Effects of an Enzymatically Depolymerized Heparin as Compared with Conventional Heparin in Healthy Volunteers

1987 ◽  
Vol 57 (01) ◽  
pp. 097-101 ◽  
Author(s):  
Thomas Mätzsch ◽  
David Bergqvist ◽  
Ulla Hedner ◽  
Per Østergaard
Keyword(s):  
Molecular Weight ◽  
Body Weight ◽  
Healthy Volunteers ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Normal Range ◽  
Factor Xa Inhibition ◽  
At Iii ◽  
Mean Molecular Weight ◽  
Enzymatic Depolymerization

SummaryA low molecular weight heparin (LMW-heparin) with a mean molecular weight of 4900 dalton was prepared by controlled enzymatic depolymerization of conventional porcine mucosal heparin. The effects of 2,500, 5,000 and 10,000 U (Xal; 29,58 and 116 mg) on factor Xa inhibition (Xal), factor Ila inhibition (Hal), APTT, AT III and platelet count were compared to those of 5,000 U (Xal; 26 mg) of conventional heparin given s. c. to 6 healthy volunteers. 5,000 U (Xal; 58 mg) of LMW-heparin was given i. v. A dose related response with regard to the Xal and the Ila-inhibitory activities with peak values at 4 hours after the s. c. injections was obtained. An increase of the Xal/IIal ratio over the time after injection was seen only after i. v. administration of the LMW-heparin. The APTT was only slightly prolonged and remained within normal range after s. c. injection. AT III and platelet counts were unaffected. The biological half life of the LMW-heparin was 111 minutes if assayed by Xa inhibition, 76 minutes if assayed by Ila inhibition and 40 minutes if assayed by APTT. A strong correlation between the Xal activities obtained and body weight was seen, indicating that LMW-heparin should be administered individually according to body weight.

Chrono-Pharmacological Study of Once Daily Curative Dose of a Low Molecular Weight Heparin (200IU antiXa/kg of Dalteparin) in Ten Healthy Volunteers

1995 ◽  
Vol 74 (02) ◽  
pp. 660-666 ◽  
Author(s):  
P Mismetti ◽  
J Reynaud ◽  
B Tardy-Poncet ◽  
S Laporte-Simitsidis ◽  
M Scully ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Healthy Volunteers ◽  
Low Molecular Weight Heparin ◽  
Pharmacological Study ◽  
Area Under The Curve ◽  
Factor Xa ◽  
Similar Efficacy ◽  
Low Molecular Weight ◽  
Thrombin Time ◽  
Once Daily

SummaryLow molecular weight heparin (LMWH) is currently prescribed for the treatment of deep vein thrombosis at the dose of 100 IU antiXa/kg twice daily or at a dose of 175 IU antiXa/kg once daily with a similar efficacy. We decided to study the chrono-pharmacology of curative dose of LMWH once daily administrated according to the one previously described with unfractionated heparin (UFH).Ten healthy volunteers participated in an open three-period crossover study according to three 24 h cycles, separated by a wash-out interval lasting 7 days: one control cycle without injection, two cycles with subcutaneous injection of 200 IU antiXa/kg of Dalteparin (Fragmin®) at 8 a.m. or at 8 p.m. Parameters of heparin activity were analysed as maximal values and area under the curve.Activated partial thromboplastin time (APTT), thrombin time (TT), prothrombin time (PT) and tissue factor pathway inhibitor (TFPI) were higher after 8 p.m. injection than after 8 a.m. injection (p <0.05) while no chrono-pharmacological variation of anti factor Xa (AXa) activity was observed. Thus the biological anticoagulant effect of 200 IU antiXa/kg of Dalteparin seems to be higher after an evening injection than after a morning injection.A chrono-therapeutic approach with LMWH, as prescribed once daily, deserves further investigation since our results suggest that a preferential injection time may optimise the clinical efficacy of these LMWH.

STUDIES ON THE ANTITHROMBOTIC ACTION OF A LOW MOLECULARWEIGHT HEPARIN OBTAINED FROM BEEF MUCOSAL ORIGIN AND PEROXIDATIVE CLEAVAGE

1987 ◽  
Author(s):  
P Bianchini ◽  
R Nonn ◽  
J Fareed ◽  
J M Walenga ◽  
A Kumar
Keyword(s):  
Molecular Weight ◽  
Structural Integrity ◽  
Factor Xa ◽  
Inhibitory Effects ◽  
Heparin Cofactor Ii ◽  
At Iii ◽  
Antithrombotic Effects ◽  
In Vitro Systems ◽  
Mean Molecular Weight

We have studied a low molecular weight heparin (LMWH) obtained by acontrolled peroxidative depolymerization of beef mucosal heparin (OP 2123, Opocrin, Corlo, Italy). This product was found to be significantly different from other LMWHs in that it exhibits the same COO-/SO2- ratios as unfractionated heparin, contains reducing end groups composed of 2-sulfated iduronic acid or 6-disulfated glucosamine and retains an identical structural integrity as that of native heparin. As opposed to most other LMWHs the oligosaccharide components of OP 2123 consist of homogeneous progressive units. In addition, the relative amount of AT-IIIaffinity components in OP 2123 were 20-30% less than other LMWHs. OP 2123 has a mean molecular weight of 6200 daltons with a potency of 90 anti-factor Xa U/mg and 68 USP U/mg. This agent produced strong antithrombotic actions in a rabbit stasis model against both an activated prothrombin complex and a prothrombin complex concentrate/Russell's viper venomcombination (ED50:(IV) 30-70 ug/kg;(SC) 0.6-1.5 mg/kg). The antithrombotic effects were comparable to other LMWHs in normal rabbits: however, in AT III depleted rabbits (immunodepleted and y thrombin depleted), OP 2123 produced stronger antithrombotic effects than most other LMWHs. The in vitro systems in contrast to other LMWHs, CP 2123 produced stronger inhibitory effects in AT III depleted plasma as measured by fibrinopeptide A generation and amidolytic anti-factor Xa and anti-factor Ila methods. The relative heparin cofactor II activity as measured by amidolytic method was also found to be higher than with most LMWHs. These results suggest that OP 2123, unlike most LMWHs, non AT III mediated actions play a major role in themendiation of the antithrombotic actions.

EFFECT OF VARIOUS HEPARIN(OID)S ON HEPARIN COFACTOR II MEDIATED ANTI-THROMBIN ACTIVITY AND INHIBITION OF THROMBIN GENERATION IN VITRO

1987 ◽  
Author(s):  
T G van Dinther ◽  
F Hol ◽  
D G Meuleman
Keyword(s):  
Molecular Weight ◽  
Thrombin Generation ◽  
Factor Xa ◽  
Weight Fraction ◽  
Blood Platelet ◽  
Low Molecular Weight ◽  
Heparin Cofactor Ii ◽  
Thrombin Activity ◽  
At Iii

The effects of various heparin(oid)s, standard heparin VII (SH), dermatan sulphate (DS), a low molecular weight fraction of heparin (UMW-H), FragminR (FRA), Org 10172 = low molecular weight heparinoid, the fraction of Org 10172 with high affinity for AT-III (HA-10172) and the low affinity fraction (LA-10172) respectively were examined on in vitro thrombin generation and inactivation.Thrombin inactivation in the presence of either heparin cofactor II (HC-II) or anti-thrombin III (AT-III) was assessed with two newly developed assays using the purified cofactors, thrombin and chromogenic substrate S2238 on microtiterplates. Thrombin generation in the presence of HC-II and AT-III was studied using purified factor Xa, prothrombin and blood platelet lysate and the residual thrombin activity was assessed amidolytically.The inhibition of the compounds on thrombin activity are summarized in the tableThe following conclusions can be drawn:- SH, LMW-H, HA-10172 and FRA potentiate the AT-III mediated inactivation of Ha more strongly than the HC-II mediated inactivation.- DS and LA-10172 show the reverse pattern of inactivation, while Org 10172 potentiates both inactivaton pathways to a similar extent.Thrombin generation in the presence of HC-II is inhibited by mw-heparin(oid)s at approx. 2-5 times lower concentrations than the HC-II mediated thrombin inactivation, while the inhibiting effect of SH in both assays is comparable.AT-III mediated thrombin generation inhibition and AT-III mediated thrombin inactivation is comparable as well for SH, LMW-H and FRA. In contrast, Org 10172 and its subfractions are approx. 10 times more potent on AT-III mediated thrombin generation inhibition than on AT-III mediated thrombin inactivation.Org 10172 shows low anti-thrombin activity and this activity is mainly mediated via FC-II.

Biological Activity of Low-Molecular-Weight Heparin Increases Over 9 Days in Patients Treated for Acute Venous Thromboembolism.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4176-4176
Author(s):  
Job Harenberg ◽  
Kai Bauer ◽  
Claudia Abletshauser
Keyword(s):  
Molecular Weight ◽  
Body Weight ◽  
Venous Thromboembolism ◽  
Low Molecular Weight Heparin ◽  
Factor Xa ◽  
The Body ◽  
Bleeding Complications ◽  
Fixed Dose ◽  
Low Molecular Weight ◽  
Acute Venous Thromboembolism

Abstract Abstract 4176 Subcutaneous (s.c.) body-weight adjusted as well as fixed dose low-molecular-weight heparin (LMWH) for treatment of acute venous thromboembolism (VTE) has been proven to be at least as effective and safe as intravenous unfractionated heparin (UFH). We hypothesized that the anticoagulant effects of LMWH may accumulate during a 9 days fixed dose therapy in patients with acute VTE. Ten patients received 8,000 IU LMWH certoparin bid s.c. for 9±1 days after having given written informed consent. The local ethics committee accepted the study protocol. Serial blood and urine were collected at days 2 and 9 and daily before and after the morning administration of the anticoagulant. The pharmacodynamic parameters were analysed on the anti-factor Xa S2222 method (aXa), heptest, thrombin generation inhibition assay (TGIA), and tissue factor pathway inhibitor activity (TFPI). The area under the activity time curves (AUC) of the parameters was compared at days 2 and 9. LMWH reached steady state levels of the S2222 and heptest assay within 24 hrs. aXa, heptest, TGIA and TFPI were 22%, 38%, 13% and 22% higher at day 9 compared to day 2. The elimination half-lives of aXa and heptest and the aXa excreted into the urine did not differ between days 2 and 9, respectively. The AUC of the aXa did not correlate with the body weight of the patients. Fixed dose, body weight-independent subcutaneous LMWH accumulated to some extend after 9 days of treatment in patients with acute VTE. However, the results of the clinical trials with the LMWH certoparin did not show more bleeding complications compared to UFH. Therapy with LMWH for more than 10 days may require dose reduction. Disclosures: Harenberg: Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Consultancy, Honoraria; Roche Diagnostics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bayer Health Care: Consultancy, Honoraria. Abletshauser:Novartis: Employment.

scholarly journals Standard and Method Independent Units for Heparin Anticoagulant Activities

1993 ◽  
Vol 70 (05) ◽  
pp. 724-728 ◽  
Author(s):  
H C Hemker ◽  
S Béguin
Keyword(s):  
Molecular Weight ◽  
Catalytic Effect ◽  
Anticoagulant Activity ◽  
Quantitative Description ◽  
Factor Xa ◽  
Assay Method ◽  
Low Molecular Weight ◽  
Laboratory Practice ◽  
Low Molecular Weight Heparins ◽  
At Iii

SummaryIt is discussed why the current USP unit of heparin anticoagulant activity necessarily will render inaccurately the anticoagulant activities of low molecular weight heparins. It is shown that the outcome is bound to vary with the method used for comparison of the sample and the standard and with the nature of the standard used. As an alternative we define a unit of heparin in terms of anti-factor Xa- and antithrombin-activity that is independent of the heparin standard and of the assay method, but that is based upon a quantitative description of the catalytic effect of heparin on AT III mediated thrombin- and factor Xa breakdown. Expression of the results of existing anti-factor Xa- and antithrombin tests in terms of these units will allow to express heparin levels in plasma in terms of concentrations of active anticoagulant material. This approach makes it possible to separate heparin pharmacodynamics from heparin pharmacokinetics. Introduction of this unit does not require adaptation of current laboratory practice but changes the way in which the results obtained are expressed.

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.

Effect Of Some Experimental Conditions On The Activity Of A Low Molecular Weight (LMW) Heparin Fraction Compared To A Hight Molecular Weight (HMW) Fraction

1981 ◽  
Author(s):  
M Aiach ◽  
C Nussas ◽  
J Mardiguian
Keyword(s):  
Molecular Weight ◽  
Incubation Time ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Experimental Conditions ◽  
Assay Procedure ◽  
At Iii ◽  
Parabolic Function ◽  
Heparin Activity ◽  
Antiprotease Activity

In this work, we aimed to demonstrate that different methods can give different results when the same pair of heparin samples are compared, even when specific antiprotease assays are performed. For this purpose, the effect of heparin on factor Xa (Xa) or thrombin (IIa) inhibition by antithrombin III (AT III) was examined in the presence of varying amounts of AT III, during different incubation times.The molecular weight of the two heparins were 5,200 (LMW) and 42,000 (HMW). Solutions containing 2 y.g per ml of heparin and a 1.4 to 15 μM freshly purified human AT III were incubated with either bovine Xa or human Ila. After a 20, 30, 60 or 90 secondes incubation at 30° C, the remaining protease activity was measured by the initial velocity of a chromogenic substrate. The method was entirely automated using a reaction rate analyser and an adapted program.The antiprotease activity of the LMW heparin (related to the HMW heparin activity) varied from 0.23 to 0.89 in the anti Xa system, from 0.30 to 0.77 in the anti Ila system. The ratio of LMW to HMW activity was a parabolic function of either AT III concentration or incubation time. No meaning differences were observed between anti Xa and anti Ila activity when the inhibiting capacity was assayed in the same experimental conditions. These results suggest that the relative activities of HMW and LMW fractions depend upon the assay procedure. AT III concentration as well as incubation time are of particular importance.

Measurement of Low Molecular Weight Heparin Ex Vivo Activities in Clinical Laboratories Using Various Anti-Xa Assays: Interlaboratory Variability and Requirement for an Agreed Low Molecular Weight Heparin Standard

1987 ◽  
Vol 58 (03) ◽  
pp. 879-883 ◽  
Author(s):  
P Sié ◽  
M F Aillaud ◽  
D de Prost ◽  
C Droullé ◽  
F Forestier ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Low Molecular Weight Heparin ◽  
Ex Vivo ◽  
Collaborative Study ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Low Molecular Weight Heparins ◽  
Clinical Laboratories ◽  
Interlaboratory Variability ◽  
Factor Xa Inhibition

SummaryThe only sensitive and convenient assay to assess the biological activity of low molecular weight heparins (LMWHs) is based on the potentiation of activated factor Xa inhibition. Several procedures for measuring the socalled anti Xa activity have been proposed. In this collaborative study including eight laboratories, we have used four different assays (three amidolytic and one clotting based methods) for measuring the anti Xa activity of ex vivo samples obtained after injecting three different LMWHs. The dispersion of the results obtained by calibration against standard heparin could be reduced by using any of the three LMWHs for calibration. A coefficient of variation less than 0.20 between values obtained in different laboratories using a variety of methods seems acceptable. However it is necessary to refer to a common international standard for expressing the results in units and to define, for each of the three products, the therapeutic range.

Studies of the Anti-Xa Activity of Human Plasma and Purified Antithrombin III

1979 ◽  
Author(s):  
T.W. Barrowcliffe ◽  
Anne C. Eggleton
Keyword(s):  
Molecular Weight ◽  
Human Plasma ◽  
Aluminium Hydroxide ◽  
Low Molecular Weight Heparin ◽  
Antithrombin Iii ◽  
Factor Xa ◽  
Inhibitory Effect ◽  
Factor Ix ◽  
Low Molecular Weight ◽  
At Iii

When samples of purified antithrombin (At III) were compared to plasma at the same At III concentration, in the absence of heparin, the anti-Xa activity of plasma was considerably higher. In the presence of heparin the anti-Xa activity of purified At III was much greater than plasma. This was shown to be due to an inhibitory effect on the heparin. At III-Factor Xa interaction in plasma which could be removed by absorption with aluminium hydroxide [Al(OH)3]. This inhibition was dependent on the molecular weight of the heparin; low molecular weight heparin was inhibited less than high molecular weight heparin, and this probably accounts for the apparently high anti-Xa activity of low molecular weight heparin.A1(OH)3 absorption of plasma also increased its anti-Xa activity in the absence of heparin. Addition of Factor IX concentrate to the absorbed plasma reduced its anti-Xa activity to that of normal plasma, and studies with purified proteins showed that this effect was due to the prothrombin in the concentrate. The addition of Factor IX concentrate or prothrombin to purified At III did not affect its anti-Xa activity.These results suggest that, in addition to At III, there is another Xa-inhibitor in plasma which competes with prothrombin for binding of Factor Xa.

Biological Activrty and Safety of the Subcutaneous Administration of High Doses of Low Molecular Weight Heparin for 8 Days in Human Volunteers

1989 ◽  
Vol 61 (03) ◽  
pp. 357-362 ◽  
Author(s):  
J Harenberg ◽  
Ch Giese ◽  
C E Dempfle ◽  
G Stehle ◽  
D L Heene
Keyword(s):  
Molecular Weight ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Chromogenic Substrate ◽  
Clotting Time ◽  
Human Volunteers ◽  
Factor Xa Inhibition ◽  
Group 2 ◽  
High Doses ◽  
Group 1

SummaryThis study reports on the biological activity and safety of high dose low molecular weight (LMW) heparin therapy administered by two subcutaneous (s.C.) injections daily for 8 days in healthy human volunteers. Group 1 received 2 × 30 aPTT units LMW heparin/kg bodyweight, and group 2 received 2 × 50 aPTT units/kg per day.In group 1, activated partial thromboplastin time (aPTT) and thrombin clotting time (TCT) were uniformly prolonged by 3-5 sec 4 hrs after s.c. administration of heparin. Heptest coagulation time values were prolonged consistently as well by 57 sec on day 1 to 68 sec on day 8. Factor Xa inhibition measured by the S 2222 chromogenic substrate method continuously increased from 0.16 units/ml on day 1 to 0.28 units/ml on day 8.In group 2 prolongation of a aPTT and TCT values increased from 6 sec on day 1 to 15 sec on day 8 and of Heptest time from 70 sec on day 1 to 110 sec on day 8. S 2222 method showed factor Xa inhibitory activity which increased from 0.5 units/ml on day 1 to 0.75 units/ml on day 8. The clinical tolerance of the treatment was good. No changes in clinical chemistry parameters were detected, except for a reversible increase of serum transaminases.The coagulation studies demonstrate accumulation of LMW heparin when high doses are given twice daily. The half life of LMW heparin of factor Xa inhibition increases with increasing doses.Heptest coagulation values were prolonged to 4-6 times the normal values during administration of heparin. S 2222 chromogenic substrate values were in the same range as upon application of high doses of unfractionated heparin. aPTT and thrombin clotting time values ranged from 1.2 to 1.5 times the starting values.

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