1/9. 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 = collagen-induced (Clic here for more details about this article) |
2/9. Severe deficiency of glycoprotein VI in a patient with gray platelet syndrome.We report a novel case of gray platelet syndrome (GPS) where a severe deficiency of the platelet collagen receptor, glycoprotein (GP) VI, accompanies classical symptoms of a low platelet count and platelets lacking alpha-granules. Dense granules were normally present. platelet aggregation with collagen was severely decreased, as was the response to convulxin (Cvx), a GPVI agonist. Quantitative analysis of GPVI using fluorescein isothiocyanate (FITC)-Cvx in flow cytometry showed its virtual absence on the patient's platelets. The GPVI deficiency was confirmed using monoclonal antibodies in Western blotting and in immunogold labeling on frozen thin sections where internal pools of GPVI were confirmed for normal platelets. The Fc receptor gamma-chain, constitutively associated with GPVI in normal platelets, was present in subnormal amounts, and the phospholipase c gamma 2-dependent activation pathway appeared to function normally. No autoantibodies to GPVI were found in the patient's serum using monoclonal antibody immobilization of platelet antigen (MAIPA). Sequencing of coding regions of the GPVI gene failed to show abnormalities, and mRNA for GPVI was present in the patient's platelets, pointing to a probable acquired defect in GPVI expression. Our results may provide a molecular explanation for the subgroup of patients with severely deficient collagen-induced platelet aggregation as previously described for GPS in the literature.- - - - - - - - - - ranking = 0.16666666666667keywords = collagen-induced (Clic here for more details about this article) |
3/9. Defective collagen-induced platelet activation in two patients with malignant haemopathies is related to a defect in the GPVI-coupled signalling pathway.The occurrence of a thrombocytopathy concomitantly to the development of a malignant haemopathy has been reported for some time, but little is known about the mechanism(s) involved in the platelet dysfunction. Platelet glycoprotein VI (GPVI) has now been identified as a principal platelet receptor for collagen. In this paper, we report the cases of two patients with a myelodysplasia and a B lymphopathy, respectively, who presented with thrombocytopathy in relation to a defective GPVI-mediated platelet reactivity to collagen. Thus, with regard to the different steps of adhesion, activation secretion or aggregation, patients' platelet responses to collagen and to the GPVI specific agonists, collagen related peptide (CRP) or convulxin were null or dramatically impaired. Platelet responses to other agonists ADP, TRAP, arachidonic acid were normal or showed only a moderate decrease. GPVI content was repeatedly normal, and binding of specific ligands, such as convulxin, satisfactory. Nevertheless, specific activating monoclonal antibodies and convulxin failed to induce platelet secretion; collagen, CRP or convulxin were unable to provoke calcium mobilisation. Furthermore, using a perfusion chamber model, we showed that ex vivo collagen-induced thrombi formation was very impaired. Taken together, these data provide evidence, for the first time, of an acquired defect in GPVI-mediated platelet reactivity to collagen, which reflects data observed in constitutional GPVI deficiencies, in two patients with malignant haemopathies.- - - - - - - - - - ranking = 0.83333333333333keywords = collagen-induced (Clic here for more details about this article) |
4/9. osteonectin is an alpha-granule component involved with thrombospondin in platelet aggregation.We previously showed that thrombospondin, a major alpha-granule glycoprotein of human platelets, forms a specific complex with osteonectin, a phosphoglycoprotein originally described in bone that is also present in human platelets. The storage organelles and the function of osteonectin in platelets are still unknown. In this study, using electron microscopy in combination with immunogold staining, the major storage organelle for platelet-secreted proteins, the alpha-granules. Furthermore, osteonectin was qualitatively and quantitatively assessed by studying normal platelets and the platelets from a patient with gray platelet syndrome. gray platelet syndrome is a rare congenital bleeding disorder characterized by a selective deficiency in morphologically recognizable platelet alpha-granules and in the alpha-granule secretory proteins. Binding of an iodinated antiosteonectin monoclonal antibody to gray platelet proteins transferred to nitrocellulose from SDS-polyacrylamide gels showed no band corresponding to osteonectin compared to control platelets. Using a polyclonal antiosteonectin antibody-based radioimmunoassay, gray platelets contained 0.2 /- 0.03 ng osteonectin per 10(6) platelets, which is only 20% of the normal platelet content of osteonectin (0.93 /- 0.16 ng per 10(6) platelets). Study of the localization of osteonectin to the surface of human platelets demonstrated that a radioiodinated antiosteonectin polyclonal antibody bound specifically to thrombin-stimulated platelets but not to resting platelets. Binding was concentration-dependent, saturable (1710 /- 453 binding sites per platelet, Kd = 1 microM), and inhibited by an excess of cold antiosteonectin polyclonal antibody. No binding was observed on the surface of thrombin-stimulated gray platelets. To gain further insights into the role of osteonectin released from activated platelets, the effect of an antiosteonectin polyclonal antibody was tested on the aggregation of washed platelets. F(ab')2 fragments from the antiosteonectin polyclonal antibody inhibited in a dose-dependent manner the aggregation of collagen-stimulated, washed human platelets without affecting collagen-induced platelet serotonin release. To characterize the mechanism through which antiosteonectin F(ab')2 fragments inhibit platelet aggregation, the expression of endogenous thrombospondin (TSP) on the surface of thrombin-activated platelets was studied using 125I-labeled anti-TSP monoclonal antibody P10. The endogenous surface expression of TSP to thrombin-stimulated platelets was significantly inhibited in the presence of antiosteonectin F(ab')2 fragments (6286 /- 2065 molecules of P10 per platelet) compared to 11,230 /- 766 molecules of P10 per platelet in the presence of nonimmune F(ab')2 fragments.(ABSTRACT TRUNCATED AT 400 WORDS)- - - - - - - - - - ranking = 0.16666666666667keywords = collagen-induced (Clic here for more details about this article) |
5/9. Acquired thrombasthenia due to GPIIb/IIIa-specific platelet autoantibodies.An otherwise healthy woman developed a hemorrhagic diathesis with fluctuating clinical symptoms and laboratory findings, but without thrombocytopenia, over 8 years. In periods of bad clinical condition, a platelet defect, characteristic of thrombasthenia, was found. In contrast to classic thrombasthenia, electrophoresis of the patient's platelet membranes revealed normal amounts of glycoproteins IIb alpha, IIb beta, and IIIa in the normal positions. Monoclonal antibodies, specific for GPIIIa and GPIIb/IIIa, respectively, bound normally to the P1A1-positive platelets from the patient. Although no antibody and no platelet function inhibitor were evident in the autologous plasma, an IgG1 antibody that was bound to the patient's platelets and was directed against GPIIb/IIIa could be demonstrated. After elution from the patient's platelets, this antibody immunoprecipitated GPIIb (both subunits), IIIa, and a 200-kilodalton (kd) band (probably undissociated GPIIb/IIIa complex) from solubilized normal platelets, but did not react with thrombasthenic platelets. Adding the eluate from the patient's platelets to normal platelet-rich plasma immediately caused concentration-dependent inhibition of adenosine diphosphate (ADP)-induced and collagen-induced aggregation and also strong inhibition of ADP-stimulated fibrinogen binding. Because it was very unlikely from the patient's medical history that the antibody was caused by alloimmunization, the hemorrhagic diathesis must be interpreted as acquired thrombasthenia due to an anti-GPIIb/IIIa autoantibody.- - - - - - - - - - ranking = 0.16666666666667keywords = collagen-induced (Clic here for more details about this article) |
6/9. Deficiency of intact thrombospondin and membrane glycoprotein Ia in platelets with defective collagen-induced aggregation and spontaneous loss of disorder.Platelets from a patient with a severe lifelong bleeding tendency, which later spontaneously disappeared, lacked intact thrombospondin and glycoprotein (GP) Ia. Before disappearance of the bleeding disorder, results of coagulation studies and platelet aggregation in response to adenosine diphosphate (ADP), arachidonic acid, thrombin, A23187, epinephrine, and ristocetin were normal. In contrast, aggregation only occurred in the presence of collagen or wheat germ agglutinin at unusually high doses of these agonists. The platelets adhered normally to purified bovine and human type I collagen, and they did not spread in the presence of methylated type I collagen. No collagen-induced clot retraction was observed. Two-dimensional gel electrophoretic analyses of platelet proteins and immunologic studies showed that intact thrombospondin and GP Ia were absent. Aggregation in response to collagen could be restored by adding thrombospondin. Disappearance of the bleeding tendency occurred at the onset of menopause; subsequent analyses revealed that thrombospondin and GP Ia were present in platelets and that collagen-induced platelet aggregation was normal. These results suggest that both thrombospondin and GP Ia are essential in collagen-induced platelet aggregation. The spontaneous disappearance of the bleeding tendency may have been related to hormonal influences.- - - - - - - - - - ranking = 1.1666666666667keywords = collagen-induced (Clic here for more details about this article) |
7/9. A novel platelet aggregating factor found in a patient with defective collagen-induced platelet aggregation and autoimmune thrombocytopenia.We found a novel platelet aggregating factor in a patient with steroid-responsive immune thrombocytopenic purpura that is associated with defective collagen-induced platelet functions. The aggregating factor and platelet functions were analyzed. The patient, a 58-year-old female, had purpura and prolonged bleeding time despite adequate platelet counts (greater than 140,000/microL) after steroid therapy. The patient's platelets responded normally to all agonists except collagen. Platelet adhesion to collagen fibrils was decreased. The patient's plasma induced irreversible aggregation and ATP release in normal platelet-rich plasma (PRP). This platelet aggregating factor was found in F(ab')2 fragments of the patient's IgG, which caused thromboxane b2 synthesis, elevation of cytoplasmic Ca2 levels, and phosphorylation of 40 kDa protein in normal platelets. platelet aggregation by the patient's IgG was inhibited by prostacyclin, dibutyryl cAMP, diltiazem, disodium ethylenediaminetetraacetate, and antimycin a plus iodoacetate, but ADP scavengers, cyclo-oxygenase inhibitors, and heparin had little or no effect. The aggregating activity of the patient's IgG absorbed to and eluted from normal platelets. The patient's Fab fragments did not induce platelet aggregation in eight of ten normal PRP but specifically inhibited aggregation induced by collagen and by the patient's IgG. The major component of an immunoprecipitate made with the patient's IgG from radiolabeled membrane proteins of normal platelet extract had a 62 kDa mol wt, while no such precipitate appeared in extracts of the patient's platelets. These results indicated that platelet aggregation by the patient's IgG was induced by the reaction of an antibody with a specific antigen on the normal platelet membrane through stimulus-response coupling. This antigen may be a collagen receptor on the platelet, most likely a polypeptide of 62 kDa under reducing condition. The defect of collagen-induced aggregation of the patient's platelets seemed to be due to alteration of the membrane protein related to this putative collagen receptor.- - - - - - - - - - ranking = 1keywords = collagen-induced (Clic here for more details about this article) |
8/9. The clinical relevance of platelet aggregation study in myeloproliferative disorders.30 unselected patients with various entities of the myeloproliferative syndrome were entered into a prospective study to evaluate the relationship between platelet aggregation abnormalities and hemostatic complications and the role of aggregation study in myeloproliferative disorders. 21 patients showed impaired collagen-induced aggregation and absent second phase epinephrine-induced response. 6 of these patients had bleeding manifestations. 4 patients hyperaggregated with ADP, collagen, epinephrine and arachidonic acid. Of these, 3 had thrombotic complications as their initial presentation. In the 6-40 months follow-up no new cases of bleeding or thromboembolic phenomena were encountered among the remaining patients. In 3 patients aggregation abnormalities heralded the specific myeloproliferative disorder by months or years. We conclude from this study that routine platelet aggregation study in classical myeloproliferative disorders is unwarranted as it is costly and does not improve the diagnostic accuracy nor yield any predictive information concerning the tendency to bleed. It is useful as an accessory investigative tool in the atypical or early myeloproliferative patient whose clinical features, blood and marrow findings although suggestive are not diagnostic of a specific myeloproliferative entity.- - - - - - - - - - ranking = 0.16666666666667keywords = collagen-induced (Clic here for more details about this article) |
9/9. Deficiency of p-selectin in a patient with grey platelet syndrome.Patient B.G. is a 29-yr-old female with a lifelong bleeding disorder characterized clinically by a highly increased bleeding time, menorrhagias, long-lasting bleeding after cuts and tooth extractions and large post-traumatic haematomas. Her coagulation tests were within normal range, platelet count was 140,000-160,000 per microliters, but platelet function was impaired as demonstrated by the absence of collagen-induced aggregation, although no abnormalities were detected in aggregation response to ADP and ristocetin. Morphologically her platelets were characterized by gigantic size-average profile area was about 2.5 times higher than that of control donors, and severe deficiency of alpha-granules-only 16% of their number in control donors. These features taken together indicated the diagnosis of grey platelet syndrome. As has been shown by quantitative immunoblotting, patient's platelets contained small amounts of alpha-granule membrane protein p-selectin-about 15% of that in control donors. The content of plasma membrane glycoproteins IIb-IIIa and Ib was not reduced, suggesting the specific deficiency of alpha-granule membrane protein. Thus, B.G. is the second patient described in the literature (see also Lages et al, J Clin Invest 1991: 87: 919-929) with combined deficiency of alpha-granules and p-selectin.- - - - - - - - - - ranking = 0.16666666666667keywords = collagen-induced (Clic here for more details about this article) |