scholarly journals Correction of symptoms of platelet storage pool deficiency in animal models for Chediak-Higashi syndrome and Hermansky-Pudlak syndrome

Blood ◽  
1985 ◽  
Vol 66 (5) ◽  
pp. 1196-1201
Author(s):  
EK Novak ◽  
MP McGarry ◽  
RT Swank
Keyword(s):  
Bone Marrow ◽  
Animal Models ◽  
Dense Granule ◽  
Whole Body ◽  
Inherited Disorders ◽  
Humoral Factors ◽  
Storage Pool ◽  
Platelet Storage ◽  
Hermansky Pudlak Syndrome ◽  
Chediak Higashi Syndrome

Two human diseases of platelet storage pool deficiency (SPD), Hermansky- Pudlak syndrome and Chediak-Higashi syndrome, are recessively inherited disorders characterized by hypopigmentation, prolonged bleeding, and normal platelet counts accompanied by a reduction in dense granule number. We have recently described seven independent recessive mutations in the mouse regulated by separate genes which are likely animal models for human SPD. Reciprocal bone marrow transplants were carried out between normal C57BL/6J mice and two of these mutants, beige and pallid, in order to test whether the platelet defects are due to a defect in platelet progenitor cells or to humoral factors. Normal and congenic mutant mice were transplanted with marrow after 950 rad whole body radiation. The long bleeding times and low serotonin concentrations of the two mutants were converted to normal values after transplantation with normal marrow. Likewise, normal mice displayed symptoms of SPD when transplanted with mutant marrow. These studies demonstrate that with each of the two mutations, platelet SPD results from a defect in bone marrow precursor cells. Also, the studies suggest that in severe cases, platelet SPD may be successfully treated by bone marrow transplantation.

scholarly journals Correction of symptoms of platelet storage pool deficiency in animal models for Chediak-Higashi syndrome and Hermansky-Pudlak syndrome

Blood ◽  
1985 ◽  
Vol 66 (5) ◽  
pp. 1196-1201 ◽  
Author(s):  
EK Novak ◽  
MP McGarry ◽  
RT Swank
Keyword(s):  
Bone Marrow ◽  
Animal Models ◽  
Dense Granule ◽  
Whole Body ◽  
Inherited Disorders ◽  
Humoral Factors ◽  
Storage Pool ◽  
Platelet Storage ◽  
Hermansky Pudlak Syndrome ◽  
Chediak Higashi Syndrome

Abstract Two human diseases of platelet storage pool deficiency (SPD), Hermansky- Pudlak syndrome and Chediak-Higashi syndrome, are recessively inherited disorders characterized by hypopigmentation, prolonged bleeding, and normal platelet counts accompanied by a reduction in dense granule number. We have recently described seven independent recessive mutations in the mouse regulated by separate genes which are likely animal models for human SPD. Reciprocal bone marrow transplants were carried out between normal C57BL/6J mice and two of these mutants, beige and pallid, in order to test whether the platelet defects are due to a defect in platelet progenitor cells or to humoral factors. Normal and congenic mutant mice were transplanted with marrow after 950 rad whole body radiation. The long bleeding times and low serotonin concentrations of the two mutants were converted to normal values after transplantation with normal marrow. Likewise, normal mice displayed symptoms of SPD when transplanted with mutant marrow. These studies demonstrate that with each of the two mutations, platelet SPD results from a defect in bone marrow precursor cells. Also, the studies suggest that in severe cases, platelet SPD may be successfully treated by bone marrow transplantation.

scholarly journals Storage pool deficiency in cattle with the Chediak-Higashi syndrome results from an absence of dense granule precursors in their megakaryocytes

Blood ◽  
1988 ◽  
Vol 72 (5) ◽  
pp. 1726-1734 ◽  
Author(s):  
M Menard ◽  
KM Meyers
Keyword(s):  
Electron Microscopy ◽  
Bone Marrow ◽  
Transmission Electron Microscopy ◽  
Membrane System ◽  
Dense Granule ◽  
Virtual Absence ◽  
Dense Granules ◽  
Storage Pool ◽  
Transmission Electron ◽  
Chediak Higashi Syndrome

Abstract Platelets from cattle with the Chediak-Higashi syndrome (CHS) have a storage pool deficiency and virtual absence of platelet dense granules. Megakaryocytes (MKs) from five control (n = 135) and five CHS (n = 133) cattle were evaluated using standard transmission electron microscopy. Osmiophilic dense granules were not observed in control or CHS MKs. In MKs from normal cattle, clear vesicles of 200- to 650-nm diameter bounded by a sharp membrane were observed. They were easily differentiated from the demarcation membrane system, endoplasmic reticulum, and alpha granules. The clear vesicles were virtually absent in MKs from CHS cattle at all stages of maturation. MKs in bone marrow samples from two control (n = 91) and two CHS (n = 61) cattle that had been processed for the uranaffin reaction were also evaluated. The clear vesicles were replaced by uranaffin-positive granules in MKs from control cattle, but positive uranaffin granules were not observed in CHS MKs. These findings indicate that the platelet dense granule storage pool deficiency in CHS cattle results from an anatomic absence of dense granule precursors in maturing and mature CHS MKs.

scholarly journals Sandy: a new mouse model for platelet storage pool deficiency

1991 ◽  
Vol 58 (1) ◽  
pp. 51-62 ◽  
Author(s):  
Richard T. Swank ◽  
Hope O. Sweet ◽  
Muriel T. Davisson ◽  
Madonna Reddington ◽  
Edward K. Novak
Keyword(s):  
Dense Granule ◽  
Recessive Mutation ◽  
Mouse Mutant ◽  
Dense Granules ◽  
Storage Pool ◽  
Platelet Storage ◽  
Autosomal Recessive Mutation ◽  
Acidification Activity ◽  
Hermansky Pudlak Syndrome ◽  
Reduced Rate

SummarySandy (sdy) is a mouse mutant with diluted pigmentation which recently arose in the DBA/2J strain. Genetic tests indicate it is caused by an autosomal recessive mutation on mouse Chromosome 13 near thecrandXtgenetic loci. This mutation is different genetically and hematologically from previously described mouse pigment mutations with storage pool deficiency (SPD). The sandy mutant has diluted pigmentation in both eyes and fur, is fully viable and has prolonged bleeding times. Platelet serotonin levels are extremely low although ATP dependent acidification activity of platelet organelles appears normal. Also, platelet dense granules are extremely reduced in number when analysed by electron microscopy of unfixed platelets. Platelets have abnormal uptake and flashing of the fluorescent dye mepacrine. Secretion of lysosomal enzymes from kidney and from thrombin-stimulated platelets is depressed 2- and 3-fold, and ceroid pigment is present in kidney. Sandy platelets have a reduced rate of aggregation induced by collagen. The sandy mutant has an unusually severe dense granule defect and thus may be an appropriate model for cases of human Hermansky-Pudlak syndrome with similarly extreme types of SPD. It represents the tenth example of a mouse mutant with simultaneous defects in melanosomes, lysosomes and/or platelet dense granules.

scholarly journals Storage pool deficiency in cattle with the Chediak-Higashi syndrome results from an absence of dense granule precursors in their megakaryocytes

Blood ◽  
1988 ◽  
Vol 72 (5) ◽  
pp. 1726-1734
Author(s):  
M Menard ◽  
KM Meyers
Keyword(s):  
Electron Microscopy ◽  
Bone Marrow ◽  
Transmission Electron Microscopy ◽  
Membrane System ◽  
Dense Granule ◽  
Virtual Absence ◽  
Dense Granules ◽  
Storage Pool ◽  
Transmission Electron ◽  
Chediak Higashi Syndrome

Platelets from cattle with the Chediak-Higashi syndrome (CHS) have a storage pool deficiency and virtual absence of platelet dense granules. Megakaryocytes (MKs) from five control (n = 135) and five CHS (n = 133) cattle were evaluated using standard transmission electron microscopy. Osmiophilic dense granules were not observed in control or CHS MKs. In MKs from normal cattle, clear vesicles of 200- to 650-nm diameter bounded by a sharp membrane were observed. They were easily differentiated from the demarcation membrane system, endoplasmic reticulum, and alpha granules. The clear vesicles were virtually absent in MKs from CHS cattle at all stages of maturation. MKs in bone marrow samples from two control (n = 91) and two CHS (n = 61) cattle that had been processed for the uranaffin reaction were also evaluated. The clear vesicles were replaced by uranaffin-positive granules in MKs from control cattle, but positive uranaffin granules were not observed in CHS MKs. These findings indicate that the platelet dense granule storage pool deficiency in CHS cattle results from an anatomic absence of dense granule precursors in maturing and mature CHS MKs.

scholarly journals Immature dense granules in platelets from mice with platelet storage pool disease

Blood ◽  
1987 ◽  
Vol 69 (5) ◽  
pp. 1300-1306 ◽  
Author(s):  
M Reddington ◽  
EK Novak ◽  
E Hurley ◽  
C Medda ◽  
MP McGarry ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Dense Granule ◽  
Mutant Mice ◽  
Normal Numbers ◽  
Group Of Seven ◽  
Dense Granules ◽  
Storage Pool ◽  
Platelet Storage ◽  
Transmission Electron ◽  
Storage Pool Disease

Mepacrine uptake into platelets and bone marrow megakaryocytes was analyzed to further characterize the dense granule defects in a group of seven mouse pigment mutants that have characteristics of platelet storage pool disease (SPD). In contrast to our previous studies using electron microscopy, this method revealed that all mutants had normal numbers of dense granules. However, total mepacrine uptake in all mutant platelets was significantly diminished to less than 50% of normal uptake. Also, the flashing phenomenon observed when normal dense granules are irradiated with ultraviolet light was either greatly diminished or absent when platelets of individual mutants were similarly irradiated. Therefore the principal defect in the mutant platelets is an inability to accumulate dense granule contents rather than an absence of the granules. Mepacrine uptake into megakaryocytes was indistinguishable in normal and mutant mice. This indicates the mutant dense granule defects appear either very late in megakaryocyte development or early in platelet formation in correlation with development of the mature dense granule. By standard transmission electron microscopy we have not been able to detect gross structural or subcellular abnormalities in either platelets or megakaryocytes of mutant mice. It appears all seven mutants produce immature or functionally abnormal dense granules.

scholarly journals Quantification of a novel dense granule protein (granulophysin) in platelets of patients with dense granule storage pool deficiency

Blood ◽  
1992 ◽  
Vol 80 (5) ◽  
pp. 1231-1237 ◽  
Author(s):  
A Shalev ◽  
G Michaud ◽  
SJ Israels ◽  
A McNicol ◽  
S Singhroy ◽  
...  
Keyword(s):  
Membrane Vesicles ◽  
Dense Granule ◽  
Enzyme Linked Immunosorbent Assay ◽  
Granule Formation ◽  
Standard Curve ◽  
Storage Pool ◽  
Granule Membrane ◽  
Hermansky Pudlak Syndrome ◽  
Novel Protein

An antigen-capture sandwich enzyme-linked immunosorbent assay (ELISA) was developed for a novel protein granulophysin, a constituent of the platelet dense granule (DG) membrane and used to characterize patients with dense granule storage pool deficiency (delta-SPD). The assay uses two monoclonal antibodies against the protein, one of which is conjugated to peroxidase. Purified DGs, an enriched source of the protein, were used for the standard curve. Granulophysin levels were only low in forms of delta-SPD associated with albinism. Granulophysin levels in platelet homogenates of 30 patients with the Hermansky-Pudlak syndrome form of delta-SPD were 1/4 to 1/5 of levels in controls or obligate heterozygotes. Two patients with the Chediak-Higashi form of delta-SPD syndrome also had markedly reduced levels of granulophysin. Patients with other forms of delta-SPD had normal levels of granulophysin. Two sisters with delta-SPD in one family had normal granulophysin present in empty dense granule membrane vesicles. Three members of another family with delta-SPD had low DG counts but normal granulophysin levels, indicating that in this group the level of granulophysin was maintained despite the reduction in granule formation. Thus, granulophysin quantitation facilitates characterization of delta-SPD patients and may provide clues to the nature of defective granules in delta-SPD subtypes.

A Functional Basis For The Platelet Storage Pool Deficiency In Chediak-Higashi Cattle

1981 ◽  
Author(s):  
K M Meyers ◽  
M Fukami ◽  
H Holmsen
Keyword(s):  
Freeze Fracture ◽  
Subcellular Fractionation ◽  
Dense Granule ◽  
Bivalent Cation ◽  
Fibrous Matrix ◽  
Dense Granules ◽  
Storage Pool ◽  
Common Basis ◽  
Platelet Storage ◽  
Amine Storage

Platelets from cattle with the morphologic homolog of the Chediak-Higashi (CH) syndrome are essentially devoid of secretable nucleotides and serotonin. There are reduced but still substantial amounts of secretable calcium and magnesium. The storage pool deficiency may be, in part, due to a functional granule defect. Platelets from CH cattle take up serotonin and protect it from degradation for several hours. If these platelets are treated with thrombin, serotonin and bivalent cations are released by mechanisms similar to that of secretion, suggesting a granule location for the released serotonin and cations. This suggestion is verified by subcellular fractionation studies where platelets are first incubated with 14C-serotonin then lysed using a French press. Organelles were then separated on a sucrose gradient by centrifugation. Serotonin in normal bovine platelets is associated with the dense granule or pellet while in CH platelets serotonin is primarily found in a region of the sucrose density zone that in normal platelets contain alpha granules. These findings suggested that some granules in CH platelets are able to acquire the bivalent cation and amine but not the nucleotide component of the bivalent cation-nucleotide-amine storage complex that is thought to occur in normal dense granules.Ultrastructural identification of the serotonin-containing CH granule is not known. There are 2 identifiable granule populations in CH platelets, alpha granules and fibrous matrix granules. Based on serial sectioning freeze fracture and morphometric studies, there are less than 4 of these granules/platelet. Mepacrine studies also demonstrate 2 granule populations. One population has an incidence of 2 per granule and characteristics of normal dense granules. Since the number of fibrous matrix granules and mepacrine granules is similar, a common basis for these granules which has at least some dense granule characteristics, i.e., mepacrine storage, is suggested.

scholarly journals Hermansky-Pudlak Syndrome Type 3 in Ashkenazi Jews and Other Non–Puerto Rican Patients with Hypopigmentation and Platelet Storage-Pool Deficiency

2001 ◽  
Vol 69 (5) ◽  
pp. 1022-1032 ◽  
Author(s):  
Marjan Huizing ◽  
Yair Anikster ◽  
Diana L. Fitzpatrick ◽  
Anna B. Jeong ◽  
Maria D’Souza ◽  
...  
Keyword(s):  
Puerto Rican ◽  
Syndrome Type ◽  
Ashkenazi Jews ◽  
Storage Pool ◽  
Platelet Storage ◽  
Hermansky Pudlak Syndrome ◽  
Type 3

scholarly journals An Investigation of ABO Blood Type and the Platelet Delta Granule Storage Pool

2021 ◽  
Vol 27 ◽  
pp. 107602962110688
Author(s):  
Ryan J. Reagans ◽  
Paula M. Kramer ◽  
Jacob A. Cichocki ◽  
William T. Gunning
Keyword(s):  
Dense Granule ◽  
Blood Type ◽  
Storage Pool ◽  
Platelet Storage ◽  
Number Of Patients ◽  
Study Population ◽  
Abo Blood Type ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
The U.S

Individuals with bleeding tendencies are more likely to have blood type O than blood types A, B, or AB. Platelet storage pool deficiencies are a lesser-known group of bleeding disorders which often go undiagnosed and may account for a significant number of patients with unexplained bleeding defects. We hypothesized that patients with platelet δ-storage pool deficiency might also have a predominance of type O blood. A retrospective review of medical records of 2,020 patients with unexplained bleeding and evaluated for δ-storage pool deficiency was performed. Correlations between dense granule numbers, blood type, and von Willebrand factor were analyzed for statistical differences. 51.5% of blood samples were blood type O compared to an incidence of 44.0% in the U.S. population. There was a significant association of vWF and blood type O but not with the delta storage pool. There is a preponderance of blood type O in the study population compared to the U.S. population. There is no statistically significant link between blood type O and lower dense granule numbers in this study.

scholarly journals Immature dense granules in platelets from mice with platelet storage pool disease

Blood ◽  
1987 ◽  
Vol 69 (5) ◽  
pp. 1300-1306 ◽  
Author(s):  
M Reddington ◽  
EK Novak ◽  
E Hurley ◽  
C Medda ◽  
MP McGarry ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Dense Granule ◽  
Mutant Mice ◽  
Normal Numbers ◽  
Group Of Seven ◽  
Dense Granules ◽  
Storage Pool ◽  
Platelet Storage ◽  
Transmission Electron ◽  
Storage Pool Disease

Abstract Mepacrine uptake into platelets and bone marrow megakaryocytes was analyzed to further characterize the dense granule defects in a group of seven mouse pigment mutants that have characteristics of platelet storage pool disease (SPD). In contrast to our previous studies using electron microscopy, this method revealed that all mutants had normal numbers of dense granules. However, total mepacrine uptake in all mutant platelets was significantly diminished to less than 50% of normal uptake. Also, the flashing phenomenon observed when normal dense granules are irradiated with ultraviolet light was either greatly diminished or absent when platelets of individual mutants were similarly irradiated. Therefore the principal defect in the mutant platelets is an inability to accumulate dense granule contents rather than an absence of the granules. Mepacrine uptake into megakaryocytes was indistinguishable in normal and mutant mice. This indicates the mutant dense granule defects appear either very late in megakaryocyte development or early in platelet formation in correlation with development of the mature dense granule. By standard transmission electron microscopy we have not been able to detect gross structural or subcellular abnormalities in either platelets or megakaryocytes of mutant mice. It appears all seven mutants produce immature or functionally abnormal dense granules.

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