Orientadores: Joyce Maria Annichino-Bizzacchi, Nicola Amanda Conran Zorzetto / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-22T04:29:01Z (GMT). No. of bitstreams: 1 Zapponi_KiaraCristinaSenger_M.pdf: 3766938 bytes, checksum: e4531f39f9f53ff883ad33f684d56647 (MD5) Previous issue date: 2012 / Resumo: Tromboembolismo venoso (TEV) é uma doença multifatorial que afeta 1-3:1000 indivíduos mundialmente. A formação do trombo venoso na superfície endotelial é um processo multicelular, de estrutura laminar composta por camadas de plaquetas, leucócitos, eritrócitos e fibrina, originando uma resposta inflamatória loco-regional. A relação entre inflamação e coagulação é bidirecional. e tem sido principalmente avaliada através de interações de proteínas entre citocinas próinflamatórias e elementos da cascata de coagulação. As células inflamatórias tais como neutrófilos, não foram previamente correlacionadas com os processos trombóticos ou pró-coagulantes. Objetivo: Avaliar as propriedades adesivas de neutrófilos, eritrócitos e plaquetas, assim como a expressão das moléculas de adesão de superfície dos neutrófilos em pacientes com TEV, correlacionando-os com marcadores sistêmicos da resposta inflamatória, presença de trombo residual e D-dímero aumentado. Pacientes e Métodos: Foram incluídos neste estudo 10 pacientes com TEV agudo atendidos no Hospital de Clínicas da Unicamp (HCUNICAMP), 30 pacientes com TEV crônico (1 a 6 anos após o evento agudo), atendidos no Hemocentro de Campinas-UNICAMP, e controles normais pareados aos pacientes por idade, gênero e etnia. A adesão de neutrófilos, eritrócitos e plaquetas foram determinados através de ensaio estático usando fibronectina (FN) e fibrinogênio (FB) como ligantes. A expressão das moléculas de adesão dos neutrófilos (CD11a, CD11b, CD18) foi avaliada por citometria de fluxo. Os níveis dos marcadores inflamatórios (IL-6, IL-8, TNF-_ e PCR) foram avaliados por ELISA e nefelometria. O trombo residual (TR) por ultrassom com Doppler e o Dímero-D (DD) por método coagulométrico. Resultados: A adesão de plaquetas ao fibrinogênio com e sem estímulo de trombina em pacientes dos grupos agudo e crônico foi semelhante ao observado nos controles normais. Da mesma forma, não houve diferença da adesão de eritrócitos à fibronectina nesses mesmos grupos analisados. No subgrupo de pacientes com alto risco de recorrência de TEV definido pela presença de altos níveis de D-dímero (>0,55mg/L) e trombo residual observou-se um aumento significativo da adesão de neutrófilos em relação aos controles (24.68% vs 19.07%, P<0.05). A atividade inflamatória também estava aumentada neste subgrupo em comparação aos outros pacientes, demonstrada pelo aumento significativo dos níveis séricos de IL-6, IL-8, TNF-_ e PCR (2.08pg/mL VS 0.90pg/mL, P=0.01; 28.72pg/mL vs 16.46pg/mL, P=0.02; 4.50pg/mL vs 2.11pg/mL, P=0.04; 0.35 pg/mL vs 0.14 pg/mL, P=0.09, respectivamente). Houve uma correlação das propriedades adesivas de neutrófilos com IL-6 (r=0.3815 e P=0.0375), e D-dímero (r=0.3831 e P=0.0367). A quantificação das proteínas de superfície (CD11a, CD11b e CD18) de neutrófilos não foi diferente entre os grupos analisados. Conclusão: Nossos resultados sugerem que pacientes com TEV não apresentam aumento das propriedades adesivas de plaquetas e eritrócitos. Entretanto, as propriedades adesivas dos neutrófilos foram aumentadas em pacientes com D-dímero aumentado e presença de trombo residual, independente da expressão quantitativa das proteínas de superfície em sua membrana. A hipótese para este aumento pode ser devido as alterações na afinidade das moléculas de adesão de superfície aos seus ligantes, como consequência do processo inflamatório associado com a hipercoagulabilidade que é característica desta doença / Abstract: Venous Thromboembolism (VTE) is a multifactorial disease that affects 1-3:1000 individuals worldwide. The venous thrombus develops via a multicellular process on the surface of the endothelium and presents a laminar structure comprised of layers of platelets, leukocytes, erythrocytes and fibrin. The relationship between inflammation and coagulation is bidirectional, and has been mainly evaluated through protein interactions between pro-inflammatory cytokines and elements of the coagulation cascade. Inflammatory cells such as neutrophils, have not been previously correlated with thrombotic or procoagulant processes. Objective: To evaluate the adhesive properties of neutrophils, erythrocytes and platelets, as well as the expression of neutrophil adhesion molecules in patients with VTE, correlating them with markers of the systemic inflammatory response, and with the presence of residual vein obstruction (RVO) and higher D-dimer (DD). Patients and Methods: Study group consisted of 30 chronic VTE patients (1-6 years after the acute episode) followed in our outpatient clinic, and 10 patients with VTE during the acute episode treated at the Hospital of Clinics (HC-UNICAMP) Campinas, as well as age, gender and ethnic background-matched healthy. Adhesive properties of neutrophils, erythrocytes and platelets were determined by a static adhesion assay using ligands such as fibrinogen (FB) and fibronectin (FN). The expression of neutrophils adhesion molecules (CD11a, CD11b, CD18) was evaluated by flow cytometry. Levels of inflammatory markers (IL-6, IL-8, TNF-_, PCR) were evaluated by ELISA and nephelometry. RVO was evaluated by Doppler ultrasound and DD by coagulometric method. Results: No significant difference could be observed in the platelets adhesion (basal: 16.37% vs. 14.59%, p=0.309; and stimulated with thrombin: 33.45% vs. 26.62%, p=0.200) and erythrocytes adhesion (7.28% vs 7.49%, p=0.859) between chronic VTE patients and healthy individuals. Similarly, no statistical differences were observed in the platelets adhesion (basal: 28.36% vs. 21.63%, p=0.109; and stimulated with thrombin: 38.45% vs. 30.15%, p=0.715) and erythrocytes adhesion (6.00% vs 4.62%, p=0.326) in the VTE acute xxii patients when compared to their respective controls. Interestingly, in patients with a higher risk of recurrent VTE (defined by the presence of high levels of DD and RVO), a significant increase in neutrophils adhesion was observed when compared to healthy individuals (24.68% vs. 19.07%, p <0.05). Inflammatory markers (IL-6, IL-8, TNF-_ and CRP) were significantly elevated (2.08pg/mL vs 0.90pg/mL, p=0.01; 28.72pg/mL vs 16.46pg/mL, p=0.02; 4.50pg/mL vs 2.11pg/mL, p=0.04; 0.35 pg/mL vs 0.14 pg/mL, p=0.09, respectively) in this subgroup of patients when compared to the other patients. Adhesive properties of neutrophils were correlated with IL-6 (r= 0.3815 and p= 0.0375) and D-dimer levels (r= 0.3831 and p= 0.0367). Neutrophils adhesion molecules (CD11a, CD11b and CD18) were not altered in any of the groups. Conclusion: Our results suggest that VTE patients do not exhibit increased adhesive properties of platelets and erythrocytes. Neutrophils adhesive properties were increased in patients with higher D-dimer levels and RVO, independently of the expression of neutrophil adhesion molecules. A hypothesis for this increase is alterations in affinity of surface adhesion molecules to their ligands, as a response to inflammatory processes associated with the hypercoagulability demonstrated in this subgroup of patients / Mestrado / Biologia Estrutural, Celular, Molecular e do Desenvolvimento / Mestra em Fisiopatologia Médica

Pulmonary embolism as a part of venous thromboembolic disease has a broad spectrum of clinical presentations from minimal disease to life-threatening right heart failure. Therapy has to be guided by the risk associated with the individual clinical state of the patient. As long as hemodynamics are entirely stable, anticoagulation is given in order to prevent early or late recurrence, thereby allowing for endogeneous thrombolysis and recovery. In hemodynamically instable patients, i.e. patients under cardiopulmonary resuscitation or in shock, there is the need for a rapid reduction of thrombus mass in order to restore right ventricular function. Systemic thrombolysis is the most feasible modality to reduce the thrombus burden of the pulmonary circulation in the short term. For hemodynamically stable patients with right ventricular dysfunction as assessed by echocardiography, there is still some controversy as to whether thrombolysis improves the long-term outcome. At the least, thrombolysis may positively modify the short-term course of acute disease in patients with an extremely low risk of bleeding. When the acute phase has been overcome, secondary prophylaxis with vitamin K antagonists has to be given. The duration of secondary prophylaxis requires an individual assessment of both the risk of recurrence and the risk of bleeding. In the near future, new anticoagulant drugs such as direct thrombin and factor Xa inhibitors will offer new treatment modalities for the acute phase as well as for secondary prophylaxis. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Study Objective Although data from the Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism (RECORD) 1-4 trials have shown a similar postoperative bleeding risk between rivaroxban and enoxaparin in patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA), anecdotal observations from local institutions have suggested that postoperative bleeding rates seemed higher in patients who received rivaroxaban than those reported in the RECORD trials. Thus, the objective of this pilot study was to assess postoperative bleeding events observed in clinical practice in patients receiving rivaroxaban after undergoing THA and TKA and to compare their results with those published in the RECORD trials. Design Retrospective cohort study with a comparator group of patients from the RECORD 1-4 trials. Setting Two institutions within a regional health care system. Patients Four hundred forty adults who received at least one dose of rivaroxaban 10 mg daily after undergoing THA or TKA in the two institutions between August 2011 and October 2013 (cohort group), and 6183 patients who received rivaroxaban in the RECORD 1-4 trials (comparator group). Measurements and Main Results Postoperative bleeding was assessed in the cohort patients versus the patients in the RECORD trials. The primary outcome, occurrence of any postoperative bleeding, was a composite of major and clinically relevant nonmajor bleeding as defined in the RECORD trials. Any postoperative bleeding occurred in 6.8% of the cohort patients versus 3.2% of the RECORD trial patients (p<0.0001); 1.4% of the cohort patients versus 0.38% of the RECORD trial patients suffered a major bleed (p=0.013). Within defined major bleeding, bleeding leading to reoperation and clinically overt extrasurgical site bleeding resulting in either a hemoglobin level decrease of at least 2 g/dl or transfusion of 2 units or greater of packed red blood cells were reported in 0.68% versus 0.19% (p=0.073) and 0.68% versus 0.13% (p=0.032), respectively, of the cohort patients versus the RECORD trial patients. Conclusion Overall, any postoperative bleeding in the cohort patients occurred significantly more frequently than that observed in the RECORD trial patients. The major bleeding rate was also significantly higher in the cohort patients, influenced by higher rates of bleeding leading to reoperation and clinically overt extrasurgical site bleeding resulting in either a hemoglobin decrease of at least 2 g/dl or transfusion of two units or greater of packed red blood cells. These findings from our pilot study are thought provoking and, thus, invite further investigation.

Patients with inflammatory bowel disease (IBD) are known to have an increased propensity for thromboembolic events. Like any patient with a high risk of event recurrence, most of these patients can be managed successfully with long-term warfarin therapy. We present the case of a 66-year-old woman with Crohn's disease who, despite careful attention to the management of her international normalized ratio, developed a new deep vein thrombosis and required inferior vena cava filter placement in addition to ongoing warfarin therapy to prevent recurrent pulmonary emboli. This report serves as a reminder to physicians to have a low threshold for diagnosing thromboembolic events in patients with IBD, even if they are presumed to be adequately anticoagulated. Known and theoretical contributing factors to this increased clotting tendency are also reviewed.

Background: Recent studies have suggested that patients with idiopathic pulmonary fibrosis (IPF) may have a higher risk of venous thromboembolism (VTE) compared to general population even though the results were inconsistent. Objective: To investigate the risk of VTE among patients with IPF. Methods: Comprehensive literature review using MEDLINE and EMBASE database were performed to identify studies that compared the risk of VTE among patients with IPF to general population. Effect estimates from each study were combined together using random effect model, generic inverse variance method of DerSimonian and Laird. Results: Out of 510 retrieved articles, 5 studies met the inclusion criteria and were included in the meta-analysis. A significant risk of VTE in patients with IPF was observed with the pooled risk ratio of 2.11 (95% confidence interval, 1.28-3.48). The heterogeneity was moderate with I2 of 64%. Conclusion: An approximately 2-fold increased risk of VTE among patients with IPF was observed in this meta-analysis.

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

Venous thromboembolism (VTE) is a serious health concern of patients undergoing orthopedic surgery. Analysis of the study site semiannual reports from January 2014 through March 2015 indicated 10 VTE events in 546 orthopedic cases. The community hospital was classed as an outlier performing in the bottom 10th percentile when compared to other hospitals. To standardize the ordering of VTE prophylaxis, the hospital developed a postoperative electronic VTE order set. The purpose of this project was to assess the difference in orthopedic VTE occurrences in the postoperative total hip arthroplasty (THA) patients before and after the implementation of the electronic VTE order set. The goal of the project was to use an electronic retrospective chart review to evaluate if the order set implementation influenced the adherence to ordering mechanical and pharmacological prophylaxis in the THA patient. Differences in the ordering of VTE prophylaxis and VTE outcomes were evaluated using a retrospective review of 325 preimplementation order set cases and 406 postimplementation order set cases. This evaluation demonstrated that appropriate pharmacological prophylaxis ordering increased and orthopedic VTE occurrences decreased after the standardized electronic order set was implemented. Social change occurred through the empowerment of clinicians when empirical evidence was provided for use at the point of care, which positively impacted patient outcomes undergoing a common surgical procedure. VTE is no longer considered a routine postoperative orthopedic complication as technology-enabled solutions have proven to be appropriate tools to combat and prevent postoperative VTE complications.

During the last several decades, venous thromboembolism (VTE) has been identified as a preventable health condition. The gaps in clinical practice have led to an increased incidence of VTE. The lack of using existing evidence-based VTE prevention guidelines in practice has limited the implementation of VTE risk assessment stratifications and affected the appropriateness and timeliness of addressing pharmacologic and mechanical prophylaxis. The purpose of the scholarly project was to educate practitioners on existing VTE prevention practice guidelines. The practice-focused question explored whether an educational learning activity on evidence-based VTE prevention guidelines improved the awareness, knowledge, and compliance with existing evidence-based VTE guidelines of practitioners that assess and treat patients at risk for VTE. The theoretical framework for the project was Lewin's change process theory. A total of 38 participants comprised registered nurses (82%), physicians (5%), nurse practitioners (2%), and nonclinical personnel (11%). A program evaluation was provided to determine the effectiveness of the project. The findings showed that practitioners participated in the learning activity to improve knowledge (48%), increase VTE awareness (43%), and would change the management and treatment of patients at risk for VTE (39%). Hospitalized patients at risk for VTE can benefit from the results of this project through a change in clinical practice that might decrease the incidence of VTE and potentially bring about social change by reducing the number of preventable deaths.

Infertility is a problem that could be treated by using In Vitro Fertilization (IVF). This procedure starts by increasing estrogen levels and then retrieving oocytes. However, studies have showed an increased risk for venous thromboembolism (VTE) and lung embolism that is correlated with the rising levels of estrogen. Microvesicles, vesicles formed from the cell membrane, increases in number in connection with IVF and diseases such as thrombosis. These vesicles can transport proteins, one of them is fetuin-B. Fetuin-B plays a role in fertilizing the egg by inhibiting ovastacin, a protein that leads to hardening of zona pellucida. Phosphatidylserine, a component of the cell membrane with strong binding capacity to annexin V, has also been studied while investigating VTE. The aim of this project was to analyze the amount of fetuin-B, ovastacin and phosphatidylserine in women undergoing IVF. The study included 55 women where three blood samples were collected from them at different time points. The tests were analyzed using flow cytometry and fluorescent antibodies targeting the proteins in question. The results showed a significant increase in fetuin-B and ovastacin after the treatment where double positive microvesicles (fetuin-B+ ovastacin+) had the highest significant difference, a rise of 78% after the hormone increase. (Fetuin-B+ annexin V+) increased over time, 205% after increasing estrogen levels, while no difference was seen for (ovastacin+ annexin V+). This thesis suggests that fetuin-B is strongly related to fertility and coagulation in women undergoing IVF. The protein has also a noticeable relationship to ovastacin. Most importantly, (fetuin-B+ ovastacin+) was suggested to be a better marker for women’s fertility than the other analyzed parameters.

La maladie veineuse thrombombolique (MVTE), associant thrombose veineuse profonde et embolie pulmonaire, peut être le premier signe d’un cancer jusque-là méconnu. Des études anciennes ont rapporté que 6 à 15% des patients étaient diagnostiqués d’un cancer occulte dans l’année suivant l’épisode de MVTE. L'identification précoce d’un cancer occulte au moment du diagnostic de la MVTE non provoquée est fondamentale car la présence d’un cancer va conditionner la prise en charge du patient, que ce soit au niveau de la thrombose ou du cancer. Actuellement, les recommandations préconisent un dépistage limité du cancer en cas de MVTE non-provoquée, basé sur un examen clinique complet (interrogatoire, examen physique), un bilan biologique de base, une radiographie thoracique ainsi que tous les examens communément admis pour le dépistage du cancer en fonction de l’âge et du sexe du patient (PSA chez les hommes, mammographie et examen gynécologique chez les femmes). La tomographie par émission de positon (TEP) au 18F-fluorodéoxyglucose (FDG) est une technique d’imagerie en pleine expansion depuis les années 2000. Elle est largement utilisée en routine clinique pour la détection des foyers tumoraux, leur bilan d’extension, l’évaluation des traitements ainsi que le bilan de possibles récidives. En revanche, aucune étude n’a aujourd’hui évalué l’intérêt de cette technique dans le dépistage du cancer chez les patients présentant une MVTE non provoquée. Afin de répondre à cette problématique, l’objectif de cette thèse a été spécifiquement d’étudier l’intérêt de la TEP au FDG pour la détection des néoplasies dans le bilan étiologique d’une MVTE non provoquée au travers des résultats de l'étude MVTEP, étude multicentrique randomisée comprenant une stratégie de dépistage limitée associée à une TEP au FDG à une stratégie limitée seule. / Venous thromboembolism (VTE), which encompasses deep vein thrombosis and pulmonary embolism, can occur as the first manifestation of an underlying occult malignancy. Previous studies reported that the incidence of undiagnosed cancer is 6% to 15% in the year following an unprovoked VTE épisode, i.e. VTE not provoked by a major risk factor.In patients with unprovoked VTE, extensive screening for cancer has been proposed in order to diagnose occult malignancy as early as possible in the hope of improving the prognosis. Current guidelines for occult cancer screening in patients with unprovoked VTE recommend limited cancer screening, including of a thorough medical history and physical examination, basic laboratory investigations, chest X-ray, as well as age-specific and gender-specific cancer screening (colon, breast, and prostate) according to national guidelines.18F-Fluorodesoxyglucose Positron Emission Tomography combined with Computed Tomography (FDG PET/CT) is routinely used for the diagnosis and staging of various malignancies. The use of FDG PET/CT might overcome the limitations of previous extensive screening strategies as it involves whole-body imaging using a single, non-invasive test. To date, there has been no formal assessment of the additional value of FDG PET/CT for occult malignancy screening in patients with unprovoked venous thromboembolism.To address this issue, we conducted a multicenter randomised controlled trial comparing a limited screening strategy to a strategy combining limited screening and FDG PET/CT in patients with unprovoked venous thromboembolism, and then assessed the additional value of FDG PET/CT in addition to a limited strategy.