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.

A NEW ONE STAGE CLOTTING ASSAY FOR HEPARIN AND LOW MOLECULAR WEIGHT HEPARINS

1987 ◽  
Author(s):  
Ch Giese ◽  
A Knodler ◽  
R Zimmermann ◽  
J Harenberg
Keyword(s):  
Molecular Weight ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Chromogenic Substrate ◽  
Clotting Time ◽  
Low Molecular Weight Heparins ◽  
One Stage ◽  
High Preference ◽  
Coagulation Tests ◽  
Plasma Assay

Heparin and its low molecular weight (LMW) derivatives are usually measured by chromogenic or fluorogenic synthetic substrate assays and by coagulation tests. Since the activated partial thromboplastin time (aPTT) and thrombin clotting time (TCT) are insensitive to LMW heparins, we report here of data obtained with heptest, a new one stage modification of the original heparin in plasma assay of Yin. The assay was compared with the antifactor Xa chromogenic substrate S2222 method, the TCT and aPTT tests in 100 patients receiving unfractionated pig intestinal mucosa heparin and 100 patients treated with low molecular weight heparin Kabi 2165. The results indicate a high correlation between the heptest and the anti Xa chromogenic substrate method, whereas the correlations were lower for the aPTT and TCT. correlations with LMW heparinThe lowest detection limit of the heptest is 0,005 heparin units per ml plasma. The test is very sensitive, simple, highly reproducable and reliable clotting assay for unfractionated and low molecular weight heparins in human plasma. The test detects with high preference the inhibition on factor Xa but also the other anticoagulant effects on die coagulation tractors.

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.

EXPERIMENTAL THROMBUS FORMATION AND HAEMOSTASIS OF DIFFERENT LOW MOLECULAR WEIGHT HEPARINS AND DOSAGES

1987 ◽  
Author(s):  
R A Zimmerman ◽  
C T Rieger ◽  
K Hübner ◽  
C W Harenber ◽  
W Kübler
Keyword(s):  
Molecular Weight ◽  
Thrombus Formation ◽  
Factor Xa ◽  
Bleeding Complications ◽  
Maximum Effect ◽  
Low Molecular Weight ◽  
Antithrombotic Effect ◽  
Low Molecular Weight Heparins ◽  
Antithrombotic Activity ◽  
Thrombosis Model

Low molecular weight heparin induces a higher anti factor Xa (a-Xa) and a lower antithrombin activity in plasma in comparison to conventional heparin. From this constellation a more pronounced antithrombotic effect and a minor incidence of bleeding Complications has been suggested.Therefore the antithrombotic activity of heparins was studied in a standardized experimental thrombosis model in rabbits. Three low molecular weight heparins with a mean molecular weight of 4.200 (heparin I),4.000 (heparin II),4.600 Dalton (heparin III) and standard heparin were tested at different dosages in 120 experiments. In the first series the dose of 60 anti Xa units (a-Xa U) given initially and 60 a-Xa U/kg/h induced a reduction of the thrombus size by 40 % (heparin I),37 % (heparin II) and 53 % (heparin III) and a prolongation of the aPTT to 45 (heparin I),66 (heparin II) and 79 sec (heparin III). The a-Xa activity was minor than 0.1 U/ml. In the second series heparins were given to aim at an a-Xa activity of 0.2-0.3 U/ml. Thereby the thrombus formation could be reduced by 84 % (heparin I), 62 % (heparin II) and 39 % (heparin III). aPTT and a-Xa activity were measured at 65.5 sec and 0.22 a-Xa U/ml (heparin I),67.3 sec and 0.3 a-Xa U/ml (heparin II) and 67.5 and 0.31 a-Xa U/ml (heparin III),respectively. In the third series the increase of the a-Xa activity to more than 0.3 U/ml showed no further reduction of the thrombus formation by heparin I, while heparins II and III already at this level reachedthe antithrombotic activity of heparin I.Our data on three different low molecular weight heparins demonstrate that already a heparin level ranging at a minimal a-Xa activity induces a clear and statistically significant antithrombotic effect. A higher heparin dosage with higher a-Xa activity increases the antithrombitic effect. At a level of 0.2-0.3 a-Xa U/ml an obvious and maximum effect could be reached, but the further elevation of the a-Xa activity produced no further antithrombotic action.

Defibrotide Augments the Anticoagulant Actions of Heparin and Low Molecular Weight Heparins

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4086-4086
Author(s):  
Jawed Fareed ◽  
Omer Iqbal ◽  
Debra Hoppensteadt ◽  
Cafer Adiguzel ◽  
Massimo Iacobelli ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Whole Blood ◽  
Thrombin Generation ◽  
Synergistic Effects ◽  
Low Molecular Weight ◽  
Inhibitory Effects ◽  
Clotting Time ◽  
Low Molecular Weight Heparins ◽  
Significant Prolongation ◽  
Antithrombotic Effects

Abstract Defibrotide represents a polydeoxyribonucleotide derived antithrombotic and antiischemic drug, which has been used in the management of vascular disorders and is currently being developed in other clinical indications. Defibrotide is a polyelectrolyte-based agent with target effects on endothelium, platelets, and blood cells. In addition, the aptameric consensus sequences in the nucleotides exhibit inhibitory effects towards thrombin and related proteases. In the anticoagulant assays defibrotide exhibits relatively weak effects (<5 USP U/mg). These studies were undertaken to study whether there is an interaction between defibrotide and unfractionated heparin (UFH) in various systems of anticoagulation. The interaction of defibrotide with commercially available low molecular weight heparins (LMWHs), enoxaparin and dalteparin, was also studied. For the first investigation, to evaluate the effect of defibrotide on the anticoagulant effects of UFH, native whole blood freshly drawn from human volunteers (n = 20) was supplemented with UFH at a fixed concentration of 5 μg/mL (0.8 U/mL), and graded amounts of defibrotide were added in a concentration range of 12.5 – 100 μg/mL. The whole blood celite Activated Clotting Time test (ACT) and the thrombin generation markers fibrinopeptide A (FPA), thrombin-antithrombin complex (TAT), and prothrombin fragment 1.2 (F1.2) were measured. Parallel controls with saline were included. While defibrotide did not produce a significant prolongation of the ACT compared to saline (128 ± 9 s vs 132 ± 7 s), it produced a concentration-dependent increase in the heparinized whole blood leading to an almost doubling of the anticoagulant action of UFH (248 ± 19 s vs 418 ± 21 s). Additional studies carried out by varying the concentrations of the two agents also revealed supraadditive to synergistic effects. Defibrotide also augmented the inhibitory effects of UFH on thrombin generation markers in a concentration-dependent fashion. Similar studies carried out with the two LMWHs did not reveal a similar interaction in the anticoagulant assays such as the ACT; however, significant interactions between defibrotide and the LMWHs were observed in the thrombin generation studies. For the second investigation, studies were carried out using plasma samples collected from heparinized patients (aPTT of 50 – 100 s). These studies also revealed that supplementation of defibrotide augmented the anticoagulant effects of UFH in a concentration-dependent fashion. While defibrotide at 12.5 μg/mL did not significantly increase the aPTT of normal plasma, when supplemented to heparinized plasmas (n = 50 with aPTT of 64.6 ± 14.0 s) it produced a strong prolongation of the clotting time (96.1 ± 20.6 s). In the third investigation, animal models of thrombosis including the rat jugular vein clamping model, demonstrated an augmentation of the antithrombotic effects of intravenously administered UFH by defibrotide. However, no augmentation of the hemorrhagic effect was observed in the rat tail bleeding model. These studies demonstrate that defibrotide exhibits a strong anticoagulant interaction with UFH and to a lesser degree LMWH. While the combination of defibrotide and UFH exhibits enhanced anticoagulant/antithrombotic activities, it does not exhibit any alteration of the hemorrhagic profile. These studies clearly suggest that defibrotide can be combined with UFH to achieve a superior anticoagulant approach with better safety/efficacy profile.

scholarly journals The anti-factor Xa range for low molecular weight heparin thromboprophylaxis

2015 ◽  
Vol 7 (4) ◽  
Author(s):  
Matthew Y. Wei ◽  
Salena M. Ward
Keyword(s):  
Molecular Weight ◽  
Low Molecular Weight Heparin ◽  
Dose Adjustment ◽  
Factor Xa ◽  
Research Data ◽  
Target Range ◽  
Low Molecular Weight ◽  
Low Molecular Weight Heparins ◽  
Therapeutic Doses ◽  
Venous Thromboses

Low molecular weight heparins (LMWHs) are now the mainstay option in the prevention and treatment of venous thromboembolism. In some patients receiving therapeutic doses of LMWH, activity can be measured by quantifying the presence of Anti-factor Xa (AFXa) for dose adjustment. However, currently there are no guidelines for LMWH monitoring in patients on thromboprophylactic, doses, despite certain patient populations may be at risk of suboptimal dosing. This review found that while the AFXa ranges for therapeutic levels of LMWHs are relatively well defined in the literature, prophylactic ranges are much less clear, thus making it difficult to interpret current research data. From the studies published to date, we concluded that a reasonable AFXa target range for LMWH deep venous thromboses prophylaxis might be 0.2-0.5 IU/mL.

PHARMACOLOGIC INEQUIVALENCE OF LOW MOLECULAR WEIGHT HEPARINS

1987 ◽  
Author(s):  
J Fareed ◽  
J M Walenga ◽  
D Hoppensteadt ◽  
R N Emanuele ◽  
A Racanell
Keyword(s):  
Molecular Weight ◽  
Animal Models ◽  
Comparative Study ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Low Molecular Weight Heparins ◽  
In Vivo Test ◽  
In Vitro Effects

Compared to unfractionated heparin, low molecular weight heparins (LMWHs) have been found to exhibit marked variations in in vitro effects due to variations in molecular weight and structure. Moreover, when the in vitro potency of these agents is equally adjusted bypharmacopeial assay (current and proposed) wide variations in the in vivo responses have been noted. These variations were strongly dependent on the route of administration. Utilizing defined animal models, a systematic comparative study of the in vivo responses of seven commercial LMWHs was undertaken. Choay Fraxiparine (CY 216} Choay CY 222, NovoLHN, Kabi Fragmin, Opocrin 2123 (OP), Hepar RD 11885 (RD), Pharmuka Enoxaparin (PK) and Choay porcine mucosal heparin (PMH) were tested in identical settings at equigravimetric dosages. The graded results are given in the following.Wide variations in the in vivo pharmacologic and toxicity responseswere noted suggesting that different LMWHs are not bioequivalent at equigravimetric levels. When these responses were expressed in anti-factor Xa or pharmacopeial potency, these differences were further magnified. The clinically reported dosimetric and safety problems may be minimized by profiling LMWHs in defined in vivo test systems to optimize their safety/efficacy ratio.

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.

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