The gene for May-Hegglin anomaly localizes to a <1-Mb region on chromosome 22q12.3-13.1.
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The May-Hegglin anomaly (MHA) is an autosomal dominant platelet disorder of unknown etiology. It is characterized by thrombocytopenia, giant platelets, and leukocyte inclusion bodies, and affected heterozygotes are predisposed to bleeding episodes. The MHA gene has recently been localized, by means of linkage analysis, to a 13.6-cM region on chromosome 22, and the complete chromosome 22 sequence has been reported. We recently performed a genome scan for the MHA gene in 29 members of a large, multigenerational Italian family, and we now confirm that the MHA locus is on chromosome 22q12. 3-13.1. The maximal two-point LOD score of 4.50 was achieved with the use of marker D22S283, at a recombination fraction of.05. Haplotype analysis narrowed the MHA critical region to 6.6 cM between markers D22S683 and D22S1177. It is of note that the chromosome 22 sequence allowed all markers to be ordered correctly, identified all the candidate genes and predicted genes, and specifically determined the physical size of the MHA region to be 0. 7 Mb. These results significantly narrow the region in which the MHA gene is located, and they represent the first use of chromosome 22 data to positionally clone a disease gene. (+info)
Ultrastructural aspects of interactions of platelets with microcrystalline collagen.
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Whole blood anticoagulated with EDTA was stirred with high concentrations of a microcrystalline bovine dermal collagen preparation in order to study the interactions of blood cells with collagen at the ultrastructural level. Blood from normal subjects and from patients congenitally deficient in Factors VIII or XII or with thrombasthenia or von Willebrands disease was used. In scanning and transmission electron microscopic studies with blood from normal subjects and patients, platelets were seen to adhere to collagen, develop cell surface undulations, form pseudopods, and undergo morphologic changes suggestive of the release reaction. Although thrombasthenic platelets adhered to collagen, pseudopods formed by these cells were remarkably angulated and nodular. Relatively few von Willebrands platelets adhered to collagen, but those platelets that did adhere underwent the usual sequence of morphologic changes. (+info)
Low-density lipoprotein activates the small GTPases Rap1 and Ral in human platelets.
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Physiological concentrations of low-density lipoprotein (LDL) sensitize blood platelets to alpha-thrombin- and collagen-induced secretion, and after prolonged contact trigger secretion independent of other agonists. Here we report that LDL activates the small GTPases Rap1 and Ral but not Ras, as assessed by specific precipitation of the GTP-bound enzymes. In unstirred suspensions, the inhibitor SB203580 blocks Rap1 activation by 60-70%, suggesting activation via p38 mitogen-activated protein kinase and a second, unidentified route. Inhibitors of cyclooxygenase (indomethacin) and the thromboxane A(2) (TxA(2)) receptor (SQ30741) induce complete inhibition, indicating that Rap1 activation is the result of TxA(2) formation. Stirring reveals a second, TxA(2)-independent Rap1 activation, which correlates quantitatively with a slow induction of dense granule secretion. Both pathways are unaffected by inhibitors of ligand binding to integrin alpha(IIb)beta(3). The results suggest that Rap1 and Ral, but not Ras, may take part in signalling routes initiated by LDL that initially enhance the sensitivity of platelets to other agonists and later trigger LDL-dependent secretion. (+info)
Improved platelet counting using two-dimensional laser light scatter.
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Clinical management of platelet disorders depends on accurate platelet counts. We evaluated a new analytic approach for platelet counting based on improved platelet discrimination. Current automated counting methods provide accurate platelet counts for most samples but often are unable to discriminate platelets accurately from nonplatelet particles such as microcytic RBCs, RBC fragments, and cellular debris that may falsely elevate platelet counts. The new approach measures 2 light-scatter angles of platelets and nonplatelet particles as they pass through a laser beam. The volume and refractive index of each platelet and particle are derived from the light-scatter measurements using the Mie scattering theory. Together, these 2 measurements provide improved platelet discrimination compared with 1-dimensional methods. With its improved discrimination, 2-dimensional platelet analysis provides more accurate platelet counts in samples containing interfering particles and may contribute to more effective clinical management of patients with platelet disorders. (+info)
Mediterranean macrothrombocytopenia.
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Platelet count, platelet size, and circulating platelet biomass concentration estimates made with an erythrocyte-calibrated electronic sizing system on EDTA-anticoagulated blood samples gave population medians and 95% ranges for 145 asymptomatic Mediterranean and 200 healthy Northern European subjects. The Mediterraneans had lower platelet counts [161,000 (89,000-290,000)/mul compared with 219,000 (148,000-323,000)/mul] and higher arithmetic mean volumes [17.8 (10.8-29.2) cu mum compared with 12.4 (9.9-15.6) cu mum], while the individual lognormal platelet size distribution profiles were comparable [geomatric standard deviations of 1.78 (1.60-1.98) against 1.70 (1.54-1.88)]; and the platelet biomass concentrations, given by count per microliter times mean volume times 10- minus 7 and expressed as a volumetric percentage of whole blood, were almost identical [0.286% (0.216%-0.379%) against 0.272% (0.201%-0.367%)]. Mediterranean macrothrombocytopenia is, therefore, considered a benign morphologic variant that requires differentiation from thrombocytopenias in which the circulating platelet biomass concentration is decreased. (+info)
A pregnancy complicated with Fechtner syndrome: a case report.
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A 21-year-old woman was diagnosed with Fechtner syndrome at 15 weeks gestation. She had a familial history of this disorder; her mother, two siblings and maternal grandmother were also affected. She presented with neither bleeding from the genital tract nor symptoms suggestive of placental abruption. Labor progressed uneventfully and resulted in the birth of a healthy female infant weighing 3436 g at 41 weeks of gestation. The puerperium was uneventful for both mother and infant. (+info)
Autosomal-dominant giant platelet syndromes: a hint of the same genetic defect as in Fechtner syndrome owing to a similar genetic linkage to chromosome 22q11-13.
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Families with 3 different syndromes characterized by autosomal dominant inheritance of low platelet count and giant platelets were studied. Fechtner syndrome is an autosomal-dominant variant of Alport syndrome manifested by nephritis, sensorineural hearing loss, and cataract formation in addition to macrothrombocytopenia and polymorphonuclear inclusion bodies. Sebastian platelet syndrome is an autosomal-dominant macrothrombocytopenia combined with neutrophil inclusions that differ from those found in May-Hegglin syndrome or Chediak-Higashi syndrome or the Dohle bodies described in patients with sepsis. These inclusions are, however, similar to those described in Fechtner syndrome. Other features of Alport syndrome, though, including deafness, cataracts, and nephritis, are absent in Sebastian platelet syndrome. Epstein syndrome is characterized by macrothrombocytopenia without neutrophil inclusions, in addition to the classical Alport manifestations-deafness, cataracts, and nephritis-and it is also inherited in an autosomal-dominant mode. We mapped the disease-causing gene to the long arm of chromosome 22 in an Italian family with Fechtner syndrome, 2 German families with the Sebastian platelet syndrome, and an American family with the Epstein syndrome. Four markers on chromosome 22q yielded an LOD score greater than 2.76. A maximal 2-point LOD score of 3.41 was obtained with the marker D22S683 at a recombination fraction of 0.00. Recombination analysis placed the disease-causing gene in a 3.37-Mb interval between the markers D22S284 and D22S693. The disease-causing gene interval in these 3 syndromes is similar to the interval described recently in an Israeli family with a slightly different Fechtner syndrome than the one described here. Recombination analysis of these 3 syndromes refines the interval containing the disease-causing gene from 5.5 Mb to 3.37 Mb. The clinical likeness and the similar interval containing the disease-causing gene suggest that the 3 different syndromes may arise from a similar genetic defect. (+info)
Platelets from a patient heterozygous for the defect of P2CYC receptors for ADP have a secretion defect despite normal thromboxane A2 production and normal granule stores: further evidence that some cases of platelet 'primary secretion defect' are heterozygous for a defect of P2CYC receptors.
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Two unrelated patients with a congenital bleeding diathesis associated with a severe defect of the platelet ADP receptor coupled to adenylate cyclase (P2(CYC)) have been described so far. In one of them, platelet secretion was shown to be abnormal. We recently showed that platelets with the primary secretion defect (PSD; characterized by abnormal secretion but normal granule stores, thromboxane A(2) production, and ADP-induced primary wave of aggregation) have a moderate defect of P2(CYC). Therefore, the interaction of ADP with the full complement of its receptors seems to be essential for normal platelet secretion, and PSD patients may be heterozygotes for the congenital severe defect of P2(CYC). In this study, we describe 2 new related patients with a severe defect of P2(CYC) and the son of one of them, who is to be considered an obligate heterozygote for the defect. The 2 patients with the severe defect had lifelong histories of abnormal bleeding, prolonged bleeding times, abnormalities of platelet aggregation and secretion, lack of inhibition of adenylate cyclase by ADP, and a deficiency of platelet-binding sites for [(33)P]2 MeS-ADP (240 and 225 sites per platelet; normal range, 530 to 1102). The son of one of them had a mildly prolonged bleeding time and abnormalities of platelet aggregation and secretion similar to those found in patients with PSD. In addition, his platelets showed a moderate defect of binding sites for [(33)P]2 MeS-ADP (430 sites per platelet) and of adenylate cyclase inhibition by ADP. This study of a family with the platelet disorder characterized by a defect of the platelet P2(CYC) receptor supports our hypothesis that the full complement of the platelet ADP receptors is essential for normal platelet secretion and that some patients with the common, ill-defined diagnosis of PSD are actually heterozygous for the defect. (+info)