Conjectures and Refutations on the Mode of Action of Heparins

Béguin, S.; Welzel, D; Dieri, Raed Al; Hemker, H.C.

doi:10.1159/000022497

Cited by 11 publications

(6 citation statements)

References 24 publications

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“…In contrast to UFH, it does not contain molecules with MW > 15 kDa, which on good grounds can be thought to be responsible for hemorrhagic complications. 13 Its specific aXa and aIIa activities are 10% higher than those of UFH. This indicates that during the production of MMWH the content of high-affinity material remains constant.…”

Section: Discussionmentioning

confidence: 97%

“…Hemker and colleagues 13,14 surmised that the main antithrombotic activity of a heparin would be localized in molecules with a definite aIIa activity and yet small enough to have high bioavailability. Moreover, experiments demonstrated that the aXa activity of heparin is only a partial expression of the therapeutic potential and that the antithrombotic effect improves with increasing chain length of heparin fragments.…”

Section: Discussionmentioning

confidence: 99%

“…This is suggested to be due to the six times higher plasma concentrations of FX compared with FV, so that 90% inhibition of FXa is required to obtain just 50% inhibition of the thrombin-generating prothrombinase. 13 In contrast to this, heparin delays as well as decreases thrombin generation in whole blood. 11 Heparin inhibits both thrombin and FXa by catalyzing their inactivation by antithrombin (AT).…”

mentioning

confidence: 99%

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Pharmacokinetic and Pharmacodynamic Characterization of a Medium-Molecular-Weight Heparin in Comparison with UFH and LMWH

Alban

Welzel²,

Hemker³

2002

Semin Thromb Hemost

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Despite the well-established medical use of heparins, the question arises whether the efficacy-safety ratio of the available heparins can still be improved. There{ore, a medium-molecular-weight heparin (MMWH), a new heparin with ^î average molecular weight of 10.5 kDa and a narrow molecular weight range (9.5 to 11.5 kDa) was developed. Its in vitro activities amount to 174.9 anti-factor Xa (aXa) U/mg and 170.0 antithrombin (aIIa) U/mg. In the presented randomized, double-blind, cross-over study in healthy volunteers, the pharmacokinetics and pharmacodynamics of MMWH are compared with those of an unfractionated heparin (UFH) and a low-molecular-weight heparin (LryVMH; enoxaparin). After subcutaneous administration of 9000 aXa-U of either heparin in 16 volunteers, the prolongation ofthe activated partial thromboplastin time (aPTT), the aXa activity, and the aIIa activities were determined at 11 time points spread over 24 hours after injection. The ex vivo analysis revealed striking pharmacodynamic and pharmacokinetic differences between the three heparins. UFH had the lowest bioavailability regarding the aPTl aXa, and aIIa activities. Enoxaparin exhibited only low aIIa activity but the highest aXa activity. Unlike UFH and enoxaparin, MMWH showed a high recovery of aIIa activiry which suggests that it combines the high potency to inhibit thrombin that characterizes UFH with the high bioavailability of the LMWHs. Consequently, substantially lower doses are needed to bring about effects comparable to those ofUFH and LMWFI.KEYWORDS: U nf ractionated hepari n, medi u m-molecu la r-weight hepa ri n, lowmolecular-weight heparin, pharmacokinetics, pharmacodynamics Objectives: Upon completion of this article, the reader should O" rO," to (1)list some of the properties of a newly developed medium-molecular-weight heparin as compared with unfractionated and low-molecular-weight heparins and (2) describe some of the findings related to the pharmacokinetics and pharmacodynamics of the new compound

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Pharmacokinetic and Pharmacodynamic Characterization of a Medium-Molecular-Weight Heparin in Comparison with UFH and LMWH

Alban

Welzel²,

Hemker³

2002

Semin Thromb Hemost

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“…However concentrations of F X (120 nmol/L) are normally 6 times higher in plasma compared with F V (20 nmol/L). Thus, in the course of the thrombin generation process, F Va is the rate limiting factor (7). When the test plasma is prediluted sevenfold, and then substituted with F V to a normal concentration both these clotting factors will be present in equimolar concentrations.…”

Section: Discussionmentioning

confidence: 99%

Effect of Melagatran on Prothrombin Time Assays Depends on the Sensitivity of the Thromboplastin and the Final Dilution of the Plasma Sample

Mattsson¹,

Menschiek-Lundin²,

Wåhlander³

et al. 2001

Thromb Haemost

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SummaryProthrombin time (PT) assays are clotting methods that measure the activity of vitamin K-dependent coagulation factors (F) II, VII, and X. There are three main types of PT assays in general usage, namely the Quick assay, Owren’s assay and PT dry chemistry test cards. PT assays were initially developed to monitor dose-adjustments of vitamin K antagonists such as warfarin. The aim of the present study was to investigate whether commercially available PT assays are suitable for evaluating the anticoagulant activity of direct thrombin inhibitors. Melagatran, a reversible direct thrombin inhibitor, was added to human plasma at concentrations ranging from 0.1 to 2.0 μmol/l. Seventeen different commercially available PT kits were used, including thirteen Quick reagents, two Owren reagents and two PT test cards. The sensitivity of the different reagents, expressed as the concentration of melagatran that doubled the prothrombin time (IC50) varied widely, with Thromboplastin S and Thromboplastin HS being the most sensitive (IC50 = 0.9 μmol/l). The reagents with apparently the lowest sensitivity were the two Owren reagents Nycotest PT and SPA 50 with an IC50 of 2.2 and 2.9 μmol/L, respectively. This is most likely due to a higher dilution of melagatran in these assays compared to the dilution in the Quick assays. The results were also dependent on the International Sensitivity Index (ISI) of each reagent. The concentration of melagatran that produced an International Normalized Ratio (INR) of 2 was calculated from dose-response curves for each assay, and these results revealed that reagents with a high ISI value gave an INR of 2 at much lower concentrations of melagatran (0.5-0.7 μmol/L) than those with an ISI-values around one (0.9-1.2 μmol/L). It was found that INR depends not only on the plasma concentration of melagatran, but also on the sensitivity of the PT reagent and on the final dilution of the plasma sample in the prothrombin time assay. Thus, since the same melagatran concentration can be associated with widely varying PT/INR results depending on the specific assay used it is concluded that PT assays and INR can not be used to monitor melagatran activity.

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“…As a consequence, this effect of heparin is inversely influenced by two MWdependent parameters. Therefore, after s.c. administration, a heparin with high MW, but not containing so called extra large molecule (25), should exhibit the best TFPI releasing potency.…”

Section: Discussionmentioning

confidence: 99%

Plasma Levels of Total and Free Tissue Factor Pathway Inhibitor (TFPI) as Individual Pharmacological Parameters of Various Heparins

Alban¹,

Gastpar²

2001

Thromb Haemost

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SummaryThe release of circulating tissue factor pathway inhibitor (TFPI) into plasma by heparins is thought to contribute to their overall anti-thrombotic activity. In the presented study in healthy volunteers, we measured the heparin-induced increase of circulating total and free TFPI antigen and the aXa- and aIIa activity after subcutaneous (s.c.) injection of 9000 aXa-U of four different heparins: unfractionated heparin (UFH) (13.0 kDa), a medium molecular weight (MW) heparin with a narrow MW range (HF) (10.5 kDa), certoparin (6.0 kDa) and enoxaparin (4.5 kDa). Based on the administration of equi-active aXa doses, certoparin induced the highest increase in total TFPI determined as AUC (p <0.01). The lowest effect was observed for UFH (p <0.0001). However, the AUC of released free TFPI significantly increased in the order: enoxaparin < UFH < certoparin < HF, showing MW dependency with the exception of UFH. Comparing the effects of equi-gravimetric heparin doses, the MW dependency becomes even more pronounced. The mismatch of UFH may be due to its poor bioavailability, which becomes obvious from its low ex vivo aXa activity. In contrast to the TFPI releasing potency, the ex vivo aXa activity continuously decreased with increasing MW. Although the ex vivo aIIa activity of the heparins increased in the same order like the release of free TFPI, there was no clear correlation. This is attributed to the fact that the aIIa activity of heparin is not only dependent on the MW, but, in contrast to its TFPI releasing effect, also on the percentage of material with high affinity to AT. In conclusion, besides the aXaand aIIa activity, the TFPI releasing effect of heparins is an additional parameter of their individual pharmacological profile.

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Conjectures and Refutations on the Mode of Action of Heparins

Cited by 11 publications

References 24 publications

Pharmacokinetic and Pharmacodynamic Characterization of a Medium-Molecular-Weight Heparin in Comparison with UFH and LMWH

Pharmacokinetic and Pharmacodynamic Characterization of a Medium-Molecular-Weight Heparin in Comparison with UFH and LMWH

Effect of Melagatran on Prothrombin Time Assays Depends on the Sensitivity of the Thromboplastin and the Final Dilution of the Plasma Sample

Plasma Levels of Total and Free Tissue Factor Pathway Inhibitor (TFPI) as Individual Pharmacological Parameters of Various Heparins

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