RESUMO
An acquired, transient bleeding disorder that predominantly affects children in Southeast Asia has been reported for the last 4 decades. The condition has been named idiopathic purpura with gray platelets (IPGP) or acquired platelet dysfunction with eosinophilia. In a retrospective review from a private pediatric clinic over an 8-year period, 10 consecutive children were diagnosed as IPGP with a mean age of 8.4 (3.7 to 16.2) years. Eosinophilia (>0.5×10/L) was absent in 1, while gray platelets were consistently found in all cases with a mean proportion of 64.5% (40% to 80%). Platelet aggregation tests were performed in 9 patients with abnormal responses consistent with platelet storage pool defect. All children recovered completely and spontaneously from 1 to 4 months after diagnosis without specific therapy. In an otherwise well child who presents abruptly with easy bruising and a platelet count >100×10/L, IPGP can be readily recognized as an acquired form of gray platelet syndrome. Eosinophilia is common but not mandatory for diagnosis.
Assuntos
Plaquetas/metabolismo , Síndrome da Plaqueta Cinza/sangue , Agregação Plaquetária , Púrpura/sangue , Adolescente , Plaquetas/patologia , Criança , Pré-Escolar , Eosinofilia/sangue , Eosinofilia/patologia , Feminino , Síndrome da Plaqueta Cinza/patologia , Humanos , Masculino , Testes de Função Placentária , Contagem de Plaquetas , Púrpura/patologia , Remissão Espontânea , Estudos RetrospectivosRESUMO
Objective- Nbeal2-/- mice, a model of human gray platelet syndrome, have reduced neutrophil granularity and impaired host defense against systemic Staphylococcus aureus infection. We here aimed to study the role of Nbeal2 deficiency in both leukocytes and platelets during gram-negative pneumonia and sepsis. Approach and Results- We studied the role of Nbeal2 in platelets and leukocytes during murine pneumonia and sepsis by Klebsiella pneumoniae. Apart from platelet α-granule deficiency and reduced neutrophil granularity, also monocyte granularity was reduced in Nbeal2-/- mice, whereas plasma levels of MPO (myeloperoxidase), elastase, NGAL (neutrophil gelatinase-associated lipocalin), and MMP-9 (matrix metalloproteinase 9), and leukocyte CD11b expression were increased. Nbeal2-/- leukocytes showed unaltered in vitro antibacterial response and phagocytosis capacity against Klebsiella, and unchanged reactive nitrogen species and cytokine production. Also during Klebsiella pneumonia and sepsis, Nbeal2-/- mice had similar bacterial growth in lung and distant body sites, with enhanced leukocyte migration to the bronchoalveolar space. Despite similar infection-induced inflammation, organ damage was increased in Nbeal2-/- mice, which was also seen during endotoxemia. Platelet-specific Nbeal2 deficiency did not influence leukocyte functions, indicating that Nbeal2 directly modifies leukocytes. Transfusion of Nbeal2-/- but not of Nbeal2+/+ platelets into thrombocytopenic mice was associated with bleeding in the lung but similar host defense, pointing at a role for platelet α-granules in maintaining vascular integrity but not host defense during Klebsiella pneumosepsis. Conclusions- These data show that Nbeal2 deficiency-resulting in gray platelet syndrome-affects platelets, neutrophils, and monocytes, with intact host defense but increased organ damage during gram-negative pneumosepsis.
Assuntos
Plaquetas/metabolismo , Proteínas Sanguíneas/deficiência , Síndrome da Plaqueta Cinza/metabolismo , Infecções por Klebsiella/metabolismo , Klebsiella pneumoniae/patogenicidade , Insuficiência de Múltiplos Órgãos/metabolismo , Pneumonia Bacteriana/metabolismo , Sepse/metabolismo , Animais , Plaquetas/microbiologia , Proteínas Sanguíneas/genética , Antígeno CD11b/sangue , Modelos Animais de Doenças , Feminino , Síndrome da Plaqueta Cinza/sangue , Síndrome da Plaqueta Cinza/genética , Interações Hospedeiro-Patógeno , Infecções por Klebsiella/sangue , Infecções por Klebsiella/genética , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/crescimento & desenvolvimento , Lipocalina-2/sangue , Masculino , Metaloproteinase 9 da Matriz/sangue , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Monócitos/microbiologia , Insuficiência de Múltiplos Órgãos/sangue , Insuficiência de Múltiplos Órgãos/genética , Insuficiência de Múltiplos Órgãos/microbiologia , Neutrófilos/metabolismo , Neutrófilos/microbiologia , Elastase Pancreática/sangue , Peroxidase/sangue , Complexo Glicoproteico GPIb-IX de Plaquetas/genética , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Transfusão de Plaquetas , Pneumonia Bacteriana/sangue , Pneumonia Bacteriana/genética , Pneumonia Bacteriana/microbiologia , Sepse/sangue , Sepse/genética , Sepse/microbiologiaRESUMO
Homozygosity/compound heterozygosity for loss of function mutations in neurobeachin-like 2 (NBEAL2) is causative for Gray platelet syndrome (GPS; MIM #139090), characterized by thrombocytopenia and large platelets lacking α-granules and cargo. Most GPS-associated NBEAL2 mutations generate nonsense codons; frameshifts causing premature translation termination and/or changes in mRNA splicing have also been observed. Data regarding NBEAL2 protein expression in GPS patients is limited. We observed absence of NBEAL2 in platelets from GPS patients with 3 different genotypes, and reduced/truncated platelet NBEAL2 has been reported for others. GPS is commonly associated with mild bleeding, but lifethreatening bleeding has been reported in some cases. A common long-term complication in GPS patients is myelofibrosis; splenomegaly is less common but sometimes of sufficient severity to merit splenectomy. Like GPS patients, mice lacking NBEAL2 expression exhibit macrothrombocytopenia, deficiency of platelet α-granules, splenomegaly, myelofibrosis, impaired platelet function and abnormalities in megakaryocyte development. Animal studies have also reported impaired platelet function in vivo using laser injury and thrombo-inflammation models. NBEAL2 is a large gene with 54 exons, and several putative functional domains have been identified in NBEAL2, including PH (pleckstrin homology) and BEACH (beige and Chediak-Higashi) domains shared with other members of a protein family that includes LYST and LRBA, also expressed by hematopoietic cells. Potential NBEAL2-interacting proteins have recently been identified, and it is expected that current and future efforts will reveal the cellular mechanisms by which NBEAL2 facilitates platelet development and supports hemostatic function.
Assuntos
Plaquetas/metabolismo , Proteínas Sanguíneas/genética , Síndrome da Plaqueta Cinza/genética , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Sanguíneas/metabolismo , Criança , Pré-Escolar , Feminino , Síndrome da Plaqueta Cinza/sangue , Síndrome da Plaqueta Cinza/metabolismo , Hemorragia/sangue , Hemorragia/genética , Hemorragia/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemAssuntos
Síndrome Linfoproliferativa Autoimune/diagnóstico , Plaquetas/patologia , Síndrome da Plaqueta Cinza/diagnóstico , Síndrome Linfoproliferativa Autoimune/sangue , Síndrome Linfoproliferativa Autoimune/patologia , Medula Óssea/patologia , Consanguinidade , Síndrome da Plaqueta Cinza/sangue , Síndrome da Plaqueta Cinza/patologia , Humanos , IrmãosRESUMO
A 71 year-old woman is admitted to Le Mans hospital center for management of a chronic skin lesion. She has no personal nor familial bleeding history and does not take any medication. In peripheral blood collected with EDTA (ethylene diamine tetra-acetate), the platelet count is elevated and the blood film shows uniformly grey platelets. In sodium citrate-collected blood, platelets show no abnormality. We describe an EDTA-related artifact that is not to be mistaken for grey platelet syndrome.
Assuntos
Anticoagulantes/farmacologia , Artefatos , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Degranulação Celular/efeitos dos fármacos , Ácido Edético/farmacologia , Idoso , Diagnóstico Diferencial , Erros de Diagnóstico/prevenção & controle , Feminino , Síndrome da Plaqueta Cinza/sangue , Síndrome da Plaqueta Cinza/diagnóstico , HumanosRESUMO
The pseudo grey platelet syndrome is a rare artifact due to the degranulation of platelets caused, in vitro, by EDTA. This phenomenon is likely to disturb the platelet numeration and it is essential not to mistake it for a grey syndrome platelet, which is a constitutional thrombopathy with macrothrombopenia, in order to avoid specialized tests, or even misdiagnosis. Indeed, these two entities are cytologically alike, as grey platelets are found on the blood smear of a sample collected on EDTA in both cases. We here describe the case of a patient admitted in Colmar's Hospital for a chronic thrombocytopenia, associating both a pseudothrombocytopenia and a pseudo grey platelet syndrome.
Assuntos
Anticoagulantes/farmacologia , Artefatos , Ácido Cítrico/farmacologia , Erros de Diagnóstico , Síndrome da Plaqueta Cinza/diagnóstico , Trombocitopenia/diagnóstico , Anticoagulantes/efeitos adversos , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Ácido Cítrico/efeitos adversos , Feminino , Síndrome da Plaqueta Cinza/sangue , Humanos , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Contagem de Plaquetas , Trombocitopenia/sangueAssuntos
Proteínas Sanguíneas/genética , Síndrome da Plaqueta Cinza/diagnóstico , Síndrome da Plaqueta Cinza/genética , Mutação , Adulto , Alelos , Criança , Feminino , Expressão Gênica , Frequência do Gene , Genótipo , Síndrome da Plaqueta Cinza/sangue , Humanos , Masculino , Fenótipo , Agregação Plaquetária , Contagem de Plaquetas , Glicoproteínas da Membrana de Plaquetas/genéticaRESUMO
The article reviews three recent publications addressing physiological and pathological aspects of platelet granules and release as well as limitations of recent screening tests for diagnosis of non-syndromic inherited δ-storage pool disease (1-3).
Assuntos
Plaquetas/fisiologia , Vesículas Secretórias/fisiologia , Diagnóstico Diferencial , Síndrome da Plaqueta Cinza/sangue , Síndrome da Plaqueta Cinza/diagnóstico , Humanos , Deficiência do Pool Plaquetário/sangue , Deficiência do Pool Plaquetário/diagnósticoRESUMO
Coagulation factor XII (fXII) is important for arterial thrombosis, but its physiological activation mechanisms are unclear. In this study, we elucidated the role of platelets and platelet-derived material in fXII activation. FXII activation was only observed upon potent platelet stimulation (with thrombin, collagen-related peptide, or calcium ionophore, but not ADP) accompanied by phosphatidylserine exposure and was localised to the platelet surface. Platelets from three patients with grey platelet syndrome did not activate fXII, which suggests that platelet-associated fXII-activating material might be released from α-granules. FXII was preferentially bound by phosphotidylserine-positive platelets and annexin V abrogated platelet-dependent fXII activation; however, artificial phosphotidylserine/phosphatidylcholine microvesicles did not support fXII activation under the conditions herein. Confocal microscopy using DAPI as a poly-phosphate marker did not reveal poly-phosphates associated with an activated platelet surface. Experimental data for fXII activation indicates an auto-inhibition mechanism (ki/ka = 180 molecules/platelet). Unlike surface-associated fXII activation, platelet secretion inhibited activated fXII (fXIIa), particularly due to a released C1-inhibitor. Platelet surface-associated fXIIa formation triggered contact pathway-dependent clotting in recalcified plasma. Computer modelling suggests that fXIIa inactivation was greatly decreased in thrombi under high blood flow due to inhibitor washout. Combined, the surface-associated fXII activation and its inhibition in solution herein may be regarded as a flow-sensitive regulator that can shift the balance between surface-associated clotting and plasma-dependent inhibition, which may explain the role of fXII at high shear and why fXII is important for thrombosis but negligible in haemostasis.
Assuntos
Inibidores dos Fatores de Coagulação Sanguínea/metabolismo , Plaquetas/metabolismo , Membrana Celular/metabolismo , Fator XII/agonistas , Fator XII/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Coagulação Sanguínea/efeitos dos fármacos , Inibidores dos Fatores de Coagulação Sanguínea/farmacologia , Micropartículas Derivadas de Células/metabolismo , Proteínas Inativadoras do Complemento 1/metabolismo , Proteínas Inativadoras do Complemento 1/farmacologia , Ativação Enzimática/efeitos dos fármacos , Fator XII/química , Fator XII/metabolismo , Família , Feminino , Síndrome da Plaqueta Cinza/sangue , Síndrome da Plaqueta Cinza/metabolismo , Humanos , Masculino , Modelos Biológicos , Ligação Proteica , Vesículas Secretórias/metabolismoRESUMO
We report a case of gray platelet syndrome (GPS) associated with immune thrombocytopenia (ITP) at presentation. A 22-year-old male patient presenting with petechiae on his limbs was diagnosed with ITP due to a gradual decrease of his platelet count to a minimum of 26 × 10(9) /liter and an elevated platelet-associated IgG (PA-IgG) level in the absence of any other specific cause of thrombocytopenia. Administration of prednisolone increased his platelet count, but this dropped again to approximately 50 × 10(9) /liter as the dose was tapered, and remained at the same level after the treatment was terminated. Thirteen years later, we reassessed the cause of the thrombocytopenia because the PA-IgG level was found to be within the normal range. There were large hypogranular platelets on the blood film and a deficit of α-granules in the platelets on electron microscopy. On this basis, we diagnosed his thrombocytopenia as GPS. To our knowledge, this is the first report of a GPS case associated with ITP at presentation. This case illustrates the importance of carefully reviewing blood film results in the differential diagnosis of thrombocytopenia.
Assuntos
Síndrome da Plaqueta Cinza/diagnóstico , Púrpura Trombocitopênica Idiopática/diagnóstico , Antígenos de Plaquetas Humanas/imunologia , Plaquetas/imunologia , Plaquetas/ultraestrutura , Grânulos Citoplasmáticos/ultraestrutura , Diagnóstico Tardio , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/imunologia , Síndrome da Plaqueta Cinza/sangue , Síndrome da Plaqueta Cinza/complicações , Síndrome da Plaqueta Cinza/genética , Humanos , Hipergamaglobulinemia/etiologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunossupressores/uso terapêutico , Masculino , Prednisolona/uso terapêutico , Púrpura/etiologia , Púrpura Trombocitopênica Idiopática/complicações , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/imunologia , Adulto JovemRESUMO
Gray platelet syndrome (GPS) is a rare inherited disorder characterized by the absence of α-granules and their constituents. It may be present with thrombocytopenia and bleeding tendency. Platelets have a large and gray appearance under light and electron microscope. A 19-year old female patient with her second relapse acute lymphoblastic leukemia had to be consolidated with allo-hematopoietic stem cell transplantation (HSCT) after achieving remission with induction chemotherapy. The only available and one mismatch compatible donor was her brother, who was previously diagnosed as GPS. Allogeneic HSCT was performed from her brother in spite of GPS, and successful neutrophil and platelet engraftment achieved at the 12th and 42nd day of reinfusion, consecutively. The engrafted and circulating thrombocytes were large and gray and had little or no α-granules under electron microscope. The patient was well with no major bleeding event and increased need for thrombocyte replacement until developing bronchiolitis obliterans organizing pneumonia and respiratory distress syndrome. Thereafter death occurred. This is the first case of successful thrombocyte engraftment with documented gray thrombocyte megakaryopoiesis after allogeneic HSCT from a GPS donor. The only noteworthy issue was the slight prolongation of engraftment.
Assuntos
Plaquetas/patologia , Síndrome da Plaqueta Cinza/sangue , Transplante de Células-Tronco Hematopoéticas/métodos , Adolescente , Plaquetas/metabolismo , Feminino , Síndrome da Plaqueta Cinza/patologia , Humanos , Contagem de Plaquetas , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirurgia , Transplante HomólogoAssuntos
Fibrina/metabolismo , Síndrome da Plaqueta Cinza/sangue , Hematoma Epidural Espinal/prevenção & controle , Derivados de Hidroxietil Amido/farmacologia , Substitutos do Plasma/farmacologia , Complicações Hematológicas na Gravidez/sangue , Tromboelastografia , Adulto , Anestesia por Condução , Coagulação Sanguínea , Ponte Cardiopulmonar , Feminino , Fibrina/análise , Gelatina/farmacologia , Hematoma Epidural Espinal/sangue , Hemostasia Cirúrgica , Humanos , Masculino , GravidezRESUMO
It is important that our speciality continues to push its boundaries. Our perfusion team has invested time lecturing to non-cardiac specialties about perfusion-led technology. This resulted in working closely with the obstetrics team to treat a pregnant patient with the bleeding disorder Gray Platelet Syndrome. In the first instance, we used our Thromboelastograph (TEG) platelet mapping programme to assess the patient. These results agreed with the platelet aggregation tests, showing a degree of platelet inhibition, but it was the overall clotting profile (basic thrombelastograph), showing a borderline hyper-coagulable state, that was of most interest and commonly seen in pregnancy. We believe a TEG result within acceptable limits could help re-adjust the risk of spinal haematomas following regional anaesthesia, thereby, reducing the risks of difficult intubation and general anaesthetic exposure to the baby. The case study describes both basic and platelet mapping thrombelastographs and their potential role in not only this patient with Gray Platelet Syndrome, but any obstetric patient where there are bleeding concerns.
Assuntos
Anestesia por Condução , Síndrome da Plaqueta Cinza/sangue , Hematoma Epidural Espinal/prevenção & controle , Complicações Hematológicas na Gravidez/sangue , Tromboelastografia , Adulto , Feminino , Hematoma Epidural Espinal/sangue , Humanos , GravidezRESUMO
Gray platelet syndrome (GPS) is an inherited bleeding disorder characterized by macrothrombocytopenia and absence of platelet α-granules resulting in typical gray platelets on peripheral smears. GPS is associated with a bleeding tendency, myelofibrosis, and splenomegaly. Reports on GPS are limited to case presentations. The causative gene and underlying pathophysiology are largely unknown. We present the results of molecular genetic analysis of 116 individuals including 25 GPS patients from 14 independent families as well as novel clinical data on the natural history of the disease. The mode of inheritance was autosomal recessive (AR) in 11 and indeterminate in 3 families. Using genome-wide linkage analysis, we mapped the AR-GPS gene to a 9.4-Mb interval on 3p21.1-3p22.1, containing 197 protein-coding genes. Sequencing of 1423 (69%) of the 2075 exons in the interval did not identify the GPS gene. Long-term follow-up data demonstrated the progressive nature of the thrombocytopenia and myelofibrosis of GPS resulting in fatal hemorrhages in some patients. We identified high serum vitamin B(12) as a consistent, novel finding in GPS. Chromosome 3p21.1-3p22.1 has not been previously linked to a platelet disorder; identification of the GPS gene will likely lead to the discovery of novel components of platelet organelle biogenesis. This study is registered at www.clinicaltrials.gov as NCT00069680 and NCT00369421.