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PubMed1992

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

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.

Adult↗
PubMed1987

Patients with a prolonged bleeding time and normal aggregation tests may have storage pool deficiency: studies on one hundred six patients.

One hundred six patients with storage pool deficiency (SPD) were studied with respect to platelet count, bleeding time, total platelet ATP and ADP, platelet serotonin, and in vitro aggregation. The diagnosis of SPD was made on basis of a prolonged bleeding time, a decreased total platelet ADP, and a diminished level of serotonin. Fifty-one patients from 34 unrelated families had congenital SPD, and 55 patients had acquired SPD. Congenital SPD was a common disorder in patients with a lifelong bleeding tendency and a prolonged bleeding time. The frequency in this group of patients was 18%, about one-half the frequency of von Willebrand's disease (vWd). Twenty-three percent of all patients had normal aggregation responses to ADP, epinephrine, and collagen; 33% had aggregation tracings typical for a secretion defect; and 44% had miscellaneous aggregation abnormalities. These findings indicate that SPD is common, heterogeneous, and not necessarily associated with in vitro aggregation abnormalities.

Bleeding Time↗
PubMed1977

The Hermansky-Pudlak syndrome. Evidence for a lowered 5-hydroxytryptamine content in platelets of heterozygotes.

A Dutch kindred with the Hermansky-Pudlak syndrome (HPS) is described. We show for the first time evidence of a lowered platelet 5-hydroxytryptamine content in obligate heterozygotes. Platelet ATP and ADP levels and ATP/ADP ratio were normal in these patients. Platelet aggregation with ADP, collagen and adrenaline was within the normal range. In contrast to the homozygous HPS patients the heterozygotes are normally pigmented and none has diaphanous irides, nystagmus or a bleeding tendency. All homozygous HPS patients have the typical triad of oculocutaneous albinism, pigmented macrophages in the bone marrow and a bleeding disorder, based on a platelet dysfunction. The platelets showed the typical characteristics of a storage pool deficiency. Their platelet factor 3 availability was decreased and the aggregation patterns showed an absent second wave with ADP, adrenaline and absent collagen aggregation. Platelet ADP levels were strongly decreased in all homozygous HPS patients, whereas ATP was lowered only in 3 out of 6 HPS patients. The 5-hydroxytryptamine content of their platelets was very low (15-20% of normal).

Adenosine Diphosphate↗
PubMed2001

Mild hypoxia causes severe pulmonary hypertension in fawn-hooded but not in Tester Moriyama rats.

The purpose of this study was to test whether the Tester Moriyama rat (TMR), a strain that has a serotonin platelet storage-pool deficiency similar to that of the fawn-hooded rat (FHR), develops severe pulmonary hypertension (PH) upon exposure to mild hypoxia. We compared hemodynamic parameters in catheterized 10-week-old FHR, TMR, and control Wistar rats that had been raised from birth to 10 weeks of age under normoxia (PI(O(2)) approximately 150 mmHg) or mild hypobaric hypoxia (PI(O(2)) approximately 120 mmHg). Mean pulmonary artery pressure and right ventricle to left ventricle plus septum weight ratio were much higher in the mildly hypoxic FHR compared with the normoxic FHR. These parameters were only increased slightly by exposure to mild hypoxia in the TMR and Wistar rats. Mild hypoxia did not affect mean systemic artery pressure in any of the rat strains. Exposure of FHR to mild hypoxia from 4 to 10 weeks of age did not lead to development of PH. Endothelin-1 (ET-1) mRNA and peptide levels were increased in the hypertensive lungs of mildly hypoxic FHR compared with the normotensive lungs of normoxic FHR, and of normoxic and mildly hypoxic TMR and Wistar rats. These results suggest that mild hypoxia causes severe PH and upregulation of lung ET-1 expression in neonatal FHR but not in neonatal TMR, and that the period from birth to 4 weeks of age is critical for the development of the severe PH in the FHR. A serotonin PSPD does not predispose rats to hypoxia-induced PH.

Animals↗
PubMed1997

Inherited disorders of platelet alpha-granules.

Platelet alpha-granules are the storage site for the internal membrane glycoprotein P-selectin and for a variety of megakaryocyte-synthesized and plasma-derived soluble proteins. Quantitative and/or qualitative abnormalities in alpha-granules are found in a number of inherited bleeding disorders, including gray platelet syndrome, alphadelta-storage pool deficiency, the Quebec platelet disorder, and in some patients with dysmegakaryopoietic thrombocytopenia. In addition, single alpha-granular protein deficiencies are seen in other bleeding disorders,including factor V deficiency, afibrinogenemia, Glanzmann's thrombasthenia, von Willebrand disease, and plasminogen-activator inhibitor-1 deficiency. The excessive bleeding that occurs in patients with inherited abnormalities of platelet alpha-granules indicates that the proteins stored within this compartment are important for normal hemostasis. The clinical and laboratory features of these different, inherited platelet storage pool disorders suggest unique molecular and biochemical defects are responsible for these conditions. However, the genetic causes of these disorders are largely unknown. This paper reviews our current knowledge of the inherited disorders of platelet alpha-granules.

Journal Article↗
PubMed1998

Flow cytometric analysis of reticulated platelets: evidence for a large proportion of non-specific labelling of dense granules by fluorescent dyes.

The labelling of platelets with thiazole orange (TO) has been utilized by various laboratories to determine the percentage of reticulated platelets within whole blood or platelet-rich plasma (PRP). A proportion of TO labelling, however, is not entirely mRNA specific and remains to be fully defined. Almost half of the total TO-positive signal within normal platelets (n = 5) was shown to be abrogated upon degranulation with 80 microM thrombin receptor activating peptide (TRAP) (P = 0.006), strongly suggesting that platelet granules are non-specifically labelling with dye. We have confirmed this hypothesis by studying TO labelling of platelets within whole blood from dense granule deficient patients, e.g. Hermansky-Pudlak syndrome (HPS) (n = 5) and storage pool disease (SPD) (n = 4). The levels of TO-positive platelets were found to be significantly lower than normal (P = 0.0003 and P = 0.0002 respectively), but not significantly different from TRAP degranulated platelets. Upon degranulation of HPS and SPD platelets there was very little further reduction in the TO signal. Incubation of normals and SPD whole blood with different concentrations of either TO or coriphosphine-O confirmed that dense granules were non-specifically labelling even at high concentrations of both dyes. These findings suggest that although TO labelling is in part RNA specific, the dense granular pool of nucleotides appears to cause a substantial amount (approximately 50%) of non-specific labelling observed under these conditions of assay. This can easily be controlled for by a degranulation step with a non-enzymatic platelet agonist such as TRAP, and may have important consequences for the eventual standardization. clinical utilization and automation of reticulated platelet assays.

Albinism, Oculocutaneous↗
PubMedDate not supplied

[The induction of an acquired storage pool deficiency of the thrombocytes by IgG antibodies in systemic lupus erythematosus and chronic polyarthritis].

Sera of patients with RA and SLE contain platelet-reactive IgG antibodies, which bring about the release of serotonin from platelets. They can also induce the aggregation of normal human platelets. In addition, such antibodies cause a decreased in vitro disaggregation of platelets after ADP exposure, as well as a significantly reduced collagen-induced aggregation. Thus, IgG platelet antibodies in RA and SLE can cause a functional impairment of patients' platelets, and may also be instrumental in systemic inflammatory rheumatoid disease by releasing proinflammatory mediators.

Adenosine Diphosphate↗
PubMed1981

Platelet aggregation independent of ADP release or prostaglandin synthesis in patients with hermansky-Pudlak syndrome.

Platelets from patients with the Hermansky-Pudlak (HPS) syndrome are deficient in the storage pool of adenine nucleotides and serotonin. As a result, the storage pool deficient (SPD) platelets develop only single waves of clumping when stimulated by threshold concentrations of aggregating agents which cause irreversible, biphasic aggregation of normal platelets. Yet, patients with HPS either have no bleeding problems or only mild symptoms. In the present study we have evaluated the importance of prostaglandin synthesis and secretion to the irreversible aggregation of HPS platelets. Results of the study demonstrate that aspirin-treated SPD platelets, which cannot form thromboxane or undergo the release reaction on stimulation by arachidonate, can still undergo irreversible aggregation in response to thrombin and ADP if treated first with epinephrine. A mechanism of membrane modulation mediated by alpha-adrenergic receptors cooperatively linked to the endoperoxide and thromboxane receptor can secure irreversible aggregation of normal or abnormal platelets despite absence of secretion and prostaglandin synthesis.

Adenosine Diphosphate↗
PubMed1984

Correlation between prolonged bleeding time and depletion of platelet dense granule ADP in patients with myelodysplastic and myeloproliferative disorders.

Nine patients with myelodysplasia or myeloproliferative syndrome were studied with respect to platelet count and volume, 51Cr and 14C-serotonin platelet kinetics, bleeding time, and platelet dense and alpha-granule contents. Platelet counts ranged from 45,000 to 293,000 platelets/microliters. The bleeding time was significantly longer (greater than 4 minutes) than the predicted value in seven of nine patients. All patients had significant dense granule storage pool depletion (thrombin-releasable ADP was 0.59 +/- 0.30 vs. 2.41 +/- 0.20 mumol per 10(11) platelets in patients compared with normal volunteers; total platelet ADP was 0.97 +/- 0.29 vs. 2.72 +/- 0.15, and total platelet ATP/ADP was 4.77 +/- 1.89 vs. 1.65 +/- 0.11). The prolongation in bleeding time correlated inversely with thrombin-releasable ADP (r = -0.637, p less than 0.01) and with total ADP (r = -0.832, p less than 0.005), and directly with the ATP/ADP ratio (r = 0.781, p less than 0.005). When autologous platelets were doubly labeled with 14C-serotonin and 51Cr to test for loss of dense granule contents, marked preferential shortening of the 14C-serotonin platelet disappearance curve with relation to 51Cr platelet survival was observed in five of the six patients (six normal participants uniformly showed 14C-serotonin platelet disappearance patterns that were 15% to 20% longer than 51Cr platelet survivals). Reduction in alpha-granule contents was less striking and occurred less frequently than dense granule depletion (two of nine values were significantly reduced for platelet factor 4 content, whereas all patients had significantly reduced dense granule ADP levels). Mean plasma levels of both platelet factor 4 and beta-thromboglobulin were elevated in patients compared with normal participants (4.1 +/- 3.2 and 26.6 +/- 12.3 vs. 1.8 +/- 1.0 and 6.0 +/- 3.6 ng/ml; p less than 0.01 and p less than 0.01, respectively). Two patients had elevated urinary platelet factor 4. There was no correlation between platelet factor 4 content and thrombin-releasable platelet ADP levels (r = 0.167, p greater than 0.1). These patients had acquired storage pool deficiency of platelet dense granule ADP that correlated directly with platelet dysfunction, as measured by prolongation of bleeding time. The reduction in dense granule constituents appears to be the consequence of an ongoing loss of dense granule contents from circulating platelets.

Adenosine Diphosphate↗
PubMed1991

Paradoxical constriction to platelets by arteries from rats with pulmonary hypertension.

We recently described the early appearance of pulmonary hypertension in the fawn-hooded rat (FHR), an animal with platelet storage pool disease also known to develop systemic hypertension at later ages. Since mediators released from aggregating platelets influence vascular tone, we hypothesized that platelet-mediated pulmonary vascular responses in FHR may be abnormal and potentially linked to the mechanism of pulmonary hypertension. To test this we examined reactivity of isolated pulmonary arteries (PA) and thoracic aortas (Ao) from young FHR with moderately severe pulmonary hypertension but normal systemic pressures. These vessels were compared with PA and Ao from control Sprague-Dawley rat (SDR). Aggregating platelets (1,000-40,000 platelets/mm3) from FHR caused dilation of SDR PA and Ao but constriction of FHR PA and Ao. Qualitatively similar responses were also observed with platelets isolated from SDR implying that abnormal responses were not simply due to the storage pool deficiency in FHR. Response to the platelet-derived endothelium-dependent vasodilator ADP was markedly impaired in FHR PA and mildly impaired in FHR Ao. Endothelium-dependent dilation to acetylcholine, but not to A23187, was mildly impaired in FHR PA while responses to both dilators were normal in FHR Ao. Endothelium-independent dilation to sodium nitroprusside was normal in both FHR PA and Ao. Constrictor sensitivity to serotonin, but not to the thromboxane A2 mimetic U-46619, was increased in FHR PA while responses to both constrictors were normal in FHR Ao. In summary, PAs from FHR with spontaneous pulmonary hypertension exhibit paradoxical constriction to both normal and storage pool deficient platelets.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1976

Platelet function in the Chediak-Higashi syndrome.

Platelet function studies were performed on two patients with the Chediak-Higashi syndrome, one of whom had a history of easy bruising unrelated to thrombocytopenia. Both patients had prolonged bleeding times, abnormal platelet aggregation, and a defect of platelet storage granules, manifested by reduced platelet ADP, an increased ATP/ADP ratio, increased adenine nucleotide specific radioactivity after 3H-adenine labeling, and decreased platelet uptake of radioactive 5-hydroxytryptamine. These findings confirm preliminary data in animals with the Chediak-Higashi syndrome, provide and explanation for impaired primary hemostasis in these patients, and illustrate another disorder in which platelet storage-pool deficiency occurs.

Adenosine Diphosphate↗
PubMed1986

Acquired von Willebrand disease and storage pool disease in chronic myelocytic leukemia.

Platelet function was evaluated in 20 patients with chronic myelocytic leukemia (CML), all Ph positive. Seven showed abnormal epinephrine-induced aggregation, while four had impaired both ADP- and collagen-induced aggregation. The platelets of all patients aggregated with arachidonic acid, thus ruling out cyclooxygenase or lipoxygenase deficiency. The intracellular concentrations of ATP and ADP were significantly below normal, and the ratio of ATP/ADP was greater than normal in all 12 patients. ATP released from platelets by Lumi-aggregometer was reduced. In four patients with abnormal ristocetin-induced aggregation, vWF:Ag, RCoF, and FVIII:C were all reduced. No significant inactivation of factor VIII was induced in normal plasma by incubation with patient's plasma. The crossed immunoelectrophoretic analysis revealed that vWF:Ag in these patients was mainly composed of more anodic component as compared with that of normal plasma. The ratio of vWF:Ag/RCoF was significantly greater than normal. A marked increase of factor VIII and a rapid return of vWF:Ag and RCoF to the baseline after the 1-deamino-8-arginine vasopressin (DDAVP) infusion were observed. Transient increase in vWF:Ag after the infusion of DDAVP appeared with less anodic forms and in the same relative proportion as that in normal plasma. The present study shows that in some patients with CML storage pool disease occurs with acquired von Willebrand disease.

Adenosine Triphosphate↗
PubMed2001

Recurrent haemoperitoneum in a mild von Willebrand's disease combined with a storage pool deficit.

Haemoperitoneum secondary to haemorrhagic corpus luteum has been described in severe bleeding disorders such as afibrinogenaemia, type 3 von Willebrand's disease and patients under oral anticoagulation. We have studied one patient who presented three episodes of severe bleeding at ovulation, requiring surgery twice, with the diagnosis of mild von Willebrand's disease and mild storage pool deficiency. Mild von Willebrand's disease (associated with other thrombopathies or coagulopathies) should be considered in this pathology, although physicians would prefer to find a severe haemorrhagic disorder as the underlying condition in these cases.

Abdomen, Acute↗
PubMed2002

Phosphotyrosine proteins in platelets from patients with storage pool disease: direct relation between granule defects and defective signal transduction.

BACKGROUND AND OBJECTIVES: Storage pool diseases (SPD) are heterogeneous disorders associated with an abnormal presence of intraplatelet granules, which cause mild to moderate bleeding diathesis. We investigated signaling through tyrosine phosphorylation of proteins occurring in platelets with total or partial absence of dense- and alpha-granules in response to activation. DESIGN AND METHODS: We included a patient with severe delta-SPD, a patient with severe alpha-SPD or gray platelet syndrome, and six patients with partial deficiency of dense or a-granules. SPD was confirmed by electron microscopy evaluation of platelet ultrastructure. Platelet function was evaluated by bleeding time determination and conventional aggregometry. Platelet suspensions were activated with collagen and thrombin to analyze changes in tyrosine phosphorylation of proteins by electrophoresis and Western-blotting. RESULTS: Bleeding times were prolonged in all the patients included. Aggregation responses were slightly decreased in delta-SPD and normal in the rest of patients. Tyrosine phosphorylation in platelets from patients with partial forms of SPD was equivalent to that observed in control platelets, absent in response to collagen and thrombin activation in delta-SPD, and deficient only to thrombin activation in alpha-SPD. INTERPRETATION AND CONCLUSIONS: Tyrosine phosphorylation of proteins in activated platelets is highly dependent on the substances contained in the dense-granules and moderately dependent on those contained in the alpha-granules. A minimum amount of intraplatelet granules ensures signaling through tyrosine phosphorylation of proteins.

Adolescent↗
PubMed2000

Platelet ultrastructural morphometry for diagnosis of partial delta-storage pool disease in patients with mild platelet dysfunction and/or thrombocytopenia of unknown origin. A study of 24 cases.

BACKGROUND AND OBJECTIVE: Exact diagnosis is sometimes difficult in patients presenting with a slight bleeding diathesis, prolonged bleeding times, non-specific aggregometric abnormalities, and/or mild thrombocytopenia. The objective of this study was to evaluate the use of platelet ultrastructural morphometry in detecting a partial d-storage pool disease in such patients. DESIGN AND METHODS: Platelets from 52 patients and 15 controls were fixed immediately in glutaraldehyde in White's saline without anticoagulant and processed for transmission electron microscopy. Using computer-assisted morphometry, the size and shape of the platelets were measured, as were the size and number per platelet of the dense- and a-granules. Ultrastructural morphology of the above and other intraplatelet structures was observed. RESULTS: Twenty-four cases were diagnosed as having a partial d-storage pool disease. Mean platelet area (2.28 microm(2)) and maximum diameter (2.58 microm) were significantly greater in patients than in control subjects (1.64 microm(2) and 2. 25 microm, respectively) but discoid shape was preserved. Mean dense-granule number was decreased, both per platelet and per microm(2) of platelet area (patients 0.22 and 0.09; controls 0.42 and 0.24). Seven patients also had a marked decrease in a-granules, resulting in a significantly lower mean number of granules per microm(2 )(patients 2.43; controls 3.15). Additionally, the patients' platelets had significant increases in both lipid droplets and surface-connected canalicular system. INTERPRETATION AND CONCLUSIONS: A partial dense-granule deficiency, sometimes associated with partial a-granule deficiency, should be borne in mind faced with patients who have a slight bleeding diathesis, non-specific platelet dysfunction tests and/or mild thrombocytopenia of unknown origin. Platelet ultrastructural morphometry is useful in diagnosing this condition.

Adolescent↗