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PubMed1988

Is there a unique sequence in heparin for interaction with heparin cofactor II? Structural and biological studies of heparin-derived oligosaccharides.

To study the structural requirements in heparin for interaction with heparin cofactor II (HC II) we have analyzed the properties of oligosaccharide fractions obtained after digestion of heparin by heparinase and gel filtration. No activation of HC II was detected in the presence of di-, tetra-, hexa-, octa-, deca-, or do-decasaccharides. The hexasaccharide pool was fractionated by ion-exchange chromatography, and the structure of the major species, obtained in a homogeneous state, was investigated by NMR. All the resonances were unambiguously assigned using correlation by homonuclear and heteronuclear scalar coupling. The six monosaccharide residues of this hexasaccharide were thus easily identified. The sequence was established through two-dimensional nuclear Overhauser effect experiments. The results indicate that this product is a hexasaccharide recently described by Linhardt et al. (Linhardt, R. J., Rice, K. G., Merchant, Z. M., Kim, Y. S., and Lohse, D. L. (1986) J. Biol. Chem. 261, 14448-14454). However, we could not confirm the anticoagulant activity observed by these authors. Moreover, none of the individual components obtained after fractionation of the hexasaccharide pool was able either to activate HC II against thrombin or to inhibit HC II activation by heparin. Thus, our data led us to conclude that no unique sequence is involved in heparin for binding to HC II and inactivation of thrombin. The interaction merely results from the highly anionic character of heparin.

Antithrombins↗
PubMed1982

Influence of heparin; of different heparin fractions and of a low molecular weight heparin-like substance on the mechanism of fibrinolysis.

The influence of different heparin fractions and of a synthetic polysulfated polysaccharide (SP54) on the fibrinolytic mechanism was examined. In vitro, a significant shortening of the euglobulin lysis time (ELT) was found after addition of standard mucosa heparin, of high MW heparin and of SP 54 respectively. Low MW heparin fractions had no influence on the ELT. Simultaneously with the shortening of the ELT an activation of factor XII and of kallikrein was observed. A similar effect was found in groups of volunteers after i.v. or s.c. injections and even after oral administration of SP 54. The effect of venous occlusion on the ELT and on the activation of factor XII was considerably increased when heparin or SP 54 was injected 2 h prior to the test. When a comparable concentration of the test substances was added to plasma samples before and after venous occlusion, the effect on the ELT was much less pronounced than after injection whilst the effect on factor XII was comparable in both tests. From these results the conclusion was drawn that activation of fibrinolysis by polysulfated polysaccharides is achieved by an endogenous pathway as well as by an increased availability of the vascular activator. The magnitude of the activation of fibrinolysis partly depends on the MW of the substance but apparently also on the degree of sulfation since a low MW substance with a high number of sulfate bonds such as SP 54 was considerably more active than the low MW fraction of standard heparin.

Adult↗
PubMed1995

N' alkylamine low molecular mass heparins (LMM-heparin-tyramine and LMM-heparin-tyramine-fitc) exhibit long lasting anticoagulant effects.

The pharmacodynamic and pharmacokinetic properties of endpoint-attached N'alkylamine derivatives of low molecular mass heparin (LMMH), low molecular mass heparin (LMMH), low molecular mass heparin-tyramine (LMMH-tyr) and low molecular mass heparin-tyramine-fluorescein-5-isothiocyanate (LMMH-tyr-fitc) were investigated ex vivo. After intravenous bolus injection of LMMH, LMMH-tyr and LMMH-tyr-fitc (150 aXa U/kg) to Sprague-Dawley rats (n = 8), LMMH-tyr and LMMH-tyr-fitc displayed decreased clearances. The beta-half-life time of the antifactor Xa (aXa) of "endpoint-attached heparins" was significantly prolonged: LMMH-tyr (125 min), LMMH-tyr-fitc (141 min) compared to LMMH (69 min). The pharmacokinetics of LMMH-tyr-fitc were measured with reversed phase high performance liquid chromatography (RP-HPLC). It showed a decreased clearance and a prolonged half-life time (132 min). The selectively tagged LMMH-tyramine and LMMH-tyramine-fitc may be used to investigate the pharmacokinetics, plasma protein and cellular binding of low molecular mass heparins.

Animals↗
PubMed1978

alpha-L-iduronate ring conformations in heparin and heparin derivatives. 13-C Nuclear-magnetic-resonance analysis and titration data for variously desulphated and periodate-oxidized heparins.

A heparin derivative that had been O/N-desulphated and re-N-acetylated was investigated by 13C n.m.r. spectroscopy and potentiometric titration. Three forms of uronic acid were observed, tentatively identified as beta-D-glucuronate, and two different forms of alpha-L-iduronate. A comparison of the n.m.r. spectra of heparin, an oligosaccharide (beta-D-glucuronate-2-acetamido-2-deoxy-alpha-D-glucose)n, and heparin that had been subjected to selective oxidation of beta-D-glucuronate, enabled the position of the anomeric carbon of the latter residue to be assigned [delta 102.9 (p.p.m.)]. Periodate oxidation of O/N-desulphated heparin destroyed in addition, approx. 40% of the alpha-L-iduronate content. The remainder of the alpha-L-iduronate residues displayed only one anomeric resonance, at delta 99.7 (p.p.m.). In another preparation, after sequential desulphation of heparin (N-desulphation, re-N-acetylation and O-desulphation) the anomeric resonance of the alpha-L-iduronate residue shifted downfield [from delta99.7 (p.p.m.) to delta 102.3]indicating a change in ring conformation. These data support the interpretation that the unsulphated alpha-L-iduronate residues may adopt two conformations. It was shown that the proportions of alpha-L-iduronate conformers are determined by the sequence of desulphation operations. Also minor components of heparin were assigned.

Heparin↗
PubMed1984

Effect of heparin, low molecular weight (LMW) heparin, and a heparin analogue on experimental venous thrombosis in the rabbit.

An experimental model based on a combination of endothelial injury and flow reduction, was used to induce jugular vein thrombosis in the rabbit. The influence of conventional heparin, a low molecular weight fragment (LMW heparin; M.W. 4 000-5 000) and a heparin analogue (sodium pentosan polysulfate) was compared. The drugs were administered intravenously during the induction of thrombosis. The control animals received Ringer's lactate. All treatments significantly reduced the frequency of thrombosis. In addition, LMW heparin caused a significant reduction of thrombus weight. Moreover, it was shown that local treatment with conventional heparin and LMW heparin after endothelial damage both reduced the frequency of thrombosis.

Animals↗
PubMed1990

Heparin-related osteoporosis in rats. A comparative study between unfractioned heparin and a low-molecular-weight heparin.

In an animal model, the effect of a high dose of conventional heparin (2 IU/g s.c. twice a day) and a low-molecular-weight heparin (LMWH; Fragmin, 1 anti-Xa U/g once a day) was compared with that of placebo on the mineral bone mass in the femur of rats. After 33 days of treatment no differences were found in the weight of the femur. But heparin-treated rats exhibited a lower density (1,249 +/- 0.046 g/ml as compared with that in control rats (p = 0.00007) and also in LMWH-treated rats (p = 0.001). Similarly, statistically significant differences have been found in ash contents. They were higher in control rats than in heparin-treated rats (p = 0.0002), and also slightly higher than in LMWH-treated rats (p = 0.01). Our findings suggest that LMWH may have a lower osteopenic effect than that of conventional heparin.

Animals↗
PubMedDate not supplied

Veno-venous bypass without systemic heparinization using a centrifugal pump: a blind comparison of a heparin bonded circuit versus a non heparin bonded circuit.

Veno-venous bypass without the use of systemic heparinization has recently become of increasing interest for application during liver transplantation and surgery on the large abdominal veins. However, possible adverse effects on blood components as demonstrated by means of hematologic and hemostatic parameters or on the occurrence of thromboembolic complications are until now not excluded. No consensus has been reached as to the efficacy of heparin coated circuits in those procedures. In the present study veno-venous bypass was performed for four hours in ten dogs using heparin coated and non coated circuits without further heparinization in a randomized blind fashion. No changes or significant intergroup differences were noted in the hematological and coagulation parameters. Macroscopic evaluation of the circuits revealed small strands of fibrin on all connector rims and clots in the center part of the pump head and at the cannula tips. The lungs showed two small emboli in large size pulmonary arteries and also two minor emboli in small size arteries. In four animals the emboli were equally divided between the two groups. As expected regarding the size of the clots no influences could be seen on hemodynamic or respiratory parameters. With Scanning Electronic Microscopy a monolayer of activated thrombocytes was observed on the surface of the bypass circuits in the coated as well as in the uncoated group. This study suggests that a veno-venous bypass without systemic heparinization is possible without serious damage to blood cellular elements or impressive activation of the coagulation system.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Interaction of heparin-binding EGF-like growth factor (HB-EGF) with the epidermal growth factor receptor: modulation by heparin, heparinase, or synthetic heparin-binding HB-EGF fragments.

The binding of heparin-binding EGF-like growth factor (HB-EGF) to the epidermal growth factor (EGF) receptor of human endometrial carcinoma cells was compared to that of EGF using an 125I-EGF radioreceptor assay. The inhibitory effect of HB-EGF on 125I-EGF binding was reversed either in the presence of heparin (but not by chondroitin sulfate) or by pre-treating the cells with heparinase. These treatments did not affect the binding of EGF to its receptor. To map potential regions in the HB-EGF molecule that mediate its heparin-dependent interaction with the EGF receptor, HB-EGF peptides were synthesized that were non-homologous to EGF. Accordingly residues 20-25 and 36-41, but not residues 8-19, of HB-EGF were found to be (i) heparin-binding and (ii) modulators of HB-EGF (but not of EGF) binding to the EGF receptor.

Amino Acid Sequence↗
PubMed2003

Novel concatameric heparin-binding peptides reverse heparin and low-molecular-weight heparin anticoagulant activities in patient plasma in vitro and in rats in vivo.

Patients given unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) for prophylaxis or treatment of thrombosis sometimes suffer serious bleeding. We showed previously that peptides containing 3 or more tandem repeats of heparin-binding consensus sequences have high affinity for LMWH and neutralize LMWH (enoxaparin) in vivo in rats and in vitro in citrate. We have now modified the (ARKKAAKA)(n) tandem repeat peptides by cyclization or by inclusion of hydrophobic tails or cysteines to promote multimerization. These peptides exhibit high-affinity binding to LMWH (dissociation constant [K(d)], approximately 50 nM), similar potencies in neutralizing anti-Factor Xa activity of UFH and enoxaparin added to normal plasma in vitro, and efficacy equivalent to or greater than protamine. Peptide (ARKKAAKA)(3)VLVLVLVL was most effective in all plasmas from enoxaparin-treated patients, and was 4- to 20-fold more effective than protamine. Several other peptide structures were effective in some patients' plasmas. All high-affinity peptides reversed inhibition of thrombin-induced clot formation by UFH. These peptides (1 mg/300 g rat) neutralized 1 U/mL anti-Factor Xa activity of enoxaparin in rats within 1 to 2 minutes. Direct blood pressure and heart rate measurements showed little or no hemodynamic effect. These heparin-binding peptides, singly or in combination, are potential candidates for clinical reversal of UFH and LMWH in humans.

Amino Acid Sequence↗
PubMed1992

Comparison of low molecular weight heparin vs. unfractionated heparin in gynecological surgery. II: Reduced dose of low molecular weight heparin.

In a double blind, randomized trial the hemorrhagic complications of a reduced dose of low molecular weight heparin (LMWH) (Fragmin, KabiPharmacia) were compared to those of the conventional dose of unfractionated heparin (UH). 2500 anti-XaU of LMWH was given once daily and UH in a dose of 5000 anti-XaU twice daily. During a one year period 141 patients undergoing gynecological surgery were included in this study. The patients were examined clinically for hematomas and for deep venous thrombosis (DVT) on the third and fifth day. Venography was performed when DVT was suspected. No patients developed clinical DVT. One woman in the LMWH group had pulmonary embolism 3 days after the prophylaxis was stopped. Two women in the LMWH group died, one from a stroke on day 2, one from cancer on day 39. There was no significant difference in serious bleeding complications between the two regimens, 20% in the LMWH group and 14% in the UH group. Even with the reduced dose of LMWH the mean plasma concentration of heparin in the LMWH group was higher (mean 0.14 anti-XaU/ml) than in the UH group (0.029 anti-XaU/ml) 3 hours after injection on the 2nd postoperative day. A reduced dose of LMWH (2500 anti XaU once daily) does not cause more bleeding complications than the conventional heparin regimen to prevent thrombosis, as was the case in our previous study with 5000 anti XaU of LMWH once daily.

Double-Blind Method↗
PubMed1999

[When lipids increase in dialysis: the role of heparin! Standard heparin increases, low-molecular-weight heparin lowers triglycerides].

Dyslipoproteinemia in patients on hemodialysis is characterized by a decrease in high density lipoprotein (HDL), cholesterol, hypertriglyceridemia, increased triglyceride-rich lipoproteins, such as very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL), a higher proportion of the small dense low density lipoprotein (small dense LDL) subfraction, and higher lipoprotein(a) concentration. The reason for the changes in triglyceride metabolism is an increase in the production of apolipoprotein B, and a decrease in the metabolism of VLDL as a consequence of decreased endothelial cell delipidation. The endothelial lipoprotein lipase, which plays a major role in this process, is released by heparin, which is essential for the function of the enzyme. Repeated administration of heparin for anticoagulation during hemodialysis apparently leads to an LPL depletion in the endothelium. This results in further exhaustion of lipolysis. Clinical studies in hemodialysis patients with high triglyceride and cholesterol levels indicate that a change from standard heparin to low-molecular-weight heparin improves the lipid profile by lowering triglycerides and cholesterol.

Cholesterol↗
PubMed2000

An NMR and molecular modeling study of the site-specific binding of histamine by heparin, chemically modified heparin, and heparin-derived oligosaccharides.

The diprotonated form of histamine binds site-specifically to heparin, a highly sulfated 1-->4 linked repeating copolymer comprised predominantly of 2-O-sulfo-alpha-L-iduronic acid (the I ring) and 2-deoxy-2-sulfamido-6-O-sulfo-alpha-D-glucopyranosyl (the A ring). The binding is mediated by electrostatic interactions. The structural features of histamine and heparin, which are required for the site-specific binding, have been identified from the results of (1)H NMR studies of the binding of histamine by six heparin-derived oligosaccharides and four chemically modified heparins and molecular modeling studies. The results indicate that the imidazolium ring of diprotonated histamine is critical for directing site-specific binding, while the ammonium group increases the binding affinity. The imidazolium ring binds within a cleft, with the A ring of an IAI triad at the top of the cleft, and the I rings forming the two sides. The H3 proton of the A ring is in the shielding cone of the imidazolium ring. The carboxylate group of the I-ring at the reducing end of the IAI triad and possibly the sulfamido group of the A-ring are essential for site-specific binding, whereas the 2-O-sulfate group of the I ring and the 6-O-sulfate group of the A ring are not. The results indicate that histamine binds to the IAI triad with the I rings in the (1)C(4) conformation. Also, the configuration of the carboxylate group is critical, as indicated by the absence of site-specific binding of histamine by the related IAG sequence, where G is alpha-D-glucuronic acid. The molecular modeling results indicate that the N1H and N3H protons of the imidazolium ring of site-specifically bound histamine are hydrogen bonded to the carboxylates of the I rings at the nonreducing and reducing ends of the IAI trisaccharide sequence.

Animals↗
PubMed2004

Effect of bivalirudin on length of stay in the recovery area after percutaneous coronary intervention compared with heparin alone, heparin + abciximab, or heparin + eptifibatide.

Three hundred nine patients were followed during their recovery area stay after percutaneous coronary intervention. Recovery area times for patients who received bivalirudin during percutaneous coronary intervention showed an average reduction in total recovery area length of stay of 36 minutes (p <0.0001) compared with patients who received heparin alone. This reduction was also seen when compared with the heparin + abciximab group (46-minute reduction, p = 0.0007), and the heparin + eptifibatide group (35-minute reduction, p = 0.0005). Patients who received bivalirudin took significantly less time for the activated clotting time (ACT) to normalize despite significantly higher average ACTs and significantly fewer subtherapeutic ACTs.

Abciximab↗
PubMed1996

Low molecular weight heparin (reviparin) in percutaneous transluminal coronary angioplasty. Results of a randomized, double-blind, unfractionated heparin and placebo-controlled, multicenter trial (REDUCE trial). Reduction of Restenosis After PTCA, Early Administration of Reviparin in a Double-Blind Unfractionated Heparin and Placebo-Controlled Evaluation.

OBJECTIVES: The specific objective of the REDUCE trial was to evaluate the effect of low molecular weight heparin on the incidence and occurrence of restenosis in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). BACKGROUND: Unfractionated heparin and its low molecular weight fragments possess antiproliferative effects and have been shown to reduce neointimal smooth muscle cell migration and proliferation in response to vascular injury in experimental studies. METHODS: The REDUCE trial is an international prospective, randomized, double-blind, multicenter study. Twenty-six centers in Europe and Canada enrolled 625 patients with single-lesion coronary artery obstructions suitable for PTCA. Three hundred six patients received reviparin as a 7,000-U bolus before PTCA, followed by 10,500 U as an infusion over 24 h and then twice-daily 3,500-U subcutaneous application for 28 days. The 306 patients in the control group received a bolus of 10,000 U of unfractionated heparin followed by an infusion of 24,000 U over 24 h. These patients then underwent 28 days of subcutaneous placebo injections. The primary end points were efficacy (defined as a reduction in the incidence of major adverse events [i.e., death, myocardial infarction, need for reintervention or bypass surgery]), absolute loss of minimal lumen diameter and incidence of restenosis during the observation period of 30 weeks after PTCA. RESULTS: Using the intention to treat analysis for all patients, 102 (33.3%) in the reviparin group and 98 (32%) in the control group have reached a primary clinical end point (relative risk [RR] 1.04, 95% confidence interval [CI] 0.83 to 1.31, p = 0.707). Likewise, no difference in late loss of minimal lumen diameter was evident for both groups. Acute events within 24 h occurred in 12 patients (3.9%) in the reviparin group and 25 (8.2%) in the control group (RR 0.49, 95% CI 0.26 to 0.92, p = 0.027) during or immediately after the initial procedure. In the control group, eight major bleeding complications occurred, and in the reviparin group, seven were observed within 35 days after PTCA. CONCLUSIONS: Reviparin use during and after coronary angioplasty did not reduce the occurrence of major clinical events or the incidence of angiographic restenosis over 30 weeks.

Angioplasty, Balloon, Coronary↗
PubMed2000

Low-molecular-weight heparin alone versus a combination of unfractionated heparin and low-molecular-weight heparin.

OBJECTIVES: We analyzed the effect of the pharmacologic combination of 2 indirect antithrombin drugs--enoxaparin (low-molecular-weight heparin) and unfractionated heparin--versus enoxaparin alone on the recurrence of ischemia. BACKGROUND: Blocking some key factors of the coagulation cascade supports the concept that an antithrombin effect is needed during the acute phase of ischemia. METHODS: This was a prospective, randomized, pilot trial in patients with an acute coronary ischemic event occurring within the previous 24 hours. A total of 126 patients were allocated to receive aspirin (200 mg/day orally) plus 1 mg/kg subcutaneous enoxaparin at 8 AM and 12.500 IU of subcutaneous unfractionated heparin at 8 PM (group A) or subcutaneous enoxaparin 1 mg/kg (group B). RESULTS: Severe recurrent ischemia provoking urgent coronary revascularization occurred in 12 patients (9.5%), 3 (5%) in group A and 9 (13%) in group B (P = .1). Refractory angina was present in 27 patients (21%), 10 (17%) in group A and 17 (25%) in group B (P = .45). The combination of severe recurrent ischemia and refractory angina occurred in 23% of group A, and 37% of group B (odds ratio 0.49; 95% confidence intervals, 0.21-1.15; P = .07). A total of 7 patients (5%) had acute nonfatal myocardial infarction develop, 3 (5%) in group A and 4 (6%) in group B. Two (1.6%) deaths were observed in the study, both in group B. The incidence of the double end point (death plus nonfatal myocardial infarction) was 5% in group A versus 9% in group B (P = .5) and the triple end point (death, nonfatal myocardial infarction, and severe recurrent ischemia) was 10.5% in group A vs 22% in group B (odds ratio 0.42, 95% confidence intervals, 0.13-1.29; P = .09). CONCLUSIONS: The combination of 2 indirect antithrombin drugs capable of intermittently blocking the coagulation system is not associated with a significant loss of safety.

Acute Disease↗
PubMed2005

Rates of clinically apparent heparin-induced thrombocytopenia for unfractionated heparin vs. low molecular weight heparin in non-surgical patients are low and similar.

With the growing use of low-molecular-weight heparins (LMWH) for the treatment and prevention of venous thromboembolism (VTE), it is important to provide an evidence-based comparison with unfractionated heparin (UFH) concerning rates of heparin-induced thrombocytopenia (HIT). Such comparisons are essential in clinical decision-making and cost-modeling. In this paper we review data regarding non-surgical (medical) patients. We conclude that the lack of uniform evaluation and standardized testing for HIT in the current literature precludes making a reliable estimate of the relative risk of HIT in UFH vs. LMWH in either the treatment or prevention of VTE in non-surgical patients. However, current data suggest that the risk of thrombocytopenia and HIT is low and similar for non-surgical patients who receive either LMWH or UFH.

Journal Article↗
PubMed2001

Randomized comparison of enoxaparin, a low-molecular-weight heparin, with unfractionated heparin adjunctive to recombinant tissue plasminogen activator thrombolysis and aspirin: second trial of Heparin and Aspirin Reperfusion Therapy (HART II).

BACKGROUND: Adjunctive unfractionated heparin (UFH) during thrombolytic therapy for acute myocardial infarction (AMI) promotes the speed and magnitude of coronary artery recanalization and reduces reocclusion. Low-molecular-weight heparins offer practical and potential pharmacological advantages over UFH in multiple applications but have not been systematically studied as adjuncts to fibrinolysis in AMI. METHODS AND RESULTS: Four hundred patients undergoing reperfusion therapy with an accelerated recombinant tissue plasminogen activator regimen and aspirin for AMI were randomly assigned to receive adjunctive therapy for at least 3 days with either enoxaparin or UFH. The study was designed to show noninferiority of enoxaparin versus UFH with regard to infarct-related artery patency. Ninety minutes after starting therapy, patency rates (thrombolysis in myocardial infarction [TIMI] flow grade 2 or 3) were 80.1% and 75.1% in the enoxaparin and UFH groups, respectively. Reocclusion at 5 to 7 days from TIMI grade 2 or 3 to TIMI 0 or 1 flow and TIMI grade 3 to TIMI 0 or 1 flow, respectively, occurred in 5.9% and 3.1% of the enoxaparin group versus 9.8% and 9.1% in the UFH group. Adverse events occurred with similar frequency in both treatment groups. CONCLUSIONS: Enoxaparin was at least as effective as UFH as an adjunct to thrombolysis, with a trend toward higher recanalization rates and less reocclusion at 5 to 7 days.

Anticoagulants↗