RESUMO
PURPOSE: Up to 30% of patients with glioblastoma (GBM) develop venous thromboembolism (VTE) over the course of the disease. Although not as high, the risk for VTE is also increased in patients with meningioma. Direct measurement of peak thrombin generation (TG) allows quantitative assessment of systemic coagulation activation in patients with GBM and meningioma. Our aim was to determine the extent of systemic coagulation activation induced by brain tumors, to measure the shift between pre- and post-operative peak TG in patients with GBM, and to assess the relationship between pre-surgical peak TG and pre-operative brain tumor volume on imaging. METHODS: Pre- and post-surgical plasma samples were obtained from successive patients with GBM and once from patients with meningioma and healthy age- and sex-matched blood donor controls. TG was measured using the calibrated automated thrombogram (CAT) assay, and tumor volumes were measured in pre-surgical MRI scans. RESULTS: Pre-surgical peak TG was higher in patients with GBM than in controls (288.6 ± 54.1 nM vs 187.1 ± 41.7 nM, respectively, P < 0.001), and, in the nine patients with GBM and paired data available, peak TG was significantly reduced after surgery (323 ± 38 nM vs 265 ± 52 nM, respectively, P = 0.007). Similarly, subjects with meningioma demonstrated higher peak TG compared to controls (242.2 ± 54.9 nM vs 177.7 ± 57.0 nM, respectively, P < 0.001). There was no association between peak TG and pre-operative tumor volume or overall survival. CONCLUSION: Our results indicate that systemic coagulation activation occurs with both meningioma and GBM, but to a greater degree in the latter. Preoperative peak TG did not correlate with tumor volume, but removal of GBM caused a significant decrease in coagulation activation.
Assuntos
Coagulação Sanguínea , Neoplasias Encefálicas , Glioblastoma , Neoplasias Meníngeas , Meningioma , Coagulação Sanguínea/fisiologia , Neoplasias Encefálicas/sangue , Glioblastoma/sangue , Humanos , Neoplasias Meníngeas/sangue , Meningioma/sangueRESUMO
Adrenal masses are commonly found on radiographic studies performed for unrelated reasons. We report on a case of a non-functioning adrenal mass from which a needle biopsy showed a nonspecific infiltrate of polyclonal plasma cells and small lymphocytes. A definitive diagnosis of the plasma cell variant of Castleman lymphadenopathy was made only after surgical excision. While the hyaline vascular variant of Castleman lymphadenopathy has been identified in adrenal glands, this is the first report of the plasma cell variant in an adrenal mass. This case particularly underscores the importance of an excisional biopsy for proper diagnosis.
RESUMO
: Primary myelofibrosis (PMF) is a clonal hematopoietic stem cell disorder characterized by fibrosis of the marrow cavity, marked megakaryocyte atypia and progressive cytopenias. Although thrombosis predominates, bleeding is the primary manifestation in up to 20% of patients and may be life-threatening. In this report, we document restoration of megakaryocyte and platelet structure and function in PMF after allogeneic hematopoietic cell transplantation (HCT). A 59-year-old man presented with recurrent episodes of postoperative bleeding preceding a diagnosis of primary myelofibrosis (PMF). Platelet aggregation and secretion studies showed abnormal responses to all agonists tested (epinephrine, ADP, arachidonic acid, U46619, collagen, ristocetin) despite the presence of thrombocytosis. After an allogeneic HCT, platelet morphology and function studies were all normal. The pathophysiology of platelet dysfunction in myeloid neoplasia is not well understood but, as highlighted in our report, restoration of platelet function by HCT supports a clonal process involving an early hematopoietic progenitor cell.
Assuntos
Transtornos Plaquetários/etiologia , Transplante de Células-Tronco Hematopoéticas , Mielofibrose Primária/etiologia , Recuperação de Função Fisiológica , Transtornos Plaquetários/terapia , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Hemorragia/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Mielofibrose Primária/complicações , Mielofibrose Primária/terapia , Trombocitose , Transplante Homólogo , Resultado do TratamentoAssuntos
Abetalipoproteinemia/diagnóstico , Abetalipoproteinemia/complicações , Idoso , Aterosclerose/complicações , Atorvastatina/efeitos adversos , Complicações do Diabetes , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hipertensão/complicações , Masculino , Doença de Parkinson/complicaçõesRESUMO
INTRODUCTION: Factor V (FV) deficiency is a rare inherited coagulation disorder associated with bleeding tendency. As a result, it has been postulated that decreased FV activity may confer protection against venous thromboembolism and atherothrombotic cardiovascular events. MATERIALS AND METHODS: Using the electronic database of the largest health care provider in Israel, we identified all adult individuals who were tested for FV activity between January 2004 and June 2017. Subjects with liver cirrhosis or FV Leiden mutation were excluded. FV activity was classified into three predefined categories; FV activity >50%, FV activity 30-50%, and FV activity ≤30%. Patients were followed from January 2004 to June 2017 for new atherothrombotic cardiovascular events (composite of myocardial infarction, stroke, and TIA) and venous thromboembolism (VTE). RESULTS: Overall 2021 individuals were included; 83.2% had FV activity >50%, 9.6% FV activity 30-50%, and 7.2% had FV activity ≤30%. Compared to individuals with FV activity >50% the adjusted HR for atherothrombotic cardiovascular events was 1.10 (95% CI, 0.63-1.90) in those with FV activity 30-50%, and 0.95 (0.49-1.8) in those with FV activity ≤30%. None of the patients with FV activity 30-50% had VTE during follow-up; therefore those with FV activity ≤50% were classified into one group. VTE incidence was lower in those with FV activity ≤50% compared to those with FV >50% activity; adjusted HRâ¯=â¯0.28 (0.09-0.91). CONCLUSION: This study suggests that decreased FV activity might be associated with decreased incidence of VTE. No significant association appears to exist between FV activity and atherothrombotic cardiovascular events.
Assuntos
Arteriosclerose/sangue , Fator V/metabolismo , Tromboembolia Venosa/sangue , Adulto , Arteriosclerose/epidemiologia , Arteriosclerose/genética , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Humanos , Israel/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/genéticaRESUMO
Historically, inhibitors to coagulation factor V (FV) most often have developed in patients treated with bovine thrombin, a topical hemostatic agent used during surgical procedures. With the advent of newer hemostatic agents, and the concurrent diminished use of bovine thrombin, the incidence of FV inhibitors has fallen. Nevertheless, FV inhibitors are occasionally seen on an idiopathic basis as well as in association with medications, malignancies, autoimmune disorders, pregnancy, and infections. Factor V inhibitors may present with life-threatening bleeding or thrombosis, or they may be discovered incidentally as a coagulation screening test abnormality. Management of patients with FV inhibitors is challenging and consists of control of bleeding and eradication of the inhibitor. In this short overview we review the role of platelet and plasma FV in hemostasis and discuss the unique characteristics, clinical features, diagnosis, treatment, and prognosis associated with FV inhibitors.
Assuntos
Fator V/antagonistas & inibidores , Animais , Autoanticorpos/sangue , Bovinos , Diagnóstico Diferencial , Fator V/imunologia , Feminino , Hemorragia/etiologia , Hemostáticos/efeitos adversos , Humanos , Gravidez , Trombina/efeitos adversosRESUMO
: Factor V inhibitors are rare and have varied clinical presentations. We report on a 76-year-old female admitted to the hospital for pneumonia and treated with multiple antibiotics. Her baseline prothrombin time was 15.6âs and the activated partial thromboplastin time was 35âs. On admission day 10, she developed arm weakness and brain imaging showed a subdural hematoma. The prothrombin time was now 59.1âs with an activated partial thromboplastin time of more than 160âs and a normal thrombin time. A mixing study did not correct the clotting times and coagulation factor assays showed a nonspecific inhibition pattern. Only factor V activity remained low with serial dilutions, however, and a 70 Bethesda Unit inhibitor was identified. Aggressive supportive care was initiated but the patient succumbed to the effects of the intracranial hemorrhage. Factor V inhibitors may display lupus anticoagulant properties and may cause catastrophic bleeding. Our case illustrates that these inhibitors can arise quickly and supports an association with antibiotics.
Assuntos
Antibacterianos/uso terapêutico , Fator V/antagonistas & inibidores , Hemorragias Intracranianas/sangue , Hemorragias Intracranianas/complicações , Inibidor de Coagulação do Lúpus/sangue , Pneumonia/complicações , Pneumonia/tratamento farmacológico , Idoso , Antibacterianos/efeitos adversos , Coagulação Sanguínea/efeitos dos fármacos , Testes de Coagulação Sanguínea , Fator V/metabolismo , Feminino , Hematoma Subdural/sangue , Hematoma Subdural/complicações , Hematoma Subdural/metabolismo , Humanos , Hemorragias Intracranianas/metabolismo , Inibidor de Coagulação do Lúpus/metabolismo , Pneumonia/sangue , Pneumonia/metabolismoAssuntos
Hemocromatose/complicações , Falência Hepática/complicações , Sangramento por Deficiência de Vitamina K/diagnóstico , Sangramento por Deficiência de Vitamina K/etiologia , Anti-Hipertensivos/administração & dosagem , Clortalidona/administração & dosagem , Hemocromatose/terapia , Hemoglobinas/metabolismo , Humanos , Hipertensão/tratamento farmacológico , Losartan/administração & dosagem , Masculino , Erros de Medicação , Pessoa de Meia-Idade , Flebotomia , Contagem de PlaquetasAssuntos
Hemorragia Bucal/etiologia , Procedimentos Cirúrgicos Bucais/efeitos adversos , Doença de von Willebrand Tipo 2/complicações , Doença de von Willebrand Tipo 2/diagnóstico , Adulto , Testes de Coagulação Sanguínea , Cauterização , Humanos , Masculino , Hemorragia Bucal/terapia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/terapia , Recidiva , SuturasRESUMO
OBJECTIVES: To describe three methods used to screen for frameshift mutations in exon 9 of the CALR gene. METHODS: Genomic DNA from 47 patients was extracted from peripheral blood and bone marrow using the EZ1 DNA Blood Kit (Qiagen, Valencia, CA) and quantified by the Quant-iT PicoGreen dsDNA Assay Kit (Invitrogen, San Diego, CA). After clinical history, cytogenetics, and molecular tests, patients were diagnosed with either clonal or nonclonal hematologic diseases. CALR screening was primarily performed using fragment analysis polymerase chain reaction, then next-generation sequencing and Sanger sequencing. RESULTS: Among the 18 patients diagnosed with clonal diseases, one had acute myeloid leukemia (positive for trisomy 8), and 17 had myeloproliferative neoplasms (MPNs), including chronic myeloid leukemia (CML), essential thrombocythemia (ET), primary myelofibrosis (PMF), and polycythemia vera (PV). Patients with CML were positive for the BCR-ABL1 fusion. Ten patients were positive for JAK2 (PMF, n = 1; ET, n = 2; PV, n = 7), and three were CALR positive (ET, n = 1; PMF, n = 2). Patients diagnosed with a nonclonal disease were negative for JAK2, BCR-ABL, and CALR mutations. CONCLUSIONS: Screening for CALR mutations is essential in BCR-ABL-negative MPNs since it not only provides valuable diagnostic and prognostic information but also identifies potential treatment targets. Since this study describes the importance of screening for known and novel biomarkers, we described in detail three methods that could be easily integrated into a clinical laboratory.
Assuntos
Calreticulina/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mieloide Aguda/diagnóstico , Policitemia Vera/diagnóstico , Mielofibrose Primária/diagnóstico , Trombocitemia Essencial/diagnóstico , Análise Mutacional de DNA , Proteínas de Fusão bcr-abl/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Janus Quinase 2/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/genética , Mutação , Policitemia Vera/genética , Mielofibrose Primária/genética , Trombocitemia Essencial/genéticaRESUMO
Küttner tumor/chronic sclerosing sialadenitis is a fibroinflammatory process that characteristically involves the submandibular gland of patients with IgG4-related disease. Histologic examination is often important to make the diagnosis because of its nonspecific clinical and radiologic findings. Microscopically, Küttner tumor should be distinguished from other entities such as extranodal marginal zone lymphoma, Sjögren's syndrome, and lymphoepithelial sialadenitis. The lesion is histologically well-demarcated with lobular architecture, extensive fibrosis, marked lymphoplasmacytic inflammation, formation of lymphoid follicles, acinar atrophy, and obliterative phlebitis, without the presence of lymphoepithelial lesions. The IgG4-to-IgG positive plasma cell ratio of >40 % is also an important feature to support the diagnosis of Küttner tumor. Moreover, flow cytometry is helpful to exclude a lymphoproliferative process. Clinicians and pathologists should consider the diagnosis of Küttner tumor in patients with elevated serum IgG4 level. Timely and accurate diagnosis is important for appropriate management.
Assuntos
Imunoglobulina G , Sialadenite/diagnóstico , Sialadenite/patologia , Doenças da Glândula Submandibular/diagnóstico , Doenças da Glândula Submandibular/patologia , Feminino , Humanos , Imunoglobulina G/sangue , Pessoa de Meia-Idade , Sialadenite/imunologia , Doenças da Glândula Submandibular/imunologiaRESUMO
Total joint arthroplasty (TJA) improves the quality of life for patients with end-stage osteoarthritis but is associated with an increased risk of venous thromboembolism (VTE), thus pharmacologic thromboprophylaxis is recommended for most patients. Patients with congenital bleeding disorders may develop severe arthropathies due to repeated hemarthroses and derive similar benefit from TJA as the general population. No guidelines for pharmacologic thromboprophylaxis in this population exist, however, as the risks and benefits are not well defined. We undertook the current study to assess the safety and efficacy of pharmacologic VTE prophylaxis in patients with congenital bleeding disorders undergoing TJA. We retrospectively reviewed the medical records of patients with bleeding disorders who underwent TJA at our academic institution between 1987 and 2012. We identified 28 patients who underwent 38 TJA procedures. Low-molecular-weight heparin (LMWH) was administered in 29 procedures (76%) and was discontinued early in 3 procedures (2 patients) due to nonjoint bleeding. No symptomatic VTE was identified, and no joint or deep wound infections were seen. Twenty-two patients accounting for 31 procedures were contacted to discuss their experience with TJA. All reported decreased pain, and 97% reported improved function after the surgery. Impressively, 97% stated that they would choose to have the surgery again. These results confirm the benefit of TJA in patients with congenital bleeding disorders and end-stage arthropathies and suggest that LMWH thromboprophylaxis is safe. No patient in our cohort developed symptomatic VTE, whether or not thromboprophylaxis was administered, thus necessity of thromboprophylaxis remains an unanswered question.
Assuntos
Artroplastia , Transtornos da Coagulação Sanguínea/terapia , Tromboembolia Venosa/prevenção & controle , Adolescente , Adulto , Idoso , Transtornos da Coagulação Sanguínea/congênito , Feminino , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Dor/prevenção & controle , Estudos Retrospectivos , Resultado do Tratamento , Tromboembolia Venosa/terapia , Adulto JovemRESUMO
Abundant, sustained expression of prosurvival Mcl-1 is an important determinant of viability and drug resistance in cancer cells. The Mcl-1 protein contains PEST sequences (enriched in proline, glutamic acid, serine, and threonine) and is normally subject to rapid turnover via multiple different pathways. One of these pathways involves a phosphodegron in the PEST region, where Thr-163 phosphorylation primes for Ser-159 phosphorylation by glycogen synthase kinase-3. Turnover via this phosphodegron-targeted pathway is reduced in Mcl-1-overexpressing BL41-3 Burkitt lymphoma and other cancer cells; turnover is further slowed in the presence of phorbol ester-induced ERK activation, resulting in Mcl-1 stabilization and an exacerbation of chemoresistance. The present studies focused on Mcl-1 dephosphorylation, which was also found to profoundly influence turnover. Exposure of BL41-3 cells to an inhibitor of protein phosphatase 2A (PP2A), okadaic acid, resulted in a rapid increase in phosphorylation at Thr-163 and Ser-159, along with a precipitous decrease in Mcl-1 expression. The decline in Mcl-1 expression preceded the appearance of cell death markers and was not slowed in the presence of phorbol ester. Upon exposure to calyculin A, which also potently inhibits PP2A, versus tautomycin, which does not, only the former increased Thr-163/Ser-159 phosphorylation and decreased Mcl-1 expression. Mcl-1 co-immunoprecipitated with PP2A upon transfection into CHO cells, and PP2A/Aα knockdown recapitulated the increase in Mcl-1 phosphorylation and decrease in expression. In sum, inhibition of PP2A prevents Mcl-1 dephosphorylation and results in rapid loss of this prosurvival protein in chemoresistant cancer cells.
Assuntos
Linfoma de Burkitt/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/química , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteína Fosfatase 2/antagonistas & inibidores , Sítios de Ligação , Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/farmacologia , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Sistema de Sinalização das MAP Quinases , Toxinas Marinhas , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Ácido Okadáico/farmacologia , Oxazóis/farmacologia , Fosforilação/efeitos dos fármacos , Proteína Fosfatase 2/genética , Proteólise , Serina/química , Acetato de Tetradecanoilforbol/farmacologia , Treonina/químicaAssuntos
Granulócitos/ultraestrutura , Leucemia Mieloide Aguda/sangue , Segunda Neoplasia Primária/sangue , Idoso , Antimetabólitos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Azacitidina/uso terapêutico , Quimioterapia Adjuvante , Decitabina , Feminino , Hematopoese/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/induzido quimicamente , Leucemia Mieloide Aguda/tratamento farmacológico , Segunda Neoplasia Primária/induzido quimicamente , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/ultraestrutura , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/tratamento farmacológico , Indução de RemissãoRESUMO
NPP4 is a type I extracellular membrane protein on brain vascular endothelium inducing platelet aggregation via the hydrolysis of Ap3A, whereas NPP1 is a type II extracellular membrane protein principally present on the surface of chondrocytes that regulates tissue mineralization. To understand the metabolism of purinergic signals resulting in the physiologic activities of the two enzymes, we report the high resolution crystal structure of human NPP4 and explore the molecular basis of its substrate specificity with NPP1. Both enzymes cleave Ap3A, but only NPP1 can hydrolyze ATP. Comparative structural analysis reveals a tripartite lysine claw in NPP1 that stabilizes the terminal phosphate of ATP, whereas the corresponding region of NPP4 contains features that hinder this binding orientation, thereby inhibiting ATP hydrolysis. Furthermore, we show that NPP1 is unable to induce platelet aggregation at physiologic concentrations reported in human blood, but it could stimulate platelet aggregation if localized at low nanomolar concentrations on vascular endothelium. The combined studies expand our understanding of NPP1 and NPP4 substrate specificity and range and provide a rational mechanism by which polymorphisms in NPP1 confer stroke resistance.
Assuntos
Trifosfato de Adenosina/química , Fosfatos de Dinucleosídeos/química , Diester Fosfórico Hidrolases/química , Pirofosfatases/química , Acidente Vascular Cerebral/enzimologia , Trifosfato de Adenosina/genética , Trifosfato de Adenosina/metabolismo , Plaquetas/enzimologia , Plaquetas/patologia , Encéfalo/enzimologia , Encéfalo/patologia , Fosfatos de Dinucleosídeos/genética , Fosfatos de Dinucleosídeos/metabolismo , Endotélio Vascular/enzimologia , Endotélio Vascular/patologia , Endotélio Vascular/fisiologia , Humanos , Diester Fosfórico Hidrolases/genética , Diester Fosfórico Hidrolases/metabolismo , Agregação Plaquetária/genética , Polimorfismo Genético , Estrutura Terciária de Proteína , Pirofosfatases/genética , Pirofosfatases/metabolismo , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia , Especificidade por SubstratoAssuntos
Medula Óssea/patologia , Imunoglobulina G/química , Cadeias lambda de Imunoglobulina/química , Paraproteinemias/patologia , Paraproteínas/química , Plasmócitos/química , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Medula Óssea/imunologia , Cristalização , Feminino , Humanos , Pessoa de Meia-Idade , Paraproteinemias/tratamento farmacológico , Paraproteinemias/imunologia , Indução de Remissão , Coloração e RotulagemRESUMO
We report a case of refractory heparin-induced thrombocytopenia with thrombosis (HITT) with prolonged thrombocytopenia and multiple thrombotic complications that failed to improve despite aggressive treatment. A 60 year old female with a prior history of venous thromboembolism was admitted with an acute pulmonary embolism, and developed HITT after several days on heparin therapy. She suffered multiple complications including bilateral venous limb gangrene, acute renal failure, and refractory thrombocytopenia, leading us to use multimodality therapy including therapeutic plasma exchange (TPE) and rituximab immunosuppression. The patient had transient improvements in her thrombocytopenia with TPE, and rituximab was added in an attempt to reduce antibody production. She eventually required bilateral limb amputation, and only after removal of the gangrenous limbs did her platelet count show sustained improvement. We discuss the possible contribution of infection to her prolonged course.
Assuntos
Anticoagulantes/efeitos adversos , Heparina/efeitos adversos , Troca Plasmática , Trombocitopenia , Trombose , Tromboembolia Venosa/tratamento farmacológico , Anticoagulantes/administração & dosagem , Feminino , Heparina/administração & dosagem , Humanos , Pessoa de Meia-Idade , Trombocitopenia/induzido quimicamente , Trombocitopenia/terapia , Trombose/induzido quimicamente , Trombose/terapiaRESUMO
To investigate an association between secondary polycythemia and venous thromboembolism (VTE) risk, we performed a case-control study to compare the prevalence of VTE in participants with secondary polycythemia due to chronic obstructive pulmonary disease (COPD; N = 86) to that in age- and sex-matched controls with COPD without secondary polycythemia (N = 86). Although there was a significant difference in mean hematocrit between cases and controls (53.5% vs 43.6%, respectively; P < .005), we identified no difference in the number of total or idiopathic VTE events in the 2 groups. Patients with VTE, however, had a significantly higher body mass index than patients without VTE. Our findings suggest that secondary polycythemia alone may not be a significant risk factor for VTE but that VTE risk in this population may be related to known risk factors such as obesity. The role of phlebotomy for VTE risk reduction secondary polycythemia is therefore questionable.