RESUMO
The platelet antibodies that cause pseudothrombocytopenia (PTCP) act only in vitro and do not produce clinical bleeding. Most studies on PTCP have focused on improving differential diagnosis with true thrombocytopenia but studies on the characteristics of patients with PTCP are limited. In this study, we aimed to evaluate the clinical and biological characteristics of 192 patients with PTCP. In addition to general variables, we evaluated automated and microscopic platelet counts, platelet clumps, platelet diameters, immature platelet fraction (IPF), and platelet antibodies. Adult women accounted for the largest subgroup of patients (n=82; 42.7%) and 67 patients (34.9%) were grouped into families. Forty-four patients (22.9%) had one or more associated autoimmune disorders (ADs); 39 relatives of these patients (19.8%) had ADs and 45 relatives (23.4%) had immune thrombocytopenia (ITP) or unspecified thrombocytopenia. Platelet cryptantibodies and/or autoantibodies were positive in 56 patients (30.1%). Most patients (n=169; 80%) had automated platelet counts >80×109/L. In all patients, microscopic platelet counts were ≥150×109/L. The platelet clump index (% increase in microscopic platelet count compared to automatic count) ranged from 30 to >7000%. Platelet diameters and IPF parameters were significantly greater in the PTCP versus healthy controls (p<0.001). A total of 17 patients (8.8%) had had previous ITP or the PTCP evolved into ITP. Our data suggest that PTCP should be considered a situation of autoimmunity; the assessment of platelet clumps has a high diagnostic value; the close association between ITP and PTCP suggests that these conditions could be different phases of the same process.
Assuntos
Púrpura Trombocitopênica Idiopática , Trombocitopenia , Adulto , Humanos , Feminino , Ácido Edético , Trombocitopenia/diagnóstico , Trombocitopenia/epidemiologia , Trombocitopenia/etiologia , Contagem de Plaquetas , Autoanticorpos , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/epidemiologia , Púrpura Trombocitopênica Idiopática/complicaçõesRESUMO
(1) Background: In a previous study, we found that two phenotypes related to platelet reactivity, measured with the PFA-100 system, were highly heritable. The aim of the present study was to identify genetic determinants that influence the variability of these phenotypes: closure time of collagen-ADP (Col-ADP) and of collagen-epinephrine (Col-Epi). (2) Methods: As part of the GAIT-2 (Genetic Analysis of Idiopathic Thrombophilia (2) Project, 935 individuals from 35 large Spanish families were studied. A genome-wide association study (GWAS) with ≈ 10 M single nucleotide polymorphisms (SNPs) was carried out with Col-ADP and Col-Epi phenotypes. (3) Results: The study yielded significant genetic signals that mapped to the ABO locus. After adjusting both phenotypes for the ABO genotype, these signals disappeared. After adjusting for von Willebrand factor (VWF) or for coagulation factor VIII (FVIII), the significant signals disappeared totally for Col-Epi phenotype but only partially for Col-ADP phenotype. (4) Conclusion: Our results suggest that the ABO locus exerts the main genetic influence on PFA-100 phenotypes. However, while the effect of the ABO locus on Col-Epi phenotype is mediated through VWF and/or FVIII, the effect of the ABO locus on Col-ADP phenotype is partly produced through VWF and/or FVIII, and partly through other mechanisms.
Assuntos
Sistema ABO de Grupos Sanguíneos/genética , Agregação Plaquetária/genética , Polimorfismo de Nucleotídeo Único , Trombofilia/genética , Fator de von Willebrand/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Fator VIII/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Testes de Função PlaquetáriaRESUMO
Abnormalities of platelet size are one of the distinguishing features of inherited thrombocytopenias (ITs), and evaluation of blood films is recommended as an essential step for differential diagnosis of these disorders. Nevertheless, what we presently know about this subject is derived mainly from anecdotal evidence. To improve knowledge in this field, we evaluated platelet size on blood films obtained from 376 patients with all 19 forms of IT identified so far and found that these conditions differ not only in mean platelet diameter, but also in platelet diameter distribution width and the percentage of platelets with increased or reduced diameters. On the basis of these findings, we propose a new classification of ITs according to platelet size. It distinguishes forms with giant platelets, with large platelets, with normal or slightly increased platelet size, and with normal or slightly decreased platelet size. We also measured platelet diameters in 87 patients with immune thrombocytopenia and identified cutoff values for mean platelet diameter and the percentage of platelets with increased or reduced size that have good diagnostic accuracy in differentiating ITs with giant platelets and with normal or slightly decreased platelet size from immune thrombocytopenia and all other forms of IT.
Assuntos
Plaquetas/patologia , Trombocitopenia/sangue , Trombocitopenia/genética , Adolescente , Adulto , Estudos de Casos e Controles , Tamanho Celular , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Perda Auditiva Neurossensorial/sangue , Perda Auditiva Neurossensorial/classificação , Perda Auditiva Neurossensorial/genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Proteínas Motores Moleculares/genética , Mutação , Cadeias Pesadas de Miosina/genética , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/diagnóstico , Trombocitopenia/classificação , Trombocitopenia/congênito , Adulto JovemRESUMO
OBJECTIVES: MYH9-related disease (MYH9-RD) is an autosomal- dominant disorder deriving from mutations in MYH9, the gene for the nonmuscle myosin heavy chain (NMMHC)-IIA. MYH9-RD has a complex phenotype including congenital features, such as thrombocytopenia, and noncongenital manifestations, namely sensorineural hearing loss (SNHL), nephropathy, cataract, and liver abnormalities. The disease is caused by a limited number of mutations affecting different regions of the NMMHC-IIA protein. SNHL is the most frequent noncongenital manifestation of MYH9-RD. However, only scarce and anecdotal information is currently available about the clinical and audiometric features of SNHL of MYH9-RD subjects. The objective of this study was to investigate the severity and propensity for progression of SNHL in a large series of MYH9-RD patients in relation to the causative NMMHC-IIA mutations. DESIGN: This study included the consecutive patients diagnosed with MYH9-RD between July 2007 and March 2012 at four participating institutions. A total of 115 audiograms were analyzed from 63 patients belonging to 45 unrelated families with different NMMHC-IIA mutations. Cross-sectional analyses of audiograms were performed. Regression analysis was performed, and age-related typical audiograms (ARTAs) were derived to characterize the type of SNHL associated with different mutations. RESULTS: Severity of SNHL appeared to depend on the specific NMMHC-IIA mutation. Patients carrying substitutions at the residue R702 located in the short functional SH1 helix had the most severe degree of SNHL, whereas patients with the p.E1841K substitution in the coiled-coil region or mutations at the nonhelical tailpiece presented a mild degree of SNHL even at advanced age. The authors also disclosed the effects of different amino acid changes at the same residue: for instance, individuals with the p.R702C mutation had more severe SNHL than those with the p.R702H mutation, and the p.R1165L substitution was associated with a higher degree of hearing loss than the p.R1165C. In general, mild SNHL was associated with a fairly flat audiogram configuration, whereas severe SNHL correlated with downsloping configurations. ARTA plots showed that the most progressive type of SNHL was associated with the p.R702C, the p.R702H, and the p.R1165L substitutions, whereas the p.R1165C mutation correlated with a milder, nonprogressive type of SNHL than the p.R1165L. ARTA for the p.E1841K mutation demonstrated a mild degree of SNHL with only mild progression, whereas the ARTA for the mutations at the nonhelical tailpiece did not show any substantial progression. CONCLUSIONS: These data provide useful tools to predict the progression and the expected degree of severity of SNHL in individual MYH9-RD patients, which is especially relevant in young patients. Consequences in clinical practice are important not only for appropriate patient counseling but also for development of customized, genotype-driven clinical management. The authors recently reported that cochlear implantation has a good outcome in MYH9-RD patients; thus, stricter follow-up and earlier intervention are recommended for patients with unfavorable genotypes.
Assuntos
Perda Auditiva Neurossensorial/genética , Proteínas Motores Moleculares/genética , Cadeias Pesadas de Miosina/genética , Trombocitopenia/congênito , Adolescente , Adulto , Idoso , Audiometria de Tons Puros , Criança , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Progressão da Doença , Feminino , Genótipo , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/etiologia , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Estudos Retrospectivos , Índice de Gravidade de Doença , Trombocitopenia/complicações , Trombocitopenia/genética , Trombocitopenia/fisiopatologia , Adulto JovemRESUMO
This study evaluated 65 pregnancies in 34 women with five different inherited platelet function disorders. Gestation was similar to that of the general population. Severe bleeds requiring blood transfusions were observed in 50% of deliveries in Glanzmann thrombasthenia (GT), but not in the patients with delta storage pool disease, Hermansky-Pudlak syndrome, P2Y12 defect or defect of thromboxane A2 receptor. Of note, severe haemorrhage also occurred in women with GT who had received prophylactic platelet transfusions, suggesting that better preventive treatments are required. Diagnosis and degree of spontaneous bleeding tendency before pregnancy were reliable parameters to predict the delivery-related bleeding risk.
Assuntos
Transtornos Plaquetários/terapia , Hemorragia/prevenção & controle , Transfusão de Plaquetas , Complicações Hematológicas na Gravidez/terapia , Adolescente , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , GravidezRESUMO
The gray platelet syndrome (GPS) is a rare congenital platelet disorder characterized by mild to moderate bleeding diathesis, macrothrombocytopenia and lack of azurophilic α-granules in platelets. Some platelet and megakaryocyte (MK) abnormalities have been described, but confirmative studies of the defects in larger patient cohorts have not been undertaken. We studied platelet function and bone marrow (BM) features in five GPS patients with NBEAL2 autosomal recessive mutations from four unrelated families. In 3/3 patients, we observed a defect in platelet responses to protease-activated receptor (PAR)1-activating peptide as the most consistent finding, either isolated or combined to defective responses to other agonists. A reduction of PAR1 receptors with normal expression of major glycoproteins on the platelet surface was also found. Thrombin-induced fibrinogen binding to platelets was severely impaired in 2/2 patients. In 4/4 patients, the BM biopsy showed fibrosis (grade 2-3) and extensive emperipolesis, with many (36-65%) MKs containing 2-4 leukocytes engulfed within the cytoplasm. Reduced immunolabeling for platelet factor 4 together with normal immunolabeling for CD63 in MKs of two patients demonstrated that GPS MKs display an alpha granule-specific defect. Increased immunolabeling for P-selectin and decreased immunolabeling for PAR1, PAR4 and c-MPL were also observed in MKs of two patients. Marked emperipolesis, specific defect of MK alpha-granule content and defect of PAR1-mediated platelet responses are present in all GPS patients that we could study in detail. These results help to further characterize the disease.
Assuntos
Plaquetas/metabolismo , Emperipolese , Síndrome da Plaqueta Cinza/metabolismo , Megacariócitos/metabolismo , Trifosfato de Adenosina/metabolismo , Idoso , Plaquetas/patologia , Proteínas Sanguíneas/genética , Medula Óssea/metabolismo , Medula Óssea/patologia , Estudos de Casos e Controles , Grânulos Citoplasmáticos/metabolismo , Grânulos Citoplasmáticos/patologia , Fibrose , Expressão Gênica , Síndrome da Plaqueta Cinza/diagnóstico , Síndrome da Plaqueta Cinza/genética , Humanos , Megacariócitos/patologia , Mutação , Ativação Plaquetária , Agregação Plaquetária , Testes de Função Plaquetária , Receptor PAR-1/genética , Receptor PAR-1/metabolismoRESUMO
Bernard-Soulier syndrome (BSS) is a rare autosomal recessive bleeding disorder characterized by defects of the GPIb-IX-V complex, a platelet receptor for von Willebrand factor (VWF). Most of the mutations identified in the genes encoding for the GP1BA (GPIbα), GP1BB (GPIbß), and GP9 (GPIX) subunits prevent expression of the complex at the platelet membrane or more rarely its interaction with VWF. As a consequence, platelets are unable to adhere to the vascular subendothelium and agglutinate in response to ristocetin. In order to collect information on BSS patients, we established an International Consortium for the study of BSS, allowing us to enrol and genotype 132 families (56 previously unreported). With 79 additional families for which molecular data were gleaned from the literature, the 211 families characterized so far have mutations in the GP1BA (28%), GP1BB (28%), or GP9 (44%) genes. There is a wide spectrum of mutations with 112 different variants, including 22 novel alterations. Consistent with the rarity of the disease, 85% of the probands carry homozygous mutations with evidence of founder effects in some geographical areas. This overview provides the first global picture of the molecular basis of BSS and will lead to improve patient diagnosis and management.
Assuntos
Síndrome de Bernard-Soulier/genética , Variação Genética , Mutação , Alelos , Síndrome de Bernard-Soulier/diagnóstico , Bases de Dados de Ácidos Nucleicos , Efeito Fundador , Humanos , Complexo Glicoproteico GPIb-IX de Plaquetas/genética , Polimorfismo de Nucleotídeo Único , Navegador , Doenças de von Willebrand/genéticaRESUMO
MYH9-related disease (MYH9-RD) is a rare autosomal-dominant disorder caused by mutations in the gene for nonmuscle myosin heavy chain IIA (NMMHC-IIA). MYH9-RD is characterized by a considerable variability in clinical evolution: patients present at birth with only thrombocytopenia, but some of them subsequently develop sensorineural deafness, cataract, and/or nephropathy often leading to end-stage renal disease (ESRD). We searched for genotype-phenotype correlations in the largest series of consecutive MYH9-RD patients collected so far (255 cases from 121 families). Association of genotypes with noncongenital features was assessed by a generalized linear regression model. The analysis defined disease evolution associated to seven different MYH9 genotypes that are responsible for 85% of MYH9-RD cases. Mutations hitting residue R702 demonstrated a complete penetrance for early-onset ESRD and deafness. The p.D1424H substitution associated with high risk of developing all the noncongenital manifestations of disease. Mutations hitting a distinct hydrophobic seam in the NMMHC-IIA head domain or substitutions at R1165 associated with high risk of deafness but low risk of nephropathy or cataract. Patients with p.E1841K, p.D1424N, and C-terminal deletions had low risk of noncongenital defects. These findings are essential to patients' clinical management and genetic counseling and are discussed in view of molecular pathogenesis of MYH9-RD.
Assuntos
Catarata/genética , Estudos de Associação Genética , Perda Auditiva Neurossensorial/genética , Proteínas Motores Moleculares/genética , Cadeias Pesadas de Miosina/genética , Trombocitopenia/congênito , Adulto , Idade de Início , Substituição de Aminoácidos , Feminino , Genótipo , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/diagnóstico , Humanos , Itália , Modelos Lineares , Masculino , Mutação , Fenótipo , Fatores de Risco , Trombocitopenia/complicações , Trombocitopenia/diagnóstico , Trombocitopenia/genéticaRESUMO
THC2, an autosomal-dominant thrombocytopenia described so far in only two families, has been ascribed to mutations in MASTL or ACBD5. Here, we show that ANKRD26, another gene within the THC2 locus, and neither MASTL nor ACBD5, is mutated in eight unrelated families. ANKRD26 was also found to be mutated in the family previously reported to have an ACBD5 mutation. We identified six different ANKRD26 mutations, which were clustered in a highly conserved 19 bp sequence located in the 5' untranslated region. Mutations were not detected in 500 controls and are absent from the 1000 Genomes database. Available data from an animal model and Dr. Watson's genome give evidence against haploinsufficiency as the pathogenetic mechanism for ANKRD26-mediated thrombocytopenia. The luciferase reporter assay suggests that these 5' UTR mutations might enhance ANKRD26 expression. ANKRD26 is the ancestor of a family of primate-specific genes termed POTE, which have been recently identified as a family of proapoptotic proteins. Dysregulation of apoptosis might therefore be the pathogenetic mechanism, as demonstrated for another thrombocytopenia, THC4. Further investigation is needed to provide evidence supporting this hypothesis.
Assuntos
Repetição de Anquirina/genética , Genes Dominantes , Mutação , Sequência de Bases , Quebra Cromossômica , Transtornos Cromossômicos/genética , Sequência Conservada/genética , Feminino , Loci Gênicos , Haploinsuficiência , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Trombocitopenia/congênito , Trombocitopenia/genéticaRESUMO
Pregnancy in women with inherited thrombocytopenias is a major matter of concern as both the mothers and the newborns are potentially at risk of bleeding. However, medical management of this condition cannot be based on evidence because of the lack of consistent information in the literature. To advance knowledge on this matter, we performed a multicentric, retrospective study evaluating 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Neither the degree of thrombocytopenia nor the severity of bleeding tendency worsened during pregnancy and the course of pregnancy did not differ from that of healthy subjects in terms of miscarriages, fetal bleeding and pre-term births. The degree of thrombocytopenia in the babies was similar to that in the mother. Only 7 of 156 affected newborns had delivery-related bleeding, but 2 of them died of cerebral hemorrhage. The frequency of delivery-related maternal bleeding ranged from 6.8% to 14.2% depending on the definition of abnormal blood loss, suggesting that the risk of abnormal blood loss was increased with respect to the general population. However, no mother died or had to undergo hysterectomy to arrest bleeding. The search for parameters predicting delivery-related bleeding in the mother suggested that hemorrhages requiring blood transfusion were more frequent in women with history of severe bleedings before pregnancy and with platelet count at delivery below 50 × 10(9)/L.
Assuntos
Complicações Hematológicas na Gravidez/diagnóstico , Complicações Hematológicas na Gravidez/epidemiologia , Trombocitopenia/diagnóstico , Trombocitopenia/epidemiologia , Adulto , Feminino , Humanos , Recém-Nascido , Gravidez , Complicações Hematológicas na Gravidez/genética , Estudos Retrospectivos , Trombocitopenia/genética , Adulto JovemRESUMO
Until recently, thrombocytopenia 2 (THC2) was considered an exceedingly rare form of autosomal dominant thrombocytopenia and only 2 families were known. However, we recently identified mutations in the 5'-untranslated region of the ANKRD26 gene in 9 THC2 families. Here we report on 12 additional pedigrees with ANKRD26 mutations, 6 of which are new. Because THC2 affected 21 of the 210 families in our database, it has to be considered one of the less rare forms of inherited thrombocytopenia. Analysis of all 21 families with ANKRD26 mutations identified to date revealed that thrombocytopenia and bleeding tendency were usually mild. Nearly all patients had no platelet macrocytosis, and this characteristic distinguishes THC2 from most other forms of inherited thrombocytopenia. In the majority of cases, platelets were deficient in glycoprotein Ia and α-granules, whereas in vitro platelet aggregation was normal. Bone marrow examination and serum thrombopoietin levels suggested that thrombocytopenia was derived from dysmegakaryopoiesis. Unexplained high values of hemoglobin and leukocytes were observed in a few cases. An unexpected finding that warrants further investigation was a high incidence of acute leukemia. Given the scarcity of distinctive characteristics, the ANKRD26-related thrombocytopenia has to be taken into consideration in the differential diagnosis of isolated thrombocytopenias.
Assuntos
Família , Trombocitopenia/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Repetição de Anquirina/genética , Criança , Estudos de Coortes , Feminino , Frequência do Gene , Humanos , Padrões de Herança/genética , Masculino , Pessoa de Meia-Idade , Mutação/fisiologia , Linhagem , Fatores de Transcrição/fisiologia , Adulto JovemRESUMO
The gray platelet syndrome is a rare inherited bleeding disorder characterized by macrothrombocytopenia and deficiency of alpha (α)-granules in platelets. The genetic defect responsible for gray platelet syndrome was recently identified in biallelic mutations in the NBEAL2 gene. We studied 11 consecutive families with inherited macrothrombocytopenia of unknown origin and α-granule deficiency. All of them underwent NBEAL2 DNA sequencing and evaluation of the platelet phenotype, including a systematic assessment of the α-granule content by immunofluorescence analysis for α-granule secretory proteins. We identified 9 novel mutations hitting the two alleles of NBEAL2 in 4 probands. They included missense, nonsense and frameshift mutations, as well as nucleotide substitutions that altered the splicing mechanisms as determined at the RNA level. All the individuals with NBEAL2 biallelic mutations showed almost complete absence of platelet α-granules. Interestingly, the 13 individuals assumed to be asymptomatic because carriers of a mutated allele had platelet macrocytosis and significant reduction of the α-granule content. However, they were not thrombocytopenic. In the remaining 7 probands, we did not identify any NBEAL2 alterations, suggesting that other genetic defect(s) are responsible for their platelet phenotype. Of note, these patients were characterized by a lower severity of the α-granule deficiency than individuals with two NBEAL2 mutated alleles. Our data extend the spectrum of mutations responsible for gray platelet syndrome and demonstrate that macrothrombocytopenia with α-granule deficiency is a genetic heterogeneous trait. In terms of practical applications, the screening of NBEAL2 is worthwhile only in patients with macrothrombocytopenia and severe reduction of the α-granules. Finally, individuals carrying one NBEAL2 mutated allele have mild laboratory abnormalities, suggesting that even haploinsufficiency has an effect on platelet phenotype.
Assuntos
Plaquetas/metabolismo , Proteínas Sanguíneas/genética , Genótipo , Síndrome da Plaqueta Cinza/genética , Síndrome da Plaqueta Cinza/metabolismo , Fenótipo , Alelos , Plaquetas/ultraestrutura , Éxons , Estudos de Associação Genética , Haploinsuficiência , Humanos , Íntrons , Mutação , Linhagem , Splicing de RNARESUMO
INTRODUCTION: Flow cytometry analysis of lymphocyte subsets in peripheral blood is a common technique in diagnostic laboratories. Abnormal values have been identified in prevalent infections, autoimmune disorders and neoplastic diseases. Reference ranges for lymphocyte subsets of a healthy population from Spain are scarce. METHODS: The study was performed on 319 healthy subjects, aged 4-88 years, from 709 individuals enrolled in the GAIT-2 Project (Genetic Analysis of Idiopathic Thrombophilia). Health status, age, sex, fertility, BMI and lifestyle (physical activity, cigarette smoking and ethanol intake) were assessed using standardized criteria. The percentage of lymphocyte subsets was determined using flow cytometry (Lymphogram™). Percentages of CD3+, CD4+, CD8+, CD19+, CD3-CD56+, CD3+CD4-CD8- double-negative (DN) T cells, CD3+CD4+CD8+ double-positive T cells and the CD4+/CD8+ ratio were recorded for each case. RESULTS: Children had a significantly higher percentage of CD19+ and DN cells than adults. Women had a significantly higher percentage of CD3+ and CD4+ and a lower percentage of natural killer cells than men. Increases in BMI were inversely associated with the percentage of DN cells. Physical activity increased the percentage of lymphocytes and DN cells. Alcohol consumers had a lower percentage of CD19+ and DN cells, and a higher percentage of CD4+. CONCLUSION: This study provides reference ranges for lymphocyte subsets of healthy children and adults in a Mediterranean population (Spain) and determines the influence of lifestyle factors on these values.
Assuntos
Subpopulações de Linfócitos/imunologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas/imunologia , Índice de Massa Corporal , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Humanos , Células Matadoras Naturais/imunologia , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Atividade Motora , Valores de Referência , Caracteres Sexuais , Espanha , Subpopulações de Linfócitos T/imunologia , Adulto JovemAssuntos
Eritrócitos/metabolismo , Predisposição Genética para Doença , Trombose , Tromboembolia Venosa , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Eritrócitos/patologia , Feminino , Haptoglobinas/genética , Haptoglobinas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Receptores da Transferrina/sangue , Receptores da Transferrina/genética , Trombose/sangue , Trombose/genética , Tromboembolia Venosa/sangueRESUMO
UNLABELLED: Splenectomy is considered the second-line of treatment in patients with chronic primary immune thrombocytopenia (ITP) in whom glucocorticoids have failed. Some patients do not respond to splenectomy or they have postoperative complications. Based on our previous experience using kinetic and scintigraphic parameters, we did a retrospective study with the aim of comparing all these parameters as a means of predicting the success of splenectomy in persistent and chronic primary ITP. Forty-one consecutive patients with chronic primary ITP refractory to prednisone, who had been splenectomized, were included in the study. The response to splenectomy was assessed by evaluating bleeding and platelet counts before and at different times after surgery. A complete platelet kinetic study was performed before the splenectomy using autologous (111) In-labeled platelets. The scintigraphic parameters measured included different indices between spleen/heart, liver/hearth, and spleen/liver. Thirty-six patients gave a complete response after splenectomy and five patients did not respond. A statistically significant difference between both groups was found with initial platelet recovery and with some scintigraphic indices which also showed a variable prediction value for the success of splenectomy. Among these indices, the spleen/liver at 30 minutes demonstrated a predictive value with a 100% of sensitivity and a 100% of specificity. CONCLUSION: some platelet kinetic parameters and scintigraphic indices, in particular the spleen/liver at 30 minutes, were useful to predict the outcome of splenectomy in persistent and chronic primary ITP and, therefore, they should be taken into account when deciding whether or not to perform a splenectomy.
Assuntos
Plaquetas/diagnóstico por imagem , Fígado/diagnóstico por imagem , Baço , Esplenectomia , Trombocitopenia/diagnóstico por imagem , Trombocitopenia/cirurgia , Adolescente , Adulto , Idoso , Plaquetas/fisiologia , Doença Crônica , Feminino , Coração/diagnóstico por imagem , Hemorragia/prevenção & controle , Humanos , Radioisótopos de Índio , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Valor Preditivo dos Testes , Prednisona/administração & dosagem , Prognóstico , Cintilografia , Estudos Retrospectivos , Sensibilidade e Especificidade , Baço/diagnóstico por imagem , Baço/cirurgia , Trombocitopenia/tratamento farmacológico , Trombocitopenia/imunologia , Trombocitopenia/patologia , Resultado do TratamentoRESUMO
OBJECTIVE: Prostanoids play a critical role in clinical areas such as inflammation, thrombosis, immune response, and cancer. Although some studies suggest that there are genes that determine variability of some prostanoid-related phenotypes, the genetic influence on these traits has not been evaluated. METHODS AND RESULTS: The relative contributions of genetic and environmental influences to the prostanoid biosynthetic pathway-related phenotypes, cyclooxygenase isoenzymes, microsomal-PGE-synthase-1 and TxA-synthase expression, and thromboxane-A(2) and prostaglandin-E(2) production by stimulated whole blood, were assessed in a sample of 308 individuals in 15 extended families. The effects of measured covariates (such as sex, age, and smoking), genes, and environmental variables shared by members of a household were quantified. Heritabilities ranging from 0.406 to 0.634 for enzyme expression and from 0.283 to 0. 751 for prostanoid production were found. CONCLUSIONS: These results demonstrate clearly the importance of genetic factors in determining variation in phenotypes that are components of the prostanoid biosynthetic pathways. The presence of such strong genetic effects suggest that it will be possible to localize previously unknown genes that influence quantitative variation in these phenotypes, some of which affect multiple aspects of cell biology, with important clinical implications.
Assuntos
Dinoprostona/biossíntese , Enzimas/genética , Tromboxano A2/biossíntese , Vasculite/genética , Vasculite/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Vasos Sanguíneos/enzimologia , Criança , Pré-Escolar , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Meio Ambiente , Enzimas/metabolismo , Feminino , Regulação Enzimológica da Expressão Gênica , Humanos , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Contagem de Plaquetas , Prostaglandina-E Sintases , Espanha , Tromboxano-A Sintase/genética , Tromboxano-A Sintase/metabolismo , Adulto JovemRESUMO
MYH9-related disease (MYH9-RD) is a rare autosomal dominant disorder caused by mutations in MYH9, the gene encoding the heavy chain of non-muscle myosin IIA. All patients present congenital macrothrombocytopenia and inclusion bodies in neutrophils. Some of them can also develop sensorineural deafness, presenile cataract, and/or progressive nephropathy leading to end-stage renal failure. We report four families, each with a novel mutation: two missense mutations, in exons 31 and 32, and two out of frame deletions in exon 40. They were associated with no bleeding diathesis, normal, or only slightly reduced platelet count and no extra-hematological manifestations, confirming that alterations of the tail domain cause a mild form of MYH9-RD with no clinically relevant defects.
Assuntos
Doenças Genéticas Inatas/genética , Doenças Hematológicas/genética , Corpos de Inclusão Intranuclear , Proteínas Motores Moleculares/genética , Mutação , Cadeias Pesadas de Miosina/genética , Neutrófilos , Adulto , Idoso , Idoso de 80 Anos ou mais , Éxons/genética , Família , Feminino , Doenças Genéticas Inatas/sangue , Doenças Hematológicas/sangue , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management.
Assuntos
Mutação em Linhagem Germinativa , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenosina Desaminase/genética , Dineínas do Axonema/genética , Estudos de Coortes , Humanos , Degradação do RNAm Mediada por Códon sem Sentido , Linhagem , Perforina/genética , Glicoproteínas da Membrana de Plaquetas/genética , RNA Helicases/genética , Receptores de Interleucina-17/genética , Proteínas de Transporte Vesicular/genética , Sequenciamento do ExomaRESUMO
MYH9-related disease (MYH9-RD) is a rare autosomal-dominant disorder caused by mutations in MYH9, the gene for the heavy chain of nonmuscle myosin IIA (NMMHC-IIA). All patients present from birth with macrothrombocytopenia, but in infancy or adult life, some of them develop sensorineural deafness, presenile cataracts, and/or progressive nephritis leading to end-stage renal failure. No consistent correlations have been identified between the 27 different MYH9 mutations identified so far and the variable clinical evolution of the disease. We have evaluated 108 consecutive MYH9-RD patients belonging to 50 unrelated pedigrees. The risk of noncongenital manifestations associated with different genotypes was estimated over time by event-free survival analysis. We demonstrated that all subjects with mutations in the motor domain of NMMHC-IIA present with severe thrombocytopenia and develop nephritis and deafness before the age of 40 years, while those with mutations in the tail domain have a much lower risk of noncongenital complications and significantly higher platelet counts. We also evaluated the clinical course of patients with mutations in the four most frequently affected residues of NMMHC-IIA (responsible for 70% of MYH9-RD cases). We concluded that mutations at residue 1933 do not induce kidney damage or cataracts and cause deafness only in the elderly, those in position 702 result in severe thrombocytopenia and produce nephritis and deafness at a juvenile age, while alterations at residue 1424 or 1841 result in intermediate clinical pictures. These findings are relevant not only to patients' clinical management but also to the elucidation of the pathogenesis of the disease.
Assuntos
Proteínas Motores Moleculares/química , Proteínas Motores Moleculares/genética , Mutação , Cadeias Pesadas de Miosina/química , Cadeias Pesadas de Miosina/genética , Trombocitopenia/genética , Adulto , Catarata/genética , Feminino , Genes Dominantes , Genótipo , Perda Auditiva Neurossensorial/genética , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Nefrite/genética , Fenótipo , Contagem de Plaquetas , Estrutura Terciária de Proteína , Síndrome , Trombocitopenia/sangueRESUMO
INTRODUCTION: Platelets play a role in the pathophysiology of venous thromboembolism (VTE). Some studies have not found an association between VTE and platelet aggregation. The PFA-100® analyser is an in vitro assay for assessing primary haemostasis. But, there are no studies to evaluate its association with VTE. We investigated the contribution of the global platelet function and aggregation in the development of VTE. MATERIAL AND METHODS: We analysed 800 individuals who were included in the RETROVE Study (Riesgo de Enfermedad TROmboembólica VEnosa). Global platelet function was evaluated as closure times (CT) with the agonists ADP and epinephrine using a PFA-100® analyser. Platelet aggregation was evaluated by Multiplate™ analyser. The VTE risk for all the parameters was calculated by unconditional logistic regression analyses considering the potential confounders: age, gender, body mass index (BMI), factor VIII (FVIII), the von Willebrand factor (vWF) and the ABO blood group system. RESULTS: The unadjusted odds ratio (OR) values ≤10th percentile for the PFAadp and PFAepi were 4.02 (95% CI, 2.76-5.95) and 3.33 (2.27-4.97). Also, after adjusting for vWF, we obtained lower OR for the PFAadp and for PFAepi: 2.24 (1.44-3.49) and 1.63 (1.04-2.59). But, the whole blood aggregation parameters did not shown an association with VTE risk. CONCLUSION: We demonstrated an association between short CT and VTE risk. Although, the whole blood aggregation parameters did not show an association with the VTE risk. This striking contrast suggests that there are other platelet function mechanisms (e.g. adhesion) that are responsible of VTE risk.