Les tiques du genre Ixodes englobent un grand nombre d’espèces dont Ixodes ricinus, objet de cette étude. Ixodes ricinus peuple les sous-bois de nos régions et la plupart des grandes forêts de l’Europe centrale et de l’est. Au cours de leur cycle parasitaire, les tiques réalisent un repas sanguin au détriment de petits mammifères (mulots, lièvres,…), mais aussi de grands mammifères tels que le cerf, la biche ou le sanglier. Elles deviennent particulièrement voraces au début du printemps et en automne, c’est pourquoi à ces époques de l’année, les promeneurs et les animaux domestiques (principalement, le chien) peuvent en être infestés. Pour mener à bien leur repas sanguin, les tiques mettent en place une série de mécanismes les rendant non seulement indécelables par l’animal parasité mais aussi leur donnant la capacité de contrecarrer les défenses de l’hôte. En effet, lors de sa fixation et durant tout le repas sanguin, la tique injecte un cocktail de facteurs bioactifs qui inhibent la sensation de douleur au moment de l’ancrage dans le derme, mais également les défenses immunitaires de l’hôte parasité. De plus, certains de ces facteurs possèdent des propriétés anti-hémostatiques garantissant la fluidité du sang pendant tout le repas.<p><p>Le Service de Biologie Moléculaire des Ectoparasites (anciennement Service de Génétique Appliquée) a identifié un grand nombre de séquences d’ARNm induites spécifiquement dans les glandes salivaires de la tique au cours de son repas sanguin. Deux d’entres-elles ont servi de point de départ à ce travail :il s’agit de seq16 (renommée Metis1) et de seq7 (renommée Ir-CPI).<p><p>Le travail sur la séquence seq16 a conduit à l’identification d’une nouvelle famille de 5 métalloprotéases (nommée Metis pour Metalloprotease from Ixodes ricinus). L’analyse des séquences a permis de les associer à certaines métalloprotéases hémorragiques de venin de serpent. Bien que les 5 métalloprotéases décrites possèdent toutes les mêmes caractéristiques au niveau de leur séquence et de leur profil d’expression dans les glandes salivaires, les résultats d’analyse phylogénétique, d’étude de variation antigénique, de leur mode d’activation et de leur spécificité d’action permettent de les diviser en 3 sous-familles. L’utilisation de la technique d’ARN interférence en in vivo et l’analyse vaccinale soulignent le rôle essentiel de la famille Metis dans les premières heures du repas de la tique et de manière générale dans la réussite du repas sanguin. Enfin, des études d’activité ont montré que certains membres de la famille ont une activité fibrino(gèno)lytique ;plus particulièrement, la protéine Metis4 possède une activité protéolytique envers la gélatine, la caséine, la fibronectine et le fibrinogène. Ces études ont montré également un mode d’activation original ;plutôt que d’être activée par une pro-séquence en amino-terminal, Metis4 s’active spontanément en perdant un peptide à son extrémité carboxy-terminale. <p><p>Le travail sur la séquence seq7 a conduit à la caractérisation d’un nouvel inhibiteur de sérines protéases. Cette protéine, nommée Ir-CPI pour « Ixodes ricinus - Contact Phase Inhibitor », possède un motif kunitz et est capable d’inhiber de manière importante la voie intrinsèque de la coagulation et dans une moindre mesure la fibrinolyse. Grâce à la technique d’ARN interférence, l’activité de la protéine recombinante a été corrélée à l’activité de la protéine native exprimée dans les glandes salivaires. Ir-CPI inhibe dans un plasma humain l’activation réciproque du facteur XII, de la prékallikréine et du facteur XI, et se fixe spécifiquement à la forme activée de ces trois facteurs. De plus, Ir-CPI est capable de bloquer la fibrinolyse en inhibant spécifiquement la plasmine. Enfin, les résultats obtenus sur deux modèles animaux indépendants établissent l’effet d’Ir-CPI comme agent anti-thrombotique en empêchant la formation de caillot et de manière remarquable sans altérer l'équilibre hémostatique.<p><p>En conclusion, ce travail a identifié des protéines anti-hémostatiques qui agissent soit comme inhibiteur de protéases empêchant la coagulation soit comme protéases facilitant la lyse du caillot. Cette redondance de protéines anti-hémostatiques illustre remarquablement la capacité de la tique à agir en synergie sur des facteurs essentiels aux mécanismes de défense de l’hôte.<p> / Doctorat en Sciences / info:eu-repo/semantics/nonPublished

Orientador: Joyce Maria Annichino-Bizzacchi / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-07T17:15:50Z (GMT). No. of bitstreams: 1 Paula_ErichViniciusde_D.pdf: 3311580 bytes, checksum: 0e2725586b5aed078f6a78de1edd1d14 (MD5) Previous issue date: 2006 / Resumo: A doença arterial oclusiva (DAO) é a principal causa de morbidade e mortalidade em países industrializados. Com o aumento da expectativa de vida da população mundial a DAO tornou-se um problema de saúde publica também em países em desenvolvimento. O tratamento de uma das formas graves de DAO, a isquemia crítica de membros inferiores (ICMI), normalmente oferece alívio temporário e muitas vezes requer a amputação do membro afetado. No Brasil, a sobrevida desses pacientes é comparável a algumas formas de câncer. Desta forma, a busca de estratégias terapêuticas alternativas à amputação é fundamental para estes pacientes. Nesse estudo, nós exploramos o papel da angiogênese terapêutica induzida por terapia gênica (TG) em modelos animais ICMI. A angiogênese terapêutica se baseia na utilização de fatores de crescimento vascular sob a forma de proteínas recombinantes ou TG. A reposição de proteína deve ser mantida por períodos prolongados e normalmente requer administração sistêmica. Isto aumenta o risco de formação de vasos em locais indesejáveis como tumores ocultos ou retina. Estudos clínicos anteriores demonstraram que a indução de angiogênese terapêutica utilizando apenas um fator pró-angiogênico é eficaz. No entanto, esses estudos sugerem que integridade destes neovasos é deficiente pela ocorrência de edema de membros inferiores ou proteinúria após a monoterapia angiogênica.Neste trabalho avaliamos a eficácia da TG combinada usando vetores não virais com os genes de dois fatores de crescimento: FGF-2 e PDGF-BB, em comparação com a transferência gênica isolada do VEGF-A. A escolha destes dois fatores deveu-se ao fato de eles atuarem em etapas distintas e complementares do processo de formação vascular: formação e estabilização dos novos vasos, respectivamente. Para este fim utilizamos o modelo de isquemia da pata posterior em ratos, e um novo método não invasivo, o 99mTc-sestamibi para avaliação da neovascularização. A expressão combinada do FGF-2 e PDGF-BB induziu a formação de neovasos com a mesma intensidade e com a mesma relevância funcional que o uso do VEGF-A isolado. No entanto, a estratégia combinada se mostrou mais atraente por induzir a formação de vasos mais íntegros, e necessitar de doses individuais 50% menores de cada gene terapêutico. Em conjunto esses dados demonstram que a TG combinada com FGF-2/PDGF-BB é eficaz e potencialmente mais segura para o tratamento da ICMI. Com o objetivo de definir fatores que afetam a resposta angiogênica pós-natal, nós investigamos o papel da trombina durante a indução de neovasos. Animais receberam diversos inibidores da coagulação imediatamente ou após 72 horas da indução de isquemia periférica. Nós documentamos que a inibição da coagulação sangüínea na fase aguda da isquemia diminui a resposta angiogênica, mas esse efeito não é observado quando a anticoagulação é iniciada após 72 horas. A ativação dos receptores celulares da trombina (e outras proteases) pode oferecer um novo alvo para otimizar a resposta angiogênica pós- natal. Em conjunto, os resultados obtidos formam a base para estudos futuros utilizando a TG combinada com FGF-2/PDGF-BB como uma alternativa potencialmente eficaz e segura paro tratamento da ICMI / Abstract: Arterial occlusive disease (AOD) is the main cause of mortality and morbidity in industrialized countries. Global improvements in life expectancy have turned it into a public health problem in developing countries as well. The treatment of one of the severe presentations of DAO, which is critical limb ischemia (CLI) normally offers temporary relief to symptoms, often requiring major amputations of the affected limb. In Brazil, the prognosis of CLI is similar to that of some forms of cancer. Therefore, new therapeutic strategies alternative to amputations are necessary for these patients. In the present work we evaluated the role of therapeutic angiogenesis induced by gene therapy (GT) in animal models of CLI. Therapeutic angiogenesis consists in the use of vascular growth factors by means of recombinant proteins or GT. When using protein formulations, therapy must be maintained for prolonged periods and normally involves systemic administration. These requirements increase the risk of inducing the formation of neovessels in undesired places such as occult malignant lesions or retina. Previous studies have demonstrated that therapeutic angiogenesis using a single pro-angiogenic factor is effective. However, these studies suggest that the new formed vessels are leaky, as evidenced by the occurrence of lower limb edema and proteinuria after pro-angiogenic monotherapy. In the present work we evaluated efficacy of a combined GT strategy using non-viral vectors expressing two vascular growth factors: FGF-2 and PDGF-BB, and compared this strategy to the gene transfer of VEGF-A alone. The choice of these two growth factors was due to their complementary roles in the process of vascular development: formation and stabilization of new vessels. In order to do so we used a hindlimb ischemia model in rats, and a new non-invasive method based on 99mTc-sestabimi scintigrapy, to evaluate the neovascularization response. Dual gene transfer of FGF-2 and PDGF-BB using non-viral vectors was able to induce a similar revascularization response as VEGF-A alone, both in terms of anatomical and functional parameters. In regard to safety, the dual gene transfer strategy was more attractive because it was able to induce more stable capillaries, and required a 50% lower individual dose of each therapeutic gene. Taken together our data demonstrate that this dual gene transfer strategy is an effective safer strategy for the treatment of CLI by therapeutic angiogenesis. In order to investigate factors that might affect the revascularization post-natal response, we further investigated the role of thrombin during the induction of neovascularization. Animals were treated with different coagulation inhibitors immediately after or 72 hours after the creatin of hindlimb ischemia in rats. We documented that the inhibition of blood coagulation in the acute phase of ischemia impairs the angiogenic response. In contrast, this effect was not observed when anticoagulation was initiated after 72 hours of ischemia. The activation of cellular receptors of thrombin and other proteases might therefore offer an new target to optimize post-natal revascularization. Based on our results, future studies using combined GT with FGF-2 and PDGF-BB are warranted in order to translate these findings into a new and safer strategy for the treatment of CLI / Doutorado / Medicina Experimental / Doutor em Fisiopatologia

Orientador: Márcia Ferreira da Rosa Sobreira / Coorientador: Annelise Carla Camplesi / Banca: Fábio Nelson Gava / Banca: Sabryna Gouveia Calazans / Resumo: Tumores mamários são frequentes em cadelas e apresenta comportamento biológico semelhante aos que ocorrem nas mulheres, tornando a cadela um excelente modelo de estudo comparativo. Os distúrbios hemostáticos são achados comuns em pacientes humanos com câncer, e os mecanismos que conduzem a ativação da coagulação no câncer envolvem o fator tissular, o fator procoagulante do câncer e as citocinas inflamatórias. E já está bem estabelecido que os componentes da hemostasia, como as plaquetas, proteínas da coagulação e da fibrinólise apresentam um papel importante no crescimento e na progressão do tumor. Assim, o objetivo deste estudo foi realizar a caracterização clínica, hematológica e histopatológica de cadelas acometidas por carcinoma mamário, bem como avaliar a integridade do sistema hemostático, através da mensuração do fibrinogênio plasmático, da contagem total de plaquetas, dos tempos de tromboplastina parcial ativada e de protrombina. Para tanto, foram utilizadas 62 cadelas. Sendo 32 acometidas por carcinoma mamário e 30 cadelas clinicamente e laboratorialmente saudáveis como grupo controle. Foram formados quatro subgrupos de acordo com o tipo e o grau histopatológico, estadiamento clínico e tamanho do tumor. Todas as cadelas acometidas por lesões mamárias foram submetidas ao exame físico das glândulas mamárias, exames de hemograma, testes de coagulação e ao exame de histopatológico. E os proprietários submetidos à anamnese por meio de questionário. A apresentação clínica ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Mammary tumors are frequently found in female dogs. These tumors have shown a biological behavior similar to breast cancer in woman. This makes female dogs an excellent comparative study model. Coagulation disorders are common in human patients with cancer. Hemostasis is activated by inflammatory cytokines, tissue and procoagulant factors. It is well established that coagulation components as platelets and coagulation and fibrinolytic proteins have an important function in the growth an progression of tumors. Thus, the aim of this paper was to characterize clinical, hematological and histopathology female dogs with mammary carcinoma and evaluate the integrity of the hemostatic system by measuring the plasma fibrinogen, the total platelet count, and the activated partial thromboplastin and prothrombin time in female dogs. Sixty-two female dogs were used in this study. Thirty-two had mammary carcinoma and thirty were laboratorial and clinically healthy to be used as the control group. Four groups were formed according to histological type and grade, clinical stage and tumor size. The 32 female dogs with carcinoma were submitted to physical mammary gland, blood count, histopathological examinations and coagulation tests and their owners were submitted to a questionnaire. The clinical characteristics of the diseased dogs were older age, pure breed, not spayed with multiple stage one nodules. Grade I and II mixed carcinomas were the most frequent. In this study, significant diffe... (Complete abstract click electronic access below) / Mestre

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No description available.

Direct factor Xa inhibitors (FXaI) account for most oral anticoagulant use. FXaI-associated bleeding events are common and are associated with substantial morbidity and mortality. Nonspecific hemostatic therapies such as prothrombin complex concentrates (PCC) are often administered for FXaI-associated bleeding. The mechanism by which these agents improve hemostasis in the setting of direct oral anticoagulation is unclear. Thrombin generation assays may effectively measure the effect of anticoagulation reversal among FXaI-treated patients when bleeding cessation would otherwise be challenging to measure. To build a research program on the utility of thrombin generation assays to measure both the impact of direct oral anticoagulation and anticoagulation reversal, we completed a review of the literature with narrative synthesis and carried out a pilot study to determine the feasibility of a full scale prospective observational study of TGA responses among patients receiving PCC for FXaI-associated major bleeding or needing urgent surgery.

Platelets are crucial components of the hemostatic machinery of the body. When the endothelial continuity is disrupted due to injury or atherosclerotic plaque rupture, one of the earliest responses to arrest the bleeding is the adhesion of circulating platelets to the exposed subendothelial collagen matrix. Subsequent intracellular signaling mediated downstream of various receptor systems leads to alpha IIb beta 3 activation, thromboxane generation, ADP release, etc., culminating in platelet clot or thrombus formation. The protein kinase family of enzymes mediates a significant number of these intracellular signaling events that culminate in platelet activation. These enzymes can be broadly classified into two classes- tyrosine kinases and serine/threonine kinases. Syk (spleen tyrosine kinase) is an important non-receptor tyrosine kinase present in platelets and plays an important role downstream of GPVI-FcR gamma chain receptor complex activation. We studied the effects of curcumin (diferuloylmethane), which is the active ingredient found in the herbal remedy and food spice turmeric, on the GPVI-mediated platelet activation. We have found that it significantly inhibits the kinase activity of Syk without affecting its phosphorylation. Pre-incubating the platelets with curcumin for only a minute resulted in a concentration-dependent inhibition of aggregation and secretion, with approximately 75% inhibition observed at 50 mM curcumin. Additionally, the activation-dependent phosphorylation of tyrosines 753/759 on PLC gamma2 and phosphorylation of tyrosine 191 on the transmembrane scaffold protein LAT, were inhibited (p&lt;0.05). However, the phosphorylation of the activation loop tyrosines 525/526 on Syk and of the tyrosine 145 on intracellular adaptor molecule SLP-76 were not significantly affected. Furthermore, the inhibitory action of curcumin on the catalytic activity of Syk was independent of any of its effects on the thromboxane generation because all our studies were performed using aspirin-treated platelets. PKC zeta is an atypical member of the PKC family of serine/threonine kinases. In this study, we have confirmed that it is expressed in human platelets and is constitutively phosphorylated at the activation loop threonine 410 as well as the turn motif threonine 560, which is an autophosphorylation site. Phosphorylation at these two residues has been shown to be important for its kinase activity. Furthermore, agonist-mediated platelet aggregation under stirring condition results in dephosphorylation of the Thr410 residue, which can be prevented by blocking integrin alpha IIb beta 3 by its antagonist SC-57101 (p&lt;0.01). The dephosphorylation of Thr410 can also be prevented by okadaic acid, a Ser/Thr protein phosphatase inhibitor, at concentrations above 100 nM. However, in PP1c gamma null mice, we did not observe any effect on the dephosphorylation, suggesting that other isoforms of PP1 or other classes of the phosphatases could be responsible for this phenomenon, at least in these knockout mice. The basal phosphorylation of Thr560, however, remained unaffected by agonist stimulation, integrin activation, integrin blockade, okadaic acid treatment and in the PP1c gamma null mice. It can be speculated that PKC zeta may be constitutively active under basal resting conditions and acts as a negative regulator of platelet activation or functional responses. The Thr560 autophosphorylation signal alone may not be sufficient to sustain its full enzymatic activity. / Physiology

Transmembrane protein 59 (tmem59) is a gene that encodes a protein involved in autophagy and apoptosis in human. A previous study in zebrafish showed that tmem59 mRNA was several folds higher in thrombocytes than those found in red blood cells (RBCs). Therefore, we hypothesized that tmem59 has a role in thrombocytes function. We injected a hybrid of control vivo-morpholino (cVMO) and tmem59 specific antisense standard oligonucleotide (tmem59SO) into adult zebrafish to knockdown tmem59.This piggyback knockdown approach resulted in fish that had more bleeding in gill bleeding assay than the control fish. The thrombocytes fromtmem59 knockdown zebrafish aggregated faster with ADP and collagen agonists. Also, the number of blood cells was reduced after the knockdown of tmem59. We also found the effects of MS-222 anesthesia on hemostasis and found that the bleeding was reduced yielding less blood and the blood cell counts increased probably due to vasoconstriction of the blood vessels. In summary, we found tmem59 is a negative regulator of hemostasis and inferred that anesthesia should be avoided in hemostasis studies.

GPR17, a uracil nucleotide cysteinyl leukotriene receptor, belongs to the GPCR (G protein coupled receptor) family. It has been shown recently that inhibiting this protein in the nervous system in mice can lead to blockage of oligodendrocyte maturation, which supports myelin repair. Interestingly, our laboratory found GPR17 in thrombocytes. However, we do not know whether it has any function in thrombocyte aggregation or the nature of the ligand. In this paper, we studied the role of GPR17 in hemostasis, which is a fundamental defense mechanism in the event of injury. Using zebrafish as a model system, our laboratory has studied specifically thrombocytes, which play a significant role in hemostasis. The major reasons to use zebrafish as a model system are that their thrombocytes are functionally equivalent to human platelets, the adult fish are amenable to knockdown experiments, and they are readily available in the market. This study was performed by using a piggy back knockdown method where we used a chemical hybrid of control morpholino and an antisense oligonucleotide sequence leads to the degradation the mRNA for GPR17. After knockdown GPR17 in thrombocytes, the percent difference of the thrombocytes aggregation between the control and knockdown blood samples was measured by flow cytometry. We used various thrombocyte agonists to study differences in aggregation between the control and knockdown blood samples. The study showed that knockdown of GPR17 resulted in no significant differences in percent thrombocyte aggregation between control and agonist treated samples except for a slight increase in collagen-treated samples. Thus, it appears that GPR17 has no significant role in hemostasis.

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