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PubMed1983

Evidence that abnormal platelet functions in human Chédiak-Higashi syndrome are the result of a lack of dense bodies.

The structure and functions of platelets from three patients with the Chédiak-Higashi syndrome were examined. Electron-microscopic observations revealed a large reduction in the number of serotonin-storage granules or dense bodies but otherwise normal ultrastructure and normal amounts of alpha-granules and catalase-positive granules. The number of mepacrine-labeled granules was also reduced. Platelets contained normal amounts of beta-thromboglobulin and Platelet Factor 4. The platelet release reaction studied with thrombin as the inducer was impaired. The serotonin uptake by the patients' platelets was low and not inhibited by reserpine, and its metabolism was increased. These findings clearly show that platelets from human Chédiak-Higashi syndrome are deficient in the storage pool of dense granule substances and suggest that this granule defect has an influence on the release mechanism of other granule constituents.

Blood Platelets↗
PubMedDate not supplied

Spectrum of platelet aggregation abnormalities in myeloproliferative diseases.

Several platelet abnormalities have been described in myeloproliferative diseases. The present study deals with 81 patients with polycythaemia vera, chronic myelogenous leukemia, essential thrombocythaemia and idiopathic myelofibrosis, and reports the analysis of the findings in platelet-induced aggregation. Platelet abnormalities induced by ADP, adrenaline and collagen were found in 41.9% of the patients. A defect of primary aggregation was documented in 13 cases and one of them showed an aggregation pattern similar to that of Glanzmann's disease. Fifteen patients had an impairment of secondary aggregation, and in one case of this group the platelet malondialdehyde and serotonin findings were consistent with a defect resembling that of typical congenital storage pool deficiency. A disturbance of the arachidonic acid pathways associated with a storage pool deficiency was found in a third patient belonging to a group with abnormalities of primary and secondary aggregation. In conclusion, platelets in myeloproliferative diseases have several defects and in a few cases their combination is similar to those of congenital diseases.

Adenosine Diphosphate↗
PubMed1989

Platelet aggregation and ATP secretion in whole blood of normal cats and cats homozygous and heterozygous for Chediak-Higashi syndrome.

A rapid and simple technique using the Whole Blood Lumi-Aggregometer was used to study storage pool disease in Chediak-Higashi homozygote and heterozygote cats. Feline Chedlak-Higashi platelets aggregated after the addition of both ADP and collagen. During platelet aggregation, ATP secretion was assayed; the whole blood aggregometer is effective in detecting decreased levels of secretable ATP in homozygote cats. No storage pool deficiency was found in heterozygote cats. However, upon analysis of impedance tracings, a decreased platelet aggregation response was seen in both homozygote and heterozygote cats. These results suggest that prolonged bleeding times in Chediak-Higashi cats may involve a mechanism in addition to a dense granule deficiency.

Adenosine Triphosphate↗
PubMed1993

Intracellular calcium mobilization in rat platelets is adversely affected by copper deficiency.

The influence of copper deficiency on the mobilization of Ca2+ from intracellular stores following ionomycin treatment or thrombin activation of rat platelets was examined using the fluorescent indicator, fura-2, to measure changes in cytosolic Ca2+ concentration ([Ca2+]i). Platelets, obtained from copper-deficient and control rats and loaded with fura-2, were suspended in medium containing 1 mM EGTA and no added Ca2+. The size of the internal Ca2+ pools in the suspended platelets was estimated from the rise in [Ca2+]i following maximal discharge of stored Ca2+ by treatment with 1 microM ionomycin. Peak [Ca2+]i following ionomycin treatment was lower in platelets from copper-deficient rats compared to control rats (148 +/- 27 nM vs. 188 +/- 17 nM), suggesting that the size of the Ca2+ storage pools was decreased by copper deficiency. Furthermore, once internal Ca2+ stores were discharged by ionomycin, [Ca2+]i remained elevated in platelets from copper-deficient rats, but decreased in control rats. These data indicate that copper deficiency may inhibit the efflux of Ca2+ from platelets after its release from internal stores by ionomycin treatment. In platelets from copper-deficient and control rats, stimulation with 0.1 U/ml thrombin led to rapid rise followed by a slow decay in [Ca2+]i. However, peak [Ca2+]i was lower in platelets from copper-deficient rats than in control rats (94 +/- 19 nM vs. 131 +/- 16 nM). These findings imply that by reducing the amount of Ca2+ available for release from intracellular stores, copper deficiency also reduces [Ca2+]i following thrombin activation in the absence of external Ca2+.

Animals↗
PubMed1984

Platelet secretion defect associated with impaired liberation of arachidonic acid and normal myosin light chain phosphorylation.

We describe four patients with impaired platelet aggregation and 14C-serotonin secretion during stimulation with adenosine diphosphate (ADP), epinephrine, collagen, and platelet-activating factor. The response to arachidonic acid was normal in all patients with regard to aggregation and in three of the four with regard to 14C-serotonin secretion. The total platelet adenosine triphosphate (ATP) and ADP content and the ATP to ADP ratio was normal in all patients, thereby excluding storage pool deficiency as the cause of the secretion defect. Studies with 3H-arachidonic acid-labeled platelets revealed that the thrombin-induced liberation of arachidonic acid from membrane-bound phospholipids was impaired in these patients. Further, platelet thromboxane B2 production, measured using a radioimmunoassay, was diminished during stimulation with ADP and thrombin, but was normal with arachidonic acid, indicating that the oxygenation of arachidonic acid was normal and that the diminished thromboxane production was due to a defect in the liberation of arachidonic acid. Release of arachidonic acid is mediated by phospholipases that are Ca++ dependent. To examine whether these patients may have a defect in making intracellular Ca++ available, another Ca++-dependent process, myosin light chain phosphorylation, was studied during thrombin stimulation. Platelets from three of the patients were found to behave the same as normal ones, suggesting that the deficiency in phospholipase activity may not be due to impaired Ca++ mobilization. Our studies demonstrate a novel group of patients with platelet secretion defects associated with impaired liberation of arachidonic acid from phospholipids. These patients exemplify a congenital defect, other than deficiencies of cyclooxygenase and thromboxane synthetase, by which thromboxane production may be impaired in platelets.

Adenosine Diphosphate↗
PubMed1998

Congenital disorders of platelet function: disorders of signal transduction and secretion.

Congenital defects in platelet function are associated with bleeding manifestations of variable intensity and arise by diverse mechanisms. Defects in platelet-vessel wall interaction (disorders of adhesion) may arise because of qualitative or quantitative abnormalities in plasma von Willebrand factor (von Willebrand disease) or in platelet glycoprotein Ib, the binding site on platelets for von Willebrand factor (Bernard-Soulier syndrome). Disorders characterized by abnormal platelet-platelet interaction (disorders of aggregation) arise because of absence of plasma fibrinogen (congenital afibrinogenemia) or because of qualitative or quantitative abnormalities in platelet glycoprotein IIb-IIIa complex (Glanzmann's thrombasthenia). Patients with abnormalities in platelet secretion and signal transduction are a heterogeneous group characterized by impaired aggregation responses and secretion of granule contents. A small proportion of these patients have deficiency of granule stores (storage pool deficiency [SPD]) or impaired production of thromboxane A2; in most, the mechanisms underlying the platelet dysfunction are unknown. Evidence is accumulating that at least some patients have abnormalities in early signal transduction events. Abnormalities in phospholipase C activation, G-protein activation, and other events (eg, protein phosphorylation) have been documented. Platelets play a major role in blood coagulation, and in Scott syndrome, there is an abnormality in platelet contribution to the mechanisms leading to thrombin generation. In most patients with inherited platelet dysfunction, the underlying mechanisms remain to be delineated. Future studies of these patients should yield valuable new information on normal platelet mechanisms.

Blood Coagulation↗
PubMed1990

Adenine nucleotides, serotonin, and aggregation properties of platelets of blue foxes (Alopex lagopus) with the Chediak-Higashi syndrome.

Bleeding times, concentrations of serotonin in whole blood, and concentrations of adenine nucleotides as well as aggregation properties of platelets were examined in 18 blue foxes with Chediak-Higashi-like syndrome (CHS) and 16 controls. A claw of each ketamine-sedated fox was cut until bleeding started and the bleeding time was recorded as the time from the first to the last drop. The bleeding time was greatly increased in CHS foxes. Platelet counts of CHS foxes were normal, but aggregation induced by adenosine diphosphate (ADP), serotonin, collagen, and arachidonate was impaired. Adrenaline and serotonin was impaired. Adrenaline and serotonin potentiated the aggregatory effect of ADP on control as well as on CHS platelets. The mean concentration of ADP in CHS platelets was about one-third that in controls, whereas adenosine triphosphate (ATP) was approximately one-half that in controls. Serotonin could not, in most cases, be detected in blood of CHS foxes. These findings suggest that the prolonged bleeding time in the CHS foxes is, at least partly, due to a storage pool deficiency. The drastically reduced, and in some cases absent, aggregation of CHS platelets in response to arachidonate suggests that defective arachidonate metabolism contributes to the impaired hemostasis.

Adenine Nucleotides↗
PubMed1984

Platelet-activating factor is a weak platelet agonist: evidence from normal human platelets and platelets with congenital secretion defects.

We have examined the effects of a novel platelet agonist, platelet activating factor (PAF), on human platelets. Irreversible aggregation and 14C-serotonin secretion in response to PAF (10(-5) M) was found to be dependent on both thromboxane production and secreted adenosine diphosphate (ADP). Liberation of arachidonic acid (AA) from membrane-bound phospholipids is a prerequisite step in platelet thromboxane production. Studies with 3H-AA-labeled platelets revealed that PAF (10(-5) M) was a weak stimulus for the mobilization of AA. In addition, PAF (10(-5) M) was found to be a weak inducer of thromboxane synthesis (mean = 6 pmol/10(8) platelets) as compared to thrombin 5 U/ml (mean = 177 pmol/10(8) platelets), measured using a radioimmunoassay for thromboxane B2. Formation of phosphatidic acid is an early step in stimulus-response coupling in platelets. Our studies indicate that PAF is a weak stimulus for phosphatidic acid formation as well. To obtain further insights into its action, we examined the effect of PAF on platelets from three groups of patients with congenital secretion defects: patients with the storage pool deficiency, those with impaired thromboxane synthesis due to impaired liberation of AA from phospholipids, and those with impaired secretion despite normal granule stores and thromboxane production. The response to PAF was impaired in all patients, providing further evidence that PAF-induced platelet activation is dependent on secreted ADP and thromboxane A2 synthesis, and occurs by mechanisms common to a number of agonists. Overall, these studies indicate that PAF is a weak platelet agonist.

Adenosine↗
PubMed1996

Peripheral serotonergic system in uremia.

Several data suggest that platelet-derived serotonin (5-HT), previously classified as a trivial modulator of blood-borne cardiovascular disease (1), may play a decisive role in various pathological processes, resulting from abnormal platelet-vessel wall interactions (2). Following platelet activation upon a contact with a damaged vessel wall, 5-HT, released from platelets upon the activation of 5-HT2 receptors, may amplify the action of other agents on vascular smooth muscle cells and platelets (3,4). Platelets play a unique role in 5-HT metabolism: they take it up, store in their dense granules and release upon stimulation. Platelet dysfunction, alteration in platelet count, their consumption and turnover are common in renal diseases (5). Storage pool deficiency regarding 5-HT and ADP was reported in renal failure (6). Previously we reported that 5HT2 receptor blockers may serve as potent antiplatelet drugs in uremic patients, which are prone to thrombotic complications (7,8). Up to date there have been a few reports dealing predominantly with 5-HT levels in renal patients. Thus, we focused on peripheral serotonergic mechanisms including 5-HT uptake and release and kinetics of its uptake in uremic patients.

Adult↗
PubMed1978

Correction of the bleeding time in patients with storage pool deficiency by infusion of cryoprecipitate.

Five patients with Hermansky-Pudlak syndrome: storage pool deficiency, albinism and ceroid containing bone marrow macrophages and three patients with uncomplicated storage pool deficiency were treated with cryoprecipitate from 16 donors. Within 2 h of transfusion, bleeding times decreased towards a third of initial values. This effect lasted for at least 4 h but had disappeared after 24 h. Six of these eight patients were also treated with an equal volume of human albumin solution. Infusion of albumin had no effect on the bleeding times. The abnormal platelet function tests and biochemical abnormalities (decreased values of platelet total adenosine diphosphate (ADP), adenosine triphosphate (ATP(I) and serotonin) remained unchanged. On four occasions infusion of cryoprecipitate twice daily protected patients with Hermansky-Pudlak syndrome and storage pool deficiency from bleeding during surgery. The mechanism of action of cryoprecipitate in this clinical situation is obscure.

Adenosine Diphosphate↗
PubMed1987

The 5-hydroxytryptamine system of blood platelets: physiology and pathophysiology.

The 5-hydroxytryptamine (5HT)-system of human blood platelets consists of a relatively specific uptake mechanism for 5HT at the plasma membrane, intracellular storage organelles (dense bodies), a metabolizing enzyme (monoaminoxidase B) and a 5HT2-receptor whose stimulation leads to activation of the phosphatidylinositide turnover, a rise in free cytoplasmic Ca2+, phosphorylation of proteins and a shape change reaction. There is neither a relevant 5HT-biosynthesis nor a marked physiological 5HT-turnover in platelets. Under physiological conditions the platelet 5HT-system may have a role as a scavenger for free extracellular 5HT and in hemostasis. Disturbances which have been described in pathophysiological states include impairment of 5HT-uptake (hypertension, migraine), impairment of 5HT-storage (storage pool deficiencies, thromboembolic disorders, hypertension) and increased sensitivity to activating agents like 5HT (cardiovascular disorders, diabetes). Besides their role in physiology and pathophysiology platelets may be useful partial models for vascular smooth muscle cells.

Blood Platelets↗
PubMedDate not supplied

Platelet function disorders in north India.

BACKGROUND: Platelet function disorders are a fairly common cause of bleeding manifestations. Although their relative types and incidence are well documented, data from India are lacking. METHODS: Between 1970 and 1991, we studied the clinical and laboratory features of 144 north Indian patients who presented to our hospital with a bleeding diathesis in whom coagulation disorders, von Willebrand's disease and a history of drug ingestion were absent. RESULTS: Isolated platelet factor 3 availability defect was the commonest (56 cases) followed by the thrombasthenias (49 cases), arachidonic acid pathway defect (26 cases), storage pool disease (8 cases) and the Bernard-Soulier syndrome (3 cases). Isolated platelet factor 3 deficiency was rare (2 cases). Two varieties of thrombasthenia were seen--the classical Glanzmann's (13 cases) and thrombopathic (36 cases). The latter was characterized by absent or sub-normal platelet aggregation with agonists along with a reduced (to less than 50% of normal) total platelet factor 3 content. This has not been reported from western countries. Patients with classical Glanzmann's thrombopathic thrombasthenia with absent platelet aggregation and isolated platelet factor 3 deficiency were severe bleeders. Their family history suggested an autosomal recessive transmission in Glanzmann's and thrombopathic thrombasthenia and a possible autosomal dominant transmission in isolated platelet factor 3 availability defect and isolated platelet factor 3 deficiency. CONCLUSION: The frequency of various types of platelet function disorders in Indians is similar to that in western populations except that the incidence of thrombopathic thrombasthenias is higher in India.

Adolescent↗
PubMedDate not supplied

Type IV Ehlers-Danlos syndrome with platelet delta-storage pool disease.

A case of type IV Ehlers-Danlos syndrome with a partial platelet delta-storage pool disease is reported. The diagnosis of Ehlers-Danlos was clinical. The platelet-dense granule deficiency was determined by ultrastructural platelet morphology. Dense bodies were decreased in number, and most showed loss or fragmentation of electron-dense material. Aggregation studies revealed a retarded response to ristocetin and arachidonic acid, which was corrected with desmopressin acetate-DDAVP.

Blood Platelet Disorders↗
PubMed1996

[Factor XI deficiency: do patients with hemorrhagic diathesis also have hemostasis defects?].

It is well known that the extent of bleeding in patients with a deficiency of factor XI does not parallel the residual factor activity. Therefore, additional hemostatic aspects must be taken into consideration. 27 patients of 18 different families--6 with severe (FXI < 0.01 to 0.09 U/ml) and 21 with moderate (FXI 0.20 to 0.252 U/ml) factor XI deficiency--were reinvestigated regarding hemostasis including bleeding time and platelet function. 16 had an enhanced bleeding tendency, while the others--including 3 with severe FXI deficiency of < 0.01 U/ml--never suffered from bleeding complications despite delicate surgery in some. All 16 of the symptomatic patients had, besides the reduction of factor XI activity to various extents, an additional hemostatic defect: 3 had a moderate alpha/delta storage pool detect of the platelets, 11 a platelet anomaly mainly characterized by reduced ADP aggregation and 2 an isolated prolonged bleeding time of unknown cause. Synthesis of platelet thromboxane was unimpaired in all patients as tested by formation of malondialdehyde after stimulation with N-ethyl maleimide. Hence, in patients with a known factor XI deficiency diagnostic and prophylactic measures before surgery should concentrate on such additional findings. Preoperative administration of desmopressin, and not replacement of factor XI, will be the treatment of choice in these cases.

Adult↗
PubMed2003

Platelet function tests using platelet aggregometry: need for repetition of the test for diagnosis of defective platelet function.

Four hundred and ninety seven patients were referred to our center for platelet aggregation studies because of spontaneous mucocutaneous bleeds. All these patients had normal complete blood count, platelet count and peripheral smears except in ten patients of Bernard Soulier Syndrome where platelet count was marginally reduced in the presence of giant platelets. Two hundred and eighty patients were found to have normal platelet aggregation to ADP, collagen, ristocetin and arachidonic acid. Out of the remaining 217 patients, 62 patients were diagnosed to have Glanzmanns thrombasthenia, 10 Bernard Soulier Syndrome, 6 storage pool deficiencies, 7 cyclooxygenase deficiencies and 72 von Willebrand disease. In all the patients with GT and BSS, diagnosis was confirmed with flow cytometry using multiple monoclonal antibodies to GPIIb-IIIa and GPIb-IX. There were sixty patients where initial platelet aggregation studies showed reduced (<30%) aggregation to either ADP, collagen, ristocetin or arachidonic acid in its various combination, however in 12 such patients (20%) the platelet aggregation studies were normal on repetition. All our platelet aggregation studies were done only after assuring that the patient is not taking any medicine for at least 7-10 days which may affect the platelet function tests. The present study shows that single atypically abnormal platelet aggregation studies should always be repeated. Finally in 48/217 patients (22%) some aggregation abnormality to one or more of the agonists persisted, although we could not categorize these patients into any clear-cut platelet disorder. None of these 48 patients platelet associated immunoglobulin was increased by flow cytometry. It is possible that large number of patients from that disorder will finally prove to be some form of platelet secretory defect. In north India similar group of defect in a large number of patients have been reported as isolated PF3 abnormality or thrombasthenic thrombopathy.

Adenosine Diphosphate↗
PubMed1988

Blood platelet calcium content and aggregation behaviour in myeloproliferative disorders and secondary thrombocytosis.

In 19 patients affected by various kinds of myeloproliferative disorders (MPD) and in 15 patients with secondary thrombocytosis (ST) due to a variety of aetiologies some tests of platelet function and chemistry were performed. The MPD patients showed slightly to excessively elevated platelet counts at the time of investigation and a great deal of them had a history of thrombotic and/or haemorrhagic events. The total calcium content of platelets was significantly lower (2P less than 0.001) in both groups of patients as compared to controls. In 14 of 19 patients with MPD platelet rich plasma did not respond to epinephrine (15 mumol/l), a concentration which induced at least weak aggregation in all patients with ST but one and also in healthy subjects. In patients with MPD the mean extent of all kinds of induced aggregation was significantly lower (2P less than 0.002) as compared to controls whereas in patients with ST in most cases this parameter did not differ significantly from that of controls. The results as a whole confirm the concept of an acquired storage pool deficiency in patients with MPD.

Adult↗
PubMed1986

A defect of platelet release reaction in a patient with SLE: impaired platelet aggregation induced by phorbol ester with a normal phosphorylation of 40K protein.

A 37-year-old female who suffered from SLE had a bleeding disorder. At the time of initial evaluation, the main disease demonstrated was a delta-storage pool deficiency. After this improved, a marked decrease of aggregation still remained, when induced by either ADP, epinephrine, collagen, A23187, thrombin, or PAF-acether. Although arachidonate-induced aggregation was slightly decreased, thromboxane B2 was produced normally in response to exogenous arachidonate. The patient's endoperoxides and/or thromboxane A2 aggregated aspirin-treated platelets, though her platelets were themselves unresponsive. Impaired aggregability induced by TPA (12-0-tetradecanoylphorbol-13-acetate) or OAG (1-oleoyl-2-acetyl-glycerol) was also found. However, the phosphorylation of P43 and P20 induced by several stimulators including CA++ ionophore was normal, using 32P-labelled platelets. It is suggested that TPA or OAG-induced platelet aggregation requires not only the phosphorylation of those proteins, but also another unknown mechanism after the phosphorylation, and that the platelet dysfunction of this patient was due to a defect of some mechanism involving Ca++ uptake or mobilization of cytoplasmic Ca++ from intracellular storage sites.

Adenosine Diphosphate↗