Effects of Ticlopidine of Platelet Function in Men with Stable Angina Pectoris

SummaryThe effects of ticlopidine (T) (500 mg daily) on platelet function were investigated in a double-blind placebo-controlled study in 38 middle-aged men with stable incapacitating angina pectoris. The in vitro platelet reactivity to aggregating agents, the platelet sensitivity to prostacyclin and the plasma levels of platelet specific proteins and fibrinogen were determined before and after 4 and 8 weeks of treatment. T exerted a potent inhibitory effect on ADP- and collagen-induced platelet aggregation. The effect of T was proportional to the pretreatment reactivity to ADP and collagen. The inhibitory effect of T on the epinephrine response was less pronounced. The plasma levels of beta-thromboglobulin, platelet factor 4 and fibrinogen were not influenced by T. The platelet inhibition of prostacyclin was potentiated by T, and it was demonstrated that T and prostacyclin had synergistic inhibitory effects on platelet aggregation.

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Platelet Function Studies in Normal Volunteers and Patients with Angina Pectoris

10.1055/s-0039-1684612 ◽

1979 ◽

Cited By ~ 1

Author(s):

J.J.C. Jonker ◽

den G.J.H. Ottolander

Keyword(s):

Platelet Aggregation ◽

Angina Pectoris ◽

Platelet Function ◽

Normal Range ◽

Double Blind ◽

Group Iii ◽

Platelet Survival ◽

Group I ◽

Group Ii

In 30 normal subjects (group I) and in 89 patients with angina pectoris we studied: the platelet survival time (PST), the platelet aggregation test I (PAT I) acc. to Breddin, the platelet aggregation ratio (PAR) acc. to Wu and Hoak and the Filtragometer log TA acc. to Hornstra. The patients were divided in two groups: 46 patients had already been treated for 6 months with Clofibrate (group II) and 43 patients with placebo (group III) in a double blind trial. The average PST (T½) was within the normal range (group I 99 hrs. group II 105,7 hrs.; group III 102,0 hrs.). About 20% of patients of group II and III had abnormally shortened T½. The PAT I was on average abnormal in group II and III (PAT I in group II 2,3; group III 2,7), but group II normalized after 12 months treatment (PAT I 1,85). The PAR was abnormal in group III, while group II was within the normal range (group I 0,87; group II 0,82; group III 0,69). The log TA results were abnormal in group II and III (group I 2, 45, group II 2,1; group III 2, 1), after 12 months treatment the patient group remained abnormal (group II 2,2; group III 2,1). We failed to find a correlation between the four platelet function tests, nor with these tests and basic laboratory values. The PAT I, the PAR and the Filtragometer seems to be valuable in the detection of abnormal platelet behavior in vitro, but it does not mean than an abnormal platelet survival in vivo occurs in the same individuals.

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PLATELET FUNCTION AND PLASMA FIBRINOGEN IN YOUNG SURVIVORS OF MYOCARDIAL INFARCTION

10.1055/s-0038-1643019 ◽

1987 ◽

Author(s):

U Berglund ◽

H von Schenk ◽

L Wallentin

Keyword(s):

Myocardial Infarction ◽

Platelet Function ◽

Platelet Reactivity ◽

Platelet Rich Plasma ◽

Inhibitory Effect ◽

Plasma Fibrinogen ◽

Women Patients ◽

Platelet Factor ◽

Young Survivors

An increased liability for thrombosis might be of pathogenetic importance in young survivors of myocardial infarction (MI). In 73 (58 men and 15 women) patients with MI below 45 years of age and 73 matched healthy controls plasma fibrinogen and platelet function tests were studied 3-6 months after the MI. At the time of the MI 77% of the patients were smokers but at the time of the investigation 27% of the patients smoked compared to 37% of the controls. Platelet aggregabi1ity was measured in vitro in platelet-rich plasma (PRP) as maximal aggregation to ADP and collagen. The platelet sensitivity to the inhibitory effect of prostacyclin (PG12) was tested by preincubation of PRP with PG12 before inducing aggregation with ADP 5 μM. Plasma levels of beta-thrombog1obuIin (BTG) and platelet factor 4 (PF4) were measured by RIA methods and plasma fibrinogen by heat precipitation. The table presents the results (means ± SE). * is p<0.04, ** is D<0.02 and ns is non significant.Severe emotional stress preceeding the MI occured in 7 patients - these cases had an increased platelet reactivity to ADP. The fibrinogen level was also elevated by smoking and obesity (multivariate analysis). Conclusion: young MI patients have elevated levels ol fibrinogen and reduced platelet sensitivity to PGI2. This might cause an increased thrombotic tendency.

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Enhancing Effect of Collagen Receptor Polymorphisms on In Vitro Platelet Reactivity to Aspirin in Healthy Subjects.

Blood ◽

10.1182/blood.v108.11.1099.1099 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1099-1099 ◽

Cited By ~ 1

Author(s):

Miho Ushida ◽

Yumiko Matsubara ◽

Shinichi Takahashi ◽

Hiroaki Ishihara ◽

Toshiro Shibano ◽

...

Keyword(s):

Platelet Aggregation ◽

Platelet Function ◽

Repeated Measures ◽

Platelet Reactivity ◽

Inhibitory Effect ◽

Antiplatelet Drug ◽

Platelet Response ◽

Individual Variations ◽

Collagen Receptor

Abstract [Background] Aspirin (ASA) is widely used as an antiplatelet drug, and a large number of clinical trials with ASA demonstrated significant efficacies for prevention and treatment of athrothrombosis. Recently, accumulating evidences indicated that there are inter-individual variations in the platelet response to ASA. The subpopulation, called ASA resistance, has the inability of response to ASA on ex vivo or in vitro platelet function tests and the poor clinical outcomes, although the mechanism underlying the variability is largely unknown. To date, genetic factors were showed to have an impact on platelet reactivity to ASA, and the inter-individual variations in platelet response to ASA was also reported to be associated with platelet sensitivity to collagen. In this study, the association between collagen-induced platelet aggregation (CIPA) and genetic polymorphisms of collagen receptors, glycoprotein (GP) Ia and GPVI, was analyzed using platelets treated by ASA (ASA +/−). We also investigated the effect of these polymorphisms on platelet thromboxane (TXB2) levels, closely related to the final stages of the arachidonate pathway inhibited by ASA. [Methods] We recruited genetically unrelated Japanese males (n=172) at their regular checkups. The mean age was 46.7±5.1 years. The subjects had no apparent hematologic or vascular disease and were not taking any medications that affect platelet function. Written informed consent was obtained from all study subjects. Platelet-rich plasma (PRP) sample was incubated with ASA [final concentration (fc) 10μM] or vehicle for 30 min at 24 degree Centigrade, and CIPA (fc 2μg/ml) test was performed on each PRP sample. Subsequently, platelet TXB2 levels were measured in the supernatant after centrifugation of each sample of CIPA test. Genotypes of the 807TC, Glu534Lys, Asn927Ser polymorphisms of GPIa and the Ser219Pro, Lys237Glu, Thr249Ala, Gln317Leu, His322Asn polymorphisms of GPVI were determined using the single-nucleotide primer extension-based method. [Results] To examine the sensitivity of platelets to ASA in vitro, we analyzed CIPA and platelet TXB2 levels in ASA(+/−). The maximum platelet aggregation and TXB2 levels in ASA(+) were significantly lower than those in ASA(−) (paired t-test, p<0.0001 and p<0.0001, respectively). Next, we investigated the association between the collagen receptor polymorphisms and the maximum platelet aggregation in ASA (+/−). For ASA(−), all genotypes of GPIa and GPVI were not associated with the maximum platelet aggregation. For ASA(+), subjects with 807TT/TC of GPIa had higher aggregation compared to those with 807CC(P=0.0135) whereas no association was observed between other polymorphisms and the maximum platelet aggregation. Moreover, repeated measures ANOVA showed that the difference in this inhibitory effect of ASA was significant between the 807TT/TC and 807CC genotypes (p=0.0253); the 807CC genotype has higher inhibitory effect of ASA. There was no association between platelet TXB2 levels and the GPIa and GPVI polymorphisms both in ASA(+) and ASA(−). [Conclusion] The 807CC genotype of GPIa polymorphism is associated with higher sensitivity to ASA in CIPA.

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The Effect of Dimethyl Sulfoxide on In Vitro Platelet Function

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648027 ◽

1976 ◽

Vol 36 (01) ◽

pp. 221-229 ◽

Cited By ~ 16

Author(s):

Charles A. Schiffer ◽

Caroline L. Whitaker ◽

Morton Schmukler ◽

Joseph Aisner ◽

Steven L. Hilbert

Keyword(s):

Platelet Count ◽

Platelet Aggregation ◽

Dimethyl Sulfoxide ◽

Platelet Function ◽

Platelet Volume ◽

Short Term ◽

Platelet Factor ◽

Short Term Exposure ◽

Structural Abnormalities

SummaryAlthough dimethyl sulfoxide (DMSO) has been used extensively as a cryopreservative for platelets there are few studies dealing with the effect of DMSO on platelet function. Using techniques similar to those employed in platelet cryopreservation platelets were incubated with final concentrations of 2-10% DMSO at 25° C. After exposure to 5 and 10% DMSO platelets remained discoid and electron micrographs revealed no structural abnormalities. There was no significant change in platelet count. In terms of injury to platelet membranes, there was no increased availability of platelet factor-3 or leakage of nucleotides, 5 hydroxytryptamine (5HT) or glycosidases with final DMSO concentrations of 2.5, 5 and 10% DMSO. Thrombin stimulated nucleotide and 5HT release was reduced by 10% DMSO. Impairment of thrombin induced glycosidase release was noted at lower DMSO concentrations and was dose related. Similarly, aggregation to ADP was progressively impaired at DMSO concentrations from 1-5% and was dose related. After the platelets exposed to DMSO were washed, however, aggregation and release returned to control values. Platelet aggregation by epinephrine was also inhibited by DMSO and this could not be corrected by washing the platelets. DMSO-plasma solutions are hypertonic but only minimal increases in platelet volume (at 10% DMSO) could be detected. Shrinkage of platelets was seen with hypertonic solutions of sodium chloride or sucrose suggesting that the rapid transmembrane passage of DMSO prevented significant shifts of water. These studies demonstrate that there are minimal irreversible alterations in in vitro platelet function after short-term exposure to DMSO.

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The Effect of Barbituric Acid Derivatives on Platelet Function in Vitro and in Vivo

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649080 ◽

1973 ◽

Vol 30 (02) ◽

pp. 315-326

Author(s):

J. Heinz Joist ◽

Jean-Pierre Cazenave ◽

J. Fraser Mustard

Keyword(s):

Platelet Aggregation ◽

Platelet Function ◽

Barbituric Acid ◽

Platelet Rich Plasma ◽

Inhibitory Effect ◽

Primary Response ◽

Sodium Pentobarbital ◽

Barbituric Acid Derivatives

SummarySodium pentobarbital (SPB) and three other barbituric acid derivatives were found to inhibit platelet function in vitro. SPB had no effect on the primary response to ADP of platelets in platelet-rich plasma (PRP) or washed platelets but inhibited secondary aggregation induced by ADP in human PRP. The drug inhibited both phases of aggregation induced by epinephrine. SPB suppressed aggregation and the release reaction induced by collagen or low concentrations of thrombin, and platelet adherence to collagen-coated glass tubes. The inhibition by SPB of platelet aggregation was readily reversible and isotopically labeled SPB did not become firmly bound to platelets. No inhibitory effect on platelet aggregation induced by ADP, collagen, or thrombin could be detected in PRP obtained from rabbits after induction of SPB-anesthesia.

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The d-Enantiomer Form of Indobufen Totally Accounts for the Anti-Cyclooxygenase and Antiplatelet Activity Ex Vivo and for the Increase in Bleeding Time by Indobufen in Man

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648422 ◽

1992 ◽

Vol 67 (02) ◽

pp. 258-263 ◽

Cited By ~ 12

Author(s):

Raffaele De Caterina ◽

Rosa Sicari ◽

An Yan ◽

Walter Bernini ◽

Daniela Giannessi ◽

...

Keyword(s):

Arachidonic Acid ◽

Platelet Aggregation ◽

Plasma Levels ◽

Bleeding Time ◽

Ex Vivo ◽

Random Sequence ◽

Antiplatelet Agent ◽

Antiplatelet Drug ◽

Double Blind

SummaryIndobufen is an antiplatelet drug able to inhibit thromboxane production and cyclooxygenase-dependent platelet aggregation by a reversible inhibition of cyclooxygenase. Indobufen exists in two enantiomeric forms, of which only d-indobufen is active in vitro in inhibiting cyclooxygenase. In order to verify that also inhibition of platelet function is totally accounted for by d-indobufen, ten patients with proven coronary artery disease (8 male, 2 female, age, mean ± S.D., 58.7 ± 7.5 years) were given, in random sequence, both 100 mg d-indobufen and 200 mg dl-indobufen as single administrations in a double-blind crossover design study with a washout period between treatments of 72 h. In all patients thromboxane (TX) B2 generation after spontaneous clotting (at 0, 1, 2, 4, 6, 8, 12, 24 h), drug plasma levels (at the same times), platelet aggregation in response to ADP, adrenaline, arachidonic acid, collagen, PAF, and bleeding time (at 0, 2, 12 h) were evaluated after each treatment. Both treatments determined peak inhibition of TXB2 production at 2 h from administration, with no statistical difference between the two treatments (97 ±3% for both treatments). At 12 h inhibition was 87 ± 6% for d-indobufen and 88 ± 6% for dl-indobufen (p = NS). Inhibition of TXB2 production correlated significantly with plasma levels of the drugs. Maximum inhibitory effect on aggregation was seen in response to collagen 1.5 pg/ml (63 ± 44% for d-indobufen and 81 ± 22% for dl-indobufen) and arachidonic acid 0.5-2 mM (78 ± 34% for d-indobufen and 88 ± 24% for dl-indobufen) at 2 h after each administration. An effect of both treatments on platelet aggregation after 12 h was present only for adrenaline 2 μM (55 ± 41% for d-indobufen and 37 ± 54% for dl-indobufen), collagen 1.5 pg/ml (69 ± 30% for d-indobufen and 51 ± 61% for dl-indobufen), arachidonic acid 0.5-2 mM (56 ± 48% for d-indobufen and 35 ± 49% for dl-indobufen). The extent of inhibition of TX production and the extent of residual platelet aggregation were never significantly different between treatments. Bleeding time prolongation was similar in the two treatment groups without showing a pronounced and long lasting effect (from 7.0 ± 2.0 min to 10.0 ± 3.0 min at 2 h and 8.0 ± 2.0 min at 12 h for d-indobufen; from 6.0 ±1.0 min to 8.5 ± 2.0 min at 2 h and 8.0 ± 1.0 min at 12 h for dl-indobufen). These results demonstrate that the biological activity of dl-indobufen as an antiplatelet agent in vivo is totally accounted for by d-indobufen.

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Inhibition of Platelet Function by Antiarrhythmic Drugs, Verapamil and Disopyramide

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657151 ◽

1982 ◽

Vol 47 (02) ◽

pp. 150-153 ◽

Cited By ~ 13

Author(s):

P Han ◽

C Boatwright ◽

N G Ardlie

Keyword(s):

Platelet Aggregation ◽

Platelet Function ◽

Antiarrhythmic Drugs ◽

Adenosine Diphosphate ◽

Inhibitory Effect ◽

Second Phase ◽

Ionophore A23187 ◽

High Concentrations ◽

Artery Disease

SummaryVarious cardiovascular drugs such as nitrates and propranolol, used in the treatment of coronary artery disease have been shown to have an antiplatelet effect. We have studied the in vitro effects of two antiarrhythmic drugs, verapamil and disopyramide, and have shown their inhibitory effect on platelet function. Verapamil, a calcium channel blocker, inhibited the second phase of platelet aggregation induced by adenosine diphosphate (ADP) and inhibited aggregation induced by collagen. Disopyramide similarly inhibited the second phase of platelet aggregation caused by ADP and aggregation induced by collagen. Either drug in synergism with propranolol inhibited ADP or collagen-induced platelet aggregation. Disopyramide at high concentrations inhibited arachidonic add whereas verapamil was without effect. Verapamil, but not disopyramide, inhibited aggregation induced by the ionophore A23187.

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Effect Of Factor XIII On Platelet Aggregation. Study Of Platelet Function And Fibrin Stabilization Inhibitors

10.1055/s-0038-1653294 ◽

1981 ◽

Author(s):

M Maamer ◽

O Demay ◽

M Aurousseau

Keyword(s):

Platelet Aggregation ◽

Acetylsalicylic Acid ◽

Platelet Function ◽

Factor Xiii ◽

Platelet Rich Plasma ◽

Inhibitory Effect ◽

Photometric Method

There is little information on the participation of Factor XIII in platelet aggregation. Using BORN’s photometric method to study platelet aggregation induced by ADP in vitro on platelet rich plasma (PRP) of rabbit; clot solubility in 1 % monochloracetic acid and incorporation of dansylcadaverin into casein (LORAND L. et al.) to measure plasma FXIII concentration ; we showed that addition of activated F.XIII (F.XIIIa) to a PRP, aggregating power of platelets was significantly increased (+ 30.4 %, p<0.00l). Addition of inactive F.XIII or thrombin + Ca++ in concentrations used to activate F.XIII, had no significant effect on platelet aggregation induced by ADP.When F.XIIIa was added to plasma in presence of F.XIII inhibitors as 3178 AQ (a new synthetic benzothiophen keton derivative) or monodansylcadaverin (DC) in concentrations of (3.27 × 10-4 M and 9.31 × 10-4 m respectively), the platelet aggregation was significantly inhibited (- 48.8 % and - 35.4 % respectively, p<0.001). This inhibitory effect was not seen when dipyridamole or Acetylsalicylic Acid (ASA) in concentrations of (6.18 × 10-4 M and 17.3 × 10-4 M respectively) ware added in PRP in presence of F.XIIIa When platelet aggregation was performed without addition of F.XIIIa the inhibitory effect of 3178 AQ and DC was respectively (- 76.6 % and - 65.1 %, p<0.001), dipyridamole (- 37.6 %, p<0.00l) and ASA (-4.1%, no significant)These results suggest that F.XIIIa increased the platelet aggregation induced by ADP and compounds which are both inhibitors of platelet aggregation and F.XIII would be more potent antithrombotic by acting on platelets and fibrin stabilization, than drugs which are inhibitors of platelet aggregation only.

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Antiplatelet effects of citalopram in patients with ischaemic stroke: A randomized, placebo-controlled, double-blind study

Scientific Reports ◽

10.1038/s41598-019-56487-8 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Kristian Lundsgaard Kraglund ◽

Janne Kaergaard Mortensen ◽

Søren Paaske Johnsen ◽

Grethe Andersen ◽

Erik Lerkevang Grove

Keyword(s):

Platelet Aggregation ◽

Ischaemic Stroke ◽

Acute Ischaemic Stroke ◽

Platelet Reactivity ◽

Significant Inhibition ◽

Controlled Study ◽

Double Blind Study ◽

Stroke Patients ◽

Double Blind ◽

Ssri Treatment

AbstractWe evaluated the effect of SSRI treatment on platelet aggregation in patients with ischaemic stroke and included patients from the randomized double-blind controlled study of citalopram in acute ischaemic stroke (TALOS). Patients on clopidogrel were included 6 months after acute ischaemic stroke. Platelet parameters, including P2Y12 platelet reactivity using the VerifyNow System, were measured at the last day of study treatment and repeated after a 14-day wash-out period. A total of 60 patients were included (n = 32 randomized to citalopram). Platelet aggregation levels did not differ between the citalopram group (mean 116, 95% CI 89 to 143) and the placebo group (mean 136, 95% CI 109 to 163) (On-treatment, p = 0.14). Similarly, there was no significant change in platelet aggregation in the citalopram group from on-treatment to post-treatment (mean difference 2.0; 95% CI −18 to 14). Platelet count, size and turnover were not affected by SSRI treatment. In conclusion, SSRI therapy did not lead to statistically significant inhibition of platelet aggregation in ischaemic stroke patients treated with clopidogrel.

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Novel 12-LOX Inhibitor ML355 Attenuates Platelet Reactivity and Impairs Thrombus Growth, Stability and Vessel Occlusion In Vivo

Blood ◽

10.1182/blood.v126.23.3442.3442 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3442-3442 ◽

Cited By ~ 1

Author(s):

Reheman Adili ◽

Theodore R Holman ◽

Michael Holinstat

Keyword(s):

Platelet Aggregation ◽

Platelet Function ◽

Platelet Adhesion ◽

Ex Vivo ◽

Platelet Reactivity ◽

Thrombus Formation ◽

Vessel Occlusion ◽

Growth Stability

Abstract Background: Adequate platelet reactivity is required for platelet adhesion and aggregation at the site of vascular injury to maintain hemostasis. However, excessive platelet reactivity can also lead to the formation of occlusive thrombi, the predominate underlying cause of myocardial infarction and stroke. While current anti-platelet treatments limit platelet function, they often result in an increased risk of bleeding. 12-lipoxygenase (12-LOX), an oxygenase highly expressed in the platelet, has been demonstrated by our lab and others to regulate PAR4 and GPVI-mediated platelet reactivity suggesting a role of 12-LOX in regulation of vivo thrombosis. However, the ability to pharmacologically target 12-LOX in vivo has not been established to date. Aims: To determine how 12-LOX regulates thrombus formation in vivo and whether platelet 12-LOX is an effective target for anti-platelet therapeutics, wild-type (WT) or 12-LOX deficient (12-LOX-/-) mice were treated with or without the 12-LOX inhibitor, ML355, and were assessed for inhibitory effects on platelet activation in vitro, ex-vivo and in vivo. Methods: The effect of the novel 12-LOX inhibitor ML355 on human platelet function was assessed in vitro by platelet aggregometry, ex vivo by perfusion chamber. In vivo thrombus formation and vessel occlusion in small and large vessels were studied in 12-LOX-/-, WT mice and mice treated with ML355 using intravital microscopy using the FeCl3 injury models. Results: Using in vitro platelet aggregation assays, ML355 dose dependently inhibited thrombin, PAR1-AP, and PAR4-AP-induced aggregation in washed human platelets. Interestingly, the negative regulatory effects of ML355 inhibition of 12-LOX can be overcome by high concentration of thrombin. Additionally, ML355 was able to attenuate ADP-induced platelet aggregation both in platelet-rich-plasma and whole blood. In ex vivo flow chamber assays, platelet adhesion and thrombus formation on collagen-coated surfaces at high shear was attenuated in both mouse and human whole blood after incubation with ML355. Further, platelet aggregation and thrombus growth in 12-LOX-/- mice was impaired in FeCl3-induced mesenteric or carotid artery thrombosis models. Thrombi in 12-LOX-/- mice were unstable and frequently form emboli, which resulted in impaired vessel occlusion or reopening. Additionally, thrombus formation and vessel occlusion was impaired in ML355 treated WT mice. Conclusions: The highly selective 12-LOX inhibitor ML355 inhibits platelets aggregation induced by various platelet agonists and ML355 inhibition of platelet function is not agonist specific. Platelet function at high shear in ex vivo conditions in both mice and human was attenuated in the presence of ML355. Thrombus growth, stability, and vessel occlusion was impaired in mice deficient for 12-LOX. Finally, the highly selective 12-LOX inhibitor ML355 attenuates thrombus formation and prevents vessel occlusion in vivo. Our data strongly indicates 12- LOX is an important determinant of platelet reactivity and inhibition of platelet 12-LOX may represent a new target for anti-platelet therapeutics. Disclosures No relevant conflicts of interest to declare.

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