[The potentiation of the heparin effect by heparinoids. 4. On the action mechanism of heparinoids].
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Animals↗
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[Comparison of activity, in the field of orthopedic traumatology, between a heparin- and heparinoid-based cream and one based only on heparinoid].
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Adolescent↗
[Preparation of semisynthetic heparinoids. III. Potentiating the anticoagulative activity of heparinoids by treatment of the products of their degradation with H2O2 solutions].
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Blood Coagulation↗
A randomized blind study comparing standard heparin and a new low molecular weight heparinoid in cardiopulmonary bypass surgery in dogs.
Postoperative hemorrhage remains a serious complication in cardiopulmonary bypass (CPB) surgery. In our study, alternative anticoagulation with a new low molecular weight (LMW) heparinoid (Org 10172) was compared with a standardized heparin regimen. A preliminary dose-finding study indicated the minimal effective heparinoid dose to be 260 anti-Xa U/kg body weight, which was comparable to the standardized heparin regime, as revealed by similar plasma anti-Xa values. The following randomized open pilot study in 12 mongrel dogs undergoing CPB showed the heparinoid to be as effective as heparin, with an additional advantageous decrease in postoperative blood loss in the Org 10172 group. Our randomized blind study in 16 mongrel dogs undergoing CPB was performed to confirm previous results. Both antithrombotic agents were effective in the prevention of clot formation within the extracorporeal circuit. Hematocrit values and erythrocyte and platelet counts showed no significant intergroup differences. Post-CPB leukocyte counts revealed a significantly more rapid increase in the group given heparinoid (P less than 0.05). In the group given heparin, the expected prolongations of both the thrombin time (TT) and activated partial thromboplastin time (APTT) were noted, whereas in the group given heparinoid, only a transient peak prolongation of the TT after dose administration was revealed, and no significant prolongation of the APTT. Mean anti-Xa plasma levels were similar during CPB, showing a rapid decrease in the group given heparin on protamine administration, as did the APTT. Assessment of the operating field indicated an elevated intraoperative blood loss in the group given heparin. Postoperative blood loss measured over a period of 2.5 hours after closure of the thorax was significantly lower in the group given heparinoid than in the heparinized animals (625 +/- 100.0 ml, mean +/- SD, and 806 +/- 178.2 ml, respectively; P less than 0.05). Our observations suggest that the LMW heparinoid Org 10172 has an increased benefit/risk ratio over standard heparin and is effective in CPB in dogs. Additional investigations in humans should verify the possibility of use of this substance as an alternative means of anticoagulation during CPB in patients in whom heparin is relatively contraindicated.
Animals↗
[Heparinoids versus nitroglycerin in the treatment of superficial phlebitis].
The purpose of this study was to evaluate the beneficial effects of transdermal nitroglycerine (TNG) in the treatment of superficial phlebitis caused by endovenous catheters and to compare them with the effects from the application of heparinoid substances. The study performed was prospective, randomized during a six-day period. One hundred patients (73 male and 27 female), aged 28-89 years (mean 67.3), participated in the study; all presented phlebitis, diagnosed by the presence of pain, erythema, edema, and fibrous cord in the area around the catheter. Among 50 subjects, two cm of NTG gel were administered to the affected zone once a day, and for the other 50 subjects, heparinoid substances were applied three times a day. The value parameters were: time for the disappearance of pain and time for reducing erythema, edema, and fibrous cord in half (all measured in hours). We found significant differences between the two treatments with TNG yielding greater improvement in terms of disappearance of pain (TNG: 50.2 +/- 39.7, heparinoids: 72.0 +/- 39.9), time for reducing erythema in half (TNG: 28.0 +/- 24.2, heparinoids: 54.6 +/- 34.5), and time for reducing fibrous cord in half (TNG: 58.3 +/- 38.4, heparinoids: 84.5 +/- 41.5). Edema was reduce before with TNG; however, this difference was not significant (TNG: 31.2 +/- 20.3, heparinoids: 33.0 +/- 25.7). We conclude that transcutaneous TNG should be applied systematically in patients with superficial phlebitis, given that it is more effective than the usual treatment with heparinoid substances.
Adult↗
[Effect of heparinoids on the blood sugar level and blood lipids in diabetes mellitus].
The paper is a clinical experimental work, studying the heparinoid effect upon blood sugar level, blood lipid fractions, endogenic heparin and lipo-brigther-becoming activity in diabetics. Heparinoids are applied in acute experiment. A total of 37 subjects were examined--22 diabetics with adult type of diabetes, 10 clinically healthy subjects and 5 diabetics examined only with 500 ml physiologic salt solution. The same patients were examined with heparin as well for a comparison. Blood sugar, NEFA, lipolyzing activity, total lipids, total cholesterol, beta-lipoproteins, total phospholipids, triglycerides and endogenic heparin were determined prior to and post infusion introduction of heparinoids. The results reveal that heparinoids have two basic biochemical effects decrease blood sugar lever in diabetics and change the blood lipid fraction level. They depend on the structural peculiarities of the preparations. Heparinoids stimulate heparin activity as well, through which they realize their biochemical effect to a certain extent. The decreasing effect on blood sugar level of heparinoids is stronger as compared with heparin.
Adolescent↗
Synthesis of new heparinoids with high anticoagulant activity.
New heparinoids were synthesized by the chemical method starting from ring-opening polymerization of anhydro sugar derivatives. Sulfation of synthetic (1----6)-alpha-linked 3-amino-3-deoxy-D-glucopyranan and its copolymers gave dextran-type heparinoids having a sulfamide group on the C-3 carbon of the sugar unit. Heparinoids with different sulfamide contents indicated that the anticoagulant activity (35.3-41.3 units/mg) is independent of the sulfamide content, while an increase in sulfamide content lowered the toxicity. Sulfation of (1----5)-alpha-D-xylofuranan and -ribofuranan provided furanan-type heparinoids the anticoagulant activities of which were higher than those of the corresponding sulfated pyranan-type polysaccharides (1----4)-beta-D-xylopyranan and -ribopyranan. The highest activity (69.1 units/mg) was shown by sulfated (1----5)-alpha-D-xylofuranan. The dextran-type heparinoid having a sulfamide group showed a high anticoagulant activity also in vivo and high lipemia-clearing activity.
Animals↗
Parenteral anticoagulation with the heparinoid Lomoparan (Org 10172) in patients with heparin induced thrombocytopenia and thrombosis.
Progressive thrombocytopenia may develop in as many as 5% of patients receiving heparin anticoagulation. In these patients, the risk of thromboembolic complications as well as continued thrombocytopenia necessitates discontinuation of heparin and initiation of an alternative anticoagulant when indicated. The heparinoid Lomoparan (Org 10172) is a mixture of several non-heparin low molecular weight glycosaminoglycans with proven anticoagulant efficacy that is generally non-reactive with platelets in the presence of plasma from patients with heparin induced thrombocytopenia, whereas standard heparin will induce platelet aggregation. We evaluated the role of heparinoid as a potential alternative anticoagulant in patients with heparin induced thrombocytopenia. During a 6 month period, we identified six patients with heparin induced thrombocytopenia who required an alternative parenteral anticoagulant, four as primary treatment for specific medical problem, and two as anticoagulation during a necessary surgical procedure. Heparinoid was used successfully in both medical and surgical patients requiring parenteral anticoagulation. In no case was there an exacerbation of the thrombocytopenia nor thromboembolic complications while on heparinoid therapy. Three of our patients sustained hemorrhagic complications, predominantly in the post-surgical setting in association with elevated anti-factor Xa levels and additional anticoagulant agents. We feel that these results confirm the utility of heparinoid anticoagulation in a select subset of patients with heparin induced thrombocytopenia who require continued parenteral anticoagulation.
Anticoagulants↗
Prevention of deep vein thrombosis following total hip replacement by low molecular weight heparinoid.
We assessed the safety and efficacy of the novel low molecular weight heparinoid Lomoparan (Org 10172) for the prevention of deep-vein thrombosis in patients undergoing elective total hip replacement in a randomized, placebo-controlled, double-blind trial in 197 consecutive patients. The heparinoid (750 anti-factor Xa-units, s.c., b.i.d.) was administered to 97 patients and 99 patients received placebo. Study medication was started preoperatively and continued for 10 days. Efficacy was assessed by bilateral phlebography at day 10, postoperatively. The incidence of deep-vein thrombosis was 56.6% and 15.5% respectively in the placebo and heparinoid treated patients (incidence reduction: 74%; P less than 0.001). This reduction was observed both for proximal-vein thrombosis (25% to 8%; P less than 0.005) and isolated calf-vein thrombosis (31% to 7%; P less than 0.001). No major hemorrhage was observed. The number of red-cell units transfused and drain-fluid loss were comparable for the two study groups. Six patients in the heparinoid group and none in the control group developed minor wound hematomas (P less than 0.05). During an 8-week post-discharge follow-up period three patients with a normal venogram at day 10 developed clinically apparent venous thromboembolism, which was confirmed by objective testing. All three patients belonged to the heparinoid-treated group. We conclude that 750 anti-factor Xa units Org 10172 s.c. twice daily starting preoperatively is safe and effectively reduces early deep-vein thrombosis following elective total hip replacement. Further studies on the incidence of post-discharge thromboembolism are required.
Aged↗
Contact activation of prekallikrein and of fibrinolysis by heparinoids and heparin.
Contact activation of plasma prekallikrein (PPK) assayed by a tripeptide chromogenic substrate, and surface-mediated fibrinolysis by the euglobulin test (both tests being insensitive to the anticoagulant effect of heparin and heparinoids) were studied. The following substances were tested: Dextran solutions of different molecular weight (M.W.), heparinoids such as dextran sulphate, pentosan and mannuronate sulphuric polyesters. Liquoid and Moranyl and various commercial therapeutic preparations of heparin. Most of these anionic polyesters are able to activate both PPK and fibrinolysis, dextran sulphate (500,000 M.W.) being the most active. Factor XII, PPK and HMWK are necessary for full activation. Besides dextran sulphate, other heparinoids such as Na pentosan polysulphate, or Na polyanhydromannuronic sulphuric acid, are also contact activators. This may explain some of their side effects observed in vivo. Non-sulphated dextrans used in therapy have no activating effect. Nine therapeutic commercial preparations of heparin were tested. They appear to have a slight activating effect on PPK but an uncertain effect on fibrinolysis. Such factor XII activability has until now been unnoticed, being masked by the anticoagulant activity of heparinoids and heparins on later phases of blood coagulation. It appears that heparin is unable to prevent contact activation in vivo as well as in vitro. This allows PPK assays during extracorporeal circulation in the presence of circulating heparin.
Dextrans↗
In vivo activity of a new heparinoid.
Org 10172 is a heparinoid prepared during the manufacture of porcine mucosal heparin. This compound has been compared with a standard commercial grade heparin in vitro and in vivo using experimental thrombosis and bleeding models in rabbits. Increasing doses of both the heparin and the heparinoid resulted in a similar prolongation of a Xa clotting time and the APTT, but the heparinoid had no effect on the thrombin clotting time over the concentration range 0-3.0 units/ml. Both preparations were antithrombotic using a stasis prophylaxis model but inhibition of thrombosis was independent of the ex vivo anti-Xa heparin levels achieved. Relative to heparin, the heparinoid failed to induce hemorrhage. A potential therapeutic advantage for Org 10172 as an antithrombotic agent for clinical use can be predicted.
Animals↗
A low-molecular-weight heparinoid compared with unfractionated heparin in the prevention of deep vein thrombosis in patients with acute ischemic stroke. A randomized, double-blind study.
OBJECTIVE: To compare the relative safety and efficacy of a low-molecular-weight heparinoid (ORG 10172) with unfractionated heparin in the prevention of deep vein thrombosis in patients with acute ischemic stroke. DESIGN: Double-blind randomized trial. SETTING: Seven Canadian university-affiliated hospitals. PARTICIPANTS: Eighty-seven patients with acute ischemic stroke resulting in lower-limb paresis. INTERVENTION: Patients received either low-molecular-weight heparinoid, 750 anti-factor Xa units twice daily, or unfractionated heparin, 5000 units subcutaneously twice daily. Treatment was continued for 14 days or until hospital discharge if sooner. MEASUREMENTS: Deep vein thrombosis was diagnosed using 125I-labeled fibrinogen leg scanning and impedance plethysmography. Venography was indicated if either test was positive. Overt hemorrhage, major or minor, was assessed clinically. RESULTS: Venous thrombosis occurred in four patients (9%) given low-molecular-weight heparinoid and in 13 patients (31%) given heparin (relative risk reduction, 71%; 95% CI, 16% to 93%. The corresponding rates for proximal vein thrombosis were 4% and 12%, respectively (relative risk reduction, 63%; P greater than 0.2). The incidence of hemorrhage was 2% in both groups. CONCLUSION: Low-molecular-weight heparinoid, given in a fixed dose of 750 anti-factor Xa units subcutaneously twice daily, is more effective than subcutaneous low-dose heparin for the prevention of deep vein thrombosis in patients with acute ischemic stroke.
Acute Disease↗
Effect of chitin heparinoids on the activation of peritoneal macrophages and on the production of monokines in mice.
Sulfonated derivatives of chitin which showed anticoagulant activity (chitin heparinoids) were studied with regard to the activation of mouse peritoneal macrophages and the production of monokines. In comparison with 70% deacetylated chitin (DAC-70), which was the most adjuvant-active derivative of chitin, all chitin heparinoids were less effective for the augmentation of cytolytic activity of peritoneal macrophages. The number of macrophages was hardly increased or decreased by intraperitoneal injection of chitin heparinoids, and the activity of circulating colony-stimulating factor was not changed by their treatment. Only N-sulfonated DAC-70 stimulated the production of interleukin-1 by thioglycolate-induced peritoneal macrophages in vitro. However, its effect was weaker than that of DAC-70. Chitin heparinoids showed no or weak mitogenic activity on normal mouse spleen cells.
Adjuvants, Immunologic↗
Comparison of a natural heparinoid with sodium and calcium heparin for their effect on the inhibitor of activated factor X.
The reaction between activated factor X (Xa) and its natural inhibitor (XaI) was accelerated in vitro by both sodium heparin and an heparinoid, which was about 3 times less potent than heparin. The s. c. administration in humans of 5,000 units of sodium and calcium heparin was followed by the detection of a plasma activity potentiating XaI. In the majority of subjects, the heparinoid was not effective. These observations indicate that the use of heparinoids should not be considered as an alternative to heparin in the prevention of thromboembolism.
Adult↗
Pregnancy associated with lupus anticoagulant and heparin induced thrombocytopenia: management with a low molecular weight heparinoid.
The management of pregnant patients with coagulopathies and heparin induced thrombocytopenia is difficult and poorly defined. We report the case of a patient who was treated with a low molecular weight heparinoid. The treatment was complicated by the delayed occurrence of thrombocytopenia and a thrombotic event. This is the first report of thrombocytopenia caused by heparinoid. It is possible that this complication could have been avoided by a shorter duration of treatment with heparinoid and the use of Vitamin K antagonists during the second trimester of pregnancy.
Adult↗
Gastrointestinal blood loss in haemodialysis patients during use of a low-molecular-weight heparinoid anticoagulant.
In a randomised cross-over study we assessed total blood loss in 14 dialysis patients using 59Fe as a marker for measurement in a whole-body counting system. In one period the patients received standard heparin, in the other ORG 10172, a new low-molecular-weight-heparinoid. Our results show no significant difference between the two study periods with regard to blood loss and dialyser blood retention. In some patients a delayed bleeding ('oozing') from the puncture site was noticed as a side-effect of treatment with the low-molecular-weight-heparinoid. We conclude that this heparinoid is effective as an anticoagulant in regular dialysis treatment, but it seems to have no advantage over standard heparinisation with regard to occult bleeding. This may be related to the prolonged plasma anti-Xa activity (30.8 h) of this compound compared to standard heparin in dialysis patients.
Adult↗
Comparison of the effect of a conventional heparin and a low molecular weight heparinoid on platelet function.
In a study comparing the in vitro effects of heparin and a low molecular weight heparinoid (Organon 10172) on aggregation of platelets from normal subjects, we have demonstrated that whereas heparin markedly enhances platelet aggregation induced by other aggregators and inhibits the anti-aggregatory effect of epoprostenol (prostacyclin, PGI2), heparinoid does not produce such effects. The use of heparinoid may thus have a significant advantage over that of heparin in situations where enhanced platelet aggregation is the main factor leading to thrombosis or where heparin treatment is followed by thrombocytopaenia.
Drug Evaluation↗
[Heparin-associated thrombocytopenia: successful therapy of patients after prospective selection of a compatible heparinoid with the heparin-induced platelet activation test].
Diagnosis of HAT type II and treatment of thromboembolic complications in these patients are difficult. Recently we have developed the heparin-induced platelet activation (HIPA) assay which allows a rapid confirmation of the tentative diagnosis of HAT type II. In vitro studies with sera of 25 patients revealed cross-reactivity to the LMW heparins Fragmin, Fraxiparin and Clexane whereas a LMW heparinoid, Org 10172 (Orgaran), did not. In a prospective study this heparinoid was selected for 10 HAT patients, for whom further parenteral anticoagulation was required. In 7 of these patients who received LMW heparins prior to laboratory investigations low platelet counts persisted under treatment with LMW heparins and 2 patients developed additional thromboembolic complications. Upon treatment with Org 10172 platelet counts normalized in 9 patients, in 1 patient thrombocytopenia was unrelated to parenteral anticoagulation, in 1 patient platelet count normalized after discontinuation of Org 10172. We conclude that the HIPA assay allows the laboratory diagnosis of HAT type II and the selection of a compatible heparin or heparinoid for further parenteral anticoagulation.
Cross Reactions↗