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PubMed1984

Auricular chondritis in fawn-hooded rats. A spontaneous disorder resembling that induced by immunization with type II collagen.

A spontaneous apparently unique auricular chondritis in the pinna of fawn-hooded rats is described. The chondritis was bilateral, with adult onset, and resulted in a marked thickening of the auricular cartilage. Microscopically, islands of proliferative cartilage were present, and at the margins between the normal cartilage and the thickened abnormal cartilage a marked cellular inflammatory response was present. The condition was familial in rats of the fawn-hooded strain and appeared to be unrelated to the platelet storage pool deficiency in this strain of rats. Biochemically no increased synthesis of pinna cartilage was detected. No histopathologic lesions were detected in other cartilaginous tissues of affected rats. The lesions in the pinna bore a striking resemblance to those induced in rats by immunization with Type II collagen. The spontaneous condition described herein may, therefore, represent a unique model of relapsing polychondritis of human beings, a disease with auricular chondritis associated with antibodies to Type II collagen.

Animals↗
PubMed1994

Genetic map of the region around grizzled (gr) and mocha (mh) on mouse chromosome 10, homologous to human 19p13.3.

Grizzled (gr) is a recessive mouse mutation resulting in a gray coat color and reduced perinatal viability. Mocha (mh) is one of several recessive mouse mutants characterized by platelet storage pool disorder, pigment abnormalities, reduced fertility, kidney function deficiencies, and, in some mutants, inner ear and natural killer cell deficiencies. Murine platelet storage pool deficient mutants may be models for Chediak-Higashi and Hermansky-Pudlak syndromes in humans. The genes for gr and mh are very closely linked to each other (0 +/- 1.2 cM). However, their relative position with respect to molecular markers was previously unknown. Thus, genetic mapping of the gr locus will also yield information about the mh location. To map these two genes genetically, we have performed an intersubspecific backcross of grizzled mice with Mus musculus castaneus. In 539 progeny tested, we found no recombination between the gr gene, the gene for anti-Muellerian hormone (Amh), and the microsatellite markers D10Mit7, D10Mit21, and D10Mit23. One recombination event for each of the flanking markers Basigin (Bsg) and D10Mit22 was identified. These closely linked markers should provide entry points for positional cloning of the gr and mh genes. The region linked to grizzled is homologous to a gene-rich region on human Chromosome 19p13.3.

Animals↗
PubMed1974

Studies of platelet 5-hydroxytryptamine (serotonin) in storage pool disease and albinism.

Platelets in patients with storage pool disease are markedly deficient in a nonmetabolic (storage) pool of ADP that is important in platelet aggregation. They are also deficient in ATP, although to a lesser degree. In seven patients with this disorder, including one with albinism, platelet 5-hydroxytryptamine (5-HT) levels were reduced in proportion to the reduction in ATP (r = 0.94). Their platelets show diminished capacity to absorb [(14)C]5-HT, and the type of defect was similar to that produced in normal platelets by reserpine, a drug known to inhibit the uptake of 5-HT by the platelet dense granules. Storage pool-deficient platelets also converted more [(3)H]5-HT to [(3)H]5-hydroxyindoleacetic acid than did normal platelets, and the platelets in one of two patients studied contained increased amounts of 5-HT metabolites. The above findings, together with those reported previously, support the conclusion that the capacity of the dense granules (which may be either diminished or functionally abnormal) for storing 5-HT is decreased in storage pool disease; as a result, the 5-HT that enters the platelet may be more exposed to monoamine oxidases present on mitochondrial membranes. This diminished storage capacity (for 5-HT) may also explain why preincubating platelet-rich plasma with 5-HT for 45 min without stirring inhibits subsequent platelet aggregation by 5-HT to a greater degree in patients with storage pool disease than in normal subjects. The latter finding is also consistent with the theory that the aggregation of platelets by 5-HT is mediated by the same receptors on the plasma membrane that are involved in its uptake. The diminished release of platelet-bound [(14)C]5-HT by collagen that we found in these patients, as well as findings in previous studies, suggests that the release reaction may also be abnormal in storage pool disease.

Adenosine Diphosphate↗
PubMed2001

The storage defects in grey platelet syndrome and alphadelta-storage pool deficiency affect alpha-granule factor V and multimerin storage without altering their proteolytic processing.

Among proteins stored in alpha-granules, multimerin and factor V share unusual features: they bind to each other, are proteolysed to unique forms and are stored eccentrically in alpha-granules. These unique features of their processing led us to study these proteins in alpha delta storage pool deficiency (alphadelta-SPD) and grey platelet syndrome (GPS, alpha-SPD), two conditions known to impair alpha-granule protein storage. Platelet factor V and multimerin were severely reduced in GPS, whereas they ranged from reduced to normal in alphadelta-SPD. The platelet levels of factor V and multimerin in these disorders indicated multimerin deficiency was not predictive of platelet factor V deficiency, although it reduced the amount of multimerin associated with platelet factor V. In GPS only, the defect in storing proteins was associated with increased multimerin and multimerin-factor V complexes in plasma. Like normal platelets, GPS and alphadelta-SPD platelets contained factor V mainly in granules. Platelet factor V and multimerin were proteolysed to normal platelet forms in GPS and alphadelta-SPD platelets, indicating that these conditions preserve some aspects of normal alpha-granule protein processing. Although we found factor V can be stored in platelets deficient in multimerin, our data indicate that multimerin storage influences the point at which multimerin binds factor V.

Blood Platelets↗
PubMed1997

Platelet prothrombinase activity and intracellular calcium responses in patients with storage pool deficiency, glycoprotein IIb-IIIa deficiency, or impaired platelet coagulant activity--a comparison with Scott syndrome.

The procoagulant activity of platelets induced by collagen, thrombin, and collagen plus thrombin, measured as their capacity to promote the conversion of prothrombin to thrombin in the presence of factors Va and Xa, was studied in patients with alpha, alpha delta, and delta storage pool deficiency (SPD), thrombasthenia, and in two new patients with isolated defects in platelet coagulant activity, and compared with that in Scott syndrome. The most significant abnormality in the new patients, whose defect may differ from that in Scott syndrome, is an impairment in collagen plus thrombin-induced prothrombinase activity in the absence of added factor Va. In one of these patients this may be caused by an abnormality in platelet alpha-granule factor V distinct from that described for factor V Quebec, alpha delta-SPD, or alpha-SPD (gray platelet syndrome). Prothrombinase activity in response to all agonists was impaired in delta-SPD and was associated with an inability of these platelets to maintain elevated intracellular calcium levels. Both the rapid decline in agonist-induced [Ca2+]i levels and the impaired prothrombinase activation in delta-SPD platelets were corrected by the addition of adenosine diphosphate (ADP) after stimulation. These findings suggest that secreted ADP may play an important role in the generation of prothrombinase activity by contributing to the maintenance of a critical [Ca2+]i level necessary to maintain aminophospholipids on the outer surface of the platelet membrane, and provide evidence that dense granules may be a major source of ADP which can contribute to calcium influx in stimulated platelets. Parallel alterations, including both increases and decreases, in the [Ca2+]i and prothrombinase responses were also observed in thrombasthenia, depending on the agonist and stirring conditions. Both responses were increased in collagen-stimulated, unstirred platelets, whereas an inability to maintain increased [Ca2+]i levels, associated with decreased prothrombinase activity in all but one atypical patient, was seen in stirred collagen plus thrombin-activated platelets. Although the parallel alterations in these responses in thrombasthenia, as in SPD, further show the close association between the generation of prothrombinase activity and the maintenance of increased intracellular Ca2+ levels, the specific role that GPIIb-IIIa may play in both these events remains unresolved. Our findings of both enhancement and inhibition of these activation-related events in thrombasthenic platelets may be related to previous conflicting reports on the promotion or inhibition of fibrin formation by GPIIb-IIIa, and could be relevant to the use of specific inhibitors of GPIIb-IIIa as antithrombotic agents. In addition, the study provides further support for the concept that the development of agents that could induce a Scott syndrome defect in normal platelets may provide a new approach to antithrombotic therapy.

Adult↗
PubMed2004

The P2Y1 receptor plays an essential role in the platelet shape change induced by collagen when TxA2 formation is prevented.

ADP and TxA2 are secondary agonists which play an important role as cofactors when platelets are activated by agonists such as collagen or thrombin. The aim of the present study was to characterize the role of the ADP receptor P2Y(1) in collagen-induced activation of washed platelets. Inhibition of P2Y(1) alone with the selective antagonist MRS2179 prolonged the lag phase preceding aggregation in response to low or high concentrations of fibrillar collagen, without affecting the maximum amplitude of aggregation or secretion. A combination of MRS2179 and aspirin resulted in complete inhibition of platelet shape change at low and high collagen concentrations, together with a profound decrease in aggregation and secretion. Scanning electron microscopy showed that these platelets had conserved the discoid morphology typical of the resting state. A lack of shape change was also observed in aspirin-treated P2Y(1)- and G(alphaq)-deficient mouse platelets and in delta-storage pool-deficient platelets from Fawn Hooded rats. In contrast, when the second ADP receptor P2Y(12) was inhibited with AR-C69931MX, aspirin-treated platelets were still able to change shape and displayed only a moderate decrease in aggregation and secretion. In conclusion, this study provides evidence that collagen requires not only the TxA2 receptor Tpalpha, but also P2Y(1), to induce platelet shape change.

Adenosine Diphosphate↗
PubMed1988

The response of platelets to epinephrine in storage pool deficiency--evidence pertaining to the role of adenosine diphosphate in mediating primary and secondary aggregation.

Aggregation responses and thromboxane (Tx) formation in ten patients with storage pool deficiency (SPD) specific to the dense granules (delta-SPD) were studied to assess further the role of dense granule adenosine diphosphate (ADP) in mediating platelet aggregation by epinephrine. The ability of epinephrine to elicit secondary aggregation (SA) responses was highly variable in delta-SPD when tested at 5 mumol/L epinephrine, but was consistently abnormal when tested over a range of concentrations. The occurrence of SA in both delta-SPD patients and normal subjects was correlated with the magnitude of the rate of primary aggregation (PA). This PA rate was normal, on average, for the entire patient group but was greater in patients with more consistent SA responses. The PA findings were related to the Kd value obtained in binding studies with 3H-yohimbine, but not with the number of alpha 2-receptor sites. Studies on Tx production (assessed by radioimmunoassay of TxB2) showed that the ability to synthesize Tx from arachidonate was not impaired in delta-SPD, and that there was an absolute positive correlation between epinephrine-induced SA and Tx production. Aggregation in delta-SPD platelets in response to the Tx receptor agonist U44069 was consistently decreased, but could be corrected by addition of ADP. The results of the study suggest that dense granule-derived ADP is not required for PA by epinephrine, but mediates SA as a synergistic agonist with TxA2. This role of ADP in SA may be elucidated more precisely by further studies on platelet activation processes in delta-SPD.

Adenosine Diphosphate↗
PubMed1996

Correction of the platelet adhesion defect in delta-storage pool deficiency at elevated hematocrit--possible role of adenosine diphosphate.

Previous studies on patients with storage pool deficiency (SPD) who are specifically deficient in platelet dense granules (delta-SPD) have suggested a role for dense granule substances, in all likelihood adenosine diphosphate (ADP), in mediating thrombus formation on subendothelium at high shear rates. The role of dense granule substances in mediating platelet adhesion appears to be more complicated Previous studies in delta-SPD suggested an adhesion defect that was strongly influenced by the patient's hematocrit (Hct) value. To explore further the possibility that red blood cells (RBCs) may influence the role that platelet storage granules play in mediating adhesion at high shear rates, we have measured adhesion (and thrombus formation) throughout a preselected range of Hct values (30% to 60%) in normal subjects and in patients with delta-SPD. The present studies confirm the defect in platelet adhesion in patients with delta-SPD, most significantly at Hct values of 30% to 40%. This defect (but not that of thrombus formation) can be completely corrected by the addition of RBCs. The correction of the platelet adhesion defect by RBCs was specific for delta-SPD; it was not observed in either von Willebrand's disease or thrombasthenia. Studies performed on normal blood under conditions that could be expected to block any effect of ADP on adhesion and an analysis of the type of adhesion defect in delta-SPD suggest that ADP may be involved in the process required for platelet spreading on the subendothelium. The corrective effect of RBCs on platelet adhesion in delta-SPD appears to be chemical rather than physical in nature, possibly due to shear-induced release of RBC ADP or to other recently described properties of RBCs that enhance collagen-induced platelet interactions.

Adenosine Diphosphate↗
PubMed1999

Morphological changes of platelets following platelet aggregation induced by collagen in Japanese Black cattle with delta-storage pool deficiency.

Electron microscopic observation was performed on platelets activated by collagen stimulation in Japanese Black cattle with delta-storage pool deficiency (delta-SPD) to identify their morphological and functional abnormalities compared from normal bovine platelets. Platelets of normal Japanese Black cattle changed their shapes to spherical and were in the phase of release reactions 5 min after the collagen (90.9 microg/ml) stimulation, and most of platelets were aggregated. On the other hand, in GSPD cattle, most of a granules were still dispersed in activated platelets, although the spherical shape change of the platelets was observed. These results suggested that there are abnormalities in the release reactions in platelets of delta-SPD cattle.

Animals↗
PubMed1997

Evidence for locus heterogeneity in Puerto Ricans with Hermansky-Pudlak syndrome.

Hermansky-Pudlak syndrome (HPS) consists of ocu-locutaneous albinism, a platelet storage-pool deficiency, and ceroid lipofuscinosis. In a recent report on the cloning of an HPS gene, all 22 Puerto Rican HPS patients were homozygous for a 16-bp duplication in exon 15. This presumably reflected a founder effect for the HPS mutation in Puerto Rico. Nevertheless, we ascertained two individuals from central Puerto Rico who lacked the 16-bp duplication, exhibited significant amounts of normal-size HPS mRNA by northern blot analysis, and had haplotypes in the HPS region that were different from the haplotype of every 16-bp-duplication patient. Moreover, these two individuals displayed no mutations in their cDNA sequences, throughout the entire HPS gene. Both patients exhibited pigment dilution, impaired visual acuity, nystagmus, a bleeding diathesis, and absent platelet dense bodies, confirming the diagnosis of HPS. These findings indicate that analysis of Puerto Rican patients for the 16-bp duplication in HPS cannot exclude the diagnosis of HPS. In addition, HPS most likely displays locus heterogeneity, consistent with the existence of several mouse strains manifesting both pigment dilution and a platelet storage-pool deficiency.

Albinism, Oculocutaneous↗
PubMed1997

Enhanced increases in cytosolic Ca2+ in ADP-stimulated platelets from patients with delta-storage pool deficiency--a possible indicator of interactions between granule-bound ADP and the membrane ADP receptor.

The possible involvement of secreted platelet substances in agonist-induced [Ca2+]i increases was investigated by comparing these increases in aspirin-treated, fura-2-loaded normal platelets and platelets from patients with storage pool deficiencies (SPD). In the presence and absence of extracellular calcium, the [Ca2+]i response induced by 10 microM ADP, but not those induced by 0.1 unit/ml thrombin, 3.3 microM U46619, or 20 microM serotonin, was significantly greater in SPD platelets than in normal platelets, and was increased to the greatest extent in SPD patients with Hermansky-Pudlak syndrome (HPS), in whom the dense granule deficiencies are the most severe. Pre-incubation of SPD-HPS and normal platelets with 0.005-5 microM ADP produced a dose-dependent inhibition of the [Ca2+]i response induced by 10 microM ADP, but did not alter the [Ca2+]i increases induced by thrombin or U46619. Within a limited range of ADP concentrations, the dose-inhibition curve of the [Ca2+]i response to 10 microM ADP was significantly shifted to the right in SPD-HPS platelets, indicating that pre-incubation with greater amounts of ADP were required to achieve the same extent of inhibition as in normal platelets. These results are consistent with a hypothesis that the smaller ADP-induced [Ca2+]i increases seen in normal platelets may result from prior interactions of dense granule ADP, released via leakage or low levels of activation, with membrane ADP receptors, causing receptor desensitization. Addition of apyrase to platelet-rich plasma prior to fura-2 loading increased the ADP-induced [Ca2+]i response in both normal and SPD-HPS platelets, suggesting that some release of ADP derived from both dense granule and non-granular sources occurs during in vitro fura-2 loading and platelet washing procedures. However, this [Ca2+]i response was also greater in SPD-HPS platelets when blood was collected with minimal manipulation directly into anticoagulant containing apyrase, raising the possibility that release of dense granule ADP resulting in receptor desensitization may also occur in vivo. Thus, in addition to enhancing platelet activation, dense granule ADP could also act to limit the ADP-mediated reactivity of platelets exposed in vivo to low levels of stimulation.

Adenosine Diphosphate↗
PubMed1998

rim2 (recombination-induced mutation 2) is a new allele of pearl and a mouse model of human Hermansky-Pudlak syndrome (HPS): genetic and physical mapping.

A mouse mutation, rim2, is one of a series of spontaneous mutations that arose from the intra-MHC recombinants between Japanese wild mouse-derived wm7 and laboratory MHC haplotypes. This mutation is single recessive and characterized by diluted coat color and hypo-pigmentation of the eyes. We mapped the rim2 gene close to an old coat color mutation, pearl (pe), on Chromosome (Chr) 13 by the high-density linkage analysis. The pearl mutant is known to have abnormalities similar to Hermansky-Pudlak syndrome (HPS), a human hemorrhagic disorder, characterized by albinism and storage pool deficiency (SPD) of dense granules in platelets. A mating cross of C57BL10/Slc-rim2/rim2 and C57BL/6J-pe/pe showed no complementation of coat color. Additionally, characteristics similar to SPD were also observed in rim2. Thus, rim2 appeared to be a new allele of the pe locus and serves as a mouse model for human HPS. We have made a YAC contig covering the rim2/pe locus toward positional cloning of the causative gene.

Albinism, Oculocutaneous↗
PubMed2000

Evaluation of platelet function by flow cytometry.

Platelet function in whole blood can be comprehensively evaluated by flow cytometry. Flow cytometry can be used to measure platelet reactivity, circulating activated platelets, platelet-platelet aggregates, leukocyte-platelet aggregates, procoagulant platelet-derived microparticles, and calcium flux. Clinical applications of whole blood flow cytometric assays of platelet function in disease states (e.g., acute coronary syndromes, angioplasty, and stroke) may include identification of patients who would benefit from additional antiplatelet therapy and prediction of ischemic events. Circulating monocyte-platelet aggregates appear to be a more sensitive marker of in vivo platelet activation than circulating P-selectin-positive platelets. Flow cytometry can also be used in the following clinical settings: monitoring of GPIIb-IIIa antagonist therapy, diagnosis of inherited deficiencies of platelet surface glycoproteins, diagnosis of storage pool disease, diagnosis of heparin-induced thrombocytopenia, and measurement of the rate of thrombopoiesis.

Antibodies, Monoclonal↗
PubMed1995

Linkage disequilibrium mapping of the gene for Hermansky-Pudlak syndrome to chromosome 10q23.1-q23.3.

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by the triad of tyrosinase-positive oculocutaneous albinism, bleeding diathesis due to storage-pool deficiency of platelets, and a lysosomal ceroid storage disease. The disorder is particularly frequent in Puerto Rico and in an isolated village in the Swiss Alps. We have used a linkage disequilibrium mapping approach to localize the HPS gene in both of these groups to a 0.6 centiMorgan interval in chromosome segment 10q23.1-q23.3. These results indicate that the Puerto Rican and Swiss forms of HPS are either allelic or that they result from mutations in very closely linked genes in this region. This region of distal chromosome 10q is syntenic to the region of mouse chromosome 19 that includes 'pale ear' (ep) and 'ruby-eye' (ru), which must be considered as potential murine homologues to human HPS.

Albinism, Oculocutaneous↗
PubMed1980

Release of human platelet factor V activity is induced by both collagen and ADP and is inhibited by aspirin.

Factor V activity in suspensions of human platelets washed by albumin density gradient separation increased in response to stimulation by both collagen and adenosine diphosphate (ADP). The appearance of factor V activity extracellularly had the characteristics of platelet secretion and was partially inhibited by aspirin and by the antimetabolites 2-deoxyglucose and antimycin A. Some increase in factor V activity was also observed in platelet suspensions during the initial response to ADP; this activity was not detected extracellularly, but remained associated with the platelets. Patients with storage pool deficiency (SPD) whose platelets are deficient only in dense granule substances released normal amounts of factor V activity, whereas decreased amounts were released in a patient whose platelets have both dense and alpha granule deficiencies. These findings suggest that a portion of platelet factor V is associated with, and released from, alpha granules.

Adenosine Diphosphate↗
PubMed1998

The pulmonary hypertensive fawn-hooded rat has a normal serotonin transporter coding sequence.

The coding sequence of the serotonin transporter gene was compared in two strains of rat-the Wistar and the fawn-hooded rat (FHR). The FHR has an inherited platelet storage-pool deficiency and a widespread impairment of serotonin storage. It is also susceptible to systemic and pulmonary hypertension. The FHR provides a model to study the genetics in human systemic and pulmonary hypertension. We measured platelet function in these two strains by measuring incorporation of radiolabeled serotonin into a platelet suspension and found significant differences in serotonin uptake and release. The coding sequence for the serotonin transporter in the FHR has yet to be reported. No differences were found in the predicted amino acid sequence between these two strains of rat, either in the platelet or the lung samples or when compared with the published sequence of the brown rat. We conclude that differences in the primary structure of the serotonin transporter gene do not account for the altered serotonin storage in the FHR strain.

Amino Acid Sequence↗