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)

Bakgrund: Djup ventrombos (DVT) är en allvarlig komplikation efter kirurgiska och ortopediska ingrepp. Detta leder till ökat lidande för patienten, längre vårdtider och därav ökade kostnader för samhället. För att förebygga DVT krävs kunskap om vilka preventiva omvårdnadsåtgärder som har effekt och hur de ska användas. Syfte: Syftet med studien var att genom en systematisk litteraturstudie se vad kunskapsläget säger om preventiva omvårdnadsåtgärder mot DVT samt vad som ser mest effektivt ut. Syftet var också att genom en enkät ta reda på hur sjuksköterskor arbetar kliniskt för att förebygga DVT. Metod: Litteraturstudie som baserades på tio orginalartiklar. Som komplement till litteraturstudien gjordes även en enkätstudie som inkluderade tio sjuksköterskor. Resultat: Tidig mobilisering tillsammans med mekanisk profylax ses som effektivt för att förebygga DVT. I många av studierna som granskats gavs patienterna lågmolekylärt heparin (LMH). Det var dock ingen lägre frekvens av DVT hos dessa patienter jämfört med de som ej fick LMH. Det var vid införandet av profylaktiska omvårdnadsåtgärder som tidig mobilisering, kompressionsstrumpor och kompressionspumpar som frekvensen av DVT sjönk. Sjuksköterskorna arbetar aktivt med förebyggande omvårdnadsåtgärder men det finns dock inga specifika riktlinjer för dessa omvårdnadsåtgärder i den kliniska verksamheten. Slutsats:  Studien visar att ett behov finns för utvecklandet av att arbeta med individanpassad profylax då patienterna utifrån olika riskgrupper har olika behov av profylaxtyper. Stor vikt bör läggas på att utveckla och implementera riktlinjer för tidig mobilisering då detta utifrån denna studies resultat har god effekt för att förebygga uppkomsten av DVT. / Background: Deep vein thrombosis is a serious complication during surgical and orthopaedic procedures. This leads to increased patient suffering, longer hospital stays and thereby also higher cost for society. To prevent DVT requires knowledge about preventive care measures that are effective, and how they will be used. Aim: The aim of this study was to examine the current state of knowledge about preventive care measures against DVT and how effective they are. The aim was also, by conducting a survey, to find out how nurses work clinically for the prevention of DVT. Study design: A literature study was conducted. The study was based on ten original articles. As a complement to the literature study a questionnaire was created and handed out to ten surgical and orthopaedic nurses. Results: Early mobilization in combination with mechanical prophylactics is seen as effective for preventing DVT. In many of the included studies patients were given low molecular weight heparin (LMH). However the frequency of DVT in these patients was not lower compared to those who did not get LMH. Instead it was at the introduction of prophylactic care measures such as early mobilization, compression stockings and compression pumps as the frequency of DVT fell. The questionnaires showed that clinical nurses worked actively with care measures. However, there were no specific guidelines for the measures in the organisation. Conclusion: The study shows that there is a need for developing methods for individual prophylactic care as patients from different risk groups have different needs. There should also be focus on developing and implementing guidelines for early mobilization as this study has shown it is effective in preventing DVT.

I assessed the accuracy of two clinical prediction rules, the d-dimer blood test and point of care ultrasound for diagnosing lower limb deep vein thrombosis. Emergency physicians were trained in ultrasound and prospectively scanned emergency department patients with suspected deep vein thrombosis. Accuracy of the Wells and AMUSE rules and the ultrasound result was compared to radiology-performed ultrasound and a 90-day clinical outcome. Univariate and multivariate analyses were performed assessing which factors were associated with the outcome. The sensitivity and specificity of the Wells score for the clinical outcome was 85.7% and 68.5%; the AMUSE score 85.7% and 54.4%. Ultrasound had a sensitivity of 91.7% and specificity of 91.7% for radiology-diagnosed thrombus and 78.6% and 95.0% for clinical outcome. The odds ratio of a positive outcome with a positive ultrasound was 65.1. After receiving the ultrasound training program, emergency physicians were unable to demonstrate sufficient accuracy to replace current diagnostic strategies.

A system for vessel characterization aimed at detecting deep vein thrombosis (DVT) in the lower limbs has been developed and evaluated using ultrasound image processing, location and force sensors measurements, blood flow information and a protocol based on the current clinical standard, compression ultrasound. The goal is to provide an objective and repeatable system to measure DVT in a rapid and standardized manner, as this has been suggested in the literature as an approach to improve overall detection of the disease. The system uses a spatial Kalman filter-based algorithm with an elliptical model in the measurement equation to detect vessel contours in transverse ultrasound images and estimate ellipse parameters, and temporal constant velocity Kalman filters for tracking vessel location in real-time. The vessel characterization also comprises building a 3-D vessel model and performing compression and blood flow assessments to calculate measures that indicate the possibility of DVT in a vessel. A user interface designed for assessing a vessel for DVT was also developed. The system and components were implemented and tested in simulations, laboratory settings, and clinical settings. Contour detection results are good, with mean and rms errors ranging from 1.47-3.64 and 3.69-9.67 pixels, respectively, in simulated and patient images, and parameter estimation errors of 5%. Experiments showed errors of 3-5 pixels for the tracking approaches. The measures for DVT were evaluated, independently and integrated in the system. The complete system was evaluated, with sensitivity of 67-100% and specificity of 50-89.5%. System learnability and memorability were evaluated in a separate user study, with good results. Contributions include a segmentation approach using a full parameter ellipse model in an extended Kalman filter, incorporating multiple measurements, an alternate sampling method for faster parameter convergence and application-specific initialization, and a tracking approach that includes a sub-sampled sum of absolutes similarity calculation and a method to detect vessel bifurcations using flow data. Further contributions include an integrated system for DVT detection that can combine ultrasound B-mode, colour flow and elastography images for vessel characterization, a system interface design focusing on usability that was evaluated with medical professionals, and system evaluations through multiple patient studies.

I assessed the accuracy of two clinical prediction rules, the d-dimer blood test and point of care ultrasound for diagnosing lower limb deep vein thrombosis. Emergency physicians were trained in ultrasound and prospectively scanned emergency department patients with suspected deep vein thrombosis. Accuracy of the Wells and AMUSE rules and the ultrasound result was compared to radiology-performed ultrasound and a 90-day clinical outcome. Univariate and multivariate analyses were performed assessing which factors were associated with the outcome. The sensitivity and specificity of the Wells score for the clinical outcome was 85.7% and 68.5%; the AMUSE score 85.7% and 54.4%. Ultrasound had a sensitivity of 91.7% and specificity of 91.7% for radiology-diagnosed thrombus and 78.6% and 95.0% for clinical outcome. The odds ratio of a positive outcome with a positive ultrasound was 65.1. After receiving the ultrasound training program, emergency physicians were unable to demonstrate sufficient accuracy to replace current diagnostic strategies.

A system for vessel characterization aimed at detecting deep vein thrombosis (DVT) in the lower limbs has been developed and evaluated using ultrasound image processing, location and force sensors measurements, blood flow information and a protocol based on the current clinical standard, compression ultrasound. The goal is to provide an objective and repeatable system to measure DVT in a rapid and standardized manner, as this has been suggested in the literature as an approach to improve overall detection of the disease. The system uses a spatial Kalman filter-based algorithm with an elliptical model in the measurement equation to detect vessel contours in transverse ultrasound images and estimate ellipse parameters, and temporal constant velocity Kalman filters for tracking vessel location in real-time. The vessel characterization also comprises building a 3-D vessel model and performing compression and blood flow assessments to calculate measures that indicate the possibility of DVT in a vessel. A user interface designed for assessing a vessel for DVT was also developed. The system and components were implemented and tested in simulations, laboratory settings, and clinical settings. Contour detection results are good, with mean and rms errors ranging from 1.47-3.64 and 3.69-9.67 pixels, respectively, in simulated and patient images, and parameter estimation errors of 5%. Experiments showed errors of 3-5 pixels for the tracking approaches. The measures for DVT were evaluated, independently and integrated in the system. The complete system was evaluated, with sensitivity of 67-100% and specificity of 50-89.5%. System learnability and memorability were evaluated in a separate user study, with good results. Contributions include a segmentation approach using a full parameter ellipse model in an extended Kalman filter, incorporating multiple measurements, an alternate sampling method for faster parameter convergence and application-specific initialization, and a tracking approach that includes a sub-sampled sum of absolutes similarity calculation and a method to detect vessel bifurcations using flow data. Further contributions include an integrated system for DVT detection that can combine ultrasound B-mode, colour flow and elastography images for vessel characterization, a system interface design focusing on usability that was evaluated with medical professionals, and system evaluations through multiple patient studies.

Made available in DSpace on 2014-06-11T19:32:44Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-11-14Bitstream added on 2014-06-13T21:04:42Z : No. of bitstreams: 1 tofano_vac_dr_botfm.pdf: 984641 bytes, checksum: d4fcddf13acc4d52c783e4c30966c9b0 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A trombose venosa profunda (TVP) caracteriza-se pela formação aguda de um trombo no interior das veias profundas. É uma doença de alta incidência e de grande importância clínica e epidemiológica devido à sua morbimortalidade, sendo atualmente, considerada multifatorial. São vários os fatores de risco genéticos e/ou adquiridos relacionados à TVP e a compreensão da interação destes, permite melhor entender esta doença, não só devido aos seus sintomas de fase aguda mas, principalmente, por sua complicação mais temida, a embolia pulmonar e, a longo prazo, a síndrome pós-trombótica (SPT), que apresenta importante morbidade, inclusive com repercussões sócio-econômicas. A avaliação a longo prazo, clínica e ultrassonográfica, de pacientes com diagnóstico de TVP, visando verificar a incidência e gravidade da SPT é necessária para a compreensão da evolução destes pacientes. Desconhecemos a existência de trabalhos em nosso meio, que avaliem a evolução tardia da TVP. Objetivo: Determinar a evolução a longo prazo de pacientes com TVP de membros, portadores de trombofilia e verificar se existem diferenças na evolução de pacientes trombofílicos e não trombofílicos. Método: Num estudo coorte retrospectivo foram avaliados os prontuários de 275 pacientes atendidos no Hospital das Clínicas da Faculdade de Medicina de Botucatu-Unesp, dos quais foram identificados 60 pacientes trombofílicos, sendo possível contactar 40 deles para consulta, dos quais 39 pacientes aceitaram participar do estudo. Foram selecionados 25 pacientes com diagnóstico de TVP, não trombofílicos, pareados para sexo e idade, para comparação com o grupo trombofílico. Durante a consulta foi preenchido um protocolo que continha as seguintes variáveis: dados demográficos, profissão, antecedentes pessoais e antecedentes obstétricos (se mulher), antecedentes familiares com relação... / Deep vein thrombosis (DVT) is characterized by the acute formation of a thrombus in the interior of the deep veins. It is a disease of high incidence and great clinical and epidemiological importance due to its morbimortality, being presently considered multifactorial. The genetic and/or acquired risk factors related to DVT are various and understanding their interaction allows a better comprehension of this illness, due to both symptoms of the acute stage and, mainly, its most feared complication, the pulmonary embolism and, in long term, the post-thrombotic syndrome (PTS), which presents important morbidity, inclusively with social and economical repercussions. The long-term clinical and ultrasound evaluation of patients with DVT diagnosis, aiming to verify the incidence and seriousness of PTS, is necessary to understand the evolution of these patients. We are not aware of the existence of works in our area which evaluate the late evolution of DVT. Objective: To determine the long-term evolution of patients with DVT of limbs, carriers of thrombophilia, and verify the existence of differences in the evolution of thrombophilic and non-thrombophilic patients. Method: In a retrospective cohort study, the medical registers of 275 patients attended at the Clinics Hospital of the School of Medicine of the Paulista State University, in Botucatu, São Paulo, Brazil, were evaluated, from which 60 thrombophilic patients were identified. It was possible to contact 40 of them for appointment, from which 39 patients accepted to participate in the study. 25 non-thrombophilic patients, paired for sex and age, were selected with DVT diagnosis, for comparison with the thrombophilic group. During the appointment, a protocol was filled in, containing the following variables: demographic data, occupation, personal antecedents and obstetric antecedents (if woman), familiar antecedents concerning thrombosis... (Complete abstract click electronic access below)

Orientador: Francisco Humberto de Abreu Maffei / Banca: Hamilton Almeida Rollo / Banca: Adilson F. Paschôa / Banca: Newton Key Hokama / Banca: Cyrillo C. Filho / Resumo: A trombose venosa profunda (TVP) caracteriza-se pela formação aguda de um trombo no interior das veias profundas. É uma doença de alta incidência e de grande importância clínica e epidemiológica devido à sua morbimortalidade, sendo atualmente, considerada multifatorial. São vários os fatores de risco genéticos e/ou adquiridos relacionados à TVP e a compreensão da interação destes, permite melhor entender esta doença, não só devido aos seus sintomas de fase aguda mas, principalmente, por sua complicação mais temida, a embolia pulmonar e, a longo prazo, a síndrome pós-trombótica (SPT), que apresenta importante morbidade, inclusive com repercussões sócio-econômicas. A avaliação a longo prazo, clínica e ultrassonográfica, de pacientes com diagnóstico de TVP, visando verificar a incidência e gravidade da SPT é necessária para a compreensão da evolução destes pacientes. Desconhecemos a existência de trabalhos em nosso meio, que avaliem a evolução tardia da TVP. Objetivo: Determinar a evolução a longo prazo de pacientes com TVP de membros, portadores de trombofilia e verificar se existem diferenças na evolução de pacientes trombofílicos e não trombofílicos. Método: Num estudo coorte retrospectivo foram avaliados os prontuários de 275 pacientes atendidos no Hospital das Clínicas da Faculdade de Medicina de Botucatu-Unesp, dos quais foram identificados 60 pacientes trombofílicos, sendo possível contactar 40 deles para consulta, dos quais 39 pacientes aceitaram participar do estudo. Foram selecionados 25 pacientes com diagnóstico de TVP, não trombofílicos, pareados para sexo e idade, para comparação com o grupo trombofílico. Durante a consulta foi preenchido um protocolo que continha as seguintes variáveis: dados demográficos, profissão, antecedentes pessoais e antecedentes obstétricos (se mulher), antecedentes familiares com relação... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Deep vein thrombosis (DVT) is characterized by the acute formation of a thrombus in the interior of the deep veins. It is a disease of high incidence and great clinical and epidemiological importance due to its morbimortality, being presently considered multifactorial. The genetic and/or acquired risk factors related to DVT are various and understanding their interaction allows a better comprehension of this illness, due to both symptoms of the acute stage and, mainly, its most feared complication, the pulmonary embolism and, in long term, the post-thrombotic syndrome (PTS), which presents important morbidity, inclusively with social and economical repercussions. The long-term clinical and ultrasound evaluation of patients with DVT diagnosis, aiming to verify the incidence and seriousness of PTS, is necessary to understand the evolution of these patients. We are not aware of the existence of works in our area which evaluate the late evolution of DVT. Objective: To determine the long-term evolution of patients with DVT of limbs, carriers of thrombophilia, and verify the existence of differences in the evolution of thrombophilic and non-thrombophilic patients. Method: In a retrospective cohort study, the medical registers of 275 patients attended at the Clinics Hospital of the School of Medicine of the Paulista State University, in Botucatu, São Paulo, Brazil, were evaluated, from which 60 thrombophilic patients were identified. It was possible to contact 40 of them for appointment, from which 39 patients accepted to participate in the study. 25 non-thrombophilic patients, paired for sex and age, were selected with DVT diagnosis, for comparison with the thrombophilic group. During the appointment, a protocol was filled in, containing the following variables: demographic data, occupation, personal antecedents and obstetric antecedents (if woman), familiar antecedents concerning thrombosis... (Complete abstract click electronic access below) / Doutor

Orientador: Francisco Humberto de Abreu Maffei / Banca: Hamilton de Almeida Rollo / Banca: José Roberto Fioretto / Banca: Fausto Miranda Junior / Banca: Jorge David Aivazoglou Carneiro / Resumo: A importância do estudo da trombose venosa profunda (TVP) em crianças e adolescentes reside no impacto desta doença sobre a qualidade de vida desta população, tendo em vista sua longa expectativa de vida e a morbidade associada ao tromboembolismo venoso. Com o passar dos anos, a síndrome pós-trombótica e a recorrência podem deixar sequelas que vão desde dor crônica nos membros, edema e até úlceras de difícil cicatrização. A TVP em crianças está sendo melhor estudada nos últimos anos. Até então, seu diagnóstico e tratamento eram baseados em experiências individuais, pequenas séries de casos ou extrapolados das recomendações para adultos. Realizamos a presente revisão para melhor compreensão da epidemiologia, fisiopatologia, etiologia, diagnóstico, tratamento desta doença / Abstract: The study of deep vein thrombosis (DVT) in children and adolescents assesses the important impact of this disease on the quality of life of this population considering its long life expectancy and morbidity associated to venous thromboembolism. Within the years, the pos-thrombotic syndrome and recurrence can cause sequelae including chronic lower limb pain, edema and even hard cicatrization ulcer. Recently, DVT in children has been studied more appropriately. Previously, its diagnosis and treatment were based on individual experience, some serial cases or comparisons with recommendations to the adult treatments. This present study has been presented to better comprehend the epidemiology, physiopathology, etiology, diagnosis, treatment and prophylaxis of the deep vein thrombosis / Doutor

A system for vessel characterization aimed at detecting deep vein thrombosis (DVT) in the lower limbs has been developed and evaluated using ultrasound image processing, location and force sensors measurements, blood flow information and a protocol based on the current clinical standard, compression ultrasound. The goal is to provide an objective and repeatable system to measure DVT in a rapid and standardized manner, as this has been suggested in the literature as an approach to improve overall detection of the disease. The system uses a spatial Kalman filter-based algorithm with an elliptical model in the measurement equation to detect vessel contours in transverse ultrasound images and estimate ellipse parameters, and temporal constant velocity Kalman filters for tracking vessel location in real-time. The vessel characterization also comprises building a 3-D vessel model and performing compression and blood flow assessments to calculate measures that indicate the possibility of DVT in a vessel. A user interface designed for assessing a vessel for DVT was also developed. The system and components were implemented and tested in simulations, laboratory settings, and clinical settings. Contour detection results are good, with mean and rms errors ranging from 1.47-3.64 and 3.69-9.67 pixels, respectively, in simulated and patient images, and parameter estimation errors of 5%. Experiments showed errors of 3-5 pixels for the tracking approaches. The measures for DVT were evaluated, independently and integrated in the system. The complete system was evaluated, with sensitivity of 67-100% and specificity of 50-89.5%. System learnability and memorability were evaluated in a separate user study, with good results. Contributions include a segmentation approach using a full parameter ellipse model in an extended Kalman filter, incorporating multiple measurements, an alternate sampling method for faster parameter convergence and application-specific initialization, and a tracking approach that includes a sub-sampled sum of absolutes similarity calculation and a method to detect vessel bifurcations using flow data. Further contributions include an integrated system for DVT detection that can combine ultrasound B-mode, colour flow and elastography images for vessel characterization, a system interface design focusing on usability that was evaluated with medical professionals, and system evaluations through multiple patient studies. / Applied Science, Faculty of / Electrical and Computer Engineering, Department of / Graduate