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PubMed1999

Polysulfated heparinoids selectively inactivate heparin-binding angiogenesis factors.

Angiogenesis is a prerequisite for tumor expansion and metastasis. The angiogenic potential of the heparin-binding growth factors acidic fibroblast growth factor (FGF) and basic FGF has been demonstrated in various publications. We studied the inhibitory effects of suramin and the polysulfated heparinoids pentosan polysulfate, dextran sulfate, and fucoidan on the action of FGF. As an experimental model, we used the adrenal cancer cell line SW 13, whose anchorage-independent growth depends on the presence of FGF. The polysulfated heparinoids inhibited FGF-induced growth and binding to the receptor at an IC50 of 0.5-3 micrograms/ml. Suramin inhibited FGF at an IC50 of 100 micrograms/ml. The polysulfated heparinoids exerted no effect on IGF-1 or TGF alpha-related growth. Suramin inhibited the anchorage-independent growth induced by IGF-1 or TGF alpha only at an IC50 of 100 micrograms/ml. Our results indicate that suramin inhibits growth factors in a nonselective way. By contrast, polysulfated heparinoids exert a selective inhibitory effect on heparin binding angiogenesis factors at an IC50, which is 100 times below the IC50 of suramin. Therefore, the administration of polysulfated heparinoids might become a novel approach to tumor therapy based on blocking angiogenesis.

Binding, Competitive↗
PubMed1992

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↗
PubMed1997

Heparinoid anticoagulation and topical fibrin sealant in heparin-induced thrombocytopenia.

The development of heparin-induced thrombocytopenia in patients who require systemic anticoagulation for cardiac and vascular operations poses a therapeutic dilemma because no alternative anticoagulants are generally available. Heparinoid (Org 10172) has been used as an alternative anticoagulant under protocol or on a compassionate use basis, and has recently been approved by the Food and Drug Administration. There is, however, no heparinoid antagonist to reverse the anticoagulation. This report describes the combined use of heparinoid anticoagulation and adjunctive fibrin sealant for topical hemostasis in a patient with heparin-induced thrombocytopenia. Recommendations for perioperative monitoring of heparinoid anticoagulation are provided.

Anticoagulants↗
PubMed1997

The platelet proaggregating and potentiating effects of unfractionated heparin, low molecular weight heparin and heparinoid in intensive care patients and healthy controls.

Heparin binds to platelets and can cause platelet proaggregating and potentiating effects, possibly causing thrombocytopenia, particularly in patients in intensive care with hyperaggregable platelets. In this study we compared the platelet proaggregating and potentiating effects of unfractionated heparin (UH), 2 low molecular weight (LMW) heparins, enoxaparin and dalteparin, and a heparinoid, danaparoid sodium (orgaran), to platelets of an ICU patient population and a normal control group. In both populations UH caused platelet aggregation in a dose-dependent manner. This occurred in the therapeutic range of the drug, with as little as 0.5 U/ml UH. The LMW heparins caused less and the heparinoid least platelet aggregation. Generally, the aggregation observed in ICU patients was greater than in the normal population. The potentiating effects of the 4 drugs in association with physiological agonists was examined. Similar patterns of potentiation were observed in both populations, with UH causing significant enhancement of platelet aggregation, the LMW heparins intermediate and heparinoid least enhancement. There was substantial variability in the individuals' platelets' reactions to the drugs, in particular to UH. Our findings suggest that UH has the greatest effect, the low molecular weight heparins an intermediate effect and the heparinoid the least propensity to cause platelet activation.

Adenosine Diphosphate↗
PubMed2001

[Cutaneous delayed hypersensitivity reactions to heparins and heparinoids].

INTRODUCTION: Due to cross-reactions between unfractionated heparins, low-molecular-weight heparins and sometimes heparinoids, cutaneous delayed hypersensitivity reactions might be a problem for the choice of therapeutic alternative. We report on two cases of sensitization to heparins and heparinoids. OBSERVATIONS: One woman developed localized skin reaction to a low-molecular-weight heparin, then a generalized maculopapular rash when an intravenous injection of unfractionated heparins was performed. The second patient had a localized then extended reaction to a low-molecular-weight heparin and was referred for the choice of a well tolerated method to obtain anticoagulation during a pulmonary surgery. METHODS: Patch tests, prick tests, intradermal and subcutaneous tests were performed with several unfractionated heparins, low-molecular-weight heparins, danaparoid and lepirudin in both cases. RESULTS: In the first case, tests performed with both heparins and heparinoid were positive and the use of lepirudin was proposed if anticoagulation was necessary. In the second case the subcutaneous danaparoid injection induced a localized reaction on the injection site. Danaparoid injections were continued associated with localized applications of dermocorticoids without any side effect. DISCUSSION: Cutaneous delayed hypersensitivity reactions occur on the injection site but can also be generalised. Cross reactions might be unexpected therefore skin-tests are necessary to guide the choice of a therapeutic alternative. In case of intolerance to both heparins and heparinoids various solutions may be proposed such as the application of topical corticosteroids on the injection site or the administration of hirudins. There is no cross sensitization between heparins and hirudins, but the use of hirudins is restricted and requires specific monitoring.

Drug Eruptions↗
PubMed1980

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↗
PubMed1998

Heparin and heparinoids in stroke.

Anticoagulation with heparin has a valuable place in prevention and management of deep venous thrombosis. However, the benefit of heparin in acute ischemic stroke and transient ischemic attack remains unclear despite its widespread use for these indications. Heparin also carries several risks, including unpredictable anticoagulation effects, bleeding, and thrombocytopenia. Low-molecular-weight heparins (LMWHs) and heparinoids have several advantages over heparin, such as higher bioavailability, more predictable anticoagulant effects, and less interaction with platelets. Heparin, LMWHs, and heparinoids have been studied in acute ischemic stroke with variable results. Of three recent, large, controlled clinical trials, only one documented a net benefit of treatment. Fewer patients treated with an LMWH within 48 hours of stroke were dead or disabled at 6 months compared with placebo-treated patients. The largest randomized clinical trial of heparin in acute stroke (the International Stroke Trial) showed that heparin was associated with a significant excess in bleeding complications but no clinical benefit at 6 months. Interim analysis of the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) study also showed an excess number of bleeding complications in the treated group without a corresponding benefit on stroke outcome at 3 months. Therefore, although heparin, LMWHs, and heparinoids continue to be used in the management of patients with acute ischemic stroke, their value in recurrent stroke prevention and in the treatment of stroke-in-progress remains unsettled. Ongoing studies may help to clarify the use of LMWHs and heparinoids in these patients.

Anticoagulants↗
PubMed1985

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↗
PubMed1992

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↗
PubMed1990

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↗
PubMed1976

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↗
PubMed1991

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↗
PubMed1996

Cross-reactivity study of low molecular weight heparins and heparinoid in heparin-induced thrombocytopenia.

Previous studies suggested that the cross-reactivity rates of low molecular weight (LMW) heparins with the antibody in heparin-induced thrombocytopenia (HIT) are more than 80%, whilst that of the LMW heparinoid (Orgaran) is relatively low at about 10%. These earlier studies were limited either in the number of patients studied, or in investigating only a single drug. They were also inadequate due to non-standardisation of testing conditions. This study compares three LMW heparins (Fragmin, Clexane, Fraxiparin) and a heparinoid (Orgaran) in their cross-reactivity rates with the HIT antibody. The sera of 45 HIT patients were tested using platelet aggregometry under standardised conditions. The cross-reactivity rates are: 7% (Orgaran), 89% (Fragmin), 83% (Clexane) and 86% (Fraxiparin). Although there are no controlled trials to determine the in vivo cross-reactivity rates of LMW heparins and heparinoid, the low in vitro cross-reactivity rate of the latter favours its use in HIT. Nevertheless, the therapeutic use of these drugs in HIT should be preceded by exclusion of in vitro cross-reactivity.

Adult↗
PubMedDate not supplied

Direct observation of fibrinogen-heparinoid complexes formation using surface plasmon resonance.

We analyzed the binding of heparinoid or heparin with fibrinogen by real-time measurement using surface plasmon resonance technology. Poly(glucosyloxyethyl methacrylate) sulfate [poly(GEMA) sulfate] and dextran sulfate were used as heparinoids. The binding ability of each sulfated polymer was estimated by having each polymer-containing buffer interact with the sensor chip surfaces that had immobilized fibrinogen. Dextran sulfate and poly(GEMA) sulfate showed high affinity to the fibrinogen in this experiment, while the heparin did not. All of the dextran sulfates were desorbed from its surface, while about 30% of the poly(GEMA) sulfate remained on the immobilized fibrinogen upon the addition of NaCl to the buffer which was done in order to analyze the desorption of poly(GEMA) sulfate or dextran sulfate from the surface of the fibrinogen. These data show that the type of binding between fibrinogen-poly(GEMA) sulfate was different from that of dextran sulfate, indicating that the interaction between fibrinogen and poly(GEMA) sulfate was caused not only by an electrostatic but also by a hydrophobic force. These results suggest that the interaction mechanism of heparinoids with fibrinogen was different from that of heparin.

Biopolymers↗
PubMed1988

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↗
PubMed2001

Pentalyte does not decrease heparinoid release but does decrease circulating thrombotic mediator activity associated with aortic occlusion-reperfusion in rabbits.

Hemorrhage and thrombosis are associated with major vascular and trauma surgery. Release of heparinoids and thrombotic mediators may contribute to these complications and have been described in rabbits after aortic occlusion-reperfusion. We hypothesized that the resuscitative fluid used could reduce heparinoid and thrombotic mediator release after aortic occlusion-reperfusion in rabbits as assessed by thromboelastographic variables (R, reaction time; alpha, angle; and G, a measure of clot strength). Anesthetized rabbits were administered lactated Ringer's solution (n = 8) or PentaLyte (n = 8) at reperfusion after 30 min of ischemia. Blood was obtained before ischemia and after 30 min of reperfusion for thromboelastography under four conditions: 1) unmodified sample, 2) platelet inhibition, 3) heparinase, and 4) platelet inhibition and heparinase. During reperfusion, unmodified samples demonstrated a significant increase in R and decrease in alpha and G that was not affected by PentaLyte. In the presence of heparinase, no significant fluid-specific thromboelastographic differences were noted. However, thrombotic mediator release (discerned by a decrease in R and an increase in alpha) during reperfusion in samples with platelet inhibition and heparinase was significantly attenuated by PentaLyte. PentaLyte administration does not decrease heparinoid release but does decrease thrombotic mediator release after aortic occlusion-reperfusion.

Animals↗
PubMed1984

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↗
PubMed2004

Activation of human macrophages by allogeneic islets preparations: inhibition by AOP-RANTES and heparinoids.

During transplantation, pancreatic islets release chemokines which promote macrophage attraction, hampering engraftment of islets. The aim of this study was to modulate chemotaxis and the immune response of human macrophages induced by islets. Human monocyte-derived macrophages of healthy subjects were exposed to supernatants of human islets. Chemotaxis, tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) release were evaluated. To modulate migration, human macrophages were incubated in the presence of aminooxypentane-regulated on activation, normal, T-cell expressed, and secreted (AOP-RANTES), a potent antagonist of CCR5. Chemotactic activity of islets supernatant was modulated by the addition of heparin or heparinoids [pentosan and calix[8S]arene (C8S)]. AOP-RANTES significantly reduced, in a dose-dependent manner, macrophage chemotaxis and cytokine release induced by islets supernatant. The chemotactic index was reduced from 3.05 +/- 0.27 to 0.71 +/- 12, TNF-alpha from 1205 +/- 52 to 202 +/- 12 pg/ml, and IL-1beta from 234 +/- 12 to 10 +/- 6 pg/ml. The trapping of chemokines by heparinoids reduced the chemotactic activity of islets supernatant from 3.05 +/- 0.27 to 1.2 +/- 0.1 with heparin or pentosan and to 1.72 +/- 0.22 with C8S, and also decreased the TNF-alpha release by human macrophages from 1205 +/- 35 to 1000 +/- 26 (C8S), 250 +/- 21 (heparin) and 320 +/- 19 (pentosan) pg/ml, and IL-1beta from 234 +/- 13 to 151 +/- 5 (C8S), 50 +/- 3 (heparin) and 57 +/- 4 (pentosan) pg/ml. In conclusion, AOP-RANTES and heparinoids inhibit human macrophage activation and migration induced by islets supernatant.

Adult↗