On the Relationship Between Molecular Mass and Anticoagulant Activity in a Low Molecular Weight Heparin (Enoxaparin)

Bendetowicz, A V; Pacaud, Elisabeth; Béguin, S.; Uzan, A.; Hemker, H.C.

doi:10.1055/s-0038-1648493

Cited by 24 publications

(21 citation statements)

References 40 publications

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“…These findings are in agreement with a recent study performed using defibrinated PPP, which also showed that inhibition of the ETP is mainly determined by the concentration of C-domain which contains the AT-binding pentasaccharide and elicits anti-FIIa activity [36]. The importance of the anti-FIIa activity of LMWHs on the inhibition of thrombin generation has also been shown in earlier studies [19,[37][38][39]. The contribution of the anti-FXa activity of LMWHs to their anticoagulant activity is still a controversial subject [40].…”

Section: Discussionsupporting

confidence: 92%

Effect of the anti‐factor Xa and anti‐factor IIa activities of low‐molecular‐weight heparins upon the phases of thrombin generation

Gerotziafas

Petropoulou

Verdy

et al. 2007

Journal of Thrombosis and Haemostasis

102

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To cite this article: Gerotziafas GT, Petropoulou AD, Verdy E, Samama MM, Elalamy I. Effect of the anti-factor Xa and anti-factor IIa activities of low-molecular-weight heparins upon the phases of thrombin generation. J Thromb Haemost 2007; 5: 955-62.Summary. Background: Low-molecular-weight heparins (LMWHs), derived from unfractionated heparin (UFH) by different depolymerization procedures, vary in both their relative abilities to enhance the inhibition of FXa (anti-FXa) and thrombin (anti-FIIa), and in their physicochemical properties. Objective: We aimed to profile the inhibition of thrombin generation induced by bemiparin, enoxaparin, nadroparin, dalteparin and tinzaparin in platelet-rich plasma (PRP), and to compare them with UFH and fondaparinux (a synthetic pentasaccharide that specifically enhances FXa inhibition). Methods: Different LMWHs, UFH or fondaparinux were added to normal PRP. Thereafter, tissue factor-triggered thrombin generation was assessed using the ThrombogramThrombinoscope Ò assay. Results: At equivalent anti-FIIa activity concentrations, LMWHs and UFH exhibited similar inhibitory effects upon thrombin generation. However, when used at equivalent anti-FXa activity concentrations, tinzaparin was significantly more active than the other LMWHs at inhibiting thrombin generation, and had similar activity to that of UFH. Enoxaparin, nadroparin and dalteparin all showed similar inhibitory activities. In these experiments, bemiparin exhibited the lowest inhibitory effect on thrombin generation of all the LMWHs. At 0.1 lg mL -1 (0.093 anti-FXa IU mL -1 ), fondaparinux inhibited the rate of thrombin generation by 50%. A 7-fold higher concentration of fondaparinux was required to inhibit the endogenous thrombin potential by 50%. Conclusions: LMWHs have a variable inhibitory effect on thrombin generation in vitro when compared by anti-FXa activity, but are similar when compared by their anti-FIIa activities. The rate of thrombin generation during the propagation phase, rather than the endogenous thrombin potential, is more sensitive to the anticoagulant activity of fondaparinux and the polysaccharide chains of LMWHs possessing only anti-FXa activity.

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Section: Discussionsupporting

confidence: 92%

Effect of the anti‐factor Xa and anti‐factor IIa activities of low‐molecular‐weight heparins upon the phases of thrombin generation

Gerotziafas

Petropoulou

Verdy

et al. 2007

Journal of Thrombosis and Haemostasis

102

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“…After repeated s.c. injections of IK-SSH (in group III) TFPI increased 5-to 8-fold. This is similar to results obtained with UFH [33,34] and LMWH [35,36]. TFPI also prolongs Heptest and aPTT in vitro [37].…”

Section: Discussionsupporting

confidence: 89%

“…The anticoagulant activity is 19.0 IU/mg (range 17-20; USP potency), antiFXa activity 27.7 IU/mg (range [25][26][27][28][29][30][31][32][33][34][35] and anti-FIIa activity 39.9 anti-thrombin units (ATU)/mg (range 35-60) as declared by the manufacturer.…”

Section: Methodsmentioning

confidence: 99%

Effects of a Supersulfated Low Molecular Weight Heparin (IK-SSH) on Different Hemostatic Parameters

Glusa

Barthel²,

Schenk³

et al. 1998

Pathophysiol Haemos Thromb

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In a phase I trial effects of a new supersulfated low molecular weight heparin (IK-SSH) on different hemostatic parameters were investigated in healthy volunteers. Parameters studied were activated partial thromboplastin time (aPTT), thrombin time, Heptest, anti-activated factor II (anti-FIIa) and anti-activated factor X (anti-FXa) activity, platelet adhesion, platelet count, platelet-induced thrombin generation time (PITT), bleeding time, antithrombin III, fibrinogen and several safety parameters. After single intravenous (i.v.) injections of IK-SSH (0.14, 0.33 and 0.66 mg/kg) aPTT, Heptest and PITT were strongly and dose-dependently prolonged. After ascending subcutaneous (s.c.) doses of IK-SSH (0.33, 0.66 and 1 mg/kg) aPTT, Heptest and PITT were prolonged in a dose-dependent manner. Repeat s.c. injections of 1 mg/kg IK-SSH for 5 days markedly prolonged aPTT, Heptest and PITT. No cumulative effects were observed. Anti-FIIa and anti-FXa activity were not or only slightly increased. Bleeding time, thrombin time and platelet adhesion were not significantly changed after i.v. and s.c. injections of IK-SSH. However, tissue factor pathway inhibitor (TFPI) concentration was markedly increased after each injection of IK-SSH and returned to the preinjection value 24 h later. IK-SSH prolongs aPTT, Heptest and PITT in a similar manner as other low molecular weight heparins but without significantly affecting thrombin time, FIIa and FXa activity. The release of TFPI may well be responsible for the prolongation of aPTT, Heptest and PITT. IK-SSH may be further developed as an antithrombotic agent.

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“…The fig ures for HAM and ACLM content were obtained from previous work [11,12). Because no conclusions as to pharmacological properties should be drawn from an experiment in which each heparin was ad ministered to 1 subject only, we will not reveal the identity of the heparins.…”

Section: Methodsmentioning

confidence: 99%

Determination of the Levels of Unfractionated and Low-Molecular-Weight Heparins in Plasma: Their Effect on Thrombin-Mediated Feedback Reactions in vivo

Hemker¹,

Béguin²,

Bendetowicz³

et al. 1991

Pathophysiol Haemos Thromb

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We define a standard independent unit (SIU) of heparin as that amount that, in plasma containing 1 μmol of ATIII, raises the (pseudo-)first-order breakdown constant of factor Xa by 1 min^-1_• These units measure all material with a high affinity for ATIII (HAM); only material above the critical chain length of 17 monosaccharide units (above critical chain length material; ACLM) catalyzes the inactivation of thrombin. An SIU of ACLM is therefore analogously defined as the amount that, in plasma containing 1 μmol of ATIII, will raise the (pseudo-)first-order breakdown constant of thrombin by 1 min^-1_• Of any given heparin preparation one can determine the specific HAM and ACLM activities in terms of SlU/mg. On the basis of the factor Xa and thrombin breakdown constants found in a plasma sample one can then determine the levels of HAM and ACLM. Preliminary experiments were carried out in plasma samples obtained after subcutaneous injection of unfractionated heparin (UFH) and of two types of low-molecular-weight heparin (LMWH). About three times more of UFH activity than of LMWH activity has to be injected to obtain the same levels of ACLM in the plasma. Only with the LMWHs significant amounts of BCLM are found, which rises higher and persists longer than the ACLM. We determined the course of thrombin generation in platelet-rich plasma (PRP) and in platelet-poor plasma (PPP), as well as in the PPP factor Xa generation curve and the course of prothrombin conversion. The observed inhibitions correlated much better with the levels of ACLM than with those of below critical chain length material. The difference between UFH and LMWHs can therefore not be explained in terms of antithrombin and anti-factor-Xa activity. The essential difference between UFH and LMWH appears in the feedback effect of thrombin in PRP, where thrombin generation is both inhibited and retarded by LMWH, while it is only retarded but hardly inhibited by UFH.

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On the Relationship Between Molecular Mass and Anticoagulant Activity in a Low Molecular Weight Heparin (Enoxaparin)

Cited by 24 publications

References 40 publications

Effect of the anti‐factor Xa and anti‐factor IIa activities of low‐molecular‐weight heparins upon the phases of thrombin generation

Effect of the anti‐factor Xa and anti‐factor IIa activities of low‐molecular‐weight heparins upon the phases of thrombin generation

Effects of a Supersulfated Low Molecular Weight Heparin (IK-SSH) on Different Hemostatic Parameters

Determination of the Levels of Unfractionated and Low-Molecular-Weight Heparins in Plasma: Their Effect on Thrombin-Mediated Feedback Reactions in vivo

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