1/44. Newly recognized cellular abnormalities in the gray platelet syndrome.The gray platelet syndrome (GPS) is a rare congenital bleeding disorder in which thrombocytopenia is associated with increased platelet size and decreased alpha-granule content. This report describes 3 new pediatric cases presenting with the classical platelet abnormalities of GPS within one family with normal parents. Examination of blood smears of the 3 patients demonstrated not only gray platelets, but also gray polymorphonuclear neutrophils (PMNs) with decreased or abnormally distributed components of secretory compartments (alkaline phosphatase, CD35, CD11b/CD18). Secondary granules were also decreased in number as assayed by immunoelectron microscopy. These data confirm that the secretory compartments in neutrophils were also deficient in this family. megakaryocytes (MKs) were cultured from the peripheral blood CD34 cells of the 3 patients for 14 days, in the presence of thrombopoietin and processed for immunoelectron microscopy. Although von willebrand factor (vWF) was virtually undetectable in platelets, vWF immunolabeling was conspicuous in cultured maturing MKs, particularly within Golgi saccules, but instead of being packaged in alpha-granules, it was released into the demarcation membrane system. In contrast, p-selectin followed a more classical pathway. Double-labeling experiments confirmed that vWF was following an intracellular pathway distinct from the one of p-selectin. In these 3 new cases of GPS, the MKs appeared to abnormally process vWF, with secretion into the extracellular space instead of normal alpha-granule packaging. Furthermore, the secretory compartment of another blood cell line, the neutrophil, was also affected in this family of GPS.- - - - - - - - - - ranking = 1keywords = membrane (Clic here for more details about this article) |
2/44. Spontaneous platelet aggregation with congenital giant platelet containing large granules and thick membrane.Inherited giant platelet disorders are a heterogeneous group of disorders. In the current study, a patient was reported with moderate bleeding tendency, giant platelets, and spontaneous platelet aggregation, which were not affected by the administration of aspirin or ticlopidine. The electron microscopy of platelets showed a black and thick plasma membrane with crystal-like fine hairs in the exterior coat and more large and variously shaped granules in the cytoplasm. The expression of glycoprotein (GP) Ib, GP IIb, and GP IIIa on platelet surface was normal, and no mutations in genes for GP Ib alpha, GP Ib beta, and GP IX were detected. These phenomena are so distinguishable from those of Mondreal platelet syndrome and other hereditary giant platelet disorders, that we propose that this patient probably has a novel platelet disorder, which has not yet been reported.- - - - - - - - - - ranking = 5keywords = membrane (Clic here for more details about this article) |
3/44. Hereditary giant platelet syndrome. Absence of collagen-induced coagulant activity and deficiency of factor-XI binding to platelets.The platelets from two related patients with the hereditary giant platelet syndrome were examined. They were larger than normal but otherwise ultrastructurally normal; they contained increased storage pools of adenine nucleotides and heparin-neutralizing activity and took up serotonin at an increased rate. They aggregated normally with ADP and collagen but failed to aggregate with bovine factor viii and ristocetin. Some change in shape occurred with ADP, and the reduction in adenylate energy change after addition of ADP to platelet-rich plasma was smaller than normal. Platelet coagulant activities including contact product forming activity, intrinsic factor-Xa forming activity and platelet factor 3 activity were normal or increased, but collagen-induced coagulant activity was absent whether tested in washed platelet suspensions or platelet-rich plasma. Platelet washing experiments showed decreased binding of factors V and VIII to hereditary giant platelets and no detectable factor xi in washed platelet suspensions. It is concluded that (1) the hereditary giant platelets studied lacked a binding mechanism for factors, V, VIII and XI; (2) the normal development of collagen-induced coagulant activity apparently depends upon the binding of factor xi to the platelet membrane; and (3) the defective prothrombin consumption observed in these patients may have resulted from the failure of their platelets to bind factor xi.- - - - - - - - - - ranking = 1keywords = membrane (Clic here for more details about this article) |
4/44. Evidence for a role for Galphai1 in mediating weak agonist-induced platelet aggregation in human platelets: reduced Galphai1 expression and defective Gi signaling in the platelets of a patient with a chronic bleeding disorder.We have examined platelet functional responses and characterized a novel signaling defect in the platelets of a patient suffering from a chronic bleeding disorder. platelet aggregation responses stimulated by weak agonists such as adenosine diphosphate (ADP) and adrenaline were severely impaired. In comparison, both aggregation and dense granule secretion were normal following activation with high doses of collagen, thrombin, or phorbol-12 myristate-13 acetate (PMA). ADP, thrombin, or thromboxane a2 (TxA2) signaling through their respective Gq-coupled receptors was normal as assessed by measuring either mobilization of intracellular calcium, diacylglycerol (DAG) generation, or pleckstrin phosphorylation. In comparison, Gi-mediated signaling induced by either thrombin, ADP, or adrenaline, examined by suppression of forskolin-stimulated rise in cyclic amp (cAMP) was impaired, indicating dysfunctional Galphai signaling. Immunoblot analysis of platelet membranes with specific antiserum against different Galpha subunits indicated normal levels of Galphai2,Galphai3,Galphaz, and Galphaq in patient platelets. However, the Galphai1level was reduced to 25% of that found in normal platelets. Analysis of platelet cDNA and gDNA revealed no abnormality in either the Galphai1 or Galphai2 gene sequences. Our studies implicate the minor expressed Galphai subtype Galphai1 as having an important role in regulating signaling pathways associated with the activation of alphaIIbbeta3 and subsequent platelet aggregation by weak agonists.- - - - - - - - - - ranking = 1keywords = membrane (Clic here for more details about this article) |
5/44. Hereditary nephritis, platelet disorders and deafness-Epstein's syndrome.A 14-year-old boy with persistent proteinuria (1.6-4.0 g/day), microscopic haematuria, moderate hypertension, macrothrombocytopenia (giant platelets, platelet number 30 x 10(9)/l) and a familial sensorineural hearing loss (the father and the brother were also affected) was studied. kidney biopsy revealed a diffuse mesangial proliferation, and a focal thickening of the glomerular basement membrane was seen on electron microscopy. A normal number of megakaryocytes was observed in bone marrow aspirates. The aggregation response of the platelets to collagen, epinephrine and adenosine diphosphate (ADP) was decreased. The platelet number was slightly diminished, platelets were of normal size in both parents and the brother, and showed a decreased aggregability in response to collagen, epinephrine and ADP in the brother and mother. No functional abnormality of the platelets was observed in the father. urinalysis and kidney function were normal in the family members. This boy with nephritis, platelet disorders and hearing loss corresponds to Epstein's syndrome.- - - - - - - - - - ranking = 1keywords = membrane (Clic here for more details about this article) |
6/44. Neutrophil secretory defect in the gray platelet syndrome: a new case.We report the case of a 60-year-old woman who was newly diagnosed for the gray platelet syndrome (GPS). This patient had long-term thrombocytopenia which had been initially misdiagnosed as idiopathic thrombocytopenic purpura (ITP). blood smear displayed characteristic gray platelets, allowing the diagnosis to be made, which was confirmed by electron microscopy (EM). Polymorphonuclear neutrophils (PMN) appeared poorly granulated on the May-Grunwald-Giemsa-stained blood smear. flow cytometry analysis of PMN demonstrated increased expression of CD35, CD11b and CD18 at resting PMN surface, without any changes after fMLP stimulation. Ultrastructural study retrieved a decreased number of myeloperoxidase (MPO)-negative secondary granules in PMN. Immunolabeling confirmed the presence of membrane proteins and the absence of soluble content in platelet and megakaryocyte (MK) alpha-granules, and the decrease of secondary granules and secretory vesicles in PMN. This new observation demonstrates that the impairment of the secretory compartment of PMN is definitely a hallmark of GPS, and that the detection of these subtle abnormalities should be searched with adequate and up-to-date technical approaches.- - - - - - - - - - ranking = 1keywords = membrane (Clic here for more details about this article) |
7/44. Variant bernard-soulier syndrome type bolzano. A congenital bleeding disorder due to a structural and functional abnormality of the platelet glycoprotein Ib-IX complex.We have studied a patient with a congenital bleeding disorder and phenotypic manifestations typical of bernard-soulier syndrome, including giant platelets with absent ristocetin-induced von willebrand factor binding. Two monoclonal antibodies reacting with distinct epitopes in the amino-terminal domain of the alpha-chain of glycoprotein (GP) Ib were used to estimate the number of GP Ib molecules on the platelet membrane. In the patient, binding of one antibody (LJ-Ib10) was approximately 50% of normal, while binding of the other (LJ-Ib1) was absent. Binding of both antibodies was reduced to approximately 50% of normal in the mother and one sister of the propositus, and their platelets exhibited approximately 70% of normal von willebrand factor binding. immunoblotting studies confirmed the presence of GP Ib alpha, as well as GP IX, in patient platelets. Antibody LJ-Ib10, but not LJ-Ib1, could immunoprecipitate the patient's GP Ib alpha from surface-labeled proteins. Thus, platelets from the propositus contained a structurally and functionally altered GP Ib-IX complex lacking a specific antibody epitope and the ability to bind von willebrand factor. In contrast, the binding of human alpha-thrombin to the patient's platelets was normal, and three classes of binding sites with high, intermediate, and low affinity could be detected. These studies define a distinct variant form of bernard-soulier syndrome and provide evidence, based on a naturally occurring mutant molecule, that the amino-terminal region of GP Ib alpha contains a von willebrand factor-binding domain distinct from the high affinity thrombin-binding site. Use of different monoclonal antibodies with distinct epitope specificities appears to be essential for a correct identification of variant bernard-soulier syndrome.- - - - - - - - - - ranking = 1keywords = membrane (Clic here for more details about this article) |
8/44. X-linked thrombocytopenia and thrombocytopathia: attenuated wiskott-aldrich syndrome. Functional and morphological studies of platelets and lymphocytes.Detailed studies on the rare disorder X-linked thrombocytopenia showed that it resembles the wiskott-aldrich syndrome (WAS) in inheritance, clinical bleeding tendency, platelet morphology, marked thrombocytopenia and microplatelets. The calculated platelet mass was 5% of normal. Functional and biochemical studies indicated qualitatively normal aggregation and release mechanisms, whereas a moderate storage pool defect was present. The classical platelet membrane glycoproteins and lymphocyte sialophorin (CD 43) were normal. The reason for the bleeding tendency was concluded to be deficient hemostatic plug formation resulting from the low platelet mass and a moderate storage pool defect. The only clear distinction from WAS was the normal immunofunctional tests, the moderate tendency to infections and the absence of eczema. We therefore consider the trait as an attenuated form of WAS. That women are affected may indicate a particular variant.- - - - - - - - - - ranking = 1keywords = membrane (Clic here for more details about this article) |
9/44. Thrombocytopathy due to a defect of the platelet membrane complex.A new type of primary thrombocytopathy is described. Three main alterations were found: (1) a defect of the aggregation reaction with ADP, epinephrine and collagen and a normal response to ristocetin and arachidonic acid; (2) a moderate deficiency of platelet procoagulant activity, and (3) a combined hypertrophy of the two membrane systems of the platelet--the open canalicular and the dense tubular. The latter defect is shown as an abnormal membrane complex situated on one of the platelet poles. This thrombocytopathy is discussed as a new variety of primary platelet disorder.- - - - - - - - - - ranking = 6keywords = membrane (Clic here for more details about this article) |
10/44. Lack of platelet response to collagen associated with an autoantibody against glycoprotein Ia: a novel cause of acquired qualitative platelet dysfunction.Platelets from a patient with an acquired hemorrhagic disorder had a severely impaired response to collagen, whereas platelet aggregation to other agonists and coagulations tests were normal. No abnormalities of the patient's platelet membrane glycoproteins (GP) were seen. Treatment of the patient with immunosuppressive agents temporarily improved both the bleeding tendency and the collagen responsiveness of the platelets. An IgG was found to be present in the plasma, directed against a protein comigrating with GPIa, and coadsorbing with GPIa to insoluble collagen fibers in a Mg2 (-)dependent manner. Furthermore, GPIa was recognized by the patient's antibody when affinity-purified GPIa-IIa was used as antigen. Finally, the GPIa-IIa complex was immunoprecipitated from a platelet lysate by patient's plasma. In addition, purified platelet specific IgG's from the patient inhibited aggregation of normal platelets induced by collagen or by wheat germ agglutinin. We conclude that the lack of response to collagen of the patient's platelets may well be due to the presence of an autoantibody against GPIa.- - - - - - - - - - ranking = 1keywords = membrane (Clic here for more details about this article) |
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