Thesis (Ph. D.)--University of Washington, 2008. / Vita. Includes bibliographical references (leaves 298-310).

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Oxidative stress is characterized by an imbalance between the production of free radicals, particularly reactive oxygen species (ROS), and the defense capacity of the organism against these species, leading to a progressive oxidative damage. Proteins are considered to be the primary target for oxidative damage, since they are major components of biological systems and may neutralize 50 to 75% of free radicals. Recently, a new class of compounds formed as a result of oxidative stress was described, referred to as advanced oxidation protein products (AOPP). The accumulation of AOPP was first described in patients with chronic renal failure on hemodialysis and subsequently it was found that this marker is involved in a number of pathological conditions such as diabetes, atherosclerosis, obesity, and acute renal failure. Previous studies have identified AOPP as a new marker of oxidative damage to proteins and a new class of inflammatory mediators promoting effects both at the cellular level, as at systemic level. In this context, different biological structures, including plasma proteins such as albumin and fibrinogen are susceptible to oxidation by ROS. It is known that albumin is the major target of oxidative stress in plasma of uremic patients, however, it has been demonstrated that the fibrinogen is also capable of undergoing oxidative modification. Whereas the oxidative and inflammatory processes are involved in the pathophysiology of a number of clinical conditions and AOPP is a biomarker which can reflect these changes, it is extremely important to evaluate the susceptibility of other proteins to the formation of these products, in addition to albumin. Thus, the aim of this study was to investigate the formation of AOPP from the fibrinogen in an in vitro model and evaluate structural and functional changes in the molecule of this pro-coagulant protein. Thus, to promote in vitro AOPP, fibrinogen was exposed to hypochlorous acid (HOCl) at various concentrations (1, 2 and 4 mM). After checking the effectiveness of fibrinogen to produce AOPP, was demonstrated that the formation of these products promotes functional alterations in fibrinogen, causing changes in their structural domains and increasing their procoagulant activity. Therefore, the fibrinogen can be considered a source of AOPP formation and deterioration caused by this process in the molecule of this protein, may be related to several pathological conditions involving coagulation system and contribute especially in the development of thrombotic processes. / O estresse oxidativo é caracterizado pelo desequilíbrio entre a produção de radicais livres, em particular espécies reativas de oxigênio (EROs), e a capacidade de defesa do organismo contra essas espécies, levando a um progressivo dano oxidativo. As proteínas são consideradas o principal alvo para o dano oxidativo, uma vez que estas são as maiores componentes dos sistemas biológicos e podem neutralizar 50 a 75% dos radicais livres. Recentemente, foi descrita uma nova classe de compostos formados em consequência do estresse oxidativo, designada como produtos proteicos de oxidação avançada (AOPP). O acúmulo de AOPP foi primeiramente descrito em pacientes com insuficiência renal crônica submetidos à hemodiálise e, posteriormente, verificou-se que este marcador está envolvido em uma série de condições patológicas, como diabetes, aterosclerose, obesidade e insuficiência renal aguda. Estudos prévios têm identificado AOPP como um novo marcador de dano oxidativo a proteínas e uma nova classe de mediadores inflamatórios, promovendo efeitos tanto a nível celular, quanto a nível sistêmico. Neste contexto, diferentes estruturas biológicas, incluindo proteínas plasmáticas como a albumina e o fibrinogênio, são passíveis a oxidação por EROs. Sabe-se que a albumina é o principal alvo do estresse oxidativo no plasma de pacientes urêmicos, no entanto, já foi demonstrado que o fibrinogênio também é passível de sofrer modificações oxidativas. Considerando que os processos inflamatórios e oxidativos estão envolvidos na fisiopatologia de uma série de condições clínicas e que AOPP é um biomarcador que pode refletir essas alterações, é de extrema relevância a avaliação da susceptibilidade de outras proteínas à formação desses produtos, além da albumina. Assim, o principal objetivo deste estudo foi investigar a formação de AOPP a partir do fibrinogênio em um modelo in vitro, bem como avaliar alterações estruturais e funcionais na molécula desta proteína pró-coagulante. Desse modo, para a promoção de AOPP in vitro, o fibrinogênio foi exposto ao ácido hipocloroso (HOCl) em diversas concentrações (1, 2 e 4mM). Após a verificação da efetividade do fibrinogênio em produzir AOPP, foi demonstrado que a formação destes produtos promove alterações funcionais no fibrinogênio, causando modificações em seus domínios estruturais e aumentando sua atividade pró-coagulante. Portanto, o fibrinogênio pode ser considerado uma fonte de formação de AOPP e as alterações provocadas por este processo na molécula desta proteína, podem estar relacionadas a diversas condições patológicas envolvendo o sistema da coagulação e contribuir especialmente, no desenvolvimento de processos trombóticos.

nÃo hà / As doenÃas cardiovasculares, incluindo a cardiopatia isquÃmica aterosclerÃtica, sÃo a princi-pal causa de morte no Brasil. A aterosclerose à doenÃa inflamatÃria crÃnica que se inicia na infÃncia, progride lentamente e se expressa dÃcadas depois. Ela principia por disfunÃÃo do endotÃlio, tem patogÃnese multifatorial e tem, como principais fatores de risco, o sexo mascu-lino, a idade, o tabagismo, a hipercolesterolemia, a hipertensÃo arterial sistÃmica (HAS), o diabetes mellitus (DM) e o antecedente familiar de doenÃa aterosclerÃtica precoce. A elevaÃÃo de vÃrios marcadores bioquÃmicos sinaliza a participaÃÃo da inflamaÃÃo na aterosclerose. O peptÃdeo natriurÃtico tipo B e o fragmento amino-terminal do pro-peptÃdeo natriurÃtico tipo B (NT-proBNP) tambÃm aumentam na aterosclerose coronÃria. Esse trabalho à um estudo ob-servacional, transversal, de uma sÃrie consecutiva de 153 pacientes internados na Enfermaria de Cardiologia do HUWC-UFC, no perÃodo de 01.08.2007 a 31.03.2008, com hipÃtese diag-nÃstica de cardiopatia isquÃmica â angina estÃvel (AE), angina instÃvel (AI) ou infarto agudo do miocÃrdio (IAM) â submetidos à cineangiocoronariografia, comparando-se o grupo porta-dor de obstruÃÃo aterosclerÃtica coronÃria angiogrÃfica (grupo A) com aquele de artÃrias co-ronÃrias angiograficamente normais (grupo B). Os critÃrios de exclusÃo foram revasculariza-ÃÃo miocÃrdica prÃvia â cirÃrgica ou percutÃnea â insuficiÃncia renal dialÃtica aguda ou crÃni-ca, neoplasia maligna, infecÃÃo, doenÃa inflamatÃria aguda ou crÃnica, doenÃa pulmonar, he-pÃtica ou hematolÃgica e cardiopatia valvar, congÃnita ou cardiomiopatia associada. Ambos os grupos foram analisados, de modo semelhante, quanto ao sexo, à idade, à escolaridade, ao Ãndice de massa corporal (IMC), à circunferÃncia abdominal (CA), ao tabagismo, ao DM, à HAS, à histÃria familiar positiva para aterosclerose precoce, ao uso de estatina, à presenÃa de sÃndrome metabÃlica (SM) e à apresentaÃÃo clÃnica como AE, AI ou IAM. Eles tambÃm fo-ram analisados em relaÃÃo ao eletrocardiograma, à radiografia do tÃrax e ao ecocardiograma, quanto à presenÃa ou nÃo de disfunÃÃo sistÃlica; ao colesterol nÃo-HDL, à HDL-colesterol, à relaÃÃo do colesterol total / HDL-colesterol < 5 e do LDL-colesterol / HDL-colesterol < 3,5; à creatinina e o ao fibrinogÃnio, ao nÃmero de leucÃcitos totais e ao de monÃcitos, à proteÃna C reativa ultra-sensÃvel e ao NT-proBNP. A comparaÃÃo dos dois grupos revelou, com signifi-cÃncia estatÃstica, à anÃlise univariada, que os pacientes do grupo A tinham prevalÃncia maior de DM e de disfunÃÃo sistÃlica, NT-proBNP &#8805; 250 pg/ml, fibrinogÃnio acima de 500 mg/dl; mais frequentemente usavam estatina e tinham monÃcitos 501 ou mais por mm3 do que aque-les do grupo B. Curiosamente, o IMC &#8805; 30 e a CA aumentada foram mais prevalentes no gru-po com artÃrias coronÃrias normais. No entanto, pela regressÃo logÃstica multivariada, os fato-res independentes para oclusÃo aterosclerÃtica coronariana angiogrÃfica foram o NT-proBNP &#8805; 250 pg/ml, o DM e o aumento do fibrinogÃnio e dos monÃcitos, mesmo consideradas a creatinina e a disfunÃÃo sistÃlica. Na amostra estudada, o modelo com ajuste de prevalÃncia desses fatores teve sensibilidade de 80,4%, especificidade de 76,9 e 79,7% de acurÃcia para o diagnÃstico de oclusÃo coronariana aterosclerÃtica angiogrÃfica. / Cardiovascular diseases, including ischemic heart disease, are the main causes of death in Brazil. Atherosclerosis is a chronic inflammatory disease that starts in the childhood, progresses slowly and shows up many decades later. It begins as an endothelial dysfunction and has as its main risk factors the male sex, age, smoking, hypercholesterolemia, arterial hypertension, diabetes mellitus and a background of early family atherosclerotic disease. The rise of many biochemical markers in the plasma signals the presence of inflammation in the atherosclerosis. The brain natriuretic peptide and the amino-terminal pro-B-type natriuretic peptide (NT-proBNP) also increase in coronary atherosclerosis. This is a cross-sectional and observational study of 153 in-patients at the Cardiology Ward of HUWC-UFC from 08.01.2007 to 03.31.2008 with the diagnostic hypothesis of Ischemic Heart Disease, i.e., stable angina, unstable angina or acute myocardial infarction. All of them underwent heart catheterization and coronary angiography. They were classified respectively as group A or B in accordance with the presence or not of angiographic atherosclerotic coronary occlusion. Patients were not included in the analysis if they had been submitted to surgical or percutaneous revascularization; had an acute or chronic dialytic kidney disease; cancer or infection; a lung, hepatic or hematopoietic disease; an acute or chronic inflammatory illness or associated myocardial, valvular or congenital heart disease. The two groups were analyzed in a similar way with regard to gender, age, level of education, body mass index, abdominal circumference, smoking, diabetes mellitus, arterial hypertension, an early atherosclerosis family history, the use of statin, presence of metabolic syndrome and clinical presentation of stable angina, unstable angina or acute myocardial infarction. The HDL-cholesterol, non HDL-cholesterol, a total cholesterol/HDL-cholesterol ratio < 5, a LDL-cholesterol/HDL-cholesterol ratio < 3.5, the creatinine and fibrinogen plasma concentration, the total leukocyte and monocyte count, the high-sensitivity C reactive protein, the NT-proBNP, the electrocardiogram, the chest radiography and the echocardiogram, with regard to the presence or not of systolic dysfunction, were also analyzed. The univariety analysis comparing both groups revealed that group Aâ patients more frequently were diabetics and had systolic dysfunction, NT-proBNP &#8805; 250 pg/ml, fibrinogen higher than 500 mg/dl, more frequent use of statin and 501 or more monocytes/mm3 than patients group B. Curiously, the body mass index &#8805; 30 and abnormal abdominal circumference were more frequently found among patients with angiographic normal coronary arteries. Nevertheless, by multivariety regression logistic analysis the independent factors for angiographic atherosclerotic coronary occlusion were the NT-proBNP &#8805; 250 pg/ml, diabetes mellitus, an increase of monocyte number and of fibrinogen plasma concentration, in spite of creatinine level and presence of systolic dysfunction. The model takes into account these factors has 80.4% sensitivity, 76.9% specificity and 79.7% of accuracy for the diagnostic of angiographic atherosclerotic coronary occlusion.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / O cÃncer de pulmÃo (CP) à uma agressÃo maligna com caracterÃsticas inflamatÃrias e muitas vezes ressecÃveis. A escolha do fibrinogÃnio e albumina deve ao fato de serem marcadores inflamatÃrios e se manifestarem em CP, muitas vezes associado à doenÃa obstrutiva crÃnica. As complicaÃÃes pulmonares ainda sÃo preocupaÃÃes nas ressecÃÃes pulmonares. O estudo avaliou o impacto da reabilitaÃÃo pulmonar nos marcadores inflamatÃrios prÃ-operatÃrios e nas complicaÃÃes pulmonares pÃs-operatÃrias de pacientes com CP. Ensaio clÃnico, controlado com 31 pacientes, com doenÃa obstrutiva de moderado a grave, estadiamento IA a IIIA, aleatorizados em: Grupo A (GA) submetido à RP e o controle Grupo B (GB) a fisioterapia respiratÃria (FR). Avaliados antes e apÃs 4 semanas do protocolo do estudo pela funÃÃo pulmonar, forÃa muscular respiratÃria, capacidade funcional, forÃa muscular de membros superiores (MMSS), capacidade mÃxima e submÃxima de exercÃcio, ansiedade e depressÃo (HADS), qualidade de vida pelo Short-Form36 (SF36), fibrinogÃnio e albumina. ApÃs a cirurgia foram analisadas as complicaÃÃes pulmonares. O GA realizou treinamento aerÃbico, de forÃa muscular perifÃrica e respiratÃria. O GB executou tÃcnicas para expansÃo pulmonar. Os grupos receberam aulas educativas e realizaram os protocolos com tempo equÃnime. O estudo foi aprovado pelo Comità de Ãtica do Hospital de Messejana. No GA houve melhora significativa da CVF passando de 65Â17 para 76Â15% previsto (p=0,003), da PImax de 78Â46 para 104Â42cmH2O (p=0,0003), da PEmax, de 78Â21 para 93Â25cmH2O (p=0,0009), aumento da distÃncia percorrida de 435Â70 para 491Â88m (p<0,0001), da carga mÃxima para MMSS de 1,0 para 2,0kg (p=0,008), da inclinaÃÃo do teste de MMII de 5Â3 para 8Â3% (p<0,0001) e velocidade de 4,9 [3,7-5,5] para 5,2 [4,4-6] (p=0,002), da capacidade submÃxima de MMII de 447Â179 para 718Â220s (p=0,002), da HADS-A de 9,9Â4,9 para 4,9Â2,7 (p<0,0001), do HADS-D de 9,05Â4,08 para 4,9Â2,1 (p<0,0001), da qualidade de vida com Coeficiente FÃsico Sumarizado (CFS) de 37,5Â9,07 para 46,15Â8,7% (p=0,004) e do fibrinogÃnio de 448,3Â129,9 para 321,6Â73,2mg/dl (p=0,0002). A albumina nÃo apresentou nenhum resultado significativo nos grupos (p>0,05). No GB houve aumento significativo da PImax 50Â22 para 70Â35(p=0,004) e reduÃÃo nÃo significante no fibrinogÃnio passando de 490,7Â199,7 para 453,3Â177,2 mg/dl(p=0,3). Nas demais variÃveis o GB nÃo apresentou resultados significantes. Quando comparados entre grupos houve diferenÃa significante nas variÃveis: teste da caminhada de 6min (p=0,0001), forÃa muscular de MMSS (p=0,009), inclinaÃÃo (p=0,0008), endurance (p=0,005), HADS-A (p=0,0002), HADS-D (p=0,04), CFS (p=0,03) e fibrinogÃnio (p=0,04). Dos 31 pacientes, 10 nÃo realizaram cirurgia. Nas complicaÃÃes pulmonares pÃs-cirÃrgicas o GA relacionados a morbidade de menor e maior relevÃncia apresentou menor percentual (p=0,002 e p=0,01 respectivamente), menor tempo de internaÃÃo hospitalar (p=0,004) e dreno torÃcico (p=0,03), percentual menor de fÃstula broncopleural (p=0,009) e menor presenÃa de broncoespasmo (p=0,002) quando comparado com GB. A RP prÃ-operatÃria teve impacto na diminuiÃÃo dos nÃveis sÃricos de fibrinogÃnio, melhora dos parÃmetros clÃnicos funcionais, qualidade de vida, ansiedade e depressÃo e reduziu o percentual de complicaÃÃes pulmonares no pÃs-operatÃrio. Na ausÃncia de RP a FR pode ser uma estratÃgia importante no prÃ-operatÃrio. / O cÃncer de pulmÃo (CP) à uma agressÃo maligna com caracterÃsticas inflamatÃrias e muitas vezes ressecÃveis. A escolha do fibrinogÃnio e albumina deve ao fato de serem marcadores inflamatÃrios e se manifestarem em CP, muitas vezes associado à doenÃa obstrutiva crÃnica. As complicaÃÃes pulmonares ainda sÃo preocupaÃÃes nas ressecÃÃes pulmonares. O estudo avaliou o impacto da reabilitaÃÃo pulmonar nos marcadores inflamatÃrios prÃ-operatÃrios e nas complicaÃÃes pulmonares pÃs-operatÃrias de pacientes com CP. Ensaio clÃnico, controlado com 31 pacientes, com doenÃa obstrutiva de moderado a grave, estadiamento IA a IIIA, aleatorizados em: Grupo A (GA) submetido à RP e o controle Grupo B (GB) a fisioterapia respiratÃria (FR). Avaliados antes e apÃs 4 semanas do protocolo do estudo pela funÃÃo pulmonar, forÃa muscular respiratÃria, capacidade funcional, forÃa muscular de membros superiores (MMSS), capacidade mÃxima e submÃxima de exercÃcio, ansiedade e depressÃo (HADS), qualidade de vida pelo Short-Form36 (SF36), fibrinogÃnio e albumina. ApÃs a cirurgia foram analisadas as complicaÃÃes pulmonares. O GA realizou treinamento aerÃbico, de forÃa muscular perifÃrica e respiratÃria. O GB executou tÃcnicas para expansÃo pulmonar. Os grupos receberam aulas educativas e realizaram os protocolos com tempo equÃnime. O estudo foi aprovado pelo Comità de Ãtica do Hospital de Messejana. No GA houve melhora significativa da CVF passando de 65Â17 para 76Â15% previsto (p=0,003), da PImax de 78Â46 para 104Â42cmH2O (p=0,0003), da PEmax, de 78Â21 para 93Â25cmH2O (p=0,0009), aumento da distÃncia percorrida de 435Â70 para 491Â88m (p<0,0001), da carga mÃxima para MMSS de 1,0 para 2,0kg (p=0,008), da inclinaÃÃo do teste de MMII de 5Â3 para 8Â3% (p<0,0001) e velocidade de 4,9 [3,7-5,5] para 5,2 [4,4-6] (p=0,002), da capacidade submÃxima de MMII de 447Â179 para 718Â220s (p=0,002), da HADS-A de 9,9Â4,9 para 4,9Â2,7 (p<0,0001), do HADS-D de 9,05Â4,08 para 4,9Â2,1 (p<0,0001), da qualidade de vida com Coeficiente FÃsico Sumarizado (CFS) de 37,5Â9,07 para 46,15Â8,7% (p=0,004) e do fibrinogÃnio de 448,3Â129,9 para 321,6Â73,2mg/dl (p=0,0002). A albumina nÃo apresentou nenhum resultado significativo nos grupos (p>0,05). No GB houve aumento significativo da PImax 50Â22 para 70Â35(p=0,004) e reduÃÃo nÃo significante no fibrinogÃnio passando de 490,7Â199,7 para 453,3Â177,2 mg/dl(p=0,3). Nas demais variÃveis o GB nÃo apresentou resultados significantes. Quando comparados entre grupos houve diferenÃa significante nas variÃveis: teste da caminhada de 6min (p=0,0001), forÃa muscular de MMSS (p=0,009), inclinaÃÃo (p=0,0008), endurance (p=0,005), HADS-A (p=0,0002), HADS-D (p=0,04), CFS (p=0,03) e fibrinogÃnio (p=0,04). Dos 31 pacientes, 10 nÃo realizaram cirurgia. Nas complicaÃÃes pulmonares pÃs-cirÃrgicas o GA relacionados a morbidade de menor e maior relevÃncia apresentou menor percentual (p=0,002 e p=0,01 respectivamente), menor tempo de internaÃÃo hospitalar (p=0,004) e dreno torÃcico (p=0,03), percentual menor de fÃstula broncopleural (p=0,009) e menor presenÃa de broncoespasmo (p=0,002) quando comparado com GB. A RP prÃ-operatÃria teve impacto na diminuiÃÃo dos nÃveis sÃricos de fibrinogÃnio, melhora dos parÃmetros clÃnicos funcionais, qualidade de vida, ansiedade e depressÃo e reduziu o percentual de complicaÃÃes pulmonares no pÃs-operatÃrio. Na ausÃncia de RP a FR pode ser uma estratÃgia importante no prÃ-operatÃrio. / O cÃncer de pulmÃo (CP) à uma agressÃo maligna com caracterÃsticas inflamatÃrias e muitas vezes ressecÃveis. A escolha do fibrinogÃnio e albumina deve ao fato de serem marcadores inflamatÃrios e se manifestarem em CP, muitas vezes associado à doenÃa obstrutiva crÃnica. As complicaÃÃes pulmonares ainda sÃo preocupaÃÃes nas ressecÃÃes pulmonares. O estudo avaliou o impacto da reabilitaÃÃo pulmonar nos marcadores inflamatÃrios prÃ-operatÃrios e nas complicaÃÃes pulmonares pÃs-operatÃrias de pacientes com CP. Ensaio clÃnico, controlado com 31 pacientes, com doenÃa obstrutiva de moderado a grave, estadiamento IA a IIIA, aleatorizados em: Grupo A (GA) submetido à RP e o controle Grupo B (GB) a fisioterapia respiratÃria (FR). Avaliados antes e apÃs 4 semanas do protocolo do estudo pela funÃÃo pulmonar, forÃa muscular respiratÃria, capacidade funcional, forÃa muscular de membros superiores (MMSS), capacidade mÃxima e submÃxima de exercÃcio, ansiedade e depressÃo (HADS), qualidade de vida pelo Short-Form36 (SF36), fibrinogÃnio e albumina. ApÃs a cirurgia foram analisadas as complicaÃÃes pulmonares. O GA realizou treinamento aerÃbico, de forÃa muscular perifÃrica e respiratÃria. O GB executou tÃcnicas para expansÃo pulmonar. Os grupos receberam aulas educativas e realizaram os protocolos com tempo equÃnime. O estudo foi aprovado pelo Comità de Ãtica do Hospital de Messejana. No GA houve melhora significativa da CVF passando de 65Â17 para 76Â15% previsto (p=0,003), da PImax de 78Â46 para 104Â42cmH2O (p=0,0003), da PEmax, de 78Â21 para 93Â25cmH2O (p=0,0009), aumento da distÃncia percorrida de 435Â70 para 491Â88m (p<0,0001), da carga mÃxima para MMSS de 1,0 para 2,0kg (p=0,008), da inclinaÃÃo do teste de MMII de 5Â3 para 8Â3% (p<0,0001) e velocidade de 4,9 [3,7-5,5] para 5,2 [4,4-6] (p=0,002), da capacidade submÃxima de MMII de 447Â179 para 718Â220s (p=0,002), da HADS-A de 9,9Â4,9 para 4,9Â2,7 (p<0,0001), do HADS-D de 9,05Â4,08 para 4,9Â2,1 (p<0,0001), da qualidade de vida com Coeficiente FÃsico Sumarizado (CFS) de 37,5Â9,07 para 46,15Â8,7% (p=0,004) e do fibrinogÃnio de 448,3Â129,9 para 321,6Â73,2mg/dl (p=0,0002). A albumina nÃo apresentou nenhum resultado significativo nos grupos (p>0,05). No GB houve aumento significativo da PImax 50Â22 para 70Â35(p=0,004) e reduÃÃo nÃo significante no fibrinogÃnio passando de 490,7Â199,7 para 453,3Â177,2 mg/dl(p=0,3). Nas demais variÃveis o GB nÃo apresentou resultados significantes. Quando comparados entre grupos houve diferenÃa significante nas variÃveis: teste da caminhada de 6min (p=0,0001), forÃa muscular de MMSS (p=0,009), inclinaÃÃo (p=0,0008), endurance (p=0,005), HADS-A (p=0,0002), HADS-D (p=0,04), CFS (p=0,03) e fibrinogÃnio (p=0,04). Dos 31 pacientes, 10 nÃo realizaram cirurgia. Nas complicaÃÃes pulmonares pÃs-cirÃrgicas o GA relacionados a morbidade de menor e maior relevÃncia apresentou menor percentual (p=0,002 e p=0,01 respectivamente), menor tempo de internaÃÃo hospitalar (p=0,004) e dreno torÃcico (p=0,03), percentual menor de fÃstula broncopleural (p=0,009) e menor presenÃa de broncoespasmo (p=0,002) quando comparado com GB. A RP prÃ-operatÃria teve impacto na diminuiÃÃo dos nÃveis sÃricos de fibrinogÃnio, melhora dos parÃmetros clÃnicos funcionais, qualidade de vida, ansiedade e depressÃo e reduziu o percentual de complicaÃÃes pulmonares no pÃs-operatÃrio. Na ausÃncia de RP a FR pode ser uma estratÃgia importante no prÃ-operatÃrio. / Lung cancer (LC) is a malignant aggression which can be also surgically treated characterized by inflammation and higher mortality rates. Pulmonary complications are still concerning. The choice of studying fibrinogen and albumin is due to the fact that they are active inflammatory markers in LC often associated with chronic obstructive pulmonary disease. Pulmonary complications subsequent to lung resection are still worrying. This study evaluated the impact of Pulmonary Rehabilitation (PR) on preoperative inflammatory markers and postoperative pulmonary complications of LC patients. Controlled clinical trial with 31 patients with moderate to severe obstructive disease, stages IA to IIIA, randomized into Group A (GA) undergone PR and the control group - Group B (GB) undergone respiratory therapy (RT). Pulmonary function, respiratory muscle strength, functional capacity, upper limbs muscle strength, maximum and submaximal exercise capacity, Hospital anxiety and depression scale (HADS), quality of life through Short-form36 (SF36), fibrinogen and albumin were evaluated before and after a 4 weeks of the survey protocols. After surgery pulmonary complications were analyzed. GA performed aerobic physical training, peripheral and respiratory muscle strength training. GB performed lung expansion techniques. Both groups received educational classes and performed the protocols in similar time. The study was approved by the institutionâs ethic committee. There was in GA significant improvements in FVC from 65Â17 to 76 15% of its predicted (p=0.003 ), in maximal inspiratory pressure (MIP) from 78Â46 to 104 42cmH2O (p=0.0003 ), in maximal expiratory pressure (MEP) from 78Â21 to 93 25cmH2O (p=0.0009 ); in walked distance from 435Â70 to 491Â88 m (p<0.0001 ), upper limb maximum load from 1.0 to 2.0 kg (p=0.008 ), in treadmill inclination from 5Â3 to 8 3% (p<0.0001 ) and speed from 4.9 [3.7 -5.5] to 5.2 [4.4 -6] (p=0.002 ), submaximal exercise capacity from 447Â179 to 718 220s (p=0.002 ), in anxiety from 9.9 Â4.9 to 4.9 Â2.7 (p<0.0001 ), and depression from 9.05 Â4.08 to 4.9 Â2.1 (p<0.0001 ), in quality of life with Physical Component Summary (PCS) from 37.5 Â9.07 to 46.15  8.7 % (p=0.004 ) and fibrinogen to 448.3 Â129.9 to 321.6  73.2 mg/dl (p=0.0002 ). Albumin has not showed significant result in both groups. In GB there was significant increase in MIP 50Â22 to 70 35 (p=0.004) and reduction in fibrinogen from 490.7  199.7 to 453.3  177.2 mg/dl (p=0.3). Other variables GB did not show any significant results. When comparing results between groups there was significant difference in the walked distance (p=0,0001), in upper limb strength (p=0,009), in inclination (p=0,0008), in endurance (p=0,005), in anxiety (p=0,0002), in depression (p=0,04), in PCS (p=0,03) and fibrinogen (p=0,04). Out of 31 patients, 10 were not operated. In postoperative pulmonary complications, GA show less greater and lesser relevance morbidity (p=0,002 and p=0,01 respectively) shorter length of hospital stay (p=0,004), less chest tube days(p=0,03), lower percentage of bronchial fistula (p=0,009) and less bronchospasm (p=0,002). When compared to GB. PR had impact on the reduction of serum fibrinogen, on clinical improvements, health related quality of life, anxiety and depression, and also reduced postoperative pulmonary complications. In the absence of PR programs, RT can be an important preoperative strategy. / Lung cancer (LC) is a malignant aggression which can be also surgically treated characterized by inflammation and higher mortality rates. Pulmonary complications are still concerning. The choice of studying fibrinogen and albumin is due to the fact that they are active inflammatory markers in LC often associated with chronic obstructive pulmonary disease. Pulmonary complications subsequent to lung resection are still worrying. This study evaluated the impact of Pulmonary Rehabilitation (PR) on preoperative inflammatory markers and postoperative pulmonary complications of LC patients. Controlled clinical trial with 31 patients with moderate to severe obstructive disease, stages IA to IIIA, randomized into Group A (GA) undergone PR and the control group - Group B (GB) undergone respiratory therapy (RT). Pulmonary function, respiratory muscle strength, functional capacity, upper limbs muscle strength, maximum and submaximal exercise capacity, Hospital anxiety and depression scale (HADS), quality of life through Short-form36 (SF36), fibrinogen and albumin were evaluated before and after a 4 weeks of the survey protocols. After surgery pulmonary complications were analyzed. GA performed aerobic physical training, peripheral and respiratory muscle strength training. GB performed lung expansion techniques. Both groups received educational classes and performed the protocols in similar time. The study was approved by the institutionâs ethic committee. There was in GA significant improvements in FVC from 65Â17 to 76 15% of its predicted (p=0.003 ), in maximal inspiratory pressure (MIP) from 78Â46 to 104 42cmH2O (p=0.0003 ), in maximal expiratory pressure (MEP) from 78Â21 to 93 25cmH2O (p=0.0009 ); in walked distance from 435Â70 to 491Â88 m (p<0.0001 ), upper limb maximum load from 1.0 to 2.0 kg (p=0.008 ), in treadmill inclination from 5Â3 to 8 3% (p<0.0001 ) and speed from 4.9 [3.7 -5.5] to 5.2 [4.4 -6] (p=0.002 ), submaximal exercise capacity from 447Â179 to 718 220s (p=0.002 ), in anxiety from 9.9 Â4.9 to 4.9 Â2.7 (p<0.0001 ), and depression from 9.05 Â4.08 to 4.9 Â2.1 (p<0.0001 ), in quality of life with Physical Component Summary (PCS) from 37.5 Â9.07 to 46.15  8.7 % (p=0.004 ) and fibrinogen to 448.3 Â129.9 to 321.6  73.2 mg/dl (p=0.0002 ). Albumin has not showed significant result in both groups. In GB there was significant increase in MIP 50Â22 to 70 35 (p=0.004) and reduction in fibrinogen from 490.7  199.7 to 453.3  177.2 mg/dl (p=0.3). Other variables GB did not show any significant results. When comparing results between groups there was significant difference in the walked distance (p=0,0001), in upper limb strength (p=0,009), in inclination (p=0,0008), in endurance (p=0,005), in anxiety (p=0,0002), in depression (p=0,04), in PCS (p=0,03) and fibrinogen (p=0,04). Out of 31 patients, 10 were not operated. In postoperative pulmonary complications, GA show less greater and lesser relevance morbidity (p=0,002 and p=0,01 respectively) shorter length of hospital stay (p=0,004), less chest tube days(p=0,03), lower percentage of bronchial fistula (p=0,009) and less bronchospasm (p=0,002). When compared to GB. PR had impact on the reduction of serum fibrinogen, on clinical improvements, health related quality of life, anxiety and depression, and also reduced postoperative pulmonary complications. In the absence of PR programs, RT can be an important preoperative strategy. / Lung cancer (LC) is a malignant aggression which can be also surgically treated characterized by inflammation and higher mortality rates. Pulmonary complications are still concerning. The choice of studying fibrinogen and albumin is due to the fact that they are active inflammatory markers in LC often associated with chronic obstructive pulmonary disease. Pulmonary complications subsequent to lung resection are still worrying. This study evaluated the impact of Pulmonary Rehabilitation (PR) on preoperative inflammatory markers and postoperative pulmonary complications of LC patients. Controlled clinical trial with 31 patients with moderate to severe obstructive disease, stages IA to IIIA, randomized into Group A (GA) undergone PR and the control group - Group B (GB) undergone respiratory therapy (RT). Pulmonary function, respiratory muscle strength, functional capacity, upper limbs muscle strength, maximum and submaximal exercise capacity, Hospital anxiety and depression scale (HADS), quality of life through Short-form36 (SF36), fibrinogen and albumin were evaluated before and after a 4 weeks of the survey protocols. After surgery pulmonary complications were analyzed. GA performed aerobic physical training, peripheral and respiratory muscle strength training. GB performed lung expansion techniques. Both groups received educational classes and performed the protocols in similar time. The study was approved by the institutionâs ethic committee. There was in GA significant improvements in FVC from 65Â17 to 76 15% of its predicted (p=0.003 ), in maximal inspiratory pressure (MIP) from 78Â46 to 104 42cmH2O (p=0.0003 ), in maximal expiratory pressure (MEP) from 78Â21 to 93 25cmH2O (p=0.0009 ); in walked distance from 435Â70 to 491Â88 m (p<0.0001 ), upper limb maximum load from 1.0 to 2.0 kg (p=0.008 ), in treadmill inclination from 5Â3 to 8 3% (p<0.0001 ) and speed from 4.9 [3.7 -5.5] to 5.2 [4.4 -6] (p=0.002 ), submaximal exercise capacity from 447Â179 to 718 220s (p=0.002 ), in anxiety from 9.9 Â4.9 to 4.9 Â2.7 (p<0.0001 ), and depression from 9.05 Â4.08 to 4.9 Â2.1 (p<0.0001 ), in quality of life with Physical Component Summary (PCS) from 37.5 Â9.07 to 46.15  8.7 % (p=0.004 ) and fibrinogen to 448.3 Â129.9 to 321.6  73.2 mg/dl (p=0.0002 ). Albumin has not showed significant result in both groups. In GB there was significant increase in MIP 50Â22 to 70 35 (p=0.004) and reduction in fibrinogen from 490.7  199.7 to 453.3  177.2 mg/dl (p=0.3). Other variables GB did not show any significant results. When comparing results between groups there was significant difference in the walked distance (p=0,0001), in upper limb strength (p=0,009), in inclination (p=0,0008), in endurance (p=0,005), in anxiety (p=0,0002), in depression (p=0,04), in PCS (p=0,03) and fibrinogen (p=0,04). Out of 31 patients, 10 were not operated. In postoperative pulmonary complications, GA show less greater and lesser relevance morbidity (p=0,002 and p=0,01 respectively) shorter length of hospital stay (p=0,004), less chest tube days(p=0,03), lower percentage of bronchial fistula (p=0,009) and less bronchospasm (p=0,002). When compared to GB. PR had impact on the reduction of serum fibrinogen, on clinical improvements, health related quality of life, anxiety and depression, and also reduced postoperative pulmonary complications. In the absence of PR programs, RT can be an important preoperative strategy.

INTRODUÇÃO: Um grande número de estudos epidemiológicos têm demonstrado que o fibrinogênio é fator de risco consistente e independente para doença cardiovascular. O fibrinogênio, além de ser um determinante de trombose arterial foi considerado fator de risco de trombose venosa. Foram avaliados os níveis plasmáticos do fibrinogênio em indivíduos que apresentaram algum tipo de trombose não influenciada por reação de fase aguda ou resposta inflamatória. MÉTODOS: Neste estudo de caso-controle realizado entre julho de 2003 a abril de 2005 foram incluídos 39 pacientes, entre 25 e 65 anos, com diagnóstico objetivamente confirmado de trombose, sem antecedentes de neoplasia e colagenose. O tempo mínimo entre a evento e a coleta da amostra de sangue foi de 6 meses. O grupo controle foi constituído de doadores e funcionários voluntários do Hemocentro Regional de Juiz de Fora. A concentração plasmática de fibrinogênio e a medida da Proteína C Reativa foram realizados nos dois grupos. RESULTADOS:Os níveis médios de fibrinogênio foram significativamente maiores nos pacientes ( 316)que no grupo controle (259), p=0,0002. a média de idade foi 48,3 para os pacientes e 45,5 para o controle. A aplicação do teste qui quadrado demonstrou que não houve diferenças significativas nos grupos de pacientes e controles (30,8% e 27%, respectivamente) em relação ao tabagismo(pvalor = 0,72). A frequência de hipertensão foi significativamente maior no grupo de pacientes (28,2%) que no controle (5,4%) (p-valor=0,008). O teste t para a diferença dos níveis médios de fibrinogênio entre os grupos de trombose venosa e arterial não apresentou resultado estatisticamente significante (p-valor = 0,69). CONCLUSÃO: Com base nos dados deste estudo, os níveis de fibrinogênio estão relacionados com trombose, independente se arterial ou venosa. / INTRODUCTION: A great number of prospective epidemiologic studies have reported that fibrinogen is consistently and independently risk factor for the cardiovascular disease. The fibrinogen, a determinant of arterial thrombosis, was also considered a risk factor for the venous thrombosis. It was valued the fibrinogen plasmatic level in patients that had showed some kind of thrombosis event without influence by acute phase reactions or ongoing inflamatory responses. METHODS: In this cases-control study, fulfilled between july 2003 and april 2005, was included 39 patients, among 25 e 65 ears, with confirmed diagnosis of thrombosis and none neoplasis and collagenosis antecedent. Six months was the minimum time between event and blood sample collect. The control group was composed by blood donor and voluntary employee of the Hemocentro Regional de Juiz de Fora. The fibrinogen plasmatic concentration and the C-reactive proteins measure was made in both groups. RESULTS: The medium levels of fibrinogen were significantly higher in patients (316) than the control group (259), p=0,0002. The age average was 48,3 for the patients and 45,5 for the control. The “qui-quadrado” test application proved there wasn’t any significatives differences in both groups, patients (30,8%) and control (27%), in the relation with smoking (p-value = 0,72). The frequency of arterial hypertension was significantly higher in patient group (28,2%) than the control group (5,4%) (p-value = 0,008). The t-test for the differences of the fibrinogen average levels between venous and arterial thrombosis didn’t present any significant statistic result. CONCLUSION: Established in this research, the higher levels of fibrinogen are associated with thrombosis, independently if arterial or venous.

Aborto espontâneo recorrente (AER) é definido pela presença de três ou mais abortos espontâneos e consecutivos que ocorreram até a 20ª semana de gestação. O AER possui origem multifatorial. Dentre os diversos fatores associados ao AER, alterações na hemostasia podem comprometer o fluxo sanguíneo na placenta e com isso pode aumentar o risco de complicações obstétricas, como o aborto. O objetivo geral deste estudo foi investigar se existe associação entre polimorfismos genéticos (no gene do fibrinogênio (FGB -455G>A e -148C>T), da trombomodulina (THBD 1418C>T), do fator V (F5 1691G>A), da protrombina (F2 20210 G>A), do PAI-1 (SERPINE1 4G/5G) e do TAFI (CPB2<i/> c.505G>A)) e os abortos espontâneos recorrentes (primários e secundários). Os objetivos específicos desse estudo foram: 1- avaliar se existe associação entre os sete polimorfismos e o período em que ocorreram as perdas fetais (precoce ou tardia) e o número de abortos recorrentes; 2- determinar se os haplótipos dos polimorfismos FGB -455G>A e FGB -148C>T estão ou não associados aos abortos primários e secundários. Foram incluídas 256 mulheres com história de abortos espontâneos recorrentes, provenientes do Ambulatório de Obstetrícia da Clínica Obstétrica do Hospital das Clínicas da Faculdade de Medicina da USP e 264 mulheres saudáveis, sem história de aborto espontâneo e que tiveram pelo menos duas gestações normais (grupo controle), pareadas segundo as idades. Amostras de sangue foram obtidas para realização das genotipagens dos polimorfismos por meio de PCR em tempo real (FGB -148C>T, FGB -455G>A, THBD 1418C>T e CBP2 c.505G>A), e PCR-RFLP (SERPINE14G/5G, F5 1691G>A e F2 20210 G>A). As frequências dos genótipos e de alelos para os sete polimorfismos foram semelhantes entre os grupos aborto primário, aborto secundário e grupo controle. Entretanto, quando foi realizada um modelo de regressão logística multivariada saturada, que incluiu as variáveis independentes: F5 1691G>A (referência GG vs GA), F2 20210G>A (referência GG vs GA), CBP2 c.505G>A (referência GG + GA vs AA), THBD 1418C>T (referência CC + CT vs TT), SERPINE1 4G/5G (referência 5G/5G vs 4G/4G + 4G/5G) FGB -455G>A (referência GG vs GA vs AA) e FGB -148C>T (referência CC vs CT vs TT), apenas o polimorfismo FGB -148C>T foi associado ao maior risco de ter aborto primário (OR: 2,91, IC 95% 1,02 - 8,29, p=0,045). Quando os haplótipos para os polimorfismos FGB -455G>A e FGB 148C>T foram considerados, foi observada maior frequência de haplótipo 455G/148T em mulheres com AER primário (3,4%) do que no grupo controle (1,1%), (p=0,030); porém esse efeito não foi observado no AER secundário. Em relação ao número de abortos consecutivos, houve uma tendência (p=0,060) a maior frequência de genótipo TT para o polimorfismo FGB -148C>T no grupo de aborto primário com até três perdas quando comparado com as mulheres do mesmo grupo, porém com número maior de perdas (>3). Em conclusão, os sete polimorfismos quando analisados separadamente, não foram associados ao AER; no entanto, em modelo multivariado de regressão logística, o genótipo TT do polimorfismo FGB 148C>T foi associado com o aumento do risco de ter AER primário. Além disso, foi encontrado maior frequência do haplótipo 455G/148T para os polimorfismos FGB -455G>A e FGB -148C>T em mulheres com aborto primário. / Recurrent pregnancy loss (RPL) is defined by the presence of three or more consecutive losses prior to 20 weeks of gestation. The RPL has multifactorial origin. Among several factors associated with RPL, changes in hemostasis may impair the blood flow in the placenta and thus may increase the risk of obstetric complications, such as pregnancy loss. The general aim of this study was to investigate the association between genetic polymorphisms (in the genes of fibrinogen (FGB -455G>A and -148C>T), thrombomodulin (THBD 1418C>T), factor V (F5 1691G>A), prothrombin (F2 20210 G>A), PAI-1 (SERPINE1 4G/5G) and TAFI (CPB2 c.505G>A)) and recurrent pregnant losses (primary and secondary). The specific aims of this study were: 1 - to evaluate the association between the seven polymorphisms and the period in which the fetal losses occurred (early or late) and the number of recurrent losses; 2 - to determine if the haplotypes of polymorphisms FGB -455G>A and FGB -148C>T present association with primary and secondary pregnant losses. We included 256 women with a RPL history, from the Ambulatory of Obstetrics from Clinical Hospital of the Medical School of USP and 264 healthy women without losses history that have had at least two normal pregnancies (control group), matched according to age. Blood samples were obtained to perform the genotyping of polymorphisms by real-time PCR (FGB -148C>T, FGB -455G>A, THBD 1418C>T and CBP2 c.505G>A), and PCR-RFLP (SERPINE1 4G/5G, F5 1691G>A and F2 20210G>A). The frequencies of genotypes and alleles for the seven genetic polymorphisms were similar in 3 groups. However, when it was performed a model of multivariate logistic regression, which included the independent variables: F5 1691G>A (GG vs GA reference), F2 20210G>A (GG vs GA reference), CBP2 c.505G>A (GG + GA reference vs AA), THBD 1418C>T (reference CC + CT vs TT), SERPINE1 4G/5G (reference 5G/5G + 4G/5G vs 4G/4G), FGB -455G>A (GG reference vs GA vs AA) and FGB - 148C>T (reference CC vs CT vs TT), only the polymorphism FGB 148C>T polymorphism was associated with a higher risk of having primary losses (OR: 2.91, 95% CI 1.02 to 8.29, p = 0.045). When the haplotypes for the polymorphisms FGB -455G>A and FGB -148C>T were considered, had a higher frequency of the haplotype 455G/148T in women with primary RPL (3.4%) than in the control group (1.1%) (p = 0.030); but this effect was not observed in secondary RPL. Regarding the number of successive pregnant losses, there was a trend (p = 0.060) to higher frequency of the TT genotype for FGB -148C>T polymorphism in the group with primary RPL up to three losses when compared with women of the same group, but with loss number higher than three. In conclusion, when the seven genetic polymorphisms were evaluated separately, they do not show association with RPL, however, in multivariate logistic regression analysis, the TT genotype of the FGB -148C>T polymorphism was associated with increased risk for primary RPL. Furthermore, it was found higher frequency of the haplotype 455G/148T for the FGB -455G>A and FGB -148 C>T polymorphisms in women with primary RPL.

No description available.

Capsaicin, prostaglandin E2 (PGE2) and polydopamine (PDA) were used to target macrophage and myofibroblast activity to reduce biomaterial-induced fibrosis. The lifetime and efficacy of implantable biomedical devices are determined by the foreign body response. Immediately after implantation, proteins nonspecifically adsorb onto the material and initiate inflammation. Macrophages recruited to the site can differentiate into M1 and M2 phenotypes and upregulate inflammation and fibrosis which interferes with the intended function. M1 macrophages secrete pro-inflammatory mediators that induce chronic inflammation and promote myofibroblast differentiation while M2 macrophages are wound healing cells that suppress inflammation and regulate fibroblast activity. The fibrotic tissue is developed by myofibroblasts which produce collagen in an unregulated fashion. Collagen thickening and biomaterial encapsulation decreases efficacy and sensitive of biomedical devices. We investigated the in vitro and in vivo effects of capsaicin, PGE2 and polydopamine surface modification on macrophages and myofibroblasts. Capsaicin and PGE2 reduced poly(lactic-co-glycolic) acid (PLGA)-induced fibrosis by promoting M2 macrophage phenotype to secrete anti-inflammatory IL-10 and suppressing myofibroblast marker α-smooth muscle actin (α-SMA). Capsaicin decreased collagen by 40% and upregulated IL-10 secretion by 35% while PGE2 reduced collagen by 55% after 14 days of implantation and 40% less collagen after 42 days. PDA was used to bind an anti-fibrotic compound to the surface of a poly(dimethyl siloxane) (PDMS-PDA) to reduce fibrosis. However, PDMS-PDA controls gave an unexpected result by reducing fibrosis to the same extent as anti-fibrotic compound bound PDMS- v PDA. PDA modification reduced cellularity by 50% and significantly decreased collagen thickness by 30%. Overall, our results showed that biomaterial-induced fibrosis can be reduced by promoting M2 macrophage activity and inhibiting myofibroblast differentiation. This research demonstrates three compounds that have potential to reduce fibrosis and extend the lifetime and efficacy of implantable biomedical devices. / Thesis / Master of Applied Science (MASc) / Capsaicin, prostaglandin E2 (PGE2) and polydopamine were used to reduce scar tissue development around implanted polymers. Biomedical devices implanted in the body can undergo severe scar tissue formation, or fibrosis, and fail. Fibrosis is described by the accumulation of collagen and encapsulation of an implanted polymer. Macrophages regulate fibrosis by secreting pro-fibrotic compounds and myofibroblasts produce unregulated amounts of collagen. In this thesis, capsaicin, PGE2 and polydopamine were incorporated into implants to target macrophage and myofibroblast activity and reduce fibrosis in mice. Capsaicin and PGE2, released from a degradable polymer, altered macrophages to secrete anti-fibrotic compounds and decreased collagen by 40% and 55%, respectively. Polydopamine surface modified implants gave an unexpected result and suppressed overall cell activity to reduce fibrosis by 30%. The research conducted shows the potential of these compounds to reduce fibrosis and extend the lifetime of implantable devices.

Motivation In the black population of South Africa, cardiovascular disease (CVD) is rapidly increasing due to urbanisation. Stroke is usually accompanied by a prothrombotic haemostatic profile. Changing lifestyle factors that accompany the urbanisation process could have a negative impact on the haemostatic profile of black South Africans. Elevated levels of pro-coagulant factors, von Willebrand factor (vWF), fibrinogen and fibrin D-dimer have been reported in the black population, which could increase the black population’s susceptibility to CVD. However, low levels of plasminogen activator inhibitor-1 (PAI-1) previously reported in the black population could contribute towards a pro-fibrinolytic state, which may counteract the hypercoagulant state. This may have a beneficial effect on the haemostatic profile of the black population. More investigation into the haemostatic profile of black South Africans is therefore needed to determine if an altered haemostatic profile exists in this group, and if so, to what extent these alterations may relate to cardiovascular dysfunction. This study included markers of both the coagulation (vWF, fibrinogen, fibrin D-dimer) and fibrinolytic (PAI-1, fibrin D-dimer and fibrinolytic potential) systems in an attempt to investigate the haemostatic profile of the black population of South Africa, and for comparison purposes that of the white population as well. The relationship of these markers’ with selected markers of cardiovascular function was also examined to determine if they could possibly contribute to an increase in cardiovascular risk, especially in the black population. Aims The aims of this study were to first compare coagulation and fibrinolysis markers in the black and white populations of South Africa. Furthermore, to determine if associations exist between the selected components of the haemostatic system and markers of cardiovascular function, especially in the black population of South Africa, who tends to be at a higher cardiovascular risk due to altered metabolic and haemostatic profiles. Methodology The Sympathetic activity and Ambulatory Blood Pressure in Africans (SABPA) study was a prospective cohort study that consisted of 409 participants at baseline (2008-2009) that were equally distributed according to both ethnicity (200 black; 209 white) and gender (black, 101 men, 99 women; white, 101 men, 108 women). At follow-up (2011/2012) the cohort totalled 359 participants (170 black, 88 men and 82 women; 189 white, 93 men and 96 women). Data from baseline measurements were used for the first two manuscripts (chapters 2 and 3), while followup data was used for the third manuscript (chapter 4). vWF, fibrinogen, PAI-1, fibrin D-dimer, CLT, serum peroxides, glutathione, glutathione peroxidase and reductase activity were determined, and ambulatory blood pressure and the retinal vessel calibres were measured. The groups were stratified by ethnicity as specified by statistical interaction terms. T-tests and chi-square tests were used to compare means and proportions, respectively. Pearson and partial regression analyses were used to determine correlations between the components of the haemostatic system and cardiovascular function markers. This was followed by multiple linear regression analyses to investigate whether independent associations exist between the variables in both ethnic groups. P-values ≤0.050 were deemed significant. Results and conclusion of each manuscript The first manuscript (chapter 2) compares the haemostatic profiles of the black and white population to determine whether ambulatory blood pressure is related to components of the haemostatic system. The black participants displayed a prothrombotic profile with significantly higher vWF, fibrinogen, PAI-1, fibrin D-dimer and a longer CLT than their white counterparts. Furthermore, partial and multiple linear regression analyses showed a positive association of systolic and diastolic blood pressure with fibrin D-dimer in the black population, while a negative association existed between ambulatory blood pressure and CLT in the white population. These associations suggest that fibrin D-dimer may contribute, at least in part, to the high prevalence of hypertension in the black population. The second manuscript (chapter 3) determined associations between markers of the haemostatic and oxidant-antioxidant systems in the black and white populations. In addition to the prothrombotic profile that exists in the black population, this group also had significantly higher serum peroxides (oxidative stress) and lower glutathione peroxidase activity (antioxidant) levels. Multiple linear regression analyses indicated positive associations between fibrinogen and serum peroxides in both populations. In the white population, an additional positive association was found between serum peroxide and CLT. In the black population, vWF and CLT were negatively associated with GPx activity. The results suggest that there are ethnic-specific relationships between the haemostatic and oxidant-antioxidant systems. The third manuscript (chapter 4) investigated the relationships between the retinal vessel calibres and components of the haemostatic system in the black and white population. The investigation focussed specifically on arteriolar diameters in the lower median, since a narrow arteriolar diameter is known to be associated with elevated blood pressure. In both ethnic groups, a narrower arteriolar calibre was accompanied by narrower venular calibres. Independent positive associations were found between the central retinal vein equivalent (CRVE) and fibrinogen in the black population, as well as vWF and CLT in the white population. In addition, independent negative associations were found between the central retinal artery equivalent and CLT in the black population and with vWF in the white population. The results suggest that haemostatic alterations are linked to early vascular changes that may differ between ethnicities. General conclusion Ethnic-specific relationships between the components of the haemostatic system and measures of cardiovascular function are evident. The prothrombotic profile that is observed in the black population, together with the adverse associations of the haemostatic components with blood pressure, a compromised oxidant-antioxidant profile, and retinal vessel calibres may contribute, at least in part, to the high cardiovascular and cerebrovascular risk evident in this population group. / PhD (Physiology), North-West University, Potchefstroom Campus, 2015

Motivation In the black population of South Africa, cardiovascular disease (CVD) is rapidly increasing due to urbanisation. Stroke is usually accompanied by a prothrombotic haemostatic profile. Changing lifestyle factors that accompany the urbanisation process could have a negative impact on the haemostatic profile of black South Africans. Elevated levels of pro-coagulant factors, von Willebrand factor (vWF), fibrinogen and fibrin D-dimer have been reported in the black population, which could increase the black population’s susceptibility to CVD. However, low levels of plasminogen activator inhibitor-1 (PAI-1) previously reported in the black population could contribute towards a pro-fibrinolytic state, which may counteract the hypercoagulant state. This may have a beneficial effect on the haemostatic profile of the black population. More investigation into the haemostatic profile of black South Africans is therefore needed to determine if an altered haemostatic profile exists in this group, and if so, to what extent these alterations may relate to cardiovascular dysfunction. This study included markers of both the coagulation (vWF, fibrinogen, fibrin D-dimer) and fibrinolytic (PAI-1, fibrin D-dimer and fibrinolytic potential) systems in an attempt to investigate the haemostatic profile of the black population of South Africa, and for comparison purposes that of the white population as well. The relationship of these markers’ with selected markers of cardiovascular function was also examined to determine if they could possibly contribute to an increase in cardiovascular risk, especially in the black population. Aims The aims of this study were to first compare coagulation and fibrinolysis markers in the black and white populations of South Africa. Furthermore, to determine if associations exist between the selected components of the haemostatic system and markers of cardiovascular function, especially in the black population of South Africa, who tends to be at a higher cardiovascular risk due to altered metabolic and haemostatic profiles. Methodology The Sympathetic activity and Ambulatory Blood Pressure in Africans (SABPA) study was a prospective cohort study that consisted of 409 participants at baseline (2008-2009) that were equally distributed according to both ethnicity (200 black; 209 white) and gender (black, 101 men, 99 women; white, 101 men, 108 women). At follow-up (2011/2012) the cohort totalled 359 participants (170 black, 88 men and 82 women; 189 white, 93 men and 96 women). Data from baseline measurements were used for the first two manuscripts (chapters 2 and 3), while followup data was used for the third manuscript (chapter 4). vWF, fibrinogen, PAI-1, fibrin D-dimer, CLT, serum peroxides, glutathione, glutathione peroxidase and reductase activity were determined, and ambulatory blood pressure and the retinal vessel calibres were measured. The groups were stratified by ethnicity as specified by statistical interaction terms. T-tests and chi-square tests were used to compare means and proportions, respectively. Pearson and partial regression analyses were used to determine correlations between the components of the haemostatic system and cardiovascular function markers. This was followed by multiple linear regression analyses to investigate whether independent associations exist between the variables in both ethnic groups. P-values ≤0.050 were deemed significant. Results and conclusion of each manuscript The first manuscript (chapter 2) compares the haemostatic profiles of the black and white population to determine whether ambulatory blood pressure is related to components of the haemostatic system. The black participants displayed a prothrombotic profile with significantly higher vWF, fibrinogen, PAI-1, fibrin D-dimer and a longer CLT than their white counterparts. Furthermore, partial and multiple linear regression analyses showed a positive association of systolic and diastolic blood pressure with fibrin D-dimer in the black population, while a negative association existed between ambulatory blood pressure and CLT in the white population. These associations suggest that fibrin D-dimer may contribute, at least in part, to the high prevalence of hypertension in the black population. The second manuscript (chapter 3) determined associations between markers of the haemostatic and oxidant-antioxidant systems in the black and white populations. In addition to the prothrombotic profile that exists in the black population, this group also had significantly higher serum peroxides (oxidative stress) and lower glutathione peroxidase activity (antioxidant) levels. Multiple linear regression analyses indicated positive associations between fibrinogen and serum peroxides in both populations. In the white population, an additional positive association was found between serum peroxide and CLT. In the black population, vWF and CLT were negatively associated with GPx activity. The results suggest that there are ethnic-specific relationships between the haemostatic and oxidant-antioxidant systems. The third manuscript (chapter 4) investigated the relationships between the retinal vessel calibres and components of the haemostatic system in the black and white population. The investigation focussed specifically on arteriolar diameters in the lower median, since a narrow arteriolar diameter is known to be associated with elevated blood pressure. In both ethnic groups, a narrower arteriolar calibre was accompanied by narrower venular calibres. Independent positive associations were found between the central retinal vein equivalent (CRVE) and fibrinogen in the black population, as well as vWF and CLT in the white population. In addition, independent negative associations were found between the central retinal artery equivalent and CLT in the black population and with vWF in the white population. The results suggest that haemostatic alterations are linked to early vascular changes that may differ between ethnicities. General conclusion Ethnic-specific relationships between the components of the haemostatic system and measures of cardiovascular function are evident. The prothrombotic profile that is observed in the black population, together with the adverse associations of the haemostatic components with blood pressure, a compromised oxidant-antioxidant profile, and retinal vessel calibres may contribute, at least in part, to the high cardiovascular and cerebrovascular risk evident in this population group. / PhD (Physiology), North-West University, Potchefstroom Campus, 2015