RESUMO
Antithrombin III (ATIII) is a potent endogenous anticoagulant that binds to heparan sulfate proteoglycans (HSPGs) on endothelial cells' surfaces. Among these HSPGs, syndecans (SDCs) are crucial as transmembrane receptors bridging extracellular ligands with intracellular signaling pathways. Specifically, syndecan-4 (SDC4) has been identified as a key receptor on endothelial cells for transmitting the signaling effects of ATIII. Meanwhile, SDCs have been implicated in facilitating the cellular internalization of SARS-CoV-2. Given the complex interactions between ATIII and SDC4, our study analyzed the impact of ATIII on the virus entry into host cells. While ATIII binds to all SDC isoforms, it shows the strongest affinity for SDC4. SDCs' heparan sulfate chains primarily influence ATIII's SDC attachment, although other parts might also play a role in ATIII's dominant affinity toward SDC4. ATIII significantly reduces SARS-CoV-2's cellular entry into cell lines expressing SDCs, suggesting a competitive inhibition mechanism at the SDC binding sites, particularly SDC4. Conversely, the virus or its spike protein decreases the availability of SDCs on the cell surface, reducing ATIII's cellular attachment and hence contributing to a procoagulant environment characteristic of COVID-19.
Assuntos
Antitrombina III , COVID-19 , SARS-CoV-2 , Sindecana-4 , Internalização do Vírus , Humanos , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , SARS-CoV-2/efeitos dos fármacos , Sindecana-4/metabolismo , COVID-19/virologia , COVID-19/metabolismo , Internalização do Vírus/efeitos dos fármacos , Antitrombina III/metabolismo , Antitrombina III/farmacologia , Ligação Proteica , Vacinas contra COVID-19/imunologia , Tratamento Farmacológico da COVID-19 , Sindecanas/metabolismo , AnimaisRESUMO
BACKGROUND: We present the case study of a 28-year-old pregnant woman with antithrombin deficiency who was treated with low-molecular-weight heparin (LMWH). METHODS: Due to severe homozygous type II antithrombin heparin binding site (HBS) deficiency, the thrombin generation (TG) was monitored in this woman via the Thrombin Generation Assay (TGA). We used Siemens diagnostic kits Berichrom® Antithrombin III (IIa) and INNOVANCE® Antithrombin (Xa) to determine antithrombin activity. We used a chromogenic method for determination of factor Xa (FXa) inhibition. RESULTS: There were no thrombotic complications during the whole pregnancy of the observed woman. Antithrombin was administered before and after delivery, which was significantly reflected in the decrease in thrombin generation. CONCLUSIONS: Consistent monitoring of thrombin generation with LMWH anticoagulant therapy administration during pregnancy together with antithrombin administration before and after delivery can improve the overall condition of pregnant women and the quality of their care.
Assuntos
Deficiência de Antitrombina III , Antitrombinas , Feminino , Humanos , Gravidez , Adulto , Antitrombinas/uso terapêutico , Antitrombina III/farmacologia , Trombina , Gestantes , Heparina de Baixo Peso Molecular/uso terapêutico , Anticoagulantes/farmacologia , Heparina/farmacologia , Deficiência de Antitrombina III/diagnóstico , Deficiência de Antitrombina III/tratamento farmacológicoRESUMO
Thromboembolic diseases are a major cause of mortality in human and the currently available anticoagulants are associated with various drawbacks, therefore the search for anticoagulants that have better safety profile is highly desirable. Compounds that are part of the dietary routine can be modified to possibly increase their anticoagulant potential. We show mannose 2,3,4,5,6-O-pentasulfate (MPS) as a synthetically modified form of mannose that has appreciable anticoagulation properties. An in silico study identified that mannose in sulfated form can bind effectively to the heparin-binding site of antithrombin (ATIII) and heparin cofactor II (HCII). Mannose was sulfated using a simple sulfation strategy-involving triethylamine-sulfur trioxide adduct. HCII and ATIII were purified from human plasma and the binding analysis using fluorometer and isothermal calorimetry showed that MPS binds at a unique site. A thrombin inhibition analysis using the chromogenic substrate showed that MPS partially enhances the activity of HCII. Further an assessment of in vitro blood coagulation assays using human plasma showed that the activated partial thromboplastin time (APTT) and prothrombin time (PT) were prolonged in the presence of MPS. A molecular dynamics simulation analysis of the HCII-MPS complex showed fluctuations in a N-terminal loop and the cofactor binding site of HCII. The results indicate that MPS is a promising lead due to its effect on the in vitro coagulation rate.Communicated by Ramaswamy H. Sarma.
Assuntos
Cofator II da Heparina , Manose , Humanos , Cofator II da Heparina/química , Cofator II da Heparina/metabolismo , Manose/farmacologia , Coagulação Sanguínea , Anticoagulantes/farmacologia , Anticoagulantes/química , Heparina/farmacologia , Antitrombina III/farmacologia , Antitrombina III/fisiologia , Antitrombinas/farmacologia , Trombina/químicaRESUMO
Blood coagulation is a self-repair process regulated by activated platelet surfaces, clotting factors, and inhibitors. Antithrombin (AT) is one such inhibitor that impedes coagulation by targeting and inactivating several key coagulation enzymes. The effect of AT is greatly enhanced in the presence of heparin, a common anticoagulant drug. When heparin binds to AT, it either bridges with the target enzyme or induces allosteric changes in AT leading to more favorable binding with the target enzyme. AT inhibition of fluid-phase enzymes caused little suppression of thrombin generation in our previous mathematical models of blood coagulation under flow. This is because in that model, flow itself was a greater inhibitor of the fluid-phase enzymes than AT. From clinical observations, it is clear that AT and heparin should have strong inhibitory effects on thrombin generation, and thus we hypothesized that AT could be inhibiting enzymes bound to activated platelet surfaces that are not subject to being washed away by flow. We extended our mathematical model to include the relevant reactions of AT inhibition at the activated platelet surfaces as well as those for unfractionated heparin and a low molecular weight heparin. Our results show that AT alone is only an effective inhibitor at low tissue factor densities, but in the presence of heparin, it can greatly alter, and in some cases shut down, thrombin generation. Additionally, we studied each target enzyme separately and found that inactivation of no single enzyme could substantially suppress thrombin generation.
Assuntos
Antitrombinas , Heparina , Antitrombinas/farmacologia , Antitrombinas/metabolismo , Heparina/farmacologia , Heparina/química , Trombina/metabolismo , Antitrombina III/metabolismo , Antitrombina III/farmacologia , Anticoagulantes/farmacologia , Coagulação Sanguínea/fisiologiaRESUMO
Renal ischemia-reperfusion (IR) produces-induced injury and is characterized by restriction of blood supply to the kidney followed by restoration and re-oxygenation of the tissue. IR injury in the kidney contributes to pathological processes known as acute renal injury (ARI). Ischemia-perfusion injury (IRI) of the left renal artery has been demonstrated in Wistar rats. A total of 32 animals were divided into four groups: control group (SHAM), IR animals with induced ischemia-reperfusion, AT-IR animals treated by antithrombin III (AT) before IR, and AT-IR-AT animals with AT administered before and after IR. IR-induced hyperproteinemia, hyperalbuminemia, hyperglobulinemia, and a significantly low A/G ratio. Exogenous administration of AT prior to IR development effectively regulates protein fraction levels by establishing normoproteinemia. The preventive effect of AT regulates serum protein levels and reduces acute inflammation by reducing globulin and establishing physiological levels of A/G ratios. The therapeutic effect of AT given after IR is not effective compared to AT administered before IR. Protein fractions can serve as an important predictive marker for the prognosis and duration of acute inflammation. Serum globulin levels and the A/G ratio may serve as effective prognostic markers in acute inflammation caused by ischemia-reperfusion injury of the kidney. A strong correlation between globulin and the A/G ratio suggests novel markers associated with acute inflammation that can lead to chronic kidney disease.
Assuntos
Antitrombina III/farmacologia , Nefropatias/prevenção & controle , Traumatismo por Reperfusão/prevenção & controle , Doença Aguda , Animais , Modelos Animais de Doenças , Nefropatias/metabolismo , Nefropatias/patologia , Ratos , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologiaRESUMO
The impact of steroid hormones estrogen and progesterone on human immunodeficiency virus type 1 (HIV-1) replication is well documented. However, the exact mechanism involved in the regulation of HIV-1 replication by estrogen and progesterone is still unclear. In the present study, we wanted to elucidate the molecular mechanisms underlying the modulation of HIV-1 replication by estrogen and progesterone. To achieve this goal, we used real-time quantitative PCR arrays (PCR arrays) to identify differentially expressed host genes in response to hormone treatments that are involved in antiviral responses. Our in vitro results suggest that treatment with high doses of estrogen and progesterone promotes the expression of host antiviral factors Secretory leukocyte protease inhibitor (SLPI) and Serpin family C member 1 (SERPIN C1) among others produced in response to HIV-1 infection. SLPI is an enzyme that inhibits human leukocyte elastase, human cathepsin G, human trypsin, neutrophil elastase, and mast cell chymase. SERPIN C1 is a plasma protease inhibitor that regulates the blood coagulation cascade by the inhibition of thrombin and other activated serine proteases of the coagulation system. A dose dependent downmodulation of HIV-1 replication was observed in monocyte-derived macrophages (MDMs) pre-treated with the two proteins SLPI and SERPIN C1. Further investigations suggests that the host antiviral factors, SLPI and SERPIN C1 act at the pre-integration stage, inhibiting HIV-1 viral entry and leading to the observed downmodulation of HIV-1 replication. Our studies would help identify molecular mechanisms and pathways involved in HIV-1 pathogenesis.
Assuntos
Antitrombina III/metabolismo , Estradiol/farmacologia , HIV-1/fisiologia , Macrófagos/virologia , Progesterona/farmacologia , Inibidor Secretado de Peptidases Leucocitárias/metabolismo , Antitrombina III/genética , Antitrombina III/farmacologia , HIV-1/efeitos dos fármacos , Humanos , Inibidor Secretado de Peptidases Leucocitárias/genética , Inibidor Secretado de Peptidases Leucocitárias/farmacologia , Regulação para Cima , Integração Viral/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
Plasmodium falciparum-derived histidine-rich protein II (HRPII) has been shown to inhibit heparin-dependent anticoagulant activity of antithrombin (AT) and induce inflammation in vitro and in vivo. In a recent study, we showed that HRPII interacts with the AT-binding vascular glycosaminoglycans (GAGs) not only to disrupt the barrier-permeability function of endothelial cells but also to inhibit the antiinflammatory signaling function of AT. Here we investigated the mechanisms of the proinflammatory function of HRPII and the protective activity of AT in cellular and animal models. We found that AT competitively inhibits the GAG-dependent HRPII-mediated activation of NF-κB and expression of intercellular cell adhesion molecule 1 (ICAM1) in endothelial cells. Furthermore, AT inhibits HRPII-mediated histone H3 citrullination and neutrophil extracellular trap (NET) formation in HL60 cells and freshly isolated human neutrophils. In vivo, HRPII induced Mac1 expression on blood neutrophils, MPO release in plasma, neutrophil infiltration, and histone H3 citrullination in the lung tissues. HRPII also induced endothelial cell activation as measured by increased ICAM1 expression and elevated vascular permeability in the lungs. AT effectively inhibited HRPII-mediated neutrophil infiltration, NET formation, and endothelial cell activation in vivo. AT also inhibited HRPII-meditated deposition of platelets and fibrin(ogen) in the lungs and circulating level of von Willebrand factor in the plasma. We conclude that AT exerts protective effects against pathogenic effects of P falciparum-derived HRPII in both cellular and animal models.
Assuntos
Antígenos de Protozoários/metabolismo , Histidina , Plasmodium falciparum , Proteínas de Protozoários/metabolismo , Animais , Anticoagulantes/farmacologia , Antitrombina III/metabolismo , Antitrombina III/farmacologia , Antitrombinas/farmacologia , Células Endoteliais/metabolismo , Histidina/metabolismo , Histidina/farmacologia , Histonas/metabolismo , InflamaçãoRESUMO
BACKGROUND: Neuroinflammation and cerebral edema development following severe traumatic brain injury (TBI) affect subsequent cognitive recovery. Independent of its anticoagulant effects, antithrombin III (AT-III) has been shown to block neurovascular inflammation after severe TBI, reduce cerebral endothelial-leukocyte interactions, and decrease blood-brain barrier permeability. We hypothesized that AT-III administration after TBI would improve post-TBI cognitive recovery, specifically enhancing learning, and memory. METHODS: Fifteen CD1 male mice were randomized to undergo severe TBI (controlled cortical impact [CCI]: velocity, 6 m/s; depth, 1 mm; diameter, 3 mm) or sham craniotomy and received either intravenous AT-III (250 IU/kg) or vehicle (VEH/saline) 15 minutes and 24 hours post-TBI. Animals underwent Morris water maze testing from 6 to 14 days postinjury consisting of cued learning trials (platform visible), spatial learning trials (platform invisible, spatial cues present), and probe (memory) trials (platform removed, spatial cues present). Intergroup differences were assessed by the Kruskal-Wallis test (p < 0.05). RESULTS: Morris water maze testing demonstrated that cumulative cued learning (overall mean time in seconds to reach the platform on days 6-8) was worst in CCI-VEH animals (26.1 ± 2.4 seconds) compared with CCI-AT-III counterparts (20.3 ± 2.1 seconds, p < 0.01). Cumulative noncued spatial learning was also worst in the CCI-VEH group (23.4 ± 1.8 seconds) but improved with AT-III (17.6 ± 1.5 seconds, p < 0.01). In probe trials, AT-III failed to significantly improve memory ability. Animals that underwent sham craniotomy demonstrated preserved learning and memory compared with all CCI counterparts (p < 0.05). CONCLUSION: Antithrombin III improves neurocognitive recovery weeks after TBI. This improvement is particularly related to improvement in learning but not memory function. Pharmacologic support of enhanced learning may support new skill acquisition or relearning to improve outcomes after TBI. LEVEL OF EVIDENCE: Therapeutic/care management, level II.
Assuntos
Antitrombina III/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Encefalopatia Traumática Crônica/tratamento farmacológico , Cognição/efeitos dos fármacos , Teste do Labirinto Aquático de Morris/efeitos dos fármacos , Animais , Encefalopatia Traumática Crônica/sangue , Sinais (Psicologia) , Modelos Animais de Doenças , Masculino , Camundongos , Distribuição AleatóriaRESUMO
BACKGROUND: Acute traumatic coagulopathy often accompanies traumatic brain injury (TBI) and may impair cognitive recovery. Antithrombin III (AT-III) reduces the hypercoagulability of TBI. Antithrombin III and heparinoids such as enoxaparin (ENX) demonstrate potent anti-inflammatory activity, reducing organ injury and modulating leukocyte (LEU) activation, independent of their anticoagulant effect. It is unknown what impact AT-III exerts on cerebral LEU activation and blood-brain barrier (BBB) permeability after TBI. We hypothesized that AT-III reduces live microcirculatory LEU-endothelial cell (EC) interactions and leakage at the BBB following TBI. METHODS: CD1 mice (n = 71) underwent either severe TBI (controlled cortical impact (CCI), 6-m/s velocity, 1-mm depth, and 4-mm diameter) or sham craniotomy and then received either AT-III (250 IU/kg), ENX (1.5 mg/kg), or vehicle (saline) every 24 hours. Forty-eight hours post-TBI, cerebral intravital microscopy visualized in vivo penumbral microvascular LEU-EC interactions and microvascular leakage to assess BBB inflammation/permeability. Body weight loss and the Garcia neurological test (motor, sensory, reflex, balance) served as surrogates of clinical recovery. RESULTS: Both AT-III and ENX similarly reduced in vivo penumbral LEU rolling and adhesion (p < 0.05). Antithrombin III also reduced live BBB leakage (p < 0.05). Antithrombin III animals demonstrated the least 48-hour body weight loss (8.4 ± 1%) versus controlled cortical impact and vehicle (11.4 ± 0.5%, p < 0.01). Garcia neurological test scores were similar among groups. CONCLUSION: Antithrombin III reduces post-TBI penumbral LEU-EC interactions in the BBB leading to reduced neuromicrovascular permeability. Antithrombin III further reduced body weight loss compared with no therapy. Further study is needed to determine if these AT-III effects on neuroinflammation affect longer-term neurocognitive recovery after TBI.
Assuntos
Antitrombina III/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Hemorragia Encefálica Traumática/tratamento farmacológico , Leucócitos/efeitos dos fármacos , Animais , Hemorragia Encefálica Traumática/sangue , Ensaios de Migração de Leucócitos , Modelos Animais de Doenças , Enoxaparina/farmacologia , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Masculino , CamundongosRESUMO
(1) Background: The endothelial glycocalyx is a primary target during the early phase of sepsis. We previously reported a newly developed recombinant non-fucosylated antithrombin has protective effects in vitro. We further evaluated the effects of this recombinant antithrombin on the glycocalyx damage in an animal model of sepsis. (2) Methods: Following endotoxin injection, in Wistar rats, circulating levels of hyaluronan, syndecan-1 and other biomarkers were evaluated in low-dose or high-dose recombinant antithrombin-treated animals and a control group (n = 7 per group). Leukocyte adhesion and blood flow were evaluated with intravital microscopy. The glycocalyx was also examined using side-stream dark-field imaging. (3) Results: The activation of coagulation was inhibited by recombinant antithrombin, leukocyte adhesion was significantly decreased, and flow was better maintained in the high-dose group (both p < 0.05). Circulating levels of syndecan-1 (p < 0.01, high-dose group) and hyaluronan (p < 0.05, low-dose group; p < 0.01, high-dose group) were significantly reduced by recombinant antithrombin treatment. Increases in lactate and decreases in albumin levels were significantly attenuated in the high-dose group (p < 0.05, respectively). The glycocalyx thickness was reduced over time in control animals, but the derangement was attenuated and microvascular perfusion was better maintained in the high-dose group recombinant antithrombin group (p < 0.05). (4) Conclusions: Recombinant antithrombin maintained vascular integrity and the microcirculation by preserving the glycocalyx in this sepsis model, effects that were more prominent with high-dose therapy.
Assuntos
Antitrombina III/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotoxinas/toxicidade , Glicocálix/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Proteínas Recombinantes/administração & dosagem , Sepse/tratamento farmacológico , Animais , Antitrombinas/farmacologia , Endotélio Vascular/metabolismo , Glicocálix/metabolismo , Ratos , Ratos Wistar , Sepse/induzido quimicamente , Sepse/patologiaRESUMO
Acylated chitosan sulfate (ChS1), a sulfated polysaccharide with high anticoagulant activity, was chemically synthesized and structurally characterized using FT-IR analysis. The beneficial structural properties and high availability of the sulfate group in ChS1 led to greater anticoagulant activity through both the intrinsic and common pathways with antithrombin III (AT III)-mediated inhibition, particularly involving coagulation factors FXa and FIIa. The analysis of the binding affinities using surface plasma resonance found that the equilibrium dissociation constant (KD) of ChS1 for FXa and FIIa in the presence of AT III was 67.4 nM and 112.6 nM, respectively, indicating the stronger interaction of the AT III/ChS1 complex with the ligands and the inhibition of activated FX and FII. The results of amidolytic assays further demonstrated the stronger inhibition of the proteolytic conversion of factor X by the intrinsic FXase complex and of FII by the prothrombinase complex. Molecular docking analysis further validated the protein-ligand interactions of ChS1 with AT III and their binding affinity.
Assuntos
Anticoagulantes/química , Anticoagulantes/farmacologia , Antitrombina III/química , Antitrombina III/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Quitosana/química , Anticoagulantes/síntese química , Testes de Coagulação Sanguínea , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Espectroscopia de Infravermelho com Transformada de Fourier , Relação Estrutura-AtividadeRESUMO
OBJECTIVES: To determine whether precardiopulmonary bypass (CPB) normalization of antithrombin levels in infants to 100% improves heparin sensitivity and anticoagulation during CPB and has beneficial effects into the postoperative period. DESIGN: Randomized, double-blinded, placebo-controlled prospective study. SETTING: Multicenter study performed in 2 academic hospitals. PARTICIPANTS: The study comprised 40 infants younger than 7 months with preoperative antithrombin levels <70% undergoing CPB surgery. INTERVENTIONS: Antithrombin levels were increased with exogenous antithrombin to 100% functional level intraoperatively before surgical incision. MEASUREMENTS AND MAIN RESULTS: Demographics, clinical variables, and blood samples were collected up to postoperative day 4. Higher first post-heparin activated clotting times (sec) were observed in the antithrombin group despite similar initial heparin dosing. There was an increase in heparin sensitivity in the antithrombin group. There was significantly lower 24-hour chest tube output (mL/kg) in the antithrombin group and lower overall blood product unit exposures in the antithrombin group as a whole. Functional antithrombin levels (%) were significantly higher in the treatment group versus placebo group until postoperative day 2. D-dimer was significantly lower in the antithrombin group than in the placebo group on postoperative day 4. CONCLUSION: Supplementation of antithrombin in infants with low antithrombin levels improves heparin sensitivity and anticoagulation during CPB without increased rates of bleeding or adverse events. Beneficial effects may be seen into the postoperative period, reflected by significantly less postoperative bleeding and exposure to blood products and reduced generation of D-dimers.
Assuntos
Deficiência de Antitrombina III/tratamento farmacológico , Antitrombina III/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Procedimentos Cirúrgicos Cardíacos/métodos , Cardiopatias Congênitas/cirurgia , Hemorragia Pós-Operatória/prevenção & controle , Cuidados Pré-Operatórios/métodos , Deficiência de Antitrombina III/sangue , Deficiência de Antitrombina III/complicações , Antitrombinas/farmacologia , Método Duplo-Cego , Feminino , Seguimentos , Cardiopatias Congênitas/sangue , Cardiopatias Congênitas/complicações , Humanos , Recém-Nascido , Masculino , Hemorragia Pós-Operatória/sangue , Estudos Prospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Antithrombin (AT) III physiological levels are decreased during septic shock and supplementation therapy could therefore be beneficial. OBJECTIVE: We hypothesized that the use of recombinant human AT could reduce disseminated intravascular coagulation (DIC) occurrence. METHODS: We conducted a randomized open label controlled experimental study. Ten female "Large White" pigs were challenged with i.v. infusion of Escherichia coli endotoxin. Two groups of 5 pigs were randomly assigned to receive either recombinant human AT 100âU/kg over 30 min (ATryn group) or 0.9% saline (control group). AT III levels, coagulation, hemostasis, inflammation parameters, hemodynamics, and microcirculatory parameters were measured over a 5-h period. Immediately after euthanasia, kidneys were withdrawn for histology evaluation. Statistical analysis was performed with nonparametric tests and Dunn's test for multiple comparisons. RESULTS: AT III activity was significantly higher in the ATryn group than in the control group from 60% (213% [203-223] vs. 104% [98-115], Pâ=â0.008, respectively) to 300 min (115% [95-124] vs. 79% [67-93], Pâ=â0.03). Recombinant human AT supplementation had no impact on hemodynamics, microcirculatory parameters, and sequential changes of coagulation parameters (platelet count, fibrinogen level, thrombin-AT complexes, and von Willebrand factor). Interleukin 6 and tumor necrosis factor α values were statistically the same for both groups throughout the study. Percentage of thrombosed glomeruli and percentage of thrombosed capillary in glomerulus were not significantly different between both groups. CONCLUSIONS: In our model of endotoxic shock, a single low dose of recombinant human AT did not prevent DIC occurrence, severity, inflammatory profile, or hemodynamic alterations.
Assuntos
Antitrombina III , Coagulação Intravascular Disseminada , Endotoxinas , Choque Séptico , Animais , Humanos , Antitrombina III/farmacologia , Modelos Animais de Doenças , Coagulação Intravascular Disseminada/sangue , Coagulação Intravascular Disseminada/induzido quimicamente , Coagulação Intravascular Disseminada/tratamento farmacológico , Endotoxinas/química , Endotoxinas/toxicidade , Escherichia coli/química , Proteínas Recombinantes/farmacologia , Choque Séptico/sangue , Choque Séptico/induzido quimicamente , Choque Séptico/tratamento farmacológico , SuínosRESUMO
Impaired fibrinolysis and complement activation in Systemic Lupus Erythematosus contributes to disease amplification including increased risk of thrombosis and tissue Ischemia/Reperfusion (IR) injury. Previous work has demonstrated complement is a key regulator of tissue injury. In these studies inhibitors had varying efficacies in attenuating injury at primary versus systemic sites, such as lung. In this study the role of coagulation factors in tissue injury and complement function was evaluated. Tissue Factor Pathway Inhibitor (TFPI), an extrinsic pathway inhibitor, and Anti-Thrombin III, the downstream common pathway inhibitor, were utilized in this study. TFPI was more effective in attenuated primary intestinal tissue injury. However both attenuated systemic lung injury. However, ATIII treatment resulting in enhanced degradation of C3 split products in lung tissue compared to TFPI. This work delineates the influence of specific early and late coagulation pathway components during initial tissue injury versus later distal systemic tissue injury mechanism.
Assuntos
Anticoagulantes/farmacologia , Antitrombina III/farmacologia , Antitrombinas/farmacologia , Intestino Delgado/efeitos dos fármacos , Lipoproteínas/farmacologia , Pulmão/efeitos dos fármacos , Lúpus Eritematoso Sistêmico , Animais , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Isquemia Mesentérica/metabolismo , Isquemia Mesentérica/patologia , Camundongos , Camundongos Endogâmicos MRL lpr , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologiaRESUMO
: 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
Acute kidney disease (AKI) leads to increased risk of progression to chronic kidney disease (CKD). Antithrombin III (ATIII) is a potent anticoagulant with anti-inflammatory properties, and we previously reported that insufficiencies of ATIII exacerbated renal ischaemia-reperfusion injury (IRI) in rats. In this study, we examined the characteristic of AKI-CKD transition in rats with two distinct AKI models. Based on our observation, left IRI plus right nephrectomy (NX-IRI) was used to determine whether ATIII had therapeutic effects in preventing CKD progression after AKI. It was observed that NX-IRI resulted in significant functional and histological damage at 5 weeks after NX-IRI compared with sham rats, which was mitigated by ATIII administration. Besides, we noticed that ATIII administration significantly reduced NX-IRI-induced interstitial fibrosis. Consistently, renal expression of collagen-1, α-smooth muscle actin and fibronectin were substantial diminished in ATIII-administered rats compared with un-treated NX-IRI rats. Furthermore, the beneficial effects of ATIII were accompanied with decreased M1-like macrophage recruitment and down-regulation of M1-like macrophage-dependent pro-inflammatory cytokines such as tumour necrosis factor α, inducible nitric oxide synthase and interleukin-1ß, indicating that ATIII prevented AKI-CKD transition via inhibiting inflammation. Overall, ATIII shows potential as a therapeutic strategy for the prevention of CKD progression after AKI.
Assuntos
Injúria Renal Aguda/prevenção & controle , Antitrombina III/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Rim/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Actinas/antagonistas & inibidores , Actinas/genética , Actinas/metabolismo , Injúria Renal Aguda/genética , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Animais , Colágeno Tipo I/antagonistas & inibidores , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Fibronectinas/antagonistas & inibidores , Fibronectinas/genética , Fibronectinas/metabolismo , Fibrose , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Rim/metabolismo , Rim/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Nefrectomia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoAssuntos
Antitrombina III/farmacologia , Nefropatias/tratamento farmacológico , Rim/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Quimiocina CXCL1/metabolismo , Modelos Animais de Doenças , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-6/metabolismo , Rim/metabolismo , Rim/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Camundongos , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologiaRESUMO
BACKGROUND: Coagulation and inflammation are closely linked during acute inflammatory conditions, such as sepsis. Antithrombin (AT) is an anticoagulant that also has anti-inflammatory activities. The effects of therapeutically administering AT III after the onset of endotoxemia or sepsis were not clear. Here, we studied the effects of administering AT III after inducing lethal endotoxemia in mice. METHODS: Mice were injected intraperitoneally with lipopolysaccharide (LPS) to induce endotoxemia. AT III was administered 3 h later. We assessed survival and the severity of endotoxemia and quantified plasma cytokine levels and biochemical markers of liver and kidney function. In the lungs, we examined neutrophil accumulation, neutrophil extracellular traps, alveolar wall thickness, and chemokine (C-X-C motif) ligand 1 (cxcl-1), cxcl-2, and high mobility group box 1 expression. RESULTS: Administering AT III reduced the severity and mortality of LPS-induced endotoxemia as indicated by 24-h survival of 84% of the mice that received LPS + AT III and only 53% of mice given LPS alone (P < 0.05). AT III treatment attenuated several changes induced in the lungs by endotoxemia including cxcl-2 mRNA expression, high mobility group box 1 protein expression, neutrophil accumulation, alveolar septal thickening, and neutrophil extracellular trap formation. AT III did not decrease plasma cytokine levels or plasma urea nitrogen levels that were upregulated as a result of LPS-induced endotoxemia. CONCLUSIONS: Administration of AT III after the onset of endotoxemia improved outcomes in a mouse model. The attenuation of lung inflammation may have a large impact on mortality and morbidity. Because lung inflammation increases the likelihood of mortality from sepsis, AT III could be a useful agent in septic patients.
Assuntos
Antitrombina III/uso terapêutico , Antitrombinas/uso terapêutico , Endotoxemia/tratamento farmacológico , Armadilhas Extracelulares/efeitos dos fármacos , Pulmão/imunologia , Animais , Antitrombina III/farmacologia , Antitrombinas/farmacologia , Citocinas/sangue , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Endotoxemia/imunologia , Endotoxemia/patologia , Proteína HMGB1/metabolismo , Testes de Função Renal , Lipopolissacarídeos , Testes de Função Hepática , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Distribuição AleatóriaRESUMO
Blood coagulation is regulated through a complex network of biochemical reactions of blood factors. The main acting enzyme is thrombin whose propagation in blood plasma leads to fibrin clot formation. Spontaneous clot formation is normally controlled through the action of different plasma inhibitors, in particular, through the thrombin binding by antithrombin. In the current study we develop a mathematical model of clot formation both in quiescent plasma and in blood flow and determine the analytical conditions on the antithrombin concentration corresponding to different regimes of blood coagulation.