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1.
Clin Hemorheol Microcirc ; 84(2): 125-139, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37066902

RESUMO

Circulating platelets are sometimes exposed to high shear rate environments due to vascular stenosis, and the effect of transiently elevated pathological high shear rates on platelet activation and aggregation function has not been clarified. The aim of this study was to investigate the effect of pathological high shear rate (8302s-1) exposure time (3.16-25.3 ms) on platelet activation and aggregation function. In addition, by adding active ingredients of antiplatelet drugs such as ASA (an active ingredient of aspirin), Ticagrelor, Tirofiban and GP1BA (platelet membrane protein GPIb inhibitor) in vitro, we studied TXA2, P2Y12-ADP, GPIIb/IIIa-fibrinogen and GPIb /IX/V-vWF receptor pathways to determine platelet activation function mediated by pathological high shear rate. In this study, we designed a set of microfluidic chips with stenosis lengths of 0.5 mm, 1 mm, 2 mm, 3 mm, and 4 mm, all with 80% stenosis, to generate pathological high shear forces that can act at different times. The whole blood flowing through the microchannels was collected by perfusion of sodium citrate anticoagulated whole blood at a physiological arterial shear rate (1500 s-1), and the expression levels of platelet surface activation markers (P-selectin and GP IIb/IIIa) and the degree of platelet aggregation were analyzed by flow cytometry; platelet aggregation patterns were observed by microscopic examination of blood smears. The results showed that shearing significantly increased platelet activation and aggregation levels compared to un-sheared whole blood, and the activation and aggregation levels increased with increasing duration of pathological high shear rate. In vitro inhibition studies showed that ASA barely inhibited the expression of P-selectin and PAC-1 on the platelet surface; Ticagrelor effectively inhibited the expression of both P-selectin and PAC-1; Tirofiban significantly inhibited the expression of PAC-1 on the platelet surface and slightly inhibited the expression of P-selectin; GP1BA significantly inhibited the expression of both. Our results suggest that transient pathological high shear rate (8302s-1) exposure can induce platelet activation in a time-dependent manner; however, the mechanism is more complex and may be due to the following reasons: transient elevated pathological high shear rate activates platelets through the GPIb/IX/V-vWF receptor pathway, and after platelet activation, its surface membrane protein GPIIb/IIIa receptors activate platelets through fibrinogen to form platelet-platelet aggregates, and further activation of active substances such as ADP and TXA2 released by platelet alpha particles, which contribute to the formation of irreversible platelet aggregation.


Assuntos
Selectina-P , Ativação Plaquetária , Humanos , Selectina-P/farmacologia , Tirofibana/farmacologia , Ticagrelor/farmacologia , Constrição Patológica , Agregação Plaquetária/fisiologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/farmacologia , Plaquetas/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Aspirina/farmacologia , Fibrinogênio , Fator de von Willebrand/metabolismo , Fator de von Willebrand/farmacologia
2.
Curr Protein Pept Sci ; 24(1): 31-42, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36380406

RESUMO

Platelets and their progenitors express high levels of integrin αIIbß3, which plays a key role in platelet functions, hemostasis, and arterial thrombosis. Because of their quick and high efficacy, the three anti-αIIbß3 drugs, abciximab, eptifibatide, and tirofiban, are regarded as potent anti-thrombotics and clinically approved by US Food and Drug Administration. However, because they interfere with the inside-out signaling of αIIbß3, which is required for stable platelet adhesion and aggregation, the application of abciximab, eptifibatide, and tirofiban is restricted to patients undergoing percutaneous coronary intervention. On the other hand, the outside-in signaling of αIIbß3 in platelets appears to be responsible for thrombus stabilization, and selective interference with the propagation of outside-in signals might signify a new therapeutic strategy to preferentially inhibit platelet-rich arterial thrombosis with less bleeding issues caused by way of compromised major hemostasis. The purpose of this review is to describe the bidirectional signal transduction of integrin αIIbß3 in platelets with a focus on outside-in signaling, more efficient and safer anti-αIIbß3 peptides, and the potential drug targets for future anti-platelet research.


Assuntos
Complexo Glicoproteico GPIIb-IIIa de Plaquetas , Trombose , Humanos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Abciximab , Tirofibana/farmacologia , Eptifibatida , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Trombose/tratamento farmacológico , Trombose/metabolismo , Transdução de Sinais
3.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 34(11): 1194-1199, 2022 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-36567565

RESUMO

OBJECTIVE: To investigate the role of platelets aggregation in the developing process of ductus arteriosus closure of newborn pups, and the effect of platelet membrane glycoprotein IIb-IIIa (GPIIb-IIIa) receptor antagonist (tirofiban). METHODS: Four 24-month-old Beagle bitches were selected and numbered 1, 2, 3, and 4 respectively, and their pups were removed by cesarean section in two batches 1-2 days before the expected date of delivery. Bitches 1 and 2 were the first batch. Eighteen newborn pups were removed after cesarean section as the control group. They were divided into three subgroups: 1-hour subgroup, 4-hour subgroup, and 12-hour subgroup according to postnatal time point, with 6 pups in each subgroup. The newborn pups were injected with normal saline 10 mL/kg via jugular vein immediately after birth. Bitches 3 and 4 were the second batch. Nineteen newborn pups were removed by cesarean section as tirofiban group. They were also divided into three subgroups: 1-hour subgroup (n = 6), 4-hour subgroup (n = 6), and 12-hour subgroup (n = 7) according to the postnatal time point. The newborn pups were injected with tirofiban hydrochloride injection 10 mL/kg (10 mL injection including 2.5 mg of tirofiban) via jugular vein immediately after birth. The diameter of ductus arteriosus was measured by echocardiography. Ductus arteriosus was removed by surgical dissection and divided into two parts. Western blotting and immunohistochemistry were used to detect the expression of platelet membrane GPIIb-IIIa, respectively. RESULTS: In the control group, 1 newborn pup died at 0.5 hour after birth in the 1-hour subgroup. The experiment was completed by 19 in the tirofiban group. Ductus arteriosus of all pups were not closed in 1-hour subgroups of the two groups, and there was no significant difference in the diameter of ductus arteriosus between the control group and the tirofiban group (mm: 1.72±0.08 vs. 1.70±0.11, P > 0.05). Ductus arteriosus of 1 newborn pup in 4-hour subgroup of the control group was closed, but the ductus arteriosus of all the newborn pups in 4-hour subgroup of the tirofiban group were not closed. The diameter of ductus arteriosus of the tirofiban group was significantly larger than that of the control group (mm: 1.52±0.15 vs. 0.95±0.48, P < 0.05). Ductus arteriosus of all pups were closed in 12-hour subgroup of the control group, but the ductus arteriosus of 2 pups of the tirofiban group were still not closed, with the diameter of ductus arteriosus of 1.0 mm and 1.1 mm, respectively. Western blotting showed that at 1-hour, 4-hour and 12-hour after birth, the expression of platelet membrane GPIIb-IIIa was gradually increased in ductus arteriosus of newborn pups of the two groups. The expression of GPIIb-IIIa in 1-hour subgroup of the tirofiban group was significantly lower than that in the control group (GPIIb-IIIa/ß-actin: 0.67±0.07 vs. 0.84±0.16, P < 0.05). The expression of GPIIb-IIIa in 4-hour and 12-hour subgroups of the tirofiban group were slightly lower than those in the control group (GPIIb-IIIa/ß-action: 0.85±0.12 vs. 0.95±0.11 in 4-hour subgroup, 1.04±0.16 vs. 1.09±0.17 in 12-hour subgroup, both P > 0.05). Immunohistochemistry showed that the change trend of platelet membrane GPIIb-IIIa in ductus arteriosus of newborn pups in both groups was similar to the results of Western blotting. CONCLUSIONS: The ductus arteriosus of newborn pups begin to close 1-4 hours after birth, and all closed at 12 hours after birth. The expression of platelet membrane GPIIb-IIIa in ductus arteriosus increase gradually after birth, and the platelet aggregation may participate in and promote ductus arteriosus closure to some extent. Tirofiban, a platelet membrane GPIIb-IIIa receptor antagonist, may delay ductus arteriosus closure of newborn pups to some extent by inhibiting platelet aggregation.


Assuntos
Canal Arterial , Agregação Plaquetária , Cães , Gravidez , Animais , Feminino , Tirofibana/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Animais Recém-Nascidos , Canal Arterial/metabolismo , Cesárea , Tirosina , Anticorpos Monoclonais/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Plaquetas/metabolismo
4.
Platelets ; 33(8): 1192-1198, 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-35701857

RESUMO

We aimed to investigate the effects of integrin αIIbß3 inhibitor tirofiban on hallmarks of platelet activation, degranulation, and aggregation during its use to analyze activated but non-complexed platelets via flow cytometry. To do so, we used washed platelets from healthy human donors. We combined aggregometry, an assay of platelet functionality, with flow cytometry and ELISA to detect and correlate, respectively, platelet aggregation, activation, and granule release. While tirofiban effectively inhibited agonist-induced platelet aggregation (thrombin receptor-activating peptide 6 (TRAP), convulxin (CVX), U46619 and IV.3), the surface expression of P-selectin and CD63 and granule release of RANTES were significantly increased, indicating that tirofiban enhances degranulation, uncoupled from aggregation. The results show that tirofiban alters the activation phenotype of platelets, something that should be considered when using tirofiban to enable flow cytometric analysis of activated but unaggregated platelet suspensions.


Assuntos
Selectina-P , Complexo Glicoproteico GPIIb-IIIa de Plaquetas , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Plaquetas/metabolismo , Quimiocina CCL5/metabolismo , Quimiocina CCL5/farmacologia , Humanos , Selectina-P/metabolismo , Ativação Plaquetária , Agregação Plaquetária , Inibidores da Agregação Plaquetária/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Receptores de Trombina/metabolismo , Tirofibana/farmacologia , Tirosina/metabolismo , Tirosina/farmacologia
5.
Platelets ; 33(2): 265-272, 2022 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33560898

RESUMO

Platelet glycoprotein IIb/IIIa inhibitors (GPIs) have been part of the adjuvant treatment of acute coronary syndrome for years. However, real-life data regarding the efficacy and safety of GPIs under the current indications are lacking in the setting of potent platelet inhibition. The objectives were to assess the efficacy and safety of abciximab versus tirofiban in patients with ST-elevation acute myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) and pretreated with ticagrelor, and to identify independent predictor factors of efficacy, bleeding and platelet drop. Three hundred sixty-two patients were divided by GPI administered. Clinical, laboratory, angiographic and outcome characteristics were compared. The primary objective was a composite efficacy endpoint (death from any cause, nonfatal myocardial infarction and nonfatal stroke) at 30 days. The secondary objectives were its individual components, safety (bleeding) and the impact on platelet count during hospital stay. The composite efficacy endpoint was similar in the abciximab and tirofiban groups (6.1% vs 7.3%; p = .632). There were also no differences in cardiovascular death (2.5% vs 2.4%; p = .958), nonfatal myocardial infarction (3% vs 4.3%; p = .521) and nonfatal stroke (0.5% vs 1.8%; p = .332). Tirofiban administration was associated with a higher incidence of bleeding (11.6% vs 22%; p = .008) with no differences in BARC ≥ 3b bleeding (3.6 vs 2.5%; p = .760). In STEMI patients undergoing PPCI with ticagrelor, abciximab and tirofiban had similar rates in the composite efficacy endpoint at 30 days. The 30-day bleeding rate was significantly higher in the tirofiban group. Tirofiban administration was an independent predictor of both bleeding and platelet count drop.


Assuntos
Abciximab/uso terapêutico , Intervenção Coronária Percutânea/métodos , Inibidores da Agregação Plaquetária/uso terapêutico , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Ticagrelor/uso terapêutico , Tirofibana/uso terapêutico , Abciximab/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/farmacologia , Infarto do Miocárdio com Supradesnível do Segmento ST/patologia , Ticagrelor/farmacologia , Tirofibana/farmacologia , Resultado do Tratamento
6.
PLoS One ; 16(3): e0247425, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33657162

RESUMO

Platelets can respond to multiple antagonists and agonists, implying that their activation state is a consequence of past exposure to these substances. While platelets are often considered as one-time responsive cells, they likely can respond to sequential application of inhibitors and stimuli. We hypothesized that the ability of platelets to sequentially respond depends on the time and type of repeated agonist application. The present proof-of-concept data show that iloprost (cAMP elevation), tirofiban (integrin αIIbß3 blocker) and Syk kinase inhibition subacutely modulated platelet aggregation, i.e. halted this process even when applied after agonist. In comparison to thrombin-activated receptor (PAR) stimulation, glycoprotein VI (GPVI) stimulation was less sensitive to time-dependent blockage of aggregation, with Syk inhibition as an exception. Furthermore, cytosolic Ca2+ measurements indicated that, when compared to PAR, prior GPVI stimulation induced a more persistent, priming activation state of platelets that influenced the response to a next agent. Overall, these data point to an unexpected priming memory of activated platelets in subacutely responding to another inhibitor or stimulus, with a higher versatility and faster offset after PAR stimulation than after GPVI stimulation.


Assuntos
Plaquetas/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Iloprosta/farmacologia , Glicoproteínas da Membrana de Plaquetas/metabolismo , Receptores de Trombina/metabolismo , Tirofibana/farmacologia , Cálcio/metabolismo , Humanos , Estudo de Prova de Conceito
7.
Thromb Haemost ; 120(11): 1548-1556, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32772348

RESUMO

BACKGROUND: For patients treated with dual antiplatelet therapy, standardized drug-specific 3-to-7 day cessation is recommended prior to major surgery to reach sufficient platelet function recovery. Here we investigated the hypothesis that supplemental fibrinogen might mitigate the inhibitory effects of antiplatelet therapy. METHODS AND RESULTS: To this end blood from healthy donors was treated in vitro with platelet inhibitors, and in vitro thrombus formation and platelet activation were assessed. Ticagrelor, acetylsalicylic acid, the combination of both, and tirofiban all markedly attenuated the formation of adherent thrombi, when whole blood was perfused through collagen-coated microchannels at physiological shear rates. Addition of fibrinogen restored in vitro thrombus formation in the presence of antiplatelet drugs and heparin. However, platelet activation, as investigated in assays of P-selectin expression and calcium flux, was not altered by fibrinogen supplementation. Most importantly, fibrinogen was able to restore in vitro thrombogenesis in patients on maintenance dual antiplatelet therapy after percutaneous coronary intervention. CONCLUSION: Thus, our in vitro data support the notion that supplementation of fibrinogen influences the perioperative hemostasis in patients undergoing surgery during antiplatelet therapy by promoting thrombogenesis without significantly interfering with platelet activation.


Assuntos
Fibrinogênio/farmacologia , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Trombose/prevenção & controle , Idoso , Aspirina/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Feminino , Hemorreologia , Heparina/farmacologia , Hirudinas/farmacologia , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Selectina-P/biossíntese , Selectina-P/genética , Ticagrelor/farmacologia , Tirofibana/farmacologia
8.
Circulation ; 142(5): 441-454, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32795098

RESUMO

BACKGROUND: Standard administration of newer oral P2Y12 inhibitors, including prasugrel or ticagrelor, provides suboptimal early inhibition of platelet aggregation (IPA) in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention. We aimed to investigate the effects of cangrelor, tirofiban, and prasugrel, administered as chewed or integral loading dose, on IPA in patients undergoing primary percutaneous coronary intervention. METHODS: The FABOLUS-FASTER trial (Facilitation Through Aggrastat or Cangrelor Bolus and Infusion Over Prasugrel: A Multicenter Randomized Open-Label Trial in Patients with ST-Elevation Myocardial Infarction Referred for Primary Percutaneous Intervention) is an investigator-initiated, multicenter, open-label, randomized study. A total of 122 P2Y12-naive patients with ST-segment-elevation myocardial infarction were randomly allocated (1:1:1) to cangrelor (n=40), tirofiban (n=40) (both administered as bolus and 2-hour infusion followed by 60 mg of prasugrel), or 60-mg loading dose of prasugrel (n=42). The latter group underwent an immediate 1:1 subrandomization to chewed (n=21) or integral (n=21) tablets administration. The trial was powered to test 3 hypotheses (noninferiority of cangrelor compared with tirofiban using a noninferiority margin of 9%, superiority of both tirofiban and cangrelor compared with chewed prasugrel, and superiority of chewed prasugrel as compared with integral prasugrel, each with α=0.016 for the primary end point, which was 30-minute IPA at light transmittance aggregometry in response to 20 µmol/L adenosine diphosphate. RESULTS: At 30 minutes, cangrelor did not satisfy noninferiority compared with tirofiban, which yielded superior IPA over cangrelor (95.0±8.9 versus 34.1±22.5; P<0.001). Cangrelor or tirofiban were both superior to chewed prasugrel (IPA, 10.5±11.0; P<0.001 for both comparisons), which did not provide higher IPA over integral prasugrel (6.3±11.4; P=0.47), despite yielding higher prasugrel active metabolite concentration (ng/mL; 62.3±82.6 versus 17.1±43.5; P=0.016). CONCLUSIONS: Cangrelor provided inferior IPA compared with tirofiban; both treatments yielded greater IPA compared with chewed prasugrel, which led to higher active metabolite concentration but not greater IPA compared with integral prasugrel. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02978040; URL: https://www.clinicaltrialsregister.eu; EudraCT 2017-001065-24.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Agregação Plaquetária/efeitos dos fármacos , Cloridrato de Prasugrel/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Tirofibana/uso terapêutico , Difosfato de Adenosina/farmacologia , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/sangue , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Aspirina/uso terapêutico , Cateterismo Cardíaco , Comorbidade , Feminino , Coração/fisiopatologia , Humanos , Infusões Intravenosas , Masculino , Mastigação , Pessoa de Meia-Idade , Intervenção Coronária Percutânea , Polimedicação , Cloridrato de Prasugrel/administração & dosagem , Cloridrato de Prasugrel/sangue , Cloridrato de Prasugrel/farmacologia , Modelos de Riscos Proporcionais , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/sangue , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Comprimidos , Tirofibana/administração & dosagem , Tirofibana/sangue , Tirofibana/farmacologia , Resultado do Tratamento
9.
Transfusion ; 60 Suppl 3: S119-S123, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32478898

RESUMO

BACKGROUND: Viscoelastic tests (VETs) are used widely to monitor hemostasis in settings such as cardiac surgery. There has also been renewed interest in cold stored platelets (CSPs) to manage bleeding in this setting. CSPs are reported to have altered hemostatic properties compared to room temperature platelets (RTPs), including activation of GPIIb/IIIa. We investigated whether the functional differences between CSP and RTP affected the performance of the PlateletMapping VET on the TEG 5000 and 6s analyzer. METHOD: Platelet concentrates were divided equally into CSP (stored at 4°C ± 2°C) and RTP (stored at 22°C ± 2°C) fractions. Whole blood was treated to induce platelet dysfunction (WBIPD) by incubating with anti-platelet drugs (1.0 µM ticagrelor and 10 µM aspirin) or by simulating cardiopulmonary bypass. WBIPD samples were then mixed with 20% by volume of CSPs or RTPs to model platelet transfusion before analysis using the PlateletMapping VET. RESULTS: Addition of CSPs to WBIPD increased the PlateletMapping MAFIBRIN and MAADP parameters with the TEG 5000 analyzer (both p < 0.0001 compared to addition of buffer alone). This effect was not observed with RTPs. The differential effect of CSPs on the MAFIBRIN corrected after pre-incubation with the GPIIb/IIIa antagonist tirofiban and was quantitatively less with the PlateletMapping test for the TEG 6s analyzer which contains the GPIIb/IIa antagonist abciximab. DISCUSSION: The PlateletMapping MAFIBRIN and MAADP test results may be misleadingly high with CSPs, particularly with the TEG 5000 analyzer, most likely due to constitutive activation of GPIIb/IIIa on CSPs during storage. TEG PlateletMapping results should be interpreted with caution following CSP transfusion.


Assuntos
Plaquetas/metabolismo , Tromboelastografia/métodos , Remoção de Componentes Sanguíneos , Plaquetas/citologia , Plaquetas/efeitos dos fármacos , Preservação de Sangue , Temperatura Baixa , Humanos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Tromboelastografia/instrumentação , Ticagrelor/farmacologia , Tirofibana/farmacologia
10.
Nanoscale ; 12(7): 4676-4685, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32048702

RESUMO

Platelets play an important role in the early stage of arterial remodeling after injury. Integrin GPIIb/IIIα (αIIbß3) regulates platelet activation in the inside-out and outside-in signaling pathways. The use of tirofiban, an integrin αIIbß3 inhibitor, in clinical therapy is limited by its short in vivo circulation time. Herein, a controlled drug-release system was formulated using CuS@mSiO2-PEG core-shell nanoparticles as near-infrared-triggered nanocarriers to release tirofiban on demand. The nanocarriers possessed good colloidal stability and very high loading efficiency for the integrin αIIbß3 inhibitor (14.5 wt% for tirofiban). Local application of αIIbß3 antagonist-tirofiban on an injured arterial wall inhibited platelet activation, which was accelerated by laser irradiation. Ex vivo platelet-promoted monocyte transmigration trans-well assays revealed decreased monocyte transmigration after platelet activation was inhibited by tirofiban. Two weeks after the wire-induced injury, the intimal area and cellular content were analyzed. The neointimal area was decreased in ApoE-/- mice with CuS@mSiO2-PEG/tirofiban and laser irradiation-promoted tirofiban release, which had limited the neointima formation. The lesions showed a decreased content of macrophages and smooth muscle cells compared with ApoE-/- mice without tirofiban inhibition. Therefore, the action of platelet-integrin αIIbß3 in neointima formation after vascular injury was successfully inhibited in vivo through the controlled release of tirofiban using a near-infrared-triggered nanocarrier, leading to the decrease of early-stage neointima formation. This study also emphasizes the role of platelets in vascular remodeling and provides a new target, namely integrin αIIbß3, for the inhibition of neointimal hyperplasia during vascular inflammation.


Assuntos
Plaquetas/metabolismo , Portadores de Fármacos , Raios Infravermelhos , Nanopartículas , Neointima/tratamento farmacológico , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Tirofibana , Animais , Plaquetas/patologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Camundongos , Camundongos Knockout para ApoE , Nanopartículas/química , Nanopartículas/uso terapêutico , Neointima/metabolismo , Neointima/patologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Células RAW 264.7 , Tirofibana/química , Tirofibana/farmacocinética , Tirofibana/farmacologia
11.
Transplant Proc ; 52(1): 419-422, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31948801

RESUMO

BACKGROUND: In the design and development of small-caliber artificial blood vessels, endothelialization is a key issue, but it is not well understood at present. Some studies have used vascular endothelial growth factor (VEGF) sustained-release methods to promote endothelial cell proliferation. However, this method is not ideal. This study has used drugs to induce endothelial cells to produce VEGF. This method in turn functions to promote cell proliferation and promote the endothelialization of artificial blood vessels. This study aimed to investigate the effect of the antiplatelet drug tirofiban on endothelial cell proliferation in vitro. METHODS: In this study, human umbilical vein endothelial cells (HUVECs) were used to determine the effect of tirofiban-stimulated cell proliferation. Analysis of cell proliferation, assayed by the Cell Counting Kit-8 assay, showed that the number of cells was increasingly higher than in the absence of tirofiban. It was also observed that heparin enhanced the tirofiban effect. The cell VEGF expression at different time points after tirofiban addition was detected by western blot analysis. RESULTS: The absorbance values of the experimental (1 µg/mL tirofiban) and the control groups (0 tirofiban) were 1.74 (SD, 0.03) and 1.51 (SD, 0.07) (P < .001), respectively, after 4 days of culture under the same conditions. The amount of VEGF produced by HUVECs gradually increased after treatment with tirofiban, reached a peak at 2 hours, and was 1.3-fold greater than the control group (P = .034). Compared with the tirofiban-only group, the absorbance value of the tirofiban and 10 µg/mL of heparin group was significantly increased (P < .001). CONCLUSIONS: Tirofiban promoted the proliferation of HUVECs by promoting the synthesis of VEGF in HUVECs. Heparin enhanced tirofiban activity in promoting HUVEC proliferation.


Assuntos
Proliferação de Células/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Tirofibana/farmacologia , Fator A de Crescimento do Endotélio Vascular/biossíntese , Células Cultivadas , Humanos
13.
J Hematol Oncol ; 12(1): 26, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30845955

RESUMO

Integrins are a family of transmembrane glycoprotein signaling receptors that can transmit bioinformation bidirectionally across the plasma membrane. Integrin αIIbß3 is expressed at a high level in platelets and their progenitors, where it plays a central role in platelet functions, hemostasis, and arterial thrombosis. Integrin αIIbß3 also participates in cancer progression, such as tumor cell proliferation and metastasis. In resting platelets, integrin αIIbß3 adopts an inactive conformation. Upon agonist stimulation, the transduction of inside-out signals leads integrin αIIbß3 to switch from a low- to high-affinity state for fibrinogen and other ligands. Ligand binding causes integrin clustering and subsequently promotes outside-in signaling, which initiates and amplifies a range of cellular events to drive essential platelet functions such as spreading, aggregation, clot retraction, and thrombus consolidation. Regulation of the bidirectional signaling of integrin αIIbß3 requires the involvement of numerous interacting proteins, which associate with the cytoplasmic tails of αIIbß3 in particular. Integrin αIIbß3 and its signaling pathways are considered promising targets for antithrombotic therapy. This review describes the bidirectional signal transduction of integrin αIIbß3 in platelets, as well as the proteins responsible for its regulation and therapeutic agents that target integrin αIIbß3 and its signaling pathways.


Assuntos
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Abciximab/farmacologia , Sequência de Aminoácidos , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Eptifibatida/farmacologia , Humanos , Terapia de Alvo Molecular , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/agonistas , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Transdução de Sinais , Tirofibana/farmacologia
14.
J Cardiovasc Transl Res ; 11(3): 201-209, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29696533

RESUMO

An unexpectedly high incidence of thrombosis in patients that received the polylactic acid bioresorbable vascular scaffold (BVS) suggests a delayed/incomplete endothelial repair with this stent. The anti-platelet agent tirofiban stimulates endothelial cell migration and proliferation, mediated by VEGF production. We investigated the tirofiban effect on the migration and adhesion of endothelial cells to BVS, in vitro. We performed human umbilical endothelial cell (HUVEC) cultures in the presence of BVS. Tirofiban, similarly to VEGF, increased the ability of HUVEC to grow on the vascular scaffold, compared to unstimulated or abciximab-treated cells. Tirofiban increased HUVEC expression of ß1 and ß3 integrins along with collagen and fibronectin. A role for ß1 integrin in the "pro-adhesive and -migratory" signals elicited by tirofiban was suggested by use of an anti-ß1-blocking antibody that prevented poly-levo-lactic acid vascular scaffold colonization. Our study suggests that tirofiban may improve the outcomes of patients receiving BVS by accelerating stent endothelization.


Assuntos
Implantes Absorvíveis , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Integrina beta1/metabolismo , Intervenção Coronária Percutânea/instrumentação , Inibidores da Agregação Plaquetária/farmacologia , Poliésteres/química , Reepitelização/efeitos dos fármacos , Stents , Tirofibana/farmacologia , Abciximab/farmacologia , Células Cultivadas , Colágeno/metabolismo , Fibronectinas/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Integrina beta3/metabolismo , Desenho de Prótese , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/farmacologia
15.
Neurosurgery ; 82(3): 268-277, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28472526

RESUMO

Thromboembolic complications remain a major risk of endovascular neurosurgery during the treatment of intracranial aneurysms, despite the use of therapeutic heparinization and oral antiplatelet therapy when indicated. Glycoprotein (GP) IIb/IIIa inhibitors target a nonredundant pathway of platelet aggregation following adhesion and activation. Initially established and implemented in the cardiovascular arena, this drug class has provided a new tool in the neurovascular armamentarium as well. Numerous case reports, case series, and retrospective reviews have evaluated the safety and efficacy of abciximab, eptifibatide, and tirofiban in the treatment of acute thromboembolic complications during the endovascular treatment of intracranial aneurysms. The use of this drug class has also been found to be beneficial as a prophylactic agent, providing ischemia protection during the placement of intracranial stents, flow diverters, and thrombogenic coils in the setting of subarachnoid hemorrhage and during elective aneurysmal embolization. While the current published literature clearly establishes efficacy and safety of GP IIb/IIIa inhibitors in the prevention of thromboembolic complications, there does not yet exist an established protocol for their administration in endovascular neurosurgery. This review provides a comprehensive evaluation of the current published literature pertaining to the use of all available GP IIb/IIIa inhibitors for thromboembolic complications, providing recommendations for dosing and administration of abciximab, eptifibatide, and tirofiban based on previously published rates of efficacy and intracranial hemorrhage.


Assuntos
Embolização Terapêutica/métodos , Procedimentos Endovasculares/métodos , Aneurisma Intracraniano/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Tromboembolia/tratamento farmacológico , Abciximab/farmacologia , Abciximab/uso terapêutico , Animais , Embolização Terapêutica/efeitos adversos , Procedimentos Endovasculares/efeitos adversos , Eptifibatida/farmacologia , Eptifibatida/uso terapêutico , Humanos , Aneurisma Intracraniano/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Estudos Retrospectivos , Tromboembolia/metabolismo , Tirofibana/farmacologia , Tirofibana/uso terapêutico , Resultado do Tratamento
16.
Brain Behav Immun ; 69: 255-263, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29195783

RESUMO

Blood-brain barrier (BBB) disruption, thrombus formation and immune-mediated inflammation are important steps in the pathophysiology of cerebral ischemia-reperfusion injury but are still inaccessible to therapeutic interventions. Recent studies have provided increasing evidence that blocking of platelet glycoprotein (GP) receptor Ib might represent a novel target in treating acute ischemic stroke. This research was conducted to explore the therapeutic efficacy and potential mechanisms of GPIbα inhibitor (anfibatide) in a model of brain ischemia-reperfusion injury in mice. Male mice underwent 90 min of right middle cerebral artery occlusion (MCAO) followed by 24 h of reperfusion. Anfibatide (1, 2, 4 ug/kg) or tirofiban were administered intravenously 1 h after reperfusion. The results showed that anfibatide could significantly reduce infarct volumes, increase the number of intact neuronal cells and improve neurobehavioral function. Moreover, anfibatide could reduce post ischemic BBB damage by attenuating increased paracellular permeability in the ischemia hemisphere significantly. Stroke-induced increases in activity and protein expression of macrophage-1 antigen (MAC-1) and P-selectin were also reduced by anfibatide intervention. Finally, anfibatide exerted antithrombotic effects upon stroke by decreased the number of microthrombi formation. This is the first demonstration of anfibatide's efficacy in protecting the BBB integrity and decreasing neutrophil inflammation response mediated by MAC-1 besides microthrombus formation inhibition in the brain during reperfusion. Anfibatide, as a promising anti-thrombo-inflammation agent, could be beneficial for the treatment of ischemic stroke.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Venenos de Crotalídeos/uso terapêutico , Fibrinolíticos/uso terapêutico , Lectinas Tipo C/uso terapêutico , Complexo Glicoproteico GPIb-IX de Plaquetas/antagonistas & inibidores , Traumatismo por Reperfusão/tratamento farmacológico , Tirofibana/uso terapêutico , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Venenos de Crotalídeos/farmacologia , Fibrinolíticos/farmacologia , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Traumatismo por Reperfusão/metabolismo , Tirofibana/farmacologia
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