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Y Cadroy

Publications and source records attributed to Y Cadroy.

46 records · Page 3Linked to original sources
PubMed1990

Distribution of 16 hemostatic laboratory variables assayed in 100 blood donors.

The aim of the present study was to establish the normal range of 16 hemostatic variables routinely assayed in our laboratory. We therefore measured the activated partial thromboplastin time, the prothrombin time, and the plasma levels of fibrinogen (Fg), factors II, V, VII + X, VIII, IX, XI, XII, von Willebrand factor-antigen (vWf), protein C (PC), total (tPS) and free (fPS) protein S-antigen, C4b binding protein (C4bBP) and fibrin degradation products (FDP), in 100 unselected adult blood donors (58 males, 42 females). We further examined the influence of age and sex on these variables. Age was shown to affect the plasma level of free PS: in comparison with a normal reference plasma, the levels of measured fPS in subjects less than or equal to 40 years (n = 67) and greater than 40 years (n = 33) were 86% (normal range: 52-143%) and 99% (60-162%), respectively (P = 0.01). The plasma levels of factors VIII, vWf, C4bBP and PS were significantly influenced by sex. This finding was particularly marked for fPS: in males (n = 31) and females (n = 36) less than or equal to 40 years, plasma levels of fPS were 94% (59-150%) and 80% (49-132%), respectively (P = 0.008). Finally, we studied the relationships existing between these factors. We found that plasma levels of most coagulation factors were interrelated. In addition, FDP values were positively correlated with plasma level of Fg (r = 0.26); P = 0.008).

Adult↗
PubMed1989

RGDV peptide selectively inhibits platelet-dependent thrombus formation in vivo. Studies using a baboon model.

Since platelet hemostatic functions are mediated in part through the binding of adhesive proteins containing an RGD (Arg-Gly-Asp) recognition sequence, and since platelet reactions may be inhibited in vitro by RGD-containing peptides, we assessed in vivo the antithrombotic activity of RGDV (Arg-Gly-Asp-Val) tetrapeptide using a baboon thrombosis model. Thrombus formation was induced by a device consisting of a tubular segment coated with type I collagen, followed by two regions of expanded diameter exhibiting disturbed flow and stasis. The thrombogenic device was incorporated into femoral arteriovenous shunts under conditions of intermediate wall shear rate (100 s-1). Thrombus formation was measured by scintillation camera imaging of 111In-platelets and by counting of 125I-fibrinogen/fibrin. Thrombus that formed on the collagen substrate was rich in platelets, while thrombus formed in the disturbed flow regions was rich in fibrin and red cells. RGDV peptide was infused proximal to the thrombogenic device to maintain local plasma concentrations of 25, 50, and 100 microM. Infused RGDV decreased the accumulation of both platelets and fibrin on the collagen substrate in a dose-response manner. At the highest dose platelet and fibrin deposition after 40 min was reduced by greater than 80% (P less than 0.01). In the region of disturbed flow, RGDV (100 microM) reduced platelet deposition by 85% (P less than 0.01) but did not reduce the accumulation of fibrin (P less than 0.3). Similarly, the peptide inhibited the release of granular proteins from platelets associated with thrombus (platelet factor 4, beta-thromboglobulin; P less than 0.01), but did not prevent the appearance of fibrinopeptide A in circulating blood (P greater than 0.1). No systemic alterations in blood pressure, bleeding time, or platelet aggregation ex vivo were produced by locally infused RGDV. The antithrombotic effects of RGDV peptide disappeared within 5 min after discontinuing the infusion. In control studies infused RGEV (Arg-Gly-Glu-Val, 100 microM) showed no antithrombotic activity. Thus, RGDV selectively blocks platelet-dependent thrombus formation in vivo.

Amino Acid Sequence↗
PubMed1989

Discrimination between platelet-mediated and coagulation-mediated mechanisms in a model of complex thrombus formation in vivo.

To study mechanisms of complex thrombus formation in vivo, and to compare the relative antithrombotic effects of anticoagulants and antiplatelet agents, a model was developed in baboons. Segments of collagen-coated tubing followed by two sequentially placed expansion chambers exhibiting disturbed flow patterns were exposed to native blood under laminar flow conditions. The device was incorporated for 1 hour into an exteriorized arteriovenous shunt in baboons under controlled blood flow (20 ml/min). Morphologic evaluation by scanning electron microscopy showed that thrombi associated with collagen were relatively rich in platelets but thrombi in the chambers were rich in fibrin and red cells. Deposition of indium 111-labeled platelets was continuously measured with a scintillation camera. Platelet deposition increased in a linear (collagen-coated segment) or exponential (chambers 1 and 2) fashion over time, with values after 40 minutes averaging 24.1 +/- 3.3 x 10(8) platelets (collagen segment), 16.7 +/- 3.4 x 10(8) platelets (chamber 1), and 8.4 +/- 2.4 x 10(8) platelets (chamber 2). Total fibrinogen deposition after 40 minutes was determined by using iodine 125-labeled baboon fibrinogen and averaged 0.58 +/- 0.14 mg in the collagen segment, 1.51 +/- 0.27 mg in chamber 1, and 0.95 +/- 0.25 mg in chamber 2. Plasma levels of beta-thromboglobulin (beta TG), platelet-factor 4 (PF4), and fibrinopeptide A (FPA) increased fourfold to fivefold after 60 minutes of blood exposure to the thrombotic device. Platelet deposition onto the collagen segment, chamber 1, and chamber 2 was linearly dependent on the circulating platelet count. Platelet accumulation in chamber 1 and chamber 2 was also dependent on the presence of the proximal collagen segment. An anticoagulating dose of standard heparin decreased platelet deposition in the chambers (p less than 0.05) but did not decrease deposition onto the collagen segment. Although beta TG and PF4 levels remained elevated after the administration of standard heparin, the elevation in plasma FPA was interrupted. Further evidence that the thrombotic process was dependent on platelets was provided by the finding that prostaglandin I2 at high concentration (35 ng/ml) decreased platelet deposition onto the collagen segment and in chambers 1 and 2, decreased beta TG and PF4 release, and reduced FPA formation. The combination of standard heparin and PGI2 produced the most potent inhibition of platelet thrombus formation and prevented the increases in plasma PF4, beta TG and FPA.

Animals↗
PubMed1989

Inhibition of platelet-dependent thrombosis by low molecular weight heparin (CY222): comparison with standard heparin.

We have compared the relative antithrombotic and antihemostatic effects of the very low molecular weight heparin CY222 with standard unfractionated heparin (SH) in a baboon model of platelet-dependent thrombosis. Thrombus formation was induced by placement of a thrombogenic device in an exteriorized femoral arteriovenous shunt under conditions of intermediate-shear blood flow. The device consisted of a collagen-coated cannular segment positioned proximal to two regions of expanded diameter exhibiting disturbed flow and stasis. Thrombus formation was measured in real time by indium 111-labeled platelet imaging. The collagen-coated surface accumulated thrombi composed largely of platelets, and the regions of disturbed flow were morphologically rich in fibrin and red cells. SH and CY222 were administered by continuous infusion for 1 hour. Although both heparin preparations abolished thrombus formation in the low-shear fibrin-rich regions at plasma levels less than 0.5 anti-Xa U/ml, platelet deposition onto the collagen surface was not reduced by either SH or CY222 at that dosage. These findings were consistent with previously observed therapeutic benefits of this level of anti-Xa activity in venous, but not arterial, thrombosis. Platelet deposition on the collagen was reduced in a dose-dependent manner by both SH and CY222 administered at doses between 1 and 5 anti-Xa U/ml. It is important to note that although heparin preparations produced profound and equivalent antithrombotic effects for platelet-dependent thrombus formation at comparable levels of anti-Xa activity, SH prolonged both the coagulation time and the bleeding time substantially more than did CY222.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Further studies on the mechanisms for the antithrombotic effects of sulfated polysaccharides in rabbits.

A recent study (Fernandez et al., Thromb. Haemostas. 1987; 57: 286-93) demonstrated that when rabbits were injected with the minimum weight of a variety of glycosaminoglycans required to inhibit tissue factor-induced thrombus formation by approximately 80%, exogenous thrombin was inactivated approximately twice as fast in the post-treatment plasmas as the pre-treatment plasmas. In this study, we investigated the relationship between inhibition of thrombus formation and the extent of thrombin inhibition ex vivo. We also investigated the relationship between inhibition of thrombus formation and inhibition of prothrombin activation ex vivo. Four sulfated polysaccharides (SPS) which influence coagulation in a variety of ways were used in this study. Unfractionated heparin and the fraction of heparin with high affinity to antithrombin III potentiate the antiproteinase activity of antithrombin III. Pentosan polysulfate potentiates the activity of heparin cofactor II. At less than 10 micrograms/ml of plasma, all three SPS also inhibit intrinsic prothrombin activation. The fourth agent, dermatan sulfate, potentiates the activity of heparin cofactor II but fails to inhibit intrinsic prothrombin activation even at concentrations which exceed 60 micrograms/ml of plasma. Inhibition of thrombus formation by each sulfated polysaccharides was linearly related to the extent of thrombin inhibition achieved ex vivo. These observations confirm the utility of catalysis of thrombin inhibition as an index for assessing antithrombotic potential of glycosaminoglycans and other sulfated polysaccharides in rabbits. With the exception of pentosan polysulfate, there was no clear relationship between inhibition of thrombus formation and inhibition of prothrombin activation ex vivo.

Animals↗
PubMed1988

Standard heparin enhances the antithrombotic activity of dermatan sulfate in the rabbit but CY 216 does not.

Standard heparin (SH) and dermatan sulfate (DS) two glycosaminoglycans with different pharmacological targets are effective antithrombotic agents in the rabbit. We have investigated the antithrombotic activity of the association DS plus SH. It was found that doses as low as 25 micrograms/kg for DS and 10 micrograms/kg for SH were ineffective when injected separately but generated a high and significant antithrombotic activity when injected together. These results were confirmed when higher doses of each compound were delivered in association. Further experiments were performed to determine if the enhancement of the antithrombotic activity of DS by HS resulted from its anti-factor IIa or anti-factor Xa activity or from its moiety without affinity to AT III. A low molecular weight heparin (CY 216) with an anti-factor Xa/anti-factor IIa ratio of 5, the synthetic pentasaccharide bearing the minimum binding sequence to antithrombin III, and a low affinity fraction of SH to AT III did not increase the antithrombotic activity of DS; in contrast a high affinity fraction of SH to AT III had the same effect than SH. We conclude that the enhancement of the antithrombotic activity of DS by SH mainly results from its anti-factor IIa activity.

Animals↗
PubMed1988

Pharmacokinetics of dermatan sulfate in the rabbit after intravenous injection.

To investigate the pharmacokinetic properties of dermatan sulfate (DS), a new potential antithrombotic agent, two different approaches were used. In the first one, DS was derivatized with 3-4 hydroxyphenyl propionic acid N hydroxysuccinimide ester (SHPP) and iodinated. The labelled derivative was injected by IV route to rabbits with increasing doses of unlabelled compound ranging from 20 to 4000 micrograms/kg. The disappearance of DS from plasma was characterized by measuring both the circulating radioactivity and the biological activity using an original assay based upon the catalysis of heparin cofactor II - thrombin formation. The radioactivity data indicated that the volume of distribution, the clearance and the half life of the tracer were independent of the dose of DS injected. DS concentrations measured by the bioassay indicated that more than 90% were cleared with half lives close to those calculated from the radioactivity data; the remaining biological activity was cleared at a slower rate. Experiments performed with bi-nephrectomized animals indicated that the kidneys play a major role in the elimination of DS or of its metabolites which may have a residual biological activity. In the second set of experiments, unlabelled DS was delivered under continuous intravenous infusion for 5 hours at 5 increasing doses ranging from 160 to 4200 micrograms/kg/h. The biological activities were used to measure the plateau concentration of DS: there was a linear relationship between the dose delivered and the plasma concentration. These data indicate that the pharmacokinetic profile of DS is very close to that of low molecular weight heparin, and quite different from that of SH.

Animals↗
PubMed1987

Antithrombotic and bleeding effects of a new synthetic direct thrombin inhibitor and of standard heparin in the rabbit.

This study reports on the anticoagulant, antithrombotic and bleeding effects of a new synthetic direct thrombin inhibitor (SDTI) in comparison with standard heparin (SH). The anticoagulant effect was determined with the thrombin clotting time (TCT) and the activated partial thromboplastin time (APTT). SDTI was more potent than SH in prolonging the TCT, but as potent as SH in prolonging the APTT. The antithrombotic effect was determined using a modified Wessler model in the rabbit, either 30 min after a continuous IV infusion of increasing doses or at various times after a single SC injection (20 mg/kg). After continuous IV infusion of 187 micrograms/kg/h of SDTI and of 60 micrograms/kg/h of SH, significant thrombus prevention effects were obtained (59 and 57% respectively). Increasing the dose of SDTI up to 3000 micrograms/kg/h did not significantly improve the antithrombotic effect. After SC injection, a significant antithrombotic effect was observed for 12 h with SDTI but for more than 24 h with SH. The bleeding effect was studied using the rabbit ear model 15 min after a continuous infusion of 7.5 and 15 mg/kg/h: the amounts of blood loss were dose-dependent and comparable for SDTI and SH. These studies also indicated that SDTI possesses a considerable shorter half-life in comparison with SH. Accordingly, the ex vivo concentrations generated after continuous IV infusion or SC injection of the same dose were higher for SH than for the SDTI.

Animals↗