Дисертації з теми "Thrombotic complications"

L'inhibiteur de la Voie du Facteur Tissulaire (TFPI) est une protéine régulatrice de la coagulation plasmatique intervenant à la phase initiale de la cascade. Il inhibe en présence de la protéine S (PS) le facteur Xa et ce complexe TFPI-Xa inactive ensuite le complexe FT-VIIa. Nous avons recherché une résistance à l'activité anticoagulante du TFPI. La sensibilité du plasma à une quantité fixe de TFPI a été évaluée sur la base d'un temps de thromboplastine diluée (TTD) réalisé avec et sans TFPI : - chez des patients ayant présenté une thrombose veineuse profonde inexpliquée ; cette résistance suspectée sur une 1ère étude n'a pas été confirmée sur la 2ème. - chez des patientes enceintes ; une résistance au TFPI acquise a été montrée et rapportée au déficit acquis en PS ; cependant le degré de résistance au TFPI ne peut pas être utilisé comme marqueur de risque de pathologie vasculaire placentaire. Chez des patients obèses l'effet inhibiteur des taux élevés de Lp(a) sur l'activité TFPI décrit in vitro n'a pas été retrouvé in vivo pas plus que l'effet de l'aspirine sur la normalisation des taux de Lp(a). Le TFPI joue un rôle dans les manifestations hémorragiques des hémophiles. Nous avons montré que les hémophiles B ont comparativement aux A des taux moindres de TFPI ce qui pourrait expliquer leur différence en terme de manifestations hémorragiques. Les taux de TFPI libre sont bien corrélés aux paramètres de la génération de thrombine surtout au temps de latence. En présence d’un anti TFPI humain la génération de thrombine est corrigée chez l'hémophile. Cette correction dépend de la concentration d'anti TFPI, est saturable et doit être étudiée sur du plasma riche en plaquettes
TFPI is a multivalent Kunitz-type proteinase inhibitor that directly inhibits FXa and produces FXa-dependent feedback inhibition of the FVIIa–TF complex. It was recently demonstrated that Protein S (PS) plays the role of TFPI cofactor by enhancing the TFPI inhibition of factor Xa in vivo. Approximately 80% of plasma TFPI circulates as a complex with plasma lipoproteins, about 5–20% circulating as free TFPI. Under quiescent conditions, approximately 50–80% of intravascular TFPI is stored in association with the endothelium. Full-length TFPI α carried in platelets constitutes 8-10% of the total amount of TFPI in the blood, corresponding to a quantity comparable to that of soluble full-length TFPI α in the plasma. We searched for resistance to TFPI activity in patients who presented idiopathic venous thrombosis at a young age. Plasma sensitivity to TFPI was evaluated on the basis of diluted prothrombin time (dPT) measured in patients and in control plasma in the presence (W) and absence (Wo) of exogenous TFPI. At the same time, dPT was measured on a reference plasma to establish a normalized ratio termed TFPI NR and defined as (dPT wTFPI/ dPT Wo TFPI) patient or control / (dPT wTFPI/ dPT Wo TFPI) reference plasma. In an initial study, we found that TFPI resistance could be considered as a new coagulation abnormality that could be related to unexplained thrombosis. In a second study, we failed to demonstrate a role of TFPI resistance in patients with venous thrombosis, abnormal TFPI NR being more likely related to the non-respect of preanalytical conditions rather than to an inherited trait. However, in another study, we showed that inherited or acquired PS deficiency was responsible for a TFPI resistance, providing an ex vivo demonstration that PS is the cofactor of TFPI activity. We showed that this TFPI resistance existed throughout pregnancy and that it disappeared when PS returned to normal values after delivery. We evaluated this TFPI resistance as a possible marker of the risk of a gestational vascular complication (GVC) in 72 patients at risk of developing a GVC. TFPI NR did not differ between GVC+ patients (n =15) and GVC– patients (n = 57). High levels of Lipoprotein(a) (Lp(a) have been shown to be an independent risk factor for cardiovascular disease, lowering of these levels not being achievable by any treatment except possibly aspirin. An in vitro study showed that TFPI activity could be inhibited by Lp(a). We did not confirm this TFPI inhibition in vivo in 20 obese patients with coronary insufficiency who had either normal Lp(a) levels (≤ 0.3 g/L; n = 15) or high Lp(a) levels (≥ 0.3 g/L; n = 5) . Moreover, we found no effect of aspirin treatment on Lp(a) whatever the initial level of Lp(a). Haemophilia B patients bleed less than haemophilia A patients. We showed that this difference in bleeding profile could be explained by lower free TFPI levels in haemophilia B patients compared to haemophilia A patients. In an ongoing study, we showed that in haemophilia A patients there was a strong correlation between the different parameters of thrombin generation (TG) and free TFPI. We also showed, in a TG assay performed in platelet-rich plasma (PRP) with a low TF concentration, that LT was sensitive to free TFPI levels whatever the type of haemophilia and whatever theseverity of the disease. We demonstrated that blocking TFPI by an anti-TFPI Antibody (Ab) allows complete correction of the TG profile in PRP. We showed that it is of major importance to perform a TG assay in PRP in order to evaluate the efficacy of anti-TFPI Ab in correcting TG parameters in haemophilia patients

La problématique de cette thèse est la caractérisation des complications liées à l’hémostase chez le patient assisté par ECMO-VA périphérique afin d’en améliorer la prévention et de rationaliser les approches antithrombotiques en usage. Dans une première étude, nous avons décrit qualitativement et quantitativement la composition des thrombi formés sur les circuits d’ECMO-VA. Nous avons observé que ces thrombi sont majoritairement composés de VWF, de fibrine et dans une moindre proportion de plaquettes et d’érythrocytes. Notre approche quantitative a également permis de mettre en évidence la présence de NETs en l’absence de toute pathologie septique active, confirmant la possibilité d’une NETose aseptique sous ECMO-VA. Par une analyse en cluster hiérarchique, nous avons identifié 2 types de thrombi pouvant relever chacun d’un mécanisme de formation différent. Dans cette étude, la localisation des thrombi sur le circuit d’ECMO-VA n’impactait pas leurs compositions, ce qui souligne l’hétérogénéité des thrombi formés sous ECMO-VA et la multiplicité des mécanismes à l’origine de la thrombinoformation dans ce contexte. Dans un second travail, nous avons comparé la performance des revêtements de surfaces des circuits d’ECMO-VA à réduire la thrombinoforation et ses conséquences cliniques. Deux des revêtements les plus utilisés en routine étaient comparés : celle à base de phosphorylcholine et à base d’héparine. Nous avons observé un taux de complications thrombotiques plus conséquent dans le groupe phosphorylcholine sans surrisque hémorragique ou de mortalité dans les deux groupes. Par ailleurs, comparativement aux thrombi issus des jonctions de circuits traités par revêtement de phosphorylcholine, ceux provenant de circuits traités par polysaccharide-albumine étaient plus pauvres en VWF. Notre travail suggère que l’intensité de l’anticoagulation devrait être modulée en fonction du type de revêtement de surface du circuit d’ECMO. Notre troisième étude avait pour but d’identifier les saignements les plus graves justifiants d’une prise en charge clinique agressive et d’un investissement plus conséquent en recherche. À cette fin, nous avons comparé l’association entre 3 classifications de saignement avec la mortalité à 28 jours. La définition ELSO déjà en usage et les classes de la classification BARC ≥ type 2 étaient associées à la mortalité et retenues donc comme définitions de l’hémorragie majeure. Les facteurs biologiques prédictifs de l’hémorragie grave d’après la définition de l’ELSO étaient la baisse du fibrinogène, du compte plaquettaire et de l’hémoglobine à la canulation. L’indice de masse corporelle et l’étiologie postcardiotomie étaient également prédictifs de la survenue de cette complication. Dans un travail additionnel portant sur la thématique de la thèse, nous avons étudié deux des tests les plus utilisés pour la surveillance de l’héparinothérapie systémique sous ECMO, le TCA et l’activité Anti-Xa afin d’identifier le plus pertinent. Pour ce faire, dans un premier objectif nous avons étudié la relation entre ces deux tests puis avons analysé dans un second objectif l’impact de facteurs biologiques d’influences sur cette relation. Ensuite, nous avons déterminé leurs associations avec les complications thrombotiques et hémorragiques. Bien qu’étant linéairement associé, le taux de discordance entre leurs mesures était de 39 % pour une fenêtre référence d’Anti-Xa de 0,3 — 0,7 UI/mL. Ni le TCA et ni l’Anti-Xa n’étaient associées aux complications thrombotiques ou hémorragiques [...]
The purpose of this dissertation is to characterize hemostasis-related complications in patients supported by peripheral VA-ECMO to improve their prevention and to optimize the antithrombotic therapeutic approaches in use. In a first study, we qualitatively and quantitatively described the composition of thrombi collected from the VA-ECMO circuits. We observed that these thrombi are mainly made of VWF, fibrin and in a lesser proportion of platelets and RBCs. Our quantitative approach also allowed us to demonstrate the presence of NETs while there was no active septic, confirming the possibility of aseptic NETosis under VA-ECMO. By hierarchical cluster analysis, we identified 2 types of thrombi, each of which may be related to a different mechanism of formation. In this study, the location of thrombi on the VA-ECMO circuit did not impact their compositions, highlighting the heterogeneity of thrombi formed within VA-ECMO and the multifactorial mechanisms that support thrombosis in this setting. In a second study, we compared the performance of surface coatings on VA-ECMO circuits to reduce thrombinoformation and its clinical consequences. Two of the most used coatings in daily practice were compared: the phosphorylcholin-based coating and the polysaccharide-albumin-based coating. We observed a higher rate of thrombotic complications in the phosphorylcholin group without any excess bleeding events or mortality in either group. In addition, compared with thrombi from phosphorylcholin-coated circuit junctions, those from polysaccharide-albumin-coated circuits were poorer in VWF. Our work suggests that the level of anticoagulation should be modulated according to the type of coating of the ECMO circuit.The aim of our third study was to identify the most relevant bleeding events that may guide clinical decision-making for more aggressive clinical management and a greater investment in research. To this end, we compared the association between 3 bleeding classifications with 28-day mortality. The ELSO definition already in use and the BARC classification classes ≥ type 2 were associated with 28-day mortality and thus retained as definitions of major bleeding. Laboratory parameters that are predictors major bleeding according to the ELSO definition were decreased fibrinogen, platelet count, and hemoglobin at cannulations. Body mass index and postcardiotomy etiology were also predictive of ELSO major bleeding. In an additional work related to the topic of the thesis, we studied two of the most used laboratory tests for the monitoring of systemic heparin during VA-ECMO, the APTT and the Anti-Xa activity, to identify the most relevant. First, we studied the relationship between these two tests and then analyzed in a second objective the impact of biological influencing factors on this relationship. Next, we determined their associations with thrombotic and hemorrhagic complications. Although linearly associated, the rate of discordance between their measurements was 39 % for an Anti-Xa reference range of 0.3 - 0.7 IU/mL. Neither APTT nor Anti-Xa was associated with thrombotic or bleeding complications. Taken together, our results highlight the heterogeneity of thrombi from peripheral VA-ECMO, the involvement of numerous causal factors that underline thrombotic and hemorrhagic complications, both not predictable by routine tests. Finally, our work underscored the need for new approaches in thrombotic or hemorrhagic complications management with targets set at an individual level considering both patient and ECMO circuit characteristics

Records of all neurosurgical inpatients admitted to Royal North Shore Hospital since 1976 have been prospectively kept in a relational database. Demographic details, diagnoses, operations and complications have been entered continuously since 1982 by the author of this study. Complications are monitored at monthly review meetings attended by medical staff. The recurrence of deep vein thrombosis (DVT) and pulmonary embolism (PE) at these meetings, despite continual improvements in patient care, prompted this study. It aims to use the database to study changes in the incidence of DVT and PE over the previous twenty years; to find what database variables predict these complications; and whether use of mechanical and pharmacological agents has had an impact on DVT and PE rate. Univariate analysis of the incidence of DVT and PE by age, sex, length of stay (LOS), admission month, diagnosis, operation and surgeon over time was run. Any significant variables were then analysed by multivariate logistic regression. The DVT rate was low by world standards, but rose from 0.6% in 1979-83 to 1.2% in 1984-88, then rose exponentially to 3.60% in 1994-98 with a significantly increasing trend over the twenty years (c2 MH =114.20, with IDF, P<0.001). PE rate doubled significantly over the twenty years from 0.6% to 1.2% (c2 MH =17.94 with 1DF, P<0.001). Age, LOS, diagnosis, operation and surgeon were significant predictors of DVT and PE. After adjustment for LOS, time period and age, vascular surgery was found to be the strongest predictor of DVT (OR=2.82, 95% CI: 2.08-3.82, c2 =43.91, P<0.01). Vascular diagnosis was the strongest diagnosis predictor. No effect of sex or month of admission was shown. After adjustment for LOS, time period and age, spinal fusion was the strongest predictor of PE (OR=4.04, 95% CI: 1.81-9.03). Anterior communicating artery aneurysm was the diagnosis most highly associated with PE. The rise in DVT rate may be due to increased complexity of surgical and nursing management, and some screening of patients with the introduction of duplex scanning. The doubling of PE rate is unexplained. The risk of brain or spinal cord haemorrhage makes prophylactic anticoagulation a difficult choice. This study reveals groupings which can be used to determine appropriate prophylaxis. Use of mechanical and pharmaceutical agents is not recorded consistently in the database, but it is known approximately when they were introduced. No impact on the rate of DVT and PE can be demonstrated by these agents. More vigilant and widespread use of mechanical prophylaxis might be just as effective in controlling DVT and PE.

Records of all neurosurgical inpatients admitted to Royal North Shore Hospital since 1976 have been prospectively kept in a relational database. Demographic details, diagnoses, operations and complications have been entered continuously since 1982 by the author of this study. Complications are monitored at monthly review meetings attended by medical staff. The recurrence of deep vein thrombosis (DVT) and pulmonary embolism (PE) at these meetings, despite continual improvements in patient care, prompted this study. It aims to use the database to study changes in the incidence of DVT and PE over the previous twenty years; to find what database variables predict these complications; and whether use of mechanical and pharmacological agents has had an impact on DVT and PE rate. Univariate analysis of the incidence of DVT and PE by age, sex, length of stay (LOS), admission month, diagnosis, operation and surgeon over time was run. Any significant variables were then analysed by multivariate logistic regression. The DVT rate was low by world standards, but rose from 0.6% in 1979-83 to 1.2% in 1984-88, then rose exponentially to 3.60% in 1994-98 with a significantly increasing trend over the twenty years (c2 MH =114.20, with IDF, P<0.001). PE rate doubled significantly over the twenty years from 0.6% to 1.2% (c2 MH =17.94 with 1DF, P<0.001). Age, LOS, diagnosis, operation and surgeon were significant predictors of DVT and PE. After adjustment for LOS, time period and age, vascular surgery was found to be the strongest predictor of DVT (OR=2.82, 95% CI: 2.08-3.82, c2 =43.91, P<0.01). Vascular diagnosis was the strongest diagnosis predictor. No effect of sex or month of admission was shown. After adjustment for LOS, time period and age, spinal fusion was the strongest predictor of PE (OR=4.04, 95% CI: 1.81-9.03). Anterior communicating artery aneurysm was the diagnosis most highly associated with PE. The rise in DVT rate may be due to increased complexity of surgical and nursing management, and some screening of patients with the introduction of duplex scanning. The doubling of PE rate is unexplained. The risk of brain or spinal cord haemorrhage makes prophylactic anticoagulation a difficult choice. This study reveals groupings which can be used to determine appropriate prophylaxis. Use of mechanical and pharmaceutical agents is not recorded consistently in the database, but it is known approximately when they were introduced. No impact on the rate of DVT and PE can be demonstrated by these agents. More vigilant and widespread use of mechanical prophylaxis might be just as effective in controlling DVT and PE.

Introduction and Aims Although relatively uncommon in children, end-stage liver failure is a potentially devastating condition that occurs secondary to either a congenital anomaly causing cholestasis, metabolic disease (MTBD), neoplasia or fulminant hepatic failure (FHF). When this occurs, patients will likely require liver transplantation (LT). LT remains the gold-standard for children with end-stage liver failure despite high morbidity and mortality associated with the complex pathophysiology of liver failure, the procedure itself and subsequent lifelong immunosuppression. Surgical complications, often grouped as either general and gastrointestinal (GI), vascular or biliary complications are commonly seen in these patients and can impact on patient morbidity, mortality and graft survival. However, new immunosuppressants, surgical techniques such as in-situ split liver grafts, delayed primary closure (DPC) and microsurgery, as well as better post-operative care involving routine anti-coagulation protocols have improved outcomes significantly. The aim of this work was to assess the impact of new surgical techniques on the incidence of complications following pediatric LT at a single tertiary liver transplant center. Materials and Methods To address these aims, this thesis includes two studies. In the first study, we assessed the impact of DPC and the risk of general and GI surgical complications. We retrospectively collected data on children under the age of 18 who underwent LT between April 1986 and May 2014. The primary outcome measured was the incidence of general and GI complications either in the early (<3 months), intermediate (3 months–1 year) or late (>1 year) post-transplant period. The second study explored the impact of split grafts, microsurgical anastomosis and routine anti-coagulation on incidence of hepatic artery thrombosis (HAT). We did this by assessing the incidence of HAT in three distinct eras between April 1986 and April 2016, which marked the introduction of microsurgical anastomosis (Era 2) and in addition, a routine anti-coagulation protocol (Era 3). The major outcome measured was incidence and management of HAT in each of the three eras. Research ethics approval was obtained from the Sydney Children’s Hospital Network Ethics Committee. Results In our first study, a positive association was found between biliary atresia (BA) patients and the incidence of bowel perforation post-LT. We confirmed that DPC with or without the use of prosthetic implants was safe and did not increase the rate of general and GI complications. The second study found that the introduction of a routine anti-coagulation protocol significantly reduced incidence of HAT independent of the introduction of microvascular anastomotic techniques. A secondary finding was that minor bleeding (not requiring operative intervention) was more common Era 3. In both studies, the use of split liver grafts was not associated with an increase in surgical complications. Conclusions Recent advances in pediatric LT are safe and in some cases have been beneficial in reducing the incidence of post-operative complications. The advent of split graft LT has decreased the organ wait time and is a safe alternative to whole or reduced grafts. DPC provides a means of difficult abdominal closure and does not increase the risk of general and GI complications. The introduction of microvascular techniques for vessel anastomosis and a routine anticoagulation protocol have been efficacious, with the later significantly reducing the incidence of HAT.

Introdução: Pacientes submetidos à amputação de membro inferior por doença arterial obstrutiva periférica (DAOP) estão em risco para o desenvolvimento de trombose venosa profunda (TVP). Há poucos estudos na literatura sobre a incidência no pós-operatório precoce e quanto aos fatores de risco no desenvolvimento da TVP no membro amputado. Objetivo: A finalidade deste estudo é avaliar, de modo prospectivo, a incidência de trombose venosa profunda pós-operatória em até 35 dias, em pacientes submetidos à amputação de membro inferior por doença arterial obstrutiva periférica, sua relação com comorbidades e com óbito. Método: De setembro de 2004 a março de 2006, foram estudados 56 pacientes (29 homens; média de idade 67,25 anos) submetidos a 62 amputações (36 transtibiais e 26 transfemorais), utilizando-se eco-Doppler no pré-operatório e aproximadamente no 7º e 31° dia de pós-operatório. Resultado: Houve TVP em 16 (25,8%) membros amputados, sendo 10 casos em amputações transfemorais e 6 casos em transtibiais. A incidência cumulativa no período até 35 dias foi de 28% (Kaplan-Meier). Houve diferença significativa na incidência de TVP entre amputações transfemorais (37,5%) e transtibiais (21,2%), p = 0,04. Outro fator de risco para TVP foi idade igual ou superior a 70 anos (48,9 vs 16,8%, p=0,021). Houve 01 caso de embolia pulmonar sintomática não fatal em paciente com TVP já diagnosticada. Não houve relação entre outras comorbidades e TVP. A trombose venosa no membro amputado não influenciou na taxa de óbito que foi de 9,7%. Conclusões: A incidência de TVP no pós-operatório recente (até 35 dias) foi elevada principalmente em pacientes com idade igual e superior a 70 anos e nas amputações transfemorais. Os pacientes com DAOP submetidos a grandes amputações devem ser considerados de alto risco para TVP, mesmo após alta hospitalar.
Introduction: Patients undergoing amputation of the lower limb due to Peripheral Arterial Disease (PAD) are at risk for developing Deep Venous Thrombosis (DVT). There are few studies in the research literature on the incidence of DVT during the early postoperative period and the risk factors for the development of DVT in the amputation stump. Objective: The goal of this prospective study was to evaluate the incidence of deep venous thrombosis during the first 35 postoperative days in patients who had undergone amputation of the lower extremity due to PAD, and its relation to comorbidities and death. Method: From September 2004 to March 2006, fifty-six patients (29 men, mean age 67.25 years) underwent 62 amputations (36 below knee amputation BKA and 26 above knee amputation- AKA), and echo- Doppler scanning on preoperative, and approximately the seventh and 31st postoperative days. Results: DVT occurred in 16 (25.8%) of the amputated extremities, (10 AKA and 06 BKA). The cumulative incidence in the 35 day postoperative period was 28% (Kaplan-Meier). There was a significant difference in the incidence of DVT between AKA (37.5%) and BKA (21.2%), p = .04. Another DVT risk factor was age equal to or above 70 years (48.9 vs. 16.8%, p= .021). There was one case of symptomatic non-fatal pulmonary embolism in a patient already diagnosed with DVT. There was no relation between other comorbidities and DVT. Venous Thrombosis in the amputation stump did not influence the mortality rate which was 9.7%. Conclusions: The incidence of DVT in the early post-operative period (up to 35 days) was elevated mainly in patients 70 years of age or older and in AKA. Patients with PAD who have recently undergone major amputations should be considered at high risk for DVT, even after hospital discharge.

A trombocitopenia induzida por heparina (TIH) é uma síndrome imunohematológica mediada por um anticorpo que causa ativação plaquetária na presença de heparina, induz à agregação plaquetária e pode estar associada a graves e paradoxais complicações trombóticas e morte. A freqüência de TIH nos pacientes que recebem heparina por mais de cinco dias é de 1% a 5%, e está relacionada a vários fatores. Este é um estudo pioneiro no Brasil, que objetivou avaliar aqui a freqüência de TIH nos pacientes em uso de heparina, a relação ao gênero, ao tipo de heparina e a associação do genótipo da FcRIIa de receptores plaquetários. Foram selecionados 278 pacientes das Unidades de Terapia Intensiva e Unidades Coronariana do InCor-HCFMUSP, que receberam anticoagulação por heparina não fracionada (HNF) e/ou heparina de baixo peso molecular (HBPM), por pelo menos 5 dias, e excluídas as possíveis causas conhecidas de trombocitopenia. Foi realizada a contagem plaquetária pré e pós terapia com heparina, e o teste de detecção do anticorpo anti-fator 4 plaquetário/heparina (ID-PaGIA, DiaMed; e Asserachrom®-HPIA, Stago). O estudo da genotipagem da FcRIIa de receptores plaquetários foi realizado pelo método de digestão com enzima de restrição alelo específica. A freqüência de TIH encontrada foi de 6 (2,2%), e a freqüência de trombocitopenia com a presença do anticorpo anti-fator 4 plaquetário foi de 24,3%. A análise do gênero do paciente não demonstrou correlação com a TIH, nem com a trombocitopenia e nem com o anticorpo anti-fator 4 plaquetário. As mulheres apresentaram mais trombose do que os homens. A trombocitopenia ocorreu com maior freqüência nos pacientes que utilizaram os dois tipos de heparina (HNF-HBPM) e, com menor freqüência, nos que utilizaram apenas HBPM. O genótipo da FcRIIa de receptores plaquetários não apresentou relação com o gênero, nem com a TIH. Este estudo determinou a freqüência de TIH em uma população brasileira com uso de heparina e auxiliou no diagnostico. O melhor teste para detectar o anticorpo anti-fator 4 plaquetário/heparina, na presença de trombocitopenia e trombose, foi o teste de imunoaglutinação ID-PaGIA (DiaMed). A utilização dos dois tipos de heparina promoveu uma maior freqüência de trombocitopenia. Porém, novos estudos precisam confirmar as relações entre o tipo de heparina, com a trombocitopenia e com a TIH
Heparin induced thrombocytopenia (HIT) is an immune-hematologic syndrome mediated by a heparin dependent antibody that causes platelet activation, platelet aggregation, and can be associated with thrombosis and death. HIT occurs in about 1-5% of patients receiving heparin therapy up to 5 days or more. Many factors influence on the frequency of HIT. This is a pioneer Brazilian study to determine the frequency of HIT on patients under heparin therapy, and the relationship of HIT with gender, heparin type and the FcRIIa platelet receptor genotype. 278 patients from the Intensive Care Unit and Cardiac Care Unit at InCor-HCFMUSP treated with Unfractionated Heparin (UFH) and/or Low Molecular Weight Heparin (LMWH) for 5 or more days were studied. Known causes of thrombocytopenia were excluded. Platelet count was monitored pre and post heparin therapy. All selected patients were tested for detection of anti-heparin/PF4 antibody (ID-PaGIA, DiaMed; and Asserachrom®-HPIA, Stago). HIT frequency found was 6 (2,2%) and the frequency of thrombocytopenia (determined by a decrease in the platelet count below 50%, after the introduction of heparin therapy) and positive anti-heparin/PF4 antibody test was 24,3%. Patients gender was not related to TIH, neither to thrombocytopenia nor to the presence of antiheparin/ PF4 antibody. Thrombosis events were more frequent in women than in men. Thrombocytopenia, related to the type of heparin, was more frequent in patients that had used both types of heparin and less frequent in those that used only LMWH. FcRIIa platelet receptor genotype was associated with neither HIT nor with gender. This study has provided the frequency of HIT in a Brazilian patient population under heparin therapy and auxiliary in the HIT diagnosis. The ID-PaGIA (DiaMed) was shown to be the best test to correlate the presence of anti-heparin/PF4 antibody to thrombocytopenia and thrombosis event. The use of both heparin types promotes more thrombocytopenia. New studies are needed to confirm the relationship between heparin type and thrombocytopenia with HIT

Bakgrund: Djup ventrombos (DVT) är en allvarlig komplikation postoperativt och kan leda till ett livshotande tillstånd för patienten. Graderade kompressionsstrumpor (GCS) används på många postoperativa avdelningar tillsammans med andra profylaktiska åtgärder för att förebygga utvecklingen av DVT. Kompressionsstrumpor används även till att förebygga posttrombotiskt syndrom (PTS) efter en DVT. PTS kan utvecklas på grund av att de venösa klaffarna skadas vid en DVT, till följd stockar sig blodet och ödem bildas vilket leder till försämrad näring- och syretillförsel till vävnaderna. Syfte: Syftet var att genom en litteraturstudie undersöka om kompressionsstrumpor hade någon effekt för att förebygga DVT postoperativt samt om kompressionsstrumpor hade någon effekt att förebygga PTS efter en DVT. Metod: Litteraturstudie som baserads på 11 RCT studier. Resultat: GCS utan andra profylaktiska åtgärder visade sig ha en god effekt för att undvika utvecklingen av DVT på patienter som genomgått en operation. Däremot visade sig användandet av GCS i kombination med andra beprövade profylax inte ha någon större effekt för att reducera uppkomsten av DVT ytterligare. Resultatet angående GCS effekt för att undvika utvecklingen av PTS visade ingen entydighet. Slutsats: GCS har en förebyggande effekt för att undvika uppkomsten av DVT. Användningen av GCS i kombination med andra profylax potentierar däremot inte effekten av preventionen för DVT. GCS verkan för att förebygga uppkomsten av PTS är inte entydigt och flera studier behövs för att se evidens kring detta.
ABSTRACT  Background: Deep vein thrombosis (DVT) is a serious complication postoperatively and can lead to a life threatening condition for the patient. Graded compression stockings (GCS) are used in many post-operative departments along with other prophylactic measures to prevent the development of DVT. Compression stockings are also used to prevent postthrombotic syndrome (PTS) after a DVT. PTS can develop because the venous valves are damaged by a DVT, as a result, the blood is stored and edema is formed, which leads to poor nutritional and oxygen supply to the tissues. Aim: The aim of the literature study was to investigate whether compression stockings had any effect in preventing DVT postoperatively, and also whether the compression stockings had any effect in preventing PTS after a DVT. Method: Literature study based on 11 RCT studies. Results: GCS without other prophylactic measures was found to have a good effect in avoiding the development of DVT in patients who underwent surgery. However, the use of GCS in combination with other proven prophylaxis was found to have no significant effect in further reducing the onset of DVT. The results regarding the GCS effect to avoid the development of PTS showed no unambiguity. Conclusion: GCS has a preventive effect to avoid the onset of DVT. However, the use of GCS in combination with other prophylaxis does not potentiate the effect of prevention for DVT. The effect of GCS in preventing the onset of PTS is not unambiguous and several studies are needed to see evidence of this.

Rationnel: Bien qu'elles constituent la majorité des thromboses veineuses des membres inférieurs, les thromboses veineuses profondes (TVP) distale et les thromboses veineuses superficielles (TVS) ont été peu étudiées et leur significativité clinique et leur prise en charge sont débattues.Méthodes: Cette thèse collige les résultats des travaux effectués par J.P. Galanaud sur les TVP distales et les TVS à partir des études épidémiologiques OPTIMEV, POST et RIETE.Résultats commentés: TVP distale: La TVP distale n'a pas le même profil de facteur de risque que la TVP proximale. Sa mortalité associée à court terme est plus faible que celle des TVP proximales mais supérieure à celle de témoins confirmant qu'il s'agit d'une entité cliniquement significative. Les différences de profil de population et de complications entre ces deux types de TVP suggèrent que le rapport bénéfice/risque du traitement anticoagulant est différent. Il n'est donc pas légitime d'extrapoler les résultats des essais des TVP proximales aux TVP distales. Des essais spécifiques sont donc nécessaires.TVS: En cas de TVS le risque de TVP concomitante est élevé. Un examen écho-doppler doit être réalisé et devra au moins explorer l'ensemble du réseau profond du membre inférieur affecté. Sexe masculin et antécédents de TVP/Embolie pulmonaire constituent des facteurs prédictifs indépendants de récidive. Si certaines TVS peuvent être traitées avec succès sans traitement anticoagulant, celles associées à un cancer ou à une atteinte saphéno-fémorale sont à haut risque de récidive y compris après un traitement anticoagulant curatif
Background: Though they represent the majority of all lower limbs thromboses, isolated distal deep-vein thrombosis (DVT) (without symptomatic pulmonary embolism (PE)) and isolated superficial vein thrombosis (SVT) (without DVT or PE) have been poorly studied. Their clinical significance and management are under debate.Methods: Data from epidemiological multicenter prospective studies OPTIMEV, POST, RIETEResults and comments: Isolated distal DVT: Distal and proximal DVTs exhibit a different risk factor profile, the latter being more associated with chronic risk factors. Three-month mortality of distal DVT patient is lower than that of proximal DVT ones but is higher than that of controls. This evidences that distal DVT is a clinically significant finding. Differences in population profile and outcomes suggests that the benefit/risk ratio of anticoagulant treatment is not similar. Data from proximal DVT clinical trials should no longer be extrapolated to distal DVT.Isolated SVT: In case of SVT the risk of concomitant DVT is high. A compression ultrasonographic exam should be performed and at least explore the whole deep venous system of the affected limb. Male gender and history of DVT/Pulmonary embolism are independent predicators of recurrence. Some SVT can be safely treated without anticoagulants. On contrary, in patients with cancer or a sapheno-femoral junction involvement, the risk of deep venous recurrence is high even upon full therapeutic dose of anticoagulants

[Truncated abstract] Cardiac surgery involving cardiopulmonary bypass is a complex procedure that results in significant changes to blood coagulation, fibrinolytic biochemistry, platelet number and function, and the vasculature. These are due to pharmacological agents which are administered, haemodilution and contact of the blood with artificial surfaces. Consequently there are significant risks of thrombosis and haemorrhage associated with this procedure. The research presented in this thesis utilises in vitro, in vivo, and a novel ex vivo model to investigate the nature of the haemostatic defect induced by cardiopulmonary bypass. The components studied include the drugs heparin, protamine sulphate, and aprotinin, different types of bypass circuitry (including heparin bonded circuits) and procedures such as acute normovolaemic haemodilution. Patient variables, such as Factor V Leiden, are also studied. Each of these components is assessed for the effects on a number of laboratory measures of haemostasis including activated partial thromboplastin time, prothrombin time, activated protein C ratio, antithrombin concentration, heparin concentration, thrombin-antithrombin complex formation, prothrombin fragment 1+2 formation, markers of platelet surface activation and secretion, activated clotting time, haemoglobin concentration and coagulation factor assays.

Habilitacijos procedūrai teikiamoje mokslo darbų apžvalgoje apibendrinama Vilniaus universiteto Širdies ir kraujagyslių ligų klinikos Širdies chirurgijos centro patirtis, pakartotinai operuojant ligonius po širdies vožtuvų protezavimo. Įvertintas mažai trombogeniškų protezų efektyvumas. Nustatyta, kad labai sunkių ligonių su infekuotais protezais mirštamumas nemažėja, nors pastaraisiais metais daugiau operuojame III funkcinės klasės ligonių ir jų operacijų rezultatai puikūs. Dėl pasiūlyto radikalesnio triburio vožtuvo nesandarumo gydymo pirminių operacijų metu, efektyviai mažėja pakartotinių šio vožtuvo operacijų. Įteisinta planinė seno rutulinio protezo pakeitimo operacija. Įdiegti nauji širdies pjūviai, įdiegtos krūtinės ląstos pjūvių atlikimo metodikos, farmakologiniai ir nefarmakologiniai perioperacinio kraujavimo stabdymo būdai efektyviai sumažina kraujavimo pavojų. Pasiūlytas originalus kairio skilvelio drenavimo būdas per atskira torakotominį pjūvį padeda sumažinti pooperacinį širdies nepakankamumą. Šiame darbe remiuosi kartu su bendradarbiais atliktų operacijų rezultatais. Šiuo metu kaip skyriaus, kuriame gydomi ligoniai su vožtuvų patologija, vadovas atlieku daugiau kaip pusę pakartotinių operacijų. Moksliniai pranešimai apie pakartotinių operacijų rezultatus buvo daryti Lietuvos, Pasaulio ir Europos kongresuose ir suvažiavimuose.
The review of scientific work presented for habilitation procedure summarizes the experience of redo operations of patients after replacement of heart valves accumulated at the Heart Surgery Centre of Vilnius University Clinic of Angiology and Cardiology. The efficacy of low thrombogenicity valve prostheses was evaluated. It was found out that the mortality rate of very severely ill patients with infected did not decrease; however the larger number of patients in functional class III were being operated during the period of recent years and the results of these operations were excellent. The rate of redo tricuspid valve operations had decreased effectively because of more radical surgery treatment of this valve during the primary operation. The operation of replacement of old ball prosthesis has been validated. The new incisions of the heart were introduced as well as new methods of performance of chest box incisions and pharmacologic and non-pharmacologic methods of perioperative hemostasis; the methods mentioned above effectively reduced the risk of bleeding. The original method of the left ventricle venting via separate thoracotomy incision enabled to reduce postoperative heart failure. This work is based on the results of operations performed in cooperation with co-workers. As a chief of the department where the patients with pathology of heart valves are treated, I am performing more than a half of redo operations. The scientific presentations concerning the results of... [to full text]

INTRODUCCIÓN: La causa más importante de mortalidad materna en los países occidentales es la enfermedad tromboembólica venosa (ETEV). El embarazo es un estado de hipercoagulabilidad que predispone a la aparición de este tipo de complicaciones, aún más si existen otros factores de riesgo, como la trombofilia. La presencia de trombofilia también se ha relacionado en las últimas décadas con la aparición con otro tipo de complicaciones gestacionales aún más frecuentes: las llamadas complicaciones vasculares gestacionales (CVG), al parecer secundarias a una disfunción o insuficiencia placentaria. JUSTIFICACIÓN Y OBJETIVOS: La evidencia científica en cuanto a la necesidad de realizar estudios de trombofilia y al manejo terapéutico en este campo es limitada, debido a la falta de ensayos clínicos randomizados y la experiencia se basa en estudios observacionales. Por este motivo se creó el proyecto TEAM, con el objetivo de conocer la prevalencia de enfermedad tromboembólica y de las complicaciones obstétricas relacionadas con la trombosis, el estudio etiológico y el manejo terapéutico que se realiza en estos casos y evaluar la efectividad y seguridad de dichos tratamientos. MATERIAL Y MÉTODOS: Se trata de un estudio multicéntrico, multidisciplinar, prospectivo y observacional en el que se incluyeron cuatro cohortes de pacientes que presentaban en la gestación actual o habían presentado en gestaciones previas complicaciones tipo trombosis o CVG: 1. Cohorte trombosis, 2. Cohorte profilaxis de trombosis, 3. Cohorte CVG, 4. Cohorte profilaxis de CVG. Para la recogida de datos se desarrolló un registro informatizado. Se analizaron las características clínicas de las diferentes cohortes y se evaluó la realización de estudios de trombofilia y la realización de tratamiento antitrombótico y el tipo en las cohortes de profilaxis. RESULTADOS: Se registraron un total de 1032 episodios y 1000 pacientes. La distribución de estos episodios fue: 57 (5.5%) trombosis, 312 (30.2%) profilaxis de trombosis, 368 (35.7%) CVG y 257 (24.9%) profilaxis de CVG. In los grupos de CVG y profilaxis de CVG las pérdidas gestacionales fueron la complicación más frecuente (65.5 and 94.2% respectively). Se realizó estudio de trombofilia en el 82.6% de pacientes de CVG y 70.2% de trombosis. Los resultados fueron positivos en el 47 y 59% de pacientes con trombosis y profilaxis de trombosis y en 21% de las cohortes de CVG. En este grupo los defectos más comunes fueron la elevación del factor VIII el genotipo ABO no-O, la presencia de anticuerpos antifosfolípidos (AAF) y la mutación F12C46T en homocigosis. Se empleó tratamiento antitrombótico en el 85% de los episodios de profilaxis de trombosis (fundamentalmenete HBPM sola) y en el 77% de los casos de profilaxis de CVG (fundamentalmente HBPM+AAS). Sólo se registraron dos complicaciones hemorrágicas mayores. La efectividad del tratamiento no se pudo evaluar en el grupo de profilaxis de trombosis, por una tasa de recurrencia muy baja (0,32%). La profilaxis con HBPM +/- AAS en el grupo de profilaxis de CVG no se relacionó con una mejora en el resultado de la gestación. CONCLUSIONES: La realización de estudios de trombofilia se realizaron a la mayoría de las pacientes en las cuatro cohortes. Los resultados fueron diferentes en el grupo de CVG, con elevada prevalencia de niveles de FVIII elevados, AAF positivos y F1246T homocigoto. La mayoría de mapacientes en el grupo de profilaxis de trombosis recibieron HBPM, pero no se encontró un beneficio significativo por el empleo de dicho tratamiento.
INTRODUCTION: Thromboembolic disease is the main cause of maternal mortality in Developed countries. Gestation is an hypercoagulable state with a predisposition to thrombosis, even more if there is another risk factor as thrombophilia. Thrombophilia has also been related with other frequent complications, the so-called vascular placental complicatons (VPC), due to placental insufficiency. There is a lack of evidence in this subject because of the absence of well-designed clinical randomized trials. OBJECTIVES: This lack of evidence conducted us to the design of the TEAM Project. The main objectives were: 1. Establish the prevalence of thrombophilia in pregnancy-related thrombosis and VPC. 2. Evaluate the clinical management of these complications. 3. Determine effectiveness and security of treatments used in this scenarios. MATERIALS AND METHODS: Multicenter, multidisciplinary, prospective and observational study. We analysed 4 patient cohorts: 1. Thrombosis cohort, 2. thrombosis prophylaxis cohort, 3. VPC cohort, 4. VPC prophylaxis cohort. We developed an informatic registry for data collection. We study clinic characteristics, performance of thrombophilia screening and antithrombotic treatments used in each cohort. RESULTADOS: A total of 1032 episodes and 1000 patients were registered. Distribution of these episodes was: 57 (5.5%) thrombosis, 312 (30.2%) thrombosis prophylaxis, 368 (35.7%) VPC and 257 (24.9%) PVC prophylaxis. In the VPC groups pregnancy loss was the most frequent complication registered (65.5 and 94.2% respectively). Thrombophilia studies were made in 82.6% patients in VPC cohort and in 70.2% of thrombosis patients. Positive results were obtained in 47 and 59% of patients in thrombosis and thrombosis prophylaxis groups and in 21% of patients with VPC. In this group the most common defects found were high levels of FVIII, no-O ABO genotype, positive antiphospholipid antibodies and homocygosity for F12C46T polymorphism. Antithrombotic treatment was used in 85% of thrombosis prophylaxis episodes, mainly with low molecular weight heparins (LMWH), and in 77% of VPC prophylaxis episodes, mainly with LMWH and aspirin. Only two major hemorrhagic complications were registered. Treatment effectiveness could not be evaluated in thrombosis prophylaxis cohort because of a very low recurrence rate (0.32%). Prophylaxis with LMWH +/- aspirin was not related with a better pregnancy outcome in VPC prophylaxis group. CONCLUSIONES: Thrombophilia studies were made to most patients in this registry i all four cohorts. Results were different in patients with thrombosis and VPC. In this group we found a high prevalence of high levels of FVIII, positive antiphospholipid antibodies and homocygosity for F12C46T polymorphism. Most patients in VPC prophylaxis group with or without thrombophilia recieved LMWH +/- aspirin, but we did not find a benefit of these treatments. Further studies with more patients will be needed to confirm our findings.

I ntrodução: A incidência de lesões venosas pós-implante transvenoso de dispositivos cardíacos eletrônicos implantáveis (DCEI) é elevada, sendo a disfunção ventricular e o uso prévio de marcapasso temporário (MPT) ipsilateral ao implante definitivo fatores de risco independentes para sua ocorrência. A utilidade de estratégias terapêuticas profiláticas para a prevenção dessa complicação ainda permanece controversa. O objetivo desse estudo clínico, randomizado e controlado foi avaliar o papel da anticoagulação oral na prevenção das lesões venosas pós-implante transvenoso de DCEI em pacientes de alto risco, analisando a influência na incidência das obstruções venosas, a segurança, a eficácia e as complicações do tratamento. Método: No período de Fevereiro/2004 a Setembro/2007 foram estudados 101 pacientes adultos submetidos ao primeiro implante transvenoso de DCEI, apresentando fração de ejeção do ventrículo esquerdo (FEVE) <=0,40 e/ou presença de MPT ipsilateral ao implante definitivo. Após o procedimento, os pacientes foram randomizados para o uso diário de placebo ou varfarina. Avaliações clínicas e laboratoriais foram realizadas periodicamente. A pesquisa de lesões venosas foi feita pela venografia por subtração digital, seis meses após o implante. A análise dos dados foi realizada segundo o princípio de \"intenção-de-tratar\". Na análise da associação das variáveis demográficas, clínicas e operatórias com a presença de lesões venosas empregou-se os testes Qui-quadrado, Exato de Fisher ou \"t\" de Student e o modelo de regressão logística foi utilizado para a identificação de fatores de risco. Resultados: As características basais foram similares nos dois grupos, não sendo encontradas diferenças significativas entre as variáveis demográficas, clínicas e operatórias. Durante o período de seguimento clínico, ocorreram seis óbitos, quatro relacionados com a progressão da insuficiência cardíaca e duas mortes súbitas. Do total de óbitos, quatro pacientes estavam alocados no Grupo Varfarina e dois no Placebo. Somente um paciente, do Grupo Varfarina, apresentou sangramento gastrintestinal, com necessidade de hospitalização e transfusão de hemoderivados. O valor médio do INR dos pacientes do Grupo Varfarina foi 2,3±0,7 enquanto que no Grupo Placebo foi 1,1±0,3, sendo que esta diferença manteve-se ao longo de todo o período de seguimento. O valor médio da hemoglobina e do hematócrito foi similar em ambos os grupos, sendo 13,9±1,6g/dL e 41,2±4,6%, no Grupo Placebo e 14,0±1,4g/dL e 41,9±3,7%, no Grupo Varfarina. Dos pacientes alocados no Grupo Varfarina, 17 (38,6%) apresentaram obstruções venosas, em comparação a 29 (60,4%) casos do Grupo Placebo, com redução absoluta do risco de 22% (RR= 0,63; IC 95%= 0,013 a 0,42). A comparação das características clínicas dos pacientes que apresentaram lesões venosas com as dos pacientes que não apresentaram mostrou que o uso de varfarina (P=0,037) esteve associado a uma menor incidência de lesões venosas e a presença da doença de Chagas (P= 0,051) esteve associada a uma maior incidência. Somente a ausência de anticoagulação oral foi identificada como fator de risco independente para a ocorrência das lesões venosas (OR= 2,424; IC 95% 1,048 - 5,606; P= 0,038). Conclusão: O uso profilático da anticoagulação mostrou-se seguro e reduziu significativamente a incidência de obstruções venosas pós-implante de DCEI nos pacientes de alto risco.
Introduction: The incidence of venous thrombosis after cardiac devices implantation is high. Ventricular dysfunction and previous transvenous temporary leads ipsilaterally to the permanent implantation are independent risk factors. The effect of prophylactic strategies to prevent these complications remains controversial. The aim of this clinical, randomized and controlled study was to evaluate the role of oral anticoagulant therapy in the prevention of these complications in high risk patients, analyzing the effect on the venous obstructions incidence, the safety, effectiveness and complications of this treatment. Method: Between February 2004 and September 2007, 101 adult patients submitted to first transvenous cardiac devices implantation, with left ventricular ejection fraction <=0.40 and/or previous transvenous temporary leads were evaluated. After device implantation, patients were randomly assigned to receive either placebo or warfarin. Periodical clinical and laboratorial evaluations were performed to anticoagulant management. Following the six-month period, every patient was submitted to a digital subtraction venography. Data analysis was performed according to the \"intention-to-treat\" principle. The association of demographic, clinical and procedure variables with the presence of venous lesions was analyzed by the Chi-square, Fisher\'s exact, or \"t\" Student tests, and logistic regression model was used to identify risk factors. Results: Baseline characteristics were similar in both groups and no significant difference was observed in demographic, clinical and procedure variables. During the follow-up period, six patients died, four related to heart failure progression and two of sudden death. Four of the patients dead were allocated in Warfarin group and two in Placebo group. Only one patient of the Warfarin group presented with gastrointestinal bleeding, requiring hospitalization and blood transfusion. The median INR of patients in the Warfarin group was 2.3 ± 0.7, whereas the median INR in the Placebo group was 1.1 ± 0.3. This difference was maintained throughout the study period. The median hemoglobin and hematocrit values were similar in both groups, with 13.9 ± 1.6g / dL and 41.2 ± 4.6% in the Placebo group and 14.0 ± 1.4g / dL and 41.9 ± 3.7% in the Warfarin group. The frequency of venous obstructions in the Warfarin group was 38.6% compared with 60.4% in the Placebo group (P=0.018), corresponding to an absolute risk reduction of 22% (RR= 0.63, 95% CI= 0.013-0.42). The comparison between obstructed and non-obstructed patients showed that warfarin use was associated with a lower incidence of venous lesions (P= 0.037) and that Chagas\' disease presence was associated with a higher incidence (P= 0.051). Logistic regression analysis showed that only absence of anticoagulant therapy (P=0.038; OR=2.424, 95% CI= 1.048 - 5.606) was a predictor of venous obstruction. Conclusion: The prophylactic use of the anticoagulation therapy has been safe and reduced the frequency of venous thrombosis after transvenous cardiac devices implantation in high risk patients.

Dans le cancer, l'activation de la cascade de coagulation et des plaquettes participent à la formation de thromboses, à la croissance tumorale, et les métastases. Ces thromboses représentent une complication clinique chez les patients atteints du cancer du pancréas. Cet état serait dû à expression par la tumeur et leurs microparticules (MPs) de facteur tissulaire (FT). Dans une première partie, nous avons identifié le FT et le FT pathway inhibitor exprimés par les MPs cancéreuses et la P-sélectine plaquettaire impliqués dans la progression tumorale, les métastases et la thrombose associée au cancer du pancréas .Nous avons montré le rôle des intégrines αvβ3 et αvβ et des "neutrophils extracellular traps" dans l’interaction des MPs cancéreuses avec les plaquettes dans des modèles murins de « deep vein thrombosis » et de blessure au laser. Nous avons alors évalué l’efficacité du clopidogrel qui présente une action anti tumorale et thrombotique. Cette étude a permis d’initier une étude clinique de phase III pour d’évaluer le potentiel thérapeutique du clopidogrel chez des patients atteints de cancer du pancréas. Dans une seconde partie, nous avons montré que des neutrophiles exprimant le FT agissent comme « starter » de la formation de thrombi. A l’inverse, dans un modèle d’inflammation stérile, nos travaux montrent le rôle de la P-sélectine plaquettaire dans le slow rolling, l’adhésion et la transmigration des neutrophiles a des temps précoses. L’ensemble de nos résultats suggère que les coopérations cellulaires entre l’endothélium, les plaquettes, les MPs et les neutrophiles constituent des mécanismes essentiels à la thrombose et l'inflammation
In cancers, the blood coagulation cascade and platelets can be activated to form thrombosis. This state will mainly due by the tumor and their microparticles (MPs) expression of tissue factor (TF), key protein of the coagulation cascade. In the first part of this study, we demonstrated that TF and the TF pathway inhibitor expressed by cancer MPs and the platelet P-selectin are involved in tumor progression, metastasis and the associated thrombosis in pancreatic cancer in mice. We showed the key role-play by αvβ3 and αvβ1 integrins and neutrophils extracellular traps in the interaction between cancer cells-derived MPs and platelets. We also evaluated the effect of clopidogrel, but not aspirin, treatment exhibits an anti-tumor action and limits thrombosis formation in preclinical models of pancreatic cancer. This study initiates a national investigation of a multicenter clinical phase III study to evaluate the therapeutic potential of clopidogrel in pancreatic cancer patients. In the second part of this study, we identified a “population of neutrophils expressing TF” that acts like a starter of the thrombus formation. At the reverse, in a sterile inflammatory model, our work showed the primordial role of platelet P-selectin in the slow rolling, the adhesion and the transmigration of neutrophils. All together our results suggest that the cooperation between the endothelium, platelets, MPs and neutrophils constitute essential mechanisms acting in the thrombosis and the inflammation

CD154 joue un rôle important dans la pathogenèse de plusieurs maladies auto-immunes, ainsi que des dysfonctionnements vasculaires. CD154 est un membre de la famille du facteur de nécrose tumorale (tumor necrosis factor, TNF) d'une importance cruciale dans l'immunité humorale. Cependant, CD154 partage également des fonctions critiques inflammatoires grâce à son interaction avec son récepteur CD40 ou des partenaires de liaison récemment identifiés, à savoir αIIbβ3, α5β1 et αMβ2. Ces réponses impliquent CD154 comme un facteur clé dans les maladies inflammatoires chroniques, notamment les maladies auto-immunes et la thrombose. L’interruption de l'interaction de CD154 avec ses récepteurs par anticorps anti-CD154 inhibe de manière significative le développement de ces maladies, bien que des effets secondaires graves ont été associés à ces traitements. Pour remédier à ces effets indésirables, d'autres approches comme des souris defficientes (Knockout), oligonucléotide antisens et ARNi ciblage ont été développés. Ces approches ont été axées sur l’interaction de CD154 avec CD40 et ne traitent pas l'interaction de CD154 avec ses autres récepteurs. Par conséquent, il existe un besoin de nouveaux traitements pour la prévention/abrogation des maladies inflammatoires ou auto-immunes qui cibles tous les récepteurs de CD154. Notre groupe a profondément étudié l'interaction structurelle/fonctionnelle de CD154 avec ses différents récepteurs. Étant donné l'importance de la structure trimérique de CD154 pour son activité biologique, nous avons généré une forme monomère de la molécule qui peut se lier spécifiquement à un récepteur sans induire l'activation intracellulaire. Cet agent est un outil thérapeutique potentiel pour le traitement de maladies reliées au CD154, tels que les événements thrombotiques.
CD154 has emerged as an important player in the pathogenesis of several autoimmune diseases, as well as vascular dysfunctions. CD154 is a member of the tumour necrosis factor family of pivotal importance in humoral immunity. However, CD154 also shares critical inflammatory functions through its interaction with its classical CD40 receptor or recently identified binding partners, namely αIIbβ3, α5β1 and αMβ2. These responses imply CD154 as a key factor in chronic inflammatory disorders including autoimmune diseases and thrombosis. Disrupting the interaction of CD154 with its receptors through anti-CD154 Abs significantly inhibits the development of these diseases, albeit serious side effects have been associated with these therapies. To overcome these adverse effects, other approaches such as knockout, antisense oligonucleotide and siRNA targeting were developed. These approaches were focused on the CD154/CD40 interaction and did not address the interaction of CD154 with its other receptors. Thus, there is a need for novel CD154 treatments for the prevention/abrogation of inflammatory or autoimmune diseases that address all CD154 receptors. Our group profoundly investigated the structural/functional interaction of CD154 with its various receptors. Given the importance of the trimeric structure of CD154 for its biological activity, we generated monomeric form of the molecule that can specifically bind to one receptor without inducing intracellular activation. This agent represents a potential therapeutic tool for the treatment of CD154-mediated diseases such as thrombotic events.

Background: Thrombosis is a common and critical consequence of cancer. Changes in thrombotic potential were examined after exercise training in patients with cancer. Methods: Eight cancer patients (65 ± 11 yrs) completed this study, five exercising and three non-exercising controls. Venous blood samples were obtained at baseline and after approximately 12 weeks of study participation. Weekly physical activity was measured using a standard, validated physical activity questionnaire. APTT, PT, fibrinogen and factor VIII were measured before and after the 12-week intervention. Results: A time x group interaction trend (p=0.067) was observed for fibrinogen. Plasma concentrations decreased in the exercise group (355 ± 49.3 mg/dL to 331 ± 19.5 mg/dL), but increased in the control group (341 ± 52.4 mg/dL to 384 ± 107.9 mg/dL). Physical activity significantly decreased over time in both groups. Conclusions: Exercise training may reduce coagulation potential in cancer patients more than usual and customary care.
School of Physical Education, Sport, and Exercise Science

Background Several case reports and studies have alluded to an increased prevalence of venous thrombosis in human immunodeficiency virus positive (HIV-positive) patients. Although a relationship between HIV infection and thrombotic disease has been suggested, the mechanisms predisposing to thrombosis have not been fully elucidated. Aim A prospective study, to determine possible coagulation factor abnormalities that could explain the predisposition to thrombosis in HIV-infected African (Black) patients, was undertaken. Method African (Black) patients, with acute upper segment deep vein thrombosis (DVT) confirmed by duplex ultrasound, were enrolled. Patients who had recognisable risk factors such as recent surgery, pregnancy or malignancy, were excluded. After informed consent, blood samples were taken for baseline tests as well as a thrombophilia screen. The control group comprised known HIV-positive African (Black) patients without DVT. Patients with DVT who were found to be HIV-negative were also analysed. Analysis was done in 2 parts: HIV-positive patients with and without thrombosis and HIV-positive and negative patients with thrombosis were compared. Results Part A: HIV-positive patients with and without thrombosis Of the 77 patients with DVT, 50 patients tested HIV-positive. These 50 patients (HIV-positive DVT-arm), as well as 56 controls (HIV-positive, no DVT), were enrolled into the study. The groups were well matched with regard to age, sex and cluster designation 4 (CD4) count. On univariate analysis, significant findings in the DVT-arm were a history of active tuberculosis on treatment, low protein C levels and a positive qualitative D-dimer, whereas on multivariate analysis, only tuberculosis and an elevated D-dimer proved to be significant. Part B: HIV-positive and negative patients with thrombosis There were 20 HIV-negative patients with DVT who met our inclusion criteria Limited assessment was done on this group owing to unavailability of some data. The mean age of the HIV positive DVT group was significantly lower than the HIV-negative group with DVT (31.78 vs. 41.45 years; p=0.005). There was no significant difference in the prevalence of tuberculosis between the HIV-positive and HIV-negative patients with thrombosis (p = 0.269). Mean protein C levels were reduced in the HIV-positive group and normal in the HIV-negative group. They were significantly lower in the HIV-positive patients compared to the negative group (p=0.02). Conclusion The findings of the study suggest a relationship between HIV, its complications and DVT. Although this study confirms HIV infection as a risk factor for thrombosis, clear pathogenetic mechanisms remain to be elucidated. In our population, tuberculosis appears to be an important risk factor predisposing patients to the development of DVT, both in the HIVpositive and negative population. Further studies will need to be done to confirm this hypothesis.
Thesis (MMed)-University of KwaZulu-Natal, Durban, 2006.