Hyperaggregability Of Serotonin-Depleted Platelets To Arachidonic Acid (AA) In SLE And Transplant Recipients

1981 ◽  
Author(s):  
D Marchesi ◽  
A Parbtani ◽  
G Frampton ◽  
M Livio ◽  
G Remuzzi ◽  
...  
Keyword(s):  
Renal Function ◽  
Arachidonic Acid ◽  
Nephrotic Syndrome ◽  
Platelet Activation ◽  
Great Majority ◽  
Transplant Recipients ◽  
Renal Microvasculature ◽  
Thrombotic Tendency ◽  
Reduced Renal Function

In a variety of renal disorders, including SLE and transplantation, in vivo platelet activation is present. This is in part a result of the nephrotic syndrome, but is also observed in patients with g.n. who are not nephrotic. As a result, intraplatelet concentrations of serotonin and other amines are depleted in patients with active nephritis. The functional capacity of such amine-depleted platelets has been little studied; Pareti et al (1980) reported defective aggregation to ADP, adrenaline and collagen in such “acquired storage pool deficiencies”. We studied aggregation thresholds to ADP, collagen and AA in 25 patients with SLE nephritis, none of whom had a nephrotic syndrome or reduced renal function. In these patients platelet activation is due principally to circulating factors. Sixteen transplant recipients were also studied. In them, activation is principally within the renal microvasculature of the allograft. We also measured intraplatelet serotonin concentrations, which were low or zero in the great majority of patients in both groups. Bleeding times were normal in all, as were platelet aggregation thresholds to ADP and collagen. AA thresholds, however, were markedly depressed (<0.32 mmol) in all transplant recipients and most patients with SLE. This specific hyperaggregability may be responsible for both persistence of disease and the thrombotic tendency observed in some patients, including those with circulating anticoagulant.

Platelet Suruival and Function in Rats with Enhanced Thrombotic Tendency

1985 ◽  
Vol 54 (04) ◽  
pp. 739-743 ◽  
Author(s):  
Federica Delaini ◽  
Elisabetta Dejana ◽  
Ine Reyers ◽  
Elisa Vicenzi ◽  
Germana De Bellis Vitti ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Nephrotic Syndrome ◽  
Platelet Function ◽  
Laboratory Tests ◽  
Thrombus Formation ◽  
The Other ◽  
Mean Survival Time ◽  
The Mean ◽  
And Function ◽  
Thrombotic Tendency

SummaryWe have investigated the relevance of some laboratory tests of platelet function in predicting conditions of thrombotic tendency. For this purpose, we studied platelet survival, platelet aggregation in response to different stimuli, TxB2 and 6-keto-PGFlα production in serum of rats bearing a nephrotic syndrome induced by adriamycin. These animals show a heavy predisposition to the development of both arterial and venous thrombosis. The mean survival time was normal in nephrotic rats in comparison to controls. As to aggregation tests, a lower aggregating response was found in ADR-treated rats using ADP or collagen as stimulating agents. With arachidonic acid (AA) we observed similar aggregating responses at lower A A concentrations, whereas at higher AA concentrations a significantly lower response was found in nephrotic rats, despite their higher TxB2 production. Also TxB2 and 6-keto-PGFlα levels in serum of nephrotic rats were significantly higher than in controls. No consistent differences were found in PGI2-activity generated by vessels of control or nephrotic rats.These data show that platelet function may appear normal or even impaired in rats with a markedly increased thrombotic tendency. On the other hand, the significance of high TxB2 levels in connection with mechanisms leading to thrombus formation remains a controversial issue.

Enhanced Affinity for Arachidonic Acid in Platelet-Rich Plasma from Rats with Adriamycin-Induced Nephrotic Syndrome

1982 ◽  
Vol 48 (03) ◽  
pp. 260-262 ◽  
Author(s):  
F Delaini ◽  
A Poggi ◽  
M B Donati
Keyword(s):  
Arachidonic Acid ◽  
Nephrotic Syndrome ◽  
Platelet Rich Plasma ◽  
Platelet Response ◽  
Heavy Proteinuria ◽  
Washed Platelet ◽  
Cyclooxygenase Activity ◽  
Stable Product ◽  
Kinetics Of ◽  
Thrombotic Tendency

SummaryWe have measured the response to arachidonic acid (AA) in platelet-rich plasma (PRP) of rats with Adriamycin-induced nephrotic syndrome. For this purpose we measured the kinetics of generation of malondialdehyde (MDA), a stable product of cyclooxygenase activity, in response to platelet stimulation with different concentrations of the substrate. The apparent Km of platelet cyclo-oxygenase for AA was similar in PRP from control rats and rats treated 1–5 days previously, whereas it was significantly reduced, as compared to controls, in PRP of rats treated 2–5 weeks previously. Such a difference was not observed when washed platelet suspensions were tested instead of PRP. Experiments with crossed platelet/plasma systems indicated that in rats treated from 2–5 weeks, a plasmatic abnormality was indeed responsible for the increased affinity of platelets for AA.It is conceivable that in this nephrotic syndrome model characterized by heavy proteinuria, some plasmatic component would be lost with the urine which is normally modulating the platelet response to AA. The observed increase in platelet affinity for AA could at least partially contribute to the enhanced thrombotic tendency reported in the same experimental model.

scholarly journals In vivo platelet activation with in vitro hyperaggregability to arachidonic acid in renal allograft recipients

1983 ◽  
Vol 23 (3) ◽  
pp. 506-513 ◽  
Author(s):  
Geoffrey Frampton ◽  
Anwar Parbtani ◽  
Donatella Marchesi ◽  
Peter Duffus ◽  
Manuela Livio ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Platelet Activation ◽  
Renal Allograft

Intrarenal Localisation Of Platelet Related Antigens, PF4, β-TG, Fibrin And Factor VIII In Patients With Glomerulonephritis

1981 ◽  
Author(s):  
P Duffus ◽  
A Parbtani ◽  
G Frampton ◽  
J S Cameron
Keyword(s):  
Factor Viii ◽  
Platelet Activation ◽  
Peripheral Circulation ◽  
Glomerular Disease ◽  
Platelet Membrane ◽  
Factor Viii Antigen ◽  
Membrane Antigens ◽  
Renal Microvasculature

In vivo platelet activation is common in glomerular disease. A strone correlation between platelet serotonin depletion and the factors in the serum which affect platelet aggregation in vitro suggests that platelet activation predominantly occurs in the peripheral circulation. However, platelet activation could occur in the renal microvasculature resulting in the deposition of platelet related antigens at this site. We studied 88 biopsies by immunofluorescence microscopy for the presence of platelet membrane antigen(s), PF4, β-TG, fibrin and factor VIII. β-TG was not observed in any of the biopsies studied. Most biopsies (92%) showed positive endothelial fluorescence for factor VIII antigen, but were otherwise negative. Biopsies from patients with usually benign forms of glomerular disease (minimal change, focal and mesangial proliferative glomerulonephritis) were mostly negative; only 8% showing weakly positive fluorescence for platelet membrane antigens and PF4. Biopsies from patients with usually progressive forms of glomerulonephritis (MCGN, membranous nephropathy, PAN, SLE) were mostly positive (85%) for platelet membrane antigen(s) and PF4. A notable exception was biopsies from patients with FSGS; only two out of 11 biopsies (18%) were positive in this group of patients. The presence of platelet related antigens in glomerulonephritis suggests platelet activation and trapping at this site as well as in the peripheral circulation.

scholarly journals Release of arachidonic acid from human platelets. A key role for the potentiation of platelet aggregability in normal subjects as well as in those with nephrotic syndrome

Blood ◽  
1978 ◽  
Vol 52 (5) ◽  
pp. 969-977 ◽  
Author(s):  
N Yoshida ◽  
N Aoki
Keyword(s):  
Arachidonic Acid ◽  
Nephrotic Syndrome ◽  
Platelet Aggregation ◽  
Normal Subjects ◽  
Human Albumin ◽  
Membrane Phospholipids ◽  
Platelet Aggregability ◽  
Induced Aggregation

Abstract Low (nonaggregating) concentrations of collagen that potentiate platelet aggregation did not induce the formation of measurable amount of malondialdehyde (MDA) but released small but significant amounts of radioactivity from 14C-arachidonic acid-labeled platelets. A major portion of the radioactive compounds released by nonaggregating concentrations of collagen existed as arachidonic acid and a minor part as thromboxane B2. The nephrotic syndrome enhances platelet aggregability, and this effect is abolished by correcting hypoalbuminemia in vitro and in vivo by the addition of albumin, which is the main carrier for free fatty acids, including arachidonic acid. Human albumin (fatty acid free) inhibited collagen-induced aggregation, MDA formation, and release of the radioactivity from 14C-arachidonic acid-labeled platelets in normals as well as in those with nephrotic syndrome. These data support our hypothesis that the main mechanism responsible for the potentiation of platelet aggregation is the release of arachidonic acid from platelet membrane phospholipids via the activation of phospholipase A2. Furthermore, enhanced platelet aggregation in the nephrotic syndrome was at least partly attributable to an increased availability of arachidonic acid released secondary to hypoalbuminemia. Albumin inhibits aggregation probably by binding to released arachidonic acid preventing arachidonic acid from being metabolized to potent aggregating substances, endoperoxides and thromboxane A2. The mechanism of release of arachidonic acid may play a key role in the potentiation of platelet aggregability in normals as well as in pathologic conditions such as the nephrotic syndrome.

scholarly journals Release of arachidonic acid from human platelets. A key role for the potentiation of platelet aggregability in normal subjects as well as in those with nephrotic syndrome

Blood ◽  
1978 ◽  
Vol 52 (5) ◽  
pp. 969-977
Author(s):  
N Yoshida ◽  
N Aoki
Keyword(s):  
Arachidonic Acid ◽  
Nephrotic Syndrome ◽  
Platelet Aggregation ◽  
Normal Subjects ◽  
Human Albumin ◽  
Membrane Phospholipids ◽  
Platelet Aggregability ◽  
Induced Aggregation

Low (nonaggregating) concentrations of collagen that potentiate platelet aggregation did not induce the formation of measurable amount of malondialdehyde (MDA) but released small but significant amounts of radioactivity from 14C-arachidonic acid-labeled platelets. A major portion of the radioactive compounds released by nonaggregating concentrations of collagen existed as arachidonic acid and a minor part as thromboxane B2. The nephrotic syndrome enhances platelet aggregability, and this effect is abolished by correcting hypoalbuminemia in vitro and in vivo by the addition of albumin, which is the main carrier for free fatty acids, including arachidonic acid. Human albumin (fatty acid free) inhibited collagen-induced aggregation, MDA formation, and release of the radioactivity from 14C-arachidonic acid-labeled platelets in normals as well as in those with nephrotic syndrome. These data support our hypothesis that the main mechanism responsible for the potentiation of platelet aggregation is the release of arachidonic acid from platelet membrane phospholipids via the activation of phospholipase A2. Furthermore, enhanced platelet aggregation in the nephrotic syndrome was at least partly attributable to an increased availability of arachidonic acid released secondary to hypoalbuminemia. Albumin inhibits aggregation probably by binding to released arachidonic acid preventing arachidonic acid from being metabolized to potent aggregating substances, endoperoxides and thromboxane A2. The mechanism of release of arachidonic acid may play a key role in the potentiation of platelet aggregability in normals as well as in pathologic conditions such as the nephrotic syndrome.

Antiphospholipid Antibodies Enhance Thrombin-Induced Platelet Activation and Thromboxane Formation

1993 ◽  
Vol 70 (04) ◽  
pp. 667-671 ◽  
Author(s):  
M E Martinuzzo ◽  
J Maclouf ◽  
L O Carreras ◽  
S Lévy-Toledano
Keyword(s):  
Platelet Aggregation ◽  
Urinary Excretion ◽  
Platelet Activation ◽  
Antiphospholipid Antibodies ◽  
Low Dose ◽  
Serotonin Release ◽  
Healthy Individuals ◽  
Thrombotic Tendency

SummaryIn a group of 6 patients with lupus anticoagulant (LA) and antiphospholipid (aPL) antibodies detected by ELISA ovemight urine and blood were simultaneously collected. A significantly increased urinary excretion of the platelet-derived thromboxane (TX) metabolite 11-dehydro-TXB2 was found in this group, as compared to 12 healthy individuals. In contrast, a small but significant reduction of the vascular prostacyclin (PGI2) metabolite 2,3-dinor-6-keto-prostaglandin F1α was observed.To further elucidate the effect of these antibodies on platelet activation we isolated the F(ab’)2 fragments from IgG of the 6 patients and 5 Controls, and we evaluated the effect of these fragments on the responses of isolated normal platelets to thrombin.Patients’ F(ab’)2 increased platelet aggregation and serotonin release of platelets stimulated by low dose thrombin (0.01 U/ml). At threshold thrombin concentration (0.05 U/ml) an enhanced TXB2 production was also observed.In summary, our results show, in addition to the altered TXA2/PGI2 balance observed in vivo, a direct stimulatory effect of aPL antibodies on platelet activation in vitro. This effect is related to recognition of phospholipid epitopes on platelets as shown by its neutralization upon preincubation with phospholipids. This phenomenon may be relevant for the thrombotic tendency of these patients.

Bone Histology and Calcium Metabolism in Patients with Nephrotic Syndrome and Normal or Reduced Renal Function

Nephron ◽  
1984 ◽  
Vol 37 (3) ◽  
pp. 153-159 ◽  
Author(s):  
Nicola Tessitore ◽  
Ermanno Bonucci ◽  
Angela D’Angelo ◽  
Bjarne Lund ◽  
Angela Corgnati ◽  
...  
Keyword(s):  
Renal Function ◽  
Nephrotic Syndrome ◽  
Calcium Metabolism ◽  
Bone Histology ◽  
Reduced Renal Function

EFFECTS OF SULFINPYRAZONE AND ITS METABOLITE G25671 ON PLATELET ACTIVATION AND DESENSITIZATION AND ON BRONCHOCONSTRICTION INDUCED BY THE PROSTAGLANDIN ENDOPEROXIDE ANALOGUE U46619

1987 ◽  
Author(s):  
M Hatmi ◽  
A Del Maschio ◽  
J Lefort ◽  
G De Gaetano ◽  
B B Varqaftiq ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Platelet Activation ◽  
Ex Vivo ◽  
Oral Treatment ◽  
Human Platelets ◽  
Cyclooxygenase Inhibitors ◽  
Before And After ◽  
A Site

In previous studies we have found (Br. 3. Pharmac. 85, 849, 1985) that a) human platelets pre-exposed to arachidonic acid or to the endoperoxide analogue, U46619 and then washed and resuspended, fail to respond to a second challenge by both arachidonic acid and U46619; b) desensitization by arachidonic acid and U46619 occurs at a site sensitive to endoperoxides / thromboxane (Tx) receptor antagonists; c) the desensitizing effects of U46619 are direct, whereas those of arachidonic acid are mediated by a cyclooxygenase-dependent metabolite. Sulfinpyrazone (100 μM) and its thioether metabolite G25671 (50 μM) are known to suppress arachidonic acid-induced platelet aggregation and TxB2 formation (Eur. 3. Pharmac, 101, 209, 1984). We now demonstrate that the presence of sulfinpyrazone or G25671 during platelet exposure to arachidonic acid or U46619 prevents desensitization. Platelet activation by the endoperoxide analogue U46619 is also prevented by sulfinpyrazone or G25671 (0.3-1 mM). The threshold aggregating concentrations of arachidonic acid and U46619 in healthy subjects before and after oral treatment with sulfinpyrazone were elevated by 2-3 fold and a good correlation between ex vivo and in vitro findings was established. We finally examined the actions of sulfinpyrazone and G25671 on the bronchoconstriction in vivo and parenchymal lung strip contraction in vitro induced by U46619. Neither drug had any preventive effect.Our results demonstrate that sulfinpyrazone and its metabolite G25671 are not only cyclooxygenase inhibitors but can also act as endoperoxide/Tx antagonists and indicate clearly that antagonism of U46619 by both drugs is selective for platelets.

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