Low Molecular Weight Heparinoid Research Articles

Time courses of the antithrombotic effects, bleeding enhancing effects and interactions with factors Xa and thrombin after administration of iow molecular weight heparinoid Org 10172 or heparin to rats

Time response curves of the anti-thrombotic effects, bleeding enhancing effects, effects on APTT, anti-Xa activities, anti-thrombin activities and thrombin generation inhibitory activities of the low molecular weight heparinoid Org 10172 and heparin have been compared in rats. The time courses of these effects were similar for heparin but quite different for Org 10172. Org 10172 induced anti-thrombotic and anti-Xa effects which lasted approximately 3 times longer than those at the same anti-xa doses of heparin, whereas the bleeding enhancing effects and effects on APTT of Org 10172 were of shorter duration than those of heparin. The half-life of the anti-thrombin effect after Org 10172 seemed somewhat longer than after heparin administration. Thrombin generation inhibition by Org 10172 showed a slightly longer duration than by heparin. The similarities between the time courses of the anti-thrombotic effect and the anti-Xa activity after Org 10172 administration suggest that the most appropriate parameter to monitor Org 10172 treatment is the plasma anti-Xa level.

Platelet activation following intravenous injection of a conventional heparin: absence of effect with a low molecular weight heparinoid (Org 10172).

1. The effects of an intravenous injection of a conventional high molecular weight heparin (HMWH) were compared with those of a low molecular weight heparinoid (Org 10172). A bolus injection of HMWH (5000 iu) was associated with: (a) a small but significant prolongation of bleeding time (BT); (b) a significant fall in PRP platelet count; (c) significantly enhanced platelet aggregation; and (d) significantly increased platelet thromboxane A2 (TXA2) release. These changes were not observed following the intravenous injection of Org 10172 (3200 anti Xa U). 2. These experiments were repeated following the oral administration of acetylsalicylic acid (ASA). HMWH again caused some enhancement of platelet aggregation despite the ASA-mediated inhibition of platelet aggregation and TXA2 release. Administration of Org 10172 to subjects taking ASA did not alter any of the platelet function indices. 3. In additional control experiments the injection of 5000 iu of HMWH was associated with a significant fall in PRP but not whole blood platelet counts. This finding suggests that the fall in PRP platelet count is a methodological artefact. 4. The HMWH also induced a significantly greater increase in serum non-esterified fatty acid (NEFA) concentrations than Org 10172. 5. The present findings indicate that Org 10172 is a less potent stimulator of platelet aggregation and lipolysis than HMWH. 6. The minor prolongation of the BT after HMWH is not compatible with enhanced aggregation but may be a consequence of alterations in the activity of coagulation factors and vascular-platelet interactions or of ongoing platelet activation accompanied by granule depletion. 7. The different effects of the two anticoagulants assessed suggests a therapeutic advantage in favour of Org 10172, especially in patients with hyperactive platelets.

Early clinical experience of a new heparinoid, ORG 10172, in prevention of deep venous thrombosis

The potential antithrombotic effect of a new low molecular weight heparinoid, Org 10172, was examined in a ramdomized, double-blind, placebo-controlled, dose-ranging pilot study of the prevention of deep venous thrombosis (DVT) in 45 high-risk patients having major thoracic or abdominal surgery for cancer. Org 10172 was given in doses of 500, 750 or 1000 U bd subcutaneously. DVT occurred in 9 of 14 patients given placebo and in 4 of 11 patients given 500 U bd but in none of the 20 patients given 750 or 1000 U bd. Operative blood loss and post-operative bleeding were not significantly different between the groups but one patient given 1000 U bd had major post-operative bleeding. Average mid-interval and trough plasma anti-Xa levels reached 0.26 and 0.20 U/ml respectively following the highest dose. It is concluded that Org 10172 is a potentially useful antithrombotic agent and that the effective and safe dose appears to be between 500 and 1000 U bd for prevention of DVT in high-risk patients.

New approaches for anticoagulation in extracorporeal therapy.

The need to fully heparinize patients undergoing extracorporeal therapy often leads to hemorrhagic complications. Two approaches have been used to solve this problem. The first involves full heparinization of blood entering the extracorporeal device followed by the elimination of heparin from the blood returned to the patient using an immobilized heparinase reactor system. Animal studies have demonstrated the successful elimination of heparin's anticoagulant activity using this reactor. The second approach uses very low molecular weight (VLMW) heparins with improved properties. Although low molecular weight heparins and heparinoids have been successfully used in hemodialysis, these preparations are polydisperse mixtures. New VLMW heparins are described which are pure, monodisperse, structurally defined drugs and show improved pharmacokinetics and greater specificity than heparin. The separation of ATIII and HCII mediated activity against factors IIa and Xa may permit extracorporeal therapy with only partial anticoagulation resulting in increased antithrombotic activity with decreased hemorrhagic side-effects. Finally, these VLMW heparins suggest certain desirable structural characteristics in the design blood compatible non-thrombotic synthetic polymers for use in extracorporeal devices.

Randomized Double-Blind, Placebo Controlled Safety Study of a Low Molecular Weight Heparinoid in Patients Undergoing Transurethral Resection of the Prostate

In preparation for an efficacy study, the effect of the low molecular weight heparinoid Org 10172 on postoperative blood loss was assessed in a randomized double-blind, placebo controlled study in patients undergoing transurethral resection of the prostate (TURP). Org 10172 and placebo were given twice daily as i.v. injection for three postoperative days starting one hour preoperatively. Three doses of Org 10172 (800, 1600, and 2400 anti-Xa units b.d.) were evaluated against placebo in three consecutive patient blocks respectively. Each block consisted of 20 patients, 15 receiving Org 10172 and 5 patients placebo. The study was discontinued after 9 patients of the third block had completed the protocol because of excessive urinary blood loss. Data analysis showed a dose-dependent increase in postoperative haemoglobin loss, this was not significant for the 800 anti-Xa units b.d. dosage but was significant in those patients treated with 1600 (p less than 0.05) and 2400 anti-Xa units b.d. (p less than 0.01). It was concluded that the heparinoid Org 10172 caused a dose dependent increase in urinary blood loss following TURP.

Placental transfer of org 10172, a low-molecular weight heparinoid, in the awake late-pregnant guinea pig

The placental transfer of Org 10172, a low-molecular weight heparinoid, was determined in 12 awake late-pregnant guinea pigs. Nine animals receiving placebo served as controls. After 5 days i.v. treatment with Org 10172 (2x300 anti-Xa U/kg/day), anti-Xa activity in fetal plasma amounted to 2.4% of the maternal concentration. The Org 10172 transfer across the placenta was also evaluated with 3H-labelled Org 10172. One hour after the administration of the latter compound, fetal Org 10172-bound 3H-activity had reached 1.5% of the maternal value. The associated extremely low placental Org 10172 transfer indicates that the Org 10172 transport across the placenta of the guinea pig is membrane-limited and that the placental permeability is negligibly low. Since the hemochorial placenta of the guinea pig closely resembles that of the human,it is likely that similar transplacental transfer properties of Org 10172 apply to man.

Low Molecular Weight Heparins and Heparinoid, a Recent Development in Anticoagulant Treatment: Application in Hemodialysis

Low Molecular Weight Heparins and Heparinoid, a Recent Development in Anticoagulant Treatment: Application in Hemodialysis

Treatment of disseminated intravascular coagulation in acute promyelocytic leukemia with low molecular weight heparinoid org 10172

Four patients with acute promyelocytic leukemia (APL) and clinical and laboratory manifestations of disseminated intravascular coagulation (DIC) were treated during induction chemotherapy with Org 10172 (Organon International), a low molecular weight heparinoid preparation. Plasma anti-Xa levels were maintained between 0.60 and 0.80 U/ml and anticoagulant activities, determined with a diluted activated partial thromboplastin time assay, ranged from 0.00 to 0.20 U/ml. Bleeding symptoms ceased and fibrinogen levels improved in the first week in all patients. In the second week, two patients developed bleeding as a result of primary fibrinolysis. It is concluded that Org 10172 may be useful in the treatment of patients with DIC. In patients with APL, inhibition of DIC will be insufficient to control all bleeding, since primary fibrinolysis may also occur.

Thrombopénie grave associée au traitement par polysulfate de pentosane

Two cases of severe thrombocytopaenia associated with acute thrombo-embolic manifestations during treatment by pentosan polysulphate, a low molecular weight heparinoid, are reported. Plasma samples from both patients caused in vitro aggregation in the presence of pentosan polysulphate. Interruption of the drug led to the recovery of the platelet count. The hypothesis of an immunoallergic mechanism similar to heparin associated thrombocytopaenia is supported. Furthermore, it seemed likely to be found with all the polysulphated glycosaminoglycans. During treatment by pentosan polysulphate, platelet count should be monitored to avoid this potentially life-threatening syndrome.

Heparin-induced platelet aggregation in anorexia nervosa and in severe peripheral vascular disease.

We have previously demonstrated that platelets obtained from patients with anorexia nervosa or severe peripheral vascular disease are hyperaggregable. Since conventional heparins are known to activate platelets in vitro and occasionally induce thrombosis and consumptive thrombocytopenia in vivo, we have investigated the direct effect of a conventional heparin on platelets obtained from patients with anorexia nervosa or severe peripheral vascular disease. Heparin at therapeutic concentrations was found to induce platelet aggregation of such platelets in vitro. In contrast, a recently developed low molecular weight heparinoid (Org 10172), at therapeutic concentrations, had no effect on these hyperaggregable platelets. We conclude that: heparin may be potentially harmful to patients with hyperaggregable platelets; thrombocytopenia and thrombosis associated with heparin therapy may be mediated through a direct effect of heparin on platelets; it is unlikely that heparin induced thrombocytopenia is always mediated by classical immunological mechanisms, especially in patients with hyperaggregable platelets; and low molecular weight heparinoids may be safer anticoagulants in patients with platelet hyperaggregability.

Effects of heparin, its low molecular weight fractions and other glycosaminoglycans on thrombus growth [formula omitted

Low molecular weight heparin fractions (LMWH) are less hemorrhagic but are as effective as standard heparin (SH) in preventing experimentally-induced venous thrombosis. The effect of LMWH in preventing extension of established thrombi is unknown. We have compared the effects of two LMWH's (CY, PK), and a low molecular weight heparinoid (a dermatan/heparin/chondroitin mixture, OH) with SH on the prevention of extension of established venous Mombi, by measuring their ability to inhibit the accretion of 125I-fibrin onto venous thrombi pre-formed in rabbit jugular veins. Anticoagulant activity was assayed ex vivo by the APTT and a chromogenic anti-Xa assay, and the antithrombotic effect of these glycosaminoglycans was related to their anticoagulant effects. Autologous thrombi were formed in both jugular veins of each rabbit. The rabbits were then injected with 125I-fibrinogen and treated with a bolus dose of glycosaminoglycan or saline, followed by a continuous infusion for 4 hours. All four glycosaminoglycans significantly inhibited 125I-fibrin accretion (p<0.001). SH, CY and PK were equipotent at doses of 42.5 – 62.5 anti-Xa U/kg/hr in preventing fibrin accretion by 50%. Higher doses had no further effect. OH was significantly more potent than the other three glycosaminoglycans at any given dose (p<0.005). There was no correlation between the antithrombotic effect and the anticoagulant effects. We conclude that these LMWH's are as effective as SH in preventing extension of established thrombosis.

Anticoagulant effects of a low molecular weight heparinoid (ORG 10172) in human volunteers and haemodialysis patients

Org 10172, a low MW heparinoid derived from animal intestinal mucosal tissue, has a mean molecular weight of 6500 D and a specific activity of 8.0 anti-Xa U/mg. Its elimination half-life after i.v. administration is 18 hours. Six human volunteers received repeated single i.v. injections of 800 and 3200 anti-Xa units of Org 10172, 5000 IU heparin or placebo. Bleeding time, platelet count and plasma betathromboglobulin were not affected by Org 10172 or heparin. Heparin stimulated ADP-induced platelet aggregation (0.2 uM; p< 0.05) and inhibited thrombin induced aggregation (0.3 U/ml; p< 0.05), while the heparinoid lacked these effects. Heparin increased plasma platelet factor 4, whereas Org 10172 had no effect. In contrast to heparin Org 10172 had only a minor effect on the activated partial thromboplastin time and thrombin time, while both compounds induced anti-Xa activity in plasma. In a crossover study in six haemodialysis patients, both heparin and Org 10172 (34.4 and 22.4 anti-Xa units/kg/body weight) succesfully prevented clotting of the extracorporeal circuit. Microscopical analysis of the artificial kidney membranes showed that the 34.4 unit Org 10172 dosage was as effective as heparin in preventing fibrin deposition. The haemostatic and coagulation effects were as expected from those observed in the volunteers except that there was a slower elimination of the plasma anti-Xa response. In addition heparin and Org 10172 (34.4 anti-Xa units/kg) inhibited the Xa-induced platelet aggregation (0.5 U/ml; p< 0.01 and p< 0.001 respectively)

The Effectiveness of a Low Molecular Weight Heparinoid in Chronic Intermittent Haemodialysis

A new low molecular weight heparinoid, Org 10172 was compared to heparin in a randomized single blind cross-over study in 55 patients with end-stage renal failure undergoing chronic intermittent haemodialysis. The heparinoid administered as a single pre-dialysis i.v. injection of 34.4 anti-Xa units/kg body weight was compared to standard heparin (loading dose 2,500 IU + continuous infusion of 1,800 IU/hr). Mean anti-Xa plasma levels reached were 0.55 and 0.94 anti-Xa units/ml midway dialysis respectively. All 110 dialysis procedures were successfully performed without clotting or bleeding complications. Analysis of the number of clotted hollow-fibres within the dialysers showed a slight statistically calculated advantage in favour of heparin. Clinically no difference was detected. In conclusion, the heparinoid seems to be a good alternative means of anticoagulation in haemodialysis. As it is administered as a single i.v. predialysis injection it will simplify the dialysis procedure.