KINETICS OF LOW MOLECULAR WEIGHT HEPARIN IN MAN DETERMINED BY PROTAMINE CHLORIDE

1987 ◽  
Author(s):  
V Bode ◽  
R Franz ◽  
D Welzel ◽  
H Wolf ◽  
C Harenberg
Keyword(s):  
Molecular Weight ◽  
Half Life ◽  
Ex Vivo ◽  
Plasma Concentrations ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Plasma Samples ◽  
Endogenous Compounds ◽  
Antifactor Xa ◽  
Kinetics Of

Low molecular weight (LMW) heparin is characterized by a higher affinity to antithrombin HI, less inhibition of thrombin and increased inhibition of factor Xa. The half life of the antifactor Xa activity of LMW heparin is doubled compared to normal heparin. However, these parameters reflect the pharmacodynamics rather than the kinetic of the compound. We, therefore, analyzed the kinetics of LMW heparin after i.v. injection in man using protamine chloride for gravimetric evaluation of LMW heparin in the plasma samples.Six healthy adults received 100 units per kg body weight normal heparin or 100 anti Xa units per kg LMW heparin (Sandoz AG, Niimberg, FRG). To serial samples of venous blood protamine chloride was added in serial dilutions until the thrombin inhibition was antagonized. Since factor Xa inhibition of LMW heparin cannot be abolished completely by protamine chloride, two amounts of protamine chloride were added to the plasma samples ex vivo, until factor Xa was inhibited up to 0,2 and 0,04 units/ml. The following maximal plasma concentrations (C max) and half lives (T/2) were calculated (average values):The pharmacokinetics of normal heparin show no differences on thrombin and factor Xa interaction. LMW heparin, however, interacts to 30 % with thrombin and to 100 % with factor Xa; the half life on factor Xa is twice as long as on thrombin; releases endogenous compounds with antifactor Xa activity, which are neutralized only hardly by protamine chloride;and these endogenous compounds mediate in part the longer half life.

Covalent Complexes Between Low Molecular Weight Heparin Fragments and Antithrombin III – Inhibition Kinetics and Turnover Parameters

1983 ◽  
Vol 49 (02) ◽  
pp. 109-115 ◽  
Author(s):  
M Hoylaerts ◽  
E Holmer ◽  
M de Mol ◽  
D Collen
Keyword(s):  
Molecular Weight ◽  
Half Life ◽  
Low Molecular Weight Heparin ◽  
Antithrombin Iii ◽  
Factor Xa ◽  
Life Time ◽  
Low Molecular Weight ◽  
High Affinity ◽  
Plasma Half Life ◽  
Covalent Complex

SummaryTwo high affinity heparin fragments (A/r 4,300 and M, 3,200) were covalently coupled to antithrombin III (J. Biol. Chem. 1982; 257: 3401-3408) with an apparent 1:1 stoichiometry and a 30-35% yield.The purified covalent complexes inhibited factor Xa with second order rate constants very similar to those obtained for antithrombin III saturated with these heparin fragments and to that obtained for the covalent complex between antithrombin III and native high affinity heparin.The disappearance rates from plasma in rabbits of both low molecular weight heparin fragments and their complexes could adequately be represented by two-compartment mammillary models. The plasma half-life (t'/j) of both low Afr-heparin fragments was approximately 2.4 hr. Covalent coupling of the fragments to antithrombin III increased this half-life about 3.5 fold (t1/2 ≃ 7.7 hr), approaching that of free antithrombin III (t1/2 ≃ 11 ± 0.4 hr) and resulting in a 30fold longer life time of factor Xa inhibitory activity in plasma as compared to that of free intact heparin (t1/2 ≃ 0.25 ± 0.04 hr).

Novel Design of Peptides to Reverse the Anticoagulant Activities of Heparin and other Glycosaminoglycans

2001 ◽  
Vol 85 (03) ◽  
pp. 482-487 ◽  
Author(s):  
Joel Gradowski ◽  
James San Antonio ◽  
Jose Martinez ◽  
Barbara Schick
Keyword(s):  
Molecular Weight ◽  
Unfractionated Heparin ◽  
Low Molecular Weight Heparin ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Heparin Binding ◽  
Antifactor Xa ◽  
Novel Design

SummaryPatients undergoing anticoagulation with unfractionated heparin, low molecular weight heparin, or danaparoid may experience excess bleeding which requires reversal of the anticoagulant agent. Protamine is at present the only agent available for reversal of unfractionated heparin. Protamine is not effective in patients who have received low molecular weight heparin or danaparoid. We have developed a series of peptides based on consensus heparin binding sequences (Verrecchio et al., J Biol Chem 2000; 275: 7701-7707) that are capable of neutralizing the anti-thrombin activity of unfractionated heparin in vitro, the antifactor Xa activity of unfractionated heparin, Enoxaparin (Lovenox) and danaparoid (Orgaran) in vitro and the anti-Factor Xa activity of Enoxaparin in vivo in rats. These peptides may serve as alternatives for Protamine reversal of UFH and may be useful for neutralization of enoxaparin and danaparoid in humans.

SUBCUTANEOUS PHARMACOKINETICS/PHARMACODYNAMICS OF A LOW MOLECULAR WEIGHT DERIVATIVE (RD 11885) AND UNFRACTIONATED HEPARIN (PM 16885) IN PRIMATES

1987 ◽  
Author(s):  
R Norm ◽  
J Fareed ◽  
I Silber ◽  
A Belo ◽  
R Fenchel ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Unfractionated Heparin ◽  
Low Molecular Weight Heparin ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Factor Xa ◽  
Repeated Administration ◽  
Treated Group ◽  
Low Molecular Weight ◽  
Thrombin Time

Subcutaneous pharmacokinetics/pharmacodynamics of a depolymerized low molecular weight heparin (RD 11885) and an unfractionated porcine mucosal heparin (PM 16885) were studied in primates (Macaca mulatta) at 0.5, 1.0 and 2.5 mg/kg/24 hr for 10 days after repeated administration. Ex vivo actions were determined using partial thromboplastin time (APTT), thrombin time (TT), IieptestR time (HT) , anti-factor Xa and anti-factor Ila assays at various time periods. Platelet counts and bleeding times were also measured. The cumulative bioavailability of RD 11885 calculated ex vivo was found to be 2-3 fold higher than PM 16885. The RD 11885 treated group exhibited a clear dissociation of the anti-factor Xa and anti-factor Ila activities. The biological half-life of RD 11885 was significantly greater than PM 16885 in all assays. No staircasing phenomenon was observed with either agent. A desensitization of the PM 16885 effects was observed. Neither agent produced any effect on the bleeding time or platelet count at any time. The pharmacokinetics/pharmacodynamics of RD 11885 were uniform and allowed the calculation of various pharmacologic parameters, whereas inconsistent results were obtained with PM 16885. These results demonstrate that this low molecular weight heparin exhibits better and more predictable bioavailability, in contrast to unfractionated heparin.

COMPARATIVE CLINICAL PHARMACOLOGY OF LOW MOLECULAR WEIGHT HEPARINS IN MAN

1987 ◽  
Author(s):  
Y Ordu ◽  
J Augustin ◽  
E V Hodenberg ◽  
V Bode ◽  
J Harenberg
Keyword(s):  
Molecular Weight ◽  
Clinical Pharmacology ◽  
Ex Vivo ◽  
Average Molecular Weight ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Pharmacological Properties ◽  
Clotting Time ◽  
Activity Time ◽  
Low Molecular Weight Heparins

Low molecular weight (LMW) heparins are obtained by diffent chemical procedures from conventional pig intestinal mucosa heparin. The LMW heparins differ in their molecular weight distribution and physicochemical properties. Therefore, we report of comparative studies on the anticoagulant and lipolytic effects of low molecular weight heparins in man.The following LMW heparins were used: BM 21-23 (Braun, Melsungen, FRG), CY 216 (Choay Laboratories, Paris, France), Heparin NM (Sandoz, Niimberg, FRG), Kabi 2165 (Kabi Vitrum AB, Stockholm, Sweden), RD Heparin (Hepar Industries, Franklin, US A), normal heparin (Braun). All heparins were administered intravenously and subcutaneously to six volunteers each.The data show considerable differences in the anticoagulant and lipolytic effects between the different low molecular weight heparins. From the area under the activity time curves (AUC) of the clotting assays for factor Xa (heptest), aPTT and thrombin clotting time the aXa/aPTT ratio ex vivo and aXa/alla ratio ex vivo were determined (table, average values)It can be seen that there are clear differences in the ex vivo ratios of the LMW heparins. There is a good correlation between the average molecular weight of the LMW heparins and the aXa/aPTT ratio after s.c. administration and of the aXa/alla ratio ex vivo after s.c. administration. Therefore, LMW heparins differ significantly in their clinical pharmacological properties.

Heptest-STAT, a new assay for monitoring of low-molecular-weight heparins, is not influenced by pregnancy-related changes of blood plasma

2009 ◽  
Vol 102 (11) ◽  
pp. 1001-1006 ◽  
Author(s):  
Ulyana Zharkowa ◽  
Elif Elmas ◽  
Parviz Ahmad-Nejad ◽  
Michael Neumaier ◽  
Martin Borggrefe ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Pregnant Women ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Plasma Samples ◽  
Third Trimester ◽  
Low Molecular Weight Heparins ◽  
Individual Calibration ◽  
Standard Calibration ◽  
In Pregnancy

SummaryMonitoring of anti-factor Xa activity is often performed during treatment with low-molecular-weight heparins (LMWHs) in pregnancy because the anticoagulant effect may decrease as pregnancy progresses, but assays for anti-factor Xa activity are unavailable in many clinical institutions caring for pregnant women. Heptest-STAT is a new clotting assay for monitoring of LMWHs, which has been optimised for use in near-patient laboratory instrumentation. It has been suggested that monitoring of LMWHs requires the use of individual calibration curves for each LMWH.We compared the dose response of four conventional LMWHs and fondaparinux in normal plasma, and plasma from women in first, second and third trimester of pregnancy. Three concentrations of LMWHs, fondaparinux, or unfractionated heparin were added to pooled plasma samples from nonpregnant women (n=10), and pregnant women in first (n=10), second (n=10) and third (n=10) trimester of pregnancy. Heptest results are not influenced by the stage of pregnancy. In contrast, dose-related aPTT prolongation declines during pregnancy. All LMWHs tested, as well as fondaparinux, display a similar doseresponse in Heptest compared to the chromogenic anti-factor Xa assay. Heptest-STAT can be used with the same standard calibration for non-pregnant and pregnant patients and for all LMWHs under investigation, including fondparinux. No individual calibrations are necessary.

Pharmacological Properties of a Low Molecular Weight Butyryl Heparin Derivative (C4-CY 216) with Long Lasting Effects

1992 ◽  
Vol 67 (03) ◽  
pp. 346-351 ◽  
Author(s):  
S Saivin ◽  
M Petitou ◽  
J C Lormeau ◽  
D Dupouy ◽  
P Sié ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Low Molecular Weight Heparin ◽  
Specific Activity ◽  
Parent Compound ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Pharmacological Properties ◽  
Factor Xa Inhibition ◽  
Antifactor Xa ◽  
Heparin Derivative

SummaryWe have investigated the pharmacological properties of an O-acylated butyryl derivative of the low molecular weight heparin CY 216 (C4-CY 216). In a purified system the ability of C4-CY 216 to catalyze thrombin and factor Xa inhibition was comparable to that of CY 216. The antithrombin and antifactor Xa catalytic efficiencies of C4-CY 216 were reduced 217 and 12 times respectively when albumin (10 mg ml-1) was added to the reagents, while those of CY 216 were essentially unchanged. In plasma, the antifactor Xa specific activity of C4-CY 216 was close to that of CY 216 but the antithrombin specific activity was 2 times lower. After bolus and continuous intravenous injection to rabbits, the clearances of the two activities of C4-CY 216 were on average half the corresponding values of CY 216. After subcutaneous injection, the bioavailability of C4-CY 216 was comparable to that of CY 216. C4-CY 216 was as potent as CY 216 in preventing venous thrombosis in the thromboplastin-Wessler model and the duration of the antithrombotic effect was longer than that of the parent compound. The chemical alteration of CY 216 did not enhance the prohaemorrhagic effect in the rat tail transection model. Therefore, the new concept of heparin derivative having a low clearance and long lasting effects that we have recently reported for unfractionated heparin may also be applied to a low molecular weight heparin.

The Relationship between Anti-Factor Xa Level and Clinical Outcome in Patients Receiving Enoxaparine Low Molecular Weight Heparin to Prevent Deep Vein Thrombosis after Hip Replacement

1989 ◽  
Vol 62 (03) ◽  
pp. 940-944 ◽  
Author(s):  
M N Levine ◽  
A Planes ◽  
J Hirsh ◽  
M Goodyear ◽  
N Vochelle ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Hip Replacement ◽  
Ex Vivo ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Once Daily ◽  
Vein Thrombosis ◽  
Postoperative Thrombosis ◽  
Deep Vein ◽  
The Relationship

SummaryStudies in experimental animals have demonstrated that there is a relationship between levels of low molecular weight (LMW) heparin and both bleeding and inhibition of thrombosis. The relationship between these outcomes and ex vivo anti-factor Xa levels has been examined in 163 patients undergoing total hip replacement who were given prophylaxis once daily with a LMW heparin (enoxaparine). Fifty patients received 60 mg of enoxaparine and 113 received 40 mg, both regimens being administered subcutaneously once daily. Blood samples for anti-factor Xa levels were collected 12 hours after the injection on the day of surgery and on days 1, 3 and 6, postoperatively. The incidence of wound hematoma was 5.3% when the maximum anti-factor Xa level was ≤0.2 units per ml, but increased to 24.5% when the anti-factor Xa level exceeded 0.2 units per ml, P = 0.0008. The incidence of postoperative thrombosis was low (6.3%) if the minimum anti-factor Xa level exceeded 0.1 units per ml, but increased to 14.6% when ≤0.1 units per ml, and to 18.8% if the anti-factor Xa level was ≤0.05 units per ml. Regression analysis revealed that there was a statistically significant relationship between anti-factor Xa level and wound hematoma, P = 0.002 and anti-factor Xa level and thrombosis, P = 0.03. These findings suggest that when enoxaparine is administered as a once daily subcutaneous injection, the 12 hour anti-factor Xa level should not exceed 0.2 units per ml to minimize bleeding and levels >0.05 units per ml should be obtained to optimize efficacy.

Production Method Affects the Pharmacokinetic and Ex Vivo Biological Properties of Low Molecular Weight Heparins

1997 ◽  
Vol 77 (02) ◽  
pp. 317-322 ◽  
Author(s):  
David Brieger ◽  
Joan Dawes
Keyword(s):  
Molecular Weight ◽  
Half Life ◽  
Ex Vivo ◽  
Production Method ◽  
Biological Properties ◽  
Size Exclusion ◽  
Cellular Interaction ◽  
Low Molecular Weight ◽  
Method Of Production ◽  
The Impact

SummaryLow molecular weight (LMW) heparins have prolonged circulating half-lives relative to unfractionated heparin, but the rates of plasma clearance differ between different LMW preparations. To determine the impact of method of production on their pharmacokinetic and ex vivo biological properties, two LMW heparins of similar molecular weight distribution, Logiparin and Fragmin, were radiolabelled with 125I, administered intravenously with 4 mg/kg of carrier drug into rabbits, and the circulating radiolabelled material and anti-Xa activity were analysed by size exclusion chromatography and affinity for antithrom#bin and Polybrene. Following administration of Logiparin, the anti-Xa amidolytic activity was eliminated with the same half-life as the anti#thrombin-binding radiolabel and was not neutralised by antibody against tissue factor pathway inhibitor (TFPI). Larger molecules were cleared preferentially and were no longer detectable 8 h post injection. These findings resemble those we have previously described for Enoxaparin. After Fragmin administration the antithrombin binding radiolabel was cleared more rapidly than the anti-Xa activity, and at late times after injection a significant amount of this activity was neutralised by antibody against TFPI. Sulphated radiolabel was eliminated with a similar half-life to the anti-Xa activity and sulphated molecules >6000 Da remained in the circulation 8 h after administra#tion. Fragmin, unlike Logiparin and Enoxaparin, has no negatively charged sulphamino group at the reducing end of the molecule. We sug#gest that this minimises cellular interaction and protects the larger molecules from elimination. They remain in the circulation, contributing to anti-Xa activity by binding TFPI. Thus the method of production of LMW heparins may significantly influence their pharmacokinetic properties and circulating anticoagulant activities.

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