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

Blood ◽  
1988 ◽  
Vol 72 (5) ◽  
pp. 1717-1725 ◽  
Author(s):  
HJ Weiss ◽  
B Lages
Keyword(s):  
Platelet Aggregation ◽  
Receptor Agonist ◽  
Adenosine Diphosphate ◽  
Normal Subjects ◽  
Dense Granule ◽  
Binding Studies ◽  
Dense Granules ◽  
Storage Pool ◽  
Receptor Sites

Abstract 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.

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

Blood ◽  
1988 ◽  
Vol 72 (5) ◽  
pp. 1717-1725 ◽  
Author(s):  
HJ Weiss ◽  
B Lages
Keyword(s):  
Platelet Aggregation ◽  
Receptor Agonist ◽  
Adenosine Diphosphate ◽  
Normal Subjects ◽  
Dense Granule ◽  
Binding Studies ◽  
Dense Granules ◽  
Storage Pool ◽  
Receptor Sites

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.

scholarly journals Platelet malondialdehyde production and aggregation responses induced by arachidonate, prostaglandin-G2, collagen, and epinephrine in 12 patients with storage pool deficiency

Blood ◽  
1981 ◽  
Vol 58 (1) ◽  
pp. 27-33
Author(s):  
HJ Weiss ◽  
B Lages
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Adenosine Diphosphate ◽  
Synthetic Pathway ◽  
Dense Granules ◽  
Storage Pool ◽  
Increased Sensitivity

We assessed the integrity of the prostaglandin synthetic pathway by measuring malondialdehyde (MDA) production and studied platelet aggregation responses to arachidonic acid and PGG2 in 12 patients with storage pool deficiency (SPD). Eight patients were deficient only in dense granules (delta-SPD) and four were deficient in both dense and alpha-granules (alpha delta-SPD). Production of MDA in response to arachidonic acid (AA), epinephrine, and collagen suggested that the transformation of AA to prostaglandin metabolites was normal in delta- SPD but abnormal in alpha delta-SPD and that the liberation of AA from phospholipids were abnormal in the majority of patients with SPD. Since the content of secretable adenosine diphosphate (ADP) is diminished in SPD platelets, the aggregation responses of these platelets to AA and PGG2 were studied to help answer the question whether these agents aggregate platelets directly or through release of endogenous ADP. Among patients with delta-SPD, aggregation by both AA and PGG2 was decreased in four albinos whose platelets were markedly deficient in ADP. In contrast, normal, or less strikingly abnormal, responses were observed in patients whose platelets either contained higher levels of platelet ADP or showed increased sensitivity to ADP. The more marked impaired responses to AA and PGG2 in patients with alpha delta-SPD suggest that substances derived from alpha-granules may also play a role in platelet aggregation by these agents. The aggregation responses in these patients with various types of SPD is consistent with a theory that granule-derived ADP mediates platelet aggregation by AA and PGG2.

scholarly journals Platelet malondialdehyde production and aggregation responses induced by arachidonate, prostaglandin-G2, collagen, and epinephrine in 12 patients with storage pool deficiency

Blood ◽  
1981 ◽  
Vol 58 (1) ◽  
pp. 27-33 ◽  
Author(s):  
HJ Weiss ◽  
B Lages
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Adenosine Diphosphate ◽  
Synthetic Pathway ◽  
Dense Granules ◽  
Storage Pool ◽  
Increased Sensitivity

Abstract We assessed the integrity of the prostaglandin synthetic pathway by measuring malondialdehyde (MDA) production and studied platelet aggregation responses to arachidonic acid and PGG2 in 12 patients with storage pool deficiency (SPD). Eight patients were deficient only in dense granules (delta-SPD) and four were deficient in both dense and alpha-granules (alpha delta-SPD). Production of MDA in response to arachidonic acid (AA), epinephrine, and collagen suggested that the transformation of AA to prostaglandin metabolites was normal in delta- SPD but abnormal in alpha delta-SPD and that the liberation of AA from phospholipids were abnormal in the majority of patients with SPD. Since the content of secretable adenosine diphosphate (ADP) is diminished in SPD platelets, the aggregation responses of these platelets to AA and PGG2 were studied to help answer the question whether these agents aggregate platelets directly or through release of endogenous ADP. Among patients with delta-SPD, aggregation by both AA and PGG2 was decreased in four albinos whose platelets were markedly deficient in ADP. In contrast, normal, or less strikingly abnormal, responses were observed in patients whose platelets either contained higher levels of platelet ADP or showed increased sensitivity to ADP. The more marked impaired responses to AA and PGG2 in patients with alpha delta-SPD suggest that substances derived from alpha-granules may also play a role in platelet aggregation by these agents. The aggregation responses in these patients with various types of SPD is consistent with a theory that granule-derived ADP mediates platelet aggregation by AA and PGG2.

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

Blood ◽  
1996 ◽  
Vol 87 (10) ◽  
pp. 4214-4222 ◽  
Author(s):  
HJ Weiss ◽  
B Lages ◽  
T Hoffmann ◽  
VT Turitto
Keyword(s):  
Platelet Adhesion ◽  
Thrombus Formation ◽  
Adenosine Diphosphate ◽  
Dense Granule ◽  
High Shear ◽  
Shear Rates ◽  
Storage Pool ◽  
Corrective Effect ◽  
High Shear Rates

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.

Platelet dense-granule centralization and the persistence of ADP secretion

1996 ◽  
Vol 270 (3) ◽  
pp. H1131-H1140 ◽  
Author(s):  
A. L. Fogelson ◽  
N. T. Wang
Keyword(s):  
Mathematical Modeling ◽  
Plasma Membrane ◽  
Human Platelet ◽  
Adenosine Diphosphate ◽  
Dense Granule ◽  
Dense Granules ◽  
Plausible Values ◽  
Key Parameter

After activation of a human platelet, its adenosine diphosphate (ADP)-containing dense granules are moved toward the platelet's center and release their ADP into the channels of the open canalicular system (OCS). Mathematical modeling is used to investigate a possible role of this centralization in prolonging the duration of ADP secretion compared with direct release at the platelet's plasma membrane. A key parameter is the degree to which the diffusion of ADP through the narrow and tortuous channels of the OCS is slower than ADP diffusion in plasma. For small but physiologically plausible values of this parameter and with use of literature-based values for the amount and concentration of dense-granule, ADP, the platelet serves as a continuing source of ADP; the concentration of ADP in the immediate environment of the platelet remains high enough to activate nearby platelets for 5-13 s, many times longer than if ADP were released directly at the plasma membrane.

scholarly journals Platelet storage pool deficiency in mouse pigment mutations associated with seven distinct genetic loci

Blood ◽  
1984 ◽  
Vol 63 (3) ◽  
pp. 536-544 ◽  
Author(s):  
EK Novak ◽  
SW Hui ◽  
RT Swank
Keyword(s):  
Lysosomal Enzyme ◽  
Human Platelet ◽  
Adenosine Diphosphate ◽  
Dense Granule ◽  
Enzyme Secretion ◽  
Dense Granules ◽  
Storage Pool ◽  
Platelet Storage ◽  
Storage Pool Disease ◽  
Experimental Injury

Abstract Seven mouse pigment mutants, which have alterations at distinct genes, are known to have a defect in kidney lysosomal enzyme secretion. Two of these, beige and pale ear, have a bleeding abnormality associated with a deficiency in the number of platelet dense granules. In the present study, five other mutants with defective lysosomal enzyme secretion-- pearl, pallid, light ear, maroon, and ruby-eye--were likewise found to have abnormally prolonged bleeding times after experimental injury. Platelet counts were similar to those of normal mice, but the platelet dense granule components serotonin, adenosine triphosphate (ATP), and adenosine diphosphate (ADP) and morphologically identifiable dense granules were markedly reduced in these mutants. The capacity to accumulate exogenous 3H-serotonin in platelets was reduced 2–3-fold. Thrombin-stimulated secretion of 3H-serotonin was slightly decreased in all mutants. However, the seven mutants could be subdivided into three groups based on the degree of secretion of lysosomal enzymes after thrombin stimulation. Thus, all seven mouse pigment mutants have symptoms consistent with platelet storage pool deficiency and may serve as useful animal models for specific types of human platelet storage pool disease. Also, the results emphasize the genetic, morphological, and functional interrelatedness of three organelles: melanosomes, lysosomes, and platelet dense granules.

scholarly journals Platelet storage pool deficiency in mouse pigment mutations associated with seven distinct genetic loci

Blood ◽  
1984 ◽  
Vol 63 (3) ◽  
pp. 536-544 ◽  
Author(s):  
EK Novak ◽  
SW Hui ◽  
RT Swank
Keyword(s):  
Lysosomal Enzyme ◽  
Human Platelet ◽  
Adenosine Diphosphate ◽  
Dense Granule ◽  
Enzyme Secretion ◽  
Dense Granules ◽  
Storage Pool ◽  
Platelet Storage ◽  
Storage Pool Disease ◽  
Experimental Injury

Seven mouse pigment mutants, which have alterations at distinct genes, are known to have a defect in kidney lysosomal enzyme secretion. Two of these, beige and pale ear, have a bleeding abnormality associated with a deficiency in the number of platelet dense granules. In the present study, five other mutants with defective lysosomal enzyme secretion-- pearl, pallid, light ear, maroon, and ruby-eye--were likewise found to have abnormally prolonged bleeding times after experimental injury. Platelet counts were similar to those of normal mice, but the platelet dense granule components serotonin, adenosine triphosphate (ATP), and adenosine diphosphate (ADP) and morphologically identifiable dense granules were markedly reduced in these mutants. The capacity to accumulate exogenous 3H-serotonin in platelets was reduced 2–3-fold. Thrombin-stimulated secretion of 3H-serotonin was slightly decreased in all mutants. However, the seven mutants could be subdivided into three groups based on the degree of secretion of lysosomal enzymes after thrombin stimulation. Thus, all seven mouse pigment mutants have symptoms consistent with platelet storage pool deficiency and may serve as useful animal models for specific types of human platelet storage pool disease. Also, the results emphasize the genetic, morphological, and functional interrelatedness of three organelles: melanosomes, lysosomes, and platelet dense granules.

scholarly journals P2X1-mediated activation of extracellular signal-regulated kinase 2 contributes to platelet secretion and aggregation induced by collagen

Blood ◽  
2002 ◽  
Vol 100 (7) ◽  
pp. 2499-2505 ◽  
Author(s):  
Cécile Oury ◽  
Emese Toth-Zsamboki ◽  
Jos Vermylen ◽  
Marc F. Hoylaerts
Keyword(s):  
Platelet Aggregation ◽  
Ion Channel ◽  
High Performance ◽  
Adenosine Diphosphate ◽  
Dense Granule ◽  
Hek293 Cells ◽  
Extracellular Signal Regulated Kinase ◽  
Dense Granules ◽  
Extracellular Signal ◽  
Erk2 Activation

Adenosine triphosphate (ATP) and its stable analog, α,β-methylene ATP, activate the platelet P2X1 ion channel, causing a rapid Ca++ influx. Here, we show that, in washed apyrase-treated platelets, α,β-methylene ATP elicits reversible extracellular signal-regulated kinase 2 (ERK2) phosphorylation through a Ca++- and protein kinase C–dependent pathway. In contrast, high-performance liquid chromatography-purified adenosine diphosphate (ADP) did not trigger ERK2 phosphorylation. α,β-Methylene ATP also activated the ERK2 pathway in P2X1-transfected HEK293 cells but not in cells expressing mutated P2X1delL nonfunctional channels. Because ATP released from the dense granules during platelet activation contributes to platelet aggregation elicited by low doses of collagen, and because collagen causes ERK2 phosphorylation, we have investigated the role of P2X1-mediated ERK2 activation in these platelet responses. We found that the antagonism of P2X1 with ADP or desensitization of this ion channel with α,β-methylene ATP both resulted in impaired ERK2 phosphorylation, ATP secretion, and platelet aggregation induced by low concentrations of collagen (≤ 1 μg/mL) without affecting the minor early dense granule release. Selective MEK1/2 inhibition by U-0126 and Ca++ chelation with EGTA (ethyleneglycoltetraacetic acid) behaved similarly, whereas the PKC inhibitor GF109203-X totally prevented collagen-induced secretion and ERK2 activation. In contrast, when elicited by high collagen concentrations (2 μg/mL), platelet aggregation and secretion no longer depended on P2X1 or ERK2 activation, as shown by the lack of their inhibition by α,β-methylene ATP or U-0126. We thus conclude that mild platelet stimulation with collagen rapidly releases ATP, which activates the P2X1-PKC-ERK2 pathway. This process enhances further degranulation of the collagen-primed granules allowing platelet aggregation to be completed.

scholarly journals Platelet Antiheparin Activity: Storage Site and Release Mechanism

Blood ◽  
1974 ◽  
Vol 44 (2) ◽  
pp. 157-168 ◽  
Author(s):  
Peter N. Walsh ◽  
Giovanna Gagnatelli
Keyword(s):  
Lysosomal Enzymes ◽  
Time Course ◽  
Adenosine Diphosphate ◽  
Normal Subjects ◽  
Human Platelets ◽  
Release Mechanism ◽  
Storage Site ◽  
Dense Granules ◽  
Storage Pool ◽  
Platelet Storage

Abstract The platelet storage and release mechanisms for the heparin-neutralizing activity (HNA), adenosine diphosphate (ADP), serotonin, and lysosomal enzymes were investigated in normal human platelets and in platelets with defective storage or release of ADP and serotonin. The time course of release of HNA from normal washed platelets by thrombin and collagen was slower than that of serotonin. Lysosomal enzymes were not released by collagen from normal washed platelets, whereas under the same conditions HNA was released. In four of six patients with storage pool deficiency, the platelets contained normal amounts of HNA but definitely decreased amounts of ADP and serotonin, whereas in the remaining two patients the total contents of ADP, serotonin, and HNA were all definitely lower than normal. In four of six patients with storage pool deficiency, the amounts and per cents of total HNA released by collagen were normal, whereas the amounts and per cents of total ADP released were diminished compared with normal. Platelets from patients with the aspirinlike platelet release defect and from aspirin-treated normal subjects contained normal quantities of ADP, serotonin, and HNA, but HNA and ADP were not released in response to collagen. It is concluded that either HNA is stored in and released from dense granules by mechanisms different from those for ADP and serotonin, or that HNA is stored in and released from granules other than the dense granules, which contain ADP and serotonin and the α-granules, which contain lysosomal enzymes.

Studies on the Interaction of Warfarin and Clofibrate in Man

1972 ◽  
Vol 27 (02) ◽  
pp. 309-318 ◽  
Author(s):  
R. A O’Reilly ◽  
M. A Sahud ◽  
A. J Robinson
Keyword(s):  
Platelet Aggregation ◽  
Oral Anticoagulant Therapy ◽  
Adenosine Diphosphate ◽  
Normal Subjects ◽  
Term Therapy ◽  
Rapid Decline ◽  
Hemorrhagic Diathesis ◽  
Platelet Adhesiveness ◽  
Clotting Factors ◽  
One Stage

SummaryTo evaluate the basis for the hemorrhagic diathesis associated with oral anticoagulant therapy plus the hypolipidemic agent clofibrate, this interaction was studied in 8 normal subjects. Administration of clofibrate 2.0 g/day alone for 14 days had no effect on the platelet count, bleeding time, platelet aggregation, plasma adenosine diphosphatase, platelet release of adenosine diphosphate and adenosine triphosphate, platelet-collagen adhesion, one-stage prothrombin time, or vitamin K-dependent clotting factors (II, VII, IX and X) but significantly reduced platelet adhesiveness and epinephrine-induced platelet aggregation. After addition of large single doses of sodium warfarin, 1.5 mg/kg body weight, to the clofibrate regimen, all values remained within the normal range, including platelet adhesiveness, except epinephrine-induced platelet aggregation. The one-stage prothrombin activity and clotting factors II and X were significantly lower with warfarin plus clofibrate than with warfarin alone, but the plasma level of warfarin was unchanged. Co-administration of sodium warfarin and clofibrate for 21 days augmented the hypoprothrombinemia observed in long-term therapy with warfarin alone but caused no significant change in the plasma warfarin level. It is concluded that the hemorrhagic complications of therapy with warfarin plus clofibrate result primarily from the more rapid decline in the activities of clotting factors II and X and perhaps also from the reduced platelet aggregation.

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