Heparin, a highly sulfated and acidic glycosaminoglycan, has been clinically used in parenteral formulations to prevent and/or treat thromboembolic disorders for more than 90 years. Actions of heparin are not limited to anticoagulation and antithrombosis. Rather heparin has several other important actions which include fat clearing, antitumor and anti-inflammatory effects. However, use of heparin for such applications has been limited by its route of administration.<p> Historically, it has been believed that heparin is not absorbed following oral administration and therefore is only available for clinical use by parenteral administration. This belief has been challenged several times by our laboratory and other researchers showing heparin binding to endothelium following oral administration as well as prevention of thrombosis and lowering blood pressure, etc. However, the site of oral heparin absorption and the mechanism responsible for absorption have not been investigated. This in vitro study was designed to address these important questions.<p> We mounted pieces of rat gastrointestinal mucosa in a vertical diffusion Ussing chamber with both sides of the mucosal membrane exposed to Krebs bicarbonate buffer solution containing mannitol on the mucosal side (lumen) and glucose on the serosal side. Electrical properties across the membrane including potential difference (PD), resistance (R), and short circuit current (Isc) were recorded following heparin addition to the mucosal buffer under different mucosal buffer pH conditions. Mucosal and serosal buffer and tissue were collected and extracted for heparin and heparin recovery was performed by gel electrophoresis and anticoagulation tests. The first chapter (chapter 4) was designed to investigate if stomach mucosal tissue is a site for unfractionated heparin (UFH) absorption when mounted in the Ussing chamber. We found that stomach mucosa is able to transport UFH in an intact form when both mucosal and serosal buffers are at neutral pH of 7.4. When the mucosal buffer pH is made more acidic, at pH 4, transport is facilitated.<p> The second study (chapter 5) was designed to investigate if stomach mucosal tissue is also capable of transporting low molecular weight heparins (LMWHs). We showed that LMWHS were transported across stomach mucosa. However, the rate of transport was faster at mucosal buffer pH of 7.4 compared to pH 4.<p> The third study (chapter 6) investigated the effect of molecular weight on rate of heparin transport across stomach mucosal tissue since pH dependency of this transport was evident from both previous studies. This study suggested that decreasing the molecular weight increases the rate of heparin transport across stomach tissue under neutral pH but not acidic pH conditions. The fourth study (chapter 7) investigated how UFH is transported across the ileal mucosa and if Peyers patches contribute to this transport. It was shown that UFH is transported across ileal mucosa containing Peyers patches at a rate faster than ileal mucosa without Peyers patches. Making the mucosal buffer pH acidic facilitated UFH transport in the absence of Peyers patches but not when ileal mucosa contained Peyers patches.<p> The final study (chapter 8) investigated the mechanism of UFH transport across stomach mucosa mounted in the Ussing chamber using pharmacological inhibitors sodium fluoride, colchicine, and amiloride. Results showed that UFH is transported across the stomach mucosa at physiological acidic pH by an active transport mechanism using metabolic energy, cytoplasmic tubule formation, and sodium-coupled systems. From this, we conclude that oral heparins are absorbed across the gastrointestinal tract. The acidic environment of the stomach is a better absorption site for UFH. On the other hand, the more basic environment of the intestine is a better site for absorption of LMWHs. UFH is mainly absorbed across the stomach mucosa by an active transport mechanism using metabolic energy, cytoplasmic tubule formation, and sodium-coupled systems. Considering the very much larger surface area of the intestine than the stomach and that intestine, especially the ileum, contains many Peyers patches where UFH transport is not pH-dependent, larger amounts of UFH may be transported across the intestinal tissue compared to the stomach.

Heparin, a highly sulfated and acidic glycosaminoglycan, has been clinically used in parenteral formulations to prevent and/or treat thromboembolic disorders for more than 90 years. Actions of heparin are not limited to anticoagulation and antithrombosis. Rather heparin has several other important actions which include fat clearing, antitumor and anti-inflammatory effects. However, use of heparin for such applications has been limited by its route of administration.<p> Historically, it has been believed that heparin is not absorbed following oral administration and therefore is only available for clinical use by parenteral administration. This belief has been challenged several times by our laboratory and other researchers showing heparin binding to endothelium following oral administration as well as prevention of thrombosis and lowering blood pressure, etc. However, the site of oral heparin absorption and the mechanism responsible for absorption have not been investigated. This in vitro study was designed to address these important questions.<p> We mounted pieces of rat gastrointestinal mucosa in a vertical diffusion Ussing chamber with both sides of the mucosal membrane exposed to Krebs bicarbonate buffer solution containing mannitol on the mucosal side (lumen) and glucose on the serosal side. Electrical properties across the membrane including potential difference (PD), resistance (R), and short circuit current (Isc) were recorded following heparin addition to the mucosal buffer under different mucosal buffer pH conditions. Mucosal and serosal buffer and tissue were collected and extracted for heparin and heparin recovery was performed by gel electrophoresis and anticoagulation tests. The first chapter (chapter 4) was designed to investigate if stomach mucosal tissue is a site for unfractionated heparin (UFH) absorption when mounted in the Ussing chamber. We found that stomach mucosa is able to transport UFH in an intact form when both mucosal and serosal buffers are at neutral pH of 7.4. When the mucosal buffer pH is made more acidic, at pH 4, transport is facilitated.<p> The second study (chapter 5) was designed to investigate if stomach mucosal tissue is also capable of transporting low molecular weight heparins (LMWHs). We showed that LMWHS were transported across stomach mucosa. However, the rate of transport was faster at mucosal buffer pH of 7.4 compared to pH 4.<p> The third study (chapter 6) investigated the effect of molecular weight on rate of heparin transport across stomach mucosal tissue since pH dependency of this transport was evident from both previous studies. This study suggested that decreasing the molecular weight increases the rate of heparin transport across stomach tissue under neutral pH but not acidic pH conditions. The fourth study (chapter 7) investigated how UFH is transported across the ileal mucosa and if Peyers patches contribute to this transport. It was shown that UFH is transported across ileal mucosa containing Peyers patches at a rate faster than ileal mucosa without Peyers patches. Making the mucosal buffer pH acidic facilitated UFH transport in the absence of Peyers patches but not when ileal mucosa contained Peyers patches.<p> The final study (chapter 8) investigated the mechanism of UFH transport across stomach mucosa mounted in the Ussing chamber using pharmacological inhibitors sodium fluoride, colchicine, and amiloride. Results showed that UFH is transported across the stomach mucosa at physiological acidic pH by an active transport mechanism using metabolic energy, cytoplasmic tubule formation, and sodium-coupled systems. From this, we conclude that oral heparins are absorbed across the gastrointestinal tract. The acidic environment of the stomach is a better absorption site for UFH. On the other hand, the more basic environment of the intestine is a better site for absorption of LMWHs. UFH is mainly absorbed across the stomach mucosa by an active transport mechanism using metabolic energy, cytoplasmic tubule formation, and sodium-coupled systems. Considering the very much larger surface area of the intestine than the stomach and that intestine, especially the ileum, contains many Peyers patches where UFH transport is not pH-dependent, larger amounts of UFH may be transported across the intestinal tissue compared to the stomach.

Heparin is a highly sulphated glycosaminoglycan. Approximately 70% of the polymer structure is represented by the disaccharide repeat unit (IdA-2S→GlcNS-6S). Variations with respect to the degree of sulphation, acetylation of the amino group and configuration of the uronic acid introduces extensive microheterogeneity within the polymer primary sequence. Heparin is not just a blood anticoagulant but has a wide ranging capability to interact with inorganic ions, proteins and drugs. Such interactions have been increasingly studied with specific reference to structure-function relationships. Heparin was subjected to a variety of chemical modifications including de-N-sulphation, de-N/O-sulphation, N-acetylation, N-propionylation, N-sulphation and carboxyl reduction. Partially modified polymers were synthesised using either less stringent solvolytic conditions or hydrochloric acid. The modified polymers were characterised using high-resolution ^1 3 C-NMR spectroscopy, Ir spectroscopy and acid-base titrations. Prior analysis of native heparin provided a set of reference spectra and titration profiles. Specific ion replacement and polarimetry were employed to study the interactions between heparin and cations. Polarimetry was further utilised to investigate the effect of polymer modification on the interaction with calcium and copper (II) ions. A study was conducted on the ability of the modified polymers to potentiate antithrombin inhibition of the cleavage of synthetic substrates by Factor Xa and thrombin. In addition, the influence of the modified heparin on capillary vessel growth in the chick CAM was investigated. Heparin and the chemically modified heparins were subjected to the bacterial enzymes heparinase II and heparinase III. Analysis of the degradation products was conducted using molecular exclusion chromatography and HPLC. The substrate specificity of the two lyases was assessed together with the potential of employing the enzymes, in conjunction with HPLC, to characterise heparins from various sources. The major conclusion are: 1) The interaction of calcium and copper (II) ions with modified polymers are fundamentally different with the amino group playing an important role in the copper (II) interaction. 2) Polysaccharide-catalysed inhibition of thrombin by antithrombin is more pronounced than for Factor AXa. The polysaccharides appear to play a subsidiary role through the formation of a simple electrostatic interaction with thrombin and antithrombin, thus bringing the protease and inhibitor together. 3) Heparinase II is active against a wide range of heparin-like polymers producing a variety of disaccharides and tetrasaccharides. Two specific glycosidic linkages are, however, resistant to the action of the enzyme. 4) Heparinase III catalyses the degradation of heparin-like polymers that are N-sulphated or N-acetylated but is inactive in those parts of the molecule in which a 2-0-sulphated uronic acid is present. 5) Enzyme-catalysed degradation followed by HPLC analysis is a viable method of characterising the disaccaride composition of heparins and heparin-like polymers.

In recent years, many countries have struggled with the fact that expenditures on health care are growing much faster than the overall level of wealth. Research objectives: 1) to conduct a meta-analysis of heparins by the means of their efficacy, safety parameters and treatment outcomes; 2) to conduct pharmacoepidemiological assessment of long-term heparins utilization in Lithuania; 3) to develop a pharmacoeconomic cost-minimization model for low-molecular-weight heparins based on reference pricing methodology; 4) to investigate heparins prescribing trends and to evaluate heparins prescription adherence to international clinical guidelines at a secondary level clinical hospital. Meta-analysis results showed that low-molecular-weight heparins could be considered interchangeable due to similar therapeutic profiles in some indications. In Lithuania consumption of heparins and corresponding costs were constantly increasing during the period of investigation; therefore it would be relevant to implement modern pharmacoeconomic methodologies to regulate costs. Cost-minimization model suggested that expenditures on this group of medicines could be decreased by nearly 70 percent. Analysis of pharmacoepidemiological study data confirmed that heparins prescription practices at the clinical hospital were insufficiently regulated. In addition this study conducted at the clinical hospital revealed non-compliance of heparins safety monitoring practices with clinical guidelines. / Pastaraisiais metais daugelyje šalių sveikatos priežiūros išlaidos augo daug greičiau nei bendras gerovės lygis, todėl yra nuolat diskutuojama, kaip šį išlaidų augimą reikėtų kontroliuoti. Darbo uždaviniai: 1) atlikti heparinų preparatų meta-analizę, palyginant jų efektyvumo ir saugumo parametrus bei gydymo baigtis; 2) atlikti heparinų preparatų ilgalaikio suvartojimo Lietuvoje farmakoepidemiologinį tyrimą; 3) suformuluoti farmakoekonominį kaštų mažinimo sprendimų modelį mažos molekulinės masės heparinų preparatų grupei, remiantis referentinės kainos metodika; 4) ištirti heparinų preparatų skyrimo tendencijas antrinio lygio klinikinėje ligoninėje ir palyginti heparinų preparatų skyrimo atitikimą tarptautinėms gairėms. Meta-analizės rezultatai parodė, jog mažos molekulinės masės heparinai gali būti tarpusavyje pa¬keičiami dėl analogiškų terapinių savybių tam tikrose indikacijose. Heparinų preparatų suvartojimas ir atitinkamos išlaidos tiriamuoju laikotarpiu Lietuvoje nuolat didėjo, todėl būtų aktualu taikyti šiuolaikines farmakoekonomines išlaidų reguliavimo metodikas. Pritaikius kaštų mažinimo modelį heparinų preparatų grupei, būtų galima sumažinti išlaidas šios grupės preparatams beveik 70 procentų. Farmakoepidemiologinio tyrimo rezultatai atskleidė, jog heparinų preparatų skyrimo praktika klinikinėje ligoninėje buvo nepakankamai reglamentuota. Taip pat heparinų preparatų saugumo parametrų stebėjimo praktika ligoninėje neatitiko tarptautinių rekomendacijų.

La formation d'un caillot de fibrine, processus clé de la coagulation sanguine, implique la polymérisation des monomères de fibrinogène en un réseau de fibres de fibrine. Bien que ce réseau contrôle l'ensemble des propriétés mécaniques du caillot et constitue le squelette sur lequel se base la reconstruction des tissus, sa structure aux échelles inférieures au micron est très mal caractérisée. Nous avons démontré que l'analyse du spectre de lumière visible transmis à travers un caillot permet de déterminer simultanément, quantitativement et en conditions quasi-physiologiques, plusieurs paramètres essentiels de cette nanostructure, à savoir le rayon et la concentration interne en protéines des fibres. Cette méthode de spectrophotométrie a montré le caractère extraordinairement poreux de ces fibres et comment l'environnement de la réaction (concentrations en fibrinogène, en thrombine, température, force ionique) influe sur leur dimension et leur porosité. Cette méthode a ensuite permis de caractériser les effets respectifs sur cette structure de différentes molécules anti-coagulantes, montrant l'action spécifique de l'enoxaparine par rapport aux héparines non-fractionnées et au pentasaccharide. Enfin, nous avons construit un prototype à vocation hospitalière (spectrophotomètre) afin d'étudier la cinétique de polymérisation de la fibrine, non seulement en système purifié en combinaison avec nos spectres de diffusion de rayons X, mais également sur des plasmas de patients présentant des troubles de l'hémostase. Des discussions sont en cours avec un laboratoire pharmaceutique afin d'intégrer cette méthode sur des appareils de diagnostic. / The formation of a fibrin clot is one of the major processes leading to blood coagulation. It involves the polymerization of fibrinogen monomers into a network of fibrin fibers. This network controls the overall mechanical properties of the clot and serves as a scaffold to promote wound healing. However its structure at scales less than one micron is very poorly characterized. We demonstrated that an analysis of the visible light spectra transmitted through fibrin clots enables the simultaneous determination, in quantitative terms and in conditions near physiological, of several key parameters of this nanostructure, i.e. the radius and the protein content of the fibers. This spectrophotometry technique has shown the extraordinary porous nature of these fibers and how the reaction parameters (fibrinogen and thrombin concentrations, temperature, ionic strength) control their size and their porosity. This method was then used to characterize the respective effects on the structure of different anticoagulant molecules, showing the specific action of enoxaparin compared with unfractionated heparin and pentasaccharide. We built a prototype (spectrophotometer), used at hospital, to study the kinetics of fibrin polymerization, not only in purified system in combination with our X-ray spectra, but also in plasmas of patients with bleeding disorders. Discussions are underway with a pharmaceutical company to integrate this method on diagnostic equipment.

Abstract The global aims of this thesis were: to evaluate if an individualised dose strategy for enoxaparin, based on lean body weight and renal function, resulted in a reduction in the prevalence of bleeding and bruising events when compared to conventional dosing; to further understand the dose-exposure-response relationship for enoxaparin using population pharmacokinetic-pharmacodynamic (PKPD) modelling. This thesis comprises seven chapters: an introduction to the current knowledge and literature pertaining to low-molecular-weight heparins (LMWHs), in particular enoxaparin; five research chapters; and a discussion. Each of the five research chapters consists of a manuscript that has been published in, accepted or submitted for peer review in a scientific journal. Preceding each chapter is a synopsis of the important features of the publication. Supplementary information that supports the findings of the publication, but could not be included in the publication, is provided at the end of the chapter. Appendices relevant to each chapter are located at the end of the thesis. Chapter one is the introduction to this thesis. It commences with an overview of the LMWHs, their mechanism of action, customary uses, licensed doses and adverse effects. There is a brief introduction to renal function and body composition; physiological factors that influence the disposition of LMWHs. As much of this thesis is centred on defining the dose-exposure-response relationship for enoxaparin, there is a critique of the existing literature relevant to each segment of this relationship, namely: dose-exposure, exposure-response and dose-response. To conclude this chapter there is a review of pharmacostatistical models and population modelling, followed by an appraisal of population PK and PKPD models that have previously been developed for enoxaparin, including the two key publications that are critical to this thesis. These two papers were the first to fully describe the dose-exposure relationship for enoxaparin in subjects with renal impairment and obesity. It is from these studies that the individualised dosing strategy, explored throughout this thesis, was developed. The specific aims of the five research chapters are then stated. Chapter two describes a confirmatory, randomised controlled trial (RCT) to compare an individualised dose of enoxaparin to conventional, label based dosing. The RCT was conducted at a major tertiary teaching hospital over an 18 month period. The primary endpoint was the prevalence of overt bleeding events and the secondary endpoint a combination of bleeding or major bruising events. A time-to-bleeding event analysis (Kaplan-Meier) was used and markers of effectiveness such as mortality and readmission were assessed out to 30 days post recruitment. Bleeding and bruising data, along with anti-Xa (aXa)-concentrations were collected for use in additional research described in chapters four and five. Chapter three details the evolution, progression and contemporary knowledge of drug dosing based on body composition and focuses on dosing in obese subjects with cardiovascular disease. The concept of dose-individualisation is explored in this chapter with reference to the methods used to normalise drug exposure across the spectrum of body compositions. Subsequently, there is a review of body size descriptors, such as lean body weight, that are used to scale dosing in the obese. Enoxaparin is used as a motivating example, with reference to data presented in Chapter two of this thesis. There is also a discussion about the type of research designs that are required to maximise information about PK parameters. This chapter was published within a book chapter which was intended for clinical practitioners in the discipline of cardiology. Chapter four is focused on the development and evaluation of population PK and PKPD models to describe the time-course of effects for enoxaparin. A population PK model linked to a proportional-odds model was used to describe the severity of an adverse event as a function of exposure and demographic variables. The final model was used to explore the likely occurrence of bleeding and bruising events in patients with obesity and / or renal impairment dosed using either the individualised or conventional dose strategies from Chapter two. Chapter five describes a study that was undertaken to evaluate the ability of the individualised dosing strategy to achieve and maintain aXa-concentrations within the therapeutic range (500 to 1000 IU L-1), by comparison to conventional dosing. As the confirmatory study focused on the prevalence of adverse events there was no assessment of the therapeutic capability of the dose strategies however, as aXa-concentrations were collected using a sparse design during the confirmatory study, the two dose strategies could not be compared using observed data. Therefore, the population PK model developed in Chapter four was used to predict individual subject concentration-time profiles to 120 hours of enoxaparin therapy. The time spent in the therapeutic, supra-therapeutic and sub-therapeutic ranges was computed for each subject and the dosing strategies statistically compared. This study also allowed the evaluation of the results from Chapter two from a dose-exposure perspective. Chapter six of this thesis describes a survey. The aim of this survey was to gain an understanding of how dosing strategies of enoxaparin vary in four countries, investigate if clinicians are prescribing according to the Product label, and determine the methods used to dose-individualise enoxaparin. In doing so, individual hospitals in the international community will be able to compare, critique or benchmark their own strategies to peer hospitals, as well as the current literature. The publication arising from this survey would assist in the dissemination of knowledge gained from the earlier chapters of this thesis. Chapter seven is the final discussion and conclusions of the thesis along with prospects for future research.

Résumé confidentiel / Résumé confidentiel

Made available in DSpace on 2014-12-17T14:03:41Z (GMT). No. of bitstreams: 1 TarcianaCGA.pdf: 634423 bytes, checksum: 54bd90fdc2abea42aaa8c6e698915963 (MD5) Previous issue date: 2006-07-18 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / Fucans are a family of sulfated homo and teropolysaccharides respectively, composed mainly of a- (1?2) and a- (1?3) linked by L-fucose residues. Properties such as the ability to act as an anti-contraceptive, to reduce cholesterol levels, and to act as an anti-tumor agent are much related. We have focused our attention on the anticoagulant properties, platelet aggregation, hemorrhagic activity and complement system in vitro of commercial fucoidan (F) and their purified fractions (F1, F2 and F3) from Fucus vesiculosus obtained from fractionation of the fucoidan with different concentrations of acetone 1, 2 and 3v. These compounds were chemically characterized and the fucoidan (F) was modified by desulfation. The anticoagulant activity of the compounds was assessment by activated partial thromboplastin time (APTT) and prothrombine time assay (PT) using citrated normal human plasma. The results of APPT test showed that F, F1 and F2 have high anticoagulants activities 240.0 s (5 ?g). The F3 showed 73.7 s in the same concentrations. The results obtained with PT test to F, F1, F2 and F3 were 81.5 s, 120.0 s, 57.1 and 32.5 s respectively with 50 ?g. The dessulfated polymer showed a decrease in the anticoagulant activity in these two tests. Platelet aggregation assay was measured turbidimetrically with platelet aggregometer by method of Born. The aggregation platelet with F and fractions F1, F2 and F3 exhibited a two-phase answer in the concentration of 5 mg/mL with maximum aggregation of 76.36 ? 10.3% ; 69.54 ? 9.40%; 75.94 ? 9.01%; 51.13 ? 9.59% respectively. However, was observed a hipoaggregate profile F (15.17 ? 5.2%), F1 (7.40 ? 3.04 %), F2 (19.1 ? 5.41%) and F3 (5.09 ? 3.02%) at 0.1 mg/mL. The hemorrhagic activity assay was carried in Wistar rats and showed that these compounds have low hemorrhagic effect when compared to heparin. The complement system ( alternative pathway was made using non-sensibilized rabbit red blood cells The results of complement system essay showed that F , F2 and F3 have action inhibitory in relation to the group control 0.544, 0.697, 0.622 and 0.958 respectively The results showed that these compounds have action on this system. Interaction of the polisaccharides with proteins C3 and C4 showed that the fraction F1 stimulated the activity assay hemolytic using red blood cells / Fucanas s?o uma fam?lia de homo e hetero polissacar?deos sulfatados, formadas por uma cadeia central com liga??es &#945;-(1&#8594;2) ou &#945;-(1&#8594;3) unidas atrav?s de res?duos de L-fucose. Propriedades como a habilidade para agir como um anticoncepcional, reduzir n?veis de colesterol, e agir como um agente anti-tumoral foram relatadas. N?s focalizamos nossa aten??o nas propriedades anticoagulantes, agrega??o plaquet?ria, atividade anti-hemost?tica e sistema de complemento in vitro do fucoidan comercial e das fra??es F1, F2 e F3 de Fucus vesiculosus obtidas atrav?s do fracionamento do fucoidan por precipta??o com acetona (1, 2 e 3v). A atividade anticoagulante dos compostos foi avaliada pelo tempo de tromboplastina parcial ativado (APTT) e o tempo de protrombina (PT) usando plasma humano citratado. Os resultados do teste de APPT mostraram que o Fucoidan (F) e as fra??es F1 e F2 t?m altas atividades anticoagulantes 240,0 s (5 ?g), enquanto que a F3 mostrou 73,7s nas mesma concentra??o. Os resultados obtidos com PT para o F, F1, F2 e F3 foram 81,5 s, 120,0 s, 57,1 e 32,5 s respectivamente usando a massa de 50 ?g. A dessulfata??o do Fucoidan demonstrou uma diminui??o da atividade anticoagulante nos dois testes. O ensaio de agrega??o plaquet?ria foi realizado no agregometro de acordo com o m?todo de Born. A agrega??o plaquet?ria induzida pelo fucoidam e pelas fra??es de F1, F2 e F3 exibiram uma resposta bif?sica na concentra??o de 5 mg/mL com amplitude m?xima de agrega??o de 76,36% ? 10,3%; 69,54% ? 9,40%; 75,94% ? 9,01%; 51,13% ? 9,59% respectivamente. Por?m, na concentra??o 0,1 mg/mL foi observada um perfil hipoagregante para o Fucoidan (15,17% ? 5,2) e para as fra??es F1 (7,4% ? 3,04%), F2 (19,1% ? 5,41) e F3 (5,09% ? 3,02%). A atividade anti-hemost?tica foi realizada com ratos machos da linhagem Wistar e demonstrou que estes compostos t?m efeito hemorr?gico residual menor do que o da heparina. A a??o dos polissacar?deos fucosilados sulfatados na via alternativa do sistema complemento foi realizada atrav?s da utiliza??o de eritr?citos de coelhos n?o sensibilizados. Os resultados para o Sistema Complemento mostraram que o F, F2 e F3 t?m a??o neste sistema, apresentando efeito inibit?rio em rela??o ao grupo controle 0,544, 0,697, 0,622 e 0,958 respectivamente. Intera??es dos polissacar?deos com as prote?nas C3 e C4 demonstraram que a fra??o F1 estimula a atividade hemol?tica do complemento usando eritr?citos de coelho. Conclu?mos que estes a??cares t?m atividade anticoagulante e atuam como inibidores do sistema complemento sendo uma valiosa droga que pode ser empregada em doen?as relacionadas com inflama??o e coagula??o sang??nea

This thesis was about thrombomebolic disease in pregnancy. The incidence of venous thromboembolism (VTE) probably increases 2- to 4-fold when a woman becomes pregnant. I looked on this problem from many aspects. I looked on health care from her gynaecologist and eventually hematologist, recognition her VTE risk, laboratory tests and her medication. I looked on effectivity of medication too.