Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 19.817
Filtrar
1.
Molecules ; 26(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34443534

RESUMO

Thrombosis is a disease that seriously endangers human health, with a high rate of mortality and disability. However, current treatments with thrombolytic drugs (such as recombinant tissue-plasminogen activator) and the oral anticoagulants (such as dabigatran and rivaroxaban) are reported to have a tendency of major or life-threatening bleeding, such as intracranial hemorrhage or massive gastrointestinal bleed with non-specific antidotes. In contrast, lumbrokinase is very specific to fibrin as a substrate and does not cause excessive bleeding. It can dissolve the fibrin by itself or convert plasminogen to plasmin by inducing endogenous t-PA activity to dissolve fibrin clots. Therefore, searching for potentially new therapeutic molecules from earthworms is significant. In this study, we first collected a strong fibrinolytic extract (PvQ) from the total protein of the Pheretima vulgaris with AKTA pure protein purification systems; its fibrinolytic bioactivity was verified by the fibrin plate assay and zebrafish thrombotic model of vascular damage. Furthermore, according to the cell culture model of human umbilical vein endothelial cells (HUVECs), the PvQ was proven to exhibit the ability to promote the secretion of tissue-type plasminogen activator (t-PA), which further illustrated that it has an indirect thrombolytic effect. Subsequently, extensive chromatographic techniques were applied to reveal the material basis of the extract. Fortunately, six novel earthworm fibrinolytic enzymes were obtained from the PvQ, and the primary sequences of those functional proteins were determined by LC-MS/MStranscriptome cross-identification and the Edman degradation assay. The secondary structures of these six fibrinolytic enzymes were determined by circular dichroism spectroscopy and the three-dimensional structures of these proteases were predicted by MODELLER 9.23 based on multi-template modelling. In addition, those six genes encoding blood clot-dissolving proteins were cloned from P. vulgaris by RT-PCR amplification, which further determined the accuracy of proteins primary sequences identifications and laid the foundation for subsequent heterologous expression.


Assuntos
Fibrinolíticos/isolamento & purificação , Fibrinolíticos/farmacologia , Oligoquetos/química , Peptídeo Hidrolases/farmacologia , Trombose/patologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Sobrevivência Celular/efeitos dos fármacos , Bases de Dados de Proteínas , Eritrócitos/efeitos dos fármacos , Fibrinólise/efeitos dos fármacos , Fibrinolíticos/química , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Modelos Moleculares , Peptídeo Hidrolases/química , Peptídeo Hidrolases/genética , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Ativador de Plasminogênio Tecidual/metabolismo , Peixe-Zebra
2.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445665

RESUMO

Mast cell disease is an epigenetically and genetically determined disease entity with very diverse clinical manifestations in potentially every system and tissue due to inap pro priate release of variable subsets of mast cell mediators together with accumulation of either morphologically normal or altered mast cells. Easy bruising, excessive bleeding, and aberrancies of erythropoiesis can frequently be observed in patients with mast cell disease. A thorough history, including a family history, will guide the appropriate work-up, and laboratory evaluations may provide clues to diagnosis. In recent years, our understanding of the involvement of coagulation and anticoagulant pathways, the fibrinolytic system, and erythropoiesis in the pathophysiology of mast cell disease has increased considerably. This review summarizes current knowledge of the impact of the disturbed hemostatic and erythropoietic balance in patients with mast cell disease and describes options of treatment.


Assuntos
Eritropoese/fisiologia , Hemostasia/fisiologia , Mastocitose/sangue , Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Eritropoese/efeitos dos fármacos , Fibrinólise/efeitos dos fármacos , Fibrinolíticos/farmacologia , Hemostasia/efeitos dos fármacos , Heparina/farmacologia , Humanos , Mastocitose/imunologia , Mastocitose/fisiopatologia
4.
Nutrients ; 13(7)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34371822

RESUMO

Tetranectin (TN), a plasminogen-binding protein originally involved in fibrinolysis and bone formation, was later identified as a secreted adipokine from human and rat adipocytes and positively correlated with adipogenesis and lipid metabolism in adipocytes. To elucidate the nutritional regulation of adipogenic TN from diets containing different sources of fatty acids (saturated, n-6, n-3) in adipocytes, we cloned the coding region of porcine TN from a cDNA library and analyzed tissue expressions in weaned piglets fed with 2% soybean oil (SB, enriched in n-6 fatty acids), docosahexaenoic acid oil (DHA, an n-3 fatty acid) or beef tallow (BT, enriched in saturated and n-9 fatty acids) for 30 d. Compared with tissues in the BT- or SB-fed group, expression of TN was reduced in the adipose, liver and lung tissues from the DHA-fed group, accompanied with lowered plasma levels of triglycerides and cholesterols. This in vivo reduction was also confirmed in porcine primary differentiated adipocytes supplemented with DHA in vitro. Then, promoter analysis was performed. A 1956-bp putative porcine TN promoter was cloned and transcription binding sites for sterol regulatory-element binding protein (SREBP)-1c or forkhead box O proteins (FoxO) were predicted on the TN promoter. Mutating binding sites on porcine TN promoters showed that transcriptional suppression of TN by DHA on promoter activity was dependent on specific response elements for SREBP-1c or FoxO. The inhibited luciferase promoter activity by DHA on the TN promoter coincides with reduced gene expression of TN, SREBP-1c, and FoxO1 in human embryonic kidney HEK293T cells supplemented with DHA. To conclude, our current study demonstrated that the adipogenic TN was negatively regulated by nutritional modulation of DHA both in pigs in vivo and in humans/pigs in vitro. The transcriptional suppression by DHA on TN expression was partly through SREBP-1c or FoxO. Therefore, down-regulation of adipogenic tetranectin associated with fibrinolysis and adipogenesis may contribute to the beneficial effects of DHA on ameliorating obesity-induced metabolic syndromes such as atherosclerosis and adipose dysfunctions.


Assuntos
Adipogenia/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/farmacologia , Fatores de Transcrição Forkhead/metabolismo , Lectinas Tipo C/efeitos dos fármacos , Proteínas de Ligação a Elemento Regulador de Esterol/metabolismo , Adipócitos/efeitos dos fármacos , Animais , Fibrinólise/efeitos dos fármacos , Células HEK293 , Humanos , Fenômenos Fisiológicos da Nutrição/genética , Suínos
5.
Biomed Pharmacother ; 139: 111569, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243622

RESUMO

BACKGROUND: Alveolar hypercoagulation and fibrinolysis inhibition were associated with the refractory hypoxemia and the high mortality in patient with acute respiratory distress syndrome (ARDS), and NF-κB pathway was confirmed to contribute to the process. Triptolide (TP) significantly inhibited NF-κB pathway and thus depressed accessive inflammatory response in ARDS. We speculate that TP could improve alveolar hypercoagulation and fibrinolytic inhibition in LPS-induced ARDS via NF-κB inactivation. PURPOSE: The aim of this experiment was to explore the efficacy and potential mechanism of TP on alveolar hypercoagulation and fibrinolysis inhibition in LPS-induced ARDS in mice. METHODS: 50 µl of LPS (5 mg/ml) was inhalationally given to C57BL/6 mice to set up ARDS model. Male mice were randomly accepted with LPS, LPS + TP (1 µg/kg, 10 µg/kg, 50 µg/kg respectively), or with NEMO Binding domain peptide (NBD), an inhibitor of NF-κB. TP (1 µg/kg, 10 µg/kg, 50 µg/kg) were intraperitoneally injected or 10 µg/50 µl of NBD solution were inhaled 30 min before LPS inhalation. A same volume of normal saline (NS) substituted for TP in mice in control. The endpoint of experiment was at 8 hours after LPS stimulation. Pulmonary tissues were taken for hematoxylin-eosin (HE) staining, wet / dry ratio and for lung injury scores (LIS). Tissue factor (TF) and plasminogen activator inhibitor (PAI)-1 in lung tissue were detected by Western-blotting and by quantitative Real-time PCR(qPCR) respectively. Concentrations of TF, PAI-1, thrombin-antithrombin complex (TAT), procollagen peptide type Ⅲ (PⅢP) and activated protein C (APC) in bronchoalveolar lavage fluid (BALF) were measured by ELISA. NF-κB activation and p65-DNA binding activity in pulmonary tissue were simultaneously determined. RESULTS: LPS stimulation resulted in pulmonary edema, neutrophils infiltration, obvious alveolar collapse, interstitial congestion, with high LIS, which were all dose-dependently ameliorated by Triptolide. LPS also dramatically promoted the expressions of TF and PAI-1 either in mRNA or in protein in lung tissue, and significantly stimulated the secretions of TF, PAI-1, TAT, PⅢP but inhibited APC production in BALF, which were all reversed by triptolide treatment in dose-dependent manner. TP dose-dependently inhibited the activation of NF-κB pathway induced by LPS, indicated by the changes of phosphorylations of p65 (p-p65), p-IKKα/ß and p-IκBα, and weakened p65-DNA binding activity. TP and NBD had same efficacies either on alveolar hypercoagulation and fibrinolysis inhibition or on NF-κB signalling pathway in ARDS mice. CONCLUSIONS: TP dose-dependently improves alveolar hypercoagulation and fibrinolysis inhibition in ARDS mice through inhibiting NF-κB signaling pathway. Our data demonstrate that TP is expected to be an effective selection in ARDS.


Assuntos
Diterpenos/farmacologia , Fibrinólise/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , NF-kappa B/metabolismo , Fenantrenos/farmacologia , Trombofilia/induzido quimicamente , Trombofilia/tratamento farmacológico , Animais , Modelos Animais de Doenças , Compostos de Epóxi/farmacologia , Pulmão/metabolismo , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Síndrome do Desconforto Respiratório , Transdução de Sinais/efeitos dos fármacos , Trombofilia/metabolismo , Tromboplastina/metabolismo
6.
Biosci Rep ; 41(8)2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34328172

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection, the cause of coronavirus disease 2019 (COVID-19), is characterized by unprecedented clinical pathologies. One of the most important pathologies, is hypercoagulation and microclots in the lungs of patients. Here we study the effect of isolated SARS-CoV-2 spike protein S1 subunit as potential inflammagen sui generis. Using scanning electron and fluorescence microscopy as well as mass spectrometry, we investigate the potential of this inflammagen to interact with platelets and fibrin(ogen) directly to cause blood hypercoagulation. Using platelet-poor plasma (PPP), we show that spike protein may interfere with blood flow. Mass spectrometry also showed that when spike protein S1 is added to healthy PPP, it results in structural changes to ß and γ fibrin(ogen), complement 3, and prothrombin. These proteins were substantially resistant to trypsinization, in the presence of spike protein S1. Here we suggest that, in part, the presence of spike protein in circulation may contribute to the hypercoagulation in COVID-19 positive patients and may cause substantial impairment of fibrinolysis. Such lytic impairment may result in the persistent large microclots we have noted here and previously in plasma samples of COVID-19 patients. This observation may have important clinical relevance in the treatment of hypercoagulability in COVID-19 patients.


Assuntos
COVID-19/patologia , Fibrina/metabolismo , Fibrinólise/fisiologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Trombose/patologia , Adulto , Idoso , Amiloide/metabolismo , Plaquetas/metabolismo , Complemento C3/metabolismo , Feminino , Fibrinogênio/metabolismo , Humanos , Pulmão/patologia , Masculino , Técnicas Analíticas Microfluídicas , Pessoa de Meia-Idade , Protrombina/metabolismo , SARS-CoV-2/metabolismo , Trombose/virologia , Tripsina/metabolismo
7.
Arq Bras Cardiol ; 117(1): 15-25, 2021 07.
Artigo em Inglês, Português | MEDLINE | ID: mdl-34320062

RESUMO

BACKGROUND: Primary percutaneous coronary intervention is considered the "gold standard" for coronary reperfusion. However, when not available, the drug-invasive strategy is an alternative method and the electrocardiogram (ECG) has been used to identify reperfusion success. OBJECTIVES: Our study aimed to assess ST-Segment changes in post-thrombolysis and their power to predict recanalization and using the angiographic scores TIMI-flow and Myocardial Blush Grade (MBG) as an ideal reperfusion criterion. METHODS: 2,215 patients with ST-Segment Elevation Myocardial Infarction (STEMI) undergoing fibrinolysis [(Tenecteplase)-TNK] and referred to coronary angiography within 24 h post-fibrinolysis or immediately referred to rescue therapy were studied. The ECG was performed pre- and 60 min-post-TNK. The patients were categorized into 2 groups: those with ideal reperfusion (TIMI-3 and MBG-3) and those with inadequate reperfusion (TIMI and MBG <3). The ECG reperfusion criterion was defined by the reduction of the ST-Segment >50%. A p-value <0.05 was considered for the analyses, with bicaudal tests. RESULTS: The ECG reperfusion criterion showed a positive predictive value of 56%; negative predictive value of 66%; sensitivity of 79%; and specificity of 40%. There was a weak positive correlation between ST-Segment reduction and ideal reperfusion angiographic data (r = 0.21; p <0.001) and low diagnostic accuracy, with an AUC of 0.60 (95%CI: 0.57-0.62). CONCLUSION: The ST-Segment reduction was not able to accurately identify patients with adequate angiographic reperfusion. Therefore, even patients with apparently successful reperfusion should be referred to angiography soon, to ensure adequate macro and microvascular coronary flow.


Assuntos
Infarto do Miocárdio , Intervenção Coronária Percutânea , Angiografia Coronária , Eletrocardiografia , Fibrinólise , Humanos , Infarto do Miocárdio/tratamento farmacológico , Reperfusão Miocárdica , Terapia Trombolítica , Resultado do Tratamento
8.
Hematology ; 26(1): 503-509, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34238131

RESUMO

OBJECTIVE: High altitude (HA), with the main feature of hypobaric hypoxia, is an independent risk factor for thrombosis. However, little is known on the alterations of fibrinolytic system in adaptation to HA. In this study, we investigated changes of fibrinolytic system parameters between individuals permanently living at HA and low altitude (LA) regions, and provided data for further studies on HA-induced thrombotic disease. MATERIAL AND METHODS: A total of 226 eligible participants, including 103 LA participants, 100 healthy HA subjects and 23 high altitude polycythemia (HAPC) patients, were recruited in this study. Six fibrinolytic parameters, i.e. fibrinogen (Fbg), D-dimer (DDi), antithrombin III (AT-III), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) and plasminogen (PLG) were analyzed respectively. PAI-1 and tPA were performed by using bio-immuno-assays and an automated coagulation analyzer was used to conduct Fbg, DDi, AT-III and PLG tests. RESULTS: Plasma levels of Fbg, DDi, PAI-1 and PLG were significantly higher in healthy HA group than in LA group (all p < 0.05), whereas tPA was significantly lower in healthy HA group. No significant difference in AT-III was observed between healthy HA and LA groups (p > 0.05). All these fibrinolytic parameters showed no significant distinctions between healthy HA subjects and HAPC patients (all p > 0.05). HGB showed no relationship with fibrinolytic parameters in HA cohort. CONCLUSION: This study demonstrates that HA environment has a significant effect on fibrinolytic system and provides a foundation for further studies on HA hypobaric hypoxia-induced thrombotic disease.


Assuntos
Altitude , Fibrinólise , Trombose/etiologia , Adulto , Idoso , Antitrombina III/análise , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Fibrinogênio/análise , Humanos , Masculino , Pessoa de Meia-Idade , Trombose/sangue , Adulto Jovem
9.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281177

RESUMO

Hypercoagulation is one of the major risk factors for ICU treatment, mechanical ventilation, and death in critically ill patients infected with SARS-CoV-2. At the same time, hypoalbuminemia is one risk factor in such patients, independent of age and comorbidities. Especially in patients with severe SARS-CoV-2-infection, albumin infusion may be essential to improve hemodynamics and to reduce the plasma level of the main marker of thromboembolism, namely, the D-dimer plasma level, as suggested by a recent report. Albumin is responsible for 80% of the oncotic pressure in the vessels. This is necessary to keep enough water within the systemic circulatory system and for the maintenance of sufficient blood pressure, as well as for sufficient blood supply for vital organs like the brain, lungs, heart, and kidney. The liver reacts to a decrease in oncotic pressure with an increase in albumin synthesis. This is normally possible through the use of amino acids from the proteins introduced with the nutrients reaching the portal blood. If these are not sufficiently provided with the diet, amino acids are delivered to the liver from muscular proteins by systemic circulation. The liver is also the source of coagulation proteins, such as fibrinogen, fibronectin, and most of the v WF VIII, which are physiological components of the extracellular matrix of the vessel wall. While albumin is the main negative acute-phase protein, fibrinogen, fibronectin, and v WF VIII are positive acute-phase proteins. Acute illnesses cause the activation of defense mechanisms (acute-phase reaction) that may lead to an increase of fibrinolysis and an increase of plasma level of fibrinogen breakdown products, mainly fibrin and D-dimer. The measurement of the plasma level of the D-dimer has been used as a marker for venous thromboembolism, where a fourfold increase of the D-dimer plasma level was used as a negative prognostic marker in critically ill SARS-CoV-2 hospitalized patients. Increased fibrinolysis can take place in ischemic peripheral sites, where the mentioned coagulation proteins can become part of the provisional clot (e.g., in the lungs). Although critically ill SARS-CoV-2-infected patients are considered septic shock patients, albumin infusions have not been considered for hemodynamic resuscitation and as anticoagulants. The role of coagulation factors as provisional components of the extracellular matrix in case of generalized peripheral ischemia due to hypoalbuminemia and hypovolemia is discussed in this review.


Assuntos
Albuminas/administração & dosagem , COVID-19/terapia , Hemodiluição/métodos , Anticoagulantes/administração & dosagem , Coagulação Sanguínea/efeitos dos fármacos , COVID-19/sangue , COVID-19/metabolismo , Estado Terminal/terapia , Fibrinólise/efeitos dos fármacos , Humanos , SARS-CoV-2/isolamento & purificação , Tromboelastografia
10.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209949

RESUMO

Fibrinolysis is a complex enzymatic process aimed at dissolving blood clots to prevent vascular occlusions. The fibrinolytic system is composed of a number of cofactors that, by regulating fibrin degradation, maintain the hemostatic balance. A dysregulation of fibrinolysis is associated with various pathological processes that result, depending on the type of abnormality, in prothrombotic or hemorrhagic states. This narrative review is focused on the congenital and acquired disorders of primary fibrinolysis in both adults and children characterized by a hyperfibrinolytic state with a bleeding phenotype.


Assuntos
Transtornos da Coagulação Sanguínea/metabolismo , Fibrinólise , Hemorragia/metabolismo , Adulto , Transtornos da Coagulação Sanguínea/etiologia , Criança , Redes Reguladoras de Genes , Hemorragia/etiologia , Humanos
11.
Int J Mol Sci ; 22(13)2021 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-34199017

RESUMO

Venoms are a rich source of potential lead compounds for drug discovery, and descriptive studies of venom form the first phase of the biodiscovery process. In this study, we investigated the pharmacological potential of crude Pseudocerastes and Eristicophis snake venoms in haematological disorders and cancer treatment. We assessed their antithrombotic potential using fibrinogen thromboelastography, fibrinogen gels with and without protease inhibitors, and colourimetric fibrinolysis assays. These assays indicated that the anticoagulant properties of the venoms are likely induced by the hydrolysis of phospholipids and by selective fibrinogenolysis. Furthermore, while most fibrinogenolysis occurred by the direct activity of snake venom metalloproteases and serine proteases, modest evidence indicated that fibrinogenolytic activity may also be mediated by selective venom phospholipases and an inhibitory venom-derived serine protease. We also found that the Pseudocerastes venoms significantly reduced the viability of human melanoma (MM96L) cells by more than 80%, while it had almost no effect on the healthy neonatal foreskin fibroblasts (NFF) as determined by viability assays. The bioactive properties of these venoms suggest that they contain a number of toxins suitable for downstream pharmacological development as candidates for antithrombotic or anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Fibrinolíticos/farmacologia , Venenos de Serpentes/farmacologia , Venenos de Víboras/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fibrinólise/efeitos dos fármacos , Humanos , Inibidores de Serino Proteinase/farmacologia
12.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202091

RESUMO

As a cell surface tissue plasminogen activator (tPA)-plasminogen receptor, the annexin A2 (A2) complex facilitates plasmin generation on the endothelial cell surface, and is an established regulator of hemostasis. Whereas A2 is overexpressed in hemorrhagic disease such as acute promyelocytic leukemia, its underexpression or impairment may result in thrombosis, as in antiphospholipid syndrome, venous thromboembolism, or atherosclerosis. Within immune response cells, A2 orchestrates membrane repair, vesicle fusion, and cytoskeletal organization, thus playing a critical role in inflammatory response and tissue injury. Dysregulation of A2 is evident in multiple human disorders, and may contribute to the pathogenesis of various inflammatory disorders. The fibrinolytic system, moreover, is central to wound healing through its ability to remodel the provisional matrix and promote angiogenesis. A2 dysfunction may also promote tissue fibrogenesis and end-organ fibrosis.


Assuntos
Anexina A2/genética , Suscetibilidade a Doenças , Fibrinólise/genética , Fibrose/etiologia , Inflamação/etiologia , Animais , Anexina A2/metabolismo , Doenças Autoimunes/etiologia , Doenças Autoimunes/metabolismo , Biomarcadores , Fibrose/metabolismo , Hemostasia/genética , Humanos , Imunidade , Inflamação/metabolismo , Especificidade de Órgãos , Regeneração
13.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203139

RESUMO

Fibrinogen is one of the key molecular players in haemostasis. Thrombin-mediated release of fibrinopeptides from fibrinogen converts this soluble protein into a network of fibrin fibres that form a building block for blood clots. Thrombin-activated factor XIII further crosslinks the fibrin fibres and incorporates antifibrinolytic proteins into the network, thus stabilising the clot. The conversion of fibrinogen to fibrin also exposes binding sites for fibrinolytic proteins to limit clot formation and avoid unwanted extension of the fibrin fibres. Altered clot structure and/or incorporation of antifibrinolytic proteins into fibrin networks disturbs the delicate equilibrium between clot formation and lysis, resulting in either unstable clots (predisposing to bleeding events) or persistent clots that are resistant to lysis (increasing risk of thrombosis). In this review, we discuss the factors responsible for alterations in fibrin(ogen) that can modulate clot stability, in turn predisposing to abnormal haemostasis. We also explore the mechanistic pathways that may allow the use of fibrinogen as a potential therapeutic target to treat vascular thrombosis or bleeding disorders. Better understanding of fibrinogen function will help to devise future effective and safe therapies to modulate thrombosis and bleeding risk, while maintaining the fine balance between clot formation and lysis.


Assuntos
Fator XIIIa/metabolismo , Fibrina/metabolismo , Fibrinogênio/metabolismo , Trombose/metabolismo , Animais , Fator XIIIa/genética , Fibrina/genética , Fibrinogênio/genética , Fibrinólise/genética , Fibrinólise/fisiologia , Humanos , Trombose/genética
14.
Int J Lab Hematol ; 43 Suppl 1: 36-42, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34288440

RESUMO

The alterations in the hemostatic balance in COVID-19 patients are strongly disturbed and contribute to a high prothrombotic status. The high rate of venous thromboembolism in COVID-19 patients goes along with derangements in coagulation laboratory parameters. Hemostasis testing has an important role in diagnosed COVID-19 patients. Elevated D-dimer levels were found to be a crucial laboratory marker in the risk assessment of thrombosis in COVID-19 patients. The diagnostic approach also includes prothrombin time and platelet count. Fibrinogen might give an indication for worsening coagulopathy. Other markers (activated partial thromboplastin time (aPTT), fibrinolysis parameters, coagulation factors, natural anticoagulants, antiphospholipid antibodies and parameters obtained by thromboelastography or thrombin generation assays) have been described as being deranged. These may help to understand the pathophysiology of thrombosis in COVID-19 patients but have currently no place in diagnosis or management in COVID-19 patients. For monitoring the heparin anticoagulant therapy, the anti-Xa assay is suggested, because the severe acute-phase reaction (high fibrinogen and high factor VIII) shortens the aPTT.


Assuntos
Testes de Coagulação Sanguínea , COVID-19/sangue , SARS-CoV-2 , Trombofilia/etiologia , Anticorpos Antifosfolipídeos/sangue , Biomarcadores/sangue , Fatores de Coagulação Sanguínea/análise , Coagulação Intravascular Disseminada/sangue , Coagulação Intravascular Disseminada/etiologia , Fator Xa/análise , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Fibrinogênio/análise , Fibrinólise , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Tempo de Tromboplastina Parcial , Contagem de Plaquetas , Tempo de Protrombina , Tromboelastografia , Trombina/biossíntese , Trombofilia/sangue , Trombofilia/tratamento farmacológico
15.
Int J Lab Hematol ; 43 Suppl 1: 29-35, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34288441

RESUMO

Vascular endothelial injury is a hallmark of acute infection at both the microvascular and macrovascular levels. The hallmark of SARS-CoV-2 infection is the current COVID-19 clinical sequelae of the pathophysiologic responses of hypercoagulability and thromboinflammation associated with acute infection. The acute lung injury that initially occurs in COVID-19 results from vascular and endothelial damage from viral injury and pathophysiologic responses that produce the COVID-19-associated coagulopathy. Clinicians should continue to focus on the vascular endothelial injury that occurs and evaluate potential therapeutic interventions that may benefit those with new infections during the current pandemic as they may also be of benefit for future pathogens that generate similar thromboinflammatory responses. The current Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) studies are important projects that will further define our management strategies. At the time of writing this report, two mRNA vaccines are now being distributed and will hopefully have a major impact on slowing the global spread and subsequent thromboinflammatory injury we see clinically in critically ill patients.


Assuntos
COVID-19/complicações , Pandemias , SARS-CoV-2 , Trombofilia/etiologia , Vasculite/etiologia , Anticoagulantes/uso terapêutico , COVID-19/sangue , COVID-19/imunologia , Criança , Coagulação Intravascular Disseminada/etiologia , Endotélio Vascular/lesões , Endotélio Vascular/fisiopatologia , Feminino , Fibrinólise , Previsões , Humanos , Pulmão/irrigação sanguínea , Pulmão/patologia , Gravidez , Complicações Infecciosas na Gravidez/sangue , Tromboembolia/etiologia , Tromboembolia/prevenção & controle
16.
Thromb Res ; 204: 81-87, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34153648

RESUMO

Enhancement of fibrinolysis constitutes a promising approach to treat thrombotic diseases. Venous thrombosis and thromboembolism risks are associated with increased plasma levels of TAFI (Thrombin Activatable Fibrinolysis Inhibitor) as well as its active form TAFIa. A new TAFIa inhibitor, namely S62798 has been identified. Its ability to enhance fibrinolysis was investigated both in vitro and in vivo in a mouse model of pulmonary thromboembolism, as well as its effect on bleeding. S62798 is a highly selective human, mouse and rat TAFIa inhibitor (IC50 = 11; 270; 178 nmol/L, respectively). It accelerates lysis of a human clot in vitro, evaluated by thromboelastometry (EC50 = 27 nmol/L). In a rat tail bleeding model, no effect of S62798 treatment was observed up to 20 mg/kg. Enhancement of endogenous fibrinolysis by S62798 was investigated in a mouse model of Tissue Factor-induced pulmonary thromboembolism. Intravenous administration of S62798 decreased pulmonary fibrin clots with a minimal effective dose of 0.03 mg/kg. Finally, effect of S62798 in combination with heparin was evaluated. When treatment of heparin was done in a curative setting, no effect was observed whereas a significantly decreased pulmonary fibrin deposition was observed in response to S62798 alone or in combination with heparin. This study demonstrates that S62798 is a potent TAFIa inhibitor with minimal risk of bleeding. In vivo, curative S62798 intravenous treatment, alone or associated with heparin, accelerated clot lysis by potentiating endogenous fibrinolysis and thus decreased pulmonary fibrin clots. S62798 is expected to be a therapeutic option for pulmonary embolism patients on top of anticoagulants.


Assuntos
Carboxipeptidase B2 , Inibidores Enzimáticos/farmacologia , Embolia Pulmonar , Animais , Carboxipeptidase B2/antagonistas & inibidores , Modelos Animais de Doenças , Tempo de Lise do Coágulo de Fibrina , Fibrinólise , Humanos , Camundongos , Embolia Pulmonar/tratamento farmacológico , Ratos
17.
Eur Rev Med Pharmacol Sci ; 25(10): 3886-3897, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34109597

RESUMO

OBJECTIVE: Platelets, blood coagulation along with fibrinolysis are greatly involved in the pathophysiology of infectious diseases induced by bacteria, parasites and virus. This phenomenon is not surprising since both the innate immunity and the hemostatic systems are two ancestral mechanisms which closely cooperate favoring host's defense against foreign invaders. However, the excessive response of these systems may be dangerous for the host itself. MATERIALS AND METHODS: We searched and retrieved the articles, using the following electronic database: MedLine and Embase. We limited our search to articles published in English, but no restrictions in terms of article type, publication year, and geography were adopted. RESULTS: The hemostatic phenotype of the infectious diseases is variable depending on the points of attack of the different involved pathogens. Infectious diseases which show a prothrombotic phenotype are bacterial sepsis, SARS-CoV-2 and malaria. However, among the bacterial sepsis, Yersinia Pestis is characterized by a profibrinolytic behavior. On the contrary, the hemorrhagic fevers, due to Dengue and Ebola virus, mainly exploit the activation of fibrinolysis secondary to a huge endothelial damage which can release a large amount of t-PA in the early phase of the diseases. CONCLUSIONS: Blood coagulation and fibrinolysis are greatly activated based on the strategy of the different infectious agents which exploit the excess of response of both systems to achieve the greatest possible virulence.


Assuntos
Coagulação Sanguínea , COVID-19/patologia , Fibrinólise , COVID-19/complicações , COVID-19/virologia , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Células Endoteliais/virologia , Eritrócitos/citologia , Eritrócitos/metabolismo , Eritrócitos/parasitologia , Humanos , Monócitos/citologia , Monócitos/metabolismo , Monócitos/virologia , SARS-CoV-2/isolamento & purificação , Tromboplastina/metabolismo , Vírus/patogenicidade
18.
Clin Lab ; 67(6)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34107636

RESUMO

BACKGROUND: The aim of the study is to investigate the coagulation status in trauma patients using thromboelastography and their association with survival and blood transfusion. METHODS: We included 452 trauma patients who visited the trauma center of Uijeongbu St. Mary's Hospital. The thromboelastography (TEG) clotting variables and routine coagulation tests were evaluated. Also, we investigated the transfusion requirement and mortality during hospitalization period. RESULTS: The mean age was 52.3 years and the mortality rate was 39/452 (8.6%). Lower GCS, longer TEG K-time, and lower TEG MA were independent factors associated with mortality. The lower MA group demonstrated the highest probability of survival (odds ratio 0.207), followed by prolonged R-time (odds ratio 0.220). The patient numbers in fibrinolysis shutdown (SD), physiologic fibrinolysis, and hyperfibrinolysis groups were 219 (52.3%), 131 (31.4%), and 68 (16.3%), respectively. The mortality rates of fibrinolysis SD group (11.9%) and hyperfibrinolysis (8.8%) were higher than the physiologic fibrinolysis groups (3.8%). The cutoff obtained from ROC analysis was found to be suitable for predicting survival. The transfusion requirements were significantly higher in the fibrinolysis SD group than in the other two groups. CONCLUSIONS: TEG based markers were shown to be more useful to make a diagnosis of coagulopathies including dysfibrinolysis and predict the survival than routine coagulation tests. Dysfunctional fibrinolysis showed higher mortality than physiologic group. If multiple integrations of each TEG markers are used, it would be helpful for prompt diagnosis and management of coagulopathies and to decrease preventable deaths in trauma.


Assuntos
Transtornos da Coagulação Sanguínea , Ferimentos e Lesões , Transtornos da Coagulação Sanguínea/diagnóstico , Testes de Coagulação Sanguínea , Transfusão de Sangue , Fibrinólise , Humanos , Pessoa de Meia-Idade , Tromboelastografia , Ferimentos e Lesões/diagnóstico
19.
Medicina (B Aires) ; 81(3): 454-457, 2021.
Artigo em Espanhol | MEDLINE | ID: mdl-34137708

RESUMO

Phlegmasia cerulea dolens (FCD) is a rare complication of deep vein thrombosis. Its cause is unknown. The main predisposing factors for the disease are neoformative processes, hypercoagulable states, congestive heart failure, pregnancy, prolonged immobilization, and surgeries on the affected limb. FCD is characterized by massive edema, severe pain, and cyanosis. The diagnosis is clinical. It is associated in most cases with pulmonary embolism and can lead to loss of the compromised limb if not treated in time. So far there is no consensus on its treatment. In clinical practice the use of anticoagulation with heparin, local thrombolysis, systemic fibrinolysis, surgical thrombectomy, fasciotomy, and inferior vena cava filter are described. In irreversible cases amputation is required. We present the case of a patient with FCD, the treatment performed and the evolution.


Assuntos
Tromboflebite , Trombose Venosa , Fibrinólise , Heparina , Humanos , Trombectomia , Tromboflebite/diagnóstico por imagem , Tromboflebite/tratamento farmacológico , Trombose Venosa/diagnóstico por imagem , Trombose Venosa/tratamento farmacológico
20.
Angiol Sosud Khir ; 27(2): 25-31, 2021.
Artigo em Russo | MEDLINE | ID: mdl-34166341

RESUMO

This review contains the data concerning the mechanisms of spontaneous fibrinolysis in pulmonary vessels and possibilities of its acceleration in pulmonary embolism. The spontaneous fibrinolysis system is known to be sequential and multifactorial, with the interaction of accelerators (t-PA and u-PA) and inhibitors (alpha-2-antiplasmin, PAI-1, TAFI). The fibrinolytic processes take place in case of prevailing reactions of accelerating factors over inhibiting ones. The endothelium of pulmonary vessels possesses pronounced antithrombogenic and profibrinolytic properties, therefore, the processes of fibrinolysis in the pulmonary vascular bed normally occur more intensively than in the vessels of the systemic circulation. The membrane proteins of the endothelium annexins A2 activate plasminogen, whereas thrombomodulin inhibits the activity of PAI-1. The main approaches to increase the fibrinolysis intensity in conditions of pulmonary embolism may be aimed at elevating the activity of fibrinolytic enzymes (enhancing the synthesis of annexins A2, the use of NMDA-receptor antagonists) and suppressing its inhibitors (the use of monoclonal antibodies to alpha-2-antiplasmin, as well as plasminogen activator inhibitor-1 (PAI-1) and thrombin-activatable fibrinolysis inhibitor (TAFI). Promising directions for future research can be the synthesis of a new generation of tissue-type plasminogen activators, and investigations of the possibility of clinical application of antithrombin and thrombomodulin, angiotensin converting enzyme inhibitors and cortisol antagonists. To meet these challenges, it is necessary to develop new models of venous thrombosis and acute pulmonary embolism in different animal species, with the assessment of the changes in the venous haemodynamics and pulmonary microcirculation on the background of administration of a new class of fibrinolytic agents.


Assuntos
Carboxipeptidase B2 , Embolia Pulmonar , Aceleração , Animais , Carboxipeptidase B2/farmacologia , Fibrinólise , Fibrinolíticos/farmacologia , Embolia Pulmonar/tratamento farmacológico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...