RESUMO
AIMS: Andexanet alfa, a specific antidote to factor Xa (FXa) inhibitors, has been approved for clinical use in several countries, including Japan, based on the results from the phase 3 trial ANNEXA-4. We aimed to assess the efficacy and safety of andexanet alfa treatment in FXa inhibitor-related acute major bleeding in patients enrolled for ANNEXA-4 in Japan. METHODS: This prespecified analysis included patients enrolled at Japanese sites in the prospective, open-label, single-arm ANNEXA-4 trial. Eligible patients had major bleeding within 18 hours of oral FXa inhibitor administration. The coprimary efficacy endpoints were percent change in anti-FXa activity and proportion of patients achieving excellent or good hemostatic efficacy 12 hours post-treatment. RESULTS: A total of 19 patients were enrolled, all of whom had intracranial hemorrhage; 16 patients were evaluable for efficacy. Median percent reduction in anti-FXa activity from baseline to nadir was 95.4% in patients taking apixaban, 96.1% in patients taking rivaroxaban, and 82.2% in patients taking edoxaban. Overall, 14/16 patients (88%) achieved excellent or good hemostasis (apixaban, 5/5; rivaroxaban, 6/7; edoxaban, 3/4). Within 30 days, treatment-related adverse events (AEs) and serious AEs occurred in 2 and 5 patients, respectively. One patient died during follow-up, and 2 patients experienced thrombotic events. CONCLUSION: Treatment with andexanet alfa rapidly reduced anti-FXa activity with favorable hemostatic efficacy in Japanese patients with acute major bleeding. Serious AEs of thrombotic events during rapid reversal of anti-FXa activity arose as particular safety concerns in this population as with previous studies.
Assuntos
Hemostáticos , Piridinas , Tiazóis , Trombose , Humanos , Inibidores do Fator Xa/efeitos adversos , Rivaroxabana/efeitos adversos , Fator Xa/uso terapêutico , Fator Xa/farmacologia , Japão , Estudos Prospectivos , Hemorragia/tratamento farmacológico , Hemorragia/prevenção & controle , Hemorragia/induzido quimicamente , Antitrombina III/uso terapêutico , Hemostáticos/uso terapêutico , Trombose/tratamento farmacológico , Fibrinolíticos , Proteínas Recombinantes/efeitos adversos , Anticoagulantes/efeitos adversosRESUMO
BACKGROUND: Coagulopathy and thrombosis are well-described complications of asparaginase therapy. However, treatment practices in pediatric hematology/oncology (PHO) patients vary widely as evidence-based guidelines for clinical management of these complications in this population are lacking. OBJECTIVE: The objective of this study was to assess management practices of asparaginase-related coagulopathy by pediatric hematologist/oncologist attending physicians. DESIGN/METHOD: Email survey sent to 2327 PHO physicians primarily practicing in the United States. RESULTS: Two hundred eighty-five (12.2%) attending physicians completed the survey. Only 4.6% (n=13/285) routinely prescribe prophylactic anticoagulation during induction chemotherapy for leukemia. Slightly more than half (n=145/250, 50.9%) of all providers perform baseline coagulation studies. Most providers that were surveyed (n=185/285, 64.9%) only replete coagulant factors if the patient experiences bleeding or bruising. One hundred thirty (n=130/285, 45.6%) physicians replace low fibrinogen. The median fibrinogen replacement was 100 mg/dL (range: 40 to 200 mg/dL) with the median target of at least 100 mg/dL (range: 50 to 200 mg/dL). A minority of physicians (n=39/250, 13.7%) replace low antithrombin. The median antithrombin cutoff activity level was 60% (range: 40% to 100%) with a median target of 75% (range: 40% to 125%). CONCLUSIONS: There is a significant variation in PHO physician practices for monitoring and management of asparaginase-associated hemostatic derangements. Evidence-based guidelines have the potential to standardize practices.
Assuntos
Transtornos da Coagulação Sanguínea , Oncologistas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Asparaginase/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Fibrinogênio/uso terapêutico , Antitrombinas/uso terapêutico , Anticoagulantes/uso terapêutico , Antitrombina III/uso terapêuticoRESUMO
OBJECTIVE: Pregnant women may develop disseminated intravascular coagulation (DIC), possibly resulting in massive maternal haemorrhage and perinatal death. The Japan guideline recommends use of antithrombin III (ATIII) for DIC in obstetrics; however, its effect remains uncertain. The present study aimed to investigate the effect of ATIII for DIC in obstetrics, using a national inpatient database in Japan. DESIGN: Nationwide observational study. SETTING: Japan. POPULATION: We used the Diagnosis Procedure Combination inpatient database to identify patients who delivered at hospital and were diagnosed with DIC from July 2010 to March 2018. METHODS: Propensity score matching analyses were performed to compare in-hospital maternal mortality and hysterectomy during hospitalisation between users and non-users of ATIII on the day of delivery. MAIN OUTCOME MEASURES: In-hospital mortality, hysterectomy. RESULTS: A total of 9920 patients were enrolled, including 4329 patients (44%) who used ATIII and 5511 patients (56%) who did not use ATIII. One-to-one propensity score matching created 3290 pairs. In-hospital maternal mortality did not differ significantly between the propensity-matched groups (0.3% in the ATIII group versus 0.5% in the control group; odds ratio 0.73; 95% CI 0.35-1.54). A significantly lower proportion of patients in the ATIII group, compared with those in the control group, underwent hysterectomy during hospitalisation (5.3% versus 8.7%; absolute risk difference -2.9%; 95% CI -4.2 to -1.6%). CONCLUSIONS: Although the present study did not show a mortality-reducing effect of ATIII for patients with DIC in obstetrics, it may have clinical benefit in terms of reducing the number of patients undergoing hysterectomy. TWEETABLE ABSTRACT: This study did not show mortality-reducing effect of antithrombin III for patients with DIC in obstetrics.
Assuntos
Coagulação Intravascular Disseminada , Obstetrícia , Antitrombina III/uso terapêutico , Coagulação Intravascular Disseminada/diagnóstico , Coagulação Intravascular Disseminada/tratamento farmacológico , Feminino , Humanos , Japão/epidemiologia , Gravidez , Pontuação de Propensão , Resultado do TratamentoRESUMO
There has been increasing research momentum to identify new therapeutic agents for the prevention or treatment of preeclampsia, drugs that can affect the underlying disease pathophysiology. Molecular targets of candidate treatments include oxidative stress, antiangiogenic factors, and the angiotensin, nitric oxide, and proinflammatory pathways. The proposed treatments undergoing preclinical and clinical trial evaluation are thought to act on placental or endothelial disease or both. Most have adopted the pragmatic strategy of repurposing drugs. Of all the therapeutic agents proposed, pravastatin has received the most interest. There are preclinical studies showing that it has pleiotropic actions that favorably impact on multiple molecular targets and can resolve a preeclampsia phenotype in many animal models. An early phase clinical trial suggests that it may have therapeutic activity. Several large prevention trials are planned or ongoing and, when completed, could definitively address whether pravastatin can prevent preeclampsia. Proton-pump inhibitors, metformin, and sulfasalazine are other drugs with preclinical evidence of multiple molecular actions that could resolve the pathophysiology of preeclampsia. These agents are also currently being evaluated in clinical trials. There have been many recent preclinical studies identifying the potential of numerous natural compounds to treat preeclampsia, such as plant extracts and micronutrients that have potent anti-inflammatory or antioxidant activity. Recent preclinical studies have also proposed novel molecular-targeted strategies, such as monoclonal antibodies targeting tumor necrosis factor alpha, placental growth factor, and short interfering RNA technology, to silence the gene expression of soluble fms-like tyrosine kinase-1 or angiotensinogen. Other treatment approaches that have transitioned to human trials (ranging from single-arm to phase III trials that have been completed or are ongoing) include folic acid, nitric oxide donors (such as L-arginine), recombinant antithrombin III, digoxin immune antigen-binding fragment, and melatonin. There have been case series showing the removal of circulating soluble fms-like tyrosine kinase-1 may help stabilize the disease and prolong pregnancy. Interestingly, there are case reports suggesting that monoclonal antibody eculizumab (complement inhibitor) may have therapeutic potential. If new agents are discovered that are proven to be effective in preventing or treating preeclampsia, the potential to improve global maternal and perinatal health will be significant.
Assuntos
Pré-Eclâmpsia/prevenção & controle , Anticorpos Monoclonais/uso terapêutico , Antioxidantes/uso terapêutico , Antitrombina III/uso terapêutico , Produtos Biológicos/uso terapêutico , Remoção de Componentes Sanguíneos , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Micronutrientes/uso terapêutico , Fator de Crescimento Placentário/uso terapêutico , Extratos Vegetais/uso terapêutico , Pravastatina/uso terapêutico , Gravidez , Inibidores da Bomba de Prótons/uso terapêutico , RNA Interferente Pequeno , Proteínas Recombinantes/uso terapêutico , Sulfassalazina/uso terapêutico , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangueAssuntos
Aneurisma Coronário/terapia , Síndrome de Linfonodos Mucocutâneos/complicações , Infarto do Miocárdio/terapia , Anticoagulantes/uso terapêutico , Antitrombina III/análise , Antitrombina III/uso terapêutico , Antitrombinas/uso terapêutico , Biomarcadores/sangue , Criança , Tomada de Decisão Clínica , Protocolos Clínicos , Aneurisma Coronário/etiologia , Fibrinogênio/análise , Fibrinolíticos/uso terapêutico , Heparina/uso terapêutico , Humanos , Infarto do Miocárdio/etiologia , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária/uso terapêutico , Prognóstico , Ativador de Plasminogênio Tecidual/uso terapêuticoRESUMO
The study investigated the safety and efficacy of two antithrombin III (ATIII) products in pediatric patients receiving extracorporeal membrane oxygenation (ECMO) by performing a retrospective analysis of patients who received either recombinant ATIII (rATIII) or human-derived ATIII (hATIII). Twenty-two patients were included in the study from January 2014 to September 2015 and all received unfractionated heparin (UFH) as anticoagulation during ECMO. In total, 86 doses of ATIII were included in the analysis in which 37 doses (43%) were rATIII and 49 doses (57%) were hATIII. Unfractionated heparin rates were also evaluated for all cases (n = 86) at 24 hours post-ATIII supplementation. The UFH rate decreased after the administration of both types of ATIII. However, neither the reduction in UFH rate between the two ATIII products (p = 0.52) nor the UFH rates pre- and post-ATIII supplementation at 24 hours (p = 0.08) reached statistical significance. There was a significant difference in cost favoring the rATIII product (p < 0.0001). An ad-hoc estimation of waste associated with ATIII supplementation showed >$100,000 in financial loss of unused drug. Future studies are warranted to evaluate the efficacy of ATIII supplementation in pediatric ECMO.
Assuntos
Anticoagulantes/uso terapêutico , Antitrombina III/uso terapêutico , Oxigenação por Membrana Extracorpórea/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Trombose/prevenção & controle , Coagulação Sanguínea/efeitos dos fármacos , Criança , Heparina/uso terapêutico , Humanos , Masculino , Estudos Retrospectivos , Trombose/etiologiaRESUMO
Hepatic sinusoidal obstruction syndrome (SOS) remains a serious complication of hematopoietic stem cell transplantation (HSCT). In this single institution retrospective case series, 18 children developed SOS after HSCT. Patients were treated with antithrombin III (ATIII), defibrotide, or ATIII followed by defibrotide. Twelve of 13 patients who were treated with ATIII therapy alone had complete resolution of SOS, including 4 of 5 children with severe SOS. In this limited cohort, ATIII was safe and successfully prevented progression of hepatic SOS following HSCT in the majority of children at our center.
Assuntos
Antitrombina III/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Criança , Seguimentos , Hepatopatia Veno-Oclusiva/etiologia , Hepatopatia Veno-Oclusiva/patologia , Humanos , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND: Endothelial dysfunction during hemorrhagic shock (HS) is associated with loss of cell-associated syndecan-1 (Sdc1) and hyperpermeability. Fresh frozen plasma (FFP) preserves Sdc1 and reduces permeability following HS, although the key mediators remain unknown. Antithrombin III (ATIII) is a plasma protein with potent anti-inflammatory and endothelial protective activity. We hypothesized that the protective effects of FFP on endothelial Sdc1 and permeability are mediated, in part, through ATIII. METHODS: ATIII and Sdc1 were measured in severely injured patients upon admission (Nâ=â125) and hospital day 3 (Nâ=â90) for correlation analysis. In vitro effects of ATIII on human lung microvascular endothelial cells (HLMVECs) were determined by pretreating cells with vehicle, FFP, ATIII-deficient FFP, or purified ATIII followed by TNFα stimulation. Sdc1 expression was measured by immunostaining and permeability by electrical impedance. To determine the role of ATIII in vivo, male mice were subjected to a fixed pressure exsanguination model of HS, followed by resuscitation with FFP, ATIII-deficient FFP, or ATIII-deficient FFP with ATIII repletion. Lung Sdc1 expression was assessed by immunostaining. RESULTS: Pearson correlation analysis showed a significant negative correlation between plasma levels of Sdc1 and ATIII (Râ=â-0.62; Pâ<â0.0001) in injured patients on hospital day 3. Also, in vitro, FFP and ATIII prevented TNFα-induced permeability (Pâ<â0.05 vs TNFα) in HLMVECs. ATIII-deficient FFP had no effect; however, ATIII restoration reestablished its protective effects in a dose-dependent manner. Similarly, FFP and ATIII prevented TNFα-induced Sdc1 shedding in HLMVECs; however, ATIII-deficient FFP did not. In mice, Sdc1 expression was increased following FFP resuscitation (1.7â±â0.5, Pâ<â0.01) vs. HS alone (1.0â±â0.3); however, no improvement was seen following ATIII-deficient FFP treatment (1.3â±â0.4, Pâ=â0.3). ATIII restoration improved Sdc1 expression (1.5â±â0.9, Pâ<â0.05) similar to that of FFP resuscitation. CONCLUSIONS: ATIII plays a role in FFP-mediated protection of endothelial Sdc1 expression and barrier function, making it a potential therapeutic target to mitigate HS-induced endothelial dysfunction. Further studies are needed to elucidate the mechanisms by which ATIII protects the endothelium.
Assuntos
Antitrombina III/uso terapêutico , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Plasma , Choque Hemorrágico/tratamento farmacológico , Choque Hemorrágico/metabolismo , Sindecana-1/metabolismo , Animais , Permeabilidade Capilar/efeitos dos fármacos , Linhagem Celular , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologiaAssuntos
Anticoagulantes/uso terapêutico , Antitrombina III/uso terapêutico , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Coagulação Sanguínea/efeitos dos fármacos , Proteína C/uso terapêutico , Sepse/tratamento farmacológico , Trombomodulina/uso terapêutico , Anticoagulantes/efeitos adversos , Antitrombina III/efeitos adversos , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/diagnóstico , Transtornos da Coagulação Sanguínea/mortalidade , Ensaios Clínicos como Assunto , Medicina Baseada em Evidências , Humanos , Proteína C/efeitos adversos , Sepse/sangue , Sepse/diagnóstico , Sepse/mortalidade , Resultado do TratamentoRESUMO
A male patient in his 70s was referred to our department. He was found to have alcoholic liver cirrhosis, esophageal varices, and portal vein thrombosis. Antithrombin III (ATIII) formulation was administered. The thrombus was almost completely lysed 2 days after administration. Because portal vein thrombosis could recur, edoxaban, a direct oral anticoagulant (DOAC), was introduced to prevent recurrence. After 4 months, he showed no recurrence of portal vein thrombosis. In the present case, the combination of an ATIII formulation as initial treatment and edoxaban as maintenance therapy was safe and effective. The combination of ATIII and edoxaban may be a treatment option for patients with portal vein thrombosis.
Assuntos
Anticoagulantes/uso terapêutico , Antitrombina III/uso terapêutico , Cirrose Hepática/complicações , Veia Porta , Piridinas/uso terapêutico , Tiazóis/uso terapêutico , Trombose/tratamento farmacológico , Idoso , Humanos , Masculino , SolubilidadeRESUMO
AIM: To study the prognostic significance of endothelial dysfunction (ED) markers in the development of adverse clinical outcome (death) in patients with atrial fibrillation (AF) within a year after cardioembolic stroke. MATERIALS AND METHODS: 260 patients with newly diagnosed (nAF), paroxysmal, persistent and permanent forms of AF who underwent stroke were included. Duration of observation-12 months. V1 - the beginning of the study: V2 - 180 (±5) days and V3 - 360 (±5) evaluated the level of von Willebrand factor (fW), antithrombin III (AT III) and plasminogen. RESULTS: During the year of follow-up, patients with AF who underwent and had a high mortality rate. During the whole period 38 (14.6%) patients died, 15 (23.0%) - in the group with nAF, 6 (9.2%) - in the group with paroxysmal AF, 7 (10.8%) - in the group with persistent AF and 10 (15.4%) - in the group with permanent AF. After a year of follow-up, the level of fW in patients with nAF was higher than in patients of all groups, and statistically significant in patients with paroxysmal and persistent forms of AF. At III was important in the group of patients with nAF and with a constant form of AF, in the same groups there was no statistically significant increase in a year of follow-up. It was found that in survivors with nAF at III (73.54±8.67%) higher (p=0.002) compared with the dead (65.77±6.01%). In the group of patients with paroxysmal AF in survivors of III (77.75±10.15%) higher (p=0.031) compared with the dead (69.25±5.80%). In patients with persistent AF, the survivors of III (76.57±9.09%) were higher (p=0.002) compared to the dead (65.60±2.21%). Taking into account the results of the analysis of the dynamics of ed markers, it can be assumed that AT III is the most accurate prognostic marker for the studied cohort of patients. CONCLUSION: Detection and correction of ED in AF in patients within a year after stroke can optimize the tactics of management of patients and improve the prognosis of the diseas.
Assuntos
Antitrombina III/uso terapêutico , Antitrombinas/uso terapêutico , Fibrilação Atrial/diagnóstico , Endotélio/fisiopatologia , Plasminogênio/metabolismo , Acidente Vascular Cerebral/complicações , Fator de von Willebrand/metabolismo , Anticoagulantes/uso terapêutico , Fibrilação Atrial/mortalidade , Biomarcadores/sangue , Humanos , Taxa de SobrevidaRESUMO
Thromboembolic complications are found in 2-3% of children with nephrotic syndrome (NS); this increased risk is caused by hypovolemia, hemoconcentration, increased number and activity of platelets, hyperfibrinogenemia and loss of coagulation inhibitors. Risk is even higher in case of additional factors e.g. congenital thrombophilia. CASE REPORT: Girl with NS aged 17 11/12 years was admitted to hospital due to respiratory tract infection with cough and back pain. NS started 9 months earlier and she had two bouts of disease, and was treated only with prednisone (current dose - 60 mg/48h). On admission she was without any abnormalities on auscultation, with BP 111/65 mmHg, HR 80 bpm, satO2 99%. Lab results showed the increase of WBC 18.3×103/µL, D-dimers 23038 µg/L and proteinuria 900 mg/dL. Other values of examined parameters were in normal limits. Chest X-ray and ECG were also normal. Presumptive diagnosis of pulmonary embolism was made and the patient was given 1000IU of antithrombin III and nadroparine (2x90IU/kg/24h s.c.). In ECHO the occlusion of left pulmonary artery and preserved blood flow in right were revealed. In angioCT clot nearly filling lumen of left pulmonary artery, clot in intermediate part of right pulmonary artery, and focus of pulmonary infarction in 10th segment of left lung were found. Doppler USG of lower limb veins did not reveal thrombi or perforator vein incompetence. Treatment with nadroparine was continued, and rapid improvement of clinical condition and disappearance of pain and cough were observed. Mycophenolate mofetil was added, which resulted in subsidence of proteinuria. Rivaroxaban was used in prophylaxis of recurrences of thromboembolism. Tests for thrombophilia revealed factor V Leiden in patient.
Assuntos
Síndrome Nefrótica/etiologia , Embolia Pulmonar/etiologia , Trombofilia/complicações , Adolescente , Anticoagulantes/uso terapêutico , Antitrombina III/uso terapêutico , Fator V , Feminino , Humanos , Ácido Micofenólico/uso terapêutico , Nadroparina/uso terapêutico , Síndrome Nefrótica/tratamento farmacológico , Embolia Pulmonar/complicações , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/tratamento farmacológico , Trombofilia/diagnóstico , Trombofilia/metabolismoRESUMO
BACKGROUND: Heparin resistance (HR) is often encountered during cardiovascular operations that require cardiopulmonary bypass. Clinical risk factors and the mechanism underlying heparin resistance are yet to be determined. The aim of this study was to elucidate the clinically valid preoperative predictors related to HR. METHODS: The study evaluated 489 patients undergoing cardiovascular operations. Of these, 25 patients presented with HR and received antithrombin III for the initiation of cardiopulmonary bypass with an effective activated coagulation time. The remaining 464 patients, who did not receive antithrombin III, served as controls (NHR). Preoperative patient demographic and laboratory data were analyzed to identify risk factors for HR. RESULTS: The preoperative laboratory data showed platelet count, fibrinogen, D-dimer, creatinine, and C-reactive protein were significantly higher in the HR group than in the NHR group. As expected, the antithrombin III level was significantly lower overall in the HR group (86.0% vs 95.5%, p = 0.009); however, 80% of the patients in the HR group showed normal antithrombin III levels preoperatively. Multivariable logistic regression analysis identified chronic aortic dissection, chronic obstructive pulmonary disease, smoking, and elevated fibrinogen levels as independent predictors for HR. CONCLUSIONS: HR was shown to be associated with preoperative high fibrinogen levels, a smoking habit, and a preoperative diagnosis of chronic, but not acute, aortic dissection, with chronic obstructive pulmonary disease as comorbidity. Administration of antithrombin III resolved HR in all of the affected patients, even when their preoperative antithrombin III level was within the normal limit.
Assuntos
Anticoagulantes/farmacologia , Ponte Cardiopulmonar , Resistência a Medicamentos , Idoso , Dissecção Aórtica/epidemiologia , Antitrombina III/uso terapêutico , Estudos de Casos e Controles , Feminino , Fibrinogênio/metabolismo , Heparina , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Fatores de Risco , Fumar/efeitos adversosRESUMO
BACKGROUND: Antithrombin III (ATIII), the predominant coagulation factor inhibitor, possesses anti-inflammatory properties and exerts renoprotective effects on renal ischemia-reperfusion injury in animal models. However, the ATIII's protective effects of ATIII on acute kidney injury (AKI) following severe acute pancreatitis (SAP) need to be confirmed. METHODS: We assessed the association between ATIII activities and the incidence of AKI in patients with SAP, and explored therapeutic effects and potential mechanisms of ATIII on kidney injury in sodium taurocholate induced SAP rat model. Rats were intravenously injected with ATIII (500âµg/kg) before or after the induction of SAP. RESULTS: The results demonstrated ATIII did not attenuate pancreatic injury, but significantly ameliorate renal dysfunction and renal histological injury. ATIII administration alleviated renal inflammation response, oxidative stress, and cell apoptosis. Moreover, ATIII attenuated tumor necrosis factor α (TNFα)-stimulated intercellular cell adhesion molecule 1(ICAM-1) and monocyte chemotactic protein 1 (MCP-1) upregulation in cultured renal tubular epithelial cells. CONCLUSION: ATIII appears to ameliorate SAP-induced kidney injury by inhibiting inflammation, oxidative stress, and apoptosis. ATIII supplementation may have a potential prophylactic and therapeutic effect on SAP induced AKI.
Assuntos
Injúria Renal Aguda/sangue , Injúria Renal Aguda/tratamento farmacológico , Antitrombina III/uso terapêutico , Pancreatite/sangue , Pancreatite/tratamento farmacológico , Doença Aguda , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Quimiocina CCL2/sangue , Humanos , Incidência , Molécula 1 de Adesão Intercelular/sangue , Masculino , Malondialdeído/sangue , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Superóxido Dismutase/sangueRESUMO
: We present a case of a 26-year-old patient with severe infective endocarditis complicated with cerebral septic emboli that required essentially complete replacement of his circulating antithrombin activity to achieve an activated coagulation time near 480âs. The need for this degree of antithrombin administration may have been secondary to ongoing systemic inflammation and consequent thrombin generation despite blood culture results demonstrating no bacteremia. In sum, ongoing loss of endogenous antithrombin activity secondary to inflammation and the need for more than 80% normal activity to conduct safe cardiopulmonary bypass may require extraordinary administration of exogenous antithrombin in similar settings.
Assuntos
Anticoagulantes/uso terapêutico , Antitrombina III/uso terapêutico , Testes de Coagulação Sanguínea/métodos , Ponte Cardiopulmonar/métodos , Endocardite/cirurgia , Valva Mitral/cirurgia , Adulto , Anticoagulantes/farmacologia , Antitrombina III/farmacologia , Ponte Cardiopulmonar/efeitos adversos , Endocardite/patologia , Humanos , MasculinoRESUMO
The aim of the present study was to determine the effects of early anticoagulation treatment on severe burns complicated by inhalation injury in a rabbit model. Under anesthetization, an electrical burns instrument (100ËC) was used to scald the backs of rabbits for 15 sec, which established a 30% III severe burns model. Treatment of the rabbits with early anticoagulation effectively improved the severe burns complicated by inhalation injuryinduced lung injury, reduced PaO2, PaCO2 and SPO2 levels, suppressed the expression of tumor necrosis factorα, interleukin (IL)1ß and IL6, and increased the activity of IL10. In addition, it was found that early anticoagulation treatment effectively suppressed the activities of caspase3 and caspase9, upregulated the protein expression of vascular endothelial growth factor (VEGF) and decreased the protein expression of proteaseactivated receptor 1 (PAR1) in the severe burns model. It was concluded that early anticoagulation treatment affected the severe burns complicated by inhalation injury in a rabbit model through the upregulation of VEGF and downregulation of PAR1 signaling pathways. Thus, early anticoagulation is a potential therapeutic option for severe burns complicated by inhalation injury.
Assuntos
Anticoagulantes/uso terapêutico , Lesão por Inalação de Fumaça/tratamento farmacológico , Animais , Anticoagulantes/farmacologia , Antitrombina III/farmacologia , Antitrombina III/uso terapêutico , Caspase 3/metabolismo , Caspase 9/metabolismo , Pressão Venosa Central/efeitos dos fármacos , Modelos Animais de Doenças , Heparina/farmacologia , Heparina/uso terapêutico , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Coelhos , Receptor PAR-1/metabolismo , Índice de Gravidade de Doença , Lesão por Inalação de Fumaça/metabolismo , Lesão por Inalação de Fumaça/patologia , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
INTRODUCTION: The aim of this study was to evaluate the efficacy and complications of recombinant antithrombin (rAT) supplementation for adult patients with disseminated intravascular coagulation (DIC) compared with conventional plasma derived AT (pAT) treatment in the intensive care unit. MATERIALS AND METHODS: This study was performed in a single national university hospital in Japan. Adult patients from April 2015 to March 2016 with DIC were divided into two groups based on the type of AT agent used: the pAT group (n=24) and the rAT group (n=21). Patient demographics, medical history, diagnosis, blood tests, various clinical scores, AT activity, complications, and clinical outcome were collected and analyzed retrospectively. RESULTS: Significantly higher SIRS and APACHEII scores were confirmed in the rAT group than the pAT group. The initial dose of AT was significantly higher in the rAT group than in the pAT group. ATIII values before and after initial supplementation and during their ten-day clinical course were statistically similar between two groups. During the same period, 10 bleeding adverse events were found and there was no significant difference between both groups. Significantly more cases of the rAT group were administered with recombinant thrombomodulin concomitantly than those of the pAT group. Despite significantly more severe patients in rAT group, the clinical outcomes were the same in each group. CONCLUSIONS: Compared with pAT, the supplementation of rAT indicates clinical effectiveness without increasing the risk of bleeding complications in adult DIC patients with low AT activity.
Assuntos
Antitrombina III/efeitos adversos , Coagulação Intravascular Disseminada/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antitrombina III/uso terapêutico , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
The gene SerpinC1 encodes a serine protease inhibitor named antithrombin III (ATIII). This protease demonstrates both anticoagulant and anti-inflammatory action. ATIII is the most important coagulation factor inhibitor, and even minor changes in ATIII can significantly alter the risk of thromboembolism. ATIII can also suppress inflammation via a coagulation-dependent or -independent effect. Moreover, apart from ATIII deficiency, ATIII and its gene SerpinC1 may also be related to many diseases (e.g. hypertension, kidney diseases). The present review summarizes how ATIII affects the progress of kidney disease and its mechanism. Further studies are required to investigate how ATIII affects renal function and the treatment.
Assuntos
Deficiência de Antitrombina III/metabolismo , Antitrombina III/metabolismo , Nefropatias/metabolismo , Tromboembolia/metabolismo , Antitrombina III/genética , Antitrombina III/uso terapêutico , Deficiência de Antitrombina III/genética , Coagulação Sanguínea/efeitos dos fármacos , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/prevenção & controle , Nefropatias/genética , Modelos Biológicos , Fatores de Risco , Transdução de Sinais , Tromboembolia/genéticaRESUMO
We previously reported that insufficiency of antithrombin III (ATIII), the major anti-coagulation molecule in vivo, exacerbated renal ischemia-reperfusion injury in animal models and possibly humans. In the present study, we investigated the relationship between ATIII level and contrast induced nephropathy (CIN) in patients and examined therapeutic effect of ATIII on CIN in Sprague-Dawley rats. Patients with low ATIII activity presented a higher incidence of acute kidney injury (AKI) following coronary angiography. ATIII (500µg/kg) was intravenously injected before or after the induction of AKI in rats. Our data demonstrated ATIII significantly attenuated the elevation of serum creatinine, blood urea nitrogen, and renal histological injury. The beneficial effects of ATIII were accompanied by diminished renal inflammatory response, oxidative stress, cell apoptosis and improved renal blood flow in rats. In conclusion, ATIII appears to attenuate CIN through inhibiting inflammation, oxidative stress, apoptosis and improving renal blood flow. ATIII administration may represent a promising strategy for the prevention and treatment of contrast-induced AKI.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Antitrombina III/uso terapêutico , Meios de Contraste/efeitos adversos , Injúria Renal Aguda/sangue , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Animais , Antitrombina III/administração & dosagem , Angiografia Coronária/efeitos adversos , Feminino , Humanos , Injeções Intravenosas , Iodo/efeitos adversos , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Sprague-DawleyRESUMO
Human islet transplantation is a viable treatment option for type 1 diabetes mellitus (T1DM). However, pancreatic islet inflammation after transplantation induced by innate immune responses is likely to hinder graft function. This is mediated by incompatibility between islets and the blood interface, known as instant blood-mediated inflammatory reaction (IBMIR). Herein we hypothesized that portal venous administration of islet cells with human recombinant antithrombin (ATryn®), a serine protease inhibitor (serpin), which plays a central role in the physiological regulation of coagulation and exerts indirect anti-inflammatory activities, may offset coagulation abnormalities such as disseminated intravascular coagulation (DIC) and IBMIR. The current prospective, randomized experiment was conducted using an established preclinical pig model. Three groups were constituted for digested pancreatic tissue transplantation (0.15 ml/kg): control, NaCl 0.9% (n = 7); gold standard, heparin (25 UI/kg) (n = 7); and human recombinant ATryn® (500 UI/kg) (n = 7). Blood samples were collected over time (T0 to 24 h), and biochemical, coagulation, and inflammatory parameters were evaluated. In both the control and heparin groups, one animal died after a portal thrombosis, while no deaths occurred in the ATryn®-treated group. As expected, islet transplantation was associated with an increase in plasma IL-6 or TNF-α levels in all three groups. However, DIC was only observed in the control group, an effect that was suppressed after ATryn® administration. ATryn® administration increased antithrombin activity by 800%, which remained at 200% for the remaining period of the study, without any hemorrhagic complications. These studies suggest that coadministration of ATryn® and pancreatic islets via intraportal transplantation may be a valuable therapeutic approach for DIC without risk for islets and subjects.