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1.
Pediatr Blood Cancer ; 67(1): e28016, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31556233

RESUMO

BACKGROUND: L-asparaginase (L-Asp)-associated thromboembolisms are serious complications in pediatrics patients with acute lymphoblastic leukemia (ALL), especially at ≥10.0 years old, but the pathogenesis remains to be clarified. PROCEDURE: We conducted a multicenter, prospective study of 72 patients with ALL aged 1.0 to 15.2 years treated with either a Berlin-Frankfurt-Münster (BFM) 95-ALL oriented regimen or Japan Association of Childhood Leukemia Study ALL-02 protocol. We divided patients into each treatment protocol and investigated the dynamic changes in coagulation and fibrinolysis using simultaneous thrombin and plasmin generation assay. Patients' plasma samples were collected at the prephase (T0), intermittent phase (T1), and postphase of L-Asp therapy (T2), and postinduction phase (T3). Measurements of endogenous thrombin potential (T-EP) and plasmin peak height (P-Peak) were compared to normal plasma. RESULTS: None of the cases developed thromboembolisms. Median ratios of T-EP and P-Peak for the controls in the JACLS group were 1.06 and 0.87 (T0), 1.04 and 0.71 (T1), 1.02 and 0.69 (T2), and 1.20 and 0.92 (T3), respectively, while those in the BFM group were 1.06 and 1.00 (T0), 1.04 and 0.64 (T1), 1.16 and 0.58 (T2), and 1.16 and 0.85 (T3), respectively. In particular, P-Peak ratios were depressed at T1 and T2 compared to T0 in the BFM group (P < .01). Moreover, P-Peak ratios in patients ≥10.0 years old were lower at T1 in the BFM group (P = .02). CONCLUSIONS: The results demonstrated that hemostatic dynamics appeared to shift to a hypercoagulable state with marked hypofibrinolysis associated with L-Asp therapy, especially in patients ≥10.0 years old following the BFM regimen.


Assuntos
Asparaginase/efeitos adversos , Transtornos da Coagulação Sanguínea/patologia , Fibrinolisina/metabolismo , Fibrinólise/efeitos dos fármacos , Hemostasia/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Trombina/metabolismo , Adolescente , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Asparaginase/administração & dosagem , Transtornos da Coagulação Sanguínea/induzido quimicamente , Transtornos da Coagulação Sanguínea/metabolismo , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Quimioterapia de Indução , Lactente , Japão , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Estudos Prospectivos
2.
Blood Coagul Fibrinolysis ; 30(7): 341-349, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31592776

RESUMO

: Changes in fibrinolysis following subarachnoid haemorrhage (SAH) and intracerebral haemorrhage (ICH) are sparsely investigated. To investigate fibrinolysis in the acute phase in SAH and ICH patients compared with healthy individuals, fibrinolysis after 24 h in ICH patients and the in-vivo effect of tranexamic acid (TXA) on fibrinolysis in SAH patients. Further, ex-vivo studies were performed by addition of several haemostatic agents to blood samples obtained at admission. Blood was sampled from 46 SAH and 41 ICH patients upon admission. In ICH patients, a second blood sample was obtained 24 h after symptom onset, and in SAH patients after TXA treatment. A sex-matched healthy control group was used for comparison. Fibrinolysis and clot stability were assessed by a dynamic fibrin clot lysis assay, and measurements of plasminogen activator inhibitor I, tissue plasminogen activator and coagulation factor XIII were performed. On admission, no difference in lysis time was found in SAH or ICH patients compared with healthy controls (all P values >0.15). For SAH and ICH patients, median plasminogen activator inhibitor I, tissue plasminogen activator and factor XIII levels were within the reference intervals. In ICH patients, lysis time remained within 24 h after symptom onset (P = 0.63). In SAH patients, the clot lysis curve showed a complete block of fibrinolysis after TXA administration. Ex-vivo addition of solulin and prothrombin complex concentrate reduced fibrinolysis (P < 0.001). SAH and ICH patients showed no hyperfibrinolysis on admission. Fibrinolysis remained normal in ICH patients, and TXA treatment obliterated fibrinolysis in SAH patients.


Assuntos
Hemorragia Cerebral/sangue , Fibrinólise , Hemorragia Subaracnóidea/sangue , Adulto , Idoso , Fatores de Coagulação Sanguínea/farmacologia , Estudos de Casos e Controles , Feminino , Tempo de Lise do Coágulo de Fibrina , Fibrinólise/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ácido Tranexâmico/farmacologia
3.
Toxicol Lett ; 316: 35-48, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31509773

RESUMO

Snake envenomation globally is attributed to an ever-increasing human population encroaching into snake territories. Responsible for many bites in Asia is the widespread genus Trimeresurus. While bites lead to haemorrhage, only a few species have had their venoms examined in detail. We found that Trimeresurus venom causes haemorrhaging by cleaving fibrinogen in a pseudo-procoagulation manner to produce weak, unstable, short-lived fibrin clots ultimately resulting in an overall anticoagulant effect due to fibrinogen depletion. The monovalent antivenom 'Thai Red Cross Green Pit Viper antivenin', varied in efficacy ranging from excellent neutralisation of T. albolabris venom through to T. gumprechti and T. mcgregori being poorly neutralised and T. hageni being unrecognised by the antivenom. While the results showing excellent neutralisation of some non-T. albolabris venoms (such as T. flavomaculaturs, T. fucatus, and T. macrops) needs to be confirmed with in vivo tests, conversely the antivenom failure T. hageni, and the very poor results against T. gumprechti and T. mcgregori, despite being conducted in the ideal scenario of preincubation of antivenom:venom, indicates that the likelihood of clinically relevant cross-reactivity for these species is low (T. gumprechti and T. mcgregori) to non-existent (T. hageni). These same latter three species were also not inhibited by the serine protease inhibitor AEBSF, suggesting that the toxins leading to a coagulotoxic effect in these species are non-serine proteases while in contrast T. albolabris coagulotoxicity was completely impeded by AEBSF, and thus driven by kallikrein-type serine proteases. There was a conspicuous lack of phylogenetic pattern in venom variation, with the most potent venoms (T. albolabris and T. hageni) being distant to each other on the organismal tree, and with the three most divergent and poorly neutralised venoms (T. gumprechti, T. hageni, and T. mcgregori) were also not each others closest relatives. This reinforces the paradigm that the fundamental dynamic evolution of venom results in organismal phylogeny being a poor predictor of venom potency or antivenom efficacy. This study provides a robust investigation on the differential venom effects from a wide range of Trimeresurus species on coagulation, highlighting differential fibrinogenolytic effects, while also investigating the relative antivenom neutralisation capabilities of the widely available Thai Red Cross Green Pit Viper antivenom. These results therefore have immediate, real-world implications for patients envenomed by Trimeresurus species.


Assuntos
Antídotos/farmacologia , Antivenenos/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Venenos de Crotalídeos/antagonistas & inibidores , Hemorragia/tratamento farmacológico , Mordeduras de Serpentes/tratamento farmacológico , Trimeresurus , Animais , Testes de Coagulação Sanguínea , Reações Cruzadas , Venenos de Crotalídeos/classificação , Venenos de Crotalídeos/imunologia , Venenos de Crotalídeos/metabolismo , Fibrinólise/efeitos dos fármacos , Hemorragia/sangue , Hemorragia/imunologia , Filogenia , Mordeduras de Serpentes/sangue , Mordeduras de Serpentes/imunologia , Trimeresurus/classificação
4.
Toxicol Lett ; 316: 171-182, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31442586

RESUMO

Australian elapid snakes are some of the most venomous snakes in the world and are unique among venomous snakes in having mutated forms of the blood clotting factor X in an activated form (FXa) as a key venom component. In human bite victims, an overdose of this activated clotting enzyme results in the systemic consumption of fibrinogen due to the large amounts of endogenous thrombin generated by the conversion of prothrombin to thrombin by venom FXa. Within Australian elapids, such procoagulant venom is currently known from the tiger snake clade (Hoplocephalus, Notechis, Paroplocephalus, and Tropidechis species), brown/taipan (Oxyuranus and Pseudonaja species) clade, and the red-bellied black snake Pseudechis porphyriacus. We used a STA-R Max coagulation analyser and TEG5000 thromboelastographers to test 47 Australian elapid venoms from 19 genera against human plasma in vitro. In addition to activity being confirmed in the two clades above, FXa-driven potent procoagulant activity was found in four additional genera (Cryptophis, Demansia, Hemiaspis, and Suta). Ontogenetic changes in procoagulant function was also identified as a feature of Suta punctata venom. Phylogenetic analysis of FX sequences confirmed that snake venom FXa toxins evolved only once, that the potency of these toxins against human plasma has increased in a stepwise fashion, and that multiple convergent amplifications of procoagulant activity within Australian elapid snakes have occurred. Cofactor dependence tests revealed all procoagulant venoms in our study, except those of the tiger snake clade, to be highly calcium-dependent, whereas phospholipid dependence was less of a feature but still displayed significant variation between venoms. Antivenom testing using CSL Tiger Snake Antivenom showed broad but differential cross-reactivity against procoagulant venoms, with P. porphyriacus and S. punctata extremely well neutralised but with Cryptophis, Demansia, and Hemiaspis less well-neutralised. The relative variation was not in accordance to genetic relatedness of the species used in antivenom production (Notechis scutatus), which underscores a fundamental principle that the rapid evolution characteristic of venoms results in organismal phylogeny being a poor predictor of antivenom efficacy. Our results have direct and immediate implications for the design of clinical management plans in the event of snakebite by such lesser known Australian elapid snake species that have been revealed in this study to be as potent as the better studied, and proven lethal, species.


Assuntos
Antivenenos/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Venenos Elapídicos/antagonistas & inibidores , Elapidae , Inibidores do Fator Xa/farmacologia , Fator Xa/metabolismo , Mordeduras de Serpentes/tratamento farmacológico , Animais , Reações Cruzadas , Venenos Elapídicos/genética , Venenos Elapídicos/imunologia , Venenos Elapídicos/metabolismo , Elapidae/classificação , Elapidae/genética , Elapidae/imunologia , Elapidae/metabolismo , Evolução Molecular , Fator Xa/genética , Fator Xa/imunologia , Fibrinólise/efeitos dos fármacos , Mutação , Filogenia , Mordeduras de Serpentes/imunologia , Mordeduras de Serpentes/metabolismo , Tromboelastografia
5.
Rev. esp. anestesiol. reanim ; 66(6): 299-306, jun.-jul. 2019. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-187538

RESUMO

Objetivo: La isquemia derivada de la aplicación del torniquete es un factor fibrinolítico que podría potenciar la eficacia del ácido tranexámico (ATx) en artroplastia total de rodilla (ATR) frente a la artroplastia total de cadera (ATC). Nuestro objetivo es comparar el efecto del ATx sobre sangrado y fibrinólisis en estas 2 artroplastias, valorando la incidencia de complicaciones. Método: Ensayo clínico prospectivo, aleatorizado y doble ciego. Los pacientes programados para ATR o ATC recibían ATx (2 infusiones 10mg/kg) o placebo. Se cuantificó sangrado y parámetros de fibrinólisis, y se detectaron complicaciones tromboembólicas con ecografía doppler y tomografía computarizada. Resultados: Fueron incluidos 44 pacientes (11 ATC y 11 ATR tratados con ATx; 11 ATC y 11 ATR fueron controles). El sangrado fue significativamente menor en el grupo tratado con ATx (promedio 921mL vs. 1383mL en ATC y 969mL vs. 1223mL en ATR) y se necesitaron menos transfusiones (ninguna frente a 5 unidades en grupo control). El ATx fue igualmente eficaz en la reducción del sangrado en ambas cirugías (reducción del 33% en ATC y del 21% en ATR). El gran incremento medio de dímero D entre el periodo basal y las 6h (1.004 a 10.284μg /L en ATC y 571 a 6.480μg /L en ATR) es atenuado por el uso de ATx (1.077 a 2.590μg/L en ATC y 655 a 2.535μg/L en ATR). No hubo diferencias significativas en eventos tromboembólicos. Conclusiones: El ATx profiláctico es igualmente efectivo en ATR y ATC para reducir sangrado. Ambas cirugías tienen efecto similar sobre la fibrinólisis


Background: Tourniquet-induced ischaemia could increase fibrinolysis and enhance tranexamic acid (TXA) efficacy in total knee arthroplasty (TKA) compared to total hip arthroplasty (THA). The aims of this study are to compare the effect of TXA on bleeding and fibrinolysis in both types of surgery, and to record thromboembolic complications. Methods: A prospective double-blind study was conducted on patients scheduled for TKA or THA who received TXA (2 bolus of 10mg/kg) or placebo. Bleeding and fibrinolysis were evaluated. Doppler-ultrasound and computed tomography were performed in order to assess any thromboembolic complications. Results: A total of 44 patients were included (11 THA and 11 TKA treated with TXA; 11 THA and 11 TKA as controls). Blood losses were significantly lower in the TXA group (mean 921mL vs 1,383mL in THA and 969mL vs 1,223mL in TKA), and no transfusions were needed with TXA, whereas 5 blood units were transfused in controls. TXA was equally effecting in reducing bleeding in both surgeries (33% in THA and 21% in TKA). The significant mean increase in D-dimers from baseline to 6 hours after surgery (1,004 ug/L to 10,284 ug/L in THA and 571 ug/L to 6,480 ug/L in TKA) was attenuated by TXA (1,077 ug/L to 2,590 ug/L in THA and 655 ug/L to 2,535 ug/L in TKA). There were no differences in thromboembolic episodes. Conclusions: Prophylactic use of tranexamic acid is equally effective in reducing bleeding in TKA and THA. Both surgeries have a similar effect on fibrinolysis


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Ácido Tranexâmico/farmacocinética , Perda Sanguínea Cirúrgica/prevenção & controle , Fibrinólise/efeitos dos fármacos , Artroplastia de Quadril/estatística & dados numéricos , Artroplastia do Joelho/estatística & dados numéricos , Estudos Prospectivos , Método Duplo-Cego , Tromboembolia/diagnóstico por imagem , Transfusão de Sangue/estatística & dados numéricos , Pré-Medicação/estatística & dados numéricos , Estudos de Casos e Controles
6.
Molecules ; 24(11)2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31174390

RESUMO

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


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Fibrinólise/efeitos dos fármacos , Pentamidina/farmacologia , Trombose/tratamento farmacológico , Testes de Coagulação Sanguínea , Fator VIIa/genética , Fator XIIa/genética , Fator XIa/genética , Fator Xa/genética , Humanos , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Trombina/química , Trombina/genética , Tempo de Trombina , Trombose/sangue , Trombose/patologia
7.
Basic Clin Pharmacol Toxicol ; 125(4): 328-336, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31059181

RESUMO

Carbon monoxide releasing molecule-2 (CORM-2), an emerging therapeutic in human medicine, enhances plasmatic coagulation and attenuates fibrinolysis in vitro in human, rabbit and horse plasma and ameliorates hypocoagulation and hyperfibrinolysis secondary to venom exposure in human plasma in vitro. Fibrinogenases in rattlesnake venom cause decreased clot strength, and in the presence of tissue plasminogen activator (tPA) in vitro, a markedly increased rate of clot lysis. CO interacts with a haem group on fibrinogen, changing its configuration so that the fibrin clot is strengthened and more resistant to fibrinolysis. We hypothesized that CORM-2 enhances coagulation and attenuates fibrinolysis in canine plasma exposed to C viridis venom. We measured the effects of C viridis venom on clot strength, rates of coagulation and fibrinolysis in both pooled canine plasma and plasma from individual naturally envenomed dogs, with and without CORM-2, using thromboelastography (TEG). We tested venom effects on coagulation using tissue factor (TF) activated TEG and on both coagulation and fibrinolysis using TF-activated TEG with added tPA. We found that 17.9 µg/mL of venom causes a mean 26.4% decrease in clot strength, a 61.8% decrease in maximum rate of thrombus generation, 75% faster clot lysis, a 226% increase in maximum rate of lysis and a 92% decrease in total clot life span (CLS). CORM-2 ameliorated these effects, increasing CLS in the presence of venom by 603%. Additionally, we showed that CORM-2 has similar effects in vitro on plasma from naturally envenomed dogs, showing promise as an adjunct therapy for snake envenomation.


Assuntos
Transtornos da Coagulação Sanguínea/tratamento farmacológico , Venenos de Crotalídeos/toxicidade , Fibrinólise/efeitos dos fármacos , Compostos Organometálicos/administração & dosagem , Mordeduras de Serpentes/tratamento farmacológico , Animais , Transtornos da Coagulação Sanguínea/induzido quimicamente , Transtornos da Coagulação Sanguínea/veterinária , Crotalus , Cães , Mordeduras de Serpentes/sangue , Mordeduras de Serpentes/veterinária , Tromboelastografia , Resultado do Tratamento
8.
PLoS One ; 14(5): e0217234, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31141522

RESUMO

The relatively rapid inhibition of microplasmin by α2-AP leads to short functional half-life of the molecule in vivo, causing inefficient clot dissolution, even after site-specific, local catheter-based delivery. Here, we describe a PEGylation approach for improving the therapeutic potential via improving the survival of microplasmin in presence of its cognate inhibitor, α2-AP, wherein a series of strategically designed cysteine analogs of micro-plasminogen were prepared and expressed in E. coli, and further modified by covalent grafting in vitro with PEG groups of different molecular sizes so as to select single or double PEG chains that increase the molecular weight and hydrodynamic radii of the conjugates, but with a minimal discernible effect on intrinsic plasmin activity and structural framework, as explored by amidolytic activity and CD-spectroscopy, respectively. Interestingly, some of the purified PEG-coupled proteins after conversion to their corresponding proteolytically active forms were found to exhibit significantly reduced inhibition rates (up to 2-fold) by α2-AP relative to that observed with wild-type microplasmin. These results indicate an interesting, and not often observed, effect of PEG groups through reduced/altered dynamics between protease and inhibitor, likely through a steric hindrance mechanism. Thus, the present study successfully identifies single- and double-site PEGylated muteins of microplasmin with significantly enhanced functional half-life through enhanced resistance to inactivation by its in vivo plasma inhibitor. Such an increased survival of bioactivity in situ, holds unmistakable potential for therapeutic exploitation, especially in ischemic strokes where a direct, catheter-based deposition within the cranium has been shown to be promising, but is currently limited by the very short in vivo bioactive half-life of the fibrin dissolving agent/s.


Assuntos
Fibrinolisina/metabolismo , Fragmentos de Peptídeos/metabolismo , Terapia Trombolítica/métodos , Escherichia coli/metabolismo , Fibrina/metabolismo , Fibrinólise/efeitos dos fármacos , Humanos , Plasminogênio/metabolismo , Polietilenoglicóis/química , Engenharia de Proteínas/métodos , Serpinas/farmacologia
9.
J Thromb Thrombolysis ; 48(1): 103-110, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30972711

RESUMO

A direct oral anticoagulant, edoxaban, is as effective as vitamin K antagonists for the treatment of venous thromboembolism (VTE). However, the mechanism underlying the treatment effect on VTE remains to be determined. The aims of this study were to evaluate the effect of edoxaban on tissue plasminogen activator (t-PA)-induced clot lysis in human plasma and to determine the roles of plasmin and thrombin-activatable fibrinolysis inhibitor (TAFI) in the profibrinolytic effect by edoxaban. Pooled human normal plasma or TAFI-deficient plasma (containing 180 ng/mL t-PA and 0.1 nM thrombomodulin) was mixed with edoxaban or an activated TAFI inhibitor, potato tuber carboxypeptidase inhibitor (PCI). Clot was induced by adding tissue factor and phospholipids. Clot lysis time and plasma plasmin-α2 antiplasmin complex (PAP) concentration were determined. Clot structure was imaged with a scanning electron microscope. In normal plasma, edoxaban at clinically relevant concentrations (75, 150, and 300 ng/mL) and PCI significantly shortened clot lysis time. PCI increased PAP concentration and a correlation between PAP concentration and percent of clot lysis was observed. Edoxaban also dose-dependently elevated PAP concentration. In TAFI-deficient plasma, the effects of edoxaban and PCI on clot lysis and PAP concentration were markedly diminished as compared with normal plasma. Fibrin fibers were thinner in clots formed in the presence of edoxaban. In conclusion, edoxaban at clinically relevant concentrations accelerates t-PA-induced fibrinolysis via increasing plasmin generation in human plasma. The effects of edoxaban is mainly dependent on TAFI. The profibrinolytic effect of edoxaban might contribute to the efficacy for the treatment of VTE.


Assuntos
Carboxipeptidase B2/farmacologia , Fibrinolisina/efeitos dos fármacos , Fibrinólise/efeitos dos fármacos , Piridinas/farmacologia , Tiazóis/farmacologia , Anticoagulantes/farmacologia , Coagulação Sanguínea , Carboxipeptidase B2/deficiência , Relação Dose-Resposta a Droga , Tempo de Lise do Coágulo de Fibrina , Fibrinolisina/análise , Fibrinolisina/biossíntese , Fibrinolisina/farmacologia , Humanos , Ativador de Plasminogênio Tecidual , Tromboembolia Venosa/tratamento farmacológico , alfa 2-Antiplasmina/análise , alfa 2-Antiplasmina/farmacologia
10.
Br J Anaesth ; 122(6): 760-766, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30952386

RESUMO

BACKGROUND: Tranexamic acid (TXA) reduces intraoperative blood loss and transfusion during paediatric craniosynostosis surgery. Additional reduction of postoperative blood loss may further reduce exposure to allogeneic blood products. We studied the effect of combined intra- and postoperative TXA treatment on postoperative blood loss in children. METHODS: Thirty children admitted for craniosynostosis surgery were randomised to combined intra- and postoperative TXA treatment or placebo. The primary endpoint was postoperative blood loss. Secondary endpoints included total blood loss, transfusion requirements, and clot stability evaluated by tissue plasminogen activator-stimulated clot lysis assay. RESULTS: TXA reduced postoperative blood loss by 18 ml kg-1 (95% confidence interval 8.9) and total blood loss from a mean of 52 ml kg-1 (standard deviation [SD]; 20) ml kg-1 to 28 (14) ml kg-1 (P<0.001). Intraoperative red blood cell (RBC) and fresh frozen plasma (FFP) transfusions were reduced in the treatment group from RBC 14.0 (5.2) ml kg-1 to 8.2 (5.1) ml kg-1 (P=0.01) and from FFP 13.0 (6.3) ml kg-1 to 7.8 (5.9) ml kg-1 (P=0.03). Postoperative RBC transfusion median was 5 (inter-quartile range [IQR] 0-6) ml kg-1 in the placebo group and 0 (0-5.7) ml kg-1 in the TXA group. Resistance to lysis was higher in the treatment group (P<0.001). CONCLUSIONS: Combined intra- and postoperative tranexamic acid treatment reduced postoperative and overall blood loss and transfusion requirements. Improved clot stability represents a possible mechanism for blood loss reduction.


Assuntos
Antifibrinolíticos/uso terapêutico , Perda Sanguínea Cirúrgica/prevenção & controle , Craniossinostoses/cirurgia , Hemorragia Pós-Operatória/prevenção & controle , Ácido Tranexâmico/uso terapêutico , Anestesia Geral/métodos , Antifibrinolíticos/administração & dosagem , Pré-Escolar , Método Duplo-Cego , Transfusão de Eritrócitos , Feminino , Fibrinólise/efeitos dos fármacos , Humanos , Lactente , Infusões Intravenosas , Masculino , Assistência Perioperatória/métodos , Ácido Tranexâmico/administração & dosagem
11.
J Thromb Thrombolysis ; 48(1): 81-87, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31030323

RESUMO

C1-inhibitor (C1INH) was shown to enhance thrombin generation (TG) in the presence of thrombomodulin (TM) by reducing production of activated protein C. Because C1INH is known to inhibit fibrinolytic system proteases, the objective of this study was to evaluate the effect of moderate (3 IU/ml) and high (16 IU/ml) C1INH concentrations on TG and plasmin generation (PG) in the presence of TM. These concentrations were evaluated based on expected maximum plasma levels following C1INH replacement therapy and recently suggested supraphysiologic dosing. TG and PG were investigated in platelet poor plasmas obtained from 21 healthy donors. An assay designed to monitor the continuous generation of the 7-amino-4-methylcoumarin fluorescence from substrates specific to thrombin or plasmin was used to evaluate the impact of C1INH activity. To characterize the C1INH effects on TG and PG, the thrombin and plasmin concentration peaks and production rates were calculated. TM addition to donor plasma shifted the concentration dependence of C1INH on TG parameters from reduction to enhancement. Conversely, PG parameters were significantly reduced by 16 IU/ml in both the presence and absence of TM. Moderate C1INH concentration (3 IU/ml) reduced TG and PG in the absence of TM but did not significantly affect these parameters in the presence of TM. Finally, 3 IU/ml of C1INH reduced PG more so than TG in the absence of TM. The presented results suggest a mechanism by which C1INH could potentiate thrombosis by inhibition of fibrinolysis.


Assuntos
Proteína Inibidora do Complemento C1/farmacologia , Fibrinolisina/antagonistas & inibidores , Trombina/efeitos dos fármacos , Trombomodulina/fisiologia , Coagulação Sanguínea , Coleta de Amostras Sanguíneas , Relação Dose-Resposta a Droga , Fibrinolisina/biossíntese , Fibrinólise/efeitos dos fármacos , Voluntários Saudáveis , Humanos , Trombina/metabolismo , Trombose/induzido quimicamente
13.
Biochem Biophys Res Commun ; 512(2): 314-318, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-30890336

RESUMO

Plasmin is a potent serin protease involved in a variety of biological functions, such as fibrinolysis and tissue remodeling. On performing an in vitro control assay to measure the activity of endogenous plasmin in cell lysates, a stimulatory effect of non-ionic detergent NP-40 on plasmin activity was discovered. Another non-ionic detergent, TX-100, also enhanced plasmin activity, while ionic detergents sodium deoxycholate and sodiem dodecyl sulfate abolished plasmin enzyme activity. Kinetic analysis of plasmin activity in the presence of NP-40 and TX-100 demonstrated an increase in Vmax; however, there was no change in Km values, suggesting that these detergents stimulate plasmin activity in a non-competitive manner. Fibrin plate assay indicates that NP-40 and TX-100 functionally stimulate plasmin activity by showing a dose-dependent increase in fibrinolysis.


Assuntos
Detergentes/farmacologia , Fibrinolisina/efeitos dos fármacos , Fibrinolisina/metabolismo , Ácido Desoxicólico/farmacologia , Fibrinólise/efeitos dos fármacos , Humanos , Técnicas In Vitro , Cinética , Octoxinol/farmacologia , Dodecilsulfato de Sódio/farmacologia
14.
Scand J Clin Lab Invest ; 79(1-2): 136-142, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30861350

RESUMO

Hyperfibrinolysis contributes to the pathophysiology of trauma-induced coagulopathy. At present, systematic administration of tranexamic acid (TXA) is recommended in all patients in the early phase of trauma. However, there is some debate regarding whether TXA is beneficial in all trauma patients. A rapid and accurate tool to diagnose hyperfibrinolysis may be useful for tailoring TXA treatment. We conducted a proof-of-concept study of consecutive adult trauma patients. A first blood sample was obtained at the time of pre-hospital care (T1). Patients received 1 g of TXA after T1. A second sample was obtained on arrival at the emergency unit (T2). We examined coagulation, fibrin and fibrinogen formation and degradation. Fibrinolysis was assessed by determining tissue plasminogen activator (t-PA) antigen and plasminogen activator inhibitor 1 (PAI-1) activity and global fibrinolysis capacity assay using a device developed by Hyphen BioMed: the Lysis Timer (GFC/LT). The study population consisted of 20 patients (42 ± 21 years, index of severity score 32 ± 21). Both coagulation and fibrinolysis were altered at T1. GFC/LT values exhibited hyperfibrinolysis only in five patients. Principal component analysis carried out at T1 showed two main axes of alteration. The major axis was related to coagulation, altered in all patients, while the second axis was related to fibrinolysis. GFC/LT was mainly influenced by PAI-1 activity while fibrin monomers were related to the severity of trauma. At T2, GFC/LT exhibited the marked effect of TXA on clot lysis time. In conclusion, GFC/LT demonstrated huge variation in the fibrinolytic response to trauma.


Assuntos
Antifibrinolíticos/uso terapêutico , Fibrinólise/efeitos dos fármacos , Fraturas Múltiplas/tratamento farmacológico , Hemoperitônio/tratamento farmacológico , Fraturas Cranianas/tratamento farmacológico , Ácido Tranexâmico/uso terapêutico , Adolescente , Adulto , Idoso , Feminino , Fibrina/metabolismo , Tempo de Lise do Coágulo de Fibrina/estatística & dados numéricos , Fibrinogênio/metabolismo , Fraturas Múltiplas/sangue , Fraturas Múltiplas/patologia , Hemoperitônio/sangue , Hemoperitônio/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/sangue , Medicina de Precisão , Análise de Componente Principal , Estudo de Prova de Conceito , Fraturas Cranianas/sangue , Fraturas Cranianas/patologia , Ativador de Plasminogênio Tecidual/sangue , Índices de Gravidade do Trauma
15.
Ann Neurol ; 85(5): 667-680, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30843275

RESUMO

OBJECTIVE: Plasminogen activator inhibitor-1 (PAI-1) is the key endogenous inhibitor of fibrinolysis, and enhances clot formation after injury. In traumatic brain injury, dysregulation of fibrinolysis may lead to sustained microthrombosis and accelerated lesion expansion. In the present study, we hypothesized that PAI-1 mediates post-traumatic malfunction of coagulation, with inhibition or genetic depletion of PAI-1 attenuating clot formation and lesion expansion after brain trauma. METHODS: We evaluated PAI-1 as a possible new target in a mouse controlled cortical impact (CCI) model of traumatic brain injury. We performed the pharmacological inhibition of PAI-1 with PAI-039 and stimulation by tranexamic acid, and we confirmed our results in PAI-1-deficient animals. RESULTS: PAI-1 mRNA was time-dependently upregulated, with a 305-fold peak 12 hours after CCI, which effectively counteracted the 2- to 3-fold increase in cerebral tissue-type/urokinase plasminogen activator expression. PAI-039 reduced brain lesion volume by 26% at 24 hours and 43% at 5 days after insult. This treatment also attenuated neuronal apoptosis and improved neurofunctional outcome. Moreover, intravital microscopy demonstrated reduced post-traumatic thrombus formation in the pericontusional cortical microvasculature. In PAI-1-deficient mice, the therapeutic effect of PAI-039 was absent. These mice also displayed 13% reduced brain damage compared with wild type. In contrast, inhibition of fibrinolysis with tranexamic acid increased lesion volume by 25% compared with vehicle. INTERPRETATION: This study identifies impaired fibrinolysis as a critical process in post-traumatic secondary brain damage and suggests that PAI-1 may be a central endogenous inhibitor of the fibrinolytic pathway, promoting a procoagulatory state and clot formation in the cerebral microvasculature. Ann Neurol 2019;85:667-680.


Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Fibrinólise/fisiologia , Serpina E2/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Lesões Encefálicas Traumáticas/tratamento farmacológico , Fibrinólise/efeitos dos fármacos , Ácidos Indolacéticos/farmacologia , Ácidos Indolacéticos/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Serpina E2/antagonistas & inibidores
16.
Int J Surg ; 65: 45-51, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30902753

RESUMO

BACKGROUND: The aim of the study was to identify the efficacy and safety of multiple doses of oral tranexamic acid (TXA) on reducing blood loss and minimizing the postoperative inflammatory and fibrinolytic responses following primary total knee arthroplasty (TKA). MATERIALS AND METHODS: In this prospective, double-blinded, randomized trial, we randomly assigned a total of 151 patients into three groups to receive 2 g of oral TXA 2 h preoperatively (group A); an additional dose of 2 g of oral TXA 4 h postoperatively (group B); or additional doses of 2 g of oral TXA at 4, 10, and 16 h postoperatively (group C). The primary outcome was total blood loss (TBL). The secondary outcomes were maximum drop in hemoglobin (Hb) and hematocrit (Hct), level of inflammatory and fibrinolytic parameters, transfusion rate, and the incidence of complications. RESULTS: The results were represented as mean ±â€¯standard deviation. The mean TBL was 607 ±â€¯254 mL in group C, 743 ±â€¯347 mL in group B (p = 0.027 vs group C), and 978 ±â€¯335 mL in group A (p<0.001 vs group C). The maximum Hb and Hct drop was 18.3 ±â€¯7.7 g/L and 0.051 ±â€¯0.025 in group C, 22.3 ±â€¯9.7 g/L and 0.070 ±â€¯0.028 in group B (p = 0.022 and p = 0.001 vs group C), 29.6 ±â€¯11.7 g/L and 0.090 ±â€¯0.034 in group A (p<0.001 and p<0.001 vs group C). In addition, C-reactive protein and interleukin-6 in group C were lower than in group A (p<0.001 and p = 0.003) and in group B (p = 0.031 and p < 0.001) on postoperative day (POD) 3. Moreover, fibrin degradation products and D-dimer in group C were lower than in groups A and B on both POD 1 and POD 3. The incidence of complications did not differ significantly between the three groups (p > 0.05). CONCLUSION: Multiple postoperative doses of oral TXA could further reduced blood loss and the drop in Hb and Hct, and diminished the postoperative inflammatory and fibrinolytic responses in primary TKA with no apparent increase in the incidence of complications. LEVEL OF EVIDENCE: Level Ⅰ, therapeutic study.


Assuntos
Antifibrinolíticos/uso terapêutico , Artroplastia do Joelho , Perda Sanguínea Cirúrgica/prevenção & controle , Fibrinólise/efeitos dos fármacos , Inflamação/prevenção & controle , Ácido Tranexâmico/uso terapêutico , Idoso , Artroplastia do Joelho/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ácido Tranexâmico/efeitos adversos
18.
Am J Cardiovasc Drugs ; 19(2): 133-171, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30714087

RESUMO

In patients with hypertension, the triad represented by endothelial dysfunction, platelet hyperactivity, and altered fibrinolytic function disturbs the equilibrium between hemostasis and fibrinolysis and translates into a hypercoagulable state, which underlies the risk of thrombotic complications. This article reviews the scientific evidence regarding some biological effects of antihypertensive drugs, which can protect patients from the adverse consequences of hypertensive disease, improving endothelial function, enhancing antioxidant activity, and restoring equilibrium between hemostatic and fibrinolytic factors. These protective effects appear not to be mediated through blood pressure reduction and are not shared by all molecules of the same pharmacological class.


Assuntos
Anti-Hipertensivos/uso terapêutico , Exercício Físico , Fibrinólise/efeitos dos fármacos , Hemostasia/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Humanos , Descanso
19.
PLoS One ; 14(2): e0211646, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30811424

RESUMO

In the present study, we investigated the capabilities of a novel ultrasonic approach for real-time control of fibrinolysis under flow conditions. Ultrasonic monitoring was performed in a specially designed experimental in vitro system. Fibrinolytic agents were automatically injected at ultrasonically determined stages of the blood clotting. The following clots dissolution in the system was investigated by means of ultrasonic monitoring. It was shown, that clots resistance to fibrinolysis significantly increases during the first 5 minutes since the formation of primary micro-clots. The efficiency of clot lysis strongly depends on the concentration of the fibrinolytic agent as well as the delay of its injection moment. The ultrasonic method was able to detect the coagulation at early stages, when timely pharmacological intervention can still prevent the formation of macroscopic clots in the experimental system. This result serves as evidence that ultrasonic methods may provide new opportunities for real-time monitoring and the early pharmacological correction of thrombotic complications in clinical practice.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Fibrinólise/efeitos dos fármacos , Fibrinolíticos/administração & dosagem , Ultrassom/métodos , Humanos , Plasminogênio/metabolismo , Terapia Trombolítica/métodos , Trombose/tratamento farmacológico , Trombose/metabolismo , Ativador de Plasminogênio Tecidual/metabolismo
20.
Medicine (Baltimore) ; 98(7): e14458, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30762760

RESUMO

BACKGROUND: Total knee arthroplasty (TKA) is a surgical procedure to replace the weight-bearing surfaces of the knee joint to relieve pain and disability. However, blood loss and fibrinolytic activity, accounting for a poor prognosis following TKA operation, were relieved by fibrinolytic inhibitor tranexamic acid (TXA). For a better application of TXA function, we explored the effect of intravenous injection (IV) of TXA combined with intra-articular injection (IA) of TXA in patients after TKA. METHODS: Patients admitted from Weifang People's Hospital from January 2015 to December 2016 who received TKA were injected with 20 mg/kg TXA by IV before TKA (n = 50), 3.0 g TXA by IA after TKA (n = 50), or combination of 20 mg/kg TXA by IV before TKA and 3.0 g TXA by IA after TKA (n = 50). Knee function was assessed using HSS, KSS, NASS, and ROM. In addition, the total blood loss (TBL), hidden blood loss (HBL), maximum hemoglobin (Hb) drop, fibrinolytic activity, as well as incidence of thromboembolism were measured. The patients were followed up for 6 months. The deadline for follow-up was June 2017 and the incidence of thromboembolism events within 6 months after operation was counted. RESULTS: HSS, KSS, NASS scores, and ROM were elevated after patients receiving TKA. Patients received IV plus IA TXA has decreased TBL, HBL, and maximum Hb drop than those received IV TXA-alone and IA TXA-alone, with reductions in FDP and D-dimer, indicating that IV plus IA TXA injection is superior to prevent blood loss and hyperfibrinolysis during TKA. Age, sex, type of femoral prosthesis, and the injection method of TXA were risk factors for HBL of patients after receiving TKA. CONCLUSIONS: The aforementioned results demonstrate that TKA is an effective surgery, and IV plus IA TXA injection functions more effectively in reducing blood loss and fibrinolytic activity in patients, which is a clinical factor of occult hemorrhage.


Assuntos
Antifibrinolíticos/administração & dosagem , Artroplastia do Joelho/efeitos adversos , Transtornos da Coagulação Sanguínea/prevenção & controle , Perda Sanguínea Cirúrgica/prevenção & controle , Complicações Intraoperatórias/prevenção & controle , Ácido Tranexâmico/administração & dosagem , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Artroplastia do Joelho/métodos , Transtornos da Coagulação Sanguínea/etiologia , Feminino , Fibrinólise/efeitos dos fármacos , Humanos , Injeções Intra-Articulares , Complicações Intraoperatórias/etiologia , Articulação do Joelho/cirurgia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
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