Correlation between leukocyte‐platelet aggregates and thrombosis in myeloproliferative neoplasms

SummaryNormal human platelets aggregated by thrombin undergo the release reaction and are not readily deaggregated by the combination of inhibitors hirudin, prostaglandin E1 (PGE1) and chymotrypsin. Released adenosine diphosphate (ADP) plays an important role in the stabilization of thrombin-induced human platelet aggregates. Since ticlopidine inhibits the platelet responses to ADP, we studied thrombin-induced aggregation and deaggregation of 14C-serotonin-labeled platelets from 12 patients with cardiovascular disease before and 7 days after the oral administration of ticlopidine, 250 mg b.i.d. Before and after ticlopidine, platelets stimulated with 1 U/ml thrombin aggregated, released about 80–90% 14C-serotinin and did not deaggregate spontaneously within 5 min from stimulation. Before ticlopidine, hirudin (5× the activity of thrombin) and PGE1 (10 μmol/1) plus chymotrypsin (10 U/ml) or plasmin (0.06 U/ml), added at the peak of platelet aggregation, caused slight or no platelet deaggregation. After ticlopidine, the extent of platelet deaggregation caused by the same inhibitors was significantly greater than before ticlopidine. The addition of ADP (10 μmol/1) to platelet suspensions 5 s after thrombin did not prevent the deaggregation of ticlopidine-treated platelets. Thus, ticlopidine facilitates the deaggregation of thrombin-induced human platelet aggregates, most probably because it inhibits the effects of ADP on platelets.

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In Vivo Effect of Suloctidil as an Antiplatelet Agent

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646799 ◽

1979 ◽

Vol 41 (03) ◽

pp. 465-474 ◽

Cited By ~ 7

Author(s):

Marcia R Stelzer ◽

Thomas S Burns ◽

Robert N Saunders

Keyword(s):

Ex Vivo ◽

Antiplatelet Agent ◽

Ratio Method ◽

Platelet Aggregate ◽

Permanent Effect ◽

Platelet Aggregates ◽

5 Ht Uptake ◽

High Doses

SummaryThe relationship between the effects of suloctidil in vivo as an antiplatelet agent and in vitro as a modifier of platelet serotonin (5-HT) parameters was investigated. Suloctidil was found to be effective in reducing platelet aggregates formation in the retired breeder rat as determined using the platelet aggregate ratio method (PAR) with an ED50 of 16.1 mg/kg 24 hours post administration. In contrast to the hypothesis that 5-HT depletion is involved in the anti-aggregatory mechanism of suloctidil, no correlation was found between platelet 5- HT content and this antiplatelet activity. Reduction of platelet 5-HT content required multiple injections of high doses (100 mg/kg/day) of suloctidil. Suloctidil administration for 8 days at 100 mg/kg/day, which lowered platelet 5-HT content by 50%, resulted in no permanent effect on ex vivo platelet 5-HT uptake or thrombin-induced release, nor alteration in the plasma 5-HT level. However, these platelets exhibited a short-lived, significant increase in percent leakage of 5-HT after 30 minutes of incubation. Therefore, suloctidil treatment at high doses may with time result in platelet 5-HT depletion, however this effect is probably not related to the primary anti-aggregatory activity of the drug.

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Accumulation of Macromolecular Particles in the Reticuloendothelial System (RES) Mediated by Platelet Aggregation and Disaggregation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651386 ◽

1969 ◽

Vol 22 (03) ◽

pp. 496-507 ◽

Cited By ~ 17

Author(s):

W.G van Aken ◽

J Vreeken

Keyword(s):

Platelet Aggregation ◽

Degradation Products ◽

Reticuloendothelial System ◽

Caproic Acid ◽

Carbon Particles ◽

Carbon Clearance ◽

Aggregation And Disaggregation ◽

Platelet Aggregates

SummaryCarbon particles cause platelet aggregation in vitro and in vivo. Prior studies established that substances which modify thrombocyte aggregation also influence the rate at which carbon is cleared from the blood.This study was performed in order to elucidate the mechanism by which the carbon-platelet aggregates specifically accumulate in the RES.Activation of fibrinolysis by urokinase or streptokinase reduced the carbon clearance rate, probably due to generated fibrinogen degradation products (FDP). Isolated FDP decreased the carbon clearance and caused disaggregation of platelets and particles in vitro. Inhibition of fibrinolysis by epsilon-amino-caproic acid (EACA), initially accelerated the disappearance of carbon and caused particle accumulation outside the RES, predominantly in the lungs. It is supposed that platelet aggregation and locally activated fibrinolysis act together in the clearance of particles. In the normal situation the RES with its well known low fibrinolytic activity, becomes the receptor of the particles.

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Lack of Stability of Aggregates after Thrombin-Induced Reaggregation of Thrombin-Degranulated Platelets

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648469 ◽

1992 ◽

Vol 67 (04) ◽

pp. 453-457 ◽

Cited By ~ 8

Author(s):

Raelene L Kinlough-Rathbone ◽

Marian A Packham ◽

Dennis W Perry ◽

J Fraser Mustard ◽

Marco Cattaneo

Keyword(s):

Von Willebrand Factor ◽

Platelet Rich Plasma ◽

Thrombus Formation ◽

Aggregate Stability ◽

Relative Importance ◽

Platelet Aggregates ◽

The Stability ◽

Von Willebrand ◽

Induced Aggregation ◽

Willebrand Factor

SummaryThe stability of platelet aggregates is influenced by the extent of the release of granule contents; if release is extensive and aggregation is prolonged, deaggregation is difficult to achieve. The relative importance of the contributions of released substances to aggregate stability are not known, although stable thrombin-induced aggregates form in platelet-rich plasma from patients with barely detectable plasma or platelet fibrinogen, and ADP stabilizes thrombin-induced aggregates of platelets from patients with delta storage pool deficiency which otherwise deaggregate more readily than normal platelets. We degranulated platelets with thrombin (0.9 U/ml caused greater than 90% loss of delta and alpha granule contents) and recovered them as individual platelets in fresh medium. The degranulated platelets were reaggregated by thrombin (2 U/ml). To prevent continuing effects of thrombin, FPRCH2C1 was added when thrombin-induced aggregation of thrombin-degranulated platelets reached its maximum. EDTA (5 mM) or EGTA (5 mM) added at maximum aggregation did not deaggregate these platelets, indicating that the stability of these aggregates does not depend on Ca2+ in the medium. Whereas with control platelets a combination of PGE1 (10 μM) and chymotrypsin(10 U/ml) was required for deaggregation, with thrombin-degranulated platelets either PGE1 or chymo-trypsin alone caused extensive deaggregation. The rate and extent of deaggregation of thrombin-degranulated platelets by a combination of PGE1 and chymotrypsin was greater than with control platelets.Electron microscope gold immunocytochemistry using antihuman fibrinogen IgG, anti-von Willebrand factor and anti-fibronectin showed a) that fibrinogen in the vacuoles of degranulated platelets was visible at focal points of platelet contact in the aggregates, but that large areas of platelet contact had no fibrinogen detectable between them; and b) in comparison to fibrinogen, little fibronectin or von Willebrand factor (vWf) was detectable in the platelets.Since the linkages between thrombin-degranulated platelets reaggregated by thrombin can be disrupted either by raising cAMP (thus making glycoprotein IIb/IIIa unavailable) or by proteolysis, these linkages are less stable than those formed between normal platelets. It might therefore be expected that platelets that take part in thrombus formation and then recirculate are likely to form less stable thrombi than platelets that have not released their granule contents.

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Effects of Bupranolol, a New β-Blocker, on Platelet Functions of Rabbit and Human in Vitro

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648052 ◽

1976 ◽

Vol 36 (02) ◽

pp. 376-387 ◽

Cited By ~ 3

Author(s):

Teruhiko Umetsu ◽

Kazuko Sanai ◽

Tadakatsu Kato

Keyword(s):

Platelet Aggregation ◽

Platelet Adhesion ◽

Human Platelets ◽

Rabbit Platelet ◽

Rabbit Platelets ◽

Β Blocker ◽

Platelet Aggregates ◽

Induced Aggregation ◽

Platelet Functions

SummaryThe effects of bupranolol, a new β-blocker, on platelet functions were investigated in vitro in rabbits and humans as compared with propranolol, a well-known β-blocker. At first, the effect of adrenaline on ADP-induced rabbit platelet aggregation was studied because adrenaline alone induces little or no aggregation of rabbit platelets. Enhancement of ADP-induced rabbit platelet aggregation by adrenaline was confirmed, as previously reported by Sinakos and Caen (1967). In addition the degree of the enhancement was proved to be markedly affected by the concentration of ADP and to increase with decreasing concentration of ADP, although the maximum aggregation (percent) was decreased.Bupranolol and propranolol inhibited the (adrenaline-ADP-)induced aggregation of rabbit platelets, bupranolol being approximately 2.4–3.2 times as effective as propranolol. Bupranolol stimulated the disaggregation of platelet aggregates induced by a combination of adrenaline and ADP, but propranolol did not. Platelet adhesion in rabbit was also inhibited by the β-blockers and bupranolol was more active than propranolol. With human platelets, aggregation induced by adrenaline was inhibited by bupranolol about 2.8–3.3 times as effectively as propranolol.From these findings. We would suggest that bupranolol might be useful for prevention or treatment of thrombosis.

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Systemic Effects of ADP-induced Platelet Aggregation and Their Modification by Aspirin and by Pyridinolcarbamate

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649115 ◽

1973 ◽

Vol 30 (01) ◽

pp. 178-190 ◽

Cited By ~ 6

Author(s):

Itsuro Kobayashi ◽

Paul Didisheim

Keyword(s):

Platelet Aggregation ◽

Venous Pressure ◽

Systemic Effects ◽

Central Venous ◽

Platelet Aggregates ◽

Induced Changes ◽

Second Wave ◽

Carotid Arterial ◽

Arterial Po2

SummaryADP, AMP, or ATP was injected rapidly intravenously in rats. ADP injection resulted in the f olio wing transient changes: a drop in platelet count, a rise in central venous pressure, a fall in carotid arterial PO2, bradycardia, arrhythmia, flutter-fibrillation, and arterial hypotension. AMP and ATP produced some of these same effects; but except for hypotension, their frequency and severity Avere much less than those following ADP.Prior intravenous administration of acetylsalicylic acid or pyridinolcarbamate, two inhibitors of the second wave of ADP-induced platelet aggregation in vitro, significantly reduced the frequency and severity of all the above ADP-induced changes except hypotension. These observations suggest that many of the changes (except hypotension) observed to follow ADP injection are produced by platelet aggregates which lodge transiently in various microcirculatory beds then rapidly disaggregate and recirculate.

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