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1.
Biochem Med (Zagreb) ; 30(1): 011002, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31839729

RESUMO

Rejection of the sample with repeated blood withdrawal is always an unwanted consequence of sample nonconformity and preanalytical errors, especially in the most vulnerable population - children. Here is presented a case with unexpected abnormal coagulation test results in a 2-year-old child with no previously documented coagulation disorder. Child is planned for tympanostomy tubes removal under the anaesthesia driven procedure, and preoperative coagulation tests revealed prolonged prothrombin time, activated partial thromboplastin time and thrombin time, with fibrinogen and antithrombin within reference intervals. From the anamnestic and clinical data, congenital coagulation disorder was excluded, and with further investigation, sample mismatch, clot presence and accidental ingestion of oral anticoagulant, heparin contamination or vitamin K deficiency were excluded too. Due to suspected EDTA carryover during blood sampling another sample was taken the same day and all tests were performed again. The results for all tests were within reference intervals confirming EDTA effect on falsely prolongation of the coagulation times in the first sample. This case can serve as alert to avoid unnecessary loss in terms of blood withdrawal repetitions and discomfort of the patients and their relatives, tests repeating, prolonging medical procedures, and probably delaying diagnosis or proper medical treatment. It is the responsibility of the laboratory specialists to continuously educate laboratory staff and other phlebotomists on the correct blood collection as well as on its importance for the patient's safety.


Assuntos
Transtornos da Coagulação Sanguínea/diagnóstico , Coleta de Amostras Sanguíneas/normas , Testes de Coagulação Sanguínea , Pré-Escolar , Erros de Diagnóstico , Ácido Edético/química , Humanos , Tempo de Tromboplastina Parcial , Fase Pré-Analítica , Tempo de Protrombina , Valores de Referência
2.
J Agric Food Chem ; 68(1): 176-184, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31850760

RESUMO

Thrombin can be used as a target for its inhibitors to prevent blood coagulation. A novel peptide (TKLTEEEKNR, PfCN) identified from αS2-casein (fragments 211-220) with high anticoagulant activity was screened and prepared. The activated partial thromboplastin time, prothrombin time, and thrombin time, at the concentration of 4 mM, prolonged about 19, 2.5 and 5.5 s, respectively. At the same concentration, the fibrinogen clotting time prolonged from 25.5 ± 0.7 to 38.3 ± 1.3 s. The thrombin inhibitory efficiency in vitro (IC50 value of 29.27 mM) and antithrombosis effect in vivo were determined. The secondary structure of thrombin, which was influenced by PfCN, indicates that PfCN can bind to thrombin. Isothermal titration calorimetry and the chromogenic substrate test showed that PfCN belongs to the bivalent thrombin inhibitor like bivalirudin. Although the effect was not as good as bivalirudin, in the animal experiment, bleeding occurred in the bivalirudin group but not in the PfCN group. Moreover, molecular docking illustrates the mechanism for the antithrombin activity of PfCN. These results indicated that PfCN could be used as an effective thrombin inhibitor with broad potential for the prevention of thrombotic acute pulmonary embolism and other thrombotic events.


Assuntos
Anticoagulantes/química , Peptídeos/química , Trombina/química , Animais , Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Domínio Catalítico , Bovinos , Humanos , Cinética , Simulação de Acoplamento Molecular , Tempo de Tromboplastina Parcial , Peptídeos/farmacologia , Tempo de Protrombina
3.
Gan To Kagaku Ryoho ; 46(11): 1733-1739, 2019 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-31748483

RESUMO

Several studies have reported increased anticoagulation effect of warfarin(WF)when combined with tyrosine kinase inhibitors(TKIs), such as gefitinib and erlotinib. However, effects of TKIs other than gefitinib and erlotinib on the anticoagulation effect of WF have not been clarified. To assess the degree and onset of prothrombin time-international normalized ratio (PT-INR)elevation and changes in WF daily doses in patients additionally receiving TKIs, this retrospective, single-center observational study compared PT-INR values and WF daily doses during WF treatment in the absence and presence of TKIs. Seven different TKIs(afatinib, alectinib, axitinib, crizotinib, pazopanib, regorafenib, and vandetanib)were prescribed during treatment with WF of venous thromboembolism in 10 cancer patients. Compared to baseline PT-INR, significant PT-INR elevations were observed in all patients during the combination therapy. The median PT-INR increased 1.6-fold from the baseline in the presence of TKIs(p<0.01), and the onset of PT-INR elevation was observed at a median of 18 days. As all patients receiving WF with the 7 TKIs showed PT-INR elevation, enhancement of the anticoagulation effect of WF in the presence of TKIs appears to be highly frequent. PT-INR should be carefully monitored, and adjusting the WF dosage may become necessary during the WF and TKI combination therapy.


Assuntos
Anticoagulantes/uso terapêutico , Varfarina/uso terapêutico , Humanos , Coeficiente Internacional Normatizado , Proteínas Tirosina Quinases , Tempo de Protrombina , Estudos Retrospectivos
4.
High Blood Press Cardiovasc Prev ; 26(5): 413-420, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31617197

RESUMO

INTRODUCTION: Population ageing in developed countries will inevitably increase the need for knee and hip replacement surgery. Over the years, direct oral anticoagulants, such as rivaroxaban, have been widely used for thromboprophylaxis in patients undergoing knee and hip replacement surgery. The study of pharmacogenetic characteristics of rivaroxaban is important for enhancing the effectiveness and safety of rivaroxaban thromboprophylaxis. AIM: Evaluation of CYP3A4, CYP3A5 and ABCB1 gene polymorphisms influence on rivaroxaban pharmacokinetics and prothrombin time dynamics in patients undergoing total hip and knee replacement surgery. METHODS: The study included 78 patients undergoing total hip and knee replacement surgery. The patients received 10 mg of rivaroxaban once a day. Genotyping of polymorphisms ABCB1 rs1045642, ABCB1 rs4148738, CYP3A4 rs35599367 and CYP3A5 rs776746 was performed. Peak steady-state and trough steady-state rivaroxaban concentrations were determined. Prothrombin time was also evaluated. RESULTS: The study revealed the following haplotypes: (1) ABCB1 rs1045642-CYP3A4 rs35599367 and (2) ABCB1 rs4148738-CYP3A4 rs35599367. The analysis of the peak steady-state rivaroxaban concentration between mutant haplotypes and wild haplotypes revealed no significant differences. However, there was a statistically significant average correlation between peak steady-state rivaroxaban concentration and prothrombin time (r = 0.421; r2 = 0.178; p < 0.001). CONCLUSION: No significant difference was identified in peak steady-state rivaroxaban concentration between mutant haplotypes and wild haplotypes. The revealed statistically significant average correlation between the prothrombin time and peak steady-state rivaroxaban concentration is important in clinical practice for assessing the anticoagulant activity of rivaroxaban.


Assuntos
Artroplastia de Quadril , Artroplastia do Joelho , Citocromo P-450 CYP3A/genética , Inibidores do Fator Xa/farmacocinética , Variantes Farmacogenômicos/genética , Rivaroxabana/farmacocinética , Trombose/prevenção & controle , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Idoso , Artroplastia de Quadril/efeitos adversos , Artroplastia do Joelho/efeitos adversos , Citocromo P-450 CYP3A/metabolismo , Monitoramento de Medicamentos/métodos , Inibidores do Fator Xa/administração & dosagem , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Protrombina , Rivaroxabana/administração & dosagem , Trombose/etiologia , Resultado do Tratamento
5.
Zhongguo Zhong Yao Za Zhi ; 44(15): 3349-3357, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602894

RESUMO

Rat model of blood stasis syndrome was prepared by subcutaneous injecting of epinephrine hydrochlorid,then the model rats were administrated by Yunnan Baiyao for 15 days. Blood rheology,coagulation function and histopathology were chosen as indicators to evaluate the successful replication of blood stasis syndrome model and the treatment effect of Yunnan Baiyao. UPLC-Q-TOF-MS was used to rapidly analyze the serum samples of blood stasis syndrome rat after 15 days Yunnan Baiyao treatment,Progenesis QI software was employed to identify the alkaloids components. The results showed that Yunnan Baiyao reduced the plasma viscosity and whole blood viscosity of rats with blood stasis syndrome,prolonged thrombin and prothrombin time,reduced fibrinogen content,and effectively improved pathological state such as inflammatory cell infiltration,blood stasis,congestion and edema of various organs in rats with blood stasis syndrome. Seven alkaloids components from Aconitum kusnezoffii,including karacolidine,senbusine B,isotalatizidine,karakoline,denudatine,talatisamine and chasmanine were found in the rat serum after Yunnan Baiyao treatment. Based on the effectiveness of Yunnan Baiyao in the treatment of blood stasis syndrome induced by epinephrine hydrochloride in rats,alkaloids components from the root of A. kusnezoffii absorbed into blood after Yunnan Baiyao treatment were clarified rapidly and accurately with the help of UPLC-Q-TOF-MS. Karacolidine,senbusine B,isotalatizidine,karakoline,denudatine,talatisamine and chasmanine are the pharmacodynamic material basis of the root of A. kusnezoffii for activating blood circulation and removing blood stasis.


Assuntos
Aconitum/química , Circulação Sanguínea/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Animais , Viscosidade Sanguínea , Tempo de Protrombina , Ratos , Tempo de Trombina
6.
An Acad Bras Cienc ; 91(3): e20180746, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576915

RESUMO

The use of ulinastatin for pancreatitis and sepsis have been described. This study was designed to evaluate the effect of ulinastatin on vascular endothelial cell damage and coagulation in pregnant women with severe pre-eclampsia (PE).From October 2015 to November 2017 at Tianjin Central Hospital of gynecology and obstetrics in China. Eighty pregnant women with severe PE, who elected to deliver by cesarean section, were randomly assigned to a control group or an ulinastatin group. The plasma concentration of von Willebrand factor (vWF) and platelet granule membrane protein (GMP-140), platelet count, fibrinogen levels, prothrombin time (PT), and partial prothrombin activation time (APTT) were recorded before combined spinal-epidural anesthesia and 40 min after administration in both groups.Ulinastatin attenuates vascular endothelial cell damage in pregnant women with PE as indicated by decreased plasma concentrations of vWF and prolonged APTT.


Assuntos
Células Endoteliais/efeitos dos fármacos , Glicoproteínas/farmacologia , Pré-Eclâmpsia/tratamento farmacológico , Inibidores da Tripsina/farmacologia , Adulto , Coagulação Sanguínea/efeitos dos fármacos , Cesárea/efeitos adversos , Feminino , Fibrinogênio/análise , Glicoproteínas/uso terapêutico , Humanos , Selectina-P/sangue , Contagem de Plaquetas , Pré-Eclâmpsia/sangue , Gravidez , Tempo de Protrombina , Valores de Referência , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Inibidores da Tripsina/uso terapêutico , Adulto Jovem , Fator de von Willebrand/análise
7.
Medicine (Baltimore) ; 98(40): e17360, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31577732

RESUMO

In neonates, congenital factor VII deficiency (FVIID) is characterized by central nervous system bleeding and gastrointestinal hemorrhage, often resulting in poor prognosis and high mortality.To improve understanding of FVIID in neonates in Asia, we retrospectively analyzed the clinical manifestations, diagnosis, treatment, clinical course, and genetic diagnosis of 2 cases of neonatal FVIID in the Department of Neonatology, Guangzhou Women and Children's Medical Center, Guangzhou, China, from January 2007 to December 2017 and performed a review of the relevant literature.Both neonates were female and presented with severe gastrointestinal tract and intracranial hemorrhage. The laboratory findings were characterized by repeated and non-vitamin K1-dependent prolonged of the prothrombin time (PT), Factor VII (FVII) activity was 1.5% and 3%, respectively. Both neonates died of severe intracranial hemorrhage, at 31 days and 6 months after birth, respectively. Gene sequencing results revealed a homozygous mutation in the FVII gene splice site (IVS7+1G>T) in both cases. Upon review of relevant literature published since 1996, we identified 19 cases of neonatal FVIID. The patients were full-term neonates with onset of symptoms mostly within 7 days after birth (73.7%), which included gastrointestinal bleeding (blood stool, vomiting blood; 31.6%), nervous system signs (drowsiness, convulsions, poor response; 26.3%), severe intracranial hemorrhage (84.2%), significantly prolonged PT with significantly decreased FVII activity (89.5%), high mortality, and disability (68.4%). Gene sequencing was performed in 9 of the 19 children evaluated and revealed a mutation in the FVII gene in all cases.FVIID can be clinically diagnosed based on the presence of prolonged PT that is difficult to correct and significantly decreased FVII activity (≤5%). As mutations in some sites are associated with severe bleeding, genetic diagnosis represents a useful tool for prenatal diagnosis of FVIID. In brief, we should pay great attention to the FVIID onset of the neonatal period, although it is rare but result in life-threatening bleeding with poor prognosis.


Assuntos
Deficiência do Fator VII/genética , Deficiência do Fator VII/patologia , China , Fator VII/metabolismo , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Tempo de Protrombina , Estudos Retrospectivos
8.
Int J Nanomedicine ; 14: 7017-7038, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564863

RESUMO

Background: Fabrication of a smart drug delivery system that could dramatically increase the efficiency of chemotherapeutic drugs and reduce the side effects is still a challenge for pharmaceutical researchers. By the emergence of nanotechnology, a huge window was opened towards this goal, and a wide type of nanocarriers were introduced for delivering the chemotherapeutic to the cancer cells, among them are cyclodextrins with the ability to host different types of hydrophobic bioactive molecules through inclusion complexation process. Aim: The aim of this study is to design and fabricate a pH-responsive theranostic nanocapsule based on cyclodextrin supramolecular nano-structure. Materials and methods: This nanostructure contains iron oxide nanoparticles in the core surrounded with three polymeric layers including polymeric ß-cyclodextrin, polyacrylic acid conjugated to sulfadiazine, and polyethylenimine functionalized with ß-cyclodextrin. Sulfadiazine is a pH-responsive hydrophobic component capable of making inclusion complex with ß-cyclodextrin available in the first and third layers. Doxorubicin, as an anti-cancer drug model, was chosen and the drug loading and release pattern were determined at normal and acidic pH. Moreover, the biocompatibility of the nanocapsule (with/without drug component) was examined using different techniques such as MTT assay, complement activation, coagulation assay, and hemolysis. Results: The results revealed the successful preparation of a spherical nanocapsule with mean size 43±1.5 nm and negatively charge of -43 mV that show 160% loading efficacy. Moreover, the nanocapsule has an on/off switching release pattern in response to pH that leads to drug released in low acidic pH. The results of the biocompatibility tests indicated that this nano drug delivery system had no effect on blood and immune components while it could affect cancer cells even at very low concentrations (0.3 µg mL-1). Conclusion: The obtained results suggest that this is a "switchable" theranostic nanocapsule with potential application as an ideal delivery system for simultaneous cancer diagnosis and therapy.


Assuntos
Nanocápsulas/química , Polietilenoimina/química , Nanomedicina Teranóstica , beta-Ciclodextrinas/química , Animais , Doxorrubicina/química , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Compostos Férricos/química , Hemólise/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Camundongos , Nanocápsulas/ultraestrutura , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Eletricidade Estática , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química , Difração de Raios X , beta-Ciclodextrinas/síntese química
9.
Gan To Kagaku Ryoho ; 46(9): 1413-1419, 2019 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-31530781

RESUMO

Few studies have evaluated the influence of anticancer drugs on the anticoagulation response to warfarin(WF). This retrospective, single-center, observationalstudy evaluated the changes in prothrombin time-internationalnormal ized ratio (PT-INR)in patients receiving a combination of WF and anticancer drugs. We compared(a)PT-INR changes between groups receiving WF and concomitantly started on either tyrosine kinase inhibitors(TKI)(WF+TKI group: n=14)or anticancer drugs other than TKI(WF+non-TKI group: n=20)and(b)PT-INR changes between groups that were started on WF concomitantly while receiving either TKI(TKI+WF group: n=16)or anticancer drugs other than TKI(non-TKI+WF group: n=13). (a)PT-INR changes were significantly larger in the WF+TKI group than in the WF+non-TKI group(2.23 vs 0.42, p<0.001). In the WF+TKI group, the WF dose was reduced after all 14 patients(100.0%)showed increased PT-INR.(b)PT-INR changes during the WF induction period were significantly larger in the TKI+WF group than in the non-TKI+WF group(2.18 vs 0.68, p<0.001). In the TKI+WF group, the WF dose was reduced after 12 patients(75.0%)showed increased PT-INR. It might be necessary to consider a reduction in WF dose when WF is administered in combination with TKIs.


Assuntos
Inibidores de Proteínas Quinases/uso terapêutico , Anticoagulantes , Humanos , Coeficiente Internacional Normatizado , Proteínas Tirosina Quinases , Tempo de Protrombina , Estudos Retrospectivos , Varfarina
10.
Lancet Haematol ; 6(10): e500-e509, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31420317

RESUMO

BACKGROUND: Rivaroxaban has been shown to be efficacious for treatment of venous thromboembolism in adults, and has a reduced risk of bleeding compared with standard anticoagulants. We aimed to develop paediatric rivaroxaban regimens for the treatment of venous thromboembolism in children and adolescents. METHODS: In this phase 2 programme, we did three studies to evaluate rivaroxaban treatment in children younger than 6 months, aged 6 months to 5 years, and aged 6-17 years. Our studies used a multicentre, single-arm design at 54 sites in Australia, Europe, Israel, Japan, and north America. We included children with objectively confirmed venous thromboembolism previously treated with low-molecular weight heparin, fondaparinux, or a vitamin K antagonist for at least 2 months or, in children who had catheter-related venous thromboembolism for at least 6 weeks. We administered rivaroxaban orally in a bodyweight-adjusted 20 mg-equivalent dose, based on physiologically-based pharmacokinetic modelling predictions and EINSTEIN-Jr phase 1 data in young adults, in either a once-daily (tablets; for those aged 6-17 years), twice-daily (in suspension; for those aged 6 months to 11 years), or three times-daily (in suspension; for those younger than 6 months) dosing regimen for 30 days (or 7 days for those younger than 6 months). The primary aim was to define rivaroxaban treatment regimens that match the target adult exposure range. The principal safety outcome was major bleeding and clinically relevant non-major bleeding. Analyses were per-protocol. The predefined efficacy outcomes were symptomatic recurrent venous thromboembolism, asymptomatic deterioration on repeat imaging at the end of the study treatment period. These trials are registered at ClinicalTrials.gov, numbers NCT02564718, NCT02309411, and NCT02234843. FINDINGS: Between Feb 11, 2013, and Dec 20, 2017, we enrolled 93 children (ten children younger than 6 months; 15 children aged 6 months to 1 year; 25 children aged 2-5 years; 32 children aged 6-11 years; and 11 children aged 12-17 years) into our study. 89 (96%) children completed study treatment (30 days of treatment, or 7 days in those younger than 6 months), and 93 (100%) children received at least one dose of study treatment and were evaluable for the primary endpoints. None of the children had a major bleed, and four (4%, 95% CI 1·2-10·6) of these children had a clinically relevant non-major bleed (three children aged 12-17 years with menorrhagia and one child aged 6-11 years with gingival bleeding). We found no symptomatic recurrent venous thromboembolism in any patients (0%, 0·0-3·9). 24 (32%) of 75 patients with repeat imaging had their thrombotic burden resolved, 43 (57%) patients improved, and eight (11%) patients were unchanged. No patient deteriorated. We confirmed therapeutic rivaroxaban exposures with once-daily dosing in children with bodyweights of at least 30 kg and with twice-daily dosing in children with bodyweights of at least 20 kg and less than 30 kg. Children with low bodyweights (<20 kg, particularly <12 kg) showed low exposures so, for future studies, rivaroxaban dosages were revised for these weight categories, to match the target adult exposure range. 61 (66%) of 93 children had adverse events during the study. Pyrexia was the most common adverse event (ten [11%] events), and anaemia and neutropenia or febrile neutropenia were the most frequent grade 3 or worse events (four [4%] events each). No children died or were discontinued from rivaroxaban because of adverse events. INTERPRETATION: Treatment with bodyweight-adjusted rivaroxaban appears to be safe in children. The treatment regimens that we confirmed in children with bodyweights of at least 20 kg and the revised treatment regimens that we predicted in those with bodyweights less than 20 kg will be evaluated in the EINSTEIN-Jr phase 3 trial in children with acute venous thromboembolism. FUNDING: Bayer AG, Janssen Research and Development.


Assuntos
Anticoagulantes/uso terapêutico , Rivaroxabana/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico , Adolescente , Anemia/etiologia , Anticoagulantes/efeitos adversos , Anticoagulantes/farmacocinética , Peso Corporal , Criança , Pré-Escolar , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Fator Xa/análise , Feminino , Meia-Vida , Hemorragia/etiologia , Humanos , Lactente , Masculino , Neutropenia/etiologia , Tempo de Protrombina , Rivaroxabana/efeitos adversos , Rivaroxabana/farmacocinética , Resultado do Tratamento , Tromboembolia Venosa/patologia
11.
Blood Coagul Fibrinolysis ; 30(6): 281-290, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31369408

RESUMO

: Thrombelastography (TEG) parameters and prothrombin time (PT), activated partial thromboplastin time (APTT) are compared and analysed. According to change of TEG parameters and assessment of haemostatic state of each patient, we try to explore the feasibility of individualized anticoagulant therapies. 87 people with hip or knee diseases awaiting arthroplasty were recruited. Haemoglobin levels and TEG parameters including R, K, α-angle, maximum amplitude, coagulation index were assessed in perioperative period. PT and APTT were assessed preoperatively. For 65 patients with normal TEG parameters, PT and APTT, we use tranexamic acid (TXA) to reduce blood loss during operation. As hypercoagulability group, 12 patients awaiting unilateral total knee arthroplasty with hypercoagulable state assessed by TEG parameters or risks for venous thromboembolism received daily 10-mg rivaroxaban until 24 h preoperatively and did not receive TXA during operation. All patients received intravenous administration of argatroban after 8 h postoperatively until day 3 and oral administration of rivaroxaban (10 mg) subsequently to prevent deep vein thrombosis or/and pulmonary embolism until 35 days postoperatively. TEG parameters have significant relationships with fibrinogen, platelet and APTT. The number of patients with abnormal haemostatic state assessed by TEG parameters is higher than that assessed by PT, APTT. TEG show hypercoagulability develops throughout perioperative period. There was no significant difference in haemoglobin concentration between hypercoagulability group and normal group in patients receiving unilateral total knee arthroplasty. TEG have higher sensitivity of perioperative abnormal haemostatic state than PT, APTT in primary arthroplasty. For patients with hypercoagulability, individualized anticoagulant therapies such as preoperative administration of rivaroxaban and not using TXA in operation is safe and effective.


Assuntos
Artroplastia de Quadril/efeitos adversos , Artroplastia do Joelho/efeitos adversos , Tromboelastografia/métodos , Anticoagulantes/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial/normas , Assistência Perioperatória , Ácidos Pipecólicos/uso terapêutico , Cuidados Pós-Operatórios , Cuidados Pré-Operatórios , Estudos Prospectivos , Tempo de Protrombina/normas , Embolia Pulmonar/prevenção & controle , Rivaroxabana/uso terapêutico , Tromboelastografia/normas , Trombofilia/diagnóstico , Trombofilia/tratamento farmacológico , Trombose Venosa/prevenção & controle
12.
Pharm Res ; 36(10): 146, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31396727

RESUMO

PURPOSE: CTB-001, a recently developed generic version of bivalirudin, an FDA-approved anticoagulant used for prophylaxis and treatment of cardiovascular diseases, has shown good efficacy and safety in clinical trials. We characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of CTB-001 by modeling and simulation analysis. METHODS: PK/PD data were collected from a randomized, double-blind, placebo-controlled, single-dose, dose-escalation phase 1 study conducted in 24 healthy Korean male subjects. PK/PD analysis was conducted sequentially by nonlinear mixed-effects modeling implemented in NONMEM®. Monte-Carlo simulations were conducted for PK, activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT). RESULTS: The CTB-101 PK was best described by a three-compartment linear model with a saturable binding peripheral compartment. All PD endpoints showed dose-response relationship, and their changes over time paralleled those of CTB-101 concentrations. A simple maximum effect model best described the aPTT, PT in INR, PT in seconds, and TT, whereas an inhibitory simple maximum effect model best described PT in percentages. The maximum duration of effect of CTB-001 on aPTT prolongation was 52.1 s. CONCLUSIONS: The modeling and simulation analysis well-characterized the PK and PD of CTB-001 in healthy Koreans, which will be valuable for identifying optimal dosing regimens of CBT-001.


Assuntos
Anticoagulantes/farmacologia , Hirudinas/farmacologia , Modelos Biológicos , Fragmentos de Peptídeos/farmacologia , Adulto , Anticoagulantes/farmacocinética , Simulação por Computador , Relação Dose-Resposta a Droga , Método Duplo-Cego , Medicamentos Genéricos , Hirudinas/farmacocinética , Humanos , Masculino , Método de Monte Carlo , Fragmentos de Peptídeos/farmacocinética , Tempo de Protrombina , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacologia , Resultado do Tratamento , Adulto Jovem
13.
Fitoterapia ; 138: 104345, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31470063

RESUMO

The present study reports the phytochemical investigation of n-butanol-soluble extracts of Glechoma longituba. Five new oleanane-type triterpenoid saponins with an 11α, 12α-epoxy unit, named glechomanosides A - E, were isolated from the n-butanol soluble fraction of G. longituba. Their chemical structures were established using HRESIMS, IR, 1D NMR, and 2D NMR techniques. The compounds were all evaluated for their antithrombus activities by monitoring thrombin time (TT), prothrombin time (PT), activated partial thromboplastin time (APTT), and antiplatelet aggregation assays. These results suggest that G. longituba might be a candidate plant source of an interesting antithrombotic activity.


Assuntos
Plaquetas/efeitos dos fármacos , Lamiaceae/química , Ácido Oleanólico/análogos & derivados , Saponinas/farmacologia , Animais , China , Feminino , Masculino , Camundongos , Estrutura Molecular , Ácido Oleanólico/isolamento & purificação , Ácido Oleanólico/farmacologia , Tempo de Tromboplastina Parcial , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Agregação Plaquetária , Tempo de Protrombina , Coelhos , Saponinas/isolamento & purificação , Tempo de Trombina
14.
Emerg Med Pract ; 21(8): 1-28, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31339254

RESUMO

Direct oral anticoagulant (DOAC) agents have become commonly used over the last 9 years for treatment and prophylaxis for thromboembolic conditions, following approvals by the United States Food and Drug Administration. These anticoagulant agents, which include a direct thrombin inhibitor and factor Xa inhibitors, offer potential advantages for patients over warfarin; however, bleeding emergencies with DOACs can present diagnostic and therapeutic challenges because, unlike traditional anticoagulants, their therapeutic effect cannot be easily monitored directly with common clotting assays. This review examines the growing body of evidence on the uses and risks of DOACs in the emergency department, including initiation of therapy and reversal strategies.


Assuntos
Anticoagulantes/efeitos adversos , Administração Oral , Anticoagulantes/uso terapêutico , Antitrombinas/efeitos adversos , Antitrombinas/uso terapêutico , Gerenciamento Clínico , Serviços Médicos de Emergência/métodos , Serviço Hospitalar de Emergência/organização & administração , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/uso terapêutico , Humanos , Tempo de Protrombina/métodos , Tomografia Computadorizada por Raios X/métodos , Ultrassonografia/métodos
15.
BMJ Case Rep ; 12(7)2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31350231

RESUMO

The oral anticoagulant warfarin is a vitamin K antagonist and is considered the first line anticoagulant in valvular atrial fibrillation. However prothrombin time should be closely monitored, drug interactions checked and compliance regarding diet ensured when the patient is on warfarin therapy. Anaemia should be looked for, evaluated for the cause and corrected since it is an independent predictor of bleeding and thrombotic episodes during warfarin therapy for atrial fibrillation We present an interesting case of anaemia which developed during warfarin therapy for atrial fibrillation. The patient was on amiodarone and was consuming leafy vegetables resulting in frequent raise in prothrombin time during which time she developed bleeding into the right femoral pseudoaneurysm which had developed following catheterisation for thrombectomy. Surgical correction of pseudoaneurysm was done, comedication was changed and diet compliance ensured which resulted in the subsequent maintenance of prothrombin time in the therapeutic range and steady haemoglobin levels.


Assuntos
Anemia/etiologia , Falso Aneurisma/etiologia , Anticoagulantes/efeitos adversos , Fibrilação Atrial/tratamento farmacológico , Spinacia oleracea/efeitos adversos , Vitamina K/antagonistas & inibidores , Varfarina/efeitos adversos , Falso Aneurisma/fisiopatologia , Falso Aneurisma/cirurgia , Cateterismo Cardíaco , Aconselhamento Diretivo , Feminino , Humanos , Pessoa de Meia-Idade , Tempo de Protrombina , Spinacia oleracea/química , Resultado do Tratamento , Vitamina K/sangue , Vitamina K/uso terapêutico
16.
Comput Methods Programs Biomed ; 177: 269-275, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31319955

RESUMO

BACKGROUND AND OBJECTIVE: In this paper, we introduce a new R package goftte for goodness-of-fit assessment based on cumulative sums of model residuals useful for checking key assumptions in the Cox regression and Fine and Gray regression models. METHODS: Monte-Carlo methods are used to approximate the null distribution of cumulative sums of model residuals. To limit the computational burden, the main routines used to approximate the null distributions are implemented in a parallel C++ programming environment. Numerical studies are carried out to evaluate the empirical type I error rates of the different testing procedures. The package and the documentation are available to users from CRAN R repositories. RESULTS: Results from simulation studies suggested that all statistical tests implemented in goftte yielded excellent control of the type I error rate even with modest sample sizes with high censoring rates. CONCLUSIONS: As compared to other R packages goftte provides new useful method for testing functionals, such as Anderson-Darling type test statistics for checking assumptions about proportional (sub-) distribution hazards. Approximations for the null distributions of test statistics have been validated through simulation experiments. Future releases will provide similar tools for checking model assumptions in multiplicative intensity models for recurrent data. The package may help to spread the use of recent advocated goodness-of-fit techniques in semiparametric regression for time-to-event data.


Assuntos
Biometria/métodos , Cirrose Hepática Biliar/diagnóstico , Modelos de Riscos Proporcionais , Software , Algoritmos , Bilirrubina/análise , Simulação por Computador , Bases de Dados Factuais , Humanos , Cirrose Hepática Biliar/sangue , Método de Monte Carlo , Linguagens de Programação , Tempo de Protrombina , Análise de Regressão
17.
Acta Med Port ; 32(6): 420-426, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31292022

RESUMO

INTRODUCTION: Excessive portal venous pressure in the liver remnant is an independent factor in the occurrence of posthepatectomy liver failure and small-for-size syndrome. The baseline portal pressure prior to hepatectomy was not considered previously. The aim of this study is to assess the impact of portal pressure change during hepatectomy on the patient outcome. MATERIAL AND METHODS: Prospective observational study including 30 patients subjected to intraoperative measurement of portal pressure before and after hepatectomy. This variation was related to the patient outcome. Control group evaluation was assessed. Patient, disease and procedure features were considered. The optimal cut-off of portal pressure variation was determined. Linear regression or logistic regression was applied to identify predictors of the outcome. RESULTS: The univariate analysis showed that portal pressure increase after hepatectomy was associated with coagulation impairment in the first 30 postoperative days (p < 0.05), and with the occurrence of major complications (p = 0.01), namely hepatic failure (p = 0.041). The multivariate analysis showed that portal venous pressure increase ≥ 2 mmHg is an independent factor for worse outcomes. DISCUSSION: As in previous studies, this study concludes that, after hepatectomy, in addition to the functional liver remnant, other factors are responsible for deterioration of liver function and patient outcome, such as the portal pressure increase and the exposure to chemotherapy prior to hepatectomy. This work may influence the definition of future indications for portal influx modulation. CONCLUSION: Patient outcomes are influenced by the portal venous pressure increase: an increment ≥ 2 mmHg after hepatectomy seems to increase the risk of major complications.


Assuntos
Transtornos da Coagulação Sanguínea/etiologia , Hepatectomia/efeitos adversos , Falência Hepática/etiologia , Pressão na Veia Porta/fisiologia , Complicações Pós-Operatórias/etiologia , Idoso , Análise de Variância , Área Sob a Curva , Determinação da Pressão Arterial/métodos , Estudos de Casos e Controles , Feminino , Hepatectomia/mortalidade , Humanos , Hipertensão , Coeficiente Internacional Normatizado , Cuidados Intraoperatórios , Modelos Lineares , Fígado/enzimologia , Falência Hepática/mortalidade , Masculino , Pessoa de Meia-Idade , Pressão na Veia Porta/efeitos dos fármacos , Cuidados Pós-Operatórios , Complicações Pós-Operatórias/mortalidade , Estudos Prospectivos , Tempo de Protrombina , Fatores de Tempo , Resultado do Tratamento
18.
Molecules ; 24(11)2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31174390

RESUMO

Pentamidine is bis-oxybenzamidine-based antiprotozoal drug. The parenteral use of pentamidine appears to affect the processes of blood coagulation and/or fibrinolysis resulting in rare but potentially life-threatening blood clot formation. Pentamidine was also found to cause disseminated intravascular coagulation syndrome. To investigate the potential underlying molecular mechanism(s) of pentamidine's effects on coagulation and fibrinolysis, we studied its effects on clotting times in normal and deficient human plasmas. Using normal plasma, pentamidine isethionate doubled the activated partial thromboplastin time at 27.5 µM, doubled the prothrombin time at 45.7 µM, and weakly doubled the thrombin time at 158.17 µM. Using plasmas deficient of factors VIIa, IXa, XIa, or XIIa, the concentrations to double the activated partial thromboplastin time were similar to that obtained using normal plasma. Pentamidine also inhibited plasmin-mediated clot lysis with half-maximal inhibitory concentration (IC50) value of ~3.6 µM. Chromogenic substrate hydrolysis assays indicated that pentamidine inhibits factor Xa and plasmin with IC50 values of 10.4 µM and 8.4 µM, respectively. Interestingly, it did not significantly inhibit thrombin, factor XIa, factor XIIIa, neutrophil elastase, or chymotrypsin at the highest concentrations tested. Michaelis-Menten kinetics and molecular modeling studies revealed that pentamidine inhibits factor Xa and plasmin in a competitive fashion. Overall, this study provides quantitative mechanistic insights into the in vitro effects of pentamidine isethionate on coagulation and fibrinolysis via the disruption of the proteolytic activity of factor Xa and plasmin.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Fibrinólise/efeitos dos fármacos , Pentamidina/farmacologia , Trombose/tratamento farmacológico , Testes de Coagulação Sanguínea , Fator VIIa/genética , Fator XIIa/genética , Fator XIa/genética , Fator Xa/genética , Humanos , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Trombina/química , Trombina/genética , Tempo de Trombina , Trombose/sangue , Trombose/patologia
19.
Vestn Otorinolaringol ; 84(2): 18-22, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31198210

RESUMO

The analysis (1998-2018) of the causes of early postoperative bleeding in 68 children with chronic lymphoproliferative syndrome and late postoperative bleeding (on the 7-10th day) in 3 children aged 3 to 17 years was performed. It was found the disorder of the platelet functional activity (adrenaline-induced platelet aggregation, adrenaline concentration - 2.5 µmol/l) in 83.8% cases (57 children). Late postoperative bleedings were developed due to the uncontrolled intake of nonsteroidal anti-inflammatory painkillers, which led to the platelet dysfunction. It has been established the decrease in the prothrombin percent by Quick in 73.5% children, and the elongation of the activated partial thromboplastin time (APTT) in the quarter of children amid the bleeding. Half of the children showed the increase of D-dimer concentration to 1.5-2 fold amid the bleeding. We offer preoperative examination: platelet count, prothrombin percent by Quick (prothrombin time), APTT and fibrinogen level. We recommend an extended hemostasis study with the detection of adhesive, aggregative and secretory functions of platelets in the children with chronic lymphoproliferative syndrome if the results of the integral screening tests differ from normal range.


Assuntos
Hemostasia , Hemostáticos , Transtornos Linfoproliferativos , Procedimentos Cirúrgicos Otorrinolaringológicos , Adolescente , Criança , Pré-Escolar , Humanos , Transtornos Linfoproliferativos/complicações , Tempo de Tromboplastina Parcial , Hemorragia Pós-Operatória/diagnóstico , Tempo de Protrombina
20.
Clin Lab ; 65(6)2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31232028

RESUMO

BACKGROUND: This study aims to evaluate the analytical properties of the DIAGON CoagXL (Budapest, Hungary) coagulation system. METHODS: The study includes a total of 212 normal, 49 pathologic plasma samples sent to our laboratory. The par-tial thromboplastin time (PTT) and activated partial thromboplastin time (aPTT) measurements were performed on the Diagon CoagXL and Stago StaR coagulometers. The precision, method comparison, carry-over, activity determination, and reference range verification studies were performed with Diagon CoagXL, the test analyzer. RESULTS: In the precision study performed with normal and pathologic plasma samples for the PT and aPTT tests, the within-day coefficient of variation (CV%) was 1.9 in the normal and 0.68 in the pathologic plasma for the PT, and for the aPTT it was 0.61 in the normal and 0.9 in the pathologic plasma. The between-day CV% was 1.6 in the normal plasma and 5.5 in the pathologic plasma for the PT and 3.7 in the normal plasma and 2.1 in the pathologic plasma for the aPTT. In the comparison study, the entire group mean ± standard deviation (mean ± SD) value for the INR was found to be 3.13 ± 1.26 in the CoagXL and 2.67 ± 0.82 in the StaR analyzer. The difference between these values was statistically significant (p < 0.006). For aPTT, mean ± SD value was found to be 39.44 ± 25.02 seconds (sec) in the CoagXL analyzer and 43.4 ± 27.63 sec in the StaR analyzer. The difference between these values was not statistically significant (p > 0.5). In the carryover study, the carryover value was -0.16 for the PT and 0 for the aPTT, which was under the allowable limit value (< 3 SD). In the percent activity determination study, regression equation of prothrombin activity (%) versus time (sec) was found as y = 341.6567 ± 37.1920x + 1.0913x2 (R2 = 0.97). The reference range verification analyses reveal that the manufacturer ranges were acceptable. CONCLUSIONS: Verification studies of CoagXL analyzer system was acceptable. But in comparison studies of PT we saw that there are still problems with recommended INR system.


Assuntos
Testes de Coagulação Sanguínea/instrumentação , Testes de Coagulação Sanguínea/métodos , Coagulação Sanguínea , Testes de Coagulação Sanguínea/normas , Humanos , Coeficiente Internacional Normatizado , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Valores de Referência , Reprodutibilidade dos Testes
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