Validating the safety of low-dose CTPA in pregnancy: results from the OPTICA (Optimised CT Pulmonary Angiography in Pregnancy) Study.

BACKGROUND: Pulmonary embolism (PE) is a leading cause of pregnancy-related mortality. CT pulmonary angiogram (CTPA) is the first-line advanced imaging modality for suspected PE in pregnancy at institutes offering low-dose techniques; however, a protocol balancing safety with low dose remains undefined. The wide range of CTPA doses reported in pregnancy suggests a lack of confidence in implementing low-dose techniques in this group. PURPOSE: To define and validate the safety, radiation dose and image quality of a low-dose CTPA protocol optimised for pregnancy. MATERIALS AND METHODS: The OPTICA study is a prospective observational study. Pregnant study participants with suspected PE underwent the same CTPA protocol between May 2018 and February 2022. The primary outcome, CTPA safety, was judged by the reference standard; the 3-month incidence of venous thromboembolism (VTE) in study participants with a negative index CTPA. Secondary outcomes defined radiation dose and image quality. Absorbed breast, maternal effective and fetal doses were estimated by Monte-Carlo simulation on gestation-matched phantoms. Image quality was assessed by signal-to-noise and contrast-to-noise ratios and a Likert score for pulmonary arterial enhancement. RESULTS: A total of 116 CTPAs were performed in 113 pregnant women of which 16 CTPAs were excluded. PE was diagnosed on 1 CTPA and out-ruled in 99. The incidence of recurrent symptomatic VTE was 0.0% (one-sided 95% CI, 2.66%) at follow-up. The mean absorbed breast dose was 2.9 ± 2.1mGy, uterine/fetal dose was 0.1 ± 0.2mGy and maternal effective dose was 1.4 ± 0.9mSv. Signal-to-noise ratio (SNR) was 11.9 ± 3.7. Contrast-to-noise ratio (CNR) was 10.4 ± 3.5. CONCLUSION: The OPTICA CTPA protocol safely excluded PE in pregnant women across all trimesters, with low fetal and maternal radiation. CLINICAL RELEVANCE: OPTICA (Optimised CT Pulmonary Angiography in Pregnancy) is the first prospective study to define the achievable radiation dose, image-quality and safety of a low-dose CT pulmonary angiogram protocol optimised for pregnancy (NCT04179487). It provides the current benchmark for safe and achievable CT pulmonary angiogram doses in the pregnant population. KEY POINTS: • Despite the increased use of CT pulmonary angiogram in pregnancy, an optimised low-dose protocol has not been defined and reported doses in pregnancy continue to vary widely. • The OPTICA (Optimised CT Pulmonary Angiography in Pregnancy) study prospectively defines the achievable dose, image quality and safety of a low-dose CT pulmonary angiogram protocol using widely available technology. • OPTICA provides a benchmark for safe and achievable CT pulmonary angiogram doses in the pregnant population.

Breast Shielding Combined With an Optimized Computed Tomography Pulmonary Angiography Pregnancy Protocol: A Special Use-Case for Shielding?

OBJECTIVES: To determine the impact of breast shields on breast dose and image quality when combined with a low-dose computed tomography pulmonary angiography (CTPA) protocol for pregnancy. METHODS: A low-dose CTPA protocol, with and without breast shields, was evaluated by anthropomorphic phantom and 20 prospectively recruited pregnant participants from January to October 2019. Thermoluminescent dosimeters measured surface and absorbed breast dose in the phantom and surface breast dose in participants. The Monte-Carlo method estimated the absorbed breast dose in participants. Image quality was assessed quantitatively by regions of interest analysis and subjectively by the Likert scale. Doses and image quality for CTPA alone were compared with CTPA with breast shields. RESULTS: Mean surface and absorbed breast dose for CTPA alone were 1.3±0.4 and 2.8±1.5 mGy in participants, and 1.5±0.7 and 1.6±0.6 mGy in the phantom. Shielding reduced surface breast dose to 0.5±0.3 and 0.7±0.2 mGy in the phantom (66%) and study participants (48%), respectively. Absorbed breast dose reduced to 0.9±0.5 mGy (46%) in the phantom.Noise increased with breast shields at lower kV settings (80 to 100 kV) in the phantom; however, in study participants there was no significant difference between shield and no-shield groups for main pulmonary artery noise (no-shield: 34±9.8, shield: 36.3±7.2, P =0.56), SNR (no-shield: 11.2±3.7, shield: 10.8±2.6, P =0.74) or contrast-to-noise ratio (no-shield: 10.0±3.3, shield: 9.3±2.4, P =0.6). Median subjective image quality scores were comparable (no-shield: 4.0, interquartile range: 3.5 to 4.4, shield: 4.3, interquartile range: 4.0 to 4.5). CONCLUSION: Combining low-dose CTPA with breast shields confers additional breast-dose savings without impacting image quality and yields breast doses approaching those of low-dose scintigraphy, suggesting breast shields play a role in protocol optimization for select groups.

Nonvalvular atrial fibrillation patients anticoagulated with rivaroxaban compared with warfarin exhibit reduced circulating extracellular vesicles with attenuated pro-inflammatory protein signatures.

BACKGROUND: Rivaroxaban, a direct oral factor Xa inhibitor, mediates anti-inflammatory and cardiovascular-protective effects besides its well-established anticoagulant properties; however, these remain poorly characterized. Extracellular vesicles (EVs) are important circulating messengers regulating a myriad of biological and pathological processes and may be highly relevant to the pathophysiology of atrial fibrillation as they reflect alterations in platelet and endothelial biology. However, the effects of rivaroxaban on circulating pro-inflammatory EVs remain unknown. OBJECTIVES: We hypothesized that rivaroxaban's anti-inflammatory properties are reflected upon differential molecular profiles of circulating EVs. METHODS: Differences in circulating EV profiles were assessed using a combination of single vesicle analysis by Nanoparticle Tracking Analysis and flow cytometry, and proteomics. RESULTS: We demonstrate, for the first time, that rivaroxaban-treated non-valvular atrial fibrillation (NVAF) patients (n=8) exhibit attenuated inflammation compared with matched warfarin controls (n=15). Circulating EV profiles were fundamentally altered. Moreover, quantitative proteomic analysis of enriched plasma EVs from six pooled biological donors per treatment group revealed a profound decrease in highly pro-inflammatory protein expression and complement factors, together with increased expression of negative regulators of inflammatory pathways. Crucially, a reduction in circulating levels of soluble P-selectin was observed in rivaroxaban-treated patients (compared with warfarin controls), which negatively correlated with the patient's time on treatment. CONCLUSION: Collectively, these data demonstrate that NVAF patients anticoagulated with rivaroxaban (compared with warfarin) exhibit both a reduced pro-inflammatory state and evidence of reduced endothelial activation. These findings are of translational relevance toward characterizing the anti-inflammatory and cardiovascular-protective mechanisms associated with rivaroxaban therapy.

Pathophysiology of the Venous Thromboembolism Risk in Preeclampsia.

Preeclampsia complicates up to 8% of pregnancies and is a leading cause of fetomaternal morbidity andmortality. Treatment options are limited, with supportive care and delivery of the placenta representing the cornerstone of current management strategies. Derangements in blood coagulation are wellrecognised in this disorder and appear to favour an increased risk of venous thromboembolism among affected women. This risk appears to be most significant in the postpartum period. The mechanisms underlying this increased thrombosis risk remain to be fully elucidated although increased expression of procoagulant factors, endothelial dysfunction, attenuation of endogenous anticoagulant activity and increased platelet activity have been implicated in the prothrombotic tendency. Preeclampsia is also occasionally complicated by life-threatening haemorrhagic events and current evidence suggests that in some severe manifestations of this disease a coagulopathy with a clinical bleeding tendency may be the predominant haemostatic abnormality. Identifying affected women at significant risk of thrombosis and managing the competing thrombotic and haemorrhagic risks continue to be a significant clinical challenge. Derangements in blood coagulation are also implicated in the pathogenesis of preeclampsia; however, the role of antiplatelet or anticoagulant drugs in the prevention and treatment of this disorder remains a source of considerable debate. In addition, the potential role of specific haemostatic markers as diagnostic or screening tools for preeclampsia has also yet to be determined. Further characterisation of the underlying molecular mechanisms would likely be of major translational relevance and could provide insights into the pathogenesis of this disease as well as the associated haemostatic dysfunction.

VTE risk assessment in pregnancy.

A State of the Art lecture, "VTE Risk Assessment in Pregnancy," was presented at the ISTH congress in Melbourne, Australia, in 2019. Venous thromboembolism (VTE) remains a leading cause of death in pregnancy and in the postpartum period. Moreover, VTE can result in lifelong disability. The elevated baseline pregnancy-associated VTE risk is further increased by additional maternal, pregnancy, and delivery characteristics, highlighting the importance of VTE risk assessment in early pregnancy, at delivery, and if risk factors change. This review will provide an overview of the impact and epidemiology of VTE in pregnancy (including reported risk factors for pregnancy-associated VTE), will address VTE risk-reduction strategies (including ongoing studies), and will provide a summary of critical knowledge gaps. Finally, throughout this review, relevant new data presented during the 2019 ISTH annual congress in Melbourne will be summarized.

Implementation of an acute DVT ambulatory care pathway in a large urban centre: current challenges and future opportunities.

BACKGROUND: Ambulatory management of isolated acute deep venous thrombosis (DVT) is the recommended standard of care in selected populations. However, in practice a significant number of patients continue to be managed as in-patients. OBJECTIVES: In this study we aimed to evaluate acute DVT treatment pathways in our emergency department (ED) in practice and to identify barriers to outpatient management. METHODS: This study was a cross-sectional analysis of prospectively collected data pertaining to consecutive patients presenting to the ED of a large, city center, academic teaching hospital over a 46 week period who were diagnosed with DVT. RESULTS: Implementation of an outpatient care pathway led to the majority of patients presenting with DVT in our institution being treated without hospital admission. Forty percent (31/78) of patients with DVT were treated with a direct oral anticoagulant (DOAC) as an outpatient in line with international best practice guidelines. CONCLUSION: The study provides a clear picture of the clinical profile and management of patients in clinical practice. Due to the lack of resources and supported infrastructure it is difficult to effectively implement outpatient venous thromboembolism (VTE) management to its full potential. Directing resources towards strategies which facilitate outpatient DVT treatment among vulnerable patient groups could represent a means of reducing hospital admissions for DVT in urban centers. Our study highlights the success and clinical limitations of the outpatient treatment model, which should become standard as part of wider VTE care.

The OPTICA study (Optimised Computed Tomography Pulmonary Angiography in Pregnancy Quality and Safety study): Rationale and design of a prospective trial assessing the quality and safety of an optimised CTPA protocol in pregnancy.

BACKGROUND: CTPA is the gold standard investigation for evaluating suspected pulmonary embolism (PE) in the general population however is sometimes considered second line in pregnant and post-partum patients with a normal CXR due to its higher breast dose and the increased radio-sensitivity of breast tissue during this period. Guidelines advocating for scintigraphy over CTPA, however, quote significantly higher breast doses than those achievable with optimised low dose strategies. Defining the radiation dose achievable with a specific low-dose CTPA protocol is therefore imperative. As decreasing dose is associated with increased image noise, demonstrating the image quality and validity of a negative low-dose CTPA in out-ruling PE in this population is necessary. METHODS: The OPTICA study is a prospective multicentre observational study aiming to validate the clinical utility and safety of an optimised low-dose CTPA protocol in pregnancy. An optimised low-dose CTPA protocol has been agreed across all study sites with equivalent CT capabilities. Pregnant women undergoing CTPA for suspected PE will be included. Independent review of CTPAs by two radiology consultants, image data analysis and 3-month patient follow up will be performed. The primary outcome is the 3-month incidence of VTE in pregnant patients in whom PE was excluded at baseline CTPA. Secondary outcomes will confirm the associated radiation dose and image quality of this protocol. The radiation dose will be calculated using the Monte Carlo method and will include maternal effective, breast and foetal doses. Image quality will be assessed objectively by measuring opacification of the main pulmonary trunk, signal-to-noise and contrast-to-noise ratios and subjectively using a grading scale and inter-reader variability of CTPA results. CONCLUSION: The OPTICA study is the first prospective trial of a low-dose CTPA protocol in the pregnant population. It will provide high-quality evidence defining the achievable dose, image quality and safety of an optimised CTPA for this population. It will assist other institutes with similar CT capabilities in achieving comparable low doses for its patients and provide an evidence base upon which modern CTPA protocols can be appropriately compared to scintigraphy in the pregnant population.

Nelarabine-induced peripheral and central neurotoxicity: can sequential MRI brain imaging help to define its natural history?

A 14-year-old boy with relapsed T cell acute lymphoblastic leukaemia received reinduction chemotherapy that included nelarabine, a purine nucleoside analogue known to cause dose-dependent neurotoxicity. Although he achieved aminimal residual disease negative remission after two cycles of chemotherapy he also developed severe, progressive peripheral and central neurotoxicities. Loss of grey-white differentiation was seen on a T2-weighted magnetic resonance imaging brain scan. This unusual clinical picture and previously unreported radiological findings are thought to be due to nelarabine toxicity. He was bridged with 6-mercaptopurine while transplant was deferred pending sustainable neurological improvement. This case posed clinical and ethical dilemmas while demonstrating previously unreported radiological features.