Association of Fibrinolytic Potential and Risk of Mortality in Cancer Patients.

Cancer is a leading cause of death, and the fibrinolytic system shows cooperative effects that facilitate the growth of tumors and the appearance of metastases. This prospective study aimed to evaluate the fibrinolytic potential in cancer patients and its association with mortality outcomes using the fluorometric method of simultaneous thrombin and plasmin generation. The study included 323 cancer patients and 148 healthy individuals. During the 12-month follow-up, 68 patients died. Compared to the control group, cancer patients showed alterations in thrombin production consistent with a hypercoagulability profile, and an increase in plasmin generation. Mortality risk was associated with two parameters of thrombin in both univariate and multivariable analysis: maximum amplitude (Wald 11.78, p < 0.001) and area under the curve (Wald 8.0, p < 0.005), while such associations were not observed for plasmin. In conclusion, this was the first study able to demonstrate the simultaneous evaluation of thrombin and plasmin generation in newly diagnosed untreated cancer patients. Patients with cancer have been observed to exhibit a hypercoagulable profile. During the study, two parameters linked to thrombin generation, MA and AUC, were identified and found to have a potential association with mortality risk. However, no associations were found with parameters related to plasmin generation.

Inhibitory effects of dabigatran etexilate, a direct thrombin inhibitor, on osteoclasts and osteoblasts.

INTRODUCTION: Anticoagulants are widely used in orthopedic surgery to decrease the risk of deep vein thrombosis. While significant bone impairment is induced by long-term heparin therapy, little is known about the effects of direct oral anticoagulants (DOACs). Herein, we investigated the effects of dabigatran etexilate (Pradaxa®), a DOAC inhibitor of thrombin, on bone cells using in vitro and ex vivo cell culture models. MATERIALS AND METHODS: Osteoblasts and osteoclasts exposed to different concentrations of dabigatran etexilate and untreated cells were assayed for cell differentiation and activity. Favorable osteogenic conditions for osteoblasts were tested using titanium with nanotopography (Ti-Nano). In addition, mice treated with a dabigatran etexilate solution had bone marrow cells analyzed for the ability to generate osteoclasts. RESULTS: Dabigatran etexilate at concentrations of 1 µg/mL and 2 µg/mL did not impact osteoclast or osteoblast viability. The drug inhibited osteoclast differentiation and activity as observed by the reduction of TRAP+ cells, resorption pits and gene and protein expression of cathepsin K. Consistently, osteoclasts from mice treated with dabigatran showed decreased area, resorptive activity, as well as gene and protein expression of cathepsin K. In osteoblast cultures, grown both on polystyrene and Ti-Nano, dabigatran etexilate reduced alkaline phosphatase (ALP) activity, matrix mineralization, gene expression of ALP and osteocalcin. CONCLUSIONS: Dabigatran etexilate inhibited osteoclast differentiation in ex vivo and in vitro models in a dose-dependent manner. Moreover, the drug reduced osteoblast activity even under optimal osteogenic conditions. This study provides new evidence regarding the negative overall impact of DOACs on bone cells.

Bleeding assessment in oral surgery: A cohort study comparing individuals on anticoagulant therapy and a non-anticoagulated group.

Some prospective studies have been designed specifically to investigate perioperative bleeding in dental surgery. The quantitative assessment of intraoperative blood loss can be useful for indicating the real risk of bleeding complications, especially in medically compromised individuals. The aim of this study was to evaluate the pattern of bleeding in individuals under vitamin K antagonist (VKA) therapy and non-anticoagulated individuals submitted to dental extractions. Perioperative bleeding was evaluated by using a total collected bleeding corrected by absorbance reading (dental bleeding score). 138 procedures were performed. When the perioperative dental bleeding score was correlated with the number of extracted teeth, the quantity of bleeding was found to be directly proportional to the procedure. Extractions of two or more teeth presented higher scores than single extractions (p = 0.003). In a comparative analysis between the VKA and non-anticoagulated groups, no significant difference in the scores was found. The previous history of complications in dental procedures (p = 0.001) and the use of additional hemostatic measures were higher in the VKA group (p = 0.017). VKA therapy did not impact significantly the volume of blood lost during dental extractions. Perioperative bleeding assessment might be a useful parameter for evaluating patients under antithrombotic treatment.

Infection of hematopoietic stem cells by Leishmania infantum increases erythropoiesis and alters the phenotypic and functional profiles of progeny.

Immunosuppression is a well-established risk factor for Visceral Leishmaniasis. Post-immunosuppression leishmaniasis is characterized by an increase of parasite burden, hematopoietic disorders and unusual clinical manifestations. Although there are many reports on bone marrow findings in VL, less is known about the relationship between parasite dynamics in this organ and the function of either hematopoietic stem cells and progenitor cells themselves. In the present study, we tackle these issues using a new approach of infecting human stem cells derived from bone marrow with L. infantum. Using this strategy, we show that human hematopoietic stem cells (hHSC) are able to phagocytize L. infantum promastigotes and release modulatory and pro-inflammatory cytokines, mainly TNF-α. Our results demonstrated that L. infantum infection in vitro enhances hematopoiesis, favoring the development of erythrocitic lineage through a mechanism yet unknown. Moreover, we found that L. infantum infection alters the phenotypic profile of the hematopoietic progeny; modifying the surface markers expression of differentiated cells. Thus, our study represents a rare opportunity to monitor the in vitro differentiation of human stem cells experimentally infected by L. infantum to better understand the consequences of the infection on phenotypic and functional profile of the cell progeny.

Adaptação Transcultural do Oral Anticoagulation Knowledge Test para o Português do Brasil / Cross-cultural Adaptation of the Oral Anticoagulation Knowledge Test to the Brazilian Portuguese

Resumo O conhecimento dos pacientes sobre o tratamento com anticoagulantes orais pode favorecer o alcance dos resultados terapêuticos e a prevenção de eventos adversos relacionados à farmacoterapia. No Brasil, observa-se a ausência de instrumentos validados para avaliação do conhecimento do paciente sobre o tratamento com a varfarina. O objetivo deste estudo foi realizar a adaptação transcultural do instrumento Oral Anticoagulation Knowledge (OAK) Test do inglês para o português do Brasil. Trata-se de estudo metodológico desenvolvido em uma clínica de anticoagulação de um hospital público universitário. O estudo compreendeu as etapas de tradução inicial, síntese das traduções, retrotradução, revisão pelo comitê de especialistas e pré-teste com 30 indivíduos. A equivalência semântica foi obtida através da análise do significado referencial e geral de cada item. A equivalência conceitual dos itens buscou demonstrar a relevância e a aceitabilidade do instrumento. Com o processo de adaptação transcultural foi obtida a versão final do OAK Test em língua portuguesa do Brasil, intitulada “Teste de Conhecimento sobre Anticoagulação Oral”. Constatou-se uma equivalência semântica e conceitual adequada entre a versão adaptada e a original, bem como uma excelente aceitabilidade desse instrumento.

Abstract Patients’ knowledge about oral anticoagulant therapy may favor the achievement of therapeutic results and the prevention of adverse pharmacotherapy-related events. Brazil lacks validated instruments for assessing the patient’s knowledge about treatment with warfarin. This study aimed to perform the cross-cultural adaptation of the Oral Anticoagulation Knowledge (OAK) Test instrument from English into Portuguese. This is a methodological study developed in an anticoagulation clinic of a public university hospital. The study included initial translation, synthesis of translations, back-translation, review by the experts committee and pre-testing with 30 individuals. We obtained semantic equivalence through the analysis of the referential and general meaning of each item. The conceptual equivalence of the items sought to demonstrate the relevance and acceptability of the instrument. The process of cross-cultural adaptation produced the final version of the OAK Test in Brazilian Portuguese entitled “Teste de Conhecimento sobre Anticoagulação Oral”. There was a suitable semantic and conceptual equivalence between the adapted version and the original version, as well as an excellent acceptability of this instrument.

Clotting Factor XIII and desmopressin improve hemostasis in uncontrolled bleeding

PURPOSE: To investigate hemostatic effects of supplementary factor XIII and desmopressin (DDAVP) in resuscitation of uncontrolled bleeding. METHODS: Fifty-four rabbits were randomized in nine groups: G1: Sham; G2: FXIII and normotensive resuscitation (NBP); G3: FXIII and permissive hypotension (PH) (MAP 60% baseline); G4: FXIII/DDAVP/NBP; G5: FXIII/DDAVP/PH; G6: NBP only; G7: FXIII no hemorrhage; G8: FXIII/DDAVP no hemorrhage; G9: PH only. Thromboelastometry and intra-abdominal blood loss were assessed. Scanning electron microscopy (EM) of the clots was performed. RESULTS: Compared to Sham, only G8 (FXIII/DDAVP w/o hemorrhage) showed clotting time (CT) significantly lower (p<0.05). NBP alone (G6) resulted in significantly prolonged CT compared to G2, G3 and G5 (p<0.05). Similarly, median alpha angle was significantly larger in G3,4,5, and 9 compared to G6 (p<0.05). Area under the curve was significantly greater in G5 than G2. Intra-abdominal blood loss was lower in G5 and G9 compared to G2 and G6. FXIII/DDAVP and PH resulted in more robust fibrin mesh by EM. CONCLUSIONS: Normotensive resuscitation provokes more bleeding and worsens coagulation compared to pH, that is partially reversed by factor XIII and desmopressin. FXIII and DDAVP can synergistically improve coagulation. Permissive hypotension reduces bleeding regardless of those agents. .

Portal vein thrombosis and budd-Chiari syndrome.

Venous thrombosis results from the convergence of vessel wall injury and/or venous stasis, known as local triggering factors, and the occurrence of acquired and/or inherited thrombophilia, also known as systemic prothrombotic risk factors. Portal vein thrombosis (PVT) and Budd-Chiari syndrome (BCS) are caused by thrombosis and/or obstruction of the extrahepatic portal veins and the hepatic venous outflow tract, respectively. Several divergent prothrombotic disorders may underlie these distinct forms of large vessel thrombosis. While cirrhotic PVT is relatively common, especially in advanced liver disease, noncirrhotic and nontumoral PVT is rare and BCS is of intermediate incidence. In this article, we review pathogenic mechanisms and current concepts of patient management.

Associação entre uso de hemocomponentes e mortalidade em cinco anos após transplante hepático / Association between the use of blood components and the five-year mortality after liver transplant / Asociación entre el uso de hemocomponentes y la mortalidad en cinco años después de transplante hepático

JUSTIFICATIVA E OBJETIVOS: A cirurgia de transplante hepático (TH) continua associada a sangramento importante em 20 por cento dos casos, e diversos autores têm demonstrado os riscos relacionados ao uso de hemocomponentes. O objetivo deste estudo foi avaliar o impacto do uso de hemocomponentes durante toda a hospitalização na sobrevida em cinco anos de pacientes submetidos a TH. MÉTODOS: Um total de 113 pacientes submetidos ao TH foi avaliado retrospectivamente. Diversas variáveis, incluindo uso de hemocomponentes no intraoperatório e durante toda a hospitalização, foram categorizadas e avaliadas por meio de análise univariada, pelo teste de Fisher. O nível de significância adotado foi de 5 por cento. Os resultados com p < 0,2 foram submetidos a uma análise multivariada pelo modelo de regressão logística multinominal. RESULTADOS: Doenças parenquimatosas, disfunção renal pré-operatória e maior tempo de internação no CTI e hospitalar se associaram a maior mortalidade em cinco anos após o TH (p < 0,05). Ao contrário do uso de hemocomponentes no intraoperatório, a transfusão acumulada de concentrado de hemácias, plasma fresco congelado e concentrado de plaquetas durante toda a internação hospitalar foi associada à maior mortalidade em cinco anos após o transplante de fígado (p < 0,01). CONCLUSÕES: O estudo alerta para a relação existente entre o uso de hemocomponentes durante a hospitalização e o aumento da mortalidade em cinco anos após o TH.

BACKGROUND AND OBJECTIVES: Liver transplant (LT) surgery is associated with significant bleeding in 20 percent of cases, and several authors have demonstrated the risks related to blood components. The objective of the present study was to evaluate the impact of using blood components during hospitalization in five-year survival of patients undergoing LT. METHODS: One hundred and thirteen patients were evaluated retrospectively. Several variables, including the use of blood components intraoperatively and throughout hospitalization, were categorized and evaluated by univariate analysis using Fisher's test. A level of significance of 5 percent was adopted. Results with p < 0.2 underwent multivariate analysis using multinomial logistic regression. RESULTS: Parenchymal diseases, preoperative renal dysfunction, and longer stay in hospital and ICU are associated with greater five-year mortality after LT (p < 0.05). Unlike the intraoperative use of blood components, the accumulated transfusion of packed red blood cell, frozen fresh plasma, and platelets during the entire hospitalization was associated with greater five-year mortality after liver transplantation (p < 0.01). CONCLUSIONS: This study emphasizes the relationship between the use of blood components during hospitalization and increased mortality in five years after LT.

JUSTIFICATIVA Y OBJETIVOS: La cirugía de transplante hepático (TH), continúa asociada al sangramiento importante en un 20 por ciento de los casos, y diversos autores ya han demostrado los riesgos relacionados con el uso de hemoderivados. El objetivo de este estudio fue evaluar el impacto del uso de hemoderivados durante toda la hospitalización en la sobrevida en cinco años de pacientes sometidos a TH. MÉTODOS: Un total de 113 pacientes sometidos a TH fueron evaluados retrospectivamente. Diversas variables, incluyendo el uso de hemoderivados en el intraoperatorio y durante toda la hospitalización, fueron categorizadas y evaluadas por medio de análisis univariado, por el test de Fisher. El nivel de significancia adoptado fue de un 5 por ciento. Los resultados con p < 0,2 fueron sometidos a un análisis multivariado por el modelo de regresión logística multinominal. RESULTADOS: Enfermedades parenquimatosas, disfunción renal preoperatoria y un mayor tiempo de internación en UCI y hospitalario, se asociaron a una mayor mortalidad en cinco años después del TH (p < 0,05). Al contrario del uso de hemoderivados en el intraoperatorio, la transfusión acumulada de concentrado de hematíes, plasma fresco congelado y concentrado de plaquetas durante todo el ingreso se asoció a una mayor mortalidad en cinco años posteriores al transplante de hígado (p < 0,01). CONCLUSIONES: El estudio es un alerta sobre la relación existente entre el uso de hemoderivados durante el ingreso y el aumento de la mortalidad en cinco años posteriores al TH.

[Association between the use of blood components and the five-year mortality after liver transplant]. / Asociación entre el uso de hemocomponentes y lamortalidad en cinco años después de transplante hepático.

BACKGROUND AND OBJECTIVES: Liver transplant (LT) surgery is associated with significant bleeding in 20% of cases, and several authors have demonstrated the risks related to blood components. The objective of the present study was to evaluate the impact of using blood components during hospitalization in five-year survival of patients undergoing LT. METHODS: One hundred and thirteen patients were evaluated retrospectively. Several variables, including the use of blood components intraoperatively and throughout hospitalization, were categorized and evaluated by univariate analysis using Fisher's test. A level of significance of 5% was adopted. Results with p < 0.2 underwent multivariate analysis using multinomial logistic regression. RESULTS: Parenchymal diseases, preoperative renal dysfunction, and longer stay in hospital and ICU are associated with greater five-year mortality after LT (p < 0.05). Unlike the intraoperative use of blood components, the accumulated transfusion of packed red blood cell, frozen fresh plasma, and platelets during the entire hospitalization was associated with greater five-year mortality after liver transplantation (p < 0.01). CONCLUSIONS: This study emphasizes the relationship between the use of blood components during hospitalization and increased mortality in five years after LT.

JAK2V617F mutation in patients with splanchnic vein thrombosis.

BACKGROUND: Splanchnic vein thrombosis can be the presenting manifestation of myeloproliferative neoplasms. However, the diagnosis of a myeloproliferative neoplasm in these patients is often problematic, and more objective criteria are needed. AIM: To determine the frequency of the mutation JAK2V617F in patients with splanchnic vein thromboses. METHODS: A consecutive series of 108 adult patients with portal vein thrombosis (n = 77) and Budd-Chiari syndrome (n = 31) referred for hemostasis evaluation was retrospectively studied, with a median follow-up of 51 months (1-104). RESULTS: One or more prothrombotic risk factors were present in 63% of the patients. Twenty-four (22%) out of the 108 patients presented the JAK2V617F, including 2 cirrhotic patients. Most had a low mutated allele burden (median 16.5%). JAK2V617F was present in all four patients with a previous diagnosis of a myeloproliferative neoplasm. In nine JAK2V617F-positive patients, the diagnosis of a myeloproliferative neoplasm was made at the thrombosis work-up, during follow-up or after JAK2V617F detection. Among the other 11 patients carrying the mutation, 2 patients have died, 4 had no evidence suggesting a myeloproliferative neoplasm, 1 had a normal bone marrow biopsy, and the other 4 could not be persuaded to undergo a biopsy. Among the patients without an overt myeloproliferative neoplasm, 15 out of 99 (15%) presented the JAK2V617F mutation. None of the JAK2V617F-negative patients have developed signs of a myeloproliferative neoplasm during follow-up. CONCLUSIONS: Our findings suggest that JAK2V617F occurs in a high proportion of patients with splanchnic vein thrombosis, and reinforces the diagnostic utility of JAK2V617F testing in this setting.

Langerhans cell histiocytosis: a 16-year experience.

OBJECTIVES: To describe the clinical course of Langerhans cell histiocytosis and to compare its outcome according to age, staging of the disease and treatment response. METHODS: Retrospective analysis of data on 33 children with Langerhans cell histiocytosis followed at Hospital das Clínicas, Universidade Federal de Minas Gerais, Brazil, between 1988 and 2004. RESULTS: Age at diagnosis ranged from 2 months to 16 years (median: 2.5 years). Seventeen children were male. The follow-up period varied from 21 days to 16.2 years (median: 3.4 years). The most common clinical manifestations at diagnosis were osteolytic lesions, enlarged lymph nodes and skin lesions. The overall survival rate for the whole group was 86.1% at 16 years (95%CI 66.6-94.6%). Deaths occurred in patients with multisystem disease and organ dysfunction at diagnosis. Those patients who had a "better" response to treatment in the sixth week were likely to have a significantly higher overall survival rate than those who showed disease progression. Overall survival rate was significantly higher for patients with single-system disease. The disease-free survival rate for the whole group was 30.9% at 16 years (95%CI 15.6-47.5%), and was significantly higher for those with single-system disease. Age groups were not associated with different disease-free survival rates. Diabetes insipidus was the most common sequela. No cases of secondary neoplasms were observed. CONCLUSION: The clinical manifestations of Langerhans cell histiocytosis vary widely, with a high relapse rate and low mortality rate.

Langerhans cell histiocytosis: a 16-year experience

OBJETIVOS: Descrever a apresentação clínica da histiocitose das células de Langerhans e comparar sua evolução de acordo com a idade, estadiamento e resposta ao tratamento. MÉTODOS: Análise retrospectiva dos dados referentes a 33 crianças com histiocitose das células de Langerhans acompanhadas no Hospital das Clínicas da Universidade Federal de Minas Gerais no período de 1988 a 2004. RESULTADOS: A idade ao diagnóstico variou de 2 meses a 16 anos (mediana: 2,5 anos). Dezessete crianças eram do sexo masculino. O tempo de seguimento variou de 21 dias a 16,2 anos (mediana: 3,4 anos). As manifestações clínicas mais comuns ao diagnóstico foram lesões osteolíticas, linfadenomegalia e lesões cutâneas. A sobrevida global para todo o grupo foi de 86,1 por cento aos 16 anos (IC95 por cento 66,6-94,6). Os óbitos ocorreram em pacientes com doença multissistêmica e disfunção orgânica ao diagnóstico. Os pacientes que apresentaram resposta "melhor" à sexta semana de tratamento apresentaram uma probabilidade estimada de sobrevida global significativamente maior em relação aos que apresentaram progressão da doença. A sobrevida global foi significativamente maior para os pacientes com doença em um único sistema. A probabilidade de sobrevida livre de eventos para todo o grupo foi de 30,9 por cento aos 16 anos (IC95 por cento 15,6-47,5), sendo significativamente maior para os portadores de doença em um único sistema. A idade não se associou com a sobrevida livre de eventos. A seqüela mais comum foi o diabetes insipidus. Não foram observados casos de neoplasias secundárias. CONCLUSÃO: A histiocitose das células de Langerhans apresenta uma grande variedade de manifestações clínicas, com alta taxa de recidivas e baixa taxa de mortalidade.

OBJECTIVES: To describe the clinical course of Langerhans cell histiocytosis and to compare its outcome according to age, staging of the disease and treatment response. METHODS: Retrospective analysis of data on 33 children with Langerhans cell histiocytosis followed at Hospital das Clínicas, Universidade Federal de Minas Gerais, Brazil, between 1988 and 2004. RESULTS: Age at diagnosis ranged from 2 months to 16 years (median: 2.5 years). Seventeen children were male. The follow-up period varied from 21 days to 16.2 years (median: 3.4 years). The most common clinical manifestations at diagnosis were osteolytic lesions, enlarged lymph nodes and skin lesions. The overall survival rate for the whole group was 86.1 percent at 16 years (95 percentCI 66.6-94.6 percent). Deaths occurred in patients with multisystem disease and organ dysfunction at diagnosis. Those patients who had a "better" response to treatment in the sixth week were likely to have a significantly higher overall survival rate than those who showed disease progression. Overall survival rate was significantly higher for patients with single-system disease. The disease-free survival rate for the whole group was 30.9 percent at 16 years (95 percentCI 15.6-47.5 percent), and was significantly higher for those with single-system disease. Age groups were not associated with different disease-free survival rates. Diabetes insipidus was the most common sequela. No cases of secondary neoplasms were observed. CONCLUSION: The clinical manifestations of Langerhans cell histiocytosis vary widely, with a high relapse rate and low mortality rate.