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No. of bitstreams: 1 brandao_gms_dr_bot.pdf: 2703945 bytes, checksum: d9034b6210add676a4f9b7cbf4c31ad3 (MD5) Previous issue date: 2016-05-25 / Pentasaccharides para o tratamento da trombose venosa profunda Questão da revisão: Os novos anticoagulantes da classe dos pentasaccharides podem ser uma alternativa eficaz e segura aos anticoagulantes convencionais utilizados na terapia padrão do tratamento da trombose venosa profunda? Visão geral: Trombose venosa profunda (TVP) é uma doença grave e potencialmente fatal que se caracteriza pela formação aguda de um coágulo de sangue nas veias profundas. Sua incidência aumenta exponencialmente com a idade e estima-se que na população geral, sua incidência seja de 5 casos em 10,000 habitantes. O tratamento padrão se faz por meio de medicamentos anticoagulantes, inicialmente pela administração de medicamentos injetáveis, as heparinas, por 5 a 7 dias e em seguida pelo uso prolongado de medicamentos de uso oral, os antagonistas da vitamina K. Entretanto, o alto risco de sangramento e a necessidade de um rigoroso controle laboratorial, permanecem como importantes limitações à terapia padrão. Os pentasaccharides são anticoagulantes sintéticos que podem apresentar vantagens em relação ao tratamento convencional como um efeito mais previsível, um regime de dosagem mais conveniente, a ausência da necessidade de controle laboratorial, ausência de interações com medicamentos e/ou alimentos, ausência da temida diminuição das plaquetas induzida pela heparina e em muitos casos melhor custo-benefício. Características chaves e resultados: Nossas buscas, realizadas até julho de 2015, identificaram 20 entre 730 registros que representavam 5 estudos elegíveis, compreendendo um total de 6981 pacientes. Os estudos compararam os pentasaccharides fondaparinux, idraparinux e idrabiotaparinux com a terapia padrão (heparina seguida por antagonista da vitamina K). O principal resultado de eficácia foi feito pela avaliação da incidência de qualquer episódio tromboembolismo venoso (novo episódio de TVP ou embolia pulmonar) durante o tratamento. E o principal resultado de danos foi incidência de sangramento. Esta revisão mostrou que os pentasaccharides (fondaparinux, e a dose de 2.5 mg de idraparinux e a dose equivalente de 3.0 mg de idrabiotaparinux) podem ser uma alternativa eficaz e segura a anticoagulação convencional para o tratamento da TVP. Qualidade da evidência: A qualidade da evidência foi considerada moderada a alta. Um único estudo incluído (Persist) poderia ser julgado potencialmente falho devido ao relevante número de pacientes que foram perdidos ou descontinuaram prematuramente o tratamento após a randomização. De forma geral, os estudos incluídos responderam diretamente as perguntas e foram considerados de boa qualidade. Os resultados dos estudos foram consistentes e os efeitos estimados foram precisos. Nós acreditamos que seja improvável que a maioria dos nossos principais resultados de eficácia e danos possam ser modificados por estudos adicionais. Entretanto, estudos futuros com os pentasaccharides de meia vida prolongada (idraparinux e idrabiotaparinux) em baixas doses podem confirmar nossas estimativas com relação a sua não inferioridade em comparação à terapia padrão. / Background: Deep vein thrombosis (DVT) is a severe disorder caused by acute formation of a clot or thrombus in the deep vein system. The incidence of DVT increases with age: from 2 to 3/10,000 in adults aged 30 to 49 years to 20/10,000 in adults aged 70 to 79 years. If left untreated, the clot can travel up to the lungs and cause a potentially life-threatening pulmonary embolism (PE). Standard treatment is based on antithrombotic therapy, initially with parenteral administration of unfractionated heparin or low molecular weight heparins (LMWH) for five to seven days, then subsequent long-term oral vitamin K antagonists (e.g. warfarin) therapy. However, hemorrhagic complications are a major concern associated with warfarin treatment. Indeed, the hemorrhagic risk of warfarin and the required laboratory control remain the Achilles’ heel of vitamin K antagonist management. The pentasaccharides have characteristics that may be favourable over conventional treatment, including a predictable effect, lack of frequent monitoring or re-dosing and few known drug interactions and absence of heparin-induced thrombocytopenia. To date, no systematic review has measured the effectiveness and safety of these drugs in the treatment of DVT. Objectives: To assess the efficacy and harms of pentasaccharides for the treatment of deep venous thrombosis. Search strategy: 1 The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched July 2015) and the Cochrane Register of Studies (last searched July 2015). We searched clinical trials databases for details of ongoing or unpublished studies and the reference lists of relevant articles retrieved by electronic searches for additional citations. Selection criteria: We included randomised controlled trials in which people with a DVTconfirmed by standard imaging techniques, were allocated to receive a pentasaccharide (fondaparinux, idraparinux or idrabiotaparinux) for the treatment of DVT. Data collection and analysis: Three review authors (GB, DJ and MS) independently extracted the data and assessed the risk of bias in the trials. Any disagreements were resolved by discussion. We performed meta-analyses when we considered heterogeneity low. The two primary outcomes were recurrent VTE and major (and clinically non-major) bleeding. Other outcomes included all-cause mortality, recurrent DVT, PE, thrombocytopenia, heparin-induced thrombocytopenia syndrome and all other adverse effects induced by the treatments . We calculated all outcomes using a relative risk (RR) with a 95% confidence interval (CI). Main results: We included 5 randomised controlled trials of 6981 participants. Two studies tested fondaparinux, while three tested idraparinux (being one tested idrabiotaparinux). We deemed all included studies to be of high methodological quality and generally low risk of bias. The quality of the evidence was generally graded as high as the outcomes were direct and effect estimates were consistent and precise, as reflected in the narrow CIs around the RRs. Meta-analysis of two studies (2658 participants) comparing fondaparinux with standard anticoagulation groups showed no difference in the risk of recurrent VTE (RR 0.88, 95% CI 0.60 to 1.29). The RR of bleeding in the initial period of treatment (RR 0.94, 95% CI 0.73 to 1.22) and three months of follow up (RR 0.61, 95% CI 0.36 to 1.01) were similar comparing both interventions. Two studies comparing idraparinux with standard therapy showed no difference in the risk of recurrent VTE during three months (RR 1.51; 95% CI 0.26, 8.90) and (RR 0.79; 95% CI 0.21; 2.91). The treatment with idraparinux clearly showed a bleeding risk with a pattern dose-response. However, at a dose of 2.5 mg idraparinux, there was no significant difference in the risk of bleeding in patients receiving idrapaparinux in comparison to standard therapy during six months of follow up (RR 0.92, 95% CI 0.69 to 1.22). One study contributed with data for the analysis (n=741 participants) that there was no significant difference in the risk of recurrent VTE during six months follow-up between idrabiotaparinux compared with idraparinux (RR 0.71, 95% CI 0.30 to 1.66). The risk of bleeding was also similar comparing the two interventions (RR 0.71, 95% CI 0.49 to 1.04). Authors' conclusions: The pentasaccharides (fondaparinux, the dose of 2.5 mg idraparinux and equimolar dose of 3.0 mg idrabiotaparinux) may be an effective and safe alternative to conventional anticoagulation treatment for acute DVT.

BACKGROUND: Though direct oral anticoagulants (DOACs) have become a standard of care in the treatment of acute deep vein thrombosis (DVT), it is our observation that physicians tend to initiate heparin or low-molecular-weight heparin, hereafter called “heparin”, for the treatment of extensive DVT or phlegmasia cerulea dolens (PCD). This might be due to a perception that heparin might relieve DVT-related symptoms more quickly than DOACs. Whether these assumptions are true has not been evaluated. METHODS: We conducted a survey of thrombosis specialists in North America to explore the practical management of anticoagulant therapy in patients with extensive DVT, and the underlying reasons for the selection of heparin over DOACs. A cross-sectional, web-based survey was distributed to thrombosis specialists who are members of four thrombosis societies. RESULTS: Eighty-nine respondents provided consent. Most respondents selected DOACs over heparin in a case scenario representing mild DVT-related symptoms and limited thrombus involvement (81% vs. 19%). Most respondents selected heparin over DOACs in a case scenario representing early stage PCD (84% vs.16.3%) or a patient with high bodyweight (72% vs. 28%). In a case scenario representing extensive DVT, 57.4% of the respondents selected heparin, whereas, 42.6% selected DOACs. In the respondents who selected heparin over DOACs, the major reason was that heparin might relieve DVT-related symptoms more quickly because of its anti-inflammatory effects. DISCUSSION: Severity of DVT-related symptoms, thrombus extent, and bodyweight play a role in the selection of anticoagulant therapy. Despite a lack of evidence to support the hypothesis with respect to which anticoagulant is superior, most thrombosis specialists selected heparin over DOACs in patients with severe DVT-related symptoms and extensive thrombus involvement. Observation of variations in the selection of anticoagulant therapy for the treatment of extensive DVT also indicates that clinical trials in this patient population are needed. / Thesis / Master of Science (MSc)

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

This thesis describes the successful development and initial evaluation of a proof-of-concept wireless monitoring system for improving the effectiveness and safety of pneumatic compression therapy to help prevent deep vein thrombosis (DVT). In the development, an important objective was to make feasible the practical and commercial deployment of such improved therapy systems in future, by focusing on a cost-effective design and implementation. Over the years, pneumatic compression has been shown to be an effective solution for the prevention of DVT. However, different problems and complications related to the use of commercial pneumatic compression de-vices that typically include automatic pressure controllers and pneumatic compression sleeves have been reported. For example, one study reported a high percentage of improperly applied or nonfunctional pneumatic compression devices in routine usage. Technical problems, non-compliance, and human error were identified as the causes behind the failed therapies. Also, it was reported that dedicated in-service instruction did not improve the proper use of the pneumatic compression controllers and sleeves. In another study, significant unanticipated variations between expected and delivered pneumatic compression therapy were reported: expected therapy delivered only an average of 77.8% of the time during the therapy, and much of the time key values related to the outcome of the therapy were found to have variations great than 10%. Specific hazards have also been reported. For example, one patient developed acute compartment syndrome after wearing a pair of pneumatic compression sleeves with faulty pressure release valves. In another case, epidural analgesia masked a malfunction resulting from a reversed connection between four-way plastic tubing of the sleeves and the controller, exposing a patient to a hazardous pressure of around 300mmHg,blocking all blood flow for a prolonged period of time. Newer models of pneumatic compression sleeves and controllers from various manufacturers claim to improve therapy by, for example, increasing the peak blood flow velocity. However, there is no evidence in the published literature to support such claims. A published review of the literature from1970-2002 reached the conclusion that the most important factors in im-proving therapy with pneumatic compression devices, particularly during and after surgery, were the degree of conformance of delivered therapy to the prescribed therapy, patient compliance, and the appropriateness of the site of compression. The inability to monitor delivered therapy and patient compliance remains a problem in efforts to improve pneumatic compression therapy. The above-described problems were addressed in the successful development of the innovative prototype described in this thesis. This wireless monitoring system should improve the effectiveness and safety of pneumatic compression therapy. Also, innovative aspects of the system design allow for cost-effective integration into existing commercial controllers and sleeves. For example, an innovative and potentially patentable usage and reprocess indicator was developed for pneumatic compression sleeves to significantly improve their safety and to reduce their cost of use per patient.

This thesis describes the successful development and initial evaluation of a proof-of-concept wireless monitoring system for improving the effectiveness and safety of pneumatic compression therapy to help prevent deep vein thrombosis (DVT). In the development, an important objective was to make feasible the practical and commercial deployment of such improved therapy systems in future, by focusing on a cost-effective design and implementation. Over the years, pneumatic compression has been shown to be an effective solution for the prevention of DVT. However, different problems and complications related to the use of commercial pneumatic compression de-vices that typically include automatic pressure controllers and pneumatic compression sleeves have been reported. For example, one study reported a high percentage of improperly applied or nonfunctional pneumatic compression devices in routine usage. Technical problems, non-compliance, and human error were identified as the causes behind the failed therapies. Also, it was reported that dedicated in-service instruction did not improve the proper use of the pneumatic compression controllers and sleeves. In another study, significant unanticipated variations between expected and delivered pneumatic compression therapy were reported: expected therapy delivered only an average of 77.8% of the time during the therapy, and much of the time key values related to the outcome of the therapy were found to have variations great than 10%. Specific hazards have also been reported. For example, one patient developed acute compartment syndrome after wearing a pair of pneumatic compression sleeves with faulty pressure release valves. In another case, epidural analgesia masked a malfunction resulting from a reversed connection between four-way plastic tubing of the sleeves and the controller, exposing a patient to a hazardous pressure of around 300mmHg,blocking all blood flow for a prolonged period of time. Newer models of pneumatic compression sleeves and controllers from various manufacturers claim to improve therapy by, for example, increasing the peak blood flow velocity. However, there is no evidence in the published literature to support such claims. A published review of the literature from1970-2002 reached the conclusion that the most important factors in im-proving therapy with pneumatic compression devices, particularly during and after surgery, were the degree of conformance of delivered therapy to the prescribed therapy, patient compliance, and the appropriateness of the site of compression. The inability to monitor delivered therapy and patient compliance remains a problem in efforts to improve pneumatic compression therapy. The above-described problems were addressed in the successful development of the innovative prototype described in this thesis. This wireless monitoring system should improve the effectiveness and safety of pneumatic compression therapy. Also, innovative aspects of the system design allow for cost-effective integration into existing commercial controllers and sleeves. For example, an innovative and potentially patentable usage and reprocess indicator was developed for pneumatic compression sleeves to significantly improve their safety and to reduce their cost of use per patient.

Made available in DSpace on 2014-06-11T19:32:44Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-05-24Bitstream added on 2014-06-13T21:04:42Z : No. of bitstreams: 1 matida_ck_dr_botfm.pdf: 889840 bytes, checksum: e2fb39fd0a8e59a674752ea187a4c74b (MD5) / 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 / 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

Orientador: Joyce Maria Annichino-Bizzacchi / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-23T22:14:32Z (GMT). No. of bitstreams: 1 Prado_LucasBessa_M.pdf: 3008068 bytes, checksum: 3758f8a952dfe1f77c113246b8e2a0bd (MD5) Previous issue date: 2013 / Resumo: A Trombose Venosa Profunda (TVP) é definida como uma oclusão parcial ou total da circulação venosa profunda. A heparina é um fármaco com ação anticoagulante e antitrombótica utilizado desde 1930. O custo, a via de administração (endovenosa ou subcutânea) e as doses repetidas são algumas das limitações do seu uso. Assim, o desenvolvimento de um produto que possa ser administrado por via subcutânea ou oral em um menor número de aplicações, torna-se um importante desafio e de grande aplicabilidade clínica. Sistemas de liberação sustentada permitem que o fármaco seja encapsulado e liberado gradativamente. Este estudo constituiu na preparação, caracterização e avaliação in vivo de nanopartículas de poli (?-caprolactona) (PCL) e quitosana como carreadores de heparina de baixo peso molecular (enoxaparina). As nanopartículas foram preparadas pelo método de dupla emulsão água/óleo/água e evaporação do solvente. A caracterização das nanopartículas foi realizada por microscopia eletrônica de varredura (MEV), onde foram observadas partículas esféricas e homogêneas. O diâmetro médio das nanopartículas foi de 512,8 ± 13,8 nm e o potencial zeta foi de +30,9 ± 1,3 mV. A eficiência de encapsulamento, analisada pelo método Azure II foi de 99,04 ± 0,001 %. A atividade anticoagulante in vivo da enoxaparina encapsulada foi avaliada pela atividade anti-Xa plasmática, através de método colorimétrico. Quando a enoxaparina livre foi administrada por via subcutânea observou-se um pico de atividade (0,5 UI/mL) em 1 hora, com um decréscimo gradual até 6 horas. A atividade anticoagulante da enoxaparina encapsulada em nanopartículas manteve-se por até 14 horas, quando foi administrada por via subcutânea, sugerindo que as nanopartículas podem permitir que a enoxaparina seja liberada de forma gradual, podendo ser uma vantagem na prática clínica. Após a administração das nanopartículas por via oral não se observou nenhuma atividade em até 14 horas, sugerindo que as nanopartículas não tenham sido absorvidas ou a enoxaparina tenha sido degradada no trato gastrointestinal. Para avaliação do efeito antitrombótico foi padronizado o modelo de TVP por estase e hipercoagulabilidade em ratos. Após administração subcutânea, houve uma significativa diminuição do tamanho do trombo formado tanto com o emprego de enoxaparina livre (p= 0,002) como após encapsulamento em nanopartículas (p= 0,0411) em comparação ao grupo controle. Quando foram administradas nanopartículas por via oral, os resultados mostraram que não houve diferença estatística em comparação ao grupo controle (p= 0,9476) e a um grupo de nanopartículas vazias (p= 0,9372). Em resumo, o método de dupla emulsão a/o/a mostrou-se eficiente para o encapsulamento de enoxaparina, proporcionando a obtenção de nanopartículas esféricas e com alta eficiência de encapsulamento. Pelos estudos in vivo, a enoxaparina encapsulada mostrou uma atividade anticoagulante com liberação sustentada, por um período superior ao obtido com a enoxaparina livre, com excelente efeito antitrombótico quando administrada por via subcutânea. Contudo, não se observou nenhum efeito anticoagulante ou antitrombótico quando as nanopartículas foram administradas por via oral. Novos experimentos com quitosanas de diferentes massas molares serão necessários na tentativa de possibilitar a absorção oral dessas nanopartículas / Abstract: Deep vein thrombosis (DVT) is defined as partial or total occlusion of the deep venous circulation. Heparin is a drug with anticoagulant and antithrombotic action used since 1930. The costs, administration vias (intravenous or subcutaneous) and the repeated doses are some limitations of its use. Thus, the development of a product that could be administered subcutaneous or orally in a smaller number of applications becomes a major challenge with huge clinical applicability. Sustained release systems allow the medication to be gradually encapsulated and released. This study was based on the preparation, characterization and in vivo evaluation of nanoparticles of poly (?-caprolactone) (PCL) and chitosan as carriers of low molecular weight heparin (enoxaparin). The nanoparticles were prepared by the double emulsion water/oil/water method and solvent evaporation. The nanoparticles characterization was performed by scanning electron microscopy (SEM), in which were observed spherical and homogeneous particles. The average diameter of the nanoparticles was 512.8 ± 13.8 nm and the zeta potential was +30.9 ± 1.3 mV. The encapsulation efficiency, analyzed by Azure II method, was 99.04 ± 0.001%. The in vivo anticoagulant activity of the encapsulated enoxaparin was evaluated by plasmatic anti-Xa activity performed by colorimetric method. When the free enoxaparin was subcutaneously administered a peak of activity was observed (0.5 IU/mL) in 1 hour with a gradual decrease until 6 hours. The anticoagulant activity of the nanoparticles encapsulated enoxaparin was kept until 14 hours when it was administered subcutaneously, suggesting that nanoparticles may allow the enoxaparin release by a gradual way, what could be an advantage on clinical practice. After the oral administration of the nanoparticles, any activity could be observed in until 14 hours, suggesting that or the nanoparticles might be not absorbed or the enoxaparin might be degraded on the gastrointestinal tract. In order to evaluate its antithrombotic effect, it was standardized a model of DVT by stasis and hypercoagulability in rats. After subcutaneous administration, there was a significative reduction on the thrombus size both with free enoxaparin (p= 0.002) and after encapsulation (p= 0.0411) in comparison with control group. When nanoparticles were administered orally, the results showed no statistical difference compared to the control group (p = 0.9476) and to a group of empty nanoparticles (p = 0.9372). In summary, the double emulsion method w/o/w was efficient for the enoxaparin encapsulation, providing the obtainment of spherical nanoparticles with high encapsulation efficiency. For in vivo studies, the encapsulated enoxaparin showed a sustained release anticoagulant activity for a higher period than that obtained with free enoxaparin, with an excellent antithrombotic effect when administered subcutaneously. However, there was no anticoagulant or antithrombotic effect when the nanoparticles were administered orally. Further experiments with chitosans of different molecular weights will be needed on the attempt to allow the oral absorption of these nanoparticles / Mestrado / Medicina Experimental / Mestre em Fisiopatologia Médica

This thesis describes the successful development and initial evaluation of a proof-of-concept wireless monitoring system for improving the effectiveness and safety of pneumatic compression therapy to help prevent deep vein thrombosis (DVT). In the development, an important objective was to make feasible the practical and commercial deployment of such improved therapy systems in future, by focusing on a cost-effective design and implementation. Over the years, pneumatic compression has been shown to be an effective solution for the prevention of DVT. However, different problems and complications related to the use of commercial pneumatic compression de-vices that typically include automatic pressure controllers and pneumatic compression sleeves have been reported. For example, one study reported a high percentage of improperly applied or nonfunctional pneumatic compression devices in routine usage. Technical problems, non-compliance, and human error were identified as the causes behind the failed therapies. Also, it was reported that dedicated in-service instruction did not improve the proper use of the pneumatic compression controllers and sleeves. In another study, significant unanticipated variations between expected and delivered pneumatic compression therapy were reported: expected therapy delivered only an average of 77.8% of the time during the therapy, and much of the time key values related to the outcome of the therapy were found to have variations great than 10%. Specific hazards have also been reported. For example, one patient developed acute compartment syndrome after wearing a pair of pneumatic compression sleeves with faulty pressure release valves. In another case, epidural analgesia masked a malfunction resulting from a reversed connection between four-way plastic tubing of the sleeves and the controller, exposing a patient to a hazardous pressure of around 300mmHg,blocking all blood flow for a prolonged period of time. Newer models of pneumatic compression sleeves and controllers from various manufacturers claim to improve therapy by, for example, increasing the peak blood flow velocity. However, there is no evidence in the published literature to support such claims. A published review of the literature from1970-2002 reached the conclusion that the most important factors in im-proving therapy with pneumatic compression devices, particularly during and after surgery, were the degree of conformance of delivered therapy to the prescribed therapy, patient compliance, and the appropriateness of the site of compression. The inability to monitor delivered therapy and patient compliance remains a problem in efforts to improve pneumatic compression therapy. The above-described problems were addressed in the successful development of the innovative prototype described in this thesis. This wireless monitoring system should improve the effectiveness and safety of pneumatic compression therapy. Also, innovative aspects of the system design allow for cost-effective integration into existing commercial controllers and sleeves. For example, an innovative and potentially patentable usage and reprocess indicator was developed for pneumatic compression sleeves to significantly improve their safety and to reduce their cost of use per patient. / Applied Science, Faculty of / Electrical and Computer Engineering, Department of / Graduate

Context: Inferior vena cava (IVC) anomalies have a 0.5% incidence rate and could be associated with other congenital abnormalities. In later stage of the disease, trophic ulcers with or without deep vein thrombosis (DVT) is consistent finding.Case Report: A 29-year-old male patient presented with recurrent lower extremity ulcers. Further workup revealed an absent infrahepatic inferior vena cava, prominently dilated azygos and hemiazygos veins with enlarged retroperitoneal collaterals without DVT.Conclusion: IVC anomaly should be suspected in a young patient presenting with unexplained venous thrombosis and recurrent ulcers of a lower extremity. IVC anomaly would inherently lead to blood flow stasis and endothelial injury. Thus per Virchow's triad, other risk factors for hypercoagulability such as physical inactivity, smoking tobacco, oral contraceptive pills should be avoided and when hereditary thrombophilias or other irreversible risk factors are present, lifelong anticoagulation should be considered.

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)