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1.
Blood ; 143(22): 2332-2335, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38635764

RESUMO

ABSTRACT: We evaluated the cost-effectiveness of prophylaxis with recombinant von Willebrand factor (rVWF) vs with plasma-derived von Willebrand factor (pdVWF) for patients with severe Von Willebrand disease. We found that rVWF is a cost-saving factor replacement compared with pdVWF across all willingness-to-pay thresholds in the United States.


Assuntos
Análise Custo-Benefício , Proteínas Recombinantes , Doenças de von Willebrand , Fator de von Willebrand , Humanos , Fator de von Willebrand/uso terapêutico , Estados Unidos , Proteínas Recombinantes/uso terapêutico , Proteínas Recombinantes/economia , Doenças de von Willebrand/economia , Feminino , Masculino
2.
Haemophilia ; 30(2): 331-335, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38240020

RESUMO

INTRODUCTION: Joint bleeds are a common and frequent complication associated with hemophilia, increasing the risk of hemophilic arthropathy. It is important to define and characterize the presence of joint complications in mild hemophilia to develop strategies to mitigate disease burden. AIMS: To characterize the prevalence, clinical characteristics of joint bleeds, and risk factors that may lead to hemarthrosis in people with mild hemophilia. METHODS: Following Institutional Review Board approval, a retrospective chart review was conducted for patients with mild hemophilia seen at the Yale Hemophilia Treatment Center or Classical Hematology Program. RESULTS: The medical records of 70 patients were reviewed. Eighty one percent were male and 19 percent were female. Twenty individuals with mild hemophilia had a history of joint bleeding, 13 were traumatic bleeds, 7 were spontaneous. The age of first joint bleed ranged from 4 to 58 years old, with an average age of 20.8-years old. Ten patients developed joint bleeds between the ages of 10 and 20 years old. The most common locations of joint bleeding were the knee (n = 11) and ankle (n = 7). Eight of 70 patients had hepatitis C (HCV), 6 experienced joint bleeding. CONCLUSIONS: In this study, almost one third of patients with mild hemophilia experienced joint bleeding, often without history of trauma. Joint range of motion was abnormal in more than a third of the patients with mild hemophilia regardless. These data highlight the need for ongoing evaluation and characterization of joint health in individuals with mild hemophilia. HIGHLIGHTS: Twenty-nine percent of individuals with mild hemophilia had history of joint bleed. PwH and mild diseases with previous or current hepatitis C had higher likelihood of joint bleeding. Approximately 15% of PwH and mild diseases had abnormal joint examinations without a confirmed history of joint bleeding.


Assuntos
Hemofilia A , Hepatite C , Humanos , Masculino , Feminino , Criança , Adolescente , Adulto Jovem , Adulto , Pré-Escolar , Pessoa de Meia-Idade , Hemofilia A/complicações , Hemartrose/complicações , Estudos Retrospectivos , Prevalência , Hepatite C/complicações
3.
Am J Hematol ; 98(9): E247-E250, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37401660

RESUMO

Prophylactic emicizumab is cost-ineffective in adults with moderate or mild hemophilia A without inhibitors at current pricing. The price of prophylactic emicizumab would need to decrease by >35% to become cost-effective in this patient population.


Assuntos
Anticorpos Biespecíficos , Hemofilia A , Adulto , Humanos , Estados Unidos , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Análise Custo-Benefício , Hemorragia/prevenção & controle , Anticorpos Biespecíficos/uso terapêutico
4.
Eur J Haematol ; 109(5): 519-525, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35871468

RESUMO

OBJECTIVES: We sought to determine risk factors for iv iron infusion-related reactions (IRR), and identify strategies for iron repletion after IRR. METHODS: We conducted a retrospective chart review of patients treated in the classical hematology clinic at Yale Cancer Center (n = 330 consecutive patients) from 2016 to 2021, who received iv ferumoxytol (60.3%), iron sucrose (14.8%), or iron dextran (10.9%). RESULTS: The iv iron IRR was noted in 58 (17.6%) patients, 62.1% of whom had previously tolerated iv iron. The severity of IRR was mild in 22, moderate in 23, and severe in 11 patients. Most (72.4%) patients who experienced IRR tolerated a subsequent iv iron infusion. On multivariable analysis, a history of non-medication allergies was associated with greater odds of IRR (odds ratio [OR] 2.12, 95% confidence interval (CI): 1.16-3.87, p = .01). No patients with type AB blood, and few with type A blood (n = 6), had IRR; compared to type A or AB together, patients with type B (OR 5.00, 95% CI: 1.56-16.06, p = .007) or type O (OR 3.71, 95% CI: 1.44-9.55, p = .007) blood had greater odds of IRR. CONCLUSIONS: This study highlights a possible association of blood type with iv iron IRR; prospective studies with larger patient numbers are warranted to explore this association.


Assuntos
Anemia Ferropriva , Óxido Ferroso-Férrico , Anemia Ferropriva/diagnóstico , Anemia Ferropriva/tratamento farmacológico , Anemia Ferropriva/epidemiologia , Dextranos/uso terapêutico , Óxido de Ferro Sacarado/efeitos adversos , Óxido Ferroso-Férrico/efeitos adversos , Humanos , Ferro/efeitos adversos , Estudos Prospectivos , Estudos Retrospectivos
5.
medRxiv ; 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33469595

RESUMO

Background: Thrombotic complications occur at high rates in hospitalized patients with COVID-19, yet the impact of intensive antithrombotic therapy on mortality is uncertain. Research Question: How does in-hospital mortality compare with intermediate- versus prophylactic-dose anticoagulation, and separately with in-hospital aspirin versus no antiplatelet therapy, in treatment of COVID-19? Study Design and Methods: Using data from 2785 hospitalized adult COVID-19 patients, we established two separate, nested cohorts of patients (1) who received intermediate- or prophylactic-dose anticoagulation ("anticoagulation cohort", N = 1624), or (2) who were not on home antiplatelet therapy and received either in-hospital aspirin or no antiplatelet therapy ("aspirin cohort", N = 1956). Propensity score matching utilizing various markers of illness severity and other patient-specific covariates yielded treatment groups with well-balanced covariates in each cohort. The primary outcome was cumulative incidence of in-hospital death. Results: Among propensity score-matched patients in the anticoagulation cohort (N = 382), in a multivariable regression model, intermediate- compared to prophylactic-dose anticoagulation was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.518 [0.308-0.872]). Among propensity-score matched patients in the aspirin cohort (N = 638), in a multivariable regression model, in-hospital aspirin compared to no antiplatelet therapy was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.522 [0.336-0.812]). Interpretation: In this propensity score-matched, observational study of COVID-19, intermediate-dose anticoagulation and aspirin were each associated with a lower cumulative incidence of in-hospital death.

6.
Am J Hematol ; 96(4): 471-479, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33476420

RESUMO

Thrombotic complications occur at high rates in hospitalized patients with COVID-19, yet the impact of intensive antithrombotic therapy on mortality is uncertain. We examined in-hospital mortality with intermediate- compared to prophylactic-dose anticoagulation, and separately with in-hospital aspirin compared to no antiplatelet therapy, in a large, retrospective study of 2785 hospitalized adult COVID-19 patients. In this analysis, we established two separate, nested cohorts of patients (a) who received intermediate- or prophylactic-dose anticoagulation ("anticoagulation cohort", N = 1624), or (b) who were not on home antiplatelet therapy and received either in-hospital aspirin or no antiplatelet therapy ("aspirin cohort", N = 1956). To minimize bias and adjust for confounding factors, we incorporated propensity score matching and multivariable regression utilizing various markers of illness severity and other patient-specific covariates, yielding treatment groups with well-balanced covariates in each cohort. The primary outcome was cumulative incidence of in-hospital death. Among propensity score-matched patients in the anticoagulation cohort (N = 382), in a multivariable regression model, intermediate- compared to prophylactic-dose anticoagulation was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.518 [0.308-0.872]). Among propensity-score matched patients in the aspirin cohort (N = 638), in a multivariable regression model, in-hospital aspirin compared to no antiplatelet therapy was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.522 [0.336-0.812]). In this propensity score-matched, observational study of COVID-19, intermediate-dose anticoagulation and aspirin were each associated with a lower cumulative incidence of in-hospital death.


Assuntos
Anticoagulantes/administração & dosagem , Aspirina/administração & dosagem , Tratamento Farmacológico da COVID-19 , COVID-19 , Mortalidade Hospitalar , Inibidores da Agregação Plaquetária/administração & dosagem , SARS-CoV-2 , Adulto , Idoso , COVID-19/mortalidade , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
7.
Lancet Haematol ; 7(8): e575-e582, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32619411

RESUMO

BACKGROUND: An important feature of severe acute respiratory syndrome coronavirus 2 pathogenesis is COVID-19-associated coagulopathy, characterised by increased thrombotic and microvascular complications. Previous studies have suggested a role for endothelial cell injury in COVID-19-associated coagulopathy. To determine whether endotheliopathy is involved in COVID-19-associated coagulopathy pathogenesis, we assessed markers of endothelial cell and platelet activation in critically and non-critically ill patients admitted to the hospital with COVID-19. METHODS: In this single-centre cross-sectional study, hospitalised adult (≥18 years) patients with laboratory-confirmed COVID-19 were identified in the medical intensive care unit (ICU) or a specialised non-ICU COVID-19 floor in our hospital. Asymptomatic, non-hospitalised controls were recruited as a comparator group for biomarkers that did not have a reference range. We assessed markers of endothelial cell and platelet activation, including von Willebrand Factor (VWF) antigen, soluble thrombomodulin, soluble P-selectin, and soluble CD40 ligand, as well as coagulation factors, endogenous anticoagulants, and fibrinolytic enzymes. We compared the level of each marker in ICU patients, non-ICU patients, and controls, where applicable. We assessed correlations between these laboratory results with clinical outcomes, including hospital discharge and mortality. Kaplan-Meier analysis was used to further explore the association between biochemical markers and survival. FINDINGS: 68 patients with COVID-19 were included in the study from April 13 to April 24, 2020, including 48 ICU and 20 non-ICU patients, as well as 13 non-hospitalised, asymptomatic controls. Markers of endothelial cell and platelet activation were significantly elevated in ICU patients compared with non-ICU patients, including VWF antigen (mean 565% [SD 199] in ICU patients vs 278% [133] in non-ICU patients; p<0·0001) and soluble P-selectin (15·9 ng/mL [4·8] vs 11·2 ng/mL [3·1]; p=0·0014). VWF antigen concentrations were also elevated above the normal range in 16 (80%) of 20 non-ICU patients. We found mortality to be significantly correlated with VWF antigen (r = 0·38; p=0·0022) and soluble thrombomodulin (r = 0·38; p=0·0078) among all patients. In all patients, soluble thrombomodulin concentrations greater than 3·26 ng/mL were associated with lower rates of hospital discharge (22 [88%] of 25 patients with low concentrations vs 13 [52%] of 25 patients with high concentrations; p=0·0050) and lower likelihood of survival on Kaplan-Meier analysis (hazard ratio 5·9, 95% CI 1·9-18·4; p=0·0087). INTERPRETATION: Our findings show that endotheliopathy is present in COVID-19 and is likely to be associated with critical illness and death. Early identification of endotheliopathy and strategies to mitigate its progression might improve outcomes in COVID-19. FUNDING: This work was supported by a gift donation from Jack Levin to the Benign Hematology programme at Yale, and the National Institutes of Health.


Assuntos
Betacoronavirus/patogenicidade , Transtornos da Coagulação Sanguínea/patologia , Infecções por Coronavirus/complicações , Endotélio Vascular/patologia , Pneumonia Viral/complicações , Doenças Vasculares/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Transtornos da Coagulação Sanguínea/etiologia , Transtornos da Coagulação Sanguínea/metabolismo , COVID-19 , Infecções por Coronavirus/virologia , Estado Terminal , Estudos Transversais , Endotélio Vascular/metabolismo , Feminino , Seguimentos , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/virologia , Prognóstico , SARS-CoV-2 , Doenças Vasculares/etiologia , Doenças Vasculares/metabolismo , Adulto Jovem
8.
Eur J Med Genet ; 63(3): 103740, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31419598

RESUMO

OBJECTIVE: To evaluate the occurrence and estimate the frequency of macrocytosis in Williams-Beuren syndrome (WBS). STUDY DESIGN: Complete blood count (CBC) data from 179 subjects with WBS aged 1-69 were collected, with common parameters assessed for trends. Z-transformed mean corpuscular volume (MCV) was compared with each laboratory's reference range as well as with control data from the National Health and Nutrition Examination Survey (NHANES) 2013-2014 data archives. RESULTS: Just over a third (35%) subjects had at least one recorded incidence of macrocytosis. In comparisons of CBC parameters with an expected population mean, MCV and MCH were greater than, while Hct and RDW were lower than, expected values. The distribution of erythrocyte MCV is shifted to the right in WBS compared to controls, as was the mean value. Despite this, anemia was absent, except in a single medically complex WBS subject. Though there was a paucity of data available of variables that could potentially cause an elevated MCV, no obvious etiology could be elucidated. CONCLUSIONS: Mild macrocytosis without anemia affects a moderate subset of WBS patients, leading to a rightward shift in the MCV distribution curve. Providers encountering isolated mild macrocytosis in WBS can consider observation over further workup.


Assuntos
Índices de Eritrócitos , Doenças Hematológicas/sangue , Síndrome de Williams/sangue , Adolescente , Adulto , Idoso , Anemia , Contagem de Células Sanguíneas , Criança , Pré-Escolar , Estudos de Coortes , Eritrócitos/citologia , Eritrócitos/metabolismo , Feminino , Doenças Hematológicas/metabolismo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Síndrome de Williams/etiologia , Síndrome de Williams/genética , Síndrome de Williams/metabolismo
9.
Artigo em Inglês | MEDLINE | ID: mdl-29428697

RESUMO

OBJECTIVE: The aim of this study was to determine the incidence of bacteremia resulting from dental cleaning and of subsequent established bloodstream infection (BSI) caused by oral microorganisms in patients with cancer with central venous catheters (CVCs). STUDY DESIGN: Twenty-six patients with cancer with CVCs and absolute neutrophil count over 1000 cells/µL received dental cleaning without antibiotic prophylaxis. Periodontal status was assessed at baseline by using the Periodontal Screening and Recording (PSR) score. Blood cultures were drawn via the CVCs at baseline, 20 minutes into cleaning, and 30 minutes and 24 hours after cleaning. Medical records were monitored for 6 months. RESULTS: Baseline blood culture results were negative in 25 patients. Nine of 25 patients (36%) had positive blood culture 20 minutes into cleaning, all associated with at least 1 microorganism typically found in the mouth. These 9 patients had significantly higher mean PSR score (3.22) compared with the other 16 (2.56; P = .035). These expected bacteremias did not persist, with blood culture results (0/25) at 30 minutes and 24 hours after cleaning showing no positivity (P = .001). There were no cases of CVC-related infection or BSI attributable to dental cleaning. CONCLUSIONS: Bacteremia resulting from dental cleaning is transient and unlikely to cause CVC-related infection or BSI in patients with absolute neutrophil count greater than 1000 cells/µL.


Assuntos
Bacteriemia/epidemiologia , Bacteriemia/etiologia , Cateterismo Venoso Central , Profilaxia Dentária/efeitos adversos , Neoplasias/complicações , Antibioticoprofilaxia , Infecções Relacionadas a Cateter/microbiologia , Infecções Relacionadas a Cateter/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice Periodontal , Estudos Prospectivos
10.
Oral Maxillofac Surg Clin North Am ; 28(4): 491-495, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27745619

RESUMO

Thrombophilia or hypercoagulable conditions can be thought of as either inherited or acquired. The inherited disorders include deficiencies of antithrombin, protein C, or protein S or the common disorders of factor V Leiden and prothrombin G20210A gene mutation. All these disorders are inherited as autosomal dominant and predispose individuals primarily to venous thrombosis. Acquired thrombophilic conditions are seen in individuals with cancer, phospholipid antibodies, and a whole host of other conditions that alter endothelial function, change blood levels of coagulant or anticoagulant proteins, activate platelets, or have other effects on coagulation proteins, platelet function, or the endothelium.


Assuntos
Transtornos Herdados da Coagulação Sanguínea/complicações , Transtornos Herdados da Coagulação Sanguínea/genética , Procedimentos Cirúrgicos Bucais , Trombofilia/complicações , Trombofilia/genética , Proteínas Antitrombina/deficiência , Humanos , Mutação , Deficiência de Proteína C/complicações , Deficiência de Proteína C/genética , Deficiência de Proteína S/complicações , Deficiência de Proteína S/genética , Fatores de Risco , Trombose Venosa/etiologia , Trombose Venosa/genética
11.
J Hosp Med ; 11(4): 276-82, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26662851

RESUMO

BACKGROUND: The optimum international normalized ratio (INR) monitoring frequency for hospitalized patients receiving warfarin is unknown. OBJECTIVE: Assess relationship between daily versus less frequent INR monitoring and overanticoagulation and warfarin-related adverse events. DESIGN: Retrospective cohort study using Medicare Patient Safety Monitoring System data. SETTING: Randomly selected acute care hospitals across the United States. PATIENTS: Patients hospitalized from 2009 to 2013 for pneumonia, acute cardiac disease, or surgery who received warfarin. INTERVENTIONS: None. MEASUREMENTS: (1) Association between frequency of INR monitoring and an INR ≥6.0 or warfarin-related adverse event. (2) Association between the rate of change of the INR and a subsequent INR ≥5.0 and ≥6.0. RESULTS: Among 8529 patients who received warfarin for ≥3 days, for 1549 (18.2%) the INR was not measured on 2 or more days. These patients had higher propensity-adjusted odds ratios (ORs) of having a warfarin-associated adverse event (OR: 1.48, 95% confidence interval [CI]: 1.02-2.17) for cardiac patients and surgical patients (OR: 1.73, 95% CI: 1.20-2.48), with no significant association for pneumonia patients. Cardiac and pneumonia patients with 1 day or more without an INR measurement had higher propensity-adjusted ORs of having an INR ≥6.0 (OR: 1.61, 95% CI: 1.07-2.41 and OR: 1.92, 95% CI: 1.36-2.71, respectively). A 1-day increase in the INR of ≥0.9 occurred in 621 patients (12.5%) and predicted a subsequent INR of ≥6.0 (positive likelihood ratio of 4.2). CONCLUSION: Daily INR measurement and recognition of a rapidly rising INR might decrease the frequency of warfarin-associated adverse events in hospitalized patients.


Assuntos
Anticoagulantes/efeitos adversos , Hospitalização , Coeficiente Internacional Normatizado , Dano ao Paciente/prevenção & controle , Varfarina/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Monitoramento de Medicamentos/métodos , Monitoramento de Medicamentos/tendências , Previsões , Parada Cardíaca/induzido quimicamente , Parada Cardíaca/epidemiologia , Hospitalização/tendências , Humanos , Coeficiente Internacional Normatizado/tendências , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/epidemiologia , Medicare/tendências , Pessoa de Meia-Idade , Dano ao Paciente/tendências , Distribuição Aleatória , Estados Unidos/epidemiologia
13.
Acta Haematol ; 128(4): 244-7, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22964848

RESUMO

BACKGROUND: Bortezomib is a novel, first-in-class peptide which reversibly inhibits the proteasome and is Food and Drug Administration approved for the treatment of multiple myeloma, non-Hodgkin lymphoma, Waldenström's macroglobulinemia, and systemic light chain amyloidosis, among others. CASE REPORT: Very few cases of bortezomib-induced cardiotoxicity have been reported in the literature, and most of them have been confounded by the previous use of anthracyclins. We reviewed the case of a 56-year-old woman with a medical history of well-controlled hypertension who was newly diagnosed with International Staging System stage I multiple myeloma. She presented with new symptoms of exertional dyspnea, paroxysmal nocturnal dyspnea, and orthopnea after a 4th cycle of a bortezomib/dexamethasone-based chemotherapy. Clinical examination was consistent with heart failure. 2-D echocardiogram showed an left ventricular ejection fraction of 25%, abnormal wall motion, severe eccentric mitral regurgitation, and moderate pericardial effusion. Coronary angiogram showed normal coronaries, and cardiac magnetic resonance did not show delayed gadolinium enhancement. CONCLUSION: We reviewed the possible mechanisms involved in cardiotoxicity caused by bortezomib, and the diagnostic methods and importance of early identification of this adverse event. Differential diagnoses such as cardiac amyloidosis and viral myocarditis are also discussed. To our knowledge, this is the first case where pericardial effusion and mitral regurgitation were described after bortezomib treatment.


Assuntos
Antineoplásicos/efeitos adversos , Ácidos Borônicos/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/efeitos adversos , Pirazinas/efeitos adversos , Amiloidose/induzido quimicamente , Amiloidose/diagnóstico , Bortezomib , Feminino , Humanos , Pessoa de Meia-Idade , Miocardite/diagnóstico
15.
Chest ; 141(2 Suppl): e495S-e530S, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22315270

RESUMO

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse drug reaction that can lead to devastating thromboembolic complications, including pulmonary embolism, ischemic limb necrosis necessitating limb amputation, acute myocardial infarction, and stroke. METHODS: The methods of this guideline follow the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. RESULTS: Among the key recommendations for this article are the following: For patients receiving heparin in whom clinicians consider the risk of HIT to be > 1%, we suggest that platelet count monitoring be performed every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first) (Grade 2C). For patients receiving heparin in whom clinicians consider the risk of HIT to be < 1%, we suggest that platelet counts not be monitored (Grade 2C). In patients with HIT with thrombosis (HITT) or isolated HIT who have normal renal function, we suggest the use of argatroban or lepirudin or danaparoid over other nonheparin anticoagulants (Grade 2C). In patients with HITT and renal insufficiency, we suggest the use of argatroban over other nonheparin anticoagulants (Grade 2C). In patients with acute HIT or subacute HIT who require urgent cardiac surgery, we suggest the use of bivalirudin over other nonheparin anticoagulants or heparin plus antiplatelet agents (Grade 2C). CONCLUSIONS: Further studies evaluating the role of fondaparinux and the new oral anticoagulants in the treatment of HIT are needed.


Assuntos
Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Medicina Baseada em Evidências , Fibrinolíticos/efeitos adversos , Fibrinolíticos/uso terapêutico , Heparina/efeitos adversos , Heparina/uso terapêutico , Sociedades Médicas , Trombocitopenia/induzido quimicamente , Trombocitopenia/tratamento farmacológico , Trombose/tratamento farmacológico , Quimioterapia Combinada , Humanos , Coeficiente Internacional Normatizado , Contagem de Plaquetas , Fatores de Risco , Trombocitopenia/sangue , Trombocitopenia/diagnóstico , Tromboembolia/sangue , Tromboembolia/induzido quimicamente , Tromboembolia/terapia , Trombose/sangue , Estados Unidos , Vitamina K/antagonistas & inibidores
16.
Adv Ther ; 28(6): 460-72, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21533567

RESUMO

Atrial fibrillation (AF) is well known as one of the leading causes of stroke and systemic embolism. Anticoagulation therapy is recommended in all patients at moderate-to-high risk of stroke. The vitamin K antagonist warfarin has traditionally been used in these patients but presents challenges in dosing and monitoring in these patients. The oral direct thrombin inhibitor dabigatran etexilate (Pradaxa®; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA) was recently approved for use in the US for preventing stroke and systemic embolism in patients with nonvalvular AF. Clinical trials have shown it to reduce the risk of stroke and systemic embolism when compared with warfarin (goal international normalized ratio [INR] 2-3) with a similar risk for severe bleeding. It can be given twice daily, with the dose adjusted for renal function. It does not have any dietary restrictions, has few drug interactions (except involving permeability [P]-glycoprotein [P-gp] agents), and does not require routine laboratory monitoring. Patients may experience significant dyspepsia with its use. Compared with warfarin there is increased risk for gastrointestinal bleeding and perhaps myocardial infarction. Currently, no reversal agent exists for use in situations of overdose or severe bleeding although some strategies have been suggested. Despite its high acquisition cost compared with warfarin, analysis using theoretical models has shown it to be cost-effective. Dabigatran offers a unique alternative to warfarin in patients with nonvalvular AF and can be beneficial in patients requiring anticoagulation therapy.


Assuntos
Antitrombinas/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Benzimidazóis/uso terapêutico , beta-Alanina/análogos & derivados , Fatores Etários , Antitrombinas/efeitos adversos , Antitrombinas/farmacocinética , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Dabigatrana , Interações Medicamentosas , Cardioversão Elétrica , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , beta-Alanina/efeitos adversos , beta-Alanina/farmacocinética , beta-Alanina/uso terapêutico
17.
Blood ; 117(26): 7136-44, 2011 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-21576699

RESUMO

The platelet glycoprotein Ib-IX-V complex (GPIb-IX-IV) is the receptor for VWF and is responsible for VWF-mediated platelet activation and aggregation. Loss of the GPIb-IX-V complex is pathogenic for Bernard-soulier Syndrome (BSS), which is characterized by macrothrombocytopenia and impaired platelet function. It remains unclear how the GPIb-IX-V complex is assembled and whether there is a role for a specific molecular chaperone in the process. In the present study, we report that the assembly of the GPIb-IX-V complex depends critically on a molecular chaperone in the endoplasmic reticulum (ER): gp96 (also known as grp94 and HSP90b1). gp96/grp94 deletion in the murine hematopoietic system results in thrombocytopenia, prolonged bleeding time, and giant platelets that are clinically indistinguishable from human BSS. Loss of gp96/grp94 in vivo and in vitro leads to the concomitant reduction in GPIb-IX complex expression due to ER-associated degradation. We further demonstrate that gp96/grp94 binds selectively to the GPIX subunit, but not to gpIbα or gpIbß. Therefore, we identify the platelet GPIX subunit of the GPIb-IX-V complex as an obligate and novel client of gp96/grp94.


Assuntos
Plaquetas/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Animais , Síndrome de Bernard-Soulier/metabolismo , Síndrome de Bernard-Soulier/fisiopatologia , Tempo de Sangramento , Plaquetas/ultraestrutura , Células da Medula Óssea/metabolismo , Células da Medula Óssea/ultraestrutura , Transplante de Medula Óssea/efeitos adversos , Células Cultivadas , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Inibidores Enzimáticos/toxicidade , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/genética , Hematopoese , Hemorragia/metabolismo , Hemorragia/fisiopatologia , Hemostasia , Megacariócitos/metabolismo , Megacariócitos/ultraestrutura , Camundongos , Camundongos Knockout , Agregação Plaquetária , Subunidades Proteicas/metabolismo , RNA Interferente Pequeno , Trombocitopenia/metabolismo , Trombocitopenia/fisiopatologia , Quimeras de Transplante/metabolismo
18.
J Hematol Oncol ; 3: 40, 2010 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-20977755

RESUMO

BACKGROUND: Heat shock protein 90 (HSP90) inhibitors have emerged as a promising class of anti-cancer drugs in both solid and hematologic malignancies. The HSP90 family includes the cytosolic HSP90 (HSP90AA1), the ER paralogue gp96 (HSP90B1) and the mitochondrial member TRAP1 (HSP90L). We evaluated the in vitro anti-tumor activity and mechanism of action of PU-H71, a novel purine scaffold HSP90 inhibitor in human multiple myeloma cell lines. METHODS: Multiple human myeloma cell lines including cells that are resistant to corticosteroids and bortezimab were treated with PU-H71, followed by analysis of cell viability, cell cycle progression and apoptosis, by flow cytometry and caspase 3 immunoblot. Induction of unfolded protein response was studied by XBP-1 s immunoblot. The role of gp96 was further assessed by small hairpin RNA knockdown of gp96 before treatment with PU-H71. RESULTS: PU-H71 has potent in vitro anti-myeloma activity in both drug-sensitive and drug-resistant cell lines. PU-H71 activates the unfolded protein response and induces caspase-dependent apoptosis. The stable gp96 knockdown human myeloma cell line was found to be more resistant to PU-H71 and other HSP90 inhibitors including 17-AAG and 17-DMAG, even though these cells are more sensitive to conventional anti-myeloma drugs. CONCLUSION: We conclude that PU-H71 is a promising drug for the treatment of myeloma. Our finding further suggests that PU-H71 and the geldanamycin analogues work in part by inhibiting the endoplasmic reticulum gp96 along with the cytosolic HSP90.


Assuntos
Antineoplásicos/farmacologia , Benzodioxóis/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Mieloma Múltiplo/tratamento farmacológico , Purinas/farmacologia , Linhagem Celular Tumoral , Fase G1/efeitos dos fármacos , Humanos , Glicoproteínas de Membrana/fisiologia , Fase S/efeitos dos fármacos , Resposta a Proteínas não Dobradas/efeitos dos fármacos
19.
Nat Commun ; 1: 79, 2010 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-20865800

RESUMO

Cytosolic HSP90 requires multiple cochaperones in folding client proteins. However, the function of gp96 (HSP90b1, grp94), an HSP90 paralogue in the endoplasmic reticulum (ER), is believed to be independent of cochaperones. Here, we demonstrate that gp96 chaperones multiple Toll-like receptors (TLRs), but not TLR3, in a manner that is dependent on another ER luminal protein, CNPY3. gp96 directly interacts with CNPY3, and the complex dissociates in the presence of adenosine triphosphate (ATP). Genetic disruption of gp96-CNPY3 interaction completely abolishes their TLR chaperone function. Moreover, we demonstrate that TLR9 forms a multimolecular complex with gp96 and CNPY3, and the binding of TLR9 to either molecule requires the presence of the other. We suggest that CNPY3 interacts with the ATP-sensitive conformation of gp96 to promote substrate loading. Our study has thus established CNPY3 as a TLR-specific cochaperone for gp96.


Assuntos
Glicoproteínas de Membrana/metabolismo , Chaperonas Moleculares/metabolismo , Receptores Toll-Like/metabolismo , Animais , Cromatografia em Gel , Cromatografia Líquida , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Immunoblotting , Imunoprecipitação , Glicoproteínas de Membrana/genética , Camundongos , Microscopia de Fluorescência , Chaperonas Moleculares/genética , Reação em Cadeia da Polimerase , Ligação Proteica/genética , Ligação Proteica/fisiologia , Dobramento de Proteína , Espectrometria de Massas em Tandem , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/metabolismo , Receptores Toll-Like/química , Receptores Toll-Like/genética , Transdução Genética , Transfecção
20.
J Mol Diagn ; 12(3): 283-91, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20228265

RESUMO

Warfarin is a widely prescribed drug that is difficult to use because of its narrow therapeutic window. Genetic polymorphisms associated with warfarin metabolism have been identified, but the clinical utility of genetic testing in warfarin dosing has not been established. External validation of published algorithms is critical to determine the best prediction for warfarin dosing in prospective trials. We used two independent datasets totaling 1095 patients to evaluate four published algorithms and a simple prediction algorithm developed in this study based on the CYP2C9*2, CYP2C9*3, and VKORC1 -1639 polymorphisms in 150 patients taking warfarin. Predicted warfarin doses were calculated and compared for accuracy with actual maintenance doses. All evaluated pharmacogenetics-based dosing algorithms performed similarly for both datasets. The proportion of variation explained (R(2)) was high (60% to 65%) in the small white-only Connecticut dataset but low (36% to 46%) in the large dataset on a diverse ethnic population from the International Warfarin Pharmacogenetics Consortium (IWPC). When comparing the percentage of patients whose predicted dosage are within 20% of actual, the IWPC algorithm performed the best overall (45.9%) for the two datasets combined while other algorithms performed nearly as well. Because no algorithm could be considered the best for all dosing ranges, it may be important to consider the nature of a local service population in choosing the most appropriate pharmacogenetics-based dosing algorithm.


Assuntos
Farmacogenética/métodos , Varfarina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Sistema Enzimático do Citocromo P-450/genética , Feminino , Genótipo , Humanos , Masculino , Farmacogenética/normas , Polimorfismo Genético/genética , Varfarina/administração & dosagem
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