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1.
ACS Nano ; 16(11): 18483-18496, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36350264

RESUMO

Most patients are at high risk of thrombosis during cancer treatment. However, the major discrepancy in the therapeutic mechanisms and microenvironment between tumors and thrombosis makes it challenging for a panacea to treat cancer while being able to eliminate the risk of thrombosis. Herein, we developed a biomimetic MnOx/Ag2S nanoflower platform with platelet membrane modification (MnOx@Ag2S@hirudin@platelet membrane: MAHP) for the long-term release of anticoagulant drugs to treat thrombosis together with tumor therapy. This MAHP platform could achieve the targeted delivery of hirudin to the thrombus site and perform the controlled release under the irradiation of near-infrared light, demonstrating effective removal of the thrombus. Moreover, MAHP could inhibit tumor progression and prolong the survival time of mice with thromboembolic complications.


Assuntos
Hirudinas , Trombose , Camundongos , Animais , Hirudinas/farmacologia , Heparina , Trombose/tratamento farmacológico , Trombose/patologia , Plaquetas , Anticoagulantes/farmacologia , Proteínas Recombinantes/farmacologia
5.
Biomed Res Int ; 2022: 5481552, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119923

RESUMO

Chronic kidney disease (CKD) is identified as a widespread chronic progressive disease jeopardizing public health which characterized by gradually loss of renal function. However, there is no efficient therapy to prevail over this disease. Our study was attempting to reveal hirudin's regulation to renal fibrosis as well as the molecular mechanism. We built renal fibrosis models on both cell and animal levels, which were subsequently given with hirudin disposal; then, we performed the transwell assay to estimate the cells' migration and had our detection to relevant proteins with western blot and immunofluorescence. Finally, we commenced both the identification and the determination to the hirudin targeted proteins and its downstream signaling pathways with the methods of network pharmacology. And the results turned out that when it was compared with the model group, the group with hirudin addition came with the suppression in the migration of renal tubular epithelial cells NRK-52E and with a conspicuous decline in the expressions of fibronectin, N-cadherin, vimentin, TGF-ß, and snail. After that, we predicted that there were 17 hirudin target points mainly involving in the PI3K-AKT signaling pathway. Our outcomes of the animal level demonstrated that the conditions of interstitial fibrosis, severe tubular dilatation or atrophy, inflammatory cell infiltration, and massive accumulation of interstitial collagen in the model group were withdrawn after the addition of hirudin. In addition, p-PDGFRß, p-PI3K, and p-AKT protein expressions were significantly reduced, and the PI3K/AKT pathway was downregulated after hirudin treatment in the model group of NRK-52E cells and animals. Therefore, we had our conclusion that hirudin is capable of suppressing the PI3K-AKT signaling pathway as well as the EMT by decreasing PDGFRß phosphorylation.


Assuntos
Nefropatias , Proteínas Proto-Oncogênicas c-akt , Animais , Caderinas/metabolismo , Regulação para Baixo , Transição Epitelial-Mesenquimal , Fibronectinas/metabolismo , Fibrose , Hirudinas/farmacologia , Nefropatias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Vimentina/metabolismo
6.
Int J Mol Sci ; 23(18)2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36142125

RESUMO

Platelet and coagulation activation are highly reciprocal processes driven by multi-molecular interactions. Activated platelets secrete several coagulation factors and expose phosphatidylserine, which supports the activation of coagulation factor proteins. On the other hand, the coagulation cascade generates known ligands for platelet receptors, such as thrombin and fibrin. Coagulation factor (F)Xa, (F)XIIIa and activated protein C (APC) can also bind to platelets, but the functional consequences are unclear. Here, we investigated the effects of the activated (anti)coagulation factors on platelets, other than thrombin. Multicolor flow cytometry and aggregation experiments revealed that the 'supernatant of (hirudin-treated) coagulated plasma' (SCP) enhanced CRP-XL-induced platelet responses, i.e., integrin αIIbß3 activation, P-selectin exposure and aggregate formation. We demonstrated that FXIIIa in combination with APC enhanced platelet activation in solution, and separately immobilized FXIIIa and APC resulted in platelet spreading. Platelet activation by FXIIIa was inhibited by molecular blockade of glycoprotein VI (GPVI) or Syk kinase. In contrast, platelet spreading on immobilized APC was inhibited by PAR1 blockade. Immobilized, but not soluble, FXIIIa and APC also enhanced in vitro adhesion and aggregation under flow. In conclusion, in coagulation, factors other than thrombin or fibrin can induce platelet activation via GPVI and PAR receptors.


Assuntos
Selectina-P , Glicoproteínas da Membrana de Plaquetas , Plaquetas/metabolismo , Fator XIIIa/metabolismo , Fibrina/metabolismo , Hirudinas/metabolismo , Hirudinas/farmacologia , Selectina-P/metabolismo , Fosfatidilserinas/metabolismo , Ativação Plaquetária , Agregação Plaquetária , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Glicoproteínas da Membrana de Plaquetas/metabolismo , Proteína C/metabolismo , Receptor PAR-1/metabolismo , Quinase Syk/metabolismo , Trombina/metabolismo , Trombina/farmacologia
7.
Clin Appl Thromb Hemost ; 28: 10760296221113344, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35942867

RESUMO

Background: Patients with diabetes mellitus (DM) are considered to increase the risk of thrombosis and bleeding. However, whether DM is an independent risk factor for events in patients anticoagulated with bivalirudin during elective percutaneous coronary intervention (PCI) is not clear. Methods: Patients anticoagulated with bivalirudin during elective PCI from January 2017 to August 2018 in 3 centers were enrolled. The primary endpoint of thrombotic events was major adverse cardiac and cerebrovascular events (MACCE, including all-cause death, myocardial infarction, ischemic revascularization, stent thrombosis, and stroke); the primary endpoint of bleeding events was Bleeding Academic Research Consortium (BARC) 2, 3 or 5 bleeding. Results: 1152 patients were finally enrolled. After one-year follow-up, 89 (7.7%) MACCE and 21 (1.8%) BARC 2, 3 or 5 bleeding occurred. Multivariate Cox regression analysis showed DM was not an independent risk factor for MACCE (hazard ratio [HR]: 1.029, 95% confidence interval [CI]: 0.674-1.573, P = .893), but peripheral artery disease (PAD) history (HR: 2.200, 95%CI: 1.290-3.751, P = .004) was an independent risk factor for MACCE. DM was not an independent risk factor for BARC 2, 3 or 5 bleeding (HR: 0.732, 95%CI: 0.293-1.831, P = .505), but PAD history (HR: 3.029, 95%CI: 1.102-8.332, P = .032) and low hemoglobin level (HR = 0.972, 95%CI: 0.947-0.998, P = .036) were independent risk factors for BARC 2, 3 or 5 bleeding. Conclusions: DM was not an independent risk factor for one-year thrombotic and bleeding events in patients anticoagulated with bivalirudin during elective PCI. More attention should be paid to PAD history and hemoglobin level to identify high-risk patients.


Assuntos
Doença da Artéria Coronariana , Diabetes Mellitus , Intervenção Coronária Percutânea , Trombose , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/cirurgia , Hemoglobinas , Hemorragia/induzido quimicamente , Hirudinas , Humanos , Fragmentos de Peptídeos , Intervenção Coronária Percutânea/efeitos adversos , Proteínas Recombinantes , Trombose/etiologia , Resultado do Tratamento
8.
Biomater Adv ; 135: 212741, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35929214

RESUMO

Surface functionalization to improve the blood compatibility is pivotal for the application of biomaterials. In this article, the surface of silicon was first functionalized with chemical groups, such as amino, quinone and phenol groups by the self-polymerization of dopamine, which were used to immobilize anticoagulant drugs hirudin. The detailed analysis and discussion about the grafting groups, morphology, wettability, the dynamic adsorption of proteins, the cytological property and the blood compatibility on the surfaces were carried on by the technology of contact angle, X-ray photoelectron spectroscopy, quartz crystal microbalance, endothelial cells culture and anticoagulant blood test in vivo. The surface with hirudin modification exhibited hydrophilic property and significantly inhibited the nonspecific adsorption of albumin, while it was more approachable to fibronectin. In vitro study displayed that the surface loaded with hirudin could promote the proliferation of endothelial cells. The evaluation of anticoagulant showed good anti-adhesion effect on platelets and the hemolysis rate decreased significantly to less than 0.4%. Activated partial thromboplastin time (APTT) of the silicon wafer loaded with hirudin can exceed 38 s, and the APTT prolongs as the hirudin concentration rises. This study suggested that such simple but effective surface functionalization technique, combining excellent anticoagulant activity together with reendothelialization potential due to the preferable fibronectin adsorption, provide great practical significance to the application of cardiovascular materials.


Assuntos
Fibronectinas , Hirudinas , Adsorção , Anticoagulantes/farmacologia , Células Endoteliais , Fibronectinas/farmacologia , Hirudinas/química , Silício/química
9.
Parasitol Res ; 121(10): 2995-3006, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36006484

RESUMO

Haematophagous leeches express a broad variety of secretory proteins in their salivary glands, among them are hirudins and hirudin-like factors. Here, we describe the identification, molecular and initial functional characterization of Tandem-Hirudin (TH), a novel salivary gland derived factor identified in the Asian medicinal leech, Hirudinaria manillensis. In contrast to the typical structure of hirudins, TH comprises two globular domains arranged in a tandem-like orientation and lacks the elongated C-terminal tail. Similar structures of thrombin inhibitors have so far been identified only in kissing bugs and ticks. Expression of TH was performed in both cell-based and cell-free bacterial systems. A subsequent functional characterization revealed no evidence for a thrombin-inhibitory potency of TH.


Assuntos
Hirudo medicinalis , Sanguessugas , Sequência de Aminoácidos , Animais , Hirudinas/metabolismo , Hirudo medicinalis/metabolismo , Sanguessugas/química , Trombina
10.
J Tradit Chin Med ; 42(4): 586-594, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35848975

RESUMO

OBJECTIVE: To explore the mechanism of hirudin in the treatment of diabetic kidney disease (DKD). METHOD: Cytoscape software was used to analyze the network between hirudin targets and active components in the treatment of DKD. The biological function and mechanism of effective targets of hirudin for DKD treatment were analyzed by the Database for Annotation, Visualization and Integrated Discovery (DAVID) database. Molecular docking technology was used to simulate the docking of key targets, and the DKD rat model was used to verify the first 4 key targets with high "Hydrogen number" among the top 10 targets verified by molecular docking. RESULTS: Total of 12334 DKD targets were screened in GeneCards, OMIM and other databases, Hirudin and DKD had 247 common target genes, and the protein interaction network got 2115 edges. The DAVID database was used for the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis, confirming that hirudin in treatment of DKD involves multiple signaling pathways such as the forkhead box O signaling pathway, the phosphatidylinositol 3-kinase-protein kinase B signaling pathway, the vascular endothelial-derived growth factor signaling pathway and other signaling pathways. The top ten key targets of hirudin in treatment of DKD were verified by molecular docking. Animal experiments showed that hirudin could decrease the expression of caspase-3 in renal tissue of DKD rats, and increase the expression of RAC-alpha serine/threonine-protein kinase, Catalase, and Heat shock protein HSP 90-alpha in renal tissue of DKD rats. CONCLUSION: This study preliminarily reveals that hirudin treats DKD through multiple targets and pathways, and molecular docking and animal experiments indicates the feasibility of this study. Hirudin may be directly or indirectly involved in the regulation of cell metabolism, oxidative stress and other mechanisms in the treatment of DKD, which will lay the foundation for future molecular biological experiments of hirudin in the treatment of DKD.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Medicamentos de Ervas Chinesas , Animais , Diabetes Mellitus/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Hirudinas/metabolismo , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , Farmacologia em Rede , Mapas de Interação de Proteínas , Ratos
11.
J Cardiothorac Vasc Anesth ; 36(10): 3841-3846, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35817672

RESUMO

OBJECTIVES: To determine the dosage of bivalirudin as the anticoagulant for cardiac surgery in neonates and infants. DESIGN: Pilot study. SETTING: Tertiary-care hospital. PARTICIPANTS: Twenty-five neonates and infants with congenital heart disease (CHD) undergoing cardiac surgery. INTERVENTIONS: The children received a 1 mg/kg bivalirudin bolus followed by a 2.5 mg/kg/h infusion as the anticoagulant for cardiac surgery. The dose was adjusted subsequently to maintain an activated clotting time (ACT) >480 s. MEASUREMENTS AND MAIN RESULTS: The mean age and weight were 5.3 months and 5.2 kg, respectively. Out of the 25 children, 16 were cyanotic. Baseline rotational thromboelastometry (ROTEM) (Tem Innovations GmbH, Munich, Germany) analysis revealed an underlying coagulation defect across EXTEM, INTEM, FIBTEM, and ADPTEM parameters. The dose of anticoagulant required was 1 mg/kg, followed by a 2.2 ± 0.4 mg/kg/h infusion. Only 1 child required an additional bolus dose. The ACT remained elevated for 4 hours after discontinuation of infusion. The mean 24-h postoperative chest tube drainage was 92 ± 36 mL. Excessive bleeding occurred in 4 children, 1 of whom required re-exploration. The platelet count remained low for 5 days, and, postoperatively, the prothrombin time and activated partial thromboplastin time remained low for 2 days. CONCLUSIONS: Effective anticoagulation was achieved with bivalirudin in the neonates and infants undergoing cardiac surgery. The dose required to maintain an ACT >480 s was 1.0 mg/kg, followed by 2.2 ± 0.4 mg/kg/h. The ACT remained elevated for 4 h after the discontinuation of bivalirudin infusion, resulting in an increased chest-tube output in some patients. Randomized, controlled trials are needed to further evaluate the safety of bivalirudin in the neonates and infants with complex congenital heart disease undergoing cardiac surgery with cardiopulmonary bypass.


Assuntos
Anticoagulantes , Procedimentos Cirúrgicos Cardíacos , Cardiopatias Congênitas , Hirudinas , Fragmentos de Peptídeos , Anticoagulantes/uso terapêutico , Cardiopatias Congênitas/cirurgia , Humanos , Lactente , Recém-Nascido , Fragmentos de Peptídeos/uso terapêutico , Projetos Piloto , Proteínas Recombinantes/uso terapêutico
12.
Drug Des Devel Ther ; 16: 1667-1678, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35677424

RESUMO

Introduction: Recombinant neorudin (EPR-hirudin, EH) was developed through the addition of an EPR (Glu-Pro-Arg) peptide to the amino terminus of hirudin, which can be recognized and cut by coagulation factors XIa (FXIa) and/or Xa (FXa). In this study, the low-bleeding antithrombotic effects of EH were evaluated utilizing experimental models of thrombosis in rabbits and rats to provide a test basis for clinical trials. Methods: The bleeding risks of EH and hirudin were first compared in mice by the tail-clipping method, and then the antithrombotic activity of EH was investigated in a rabbit model of arteriovenous bypass thrombosis and a rat model of thrombotic cerebral infarction. Results: In mice, intravenous administration of EH at 1.5 mg/kg and 3 mg/kg did not affect the bleeding time compared with normal saline, while the administration of hirudin at 1.5 mg/kg prolonged the bleeding time by over 3 times the administration of normal saline. Furthermore, intravenous administration of EH had a significant dose-dependent inhibitory effect on the formation and development of arteriovenous bypass thrombosis and thrombotic cerebral infarction. Compared with an equimolar dose of hirudin, the antithrombotic effect of EH was similar, while the bleeding side effects were significantly attenuated. Moreover, when the antithrombotic effects were similar, EH had a shorter bleeding time and was associated with less bleeding than low molecular weight heparin (LMWH). EH had a therapeutic effect on thrombotic cerebral infarction without increasing the occurrence of cerebral hemorrhage. Conclusion: The findings from the preclinical animal models used in this study showed that EH could not only effectively inhibit thrombus formation but also reduce the risk of bleeding.


Assuntos
Hirudinas , Trombose , Animais , Infarto Cerebral/tratamento farmacológico , Fibrinolíticos/uso terapêutico , Hemorragia/tratamento farmacológico , Heparina de Baixo Peso Molecular/uso terapêutico , Hirudinas/farmacologia , Camundongos , Coelhos , Ratos , Proteínas Recombinantes , Solução Salina , Trombose/tratamento farmacológico
13.
Int Immunopharmacol ; 110: 108967, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35724604

RESUMO

Acute ischemic stroke is a severe condition that a vessel supplying blood to the brain is abruptly blocked mostly due to cerebral thrombosis and embolism. There is a dearth of the effective prevention and early intervention strategies. NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated neuroinflammation plays a crucial role in the pathophysiology of ischemic stroke. Hirudin is a secretion from the salivary glands of the leech Hirudo medicinalis and has a role in regulating inflammation. In this study, hirudin with a dose of 10-40 mg/kg was given to middle cerebral artery occlusion/reperfusion mice. Hirudin markedly constrained cerebral infarct area in a dose-dependent manner, and significantly improved locomotor disability at 40 mg/kg dose. Similar to MCC950, a selective NLRP3 inflammasome inhibitor, hirudin inhibited M1 polarization and promoted M2 polarization. It also strikingly suppressed the ischemia-induced overexpression of NLRP3 and its downstream components, caspase-1, apoptosis-associated speck-like protein (ASC), and interleukin-1ß (IL-1ß). Hirudin and MCC950 equivalently protected viability and death of BV-2 microglia cells against oxygen-glucose deprivation/reperfusion (OGD/R), an in vitro cell model of brain ischemia. Both agents had similar effects in normalizing the OGD/R-evoked aberrant microglial profiles and NLRP3 pathway dysregulation as observed in the mice. These results demonstrated anti-ischemic effects of hirudin and its association with the inhibition of microglial NLRP3 inflammasome-mediated neuroinflammation. Hirudin is a promising agent for the early intervention of acute ischemic stroke.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Hirudinas , Inflamassomos/metabolismo , AVC Isquêmico/tratamento farmacológico , Camundongos , Microglia/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Doenças Neuroinflamatórias , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo
14.
Int J Artif Organs ; 45(8): 688-694, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35708334

RESUMO

INTRODUCTION: Unfractionated heparin is the most commonly utilized anticoagulant in extracorporeal membrane oxygenation (ECMO) due to clinician familiarity, ease of reversal, and low cost compared to alternative agents. However, heparin's anticoagulant effect can be unpredictable and its use accompanies a risk of heparin induced thrombocytopenia (HIT). Successful use of bivalirudin as an alternative to heparin in non-HIT ECMO patients has previously been described. However, there is a paucity of data regarding its utilization in patients with confirmed HIT on ECMO. METHODS: This single-center retrospective chart review at Cleveland Clinic Main Campus included 12 ECMO patients who were managed with bivalirudin for a new diagnosis of HIT. Descriptive statistical analyses were performed utilizing median with interquartile range and number with percent as appropriate. RESULTS: Of the 12 patients included, median ECMO duration was 328.5 (218.8-502.1) h and venoarterial ECMO was the most common configuration. No patients experienced the primary outcome of in-circuit thrombosis while on bivalirudin. One patient developed a deep vein thrombosis 22.5 h after switching from heparin to bivalirudin. Major bleeding occurred during bivalirudin therapy in 8 (66.7%) patients. CONCLUSIONS: Overall, our study results suggest that bivalirudin is effective for the management of HIT and did not show evidence of in-circuit thrombosis. A high incidence of major bleeding was observed with bivalirudin use within this study. Clinicians should view bivalirudin as an acceptable agent for the treatment of HIT in the ECMO population, but must consider bleeding risk given the lack of effective reversal agents.


Assuntos
Oxigenação por Membrana Extracorpórea , Trombocitopenia , Trombose , Anticoagulantes/efeitos adversos , Oxigenação por Membrana Extracorpórea/métodos , Hemorragia/induzido quimicamente , Hemorragia/terapia , Heparina/efeitos adversos , Hirudinas , Humanos , Fragmentos de Peptídeos/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Trombocitopenia/induzido quimicamente , Trombocitopenia/tratamento farmacológico , Trombose/tratamento farmacológico , Trombose/etiologia
15.
BMC Cardiovasc Disord ; 22(1): 290, 2022 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-35752771

RESUMO

BACKGROUND: This prospective, multi-center, intensive monitoring study aimed to systematically assess the occurrence of adverse events (AEs) and adverse drug reactions (ADRs), especially thrombocytopenia and bleeding, as well as their risk factors in Chinese ST-segment elevation myocardial infraction (STEMI) patients receiving bivalirudin as anticoagulant for percutaneous coronary intervention (PCI). METHODS: In total, 1244 STEMI patients undergoing PCI and receiving bivalirudin as anticoagulant were enrolled in the present study. Safety data were collected from hospital admission to 72 h after bivalirudin administration; in addition, patients were further followed up at the 30th day with safety data collected at that time. RESULTS: AEs, severe AEs, ADRs and severe ADRs were reported in 224 (18.0%), 15 (1.2%), 49 (3.9%) and 5 (0.4%) patients, respectively. Importantly, 4 (0.3%) patients were submitted to hospitalization and 6 (0.5%) patients died due to AEs, while 1 (0.1%) patient was submitted to hospitalization but no (0.0%) patient died due to ADRs. Meanwhile, thrombocytopenia and bleeding occurred in 24 (1.9%) and 21 (1.7%) patients, respectively. Further multivariate logistic analysis identified several important independent factors related to AEs, ADRs, thrombocytopenia or bleeding, which included history of cardiac surgery and renal function impairment, high CRUSADE risk stratification, elective operation and combination with glycoprotein IIb/IIIa inhibitors. Moreover, 4 multivariate models were constructed based on the above-mentioned factors, which all showed acceptable predictive value for AEs, ADRs, thrombocytopenia and bleeding, respectively. CONCLUSION: Bivalirudin is a well-tolerant anticoagulant in Chinese STEMI patients undergoing PCI procedure.


Assuntos
Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Trombocitopenia , Anticoagulantes/efeitos adversos , Antitrombinas/efeitos adversos , China/epidemiologia , Hemorragia/induzido quimicamente , Heparina , Hirudinas/efeitos adversos , Humanos , Fragmentos de Peptídeos/efeitos adversos , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/métodos , Estudos Prospectivos , Proteínas Recombinantes/efeitos adversos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Trombocitopenia/induzido quimicamente , Resultado do Tratamento
16.
Pediatr Crit Care Med ; 23(10): e465-e475, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35687091

RESUMO

OBJECTIVES: Bivalirudin is a direct thrombin inhibitor that is being increasingly used for anticoagulation in children after ventricular assist device (VAD) implantation. While the data on bivalirudin use in pulsatile flow VADs are growing, reports on its use in patients on continuous flow (CF) VAD as well as comparisons of associated outcomes with unfractionated heparin (UFH) remain limited. DESIGN: Retrospective cohort study. SETTING: Single tertiary-quaternary referral center. PATIENTS: All patients less than 21 years old on CF-VAD support who received bivalirudin or UFH for anticoagulation between the years 2016 and 2020. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: Clinical characteristics compared between the cohorts included time to target range of anticoagulation, markers of hemolysis, and prevalence of hemocompatibility-related adverse events such as major hemorrhagic complications, ischemic stroke, and pump thrombosis. In 42 unique patients (41 HeartWare HVAD [Medtronic, Minneapolis, MN], one HeartMate 3 LVAD [Abbott Laboratories, Abbott Park, IL]) during the study period, a total of 67 encounters of IV anticoagulation infusions (29 UFH and 38 bivalirudin) were retrospectively reviewed. In comparison with use of UFH, bivalirudin was associated with lesser odds of major bleeding complications (odds ratio [OR], 0.29; 95% CI, 0.09-0.97; p = 0.038). We failed to identify any difference in odds of major thrombotic complications (OR, 2.53; 95% CI, 0.47-13.59; p = 0.450). Eight of the patients (28%) on UFH were switched to bivalirudin due to hemorrhagic or thrombotic complications or inability to achieve therapeutic anticoagulation, while two of the patients (5%) on bivalirudin were switched to UFH due to hemorrhagic complications. Bivalirudin was used for a "washout" in eight cases with concern for pump thrombosis-six had resolution of the pump thrombosis, while two needed pump exchange. CONCLUSIONS: Use of bivalirudin for anticoagulation in patients on CF-VAD support was associated with lesser odds of hemorrhagic complications compared with use of UFH. Bivalirudin "washout" was successful in medical management of six of eight cases of possible pump thrombosis.


Assuntos
Coração Auxiliar , Trombose , Adulto , Anticoagulantes/efeitos adversos , Antitrombinas/efeitos adversos , Criança , Coração Auxiliar/efeitos adversos , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Heparina/efeitos adversos , Hirudinas/efeitos adversos , Humanos , Fragmentos de Peptídeos/efeitos adversos , Proteínas Recombinantes/efeitos adversos , Estudos Retrospectivos , Trombose/epidemiologia , Trombose/etiologia , Trombose/prevenção & controle , Resultado do Tratamento , Adulto Jovem
17.
Biomed Res Int ; 2022: 6043698, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35496058

RESUMO

Excessive inflammation is responsible for arteriovenous fistula (AVF) failure, which determines the therapeutic effect of chronic renal failure (CRF). Macrophage polarization is of great significance in the inflammatory response. Hirudin (Hiru) has been reported to possess a definite anti-inflammatory effect. This study is to uncover the impacts of Hiru on classically (M1)/alternatively (M2) macrophage polarization in the CRF rat model and rat vascular smooth muscle cells (VSMCs). After the CRF rat model was administrated with different concentrations of Hiru, blood urea nitrogen (BUN) and serum creatinine (Scr) levels were tested. H&E staining was to detect vascular injury, and IHC assay was to analyze inducible nitric oxide synthase (iNOS) and arginase-1 (Arg-1) expressions in vascular tissues. Levels of inflammatory factors were examined by ELISA. Besides, western blot was to estimate the levels of marker proteins related to macrophage, proliferation, and apoptosis. CCK-8 was to measure cell viability. We discovered that Hiru alleviated renal function injury and vascular injury, exacerbated VSMC hyperplasia, and stimulated the differentiation and activation of M1 macrophage towards M2 macrophage in vivo. Moreover, after treatment with lipopolysaccharide (LPS)/IFN-gamma (IFN-γ), the increased M1/M2 ratio and enhanced levels of inflammatory factors were observed. Furthermore, Hiru boosted the proliferation and ameliorated the inflammatory response and apoptosis of rat VSMCs during the process of coincubation of M1-conditioned medium (CM). Collectively, Hiru played a protective role against vascular injury in CRF directly or through its influence on M1 macrophage polarization and inflammation.


Assuntos
Falência Renal Crônica , Insuficiência Renal Crônica , Lesões do Sistema Vascular , Animais , Feminino , Hirudinas/farmacologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Falência Renal Crônica/metabolismo , Macrófagos/metabolismo , Masculino , Ratos , Insuficiência Renal Crônica/metabolismo
18.
Curr Opin Pediatr ; 34(3): 255-260, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35634698

RESUMO

PURPOSE OF REVIEW: This review summarizes the current literature surrounding the use of bivalirudin as an alternative anticoagulant for pediatric extracorporeal membrane oxygenation (ECMO) patients. RECENT FINDINGS: Recent single center studies describe that bivalirudin may be associated with decreased blood product transfusion, decreased cost and similar clinical outcomes for pediatric ECMO patients who have failed unfractionated heparin (UFH) anticoagulation. aPTT is the most common test to monitor bivalirudin but has several limitations. Other tests including dilute thrombin time (dTT) and viscoelastic assays are promising but more study is needed. Current evidence suggests that bivalirudin is a well tolerated and effective alternative anticoagulant for pediatric ECMO patients who have failed UFH anticoagulation but prospective studies are needed to confirm these results. SUMMARY: Bivalirudin is a promising alternative anticoagulant for pediatric ECMO patients who have failed UFH. Large prospective, multicenter studies are needed to confirm safety and efficacy.


Assuntos
Oxigenação por Membrana Extracorpórea , Anticoagulantes/efeitos adversos , Criança , Oxigenação por Membrana Extracorpórea/métodos , Heparina/efeitos adversos , Heparina/uso terapêutico , Hirudinas , Humanos , Fragmentos de Peptídeos , Estudos Prospectivos , Proteínas Recombinantes
19.
J Thromb Haemost ; 20(8): 1808-1817, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35587545

RESUMO

BACKGROUND: Several leech species of the genera Hirudo, Hirudinaria, and Whitmania are widely used in traditional Chinese medicine (TCM) for the oral treatment of disorders associated with blood stasis. Among them, the non-hematophagous leech Whitmania pigra expresses a variety of components that have the potential to act on the vertebrate blood coagulation system. OBJECTIVE: Whether the thrombin inhibitor hirudin, probably the most prominent leech-derived anticoagulant, is actually present in Whitmania pigra, is still a matter of debate. To answer that open question was the aim of the study. METHODS: We identified several putative hirudin-encoding sequences in transcriptome data of Whitmania pigra. Upon gene synthesis and molecular cloning the respective recombinant proteins were expressed in Escherichia coli, purified, processed, and eventually functionally characterized for thrombin-inhibitory potencies in coagulation assays. RESULTS: We were successful in the identification and functional characterization of several putative hirudins in Whitmania pigra. Some, but not all, of these factors are indeed thrombin inhibitors. Whitmania pigra hence expresses both hirudins (factors that inhibit thrombin) and hirudin-like factors (that do not or only very weakly inhibit thrombin). Furthermore, we revealed the exon/intron structures of the corresponding genes. Coding sequences of some putative hirudins of Whitmania pigra were present also in transcriptome datasets of Hirudo nipponia, a hematophagous leech that is likewise used in TCM. CONCLUSIONS: Based on both structural and functional data we provide very strong evidence for the expression of hirudins in Whitmania pigra. This is the first description of hirudins in a non-hematophagous leech.


Assuntos
Hirudinas , Sanguessugas , Sequência de Aminoácidos , Animais , Anticoagulantes/metabolismo , Coagulação Sanguínea , Hirudinas/genética , Hirudinas/farmacologia , Sanguessugas/química , Sanguessugas/genética , Sanguessugas/metabolismo , Trombina/metabolismo
20.
J Cardiothorac Vasc Anesth ; 36(8 Pt B): 2961-2967, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35428549

RESUMO

OBJECTIVES: To compare heparin-based anticoagulation and bivalirudin-based anticoagulation within the context of critically ill patients with a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. DESIGN: An observational study. SETTING: At the intensive care unit of a university hospital. PARTICIPANTS AND INTERVENTIONS: Critically ill patients with a SARS-CoV-2 infection receiving full anticoagulation with heparin or bivalirudin. MEASUREMENTS AND MAIN RESULTS: Twenty-three patients received full anticoagulation with bivalirudin and 60 with heparin. Despite patients in the bivalirudin group having higher mortality risk scores (SAPS II 60 ± 16 v 39 ±7, p < 0.001) and a higher need for extracorporeal support compared to the heparin group, hospital mortality was comparable (57% v 45, p = 0.3). No difference in thromboembolic complications was observed, and bleeding events were more frequent in patients treated with bivalirudin (65% v 40%, p = 0.01). Similar results were confirmed in the subgroup analysis of patients undergoing intravenous anticoagulation; in addition to comparable thrombotic complications occurrence and thrombocytopenia rate, however, no difference in the bleeding rate was observed (65% v 35%, p = 0.08). CONCLUSIONS: Although heparin is the most used anticoagulant in the intensive care setting, bivalirudin-based anticoagulation was safe and effective in a cohort of critically ill patients with SARS-CoV-2. Bivalirudin may be given full consideration as an anticoagulation strategy for critically ill patients with SARS-CoV-2, especially in those with thrombocytopenia and on extracorporeal support.


Assuntos
COVID-19 , Oxigenação por Membrana Extracorpórea , Trombocitopenia , Anticoagulantes , Antitrombinas/uso terapêutico , COVID-19/complicações , Estado Terminal/terapia , Oxigenação por Membrana Extracorpórea/métodos , Fibrinolíticos , Hemorragia/induzido quimicamente , Heparina/efeitos adversos , Hirudinas , Humanos , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , SARS-CoV-2 , Trombocitopenia/induzido quimicamente
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