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Delay from the last intake of drug could be an important and unexplored variable in the biological response to antiplatelet agents after acute coronary syndrome (ACS) discharge. The objective was to define the impact of the delay from P2Y12 blocker intake on the platelet inhibition level. We compared ticagrelor-, prasugrel-, and clopidogrel-treated patients. All consecutive patients, who had been addressed between 2013 and 2014 for ACS, treated with aspirin and a P2Y12 blocker as maintenance dose, were eligible. One month after discharge, blood sample and a questionnaire were proposed to the patient by a nurse blinded to the protocol. On this questionnaire, three questions about name of the drug, regularity of the intakes, and hour of the last intake were collected. The response to antiplatelet therapy was assessed using platelet reactivity index vasodilator-stimulated phosphoprotein (PRI VASP) and % of adenosine-5'-diphosphate-induced aggregation (%ADP).The primary objective of this study was to evaluate the correlation between platelet inhibition and delay from drug intake. We enrolled 474 ACS treated with clopidogrel 75 mg in 182 cases (38% patients), prasugrel in 190 cases (40%), or ticagrelor in 102 patients (22%). We observed a significant correlation between delay from intake and PRI VASP and %ADP for ticagrelor (r = 0.25, p = 0.01; r = 0.21, p = 0.03; respectively). On clopidogrel (r = 0.09, p = 0.24; r = 0.02, p = 0.80; respectively) and prasugrel (r = 0.02, p = 0.82; r = 0.11, p = 0.12 respectively), no correlation exists. In conclusion, ticagrelor, unlike thienopyridines, is associated with a significant correlation between delay from the last intake and platelet inhibition.
Assuntos
Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/tratamento farmacológico , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Receptores Purinérgicos P2Y12/metabolismo , Tempo para o Tratamento , Síndrome Coronariana Aguda/diagnóstico , Idoso , Biomarcadores , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Inibidores da Agregação Plaquetária/uso terapêutico , Testes de Função Plaquetária , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Fatores de Risco , Resultado do TratamentoRESUMO
Leukocyte adhesion deficiency type III is a recently described condition involving a Glanzmann-type bleeding syndrome and leukocyte adhesion deficiency. This was ascribed to a defect of the FERMT3 gene resulting in abnormal expression of kindlin-3, a protein expressed in hematopoietic cells with a major role in the regulation of integrin activation. In this article, we describe a patient with a new mutation of FERMT3 and lack of kindlin-3 expression in platelets and leukocytes. We assayed quantitatively the first steps of kindlin-3-defective leukocyte adhesion, namely, initial bond formation, bond strengthening, and early spreading. Initial bond formation was readily stimulated with neutrophils stimulated by fMLF, and neutrophils and lymphocytes stimulated by a phorbol ester or Mn(2+). In contrast, attachment strengthening was defective in the patient's lymphocytes treated with PMA or Mn(2+), or fMLF-stimulated neutrophils. However, attachment strengthening was normal in patient's neutrophils treated with phorbol ester or Mn(2+). In addition, the patient's T lymphocytes displayed defective integrin-mediated spreading and a moderate but significant decrease of spreading on anti-CD3-coated surfaces. Patient's neutrophils displayed a drastic alteration of integrin-mediated spreading after fMLF or PMA stimulation, whereas signaling-independent Mn(2+) allowed significant spreading. In conclusion, the consequences of kindlin-3 deficiency on ß(2) integrin function depend on both cell type and the stimulus used for integrin activation. Our results suggest looking for a possible kindlin-3 involvement in membrane dynamical event independent of integrin-mediated adhesion.
Assuntos
Plaquetas/metabolismo , Síndrome da Aderência Leucocítica Deficitária/genética , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Proteínas de Neoplasias/deficiência , Proteínas de Neoplasias/genética , Neutrófilos/metabolismo , Sequência de Aminoácidos , Sequência de Bases , Adesão Celular/genética , Separação Celular , Pré-Escolar , Feminino , Citometria de Fluxo , Humanos , Immunoblotting , Integrina alfa2/genética , Integrinas/metabolismo , Síndrome da Aderência Leucocítica Deficitária/metabolismo , Síndrome da Aderência Leucocítica Deficitária/fisiopatologia , Masculino , Dados de Sequência Molecular , Mutação , Linhagem , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Background: Traumatic hemorrhage guidelines include point-of-care viscoelastic tests as a standard of care. Quantra (Hemosonics) is a device based on sonic estimation of elasticity via resonance (SEER) sonorheometry to assess whole blood clot formation. Objectives: Our study aimed to assess the ability of an early SEER evaluation to detect blood coagulation test abnormalities in trauma patients. Methods: We conducted an observational retrospective cohort study with data collected at hospital admission of consecutive multiple trauma patients from September 2020 to February 2022 at a regional level 1 trauma center. We performed a receiving operator characteristic curve analysis to determine the ability of the SEER device to detect blood coagulation test abnormalities. Four values on the SEER device were analyzed: clot formation time, clot stiffness (CS), platelet contribution to CS, and fibrinogen contribution to CS. Results: A total of 156 trauma patients were analyzed. The clot formation time value predicted an activated partial thromboplastin time ratio of >1.5 with an area under the curve (AUC) of 0.93 (95% CI, 0.86-0.99). The AUC of the CS value in detecting an international normalized ratio of prothrombin time of >1.5 was 0.87 (95% CI, 0.79-0.95). The AUC of fibrinogen contribution to CS to detect a fibrinogen concentration of <1.5 g/L was 0.87 (95% CI, 0.80-0.94). The AUC of platelet contribution to CS to detect a platelet concentration of <50 G/L was 0.99 (95% CI, 0.99-1.00). Conclusion: Our results suggest that the SEER device may be useful for the detection of blood coagulation test abnormalities at trauma admission.
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BACKGROUND: Studies have addressed the benefit of tailored therapy based on initial response to clopidogrel loading dose. However, the appropriate timing for platelet testing remains uncertain. METHODS: The present study was performed to compare initial clopidogrel response after 600 mg loading dose and 1-month platelet response and their relationship with ischemic and bleedings events. A total of 475 patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention have been included in the present study. All patients were treated with 600 mg clopidogrel followed by 150 mg daily. Clopidogrel low response was defined by high on-treatment platelet reactivity (HPR) with vasoactive stimulated phosphoprotein >50%, and "hyperresponse," as platelet reactivity index vasoactive stimulated phosphoprotein (PRI VASP) <95th percentile after 600 mg. RESULTS: After 600 mg, 210 patients were identified with HPR (44%), and 23 patients (5%), with hyperresponse (PRI VASP <8%). At 1 month on 150 mg clopidogrel daily, 184 patients (39%) had HPR (39%), 14 patients (3 %) had hyperresponse, and mean PRI VASP was significantly lower (43% ± 19% vs 46% ± 21%, P = .04). At 1 month, among the 210 patients with HPR after 600 mg, 127 (60%) remained, whereas among the 265 patients responders after 600 mg, only 57 (22%) remained with HPR (60% vs 22%, P < .0001). Initial response was significantly associated with risk of stent thrombosis and bleeding complications, whereas 1-month assessment was only linked with bleeding events. CONCLUSION: In conclusion, the present study showed that initial clopidogrel response in patients with acute coronary syndrome is not a reliable predictor of response to maintenance therapy and their values for prediction of clinical outcome are likely to be different.
Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/cirurgia , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária/administração & dosagem , Ticlopidina/análogos & derivados , Idoso , Moléculas de Adesão Celular/efeitos dos fármacos , Moléculas de Adesão Celular/metabolismo , Clopidogrel , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Incidência , Masculino , Proteínas dos Microfilamentos/efeitos dos fármacos , Proteínas dos Microfilamentos/metabolismo , Pessoa de Meia-Idade , Fosfoproteínas/efeitos dos fármacos , Fosfoproteínas/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Período Pós-Operatório , Estudos Prospectivos , Stents , Ticlopidina/administração & dosagem , Resultado do TratamentoRESUMO
Adverses pregnancy outcomes are commonly encountered with autoimmune disease (AID). Although anti-nuclear antibodies (ANA) are often present several years before AID diagnosis, the importance of ANA testing has not been evaluated in this context. The objective of this study was to determine if ANA discovery after obstetrical complications is associated with a diagnosis of AID and improves the prognosis of subsequent pregnancies. All patients presented at the multidisciplinary board meeting (MBM) "Thrombophilia and Pregnancy", whose ANA were discovered after an obstetrical complication, were included in a multicenter descriptive study. All patients were referred to an internal medicine consultation for diagnosis. Data were collected retrospectively by computer chart analysis and updated by phone. A total of 404 patients were included, of which 50 (12.4 %) had a diagnosis of AID related to ANA. Patients with AID had higher ANA levels (p < 0.001), with more frequent specificity (26%, versus 6.7%, p < 0.0001), and more often persistent (84% versus 30.8%, p < 0.0001) compared to patients without AID. Subsequent pregnancy outcomes were not significantly affected by ANA levels and AID diagnoses. Our study shows that the discovery of ANA after obstetrical complications may lead to an early diagnosis of AID. It makes us reconsider the systematic determination of ANA after an obstetrical event because in the case where ANA are found positive, an adapted follow-up would reduce the negative impact of ANA presence on subsequent pregnancies.
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Anticorpos Antinucleares/sangue , Síndrome Antifosfolipídica/diagnóstico , Doenças Autoimunes/diagnóstico , Biomarcadores/sangue , Complicações na Gravidez/diagnóstico , Trombofilia/diagnóstico , Adulto , Anticorpos Antifosfolipídeos/sangue , Feminino , Humanos , Gravidez , Resultado da Gravidez , Estudos RetrospectivosRESUMO
BACKGROUND: The presence of neutrophils in the lung was identified as a factor associated with CLAD but requires invasive samples. The aim of this study was to assess the kinetics of peripheral blood neutrophils after lung transplantation as early predictor of CLAD. METHODS: We retrospectively included all recipients transplanted in our center between 2009 and 2014. Kinetics of blood neutrophils were evaluated to predict early CLAD by mathematical modeling using unadjusted and adjusted analyses. RESULTS: 103 patients were included, 80 in the stable group and 23 in the CLAD group. Bacterial infections at 1 year were associated with CLAD occurrence. Neutrophils demonstrated a high increase postoperatively and then a progressive decrease until normal range. Recipients with CLAD had higher neutrophil counts (mixed effect coefficient beta over 3 years = +1.36 G/L, 95% Confidence Interval [0.99-1.92], p < .001). A coefficient of celerity (S for speed) was calculated to model the kinetics of return to the norm before CLAD occurrence. After adjustment, lower values of S (slower decrease of neutrophils) were associated with CLAD (Odds Ratio = 0.26, 95% Confidence Interval [0.08-0.66], p = .01). CONCLUSION: A slower return to the normal range of blood neutrophils was early associated with CLAD occurrence.
Assuntos
Biologia Computacional/métodos , Rejeição de Enxerto/diagnóstico , Transplante de Pulmão , Modelos Teóricos , Neutrófilos/imunologia , Adulto , Aloenxertos/imunologia , Doença Crônica , Feminino , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos RetrospectivosRESUMO
Antiplatelet therapy through inhibition of the adenosine diphosphate (ADP)/P2Y12 pathway is commonly used in the treatment of acute coronary syndrome (ACS). Although efficient in preventing platelet activation and thrombus formation, it increases the risk of bleeding complications. In patients with ACS receiving platelet aggregation inhibitors, that is, P2Y12 blockers (n = 923), we investigated the relationship between plasma and platelet-associated CD40L levels and bleeding events (n = 71). Treatment with P2Y12 inhibitors in patients with ACS did not affect plasma-soluble CD40L levels, but decreased platelet CD40L surface expression (pCD40L) and platelet-released CD40L (rCD40L) levels in response to stimulation as compared to healthy controls. In vitro inhibition of the ADP pathway in healthy control platelets reduced both pCD40L and rCD40L levels. In a multivariable analysis, the reduced pCD40L level observed in ACS patients was significantly associated with the risk of bleeding occurrence (adjusted odds ratio = 0.15; 95% confidence interval = 0.034-0.67). P2Y12 inhibitor-treated (ticagrelor) mice exhibited a 2.5-fold increase in tail bleeding duration compared with controls. A significant reduction in bleeding duration was observed on CD40L+/+ but not CD40L-/- platelet infusion. In addition, CD40L blockade in P2Y12 inhibitor-treated blood samples from a healthy human reduced thrombus growth over immobilized collagen under arterial flow. In conclusion, measurement of pCD40L may offer a novel approach to assessing bleeding risk in patients with ACS who are being treated with P2Y12 inhibitors.
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Southeast asian ovalocytosis (SAO) is characterized by macro-ovalocytes and ovalo-stomatocytes on blood smear. SAO is common in Malaisia and Papua-New-Guinea where upwards to 40 per cent of the population is affected in some coastal region. Inherited in an autosomal dominant way, illness results from deletion of codons 400-408 in SLC4A1 gene which encodes for band 3 erythrocyte membrane protein. This deletion is responsible for an unusual erythrocyte stiffness and oval shape of the cells on blood smear. Heterozygous carriers are usually asymptomatic whereas homozygous are not viable without an intensive antenatal care. Here, we describe 4 patients diagnosed incidentally by cytogram appearance of the Advia® 2120i (Siemens) representing hemoglobin concentration according to red blood mean cellular volume (GR/VCH).
Assuntos
Células Sanguíneas/patologia , Eliptocitose Hereditária/diagnóstico , Achados Incidentais , Adulto , Citodiagnóstico/métodos , Citodiagnóstico/normas , Eliptocitose Hereditária/sangue , Eliptocitose Hereditária/patologia , Índices de Eritrócitos , Feminino , Testes Hematológicos , Humanos , Masculino , Pessoa de Meia-Idade , Gravidez , Complicações Hematológicas na Gravidez/sangue , Complicações Hematológicas na Gravidez/diagnóstico , Complicações Hematológicas na Gravidez/patologia , Adulto JovemRESUMO
AIM: To investigate whether the interactions of CYP2C19*2 and CYP2C19*17 with smoking are associated with the levels of P2Y12 receptor inhibition and CRP, in on-thienopyridine post-stenting patients. METHODS & RESULTS: At 1-month follow-up, the interactions of smoking and CYP2C19 polymorphisms on the vasodilator-stimulated phosphoprotein - platelet reactivity index (VASP PRI), and CRP were explored in three metabolizing groups (1128 patients) as follow: poor metabolizers (*2 carriers/*17 noncarriers); intermediate metabolizers (*2 carriers/*17 carriers or *2 noncarriers/*17 noncarriers); and ultrarapidmetabolizers (*2 allele noncarriers/*17 carriers). The interactions of metabolizing status and smoking was significant for CRP (p = 0.001) but not for VASP PRI (p = 0.734). CONCLUSION: Interaction between CYP2C19 polymorphisms and smoking modifies on-treatment CRP level of post-stenting, on-thienopyridine patients. This effect seems to be independent to the level of P2Y12 receptor inhibition.
Assuntos
Inflamação/genética , Inibidores da Agregação Plaquetária/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Fumar/genética , Tienopiridinas/uso terapêutico , Idoso , Proteína C-Reativa/genética , Citocromo P-450 CYP2C19/genética , Feminino , Genótipo , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Fosfoproteínas/metabolismo , Inibidores da Agregação Plaquetária/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Stents , Tienopiridinas/efeitos adversos , Vasodilatação/fisiologiaRESUMO
The nature of an inherited platelet disorder was investigated in three siblings affected by severe bleeding. Using whole-exome sequencing, we identified the culprit mutation (cG742T) in the RAS guanyl-releasing protein-2 (RASGRP2) gene coding for calcium- and DAG-regulated guanine exchange factor-1 (CalDAG-GEFI). Platelets from individuals carrying the mutation present a reduced ability to activate Rap1 and to perform proper αIIbß3 integrin inside-out signaling. Expression of CalDAG-GEFI mutant in HEK293T cells abolished Rap1 activation upon stimulation. Nevertheless, the PKC- and ADP-dependent pathways allow residual platelet activation in the absence of functional CalDAG-GEFI. The mutation impairs the platelet's ability to form thrombi under flow and spread normally as a consequence of reduced Rac1 GTP-binding. Functional deficiencies were confined to platelets and megakaryocytes with no leukocyte alteration. This contrasts with the phenotype seen in type III leukocyte adhesion deficiency caused by the absence of kindlin-3. Heterozygous did not suffer from bleeding and have normal platelet aggregation; however, their platelets mimicked homozygous ones by failing to undergo normal adhesion under flow and spreading. Rescue experiments on cultured patient megakaryocytes corrected the functional deficiency after transfection with wild-type RASGRP2. Remarkably, the presence of a single normal allele is sufficient to prevent bleeding, making CalDAG-GEFI a novel and potentially safe therapeutic target to prevent thrombosis.
Assuntos
Transtornos Herdados da Coagulação Sanguínea , Plaquetas , Fatores de Troca do Nucleotídeo Guanina , Hemorragia , Mutação , Agregação Plaquetária/genética , Difosfato de Adenosina/genética , Difosfato de Adenosina/metabolismo , Transtornos Herdados da Coagulação Sanguínea/genética , Transtornos Herdados da Coagulação Sanguínea/metabolismo , Transtornos Herdados da Coagulação Sanguínea/patologia , Plaquetas/metabolismo , Plaquetas/patologia , Linhagem Celular , Feminino , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Guanosina Trifosfato/genética , Guanosina Trifosfato/metabolismo , Hemorragia/genética , Hemorragia/metabolismo , Hemorragia/patologia , Heterozigoto , Homozigoto , Humanos , Masculino , Megacariócitos/metabolismo , Megacariócitos/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Complexo Shelterina , Proteínas de Ligação a Telômeros/genética , Proteínas de Ligação a Telômeros/metabolismoRESUMO
OBJECTIVES: This study was designed to define the hyperresponse to thienopyridine (very low on-treatment platelet reactivity [VLTPR]) as the most predictive threshold value of platelet reactivity index vasodilator-stimulated phosphoprotein (PRI VASP) for the prediction of non-access site-related bleeding events. We also aimed to identify predictors of bleeding and VLTPR in patients treated with thienopyridines. BACKGROUND: New P2Y12 blockers and platelet monitoring has been proposed to optimize platelet inhibition after acute coronary syndromes and improve ischemic outcomes. However, bleeding complications remain the Achilles' heel of antiplatelet therapy, and platelet monitoring could be useful to evaluate this risk. METHODS: A total of 1,542 consecutive patients undergoing coronary stenting for ACS were included in the present study (287 taking clopidogrel 75 mg, 868 taking clopidogrel 150 mg, and 387 taking prasugrel 10 mg). RESULTS: During 6-month follow-up, 9% of patients (n = 139) experienced nonaccess site-related Bleeding Academic Research Consortium bleeding complications. These patients were more often women and nondiabetic and had lower PRI VASP values than others (p < 0.001). Receiver-operating characteristic curve analysis (0.71, p < 0.01) identified a threshold value for VLTPR of PRI VASP ≤10% to predict bleeding events with a sensitivity of 17% and a specificity of 97%. Although prasugrel was the main predictor of VLTPR in the whole population (odds ratio: 10.2, 95% confidence interval: 3.0 to -34.2; p < 0.001), VLTPR was the strongest and independent predictor of bleeding (odds ratio: 4.7, 95% confidence interval: 2.7 to 8.3; p < 0.001). CONCLUSIONS: The present study identified VLTPR (PRI VASP ≤10%) as the strongest predictor of bleeding complications in patients treated with thienopyridines. This marker could be useful for tailored therapy and bleeding prevention.
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Síndrome Coronariana Aguda/terapia , Hemorragia/induzido quimicamente , Intervenção Coronária Percutânea , Piperazinas/efeitos adversos , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/efeitos adversos , Tiofenos/efeitos adversos , Ticlopidina/análogos & derivados , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Biomarcadores/sangue , Moléculas de Adesão Celular/sangue , Clopidogrel , Trombose Coronária/sangue , Trombose Coronária/etiologia , Trombose Coronária/prevenção & controle , Resistência a Medicamentos , Feminino , Hemorragia/sangue , Hemorragia/prevenção & controle , Humanos , Modelos Logísticos , Masculino , Proteínas dos Microfilamentos/sangue , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Intervenção Coronária Percutânea/efeitos adversos , Fosfoproteínas/sangue , Fosforilação , Testes de Função Plaquetária , Cloridrato de Prasugrel , Estudos Prospectivos , Curva ROC , Medição de Risco , Fatores de Risco , Ticlopidina/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
The present study was performed to compare the influence of cytochrome P459 2C19 (CYP2C19) *2 and *17 genetic variants on the platelet response to clopidogrel and prasugrel maintenance therapy and to assess the relation between platelet reactivity and bleeding complications. A total of 730 patients were included (517 patients treated with clopidogrel 150 mg/day and 213 discharged with prasugrel 10 mg). Platelet reactivity was assessed at 1 month with the platelet reactivity index vasodilator-stimulated phosphoprotein (PRI VASP). High on-treatment platelet reactivity was defined as PRI VASP >50% and low on-treatment platelet reactivity (LTPR) as PRI VASP <20%. The patients were classified according to their genotypes as poor metabolizers (*2/non *17), intermediate metabolizers (*2/*17 or non *2/non *17) and ultrametabolizers (non *2/*17). At 1 month, the prasugrel response was significantly better than the clopidogrel response in all groups of patients, with a lower incidence of high on-treatment platelet reactivity but a greater incidence of LTPR, regardless of the genetic variants. The genetic distribution had a significant effect on the mean PRI VASP values, the incidence of high on-treatment platelet reactivity, and LTPR with both clopidogrel and prasugrel (p <0.05 for all). LTPR identified a group of patients at a greater risk of bleeding (odds ratio 4.8, 95% confidence interval 2.7 to 8.3; p <0.0001). In conclusion, the present study showed that both clopidogrel and prasugrel have genetic modulation by CYP2C19 *2 and *17 alleles and that prasugrel provides greater platelet inhibition, regardless of the genotypes. In addition, LTPR was associated with a greater risk of bleeding.
Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/genética , Hidrocarboneto de Aril Hidroxilases/genética , Plaquetas/efeitos dos fármacos , Hemorragia/genética , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/genética , Piperazinas/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Tiofenos/uso terapêutico , Ticlopidina/análogos & derivados , Síndrome Coronariana Aguda/metabolismo , Alelos , Moléculas de Adesão Celular , Clopidogrel , Citocromo P-450 CYP2C19 , Feminino , Variação Genética , Genótipo , Humanos , Masculino , Proteínas dos Microfilamentos , Pessoa de Meia-Idade , Infarto do Miocárdio/metabolismo , Fosfoproteínas , Piperazinas/administração & dosagem , Reação em Cadeia da Polimerase , Cloridrato de Prasugrel , Estudos Prospectivos , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Fatores de Risco , Tiofenos/administração & dosagem , Ticlopidina/administração & dosagem , Ticlopidina/uso terapêutico , Resultado do TratamentoRESUMO
INTRODUCTION: Inter-individual variability in clopidogrel responsiveness is dependent on genetic polymorphisms. We aimed to investigate the impact of 3 genetic polymorphisms involved in clopidogrel metabolism on a strategy of dose-adjustment according to platelet reactivity (PR) monitoring. MATERIAL AND METHODS: [corrected] This prospective multicenter study enrolled 498 ACS patients undergoing PCI. PR was measured using the Vasodilator-Stimulated Phosphoprotein index (VASP) and a cut-off value of ≥50% defined high on-treatment platelet reactivity (HTPR). Genetic polymorphisms of cytochrome (CYP) 2C19, Paraxonase-1 (PON1) and ABCB1 were determined by allele specific PCR. Dose-adjustment was performed using up-to 3 additional loading doses (LD) of 600mg clopidogrel in order to obtain a VASP <50% in patients with HTPR following the first LD. RESULTS: CYP 2C19 2*polymorphism (p=0.02), but neither PON1 (p=0.8) nor ABCB1 genotype (p=0.9), was significantly associated with HTPR. The dose-adjustment strategy failed in 11% of patients. ABCB1 polymorphism was significantly associated with a failed dose-adjustment (FDA) (p=0.04). No relation was found between the other genotypes and the efficacy of LD adjustment. In multivariate analysis, BMI and ABCB1 polymorphism were the only factors significantly associated with FDA (p=0.005 and p=0.04 respectively). CONCLUSION: While CYP 2C19 2* is associated with HTPR after 600mg of clopidogrel, ABCB1 is responsible for the failure of a strategy of loading dose-adjustment according to PR monitoring. These findings may help to define a therapeutic strategy to optimize anti-platelet therapy in ACS patients undergoing PCI.
Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Plaquetas/efeitos dos fármacos , Inibidores da Agregação Plaquetária/administração & dosagem , Polimorfismo Genético , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Ticlopidina/análogos & derivados , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Síndrome Coronariana Aguda/genética , Síndrome Coronariana Aguda/metabolismo , Idoso , Hidrocarboneto de Aril Hidroxilases/genética , Arildialquilfosfatase/genética , Plaquetas/metabolismo , Moléculas de Adesão Celular/metabolismo , Clopidogrel , Citocromo P-450 CYP2C19 , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Masculino , Proteínas dos Microfilamentos/metabolismo , Pessoa de Meia-Idade , Fosfoproteínas/metabolismo , Inibidores da Agregação Plaquetária/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Antagonistas do Receptor Purinérgico P2Y/metabolismo , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2Y12/metabolismo , Ticlopidina/administração & dosagem , Ticlopidina/metabolismo , Ticlopidina/farmacologiaRESUMO
OBJECTIVES: The present study was designed to assess the effect of genetic variants on chronic biological response to prasugrel and bleeding complications. BACKGROUND: CYP2C19*2 loss-of-function allele and CYP2C19*17 gain-of-function allele have been linked with response to clopidogrel, but preliminary data did not show any significant influence of these alleles on prasugrel effect. METHODS: A total of 213 patients undergoing successful coronary stenting for acute coronary syndrome and discharged with prasugrel 10 mg daily were included. Prasugrel response was assessed at 1 month with the platelet reactivity index (PRI) vasodilator-stimulated phosphoprotein (VASP) and high on-treatment platelet reactivity (HTPR) defined as PRI VASP > 50% and hyper-response as PRI VASP <75th percentile (PRI VASP < 17%). CYP2C19*2 and CYP2C19*17 genotyping were performed. RESULTS: Carriers of loss-of-function *2 allele had significantly higher PRI VASP than noncarriers (33 ± 15% vs. 27 ± 14%, p = 0.03) and higher rate of HTPR (16% vs. 4%, p = 0.01). Conversely, carriers of *17 gain-of-function allele had significantly lower PRI VASP than noncarriers (25 ± 13% vs. 31 ± 15%, p = 0.03, p = 0.03), lower rate of HTPR (1% vs. 10%, p = 0.02), higher rate of hyper-response (34% vs. 21%, p = 0.02), and higher rate of bleeding complications than noncarriers: 23% versus 11%, (odds ratio [95% confidence interval]: 2.5 [1.2 to 5.4]; p = 0.02). No significant influence of genotypes on platelet reactivity assessed by adenosine diphosphate-induced platelet aggregation was observed. CONCLUSIONS: The present study shows a significant influence of CYP2C19*2 and *17 alleles on response to chronic treatment by prasugrel 10 mg daily and occurrence of bleeding complications.
Assuntos
Síndrome Coronariana Aguda/cirurgia , Alelos , Hidrocarboneto de Aril Hidroxilases/genética , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Hemorragia/induzido quimicamente , Hemorragia/genética , Piperazinas/uso terapêutico , Complicações Pós-Operatórias/induzido quimicamente , Complicações Pós-Operatórias/genética , Tiofenos/uso terapêutico , Citocromo P-450 CYP2C19 , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Piperazinas/farmacologia , Cloridrato de Prasugrel , Estudos Prospectivos , Fatores de Risco , Tiofenos/efeitos adversos , Tiofenos/farmacologiaRESUMO
Specific data about the clopidogrel response in elderly patients are lacking. The present study was performed to compare the platelet reactivity and clopidogrel response between patients aged > 75 years and < 75 years undergoing percutaneous coronary intervention for non-ST-segment elevation acute coronary syndrome. A total of 689 patients were enrolled, including 162 patients aged > 75 years and 527 younger patients. All patients received a loading dose of 600 mg clopidogrel followed by 150 mg/day. Post-treatment platelet reactivity was assessed by adenosine diphosphate 10 µmol/L-induced platelet aggregation and the specific pharmacologic response to clopidogrel by the platelet reactivity index vasoactive stimulated phosphoprotein. High post-treatment platelet reactivity was defined as adenosine diphosphate 10 µmol/L-induced platelet aggregation >70%. Clinical events were recorded during 1 month of follow-up. The patients > 75 years old had a greater rate of both ischemic and bleeding complications (p = 0.04 and p = 0.03, respectively). The post-treatment platelet reactivity in response to both the loading and the maintenance clopidogrel dose was greater in patients > 75 years old than in the younger patients: 50 ± 17% versus 45 ± 17% (p = 0.002) and 57 ± 15% versus 53 ± 16% (p = 0.0005), respectively. The rate of high post-treatment platelet reactivity was significantly greater in patients aged > 75 years after 600 mg and 150 mg clopidogrel: 14% versus 9% (p = 0.04) and 23% versus 15% (p = 0.02), respectively. In contrast, the pharmacologic response to clopidogrel was not impaired in patients > 75 years after loading and maintenance doses: 43 ± 21% versus 46 ± 21% (p = 0.17) and 38 ± 18% versus 39 ± 18% (p = 0.55), respectively. In conclusion, patients aged > 75 years have an impaired prognosis after acute coronary syndrome. They display greater post-treatment platelet reactivity. However, this greater platelet reactivity does not seem to be related to an impaired specific response to clopidogrel.
Assuntos
Síndrome Coronariana Aguda/terapia , Angioplastia Coronária com Balão , Inibidores da Agregação Plaquetária/administração & dosagem , Agregação Plaquetária/efeitos dos fármacos , Ticlopidina/análogos & derivados , Síndrome Coronariana Aguda/epidemiologia , Difosfato de Adenosina , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Aspirina/administração & dosagem , Clopidogrel , Resistência a Medicamentos , Seguimentos , Hemorragia/epidemiologia , Humanos , Pessoa de Meia-Idade , Isquemia Miocárdica/epidemiologia , Estudos Prospectivos , Recidiva , Stents , Ticlopidina/administração & dosagemAssuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Plaquetas/efeitos dos fármacos , Doença da Artéria Coronariana/tratamento farmacológico , Uso Off-Label , Piperazinas/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Tiofenos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cloridrato de PrasugrelAssuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Substituição de Medicamentos , Piperazinas/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Tiofenos/uso terapêutico , Ticlopidina/análogos & derivados , Síndrome Coronariana Aguda/cirurgia , Clopidogrel , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea , Piperazinas/efeitos adversos , Cloridrato de Prasugrel , Estudos Prospectivos , Tiofenos/efeitos adversos , Ticlopidina/efeitos adversos , Ticlopidina/uso terapêutico , Resultado do TratamentoRESUMO
Clostridium difficile pathogenicity is mediated mainly by its A and B toxins, but the colonization process is thought to be a necessary preliminary step in the course of infection. The aim of this study was to characterize the Cwp84 protease of C. difficile, which is highly immunogenic in patients with C. difficile-associated disease and is potentially involved in the pathogenic process. Cwp84 was purified as a recombinant His-tagged protein, and specific antibodies were generated in rabbits. Treatment of multiple-band-containing eluted fractions with a reducing agent or with trypsin led to accumulation of a unique protein species with an estimated molecular mass of 61 kDa, corresponding most likely to mature autoprocessed Cwp84 (mCwp84). mCwp84 showed concentration-dependent caseinolytic activity, with maximum activity at pH 7.5. The Cwp84 activity was inhibited by various cysteine protease inhibitors, such as the specific inhibitor E64, and the anti-Cwp84-specific antibodies. Using fractionation experiments followed by immunoblot detection, the protease was found to be associated with the S-layer proteins, mostly as a nonmature species. Proteolytic assays were performed with extracellular matrix proteins to assess the putative role of Cwp84 in the pathogenicity of C. difficile. No degrading activity was detected with type IV collagen. In contrast, Cwp84 exhibited degrading activity with fibronectin, laminin, and vitronectin, which was neutralized by the E64 inhibitor and specific antibodies. In vivo, this proteolytic activity could contribute to the degradation of the host tissue integrity and to the dissemination of the infection.