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PubMed1992

[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↗
PubMed1991

Interaction of heparinoids with platelets: comparison with heparin and low molecular weight heparins.

Heparin interacts with platelets to impair collagen-induced aggregation and adhesion to collagen. Low molecular weight heparin and heparinoids have little or no inhibitory activity in these platelet-collagen interactions. Thrombin-induced aggregation of platelets is inhibited by any of the glycosaminoglycans that will block the action of thrombin on fibrinogen. However, heparin is a much more potent inhibitor than low molecular weight heparins or heparinoids at equigravimetric concentrations in these reactions. The inhibition of ristocetin or asialo-von Willebrand factor aggregation of platelets is partially blocked by high dose heparin but not by low molecular weight heparin or heparinoids. The heparin-induced IgG antibody, produced to a heparin-platelet complex, aggregates platelets strongly in the presence of heparin, less strongly in the presence of low molecular weight heparins and pentosan polysulfate and not at all with dermatan sulfate or the pentasaccharide. Heparan sulfate does interact with platelets and this antibody, which is of interest because of the heparan sulfate on endothelial cells. Clinical information to date suggests a low incidence of heparin antibodies in patients receiving only low molecular weight heparin of the depolymerized type. Whether long-term clinical use of low molecular weight heparins, heparan sulfate, and dermatan sulfate will give rise to specific antibodies that would cause a similar problem as heparin remains to be seen.

Autoantibodies↗
PubMed1985

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.

Adult↗
PubMed1984

Effect of heparin and heparinoids on platelet aggregation.

Biological effectiveness of bovine lung heparin and porcine mucosal heparin was tested in vitro and compared with the effectiveness of 12 semisynthetic heparinoids obtained by sulfation of waste heparin mucopolysaccharides and other biomolecules. Equieffective concentrations of these substances were determined in the sense of prolongation of the thrombin time and the APTT, inhibition of the thrombin- and collagen-induced aggregation, and potentiation of the primary ADP-induced aggregation. The influence of sulfation was proved on the biological effectiveness as well as the significance of the proper choice of the parent structure. Some polycondensates of the polysaccharide type were effective altogether with the sulfated waste heparin mucopolysaccharides. On the contrary, protein structures and low molecular weight glycosides exhibited little or no activity. The effective substances were related to heparin not only by the anticoagulant activity but also by the inhibitory action on the thrombin- and collagen-induced platelet aggregation. Contrary to heparin, higher concentrations of the studied heparinoids strongly potentiated the ADP-induced aggregation response. Strong inhibition of the collagen-induced aggregation was proved after administration of heparin to patients with end-stage renal failure on days without haemodialysis. Less significant changes in the secondary aggregation were observed also after administration of S-heparin (one of the studied heparinoids) to volunteers in the form of the rectal suppositories.

Adenosine Diphosphate↗
PubMed1993

Can low molecular weight heparins and heparinoids be safely given to patients with heparin-induced thrombocytopenia syndrome?

BACKGROUND: Low molecular weight heparin (LMWH) and heparinoids have been offered as alternatives to unfractionated heparin (UH) to patients with heparin-associated antiplatelet antibodies (HAAb) and heparin-induced thrombocytopenia syndrome (HIT). Some of these patients have had continued HIT in the presence of the UH substitutes. It would seem important to know whether the heparin substitute is likely to cause patients' platelets to aggregate before administering the substitute to patients with HAAb. METHODS: Patients with HIT were identified as having HAAb by positive platelet aggregometry testing with commercial UH. Plasmas from 51 patients with HAAb were tested for the ability to aggregate platelets in the presence of two LMWHs (Mono-Embolex NM and Fragmin) and one heparinoid (Org 10172). RESULTS: The proportions of plasmas reacting to each UH substitute are Mono-Embolex NM, 60.8%; Fragmin, 25.5%; and Org 10172, 19.6%. Although Fragmin and Org 10172 aggregated platelets in the presence of HAAb significantly less often than Mono-Embolex NM (p < 0.001), a patient with HAAb has a substantial chance of reacting to one of these UH substitutes. CONCLUSIONS: Before giving a LMWH or heparinoid to a patient with HAAb, one should determine with in vitro testing that the patient's HAAb will not cause platelet aggregation in the presence of the heparin substitute.

Adolescent↗
PubMed1992

Heparin-associated thrombocytopenia: successful therapy with the heparinoid Org 10172 in a patient showing cross-reaction to LMW heparins.

A patient suffering from heparin-associated thrombocytopenia (HAT), recurrent arteriothromboses, and acute renal failure after treatment with standard heparin is described. He failed to improve when therapy was continued with low-molecular-weight (LMW) heparin (Fragmin, Kabi Pfrimmer, Erlangen, FRG). By means of the in vitro heparin-induced platelet activation (HIPA) assay it was shown that standard heparin and the LMW heparins Fragmin and Fraxiparin (Sanofi Labaz, Munich, FRG), as well as the enoxaparine Clexane (Nattermann, Cologne, FRG), all induced platelet activation with the patient's serum. In contrast, the LMW heparinoid Org 10172 (Organon, Oss, The Netherlands) did not cause platelet activation. When the patient was subsequently treated by parenteral administration of Org 10172 as anticoagulant over a period of several weeks the number of platelets rapidly increased and the patient almost completely recovered. This case shows that strong in vivo and in vitro cross-reactivity between standard heparin and LMW heparins may occur, but can be avoided by the use of a novel heparinoid, Org 10172. The HIPA assay provides a simple and sensitive laboratory method for the choice of an innocuous heparin or heparinoid for continued parenteral anticoagulation.

Aged↗
PubMed1995

Heparinoids with low anticoagulant potency attenuate postischemic endothelial cell dysfunction.

PURPOSE: Although standard heparin has been demonstrated to reduce endothelial cell dysfunction in acute ischemia-reperfusion injury, its mechanism of action remains unknown. We hypothesized that heparin's salutary endothelial effects are independent of its conventional anticoagulant activity and are not caused by nonspecific polyanion effects. METHODS: Isolated rat hindlimbs were perfused at constant pressure with an albumin-enriched crystalloid buffer. After 60 minutes of normothermic ischemia, endothelial function was assessed by measurement of endothelial-dependent vasodilation by log increment infusion of acetylcholine. Endothelial-independent vasodilation was measured by exposure to nitroprusside. Some groups were pretreated with heparinoids possessing minimal or intermediate anticoagulant activity. RESULTS: Treatment with heparinoids with low anticoagulant activity significantly increased endothelial-dependent vasodilation when compared with the nontreated ischemic group and were statistically indistinguishable from the nonischemic control. Treatment with dextran sulfate, a randomly sulfated polymer with size and charge characteristics similar to heparin, did not change postischemic vasodilation. Endothelial-independent vasodilation was largely unaffected by ischemia-reperfusion or drug treatment. CONCLUSIONS: A heparinoid with negligible antithrombin-binding activity (Astenose) attenuated postischemic endothelial dysfunction, suggesting that its mechanism of action was independent of anticoagulant activity. Failure of dextran sulfate to be protective implied that the effect was not caused by nonspecific polyanion action.

Acute Disease↗
PubMed1989

Heparin-induced thrombocytopenia: studies with a new low molecular weight heparinoid, Org 10172.

Studies were performed to determine the cross-reaction rate of the heparin-dependent antibody with Org 10172, a new low molecular weight heparinoid, and to investigate the effect of Org 10172 on platelet activation induced by the antibody. The plasmas of 17 patients with thrombocytopenia induced by standard heparin were shown, by platelet aggregation studies, to contain the heparin-dependent antibody. Of these 17 patient plasmas, only three cross-reacted with the heparinoid, producing a cross-reaction rate of 18%. When Org 10172 was added to a reaction mixture containing normal platelet-rich plasma, patient plasma, and standard heparin with non-cross-reacting plasmas, it inhibited platelet aggregation and thromboxane B2 production induced by the antibody, provided that the ratio of Org 10172 concentration (anti-Xa U/mL) to standard heparin concentration (IU/mL) exceeded 2.5 to 5.0. This inhibitory effect was observed only with platelet activation mediated by the antibody, but not by collagen (2 micrograms/mL) or ADP (5.0 mumol/L). Additionally, three of 17 patients with serious thrombosis, whose plasma showed no cross-reaction with the heparinoid, received Org 10172 treatment with a good response in each case. These findings suggest that Org 10172 may be a useful drug for the treatment of heparin-induced thrombocytopenia.

Antigen-Antibody Reactions↗
PubMed1999

[Allergy to heparin, heparinoids, and recombinant hirudin. Diagnostic and therapeutic alternatives].

The pathogenesis of allergic reactions to heparin is poorly understood. Clinically, this phenomenon is very relevant because of its increasing incidence and the resulting therapeutic difficulties. Since Plancherel's first description in 1952, nearly 70 cases have been reported in the literature, among which female patients dominate. Heparin causes all kind of allergic reactions from type I to type IV. The most dangerous hypersensitivity reaction is heparin-induced thrombocytopenia (HIT), which is a type II antibody-mediated reaction. Heparin is a mucopolysaccharide with strong protein binding potency, which seems to play an important pathogenetic role, as the heparin molecule adheres to unknown dermal or subcutaneous proteins. The heparin group contains a variety of structures with varying molecular weights. The allergen has yet to be identified. Several cross-reactions between high- and low-molecular weight heparins have been demonstrated as well as between heparin and heparinoids so that there may be more than one epitope of the heparin molecule with allergic potency. Allergic reactions after the use of alternate drugs such as heparinoids and hirudin also causes severe therapeutic difficulties.

Drug Hypersensitivity↗
PubMed1996

Quantitative determination of heparinoid mimetics in human and rat plasma by micellar electrokinetic chromatography.

The investigated new class of heparinoid mimetics are spaced persulfated carbohydrates designed to increase the success rate of angioplasty and bypass surgery by preventing restenosis without increasing the risk of bleeding. Due to the presence of sulfate groups, these compounds are highly charged and, for preclinical kinetic investigations only small sample volumes of rat plasma were available. Therefore, capillary electrophoresis (CE) was applied. A bioanalytical method based on micellar elektrokinetic chromatography (MEKC) with UV-detection was developed for the selective quantitation of heparinoid mimetics (e.g., Ro 48-0843, Ro 48-3151, Ro 47-6199 and Ro 48-8722) in plasma. Using this method, only small volumes of plasma were required, which could be introduced directly into the separation capillary after 1:1 dilution with 100 mM aqueous sodium dodecyl sulfate (SDS). For increased sample throughput, an additional ultrafiltration step was performed after SDS-dilution of the plasma sample, improving both reproducibility and robustness of the method considerably. The sensitivity of the new method (3 micrograms/ml) was sufficient to follow plasma levels in pharmacokinetic studies. The practicability of this easy and rapid assay was demonstrated by the analysis of more than 350 plasma samples from pharmacokinetic studies performed in rats.

Animals↗
PubMed1983

The effects of antithrombin III, heparin and a novel heparinoid infusions on the bleeding tendency using an experimental model in the rat.

The effects of selective increase of plasma AT-III concentration (to 2 U/ml and 8 U/ml) in the presence or absence of low dose commercial heparin and a novel natural heparinoid (Org 10172) on APTT, clotting factors and bleeding were investigated in an experimental model in rats. Slight increases in the APTT were observed with: a. Org 10172, b. both AT-III doses and c. combinations hereoff. However, synergism was observed in the prolongations of the APTT when the AT-III concentrate (70 U/kg and 500 U/kg) was combined with both heparin dosages. AT-III concentrates (70 U/kg and 500 U/kg) or Org 10172 (2,5 mg/kg) separately or in combination showed no effect on bleeding. Heparin (0, 125 and 0,25 mg/kg i.v.) also showed no effect on bleeding neither if they were combined with the lower dose AT-III. However, heparin (both dosages) combined with 500 U/kg of AT-III concentrates significant increased blood loss. These observations suggest that infusion of AT-III concentrate additionally to low dose heparin therapy did not increase bleeding in the rat model used provided that extreme high AT-III plasma levels (8 U/ml) were avoided. The novel natural heparinoid Org 10172 alone or combined with either AT-III dosage induced no increased bleeding.

Animals↗
PubMed1993

Pregnancy complicated by heparin associated thrombocytopenia: management by a prospectively in vitro selected heparinoid (Org 10172).

A pregnant woman treated with unfractionated heparin for pelvic vein thrombosis in the 26th week of her first pregnancy developed heparin-associated thrombocytopenia. Diagnosis was verified by the heparin induced platelet activation (HIPA) assay, which revealed cross reactivity to various LMW heparins, but not to the LMW heparinoid Org 10172. Upon intravenous (i.v.) anticoagulation with the heparinoid Org 10172 the platelet count returned to normal within 6 days and remained stable throughout the entire treatment period. After 3 weeks i.v. treatment with Org 10172, administration was changed to the subcutaneous route. At term a healthy boy was delivered spontaneously. No Org 10172 was detected in the cord blood, while therapeutic levels were measured in the maternal blood. The infant's platelet count was normal, but serum from the cord blood induced platelet activation in the presence of heparin, indicating the transplacental passage of heparin-dependent maternal antibodies.

Adult↗
PubMed1992

Synthesis and non-thrombogenicity of heparinoid polyurethaneureas.

Unsaturated polyurethaneureas were synthesized from 4,4'-diphenylmethane diisocyanate, 1,2-diaminopropane and polybutadiene containing hydroxyl groups at both ends of a chain. The polyurethaneureas were cast as a film and subsequently treated with N-chlorosulphonyl isocyanate to produce sulphamate and carboxylate groups on the film surface. The level of in vitro non-thrombogenicity increased with increasing degree of modification. The high blood compatibility is attributed to the low level of platelet stimulation and to heparinoid activity. It was observed that platelet stimulation depends on the surface structure of the original polyurethaneura, and that the heparinoid activity is related with the presence of sulphamate and carboxylate groups.

Animals↗
PubMed2004

Effect of donor treatment with heparinoids on graft function after intraportal transplantation of a marginal islet mass: an experimental study.

Heparinoids interact with factors that are involved in ischemia-reperfusion injury and thus may prevent organ injury. We therefore studied the effects on subsequent intraportal islet transplantation of systemic administration of unfractionated and N-desulphated heparin to donors prior to pancreatectomy. Donor rats were given an intravenous injection of either heparin (1.3 mg/kg or 13.3 mg/kg; 200 U/kg or 2000 U/kg, respectively) or N-desulphated heparin (50 mg/kg; approximately 5 U/kg) at 5 to 10 minutes prior to pancreas procurement. Five hundred freshly isolated islets were injected intraportally into syngeneic male Lewis recipients that had developed streptozotocin-induced diabetes. Blood glucose and body weight were monitored for 5 weeks thereafter. Rats transplanted with islets from donors given high dose heparin showed a fall in blood glucose from 25.1 +/- 1.4 to 11.0 +/- 2.7 mmol/L (P <.01) with 60% of animals euglycemic within the first week. In contrast, the controls, did not show a fall in glucose levels at 1 week and none had become euglycaemic. Normalization of glycemia was slower in recipients of islets from animals treated with the lower dose of heparin. Results were intermediate with islets from donors given N-desulphated heparin. Nevertheless, all heparinoids used in this study caused more than a doubling of the number of animals achieving normoglycemia by 3 to 4 weeks. We hypothesize that pretreatment of the donor with heparin protects islet integrity during procurement and isolation and hence accelerates islet engraftment and remodelling. Since the effect was seen with N-desulphated heparin, which has negligible anticoagulant properties, we believe the mechanism to be independent of the anticoagulant activity.

Animals↗
PubMed1989

The anti-inflammatory effect of organo-heparinoid cream after bilateral mandibular osteotomies.

The aim of the present study was to compare the effect on swelling after bilateral osteotomies of the mandible of treatment with organo-heparinoid (Hirudoid) cream and that of a placebo cream. 12 patients (7 female, 5 male), median age of 29.5 years, were included in the study. 5 patients received bilateral sagittal-split procedures for symmetrical mandibular advancement, and 7 patients received bilateral mandibular osteotomies for symmetrical mandibular set-back. Each of the 2 operated sides were randomized for treatment with active medication or placebo; 1.5 g of the active- or placebo cream were carefully rubbed into the skin above the masseteric muscle 4 times a day for 4 days. Periodic identical CT-scans were performed to evaluate swelling; patients were CT-scanned preoperatively and once or twice postoperatively. 3 variables were used to assess the swelling: (1) thickness of the subcutis; (2) maximum thickness of the masseteric muscle; (3) cross-sectional area of the soft tissues facial to the ramus of the mandible. No significant differences in postoperative swelling could be demonstrated between the 2 treatments. There were no detectable systemic effects of the treatment with organo-heparinoid.

Adult↗
PubMed2004

Design and synthesis of dimeric heparinoid mimetics.

Synthetic oligosaccharide constructs exhibiting tailored and well-defined heparan sulfate (HS) like sequences offer the potential to modulate dynamic HS-dependent biomolecular recognition processes. We report an efficient strategy for the generation of HS-like fragments [GlcA-beta-(1,4)-GlcNAc] and related dimerized (gemini) disaccharides (4a and 4b) via n-pentenyl glycoside formation. When a convergent synthetic approach was utilized, construction of target molecules was achieved through a combination of chemoselective protection/deprotection protocols, imidate and n-pentenyl glycosylations, and functional group manipulations followed by ozonolysis and reductive amination. For example, glycosylation of a 2-azido glycoside (25) with a trichloroacetimidate glucuronic acid donor (13), using a catalytic amount of TMSOTf, furnished heparin-like disaccharides (28a and 28b) that were equipped with an n-pentenyl tether at the anomeric end. In turn, heparinoid-like gemini disaccharides (4a and 4b) were produced by selective transformation of the olefinic unit in the n-pentenyl glycoside to the four-carbon aldehyde followed by reductive amination with ethylenediamine. The described synthetic approach provides access to structural variants of small heparinoid oligomers as versatile building blocks for generating novel HS mimetic pharmacotherapeutics, diagnostic reagents, and biomaterials.

Carbohydrate Sequence↗
PubMed2000

Hepatoenteric ischemia-reperfusion increases circulating heparinoid activity in rabbits.

PURPOSE: The purpose of this study was to determine if an increase in circulating heparinoid activity contributes to the hemostatic abnormalities associated with hepatoenteric ischemia-reperfusion. MATERIALS AND METHODS: Anesthetized rabbit (n = 18) underwent thoracic aorta occlusion for 30 minutes with a balloon catheter, followed by 30 minutes of reperfusion. Blood samples were obtained after 30 minutes of equilibration and 30 minutes of reperfusion. Hemostatic function was assessed by changes in the thrombelastographic variables R (reaction time), alpha (a measure of the speed of clot formation), and G (a measure of clot strength). Thrombelastography was performed on blood without platelet inhibition in the presence or absence of heparinase (n = 9 rabbits). Additional samples (n = 9) were exposed to cytochalasin D (platelet inhibitor) with or without heparinase. RESULTS: Compared with preischemic values, blood samples with intact platelet function obtained during reperfusion demonstrated a decrease in hemostatic function evidenced by a significant (P<.05) increase in R, decrease in alpha, and decrease in G. R, alpha, and G values of samples without platelet inhibition exposed to heparinase did not significantly change after ischemia. Blood samples exposed to cytochalasin D displayed a similar pattern. CONCLUSION: An increase in circulating heparinoid activity significantly contributes to the hemostatic disorder associated with hepatoenteric ischemia-reperfusion in rabbits.

Animals↗
PubMed1999

Heparinoids: structure, biological activities and therapeutic applications.

Heparin is an important polyanionic drug having a wide variety of different biological activities. Substantial research effort has focused on the preparation of improved heparins and heparin analogues that might exhibit higher specificity and decreased side effects. These heparin analogues or heparinoids include sulfated polysaccharides from plant and animal origin, synthetic derivatives of polysaccharides, and acidic oligosaccharides and their small synthetic analogues. The structure, biological activities and therapeutic potential of these heparinoids are discussed.

Carbohydrate Conformation↗