of quercetin—isorhamnetin and tamarixetin—and explore potential interactions with aspirin. Isorhamnetin and tamarixetin inhibited human platelet aggregation, and suppressed activatory processes including granule secretion, integrin αIIbβ3 function, calcium mobilization, and spleen tyrosine kinase (Syk)/linker for activation of T cells (LAT) phosphorylation downstream of glycoprotein VI with similar potency to quercetin. All three flavonoids attenuated thrombus formation in an in vitro microfluidic model, and isoquercetin, a 3-O-glucoside of quercetin, inhibited thrombosis in a murine laser injury model. Isorhamnetin, tamarixetin, and quercetin enhanced the antiplatelet effects of aspirin more-than-additively in a plate-based aggregometry assay, reducing aspirin IC50 values by an order of magnitude, with this synergy maintained in a whole blood test of platelet function. Our data provide mechanistic evidence for the antiplatelet activity of two quercetin metabolites, isorhamnetin and tamarixetin, and suggest a potential antithrombotic role for these flavonoids. In combination with their interactions with aspirin, this may represent a novel avenue of investigation for the development of new antithrombotic strategies and management of current therapies

Novel anti-platelet properties of dietary cucurbitacins

Cucurbitacins are naturally occurring tetracyclic terpenes, present in foods such as cucumber and pumpkin, which elicit a range of anti-tumour, anti-inflammatory and anti-atherosclerotic effects. These dietary compounds modulate cellular functions through a variety of mechanisms, including dysregulation of the actin cytoskeleton and disruption of integrin function. Integrin outside-in signalling and cytoskeletal rearrangements are critical for stable thrombus formation and clot retraction following platelet adhesion at the site of vessel damage. We investigated the effects of cucurbitacins on platelet function and thrombus formation using human washed platelets, platelet rich plasma and whole blood in in vitro platelet function assays. We identified potent anti-platelet and anti-thrombotic effects of cucurbitacins B,E and I in human platelets. Treatment of platelets with cucurbitacins resulted in attenuation of platelet aggregation and fibrinogen binding evoked by ADP, TRAP6, collagen and CRP-XL. However, treatment with cucurbitacins did not significantly alter signalling events such as alpha granule secretion or mobilisation of intracellular calcium. We found that cucurbitacins potently inhibit integrin-mediated events, including adhesion and spreading on fibrinogen, fibronectin, collagen and laminin surfaces and cause a significant attenuation of clot retraction. Further investigation of cytoskeletal dynamics found treatment with cucurbitacins increased F actin polymerisation in a manner similar Jasplakinolide which has previously been shown to impair integrin activation, platelet spreading and clot retraction. The inhibitory effects of cucurbitacins on platelet integrin function and cytoskeletal dynamics resulted in the formation of highly unstable thrombi with reduced density under conditions of arterial shear. Our research identifies, anti-platelet and anti-thrombotic effects of dietary cucurbitacins that are linked to dysregulation of platelet cytoskeletal dynamics and integrin activity

Prevalence of eating disorders in pregnant women

Objective To estimate prevalence of lifetime and current eating disorders (ED) in a sample of pregnant women in South‐East London and to describe their sociodemographic and clinical characteristics. Method Secondary analysis of data from a cross‐sectional survey. Using a stratified sampling design, 545 pregnant women were recruited. Diagnostic interviews were administered to assess lifetime and current ED, depression, anxiety, and borderline personality disorder. Data were extracted from maternity records to assess identification of ED in antenatal care. Estimates of population prevalence of ED were obtained using sampling weights to account for the stratified sampling design. Results Weighted prevalence of lifetime ED was 15.35% (95% confidence interval [CI] [11.80, 19.71]), and current ED was 1.47% (95% CI [0.64, 3.35]). Depression, anxiety, and history of deliberate self‐harm or attempted suicide were common in pregnant women with ED. Identification of ED in antenatal care was low. Conclusions Findings indicate that by early pregnancy, a significant proportion of pregnant women will have had ED, although less typically during pregnancy, and psychiatric comorbidity is common. Yet ED were poorly recognised in antenatal care. The findings highlight the importance of increasing awareness about maternal ED to improve identification and response to the healthcare needs of pregnant women with ED

Severe platelet dysfunction in NHL patients receiving ibrutinib is absent in patients receiving acalabrutinib

The Bruton’s tyrosine kinase (Btk) inhibitor ibrutinib induces platelet dysfunction and causes increased risk of bleeding. Off-target inhibition of Tec is believed to contribute to platelet dysfunction and other side-effects of ibrutinib. The second generation Btk inhibitor acalabrutinib was developed with improved specificity for Btk over Tec. We investigated platelet function in patients with Non-Hodgkin Lymphoma (NHL) receiving ibrutinib or acalabrutinib by aggregometry and by measuring thrombus formation on collagen under arterial shear. Both patient groups had similarly dysfunctional aggregation responses to collagen and collagen-related peptide (CRP-XL) and comparison with mechanistic experiments in which platelets from healthy donors were treated with the Btk inhibitors suggested that both drugs inhibit platelet Btk and Tec at physiological concentrations. Only ibrutinib caused dysfunctional thrombus formation, while size and morphology of thrombi following acalabrutinib treatment were of normal size and morphology. We found that ibrutinib but not acalabrutinib inhibited SFKs and that SFKs have a critical role in platelet adhesion to collagen that is likely to underpin unstable thrombus formation observed in ibrutinib patients. We found that platelet function was enhanced by increasing levels of vWF and FVIII ex vivo by addition of intermediate purity FVIII (haemate P) to blood from patients, resulting in consistently larger thrombi. We conclude that acalabrutinib avoids major platelet dysfunction associated with ibrutinib therapy, and platelet function may be enhanced in patients with B-cell NHL by increasing plasma vWF and FVIII