RESUMO
Recent reports have raised concerns regarding potential risk factors for inhibitor development. In Israel, all haemophilia patients (n = 479) are followed by the National Hemophilia Center. Most children are neonatally exposed to factor concentrate (due to circumcision performed at the age of 8 days). The impact of early exposure and recombinant FVIII products (rFVIII) administration (approved in Israel since 1996) upon inhibitor occurrence in our cohort of haemophilia A (HA) patients was analysed. Two hundred ninety-two consecutive paediatric cases with a first symptomatic onset of HA were enrolled and followed over a median time of 7 years [min-max: 9 months to 17 years]. Study endpoint was inhibitor development against factor VIII. In addition, the treatment regimens applied, i.e. bolus administration or 'continuous infusion' and the family history of inhibitor development were investigated. During the follow-up period 31/292 children (10.6%) developed high titre inhibitors. Inhibitors occurred in 14/43 (32.5%) HA patients neonatally exposed to rFVIII, as compared to 22/249 previously treated with Plasma Derived (PD) products (8.8%). The odds ratio for inhibitor formation in rFVIII treated HA patients was 3.43 (95% CI: 1.36-8.65). Transient inhibitor evolved among 2/43 paediatric HA patients, only among those treated with rFVIII. The risk of inhibitor detection significantly increased among HA children treated by continuous infusion (P = 0.025). Our experience shows that the risk of inhibitor formation may be increased by early exposure to recombinant concentrates. The multiple variables affecting inhibitor incidence deserve further attention by larger prospective studies.
Assuntos
Autoanticorpos/sangue , Inibidores dos Fatores de Coagulação Sanguínea/metabolismo , Fator VIII/efeitos adversos , Hemofilia A/tratamento farmacológico , Hemofilia A/imunologia , Proteínas Recombinantes/efeitos adversos , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Fator VIII/uso terapêutico , Feminino , Humanos , Lactente , Israel , Masculino , Proteínas Recombinantes/uso terapêuticoRESUMO
Severe FXI deficiency is a rare injury-related bleeding disorder. In patients with FXI inhibitors, surgeries may be treated using recombinant activated factor VII; however, treatment safety is a major concern and the best dosing regimen as well as mode of administration is still to be defined. We describe four patients with severe factor XI deficiency and inhibitors to FXI, undergoing eight (four major) surgical procedures treated with continuous infusion of rFVIIa. Following acute MI that evolved after surgery of our first patient, all other patients were treated with low-dose bolus rFVIIa followed by low-dose continuous infusion of rFVIIa. Haemostasis was successfully achieved and no further thrombotic complications occurred. To support our clinical results ex-vivo thromboelastography studies were performed, demonstrating the differences of clot formation and lysis between patients with FXI deficiency and healthy controls and suggesting that low-dose rFVIIa corrects coagulation similarly to high-dose rFVIIa in FXI deficiency. Recombinant FVIIa at low doses may effectively induce haemostasis and seems to be a safe treatment mode in patients with FXI deficiency and inhibitors undergoing surgeries.
Assuntos
Inibidores dos Fatores de Coagulação Sanguínea/administração & dosagem , Fator VIIa/administração & dosagem , Deficiência do Fator XI/tratamento farmacológico , Hemostáticos/administração & dosagem , Complicações Pós-Operatórias/prevenção & controle , Hemorragia Pós-Operatória/prevenção & controle , Protocolos Clínicos , Relação Dose-Resposta a Droga , Esquema de Medicação , Deficiência do Fator XI/complicações , Hemostasia Cirúrgica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/tratamento farmacológico , Hemorragia Pós-Operatória/tratamento farmacológico , Proteínas Recombinantes/administração & dosagemRESUMO
Bolus injection (BI) of sucrose-formulated recombinant factor VIII (rFVIII-FS) is an approved treatment for haemophilia patients undergoing major surgery. Continuous infusion (CI) during surgery has potential benefits by providing steady administration of replacement factor to the patient, avoiding high peaks and low troughs. We tested the stability of rFVIII-FS under CI conditions and conducted a single-centre, open-label, phase III study to evaluate the efficacy and safety of CI using rFVIII-FS in haemophilia A patients undergoing surgery. Patients received bolus rFVIII-FS to achieve >or=80% FVIII levels 30-60 min presurgery, followed by CI of rFVIII-FS at a rate calculated to maintain haemostatic factor levels until days 8-10 post surgery. The rate of infusion was adjusted according to daily calculations derived from the actual clearance. The stability of rFVIII-FS was found to be appropriate for CI for 7 days under the same conditions as clinical settings. Fourteen patients (mean age 37.8 years) receiving on-demand FVIII treatment without a history of inhibitors underwent 15 surgical procedures including joint replacements, synovectomies, multiple tooth extractions, and cholecystectomy. Bleeding was similar to that observed in non-haemophilia patients undergoing similar operations in the same department. Haemostasis during surgery was considered by the attending surgeons as 'excellent' or 'good' in all cases; study investigators rated all 15 cases as 'excellent' overall. There were no adverse events, including inhibitor formation, related to rFVIII-FS. rFVIII-FS was found to be suitable for use in CI in haemophilia A patients undergoing major surgery.
Assuntos
Inibidores dos Fatores de Coagulação Sanguínea/uso terapêutico , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemostasia/efeitos dos fármacos , Hemostáticos/uso terapêutico , Sacarose/uso terapêutico , Adulto , Fator VIII/farmacocinética , Hemofilia A/cirurgia , Hemostáticos/farmacocinética , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Hemorragia Pós-Operatória/tratamento farmacológico , Cuidados Pré-Operatórios , Sacarose/farmacocinética , Resultado do TratamentoRESUMO
Non-invasive biomarkers have gained popularity for estimating fibrosis stage. In our hepatitis C-infected haemophilia patients, Fibrotest (FT) correctly identified clinically advanced or minimal liver disease. More accurate tests, like the FibroMeters, have recently been validated. The aim of the study was to improve the estimation of liver fibrosis in hepatitis C-infected haemophiliacs using a combination of biomarkers and FibroMeters. One hundred and thirty-two hepatitis C-infected haemophilia patients (124 male, mean age: 39+/-14 years) were evaluated. The following biomarkers were used: FT, AST-to-platelet ratio index (APRI), Forns index, hyaluronic acid and FibroMeter. We applied a published algorithm suggesting that if FT is in concordance with APRI and/or Forns score, then the FT concurs with liver biopsy for estimation of fibrosis. Concordance of three or more biomarkers was present in 43.2% (57/132) of the patients. This high discordance rate was mainly because of indeterminate scores. Significant fibrosis (F2-F4) was estimated at 34.8% (46/132) and 37.9% (50/132) by the FT and FibroMeter respectively. The discordance rate between the FT and FibroMeter was 16.7% (22/132), (P<0.01 vs. other biomarkers). Using the algorithm, liver histology could be confidently estimated in 69.7% (92/132) of the patients. Concordance between the FT and FibroMeter in those patients who met the terms of the algorithm was 90.2% (83/92). Discordance between biomarkers is significant, and is mainly because of biomarkers with indeterminate results. The concordance rate between FT and FibroMeter is higher compared with the other biomarkers. Practical combination of tests may potentially limit the need of liver biopsy in the majority of haemophilia patients.
Assuntos
Biomarcadores/análise , Hemofilia A/complicações , Hepatite C Crônica/sangue , Cirrose Hepática/diagnóstico , Adulto , Algoritmos , Progressão da Doença , Métodos Epidemiológicos , Humanos , Cirrose Hepática/virologia , Masculino , Valor Preditivo dos Testes , Carga ViralRESUMO
Liver biopsy remains the gold standard for the evaluation of fibrosis despite its risks and limitations, especially in haemophilia patients. Recently, non-invasive biomarkers have been used to assess histological features. The most thoroughly evaluated biomarker is the FibroTest (FT) (AUROC 0.80 for fibrosis stages F2F3F4 vs. F0F1). To estimate liver fibrosis in haemophilia patients infected with hepatitis C (HCV) using non-invasive biomarkers without liver biopsy. One hundred and thirty-two haemophilia patients (124 male, mean age 38 +/- 14 years) with anti-HCV antibodies were evaluated. These patients were stratified into several groups: patients with features of advanced liver disease - seven, persistently HCV RNA-negative - 21, persistently normal liver function tests (LFTs)- 24, HCV/HIV co-infected - 27. The following biomarkers of fibrosis were used: FT, AST-to-platelet ratio index (APRI), Forns index, age-platelet index and hyaluronic acid. The obtained scores were correlated with the clinical features of the patients. Estimated by the FT, the distribution of the stage of fibrosis in the 132 patients was F0F1 = 65% (86/132), F2 = 5% (7/132), F3 = 13% (17/132) and F4 = 17% (22/132). Using FT, all patients with clinical suspicion of advanced liver disease were classified as F3F4, whereas patients with persistently HCV RNA-negative were all classified as F0F1. Twenty-one per cent (5/24) of the patients with persistently normal LFTs had fibrosis stage F3F4. The proportion of F3F4 among HCV/HIV co-infected patients was significantly higher than among HCV mono-infected (52% vs. 33%; P = 0.05). Concordance of three or more biomarkers was present in 43% (57/132) of the patients. Liver biopsy could be avoided in 70% (92/132) using a practical assumption that if FT is in concordance with APRI and/or Forns, then we may confidently rely on the biomarker. Concordance rate for patients with presumably advanced or minimal liver disease was excellent (100% and 95% respectively). In our HCV-infected haemophilia patients, FT correctly identified clinically advanced or minimal liver disease. Discordance among the various biomarkers of fibrosis was considerate; nevertheless, practical combination of FT, APRI, and Forns may predict stage of fibrosis with accuracy, potentially avoiding liver biopsy in the majority of the patients.
Assuntos
Hemofilia A/complicações , Hepatite C Crônica/complicações , Cirrose Hepática/diagnóstico , Adulto , Biomarcadores/sangue , Biópsia , Transtornos Herdados da Coagulação Sanguínea/complicações , Contraindicações , Feminino , Humanos , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Índice de Gravidade de DoençaRESUMO
Haemophilia patients who received non-virucidally treated large pool clotting factors before 1987 have a high rate of chronic hepatitis C viral infection (HCV). Some patients are coinfected with HIV. Haemophilia patients and other coagulation disorders were treated at one centre since the beginning of the 1970, and the Israeli National Hemophilia Center (INHC) was officially founded in 1987. To characterize patients with HCV as well as patients with HCV/HIV coinfection at the INHC. Patients with haemophilia and other coagulation disorders positive for HCV antibodies were evaluated between 2001 and 2004. Demographic data, type and severity of coagulation disorder, frequency of coagulation factor usage and treatment with concentrated clotting factors prior to 1987 were recorded. Liver enzymes, viral load, genotype and data supporting advanced liver disease were evaluated. About 179 of 239 haemophilia patients (75%) tested positive for anti-HCV antibodies. Our cohort consisted of 165 patients in whom clinical, biochemical and virological data were available. About 117 patients had active HCV infection with HCV-RNA-positive, and 27 were HCV/HIV coinfected. Twenty-one patients (13%) persistently tested HCV-RNA-negative, hence were considered to clear their HCV infection. There was no former USSR immigrants among HCV/HIV coinfected compared with HCV-infected or HCV-RNA-negative groups (0 vs. 30% and 38%, respectively; P < 0.001). HCV-RNA-negative patients used concentrated coagulation factor less frequently than HCV or HCV/HIV-infected patients (48% vs. 73%; P = 0.023, and 48% vs. 74%; P = 0.043, respectively). The use of concentrated clotting factors before 1987 was significantly more frequent in HCV/HIV than in either HCV-infected or HCV-RNA-negative patients (96% vs. 49% and 48%, respectively; P < 0.001). Compared with HCV/HIV subjects, patients with HCV monoinfection were characterized by a higher proportion of infection with genotype 1 (80% vs. 61%; P = 0.027). The rate of persistently normal liver enzymes in these patients was higher (24% vs. 7%; P = 0.05) than in the HCV/HIV-coinfected patients. Advanced liver disease was significantly more common in patients with HCV/HIV-coinfection than in HCV-monoinfected patients (11% vs. 3%; P = 0.045). The majority of haemophilia patients are infected with HCV. Viral clearance occurred in a minority of these patients. HCV monoinfected and HCV/HIV coinfected differ clinically and prognostically.
Assuntos
Transtornos da Coagulação Sanguínea/imunologia , Hemofilia A/imunologia , Adolescente , Adulto , Idoso , Anticorpos Antivirais/análise , Terapia Antirretroviral de Alta Atividade/métodos , Transtornos da Coagulação Sanguínea/mortalidade , Transtornos da Coagulação Sanguínea/virologia , Estudos de Coortes , Genótipo , Infecções por HIV/imunologia , Infecções por HIV/mortalidade , Infecções por HIV/virologia , Hemofilia A/mortalidade , Hemofilia A/virologia , Hepatite C Crônica/imunologia , Hepatite C Crônica/mortalidade , Hepatite C Crônica/virologia , Humanos , Israel/epidemiologia , Hepatopatias/complicações , Hepatopatias/imunologia , Hepatopatias/virologia , Pessoa de Meia-Idade , Prognóstico , RNA Viral/análise , Carga ViralRESUMO
BACKGROUND: Glanzmann thrombasthenia (GT) is an autosomal recessive bleeding disorder characterized by lack of platelet aggregation induced by most agonists. The disease is caused by mutations in either alpha(IIb)[glycoprotein (GP) IIb] or beta(3) (GPIIIa) genes that lead to a lack or dysfunction of the integrin alpha(IIb)beta(3) which serves as a fibrinogen receptor. PATIENTS: Mucocutaneous bleeding manifestations and platelet dysfunction consistent with GT were observed in three members of a Cypriot family: a 3-year-old proband, her father and her paternal uncle. OBJECTIVE: To determine the molecular basis of GT in this family and to characterize possible biochemical and structural defects. RESULTS: Analysis of the patients' platelets by fluorescence-activated cell sorting demonstrated trace amounts of beta(3), no alpha(IIb) and no alpha(IIb)beta(3) on the membrane. Sequence analysis revealed a novel T607G transversion in exon 5 of the alpha(IIb) gene predicting a Phe171Cys alteration that created a PstI recognition site. All three patients were homozygous for the mutation, the mother and paternal grandparents of the proband were heterozygous, whereas 110 healthy subjects lacked this transversion. Chinese hamster ovary cells cotransfected with cDNAs of mutated alpha(IIb) and wild-type beta(3) failed to express alpha(IIb)beta(3) as shown by immunoprecipitation and immunohistochemistry experiments. Structural analysis of the alpha(IIb)beta(3) model, which was based on the crystal structure of alpha(v)beta(3), indicated that Phe171 plays an essential role in the interface between the beta-propeller domain of alpha(IIb) and the betaA domain of beta(3). CONCLUSIONS: A novel Phe171Cys mutation in the alpha(IIb) gene of patients with GT is associated with abrogation of alpha(IIb)beta(3) complex formation.
Assuntos
Mutação de Sentido Incorreto/fisiologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genética , Glicoproteína IIb da Membrana de Plaquetas/genética , Trombastenia/genética , Adulto , Plaquetas/química , Pré-Escolar , Análise Mutacional de DNA , Saúde da Família , Feminino , Homozigoto , Humanos , Masculino , Linhagem , Ligação Proteica/genética , Trombastenia/etiologiaRESUMO
New bone formation requires sufficient number of osteogenic progenitors capable of forming the bone desired. The site of engraftment must be filled with a matrix that facilitates attachment, migration and differentiation of osteoblastic progenitors. It is also necessary that the cells receive stimuli by growth factors that allow them to progress toward a bone phenotype. Another critical step in new tissue formation is the construction of new blood vessels--angiogenesis. Platelets contain growth factors that induce osteoinductive stimuli and accelerate angiogenesis. One strategy for harnessing this benefit is to apply platelet rich plasma (PRP) to bone graft site. The present article review platelets and growth factors physiology. We discuss the interaction between growth factors, thrombin and cells that form bone and blood vessels: osteoblasts, mesenchimal stem cells and endothelial cells. Methods and defaults of PRP preparation and safety issues are presented. The knowledge of platelet physiology and the mechanism by which growth factors effect cell proliferation and differentiation allow the dental surgeon to properly use this treatment modality and to achieve the ultimate goal of durable and effectively functioning bone.
Assuntos
Plaquetas , Transplante Ósseo , Plaquetas/fisiologia , Substâncias de Crescimento/fisiologia , Humanos , Neovascularização Fisiológica/fisiologia , Osteogênese/fisiologiaRESUMO
Recombinant activated factor VII (rFVIIa, NovoSeven) represents an effective treatment for hemophilia patients with inhibitors, but no consensus as to the best dosing regimen exists. We assessed the efficacy and safety of a rFVIIa 'megadose' (300 micro g kg(-1) bolus) as treatment for bleeds in three young inhibitor patients. Of 114 bleeds, 95 responded to a single dose. Pain relief was faster and therapy duration significantly shorter than with continuous infusion (CI) regimens or standard boluses (90 micro g kg(-1) every 3 h). Rebleeding occurred in 9.6% of cases and 19/114 episodes required a second bolus injection. Although rFVIIa consumption per bleed (median: 300 micro g kg(-1)) was higher than with standard boluses (180-270 micro g kg(-1)), patients found single bolus administration more convenient than recurrent injections or CI. With two exceptions, no complications occurred within 3 h of treatment, despite high FVII:C levels (median: 27.4 U mL(-1); range: 19.8-54 U mL(-1)). Treatment of bleeds with a rFVIIa megadose in young inhibitor patients is effective and well tolerated.
Assuntos
Fator VII/administração & dosagem , Hemofilia A/tratamento farmacológico , Hemorragia/prevenção & controle , Proteínas Recombinantes/administração & dosagem , Adulto , Relação Dose-Resposta a Droga , Avaliação de Medicamentos , Fator VIIa , Hemofilia A/complicações , Hemorragia/etiologia , Humanos , Infusões Parenterais , Injeções , Dor/tratamento farmacológico , Dor/prevenção & controle , Prevenção Secundária , Fatores de TempoRESUMO
OBJECTIVE: We describe a possible relationship between inferior vena cava anomalies and extensive thrombosis of the inferior vena cava and the iliac and femoral veins. CONCLUSION: An anomaly of the inferior vena cava should be considered in young patients who present with deep vein thrombosis of the femoral and iliac veins. Coagulation abnormalities, frequently found in these patients, may be a contributory factor.
Assuntos
Veia Femoral , Veia Ilíaca , Tomografia Computadorizada por Raios X , Veia Cava Inferior/anormalidades , Veia Cava Inferior/diagnóstico por imagem , Trombose Venosa/complicações , Trombose Venosa/diagnóstico por imagem , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos RetrospectivosRESUMO
The present study was undertaken to evaluate stability, pharmacokinetic profile and efficacy of continuous infusion of 8Y in patients with different types of von Willebrand disease (vWD). Following reconstitution, 8Y levels of von Willebrand factor ristocetin cofactor (vWF:Rco), vWF antigen and factor VIII coagulant activity (FVIII:C) decreased to about 80% of the baseline levels; addition of low molecular weight heparin decreased the level of FVIII:C even further. Reconstituted 8Y was found to be sterile for up to 6 days postreconstitution. Ten vWD patients (four with type 2A, three with type 3, two with type 1 and one with 2N) underwent pharmacokinetic analysis. The recovery of vWF: RCo was significantly lower in patients with type 3 vWD (1.4 +/- 0.05% U(-1) kg(-1)) compared with that of the patients with types 1 (2.3 +/- 0.52% U(-1) kg(-1)) or 2A (2.0 +/- 0.06% U(-1) kg(-1)) vWD (P = 0.015). Type 3 vWD patients exhibited significantly higher vWF:RCo clearance (5.1 +/- 1.1 mL kg(-1) h(-1)) compared with that of patients with type 2A (2.8 +/- 0.7 mL kg(-1) h(-1)) and type 1 (2.6 +/- 1.0 mL kg(-1) h(-1)) vWD (P = 0.028). Accordingly, terminal half-life was lower in patients with type 3 vWD (8.0 +/- 0.6 h(-1)) compared with type 2A (12.7 +/- 5.9 h(-1)) or type 1 (14 +/- 1.2 h(-1)) vWD patients. Multimeric pattern of vWF from patients' plasma was similar to that of 8Y. In two patients treated with 8Y by continuous infusion for prevention or treatment of bleeding haemostasis was achieved. Thus, 8Y is suitable and haemostatically effective for continuous infusion treatment in patients with vWD.
Assuntos
Avaliação de Medicamentos/métodos , Fator VIII/administração & dosagem , Doenças de von Willebrand/terapia , Fator de von Willebrand/administração & dosagem , Adulto , Idoso , Perda Sanguínea Cirúrgica/prevenção & controle , Fator VIII/análise , Fator VIII/farmacocinética , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Hemorragia Pós-Operatória/terapia , Hemorragia Pós-Parto/terapia , Gravidez , Complicações Hematológicas na Gravidez/sangue , Complicações Hematológicas na Gravidez/classificação , Complicações Hematológicas na Gravidez/terapia , Doenças de von Willebrand/sangue , Doenças de von Willebrand/classificação , Fator de von Willebrand/análise , Fator de von Willebrand/farmacocinéticaRESUMO
BACKGROUND: Recombinant activated factor VII (rFVIIa) was approved for treatment of hemorrhages in patients with hemophilia who develop inhibitors to factors VIII or IX. Conditions with increased thromboembolic risk, including trauma with or without disseminated intravascular coagulation, were considered a contraindication for the drug. The mechanism of action of rFVIIa suggests enhancement of hemostasis limited to the site of injury without systemic activation of the coagulation cascade. Therefore, use of the drug in trauma patients suffering uncontrolled hemorrhage appears to be rational. METHODS: Seven massively bleeding, multitransfused (median, 40 units [range, 25-49 units] of packed cells), coagulopathic trauma patients were treated with rFVIIa (median, 120 microg/kg [range, 120-212 microg/kg]) after failure of conventional measures to achieve hemostasis. RESULTS: Administration of rFVIIa resulted in cessation of the diffuse bleed, with significant decrease of blood requirements to 2 units (range, 1-2 units) of packed cells (p < 0.05); shortening of prothrombin time and activated partial thromboplastin time from 24 seconds (range, 20-31.8 seconds) to 10.1 seconds (range, 8-12 seconds) (p < 0.005) and 79 seconds (range, 46-110 seconds) to 41 seconds (range, 28-46 seconds) (p < 0.05), respectively; and an increase of FVII level from 0.7 IU/mL (range, 0.7-0.92 IU/mL) to 23.7 IU/mL (range, 18-44 IU/mL) (p < 0.05). Three of the seven patients died of reasons other than bleeding or thromboembolism. CONCLUSION: The results of this report suggest that in trauma patients rFVIIa may play a role as an adjunctive hemostatic measure, in addition to surgical hemostatic techniques, and provides the motivation for controlled animal and clinical trials.
Assuntos
Fator VII/uso terapêutico , Hemorragia/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Ferimentos e Lesões/mortalidade , Adolescente , Adulto , Idoso , Fator VIIa , Feminino , Hemorragia/etiologia , Hemostasia , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Ferimentos e Lesões/fisiopatologiaRESUMO
Acquired von Willebrand syndrome (AVWS) has been associated mainly with monoclonal gammopathy of uncertain significance (MGUS), clonal lymphoproliferative or myeloproliferative disorders and autoimmunity. In the present work we studied 6 patients with AVWS: four with MGUS IgG (lambda or kappa), one with small lymphocytic lymphoma and one with agnogenic myeloid metaplasia (AMM). All the patients underwent a pharmacokinetic analysis at presentation in order to study potential differences in recovery, clearance (CL) or terminal half-life (THL) following administration of von Willebrand factor (VWF) concentrate. In all the patients with AVWS an increase in clearance and a decrease in THL was observed as compared to these parameters in patients with hereditary type 3 von Willebrand disease (VWD). No difference in recovery was observed among the groups. The increase in clearance and the decrease in THL were significantly more pronounced in the group of MGUS patients (57.93 +/- 25.6 ml/h/kg, and 1.39 +/- 0.5 h, respectively) as compared to these parameters in the AMM (8.06 ml/h/kg, and 6.96 h, respectively) or the lymphoma (4.76 ml/h/kg, and 6.76 h. respectively) patients (p = 0.03 for clearance and 0.001 for THL). These data indicate that the pharmacokinetic analysis can be a useful tool to distinguish between MGUS-related and other causes of AVWS, and to plan an appropriate treatment accordingly.
Assuntos
Fator VIII/farmacocinética , Doenças de von Willebrand/diagnóstico , Fator de von Willebrand/farmacocinética , Idoso , Tempo de Sangramento , Fator VIII/administração & dosagem , Feminino , Meia-Vida , Humanos , Leucemia Linfocítica Crônica de Células B/complicações , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/complicações , Mielofibrose Primária/complicações , Ristocetina , Doenças de von Willebrand/tratamento farmacológico , Doenças de von Willebrand/etiologia , Fator de von Willebrand/administração & dosagemRESUMO
Cell adhesion is mediated by the integrin adhesion receptors. Receptor-ligand interaction involves conformational changes in the receptor, but the underlying mechanism remains unclear. Our earlier work implied a role for sulfhydryls in integrin response to ligand binding in the intact blood platelet. We now show that non-penetrating blockers of free sulfhydryls inhibit beta(1) and beta(3) integrin-mediated platelet adhesion regardless of the affinity state of the integrin. Removal of the inhibitors prior to adhesion fully restores adhesion despite the irreversible nature of inhibitor-thiol interaction, indicating sulfhydryl exposure in response to adhesion. We further show that blocking protein disulfide isomerase (PDI) inhibits adhesion. These data indicate that: (a) ecto-sulfhydryls are necessary for integrin-mediated platelet adhesion; (b) disulfide exchange takes place during this process; (c) surface PDI is involved in integrin-mediated adhesion.
Assuntos
Plaquetas/citologia , Integrinas/metabolismo , Isomerases de Dissulfetos de Proteínas/fisiologia , 4-Cloromercuriobenzenossulfonato/farmacologia , Adesão Celular , Colágeno/metabolismo , Dissulfetos , Etilmaleimida/farmacologia , Fibrinogênio/metabolismo , Fibronectinas/metabolismo , Humanos , Magnésio/farmacologia , Proteínas de Membrana/metabolismo , Ligação Proteica , Conformação Proteica , Isomerases de Dissulfetos de Proteínas/metabolismo , Compostos de Amônio Quaternário/farmacologia , Reagentes de Sulfidrila/farmacologiaRESUMO
Six hemophilia A patients with inhibitors were treated with a continuous infusion of recombinant activated factor VII (rFVIIa) for various bleeding episodes. Bleeding episodes (n = 101) were treated according to a 12 h regular dose protocol or a shortened (6 h) augmented dose protocol. Patient response to therapy was assessed by symptomatic improvement within predefined timeframes. Although patient number was limited, both protocols appeared similar with respect to the proportion of patients responding to therapy; however, the augmented dose protocol appeared to be superior to the regular dose protocol with shorter response time, shorter duration of therapy and possibly lower rFVIIa requirements. Further studies are needed to define the efficacy of rFVIIa augmented dose administered as continuous infusion in treating hemophilia patients with inhibitors during major bleeding episodes, trauma and surgery.
Assuntos
Fator VIIa/administração & dosagem , Hemofilia A/tratamento farmacológico , Proteínas Recombinantes/administração & dosagem , Adolescente , Adulto , Anticorpos/sangue , Anticorpos/imunologia , Criança , Pré-Escolar , Esquema de Medicação , Hemofilia A/sangue , Hemofilia A/imunologia , Hemorragia/tratamento farmacológico , HumanosRESUMO
A 48-year-old woman who was treated for thyrotoxicosis with methimazole developed agranulocytosis. The methimazole was stopped and treatment with subcutaneous granulocyte colony-stimulating factor (G-CSF) was initiated. Administration of the drug for 8 days did not effectively shorten the recovery period compared with the average reported in the literature without the drug, and may have triggered additional iatrogenic complications. A search of the literature yielded 15 instances of severe antithyroid-drug-induced granulocytopenia (ATDIA) (granulocyte count of less than 0.1 x 10(9)/L) treated with G-CSF. Of the 16 patients, including the 1 reported here, only 3 displayed significant shortening of the agranulocytic period after treatment. We conclude that routine therapeutic application of G-CSF in afebrile severe ATDIG is not justified, and in some cases may generate a cascade of iatrogenic adverse events.
Assuntos
Agranulocitose/induzido quimicamente , Agranulocitose/terapia , Antitireóideos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Metimazol/efeitos adversos , Idoso , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Tireotoxicose/tratamento farmacológico , Fatores de TempoRESUMO
Philadelphia-negative (Ph-neg) essential thrombocythemia (ET), polycythemia vera (PV) and idiopathic myelofibrosis (IMF) form a syndrome of related chronic myeloproliferative disorders (MPD) characterized by expansion of one or more of the hematopoietic progenitors. Based on our previous finding of BCR-ABL transcripts in bone marrow aspirates of 12/25 Ph-neg ET patients, we have expanded our study up to 40 patients. Here we describe the rational for performing this study and report 19 of 40 patients who have BCR-ABL transcripts in their BM, 11 of them carry b3a2 and 8 carry b2a2. The two groups, BCR-ABL positive and negative, were completely identical with regard to clinical characteristics and laboratory data. We also report preliminary results of our attempt to examine concordance or discordance of BCR-ABL expression in the peripheral blood and bone marrow of Ph-neg ET patients.
Assuntos
Medula Óssea/química , Genes abl/genética , Cromossomo Filadélfia , Trombocitemia Essencial/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da PolimeraseRESUMO
Thrombotic complications in non-Hodgkin's lymphoma often originate in the large veins. We describe a patient with refractory advanced high-grade lymphoma who presented with the rare complication of extensive cutaneous necrosis due to thrombosis of dermal vessels; there was also a recent new peak of monoclonal IgM-kappa protein. Direct immunofluorescence demonstrated immune deposits with complement in the dermal vessel wall. Based on these observations and on published data, we suggest that these complexes were the trigger for the thrombotic events and that the monoclonal IgM acted as xenoreactive antibodies, initiating a cascade of events. The first step of this cascade was activation of the complement and the membrane attack complex, which caused secretion of IL-1 alpha by endothelial cells, followed by overexpression of tissue factor on the surface of the dermal vessel wall endothelium. Dermal vessel thrombosis was the final event in this cascade.
Assuntos
Linfoma não Hodgkin/complicações , Síndromes Paraneoplásicas/patologia , Dermatopatias/etiologia , Pele/patologia , Tromboembolia/etiologia , Tromboembolia/patologia , Humanos , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Necrose , Dermatopatias/patologiaRESUMO
One of the diagnostic criteria of essential thrombocythemia (ET) is the absence of the Philadelphia chromosome (Ph-neg). On the molecular level, Ph-neg ET patients may carry BCR-ABL transcript. The natural history of BCR-ABL positive Ph-neg ET patients is undetermined. We examined the BCR-ABL status by reverse transcriptase two-step nested polymerase chain reaction in bone marrow aspirates of 25 Ph-neg ET patients. We found 12 BCR-ABL positive and 13 BCR-ABL negative patients in the study group. The comparison showed that the two groups had similar clinical and laboratory characteristics, except for a significant increased patients' age and decreased polymorphonuclear cell count in the BCR-ABL positive group. During a median follow-up of 20 and 22.5 months for the BCR-ABL negative and positive groups, respectively, there was neither blastic transformation nor unrelated death in both groups. We conclude that it is important to look for BCR-ABL transcript in Ph-neg ET patients and to follow them closely to investigate the nature of this translocation in this group of patients.