scholarly journals Sex differences in the antithrombotic effects of aspirin

Blood ◽  
1978 ◽  
Vol 52 (5) ◽  
pp. 1073-1076 ◽  
Author(s):  
JG Kelton ◽  
J Hirsh ◽  
CJ Carter ◽  
MR Buchanan
Keyword(s):  
Clinical Trials ◽  
Animal Model ◽  
Arterial Thrombosis ◽  
Sodium Salicylate ◽  
Inhibitory Effect ◽  
Prostaglandin Synthesis ◽  
Antithrombotic Effect ◽  
Antithrombotic Agent ◽  
Male And Female ◽  
Antithrombotic Effects

Abstract Aspirin inhibits platelet function by acetylating platelet cyclooxygenase. Recent clinical trials indicate that aspirin is a promising antithrombotic agent against both venous and arterial thrombosis, but somewhat surprisingly this protective effect appears to be limited to males. To examine the potential sex-related differences in response to aspirin, we developed an animal model for quantitating fibrin accretion into an injury-induced thrombus and used it to study the effects of aspirin on thrombus size in male and female rabbits. Platelet prostaglandin synthesis was estimated by assay of platelet malondialdehyde and was significantly decreased in both male and female rabbits following treatment with 10 mg/kg aspirin (p less than 0.001). This inhibitory effect was not different for platelets from male and female rabbits. Thrombus size was significantly decreased in aspirin- treated male rabbits when compared to controls (p less than 0.05), but this aspirin effect was not apparent in female rabbits or rabbits of either sex treated with 10 mg/kg sodium salicylate. These findings support the results of clinical trials that were obtained by retrospective subgroup analysis. The reason for the sex difference is not known, but the findings raise an important issue in relationship to this mechanism of the antithrombotic effect of aspirin.

scholarly journals Sex differences in the antithrombotic effects of aspirin

Blood ◽  
1978 ◽  
Vol 52 (5) ◽  
pp. 1073-1076 ◽  
Author(s):  
JG Kelton ◽  
J Hirsh ◽  
CJ Carter ◽  
MR Buchanan
Keyword(s):  
Clinical Trials ◽  
Animal Model ◽  
Arterial Thrombosis ◽  
Sodium Salicylate ◽  
Inhibitory Effect ◽  
Prostaglandin Synthesis ◽  
Antithrombotic Effect ◽  
Antithrombotic Agent ◽  
Male And Female ◽  
Antithrombotic Effects

Aspirin inhibits platelet function by acetylating platelet cyclooxygenase. Recent clinical trials indicate that aspirin is a promising antithrombotic agent against both venous and arterial thrombosis, but somewhat surprisingly this protective effect appears to be limited to males. To examine the potential sex-related differences in response to aspirin, we developed an animal model for quantitating fibrin accretion into an injury-induced thrombus and used it to study the effects of aspirin on thrombus size in male and female rabbits. Platelet prostaglandin synthesis was estimated by assay of platelet malondialdehyde and was significantly decreased in both male and female rabbits following treatment with 10 mg/kg aspirin (p less than 0.001). This inhibitory effect was not different for platelets from male and female rabbits. Thrombus size was significantly decreased in aspirin- treated male rabbits when compared to controls (p less than 0.05), but this aspirin effect was not apparent in female rabbits or rabbits of either sex treated with 10 mg/kg sodium salicylate. These findings support the results of clinical trials that were obtained by retrospective subgroup analysis. The reason for the sex difference is not known, but the findings raise an important issue in relationship to this mechanism of the antithrombotic effect of aspirin.

scholarly journals Antithrombotic effect of a monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor in an experimental animal model

Blood ◽  
1986 ◽  
Vol 68 (3) ◽  
pp. 783-786 ◽  
Author(s):  
BS Coller ◽  
JD Folts ◽  
LE Scudder ◽  
SR Smith
Keyword(s):  
Monoclonal Antibody ◽  
Animal Model ◽  
Platelet Aggregation ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Platelet Glycoprotein ◽  
Antithrombotic Effect ◽  
Antithrombotic Agent ◽  
Antithrombotic Effects ◽  
Platelet Thrombus

A murine monoclonal antibody directed at the platelet glycoprotein IIb/IIIa complex, which blocks platelet aggregation ex vivo, was tested for its antithrombotic effects in an established animal model of acute platelet thrombus formation in partially stenosed arteries. Infusion of 0.7 to 0.8 mg/kg of the F(ab')2 fragment of the antibody completely blocked new thrombus formation despite multiple provocations, making it the most potent antithrombotic agent tested in this model.

scholarly journals Antithrombotic effect of a monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor in an experimental animal model

Blood ◽  
1986 ◽  
Vol 68 (3) ◽  
pp. 783-786 ◽  
Author(s):  
BS Coller ◽  
JD Folts ◽  
LE Scudder ◽  
SR Smith
Keyword(s):  
Monoclonal Antibody ◽  
Animal Model ◽  
Platelet Aggregation ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Platelet Glycoprotein ◽  
Antithrombotic Effect ◽  
Antithrombotic Agent ◽  
Antithrombotic Effects ◽  
Platelet Thrombus

Abstract A murine monoclonal antibody directed at the platelet glycoprotein IIb/IIIa complex, which blocks platelet aggregation ex vivo, was tested for its antithrombotic effects in an established animal model of acute platelet thrombus formation in partially stenosed arteries. Infusion of 0.7 to 0.8 mg/kg of the F(ab')2 fragment of the antibody completely blocked new thrombus formation despite multiple provocations, making it the most potent antithrombotic agent tested in this model.

scholarly journals Pharmacokinetic and antithrombotic properties of two pentasaccharides with high affinity to antithrombin III in the rabbit: comparison with CY216

Blood ◽  
1994 ◽  
Vol 84 (8) ◽  
pp. 2571-2577 ◽  
Author(s):  
D Carrie ◽  
C Caranobe ◽  
S Saivin ◽  
G Houin ◽  
M Petitou ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Antithrombin Iii ◽  
Subcutaneous Administration ◽  
Inhibitory Effect ◽  
Low Molecular Weight ◽  
Antithrombotic Effect ◽  
High Affinity ◽  
Antithrombotic Effects ◽  
Antifactor Xa ◽  
Inhibitory Agents

This study compares the pharmacokinetic and the antithrombotic properties of two pentasaccharides with high affinity to antithrombin III with those of a conventional low molecular weight heparin, CY216, in the rabbit. On a weight basis, SR 90107A/ORG 31540 (natural pentasaccharide [NPS]) and SR 80027A/ORG 31550 (sulfated pentasaccharide [SPS]) were, respectively, 4.7 and 26 times more potent antifactor Xa inhibitory agents than CY216. They were devoid of antithrombin activity, whereas the antifactor Xa/antithrombin ratio of CY216 was 3.8. After bolus intravenous administration, the clearance (mL/kg/h) of CY216 decreased from 91 +/- 27 for the dose of 12.5 U/kg to 49 +/- 14 for the dose of 50 U/kg and then remained constant up to the highest dose tested (500 U/kg). The clearance of NPS was unrelated to the dose and comparable to that of CY216 over 50 U/kg, whereas that of SPS was 10 times lower. Consistent results were observed after continuous intravenous infusions for 9 hours and subcutaneous administration. The duration of the antithrombotic effect was compared after a single subcutaneous injection of 250 U/kg of either compound in the stasis-Wessler model using human serum as thrombogenic stimulus. Two hours after the injection, the three compounds provided a thrombus prevention of greater than 95% and mean plasma activities of 0.8, 0.9, and 1.9 U/mL for CY216, NPS, and SPS, respectively. Twelve hours after injection, the antithrombotic effects of CY216 and NPS had totally vanished, whereas that of SPS was 68%. At that time, the plasma anti-Xa activities were less than 0.06 U/mL for CY216 and NPS, but 1.1 U/mL for SPS. For the latter compound, significant antithrombotic effects and detectable anti-Xa activities were still recorded 48 hours after the injection. The antithrombotic potency of the three compounds was also compared as their ability to inhibit the growth of a standardized venous thrombosis during 4 hours. The lowest total doses providing the maximum inhibitory effect were 3,125, 1,428, and 62 micrograms/kg for CY216, NPS, and SPS, respectively. These doses generated mean steady state antifactor Xa activities of 1.06, 1.5, and 1.2 anti-Xa U/mL, respectively. These observations indicate that the amplification mechanisms triggered by thrombin bound to fibrin and leading to the generation of new thrombin are essential to ensure venous thrombosis growth and that these mechanisms may be efficiently inhibited by pure antifactor Xa targeting agents.

A Discussion on Experiments and Experimentation: NIH to Balance Sex in Cell and Animal Studies

2015 ◽  
Vol 1 (1) ◽  
pp. 1-13 ◽  
Author(s):  
Daphna Joel ◽  
Anelis Kaiser ◽  
Sarah S. Richardson ◽  
Stacey A. Ritz ◽  
Deboleena Roy ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Animal Model ◽  
Cell Line ◽  
Animal Studies ◽  
National Institutes Of Health ◽  
Preclinical Studies ◽  
Male And Female ◽  
Nih Policy

In 2014, the National Institutes of Health (NIH) proposed a new policy to promote “sex parity” in research.  As an extension to the 1993 NIH Revitalization Act which mandated the inclusion of women and minorities in clinical trials, the new NIH policy will require scientists to include “sex” as a variable in both animal model and in vitro cell line-based research.  The end goal is to ensure that NIH funded scientists “balance male and female cells and animals in preclinical studies in all future applications” (Clayton and Collins 2014, 283). The curators of this section asked four interdisciplinary scholars to discuss this proposed policy.

scholarly journals Pharmacokinetic and antithrombotic properties of two pentasaccharides with high affinity to antithrombin III in the rabbit: comparison with CY216

Blood ◽  
1994 ◽  
Vol 84 (8) ◽  
pp. 2571-2577 ◽  
Author(s):  
D Carrie ◽  
C Caranobe ◽  
S Saivin ◽  
G Houin ◽  
M Petitou ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Antithrombin Iii ◽  
Subcutaneous Administration ◽  
Inhibitory Effect ◽  
Low Molecular Weight ◽  
Antithrombotic Effect ◽  
High Affinity ◽  
Antithrombotic Effects ◽  
Antifactor Xa ◽  
Inhibitory Agents

Abstract This study compares the pharmacokinetic and the antithrombotic properties of two pentasaccharides with high affinity to antithrombin III with those of a conventional low molecular weight heparin, CY216, in the rabbit. On a weight basis, SR 90107A/ORG 31540 (natural pentasaccharide [NPS]) and SR 80027A/ORG 31550 (sulfated pentasaccharide [SPS]) were, respectively, 4.7 and 26 times more potent antifactor Xa inhibitory agents than CY216. They were devoid of antithrombin activity, whereas the antifactor Xa/antithrombin ratio of CY216 was 3.8. After bolus intravenous administration, the clearance (mL/kg/h) of CY216 decreased from 91 +/- 27 for the dose of 12.5 U/kg to 49 +/- 14 for the dose of 50 U/kg and then remained constant up to the highest dose tested (500 U/kg). The clearance of NPS was unrelated to the dose and comparable to that of CY216 over 50 U/kg, whereas that of SPS was 10 times lower. Consistent results were observed after continuous intravenous infusions for 9 hours and subcutaneous administration. The duration of the antithrombotic effect was compared after a single subcutaneous injection of 250 U/kg of either compound in the stasis-Wessler model using human serum as thrombogenic stimulus. Two hours after the injection, the three compounds provided a thrombus prevention of greater than 95% and mean plasma activities of 0.8, 0.9, and 1.9 U/mL for CY216, NPS, and SPS, respectively. Twelve hours after injection, the antithrombotic effects of CY216 and NPS had totally vanished, whereas that of SPS was 68%. At that time, the plasma anti-Xa activities were less than 0.06 U/mL for CY216 and NPS, but 1.1 U/mL for SPS. For the latter compound, significant antithrombotic effects and detectable anti-Xa activities were still recorded 48 hours after the injection. The antithrombotic potency of the three compounds was also compared as their ability to inhibit the growth of a standardized venous thrombosis during 4 hours. The lowest total doses providing the maximum inhibitory effect were 3,125, 1,428, and 62 micrograms/kg for CY216, NPS, and SPS, respectively. These doses generated mean steady state antifactor Xa activities of 1.06, 1.5, and 1.2 anti-Xa U/mL, respectively. These observations indicate that the amplification mechanisms triggered by thrombin bound to fibrin and leading to the generation of new thrombin are essential to ensure venous thrombosis growth and that these mechanisms may be efficiently inhibited by pure antifactor Xa targeting agents.

Comparison of the Inhibitory Effects of the TXA2 Receptor Antagonist, Vapiprost, and Other Antiplatelet Drugs on Arterial Thrombosis in Rats: Possible Role of TXA2

1992 ◽  
Vol 68 (04) ◽  
pp. 460-463 ◽  
Author(s):  
Yoshiharu Takiguchi ◽  
Kouichirou Wada ◽  
Mitsuyoshi Nakashima
Keyword(s):  
Platelet Aggregation ◽  
Receptor Antagonist ◽  
Arterial Thrombosis ◽  
Ex Vivo ◽  
Antiplatelet Drugs ◽  
Dependent Manner ◽  
Antithrombotic Effect ◽  
Antiplatelet Effect ◽  
Antithrombotic Effects

SummaryThe antithrombotic effect of the thromboxane A2 receptor antagonist, vapiprost, was compared with those of other antiplatelet drugs using an arterial thrombosis model which utilized photochemical reaction in the rat femoral artery. Vapiprost prolonged the time required to occlude the artery with thrombus and inhibited collagen-induced rat platelet aggregation in whole blood ex vivo, in a dose-dependent manner. The potency ranking of antithrombotic effect was vapiprost > ketanserin (serotonin 5-HT2 receptor antagonist) >> ticlopidine (inhibitor of ADP-induced platelet aggregation) = dipyridamole (adenosine uptake inhibitor) >aspirin (cyclooxygenase inhibitor). On the other hand, the ranking of antiplatelet effect was ticlopidine ≥vapiprost ≥aspirin. Ketanserin and dipyridamole were ineffective. Relative to their antiplatelet effect, vapiprost and ketanserin had powerful antithrombotic effects. It is possible that the potent antithrombotic effects of vapiprost and ketanserin in vivo reflect the ability of these drugs to inhibit mediator-induced vascular contractions in addition to platelet aggregation. The results of the present study also suggest that TXA2 may play an important role in thrombogenesis in rats.

A Sex Difference in the Effect of Aspirin on “Spontaneous” Platelet Aggregation in Whole Blood

1983 ◽  
Vol 50 (04) ◽  
pp. 773-774 ◽  
Author(s):  
M J G Harrison ◽  
E Weisblatt
Keyword(s):  
Clinical Trials ◽  
Platelet Count ◽  
Platelet Aggregation ◽  
Sex Difference ◽  
Whole Blood ◽  
Antithrombotic Agent ◽  
Male And Female ◽  
Spontaneous Aggregation ◽  
Spontaneous Platelet Aggregation

SummaryPlatelet aggregation can be measured in whole blood by monitoring the fall in single platelet count in an electronic platelet counter. The aggregation that occurs when whole blood is stirred in a small cuvette (“spontaneous aggregation”) or upon the addition of collagen has been studied in citrated whole blood from male and female volunteers. Aspirin 40 μg ml/1 inhibited aggregation induced by collagen in both sexes but spontaneous aggregation was only affected by aspirin in males. These results may help explain the sex difference apparent in the results of some clinical trials of aspirin as an antithrombotic agent.

Ecarin Clotting Time: a Predictive Coagulation Assay for the Antithrombotic Activity of Argatroban in the Rat

1998 ◽  
Vol 79 (01) ◽  
pp. 228-233 ◽  
Author(s):  
Catherine Lunven ◽  
Christine Girardot ◽  
Irène Lechaire ◽  
Denise Girard ◽  
Marie-Christine Charles ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Arterial Thrombosis ◽  
Predictive Marker ◽  
Clotting Time ◽  
Antithrombotic Effect ◽  
Antithrombotic Activity ◽  
Thrombosis Model ◽  
Antithrombotic Effects ◽  
Ecarin Clotting Time ◽  
Predictive Assay

SummaryWe studied the use of the Ecarin Clotting Time (ECT) as a predictive assay of the antithrombotic effects of argatroban in a new tissue factor-dependent model of venous thrombosis and a model of arterial thrombosis in the rat. Heparin was used as a reference anticoagulant.Infusions of argatroban dose-dependently increased the ECT across the range of doses required for antithrombotic activity in models of venous and arterial thrombosis (1.25-40 μg/kg/min). The TT was only useful as a marker in the case of venous thrombosis, since, in the arterial thrombosis model, the clotting times were >200 s in the majority of animals receiving antithrombotic doses. The aPTT is not sufficiently sensitive to be predictive of an antithrombotic effect in the venous model, and shows only modest increases in the arterial thrombosis model. Heparin did not significantly increase the ECT at antithrombotic doses in the venous thrombosis model, and only increased the ECT by 53% at 40 μg/kg/min in the arterial model, despite a marked antithrombotic effect. Both the TT and aPTT were dose-dependently increased by heparin at doses active in the venous model, whereas both parameters were >200 s at doses active in the arterial thrombosis model.Thus, the ECT provides a predictive marker for the antithrombotic activity of argatroban in both venous and arterial thrombosis, at least in the rat.

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