Imbalances in serum angiopoietin concentrations are early predictors of septic shock development in patients with post chemotherapy febrile neutropenia

Background: Febrile neutropenia carries a high risk of sepsis complications, and the identification of biomarkers capable to identify high risk patients is a great challenge. Angiopoietins (Ang -) are cytokines involved in the control microvascular permeability. It is accepted that Ang-1 expression maintains endothelial barrier integrity, and that Ang-2 acts as an antagonizing cytokine with barrier-disrupting functions in inflammatory situations. Ang-2 levels have been recently correlated with sepsis mortality in intensive care units. Methods: We prospectively evaluated concentrations of Ang-1 and Ang-2 at different time-points during febrile neutropenia, and explored the diagnostic accuracy of these mediators as potential predictors of poor outcome in this clinical setting before the development of sepsis complications. Results: Patients that evolved with septic shock (n = 10) presented higher levels of Ang-2 measured 48 hours after fever onset, and of the Ang-2/Ang-1 ratio at the time of fever onset compared to patients with non-complicated sepsis (n = 31). These levels correlated with sepsis severity scores. Conclusions: Our data suggest that imbalances in the concentrations of Ang-1 and Ang-2 are independent and early markers of the risk of developing septic shock and of sepsis mortality in febrile neutropenia, and larger studies are warranted to validate their clinical usefulness. Therapeutic strategies that manipulate this Ang-2/Ang-1 imbalance can potentially offer new and promising treatments for sepsis in febrile neutropenia

Allelic Frequencies Of Three Vntrs In Intron 40 Of The Human Von Willebrand Factor Gene In Types 1, 2, And 3 Von Willebrand Disease Patients And Controls Of A Brazilian Population.

Intron 40 of the human von Willebrand factor (vWF) gene contains a polymorphic region with three variable-number tandem repeats (VNTRs), type (ATCT)n. In the present report, we evaluated the allelic frequencies of these three VNTRs in a population constituted by 51 Brazilian Caucasian and 25 Types 1, 2, and 3 von Willebrand disease (vWD) patients, and performed segregation analysis in eight families affected by vWD Types 1 and 2. Three pairs of primers were used to amplify independently nucleotides 1640-1794 (VNTR 3), 1890-1991 (VNTR 1), and 2215-2396 (VNTR 2) from intron 40. The observed heterozygosities (0.86, 0.66, and 0.66 for VNTRs 3, 1, and 2, respectively) were in accordance with the expected heterozygosities derived from the allele frequencies (0.81, 0.64, and 0.70, respectively). Although the three VNTRs were highly polymorphic, VNTR 3 showed the highest values of heterozygosity [Haemostasis 25 (1995) 264; Hum. Mol. Genet. 1 (1992) 287.].100489-9

Leprosy And Acquired Factor Viii Inhibitor: A Case Report.

62155-

[detection Of Hemophilia A Gene Carriers In A Brazilian Population].

The identification of carriers for the hemophilia A gene was carried out in 20 families of hemophilia A patients. The detection of the carriers was performed on the basis of the study of restriction length fragment polymorphism (RLFPs) for the enzymes BclI and HindIII. The procedures for the determination of RLFPs included the amplification of fragment of the factor VIII gene by the polymerase chain reaction (PCR) followed by digestion with the appropriate enzyme. We studied 84 relatives of the patients with hemophilia A and was possible to detect carriers in 76% of the families. The results presented here indicate that is possible to identify carriers for hemophilia A in most of the families of patients from the Brazilian population employing a limited number of RFLPs.39126-3

Three Novel Mutations In The Activin Receptor-like Kinase 1 (alk-1) Gene In Hereditary Hemorrhagic Telangiectasia Type 2 In Brazilian Patients.

Hereditary hemorrhagic telangiectasia (HHT) or Osler-Rendu-Weber disease is a systemic fibrovascular dysplasia with an autosomal dominant inheritance pattern. Mutations in two genes, endoglin and ALK-1, are known to cause HHT, both of which mediate signaling by transforming growth factor beta ligands in vascular endothelial cells. Ten patients were analyzed. Diagnosis of HHT was carried out by means of family history, recurrent bleeding, and the presence of multiple telangiectases lesions. Conformation-sensitive gel electrophoresis analyses with consistent abnormal migration patterns were cloned and sequenced using the MegaBace 1000 DNA automated analyzer. Three novel mutations were identified in the coding sequence of the ALK-1 gene in five patients and their families, which demonstrated clinical manifestations of HHT type 2. These mutations included a G insertion and a T deletion of single base pairs in exons 3 and 7, as well as missense mutations in exons 7 and 8 of the ALK-1 gene. These data indicate that loss-of-function mutations in a single allele of the ALK1 locus are sufficient to contribute to defects in maintaining endothelial integrity. We suggest the high rate of mutation detection and the small size of the ALK-1 gene make genomic sequencing a viable diagnostic test for HHT2.52237-4

Prothrombin Mutant, Factor V Leiden, And Thermolabile Variant Of Methylenetetrahydrofolate Reductase Among Patients With Sickle Cell Disease In Brazil.

The prevalence of the prothrombin gene variant (allele 20.210 A), factor V Leiden mutation, and homozygosity for transition 677C-->T in the methylenetetrahydrofolate reductase (MTHFR) gene was determined among patients with sickle cell disease (SCD). The group included 73 patients with median age of 32.3 years with a diagnosis of sickle cell anemia in 53 patients, hemoglobinopathy SC in 16 patients, and four with S/beta(0) thalassemia. Vascular complications such as ischemic stroke or deep vein thrombosis were diagnosed in nine patients. Heterozygosity for the prothrombin gene variant or factor V Leiden mutation was identified in four patients. However, only one patient, who developed ischemic stroke, was identified as a carrier of factor V Leiden mutation. None of the patients presented homozygosity for the thermolabile variant of the MTHFR. These data suggest a low clinical impact of inherited hypercoagulability risk factors in developing thrombosis, occlusive stroke, or mortality data among patients with SCD in Brazil.5946-5

The Impact Of The Search For Thrombophilia Risk Factors Among Antiphospholipid Syndrome Patients With Thrombosis.

Thrombosis is a major clinical feature of the antiphospholipid syndrome. Interactions between genetic and acquired factors could contribute to thrombosis development. In this study, we evaluated 40 patients with antiphospholipid syndrome and thrombosis, 31 primary and nine secondary to systemic lupus erythemathosus, to estimate the carrier rates of factor V Leiden, 20210A --> G prothrombin variant and 677C --> T in the MTHFR gene. Protein C, protein S and antithrombin were measured in 30 patients, with a median of 100.66 +/- 23.86, 93.57 +/- 36.44 and 98.8 +/- 5.67%, respectively. None of the patients were deficient on these natural anticoagulants. No significant variation was found between the patient group and the controls, regarding the prevalence of homozygotes for the mutated 677T allele (2.5 versus 5.4%), or heterozygotes for factor V Leiden (0 versus 0.7%). Despite the fact that these mutations are relatively common in Brazilian thrombophilic patients, its low prevalence in this cohort of patients suggest that these genetic alterations are not risk factors for thrombosis in antiphospholipid syndrome. The prevalence of the mutated allele 20210A of the prothrombin gene was higher in patients when compared with controls (5 versus 0.7%; P = 0.01), suggesting that prothrombin variant could increase the risk of thrombosis in patients with antiphospholipid syndrome.11679-8

Antithrombin Deficiency In Brazilian Patients With Venous Thrombosis: Molecular Characterization Of A Single Splice Site Mutation, An Insertion And A De Novo Point Mutation.

The prevalence of antithrombin (AT) deficiency in 342 unselected Brazilian patients with venous thrombosis was 1.16%, which increased to 3% when only patients under the age of 50 or with a familial history of thrombosis were considered. In two patients, a clinical (contraceptive use) or genetic risk factor (factor V Leiden and C677T in the methylene tetrahydrofolate reductase gene [MTHFR]) was identified and corroborated the hypothesis that an interaction of factors accounted for the appearance of thrombosis. However, no risk factor other than AT deficiency was identified in one patient with an important clinical and family history of spontaneous thrombosis. Three mutations were identified in these patients: a G-->A transition in intron 5 at position +1 (5'-->3'), three base insertions corresponding to arginine at position 5383 in exon 3A, and a G-->A transition at 13328, corresponding to an Ala404Thr de novo mutation. The polymorphisms in the genes coding for coagulation factors XII and XIII and fibrinogen normally associated with an increased risk for venous thrombosis were not related to thrombosis in these patients. This is the first study in South America to assess the prevalence of AT deficiency and to report the molecular characterization of the mutations involved.104397-40