OBJECTIVES: Clot in transit represents a life-threatening manifestation of venous thromboembolism of which we have limited understanding. This study was designed to describe the risk factors, clinical characteristics and outcomes associated with the development of a clot in transit as well as death within clot in transit patients. METHODS: We enrolled 1,093 consecutive patients into our single-center Pulmonary Embolism Response Team Registry. We compared 76 patients who had a clot in transit to 589 pulmonary embolism patients who did not have a clot in transit. RESULTS: Clot in transit was present in 11.4% of patients who received an echocardiogram to look for it. Multivariate analysis showed congestive heart failure (OR 2.954, 95% CI 1.349 – 6.467, P = 0.0068), a pre-existing inferior vena cava filter (OR 2.777, 95% CI 1.204 – 6.407, P = 0.0167), and hemodynamic collapse (OR 3.495, 95% CI 1.129 – 10.823, P = 0.0300) to be independent predictors of clot in transit. All-cause mortality by 30 days was higher in clot in transit patients (24.3% vs 9.7%, P < 0.001). All-cause mortality by 7 days within clot in transit patients was associated with hemodynamic collapse (45.5% vs 12.3%, P = 0.018) and mental status change (63.6% vs 21.5%, P = 0.008). CONCLUSIONS: The presence of congestive heart failure, a pre-existing inferior vena cava filter, and hemodynamic collapse are independent predictors of clot in transit and should alert physicians to patients who may require an echocardiogram. The mortality for clot in transit is high even when compared to a more severe pulmonary embolism population. Clot in transit represents a high-risk finding that may require more aggressive interventions. / 2020-06-14T00:00:00Z

INTRODUCTION: Cirrhosis is a significant cause of mortality and morbidity worldwide. Recent studies suggested that cirrhosis is associated with an increased risk of venous thromboembolism (VTE), which disproves the old belief that chronic liver disease coagulopathy is considered protective against VTE. We conducted a retrospective study which is to our knowledge the first of its kind to assess clinical characteristics and outcomes of decompensated cirrhosis (DC) patients admitted with acute pulmonary embolism (APE). METHODOLOGY: We used the National Inpatient Sample database for the years 2016-2019. All adults admitted to the hospitals with a primary diagnosis of APE were included. Patients less than 18 years old, missing race, gender, or age were excluded. Patients were divided into two groups, either having DC or not. A multivariate logistic regression model was built by using only variables associated with the outcome of interest on univariable regression analysis at P < 0.05. RESULTS: 142 million discharges were included in the NIS database between the years 2016 and 2019, of which 1,294,039 met the study inclusion criteria, 6,200 patients (0.5%) had DC. For adult patients admitted to the hospitals with APE, odds of inpatient all-cause mortality were higher in the DC group than in patients without DC; OR of 1.996 (95% CI, 1.691-2.356, P-value < 0.000). Also, vasopressor use, mechanical ventilation, and cardiac arrest were more likely to occur in the DC group, OR of 1.506 (95% CI, 1.254-1.809, P-value < 0.000), OR of 1.479 (95% CI, 1.026-2.132, P-value 0.036), OR of 1.362 (95% CI, 1.050-1.767, P-value 0.020), respectively. In addition, DC patients tend to have higher total hospital charges and longer hospital length of stay, coefficient of 14521 (95% CI, 6752-22289, P-value < 0.000), and a coefficient of 1.399 (95% CI, 0.848-1.950, P-value < 0.000), respectively. CONCLUSION: This study demonstrates that DC is a powerful predictor of worse hospital outcomes in patients admitted with APE. An imbalance between clotting factors and natural anticoagulants produced by the liver is believed to be the primary etiology of thrombosis in patients with DC. The burden of APE can be much more catastrophic in cirrhotic than in non-cirrhotic patients; therefore, those patients require closer monitoring and more aggressive treatment.

Le but de notre travail a été d’évaluer l’effet de la réduction de la dose d’irradiation en TDM multibarrette quant à la performance diagnostique, la confiance de l’observateur dans le diagnostic proposé, la capacité à suggérer un diagnostic alternatif dans quelques pathologies courantes et/ou caractérisées par des situations de faibles contrastes entre les structures anatomiques normales ou pathologiques. Nous avons donc comparé ces paramètres entre des TDM à doses réduites et à doses standard telles que couramment rapportées dans la littérature dans les circonstances suivantes : • La suspicion clinique de colique néphrétique: le contraste naturel élevé du calcium avec les structures voisines suggère de pouvoir réduire fortement la dose, dans une pathologie potentiellement récidivante et qui intéresse des patients jeunes dont le pronostic est excellent. Notre étude a montré qu’une dose 10 fois inférieure à celle générée par des examens TDM courants permet des performances diagnostiques semblables à la TDM à dose conventionnelle. • La suspicion clinique de sinusite chronique: le contraste naturel élevé entre l’air des cavités sinusales, la muqueuse nasale et les os de la face permet de réduire fortement la dose, dans cette pathologie potentiellement récidivante et qui intéresse des patients jeunes dont le pronostic est excellent. Notre étude a montré qu’une dose 10 à 25 fois inférieure à celle générée par des examens TDM courants, et dès lors inférieure à celle générée par quatre incidences radiographiques, permet des performances diagnostiques semblables à la TDM à dose conventionnelle. • La suspicion clinique d’appendicite aiguë: L’appendice est situé dans une atmosphère anatomique caractérisée par un faible contraste entre les structures. Néanmoins, comme l’appendicite est une pathologie qui concerne l’adolescent et l’adulte jeune, nous avons tenté de réduire la dose des TDM dans ce contexte. Notre étude a montré qu’une dose 3 à 10 fois inférieure à celle générée par des examens TDM courants, et dès lors inférieure à celle générée par trois incidences radiographiques, permet des performances diagnostiques semblables à la TDM à dose conventionnelle. • La suspicion clinique de diverticulite aiguë du colon: la diverticulite aiguë du colon est également caractérisée par une atmosphère anatomique de faible contraste entre les structures. Néanmoins, comme cette pathologie peut concerner l’adulte jeune et récidiver, nous avons tenté de réduire la dose des TDM dans ce contexte. Notre étude a montré qu’une dose 3 à 10 fois inférieure à celle générée par des examens TDM courants, permet des performances diagnostiques semblables à la TDM à dose conventionnelle. • Le diagnostic d’embolie pulmonaire aiguë: la TDM spiralée occupe une position centrale dans le diagnostic d’embolie pulmonaire aiguë mais impose l’injection intraveineuse de produit de contraste iodé. La comparaison d’images obtenues à des doses variables d’irradiation a nécessité leur traitement à posteriori pour simuler la réduction de dose. Notre étude a montré qu’une dose 9 fois inférieure à celle générée par des examens TDM conventionnels permet des performances diagnostiques semblables. Ces investigations ont été complétées par l’investigation de l’influence du genre, de l’indice de masse corporelle et de l’âge sur la modulation automatique du courant au tube radiogène (6). Cette investigation a montré que la modulation automatique ne réduit la dose d’irradiation que d’au plus 20% avec peu ou pas de différence en fonction du genre, de l’âge ou de l’indice de masse corporel des patients ; indiquant ainsi qu’elle ne pouvait pas remplacer la réduction de la charge volontaire de l’opérateur.

Background: Pulmonary embolism (PE) accounts for almost 40% of perioperative deaths after bariatric surgery. Placement of prophylactic inferior vena cava (IVC) filter before bariatric surgery to improve outcomes has shown varied results. We performed a meta-analysis to evaluate postoperative outcomes associated with the preoperative placement of IVC filters in these patients. Methods: A systematic review was conducted by three investigators independently in PubMed, EMBASE, the Web of Science and Scopus until February 28, 2013. Our search was restricted to studies in adult patients undergoing bariatric surgery with and without IVC filters. Primary outcomes were postoperative deep vein thrombosis (DVT), pulmonary embolism (PE), and postoperative mortality. Meta-analysis used random effects models to account for heterogeneity, and Sidik-Jonkman method to account for scarcity of outcomes and studies. Associations are shown as Relative Risks (RR) and 95% Confidence Intervals (CI). Results: Seven observational studies were identified (n=102,767), with weighted average incidences of DVT (0.9%), PE (1.6%), and mortality (1.0%) for a follow-up ranging from 3 weeks to 3 months. Use of IVC filters was associated with an approximately 3-fold higher risk of DVT and death that was nominally significant for the former outcome, but not the latter (RR 2.81, 95%CI 1.33-5.97, p=0.007; and RR 3.27, 95% CI 0.78-13.64, p=0.1, respectively); there was no difference in the risk of PE (RR 1.02, 95%CI 0.31-3.77, p=0.9). Moderate to high heterogeneity of effects was noted across studies. Conclusions: Placement of IVC filter before bariatric surgery is associated with higher risk of postoperative DVT and mortality. A similar risk of PE in patients with and without IVC filter placement cannot exclude a benefit, given the potential large imbalance in risk at baseline. Randomized trials are needed before IVC placement can be recommended. / Revisión por pares

Diana.sobieraj@hhchealth.org / Objective To systematically review the literature and to quantitatively evaluate the efficacy and safety of extended pharmacologic treatment of venous thromboembolism (VTE) through network meta-analysis (NMA). Methods A systematic literature search (MEDLINE, Embase, Cochrane CENTRAL, through September 2014) and searching of reference lists of included studies and relevant reviews was conducted to identify randomized controlled trials of patients who completed initial anticoagulant treatment for VTE and then randomized for the extension study; compared extension of anticoagulant treatment to placebo or active control; and reported at least one outcome of interest (VTE or a composite of major bleeding or clinically relevant non-major bleeding). A random-effects Frequentist approach to NMA was used to calculate relative risks with 95% confidence intervals. Results Ten trials (n=11,079) were included. Risk of bias (assessed with the Cochrane tool) was low in most domains assessed across the included trials. Apixaban (2.5mg and 5mg), dabigatran, rivaroxaban, idraparinux and vitamin K antagonists (VKA) each significantly reduced the risk of VTE recurrence compared to placebo, ranging from a 73% reduction with idraparinux to 86% with VKAs. With exception of idraparinux, all active therapies significantly reduced VTE recurrence risk versus aspirin, ranging from a 73% reduction with either apixaban 2.5mg or rivaroxaban to 80% with VKAs. Apixaban and aspirin were the only therapies that did not increase composite bleeding risk significantly compared to placebo. All active therapies except aspirin increased risk of composite bleeding by 2 to 4-fold compared to apixaban 2.5mg, with no difference found between the two apixaban doses. Conclusion Extended treatment of VTE is a reasonable approach to provide continued protection from VTE recurrence although bleeding risk is variable across therapeutic options. Our results indicate that apixaban, dabigatran, rivaroxaban, idraparinux and VKAs all reduced VTE recurrence when compared to placebo. Apixaban appears to have a more favorable safety profile compared to other therapies. / Revisión por pares

Orientador: Heitor Moreno Junior / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-19T02:49:22Z (GMT). No. of bitstreams: 1 Pereira_DanielJose_M.pdf: 8289618 bytes, checksum: f81b30485257dfeb1919e76b99cecc7d (MD5) Previous issue date: 2011 / Resumo: Introdução: estudos experimentais de embolia pulmonar (EP) são habitualmente realizados sob ventilação mecânica. Como a maioria dos pacientes com suspeita de EP adentra os Serviços de Emergência em respiração espontânea e em ar ambiente, estudos que medissem as variáveis hemodinâmicas, gasométricas e capnográficas, nestas condições, em muito contribuiriam para compreensão mais específica das alterações cardiopulmonares e gasométricas na fase aguda da doença. Observa-se que faltam na literatura estudos experimentais que avaliem animais em tais condições. Objetivo: o objetivo do presente estudo foi submeter à EP animais sob ventilação espontânea e sem oxigênio suplementar. A EP por coágulos autólogos foi induzida em seis porcos e os registros cardiorrespiratórios e gasométricos foram realizados no pré e pós-EP. O valor da pressão média de artéria pulmonar (PMAP) "quase fatal" foi previamente determinada. Resultados: a presença de choque obstrutivo agudo pôde ser evidenciada pelo aumento da PMAP (de 17,8±3,5 para 41,7±3,3mmHg) (P<0,0001) e pela queda do débito cardíaco (de 4,9±1,0 para 2,7±1,0L/min) (P<0,003). Consequentemente, a presença de acidose metabólica pode ser constatada (de 2,4±0,6 para 5,7±1,8mmol/L) (P<0,0001). Observou-se ainda a presença de hipoxemia (de 73,5±12,7 para 40,3±4,6mmHg) (P<0,0001), porém, a PaCO2 não variou (de 44,9±4,4 para 48,2±6,0mmHg) (NS). Houve expressivos aumentos, tanto para P(a-et)CO2 (de 4,8±2,8 para 37,2±5,8mmHg) quanto para a P(A-a)O2 (de 8,2±8,9 para 37,2±10,3mmHg) (P<0,0001). Como tentativa de compensação à acidose metabólica, evidenciou-se significativo aumento do volume minuto alveolar total (de 4,0±0,9 para 10,6±2,9L/min) (P<0,0001). Conclusão: neste modelo, a PMAP quase fatal foi de 2 a 2,5 vezes a PMAP basal e as variáveis capnográficas, associadas a gasometria arterial e venosa, mostraram-se eficazes em discriminar um quadro obstrutivo agudo / Abstract: Introduction: Experimental studies on pulmonary embolism (PE) are usually performed under mechanical ventilation. Most patients with suspicion of PE enter the Emergency Services in spontaneous breathing and environmental air. Thus, under these conditions, measurements of hemodynamic, gasometric and capnographic variables contribute largely to a more specific comprehension of cardiopulmonary and gasometric alterations in the acute phase of the disease. Studies which evaluated animals under conditions are lacking. Objective: This study aimed to submit animals under spontaneous ventilation and without supplemental oxygen to PE. PE was induced in six pigs using autologous blood clots, and cardiorespiratory and gasometric records were performed before and after PE. The values of "near fatal" mean pulmonary arterial pressure (MPAP) were previously determined. Results: The presence of obstructive shock could be evidenced by increased MPAP (from 17.8±3.5 to 41.7±3.3mmHg) (p<0.0001) and decreased cardiac output (from 4.9±1.0 to 2.7±1.0L/min) (p<0.003). Consequently, metabolic acidosis occurred (Lac art)(from 2.4±0.6 to 5.7±1.8mmol/L) (p<0.0001). It was observed hypoxemia (from 73.5±12.7 to 40.3±4.6mmHg) (p<0.0001); however, PaCO2 did not vary (from 44.9±4.4 to 48.2±6.0mmHg) (NS). There were significant increases in both P(a-et)CO2 (from 4.8±2.8 to 37.2±5.8mmHg) and P(A-a)O2 (from 8.2±8.9 to 37.2±10.3mmHg) (p<0.0001). There was also a significant increase in the total alveolar minute volume (from 4.0±0.9 to 10.6±2.9L/min) (p<0.0001). Conclusion: In this model, the near fatal MPAP was from 2 to 2.5 times the basal MPAP; and the capnographic variables, associated with arterial and venous gasometry, showed effective in discriminating an acute obstructive profile / Mestrado / Farmacologia / Mestre em Farmacologia

INTRODUCTION: Pulmonary embolism (PE) is a major cause of mortality during pregnancy. It is estimated that about 20% of maternal deaths in north america are due to PE. A lung V/Q study in a standard (non-gravid) patient typically consists of a low dosage ventilation study followed by a higher dosage perfusion study. In some centers however, perfusion-only imaging, without accompanying ventilation imaging has been employed. In this method, a several-fold lower dose of radioactivity is used. Perfusion-only imaging has multiple advantages. In addition to reduction of radiation dose to the mother and the fetus, there is decreased cost to the health-care system as well as improved patient convenience and shortened hospital workflow. OBJECTIVES: The present study aimed at assessing the negative predictive value (among other diagnostic accuracy measures) of perfusion-only imaging in a large group of pregnant patients with suspected pulmonary embolism. METHODS: This study was a retrospective cohort study of the entire pregnant patients with suspected PE who underwent V/Q scan at The Ottawa Hospital and their V/Q scans were available in the PACS system. After acquiring REB approval, a comprehensive search in the PACS (Picture Archiving and Communication System) was conducted to find pregnant patients who were assessed for PE in our division since 2004 (the earliest date the V/Q images were available in our system). A statistical consultation was made before the initiation of data collection and at the time of data analysis. All patients who met the inclusion criteria were included. Initially a nuclear medicine resident with 2 years of experience read all the perfusion- only images. The PISAPED criteria were used for image interpretation. Then the results were compared against the reports made by nuclear medicine staffs that were available to us in our electronic system and a final interpretation was made after such comparison. The follow-up clinical notes were used as the gold standard to make a final diagnosis of PE. Finally, diagnostic accuracy measures were calculated. RESULTS: A total of 364 patients were included. Mean maternal age at the time of lung V/Q scan was 30.3 years-old (SD=5.8) ranging from 16 to 51 years-old. From a total of 362 lung perfusion scans, 316/362 (87.3%) scans interpreted as normal, 17/362 (4.7%) scans were interpreted as high probability and 29/362 (8.0%) scans were interpreted as non-diagnostic. Pulmonary embolism was diagnosed in a total of 15 patients directly after performing lung scan. None of the patients with normal perfusion-only scans were diagnosed later with PE, proving a negative predictive value of 100%. The sensitivity and specificity of perfusion-only imaging after including the non-diagnostic studies were 100% (100% to 100%) and 99.1% (88.1% to 94.1%), respectively with a negative predictive value of 100% (100% to 100%) and a positive predictive value of 32.6% (19.1% to 46.2%). Conclusion: The results of the current study show that perfusion-only imaging has a very high negative predictive value for PE in pregnant population and therefore can exclude PE with a very high degree of accuracy.

Pulmonary embolism (PE) is a common clinical problem affecting 600,000 patients per year in the United States. Although the diagnosis can be easily confirmed by imaging techniques, such as computed tomographic angiography of the chest, the identification of underlying mechanism leading to PE is important for appropriate duration of anticoagulation, and prevention of subsequent episodes. The differential diagnosis of underlying mechanism is broad and must include careful review of medication history. Drug-related thromboembolic disease can be easily missed and may have catastrophic consequences. The identification of the culprit drug is important for prevention of subsequent episodes and choosing appropriate duration of anticoagulation. We report a case of a middle-aged man who developed PE after administration of intravenous immunoglobulin.

Venous thromboembolism (VTE) is a chronic illness that affects nearly 10 million people every year worldwide. Anticoagulant therapy with direct oral anticoagulants is the mainstay of treatment for patients with VTE, and should be continued for at least 3-6 months. Thereafter, a decision should be made to discontinue anticoagulation or continue it indefinitely. This decision is most challenging for patients with a first unprovoked VTE because of uncertainty in estimates for the long-term benefits (e.g., reduction in recurrent VTE) and harms (e.g., increase in major bleeding) of extended anticoagulation, and the trade-offs between them. The overarching aim of this doctoral thesis was to address these key evidence gaps that are pertinent to making decisions regarding the duration of anticoagulation for patients with a first unprovoked VTE. The first three studies of this thesis synthesized contemporary and reliable estimates for the long-term risks and consequences of recurrent VTE and major bleeding, with and without extended anticoagulation (parameters that can influence the clinical and cost-effectiveness of discontinuing versus continuing anticoagulation indefinitely). Broadly, these systematic reviews and meta-analyses found that: 1) the long-term risks and consequences of major bleeding during extended anticoagulation are considerable, particularly with vitamin K antagonists as well as in older patients, patients using antiplatelet therapy, and in patients with kidney disease, a history of bleeding, or anemia; and 2) the long-term risks of recurrent VTE during extended anticoagulation and major bleeding after discontinuing anticoagulation are reassuringly low but not negligible. The fourth study incorporated the synthesized evidence to compare the lifetime clinical benefits, harms, and costs of discontinuing versus continuing anticoagulation indefinitely. This decision analytic modelling study showed that indefinite anticoagulation is unlikely to either result in a net clinical benefit or be cost-effective in all (i.e., unselected) patients with a first unprovoked VTE. Findings from this thesis can serve to impact clinical practice and health policy by informing patient prognosis to guide shared decision-making regarding the duration of treatment for unprovoked VTE, and informing future research to ultimately identify which patients should receive anticoagulation indefinitely in order to maximize health benefits for the available healthcare resources.

Whether a patient presents with deep vein thrombosis (DVT) or pulmonary embolism (PE) varies based on clinical factors. Patients with factor V Leiden (FVL) typically present with DVT while cancer patients present with PE. The biological mechanisms that determine DVT stability in the progression of DVT to PE are not known. Thus, little is known about the mechanism of thrombus stability, the factors involved, or the effect of anticoagulants on embolization and PE burden. In order to answer these questions, we first need to (i) develop a mouse model to evaluate DVT stability and its relationship with PE burden when treated with anticoagulants, (ii) determine if anticoagulants, by inhibiting thrombin, require FXIII to decrease thrombus stability, (iii) determine the effects of attenuating fibrinolysis, using epsilon aminocaproic acid (ε-ACA or EACA), supplemental FXIII and α2-AP, on clot stability and (iv) utilize our model to explain the FVL paradox. For our thrombus stability model, the femoral vein of C57BL/6, FXIII deficient (FXIII-/-), FVL heterozygous, or FVL homozygous female mice was subjected to ferric chloride (FeCl3) injury to initiate a non-occlusive thrombus. Treatment with saline, dalteparin, dabigatran, EACA or FXIII was administered 12 minutes after thrombus formation. Intravital videomicroscopy recorded the thrombus sizes and embolic events leaving the thrombus for 2 hours. Lungs were harvested, sectioned and stained for the presence of PE. Total and large embolic events were highest after dabigatran treatment compared to saline or dalteparin in wild-type (WT) mice. Variations in amounts of embolic events were not attributed to variations in thrombus size since thrombus size was similar between the groups. The number of emboli per lung slice was higher in dabigatran-treated mice. Large embolic events correlated positively with the number of emboli per lung slice independent of treatment. Dabigatran treatment in FXIII-/- mice did not alter embolization patterns suggesting that FXIII is required for dabigatran to decrease thrombus stability. EACA increases thrombus size significantly and therefore would not be a feasible alternative to IVC filters, as it will increase DVT size. FXIII marginally increased thrombus size. Treatment with FXIII decreases total and large embolic events in saline-, dalteparin- or dabigatran-treated mice, similar to EACA-treated mice. The number of emboli per lung slice was reduced after treatment with FXIII and EACA compared to non-treated mice. PE burden was not significantly different between FXIII anticoagulated mice or EACA-treated mice. The large embolic events correlate positively with PE burden. FVL heterozygous and homozygous mice had significantly reduced embolization and thrombus size grew significantly over time, this contrasted with WT mice, where thrombus size remained similar to the initial injury. PE burden was significantly reduced in the FVL mice compared to WT. Collectively, these data shows that we have successfully developed a mouse model of acute venous thrombus stability that can quantify emboli and PE burden. Consistent with clinical data, dabigatran, a DTI, was shown to acutely decrease thrombus stability and increase PE burden compared to LMWH or saline; an effect that was FXIII-dependent. Also, attenuating fibrinolysis with EACA, but not FXIII, increases thrombus size; but both increase DVT stability and decrease PE burden. Supplementing α2-AP did not alter thrombus stability. This suggests that administration of FXIII may be a better treatment option for DVT patients who are bleeding than EACA, since EACA may increase DVT size. Lastly, our model can explain the FVL paradox. Those with FVL have stable thrombus formation leading to an increased incidence of symptomatic DVT and a decreased risk of PE. / Thesis / Doctor of Philosophy (PhD)