Bleeding Disorders in Bothrops atrox Envenomations in the Brazilian Amazon: Participation of Hemostatic Factors and the Impact of Tissue Factor

Bleeding is a common hemostatic disorder that occurs in Bothrops envenomations. We evaluated the changes in coagulation, fibrinolysis components, and platelets in Bothrops atrox envenomations with bleeding. This is an observational study with B. atrox snakebite patients (n = 100) treated in Manaus, Brazilian Amazon. Bleeding was recorded on admission and during hospitalization. We found that the platelet count in our patients presented a weak correlation to tissue factor, factor II, and plasminogen. Tissue factor presented weak correlation to factor V, II, D-dimer, plasminogen, alpha 2-antiplasmin, and moderate correlation to fibrinogen and fibrin/fibrinogen degradation product (FDP). Patients with systemic bleeding (n = 20) presented low levels of factor V, II, fibrinogen, plasminogen, and alpha 2-antiplasmin, and high levels of tissue factor and FDP compared to those without bleeding. Patients with only local bleeding (n = 41) and without bleeding showed similar levels of hemostatic factors. Thrombocytopenia was observed mainly in patients with systemic bleeding and increased levels of serum venom. No association was found between venom levels and systemic bleeding, or between venom levels and clinical severity of envenomation. This is the first report that shows the participation of the extrinsic coagulation pathway in the consumption coagulopathy of B. atrox envenomations with systemic bleeding due to tissue factor release.

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Thrombophilia and risk of VTE recurrence according to the age at the time of first VTE manifestation

VASA ◽

10.1024/0301-1526/a000447 ◽

2015 ◽

Vol 44 (4) ◽

pp. 313-323 ◽

Cited By ~ 6

Author(s):

Lea Weingarz ◽

Marc Schindewolf ◽

Jan Schwonberg ◽

Carola Hecking ◽

Zsuzsanna Wolf ◽

...

Keyword(s):

Factor V Leiden ◽

Cox Proportional Hazards ◽

First Episode ◽

Factor V ◽

Factor V Leiden Mutation ◽

Younger Patients ◽

Risk Of Recurrence ◽

G20210a Mutation ◽

Increased Risk ◽

The Impact

Abstract. Background: Whether screening for thrombophilia is useful for patients after a first episode of venous thromboembolism (VTE) is a controversial issue. However, the impact of thrombophilia on the risk of recurrence may vary depending on the patient’s age at the time of the first VTE. Patients and methods: Of 1221 VTE patients (42 % males) registered in the MAISTHRO (MAin-ISar-THROmbosis) registry, 261 experienced VTE recurrence during a 5-year follow-up after the discontinuation of anticoagulant therapy. Results: Thrombophilia was more common among patients with VTE recurrence than those without (58.6 % vs. 50.3 %; p = 0.017). Stratifying patients by the age at the time of their initial VTE, Cox proportional hazards analyses adjusted for age, sex and the presence or absence of established risk factors revealed a heterozygous prothrombin (PT) G20210A mutation (hazard ratio (HR) 2.65; 95 %-confidence interval (CI) 1.71 - 4.12; p < 0.001), homozygosity/double heterozygosity for the factor V Leiden and/or PT mutation (HR 2.35; 95 %-CI 1.09 - 5.07, p = 0.030), and an antithrombin deficiency (HR 2.12; 95 %-CI 1.12 - 4.10; p = 0.021) to predict recurrent VTE in patients aged 40 years or older, whereas lupus anticoagulants (HR 3.05; 95%-CI 1.40 - 6.66; p = 0.005) increased the risk of recurrence in younger patients. Subgroup analyses revealed an increased risk of recurrence for a heterozygous factor V Leiden mutation only in young females without hormonal treatment whereas the predictive value of a heterozygous PT mutation was restricted to males over the age of 40 years. Conclusions: Our data do not support a preference of younger patients for thrombophilia testing after a first venous thromboembolic event.

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Self-Damping Mechanism in Blood Coagulation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647672 ◽

1974 ◽

Vol 32 (01) ◽

pp. 057-064 ◽

Cited By ~ 3

Author(s):

Y Nemerson ◽

S.A Silverberg ◽

J Jesty

Keyword(s):

Tissue Factor ◽

Blood Coagulation ◽

Calcium Ions ◽

Control Mechanism ◽

Factor Vii ◽

Damping Factor ◽

Factor V ◽

Factor X ◽

Extrinsic Pathway ◽

Two Systems

SummaryTwo reactions of the extrinsic pathway of coagulation, the activations of Factor X and prothrombin, have been studied in purified systems and shown to be self-damping. Factor X was activated by the tissue factor - Factor VII complex, and prothrombin by two systems: the coagulant protein of Taipan venom, and the physiological complex of activated Factor X, Factor V, lipid, and calcium ions. In each case the yield of enzyme, activated Factor X or thrombin, is a function of the concentration of activator. These and other observations are considered as a basis for a control mechanism in coagulation.

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Bleeding Classification in Clinical Trials: Observer Variability and Clinical Relevance

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657713 ◽

1997 ◽

Vol 78 (04) ◽

pp. 1189-1192 ◽

Cited By ~ 22

Author(s):

Yvonne P Graafsma ◽

Martin H Prins ◽

Anthonie W A Lensing ◽

Rob J de Haan ◽

Menno V Huisman ◽

...

Keyword(s):

Major Bleeding ◽

Clinical Relevance ◽

Area Under The Curve ◽

Weighted Kappa ◽

Clinical Severity ◽

Minor Bleeding ◽

Recent Trial ◽

Bleeding Episodes ◽

The Impact ◽

Adjudication Committee

SummaryTo evaluate the bleeding classification in a recent trial on venous thrombosis treatment, a selection of reported bleeding episodes was adjudicated twice by an independent committee and graded by the treating physician and independent clinical experts on the clinical severity and impact on the patient’s life.The kappa values for the dichotomy major bleeding versus minor or no bleeding were 0.79 (95% CI, 0.57-1.0) for the agreement between the two members of the adjudication committee and 0.77 (95% CI, 0.52-1.0) for the agreement between both adjudication sessions. The kappa values for the dichotomy major or minor bleeding versus no bleeding were 0.42 and 0.44. The weighted kappa values for the agreement between the treating physician and the independent experts were 0.76 for the Clinical severity and 0.79 for the impact on the patient’s life (95% CI, 0.63-0.88 and 0.70-0.89). The association between the adjudication result expressed as major bleeding or minor or no bleeding and the Clinical grading by the treating physician resulted in an ROC curve with an area under the curve of 0.98 for the Clinical severity and 0.99 for the impact on the patient’s life. The dichotomy major or minor bleeding versus no bleeding resulted in areas under the curve of 0.70 and 0.66.In conCIusion, the applied criteria for major bleeding are reproducible and Clinically relevant. The criteria for minor bleeding are not reproducible and are less associated with the observed Clinical relevance.

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Surgical Site Infection Following Caesarean Section by Acinetobacter Species: A Report from a Hyperendemic Setting in the Brazilian Amazon Region

Microorganisms ◽

10.3390/microorganisms9040743 ◽

2021 ◽

Vol 9 (4) ◽

pp. 743

Author(s):

Blenda Gonçalves Cabral ◽

Danielle Murici Brasiliense ◽

Ismari Perini Furlaneto ◽

Yan Corrêa Rodrigues ◽

Karla Valéria Batista Lima

Keyword(s):

Caesarean Section ◽

Surgical Site Infection ◽

Carbapenem Resistance ◽

Brazilian Amazon ◽

Amazon Region ◽

Site Infection ◽

Acinetobacter Species ◽

Brazilian Amazon Region ◽

Acinetobacter Spp ◽

The Impact

Surgical site infection (SSI) following caesarean section is associated with increased morbidity, mortality, and significant health care costs. This study evaluated the epidemiological, clinical, and microbiological features of Acinetobacter spp. in women with SSIs who have undergone caesarean section at a referral hospital in the Brazilian Amazon region. This study included 69 women with post-caesarean SSI by Acinetobacter spp. admitted to the hospital between January 2012 and May 2015. The 69 Acinetobacter isolates were subjected to molecular species identification, antimicrobial susceptibility testing, detection of carbapenemase-encoding genes, and genotyping. The main complications of post-caesarean SSI by Acinetobacter were inadequate and prolonged antibiotic therapy, sepsis, prolonged hospitalization, and re-suture procedures. A. baumannii, A. nosocomialis and A. colistiniresistens species were identified among the isolates. Carbapenem resistance was associated with OXA-23-producing A. baumannii isolates and IMP-1-producing A. nosocomialis isolate. Patients with multidrug-resistant A. baumannii infection showed worse clinical courses. Dissemination of persistent epidemic clones was observed, and the main clonal complexes (CC) for A. baumannii were CC231 and CC236 (Oxford scheme) and CC1 and CC15 (Pasteur scheme). This is the first report of a long-term Acinetobacter spp. outbreak in women who underwent caesarean section at a Brazilian hospital. This study demonstrates the impact of multidrug resistance on the clinical course of post-caesarean infections.

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The association between a conditional cash transfer programme and malaria incidence: a longitudinal ecological study in the Brazilian Amazon between 2004 and 2015

BMC Public Health ◽

10.1186/s12889-021-11255-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Layana Costa Alves ◽

Mauro Niskier Sanchez ◽

Thomas Hone ◽

Luiz Felipe Pinto ◽

Joilda Silva Nery ◽

...

Keyword(s):

Fixed Effects ◽

Negative Binomial ◽

Malaria Incidence ◽

Panel Study ◽

Negative Binomial Regression ◽

Brazilian Amazon ◽

Conditional Cash Transfer ◽

Cash Transfer ◽

Percentage Point Increase ◽

The Impact

Abstract Background Malaria causes 400 thousand deaths worldwide annually. In 2018, 25% (187,693) of the total malaria cases in the Americas were in Brazil, with nearly all (99%) Brazilian cases in the Amazon region. The Bolsa Família Programme (BFP) is a conditional cash transfer (CCT) programme launched in 2003 to reduce poverty and has led to improvements in health outcomes. CCT programmes may reduce the burden of malaria by alleviating poverty and by promoting access to healthcare, however this relationship is underexplored. This study investigated the association between BFP coverage and malaria incidence in Brazil. Methods A longitudinal panel study was conducted of 807 municipalities in the Brazilian Amazon between 2004 and 2015. Negative binomial regression models adjusted for demographic and socioeconomic covariates and time trends were employed with fixed effects specifications. Results A one percentage point increase in municipal BFP coverage was associated with a 0.3% decrease in the incidence of malaria (RR = 0.997; 95% CI = 0.994–0.998). The average municipal BFP coverage increased 24 percentage points over the period 2004–2015 corresponding to be a reduction of 7.2% in the malaria incidence. Conclusions Higher coverage of the BFP was associated with a reduction in the incidence of malaria. CCT programmes should be encouraged in endemic regions for malaria in order to mitigate the impact of disease and poverty itself in these settings.

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The procoagulant effects of factor V Leiden may be balanced against decreased levels of factor V and do not reflect in vivo thrombin formation in newborns

Thrombosis and Haemostasis ◽

10.1160/th05-05-0375 ◽

2006 ◽

Vol 95 (03) ◽

pp. 434-440 ◽

Cited By ~ 4

Author(s):

Satu Hyytiäinen ◽

Ulla Wartiovaara-Kautto ◽

Veli-Matti Ulander ◽

Risto Kaaja ◽

Markku Heikinheimo ◽

...

Keyword(s):

Tissue Factor ◽

Platelet Rich Plasma ◽

Venous Blood ◽

Factor V Leiden ◽

Factor V ◽

Cord Plasma ◽

Adult Plasma ◽

Thrombin Formation

SummaryThrombin regulation in newborns remains incompletely understood.We studied tissue factor-initiated thrombin formation in cord plasma in vitro, and the effects of Factor VLeiden (FVL) heterozygosity on thrombin regulation both in vitro and in vivo in newborns. Pregnant women with known thrombophilia (n=27) were enrolled in the study. Cord blood and venous blood at the age of 14 days were collected from 11 FVL heterozygous newborns (FVL-positive) and from 16 FVL-negative newborns. Prothrombin fragment F1+2 and coagulation factors were measured. Tissue factor-initiated thrombin formation was studied in cord platelet-poor plasma (PPP) of FVL-negative and -positive newborns, and in both PPP and platelet-rich plasma (PRP) of healthy controls. The endogenous thrombin potential (ETP) in cord PPP or PRP was ∼60% of that in adult plasma, while thrombin formation started ∼55% and ∼40% earlier in cord PPP and PRP, respectively. Further, in FVL-positive newborns thrombin formation started significantly earlier than in FVL-negative newborns. Exogenous activated protein C (APC) decreased ETP significantly more in cord than in adult PRP. In FVL-negative cord plasma 5nM APC decreased ETP by 17.4±3.5% (mean±SEM) compared with only 3.5±3.8% in FVL-positive cord plasma (p=0.01). FVL-positive newborns showed similar levels of F1+2 but significantly decreased levels of factor V compared with FVL negative newborns both in cord plasma (FV 0.82±0.07 U/ml vs. 0.98±0.05 U/ml, p=0.03) and at the age of two weeks (FV 1.15±0.04 U/ml vs. 1.32±0.05 U/ml, p=0.03). In conclusion, newborn plasma showed more rapid thrombin formation and enhanced sensitivity to APC compared with adult plasma. FVL conveyed APC resistance and a procoagulant effect in newborn plasma. Lack of elevated F1+2 levels in FVL-positive infants, however, suggested the existence of balancing mechanisms; one could be the observed lower level of factor V in FVL heterozygous newborns.

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Inadequate management of natural ecosystem in the Brazilian Amazon region results in the emergence and reemergence of arboviruses

Cadernos de Saúde Pública ◽

10.1590/s0102-311x2001000700025 ◽

2001 ◽

Vol 17 (suppl) ◽

pp. S155-S164 ◽

Cited By ~ 81

Author(s):

Pedro F. C. Vasconcelos ◽

Amélia P. A. Travassos da Rosa ◽

Sueli G. Rodrigues ◽

Elizabeth S. Travassos da Rosa ◽

Nicolas Dégallier ◽

...

Keyword(s):

Environmental Changes ◽

Epidemiological Data ◽

Brazilian Amazon ◽

Host Population ◽

Amazon Region ◽

Laboratory Animals ◽

Natural Ecosystem ◽

Brazilian Amazon Region ◽

Mining Dam ◽

The Impact

A total of 187 different species of arboviruses and other viruses in vertebrates were identified at the Evandro Chagas Institute (IEC) from 1954 to 1998, among more than 10,000 arbovirus strains isolated from humans, hematophagous insects, and wild and sentinel vertebrates. Despite intensive studies in the Brazilian Amazon region, especially in Pará State, very little is known about most of these viruses, except for information on date, time, source, and method of isolation, as well as their capacity to infect laboratory animals. This paper reviews ecological and epidemiological data and analyzes the impact of vector and host population changes on various viruses as a result of profound changes in the natural environment. Deforestation, mining, dam and highway construction, human colonization, and urbanization were the main manmade environmental changes associated with the emergence and/or reemergence of relevant arboviruses, including some known pathogens for humans.

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Thromboembolic events in Fabry disease and the impact of factor V Leiden

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2014.12.153 ◽

2015 ◽

Vol 114 (2) ◽

pp. S71-S72

Author(s):

Malte Lenders ◽

Nesrin Karabul ◽

Thomas Duning ◽

Boris Schmitz ◽

Michael Schelleckes ◽

...

Keyword(s):

Fabry Disease ◽

Factor V Leiden ◽

Factor V ◽

Thromboembolic Events ◽

The Impact

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Epidemiology, species distribution, and outcome of nosocomial Candida spp. bloodstream infection in Shanghai: an 11-year retrospective analysis in a tertiary care hospital

Annals of Clinical Microbiology and Antimicrobials ◽

10.1186/s12941-021-00441-y ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Yan-Jun Zheng ◽

Ting Xie ◽

Lin Wu ◽

Xiao-Ying Liu ◽

Ling Zhu ◽

...

Keyword(s):

Risk Factors ◽

Mortality Rate ◽

Antifungal Therapy ◽

Species Distribution ◽

Tertiary Care Hospital ◽

Tertiary Care ◽

Clinical Severity ◽

Severe Neutropenia ◽

Care Hospital ◽

The Impact

Abstract Background The incidence of Candida bloodstream infections (BSIs), has increased over time. In this study, we aimed to describe the current epidemiology of Candida BSI in a large tertiary care hospital in Shanghai and to determine the risk factors of 28-day mortality and the impact of antifungal therapy on clinical outcomes. Methods All consecutive adult inpatients with Candida BSI at Ruijin Hospital between January 1, 2008, and December 31, 2018, were enrolled. Underlying diseases, clinical severity, species distribution, antifungal therapy, and their impact on the outcomes were analyzed. Results Among the 370 inpatients with 393 consecutive episodes of Candida BSI, the incidence of nosocomial Candida BSI was 0.39 episodes/1000 hospitalized patients. Of the 393 cases, 299 (76.1%) were treated with antifungal therapy (247 and 52 were treated with early appropriate and targeted antifungal therapy, respectively). The overall 28-day mortality rate was 28.5%, which was significantly lower in those who received early appropriate (25.5%) or targeted (23.1%) antifungal therapy than in those who did not (39.4%; P = 0.012 and P = 0.046, respectively). In multivariate Cox regression analysis, age, chronic renal failure, mechanical ventilation, and severe neutropenia were found to be independent risk factors of the 28-day mortality rate. Patients who received antifungal therapy had a lower mortality risk than did those who did not. Conclusions The incidence of Candida BSI has increased steadily in the past 11 years at our tertiary care hospital in Shanghai. Antifungal therapy influenced short-term survival, but no significant difference in mortality was observed between patients who received early appropriate and targeted antifungal therapy.

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Hypertrophic cardiomyopathy-linked variants of cardiac myosin-binding protein C3 display altered molecular properties and actin interaction

Biochemical Journal ◽

10.1042/bcj20180685 ◽

2018 ◽

Vol 475 (24) ◽

pp. 3933-3948 ◽

Cited By ~ 4

Author(s):

Sahar I. Da'as ◽

Khalid Fakhro ◽

Angelos Thanassoulas ◽

Navaneethakrishnan Krishnamoorthy ◽

Alaaeldin Saleh ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Binding Protein ◽

Clinical Severity ◽

Actin Binding ◽

Cardiac Myosin ◽

C2 Domains ◽

Cardiac Phenotype ◽

Myosin Binding Protein ◽

Myosin Binding ◽

The Impact

The most common inherited cardiac disorder, hypertrophic cardiomyopathy (HCM), is characterized by thickening of heart muscle, for which genetic mutations in cardiac myosin-binding protein C3 (c-MYBPC3) gene, is the leading cause. Notably, patients with HCM display a heterogeneous clinical presentation, onset and prognosis. Thus, delineating the molecular mechanisms that explain how disparate c-MYBPC3 variants lead to HCM is essential for correlating the impact of specific genotypes on clinical severity. Herein, five c-MYBPC3 missense variants clinically associated with HCM were investigated; namely V1 (R177H), V2 (A216T), V3 (E258K), V4 (E441K) and double mutation V5 (V3 + V4), all located within the C1 and C2 domains of MyBP-C, a region known to interact with sarcomeric protein, actin. Injection of the variant complementary RNAs in zebrafish embryos was observed to recapitulate phenotypic aspects of HCM in patients. Interestingly, V3- and V5-cRNA injection produced the most severe zebrafish cardiac phenotype, exhibiting increased diastolic/systolic myocardial thickness and significantly reduced heart rate compared with control zebrafish. Molecular analysis of recombinant C0–C2 protein fragments revealed that c-MYBPC3 variants alter the C0–C2 domain secondary structure, thermodynamic stability and importantly, result in a reduced binding affinity to cardiac actin. V5 (double mutant), displayed the greatest protein instability with concomitant loss of actin-binding function. Our study provides specific mechanistic insight into how c-MYBPC3 pathogenic variants alter both functional and structural characteristics of C0–C2 domains leading to impaired actin interaction and reduced contractility, which may provide a basis for elucidating the disease mechanism in HCM patients with c-MYBPC3 mutations.

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