Are molecular weight and anti-Xa activity sufficient to predict the antithrombotic power of heparin fractions

Doutremépuich, Christian; Bousquet, F; Toulemonde, F

doi:10.1016/0049-3848(86)90172-6

Cited by 7 publications

(2 citation statements)

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“…22,23 The action of heparin fractions or fragments appears not only directed against Factor Xa, but most probably against both Factor Xa and thrombin. In the literature, this can be found especially in Hemker et al's work.…”

Section: Discussionmentioning

confidence: 99%

Laboratory Control of Heparin and Heparin Fragment Treatment: An Experimental Study

Doutremépuich¹,

Lalanne²,

Guyot³

et al. 1989

Semin Thromb Hemost

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Native heparin is an heterogeneous substance with molecular weight between 2000 and 30,000 d. Low molecular weight heparin (LMWH) obtained after chemical and enzymatic reactions from unfractionated heparin 1,2 has low anticoagulant effect, but high antithrombotic activity, which may be higher than standard heparin activity. 3-5 Until now, plasmatic anti-Xa activity was the only biologic test used to control LMW heparin therapeutic activity in humans. However, researchers have recently demonstrated that LMW heparin antithrombotic effect was not correlated to plasmatic anti-Xa activity. [6][7][8][9][10][11] In view of the very interesting prospects offered by the LMWH therapeutic advantages, 4,12-15 it was necessary to determine which biologic test best adapted to reflect the ex vivo antithrombotic activity of fractions and, then, to give a better clinical control. MATERIAL AND METHODSThe heparin and LMWH used included, unfractionated heparin (Calciparine lot 301.1 176 USP/mg, 170 ICU/mg) and LMWH (CY 222, lot 81.051 DP, 25 USP/mg, 250 ICU mg), with a molecular weight 2500 d. These drugs were obtained from Institut Choay (Paris, France), and their activities established from standard curves (3rd heparin standard, WHO).The placebo used was isotonic saline solution. Animals (n = 198) were Wistar male rats from Janvier Breeding Center (Berthevin, France). Mean weight was 250 gr. Experimental venous thrombosis 16-18 was induced as follows: After fasting for 12 hours, the rats were anesthetized subcutaneously by ketamine injection (100 mg/kg body weight). The inferior vena cava was dissected free, and a ligature was applied just below the left renal venous branch at time zero. Two hours after ligature the two products to be tested were randomly administered: four heparin groups, four CY 222 groups, and one placebo group. Each group included 22 rats. The different dosages tested were: 4, 2, 1, and 0.5 mg/kg body weight, and 1 ml saline solution was injected as placebo.At 6 hours, the rats were anesthetized again. After intracardiac blood sampling, plasma was prepared from 9% citrated blood for ex vivo study. Then the thrombi were extracted.After sampling, each thrombus was placed in a drying cupboard at 40°C for 24 hours. Then the dried clot was weighed.Biologic activity was tested with different methods and compared with the standard curve established from the 3rd international heparin standard (WHO): activated partial thromboplastin time (APTT; CK Prest, Stago, Asnieres, France); Anti-Xa (Heptest [HPT], Haemachem, St. Louis, MO; Hepaclot [HPC], Stago; chromogenic method [SUB] CBS 31.39 Stachrom Heparin, Stago); Anti-IIa (chromogenic method [SUB] CBS 34.47 Hepachrom Ha, Stago). The method 19 for the measurement of fibrinolytic activity was as follows:1. Preparation of euglobulin solution: lots prepared from each animal's plasma were suspended in 1.5 ml of distilled water, then kept at 4°C for 10 minutes after

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Section: Discussionmentioning

confidence: 99%

Laboratory Control of Heparin and Heparin Fragment Treatment: An Experimental Study

Doutremépuich¹,

Lalanne²,

Guyot³

et al. 1989

Semin Thromb Hemost

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“…It is possible that factor Xa can be 'protected' from the inhibi tor action of the heparin-antithrombin III complex in prothrombinase by binding to phospholipid [47], platelets [48][49][50], or tis sue factor [48,51]. Some other factors, pos sibly a molecular-weight-dependent vascular wall interaction or a heparin-binding protein such as placental protein 5, may also contrib ute to the antithrombotic effect of glucosaminoglycans [40-42, [52][53][54][55][56]. In short, all these findings refute the earlier hypothesis that the antithrombotic properties of low-molecularweight heparins are mainly due to their abil ity to catalyze the inhibition of factor Xa.…”

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confidence: 99%

Heparin and Thrombosis: A Seventy Year Long Story

Verstraete

1990

Pathophysiol Haemos Thromb

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Heparin was a chance discovery made by a medical student who was searching for a clot-promoting activity in various tissue extracts and found an inhibitor of coagulation. It has taken 20 years from the discovery of heparin in 1916 to its therapeutic use (1937). This long delay was mainly due to problems with the purification and extraction on large scale of the active material. Standard unfractionated heparin is a mixture of mucopolysaccharide chains of various length that may range from 5,000 to 30,000 daltons. Heparin is only effective as an anticoagulant in the presence of a plasma protein, termed antithrombin III, with which it forms a complex. High- and low-affinity heparin are two types that readily bind or do not bind to antithrombin III. The pharmacokinetics of unfractionated heparin are compatible with a model based on the combination of a saturable and a linear mechanism. Low-molecular-weight heparins have been produced by a variety of techniques, and their molecular weights range from 3,000 to 9,000 daltons. These preparations have a ratio of anti-Xa activity to anti-II activity of approximately 4, while it is 1 for unfractionated heparin. After intravenous administration of low-molecular-weight heparins, the half-life of the antifactor Xa activity is considerably longer than for unfractionated heparin, while the anti-factor II half-lives are similar. In contrast to unfractionated heparin, low-molecular-weight heparin is virtually completely absorbed after subcutaneous administration, and its biological half-life is almost twice as long. In spite of certain differences with regard to the ratio between factor Xa and Ila inhibition, the various low-molecular-weight preparations show a rather similar absorption pattern. Low-molecular-weight heparins interact less with platelets than unfractionated heparin; nevertheless, a lower bleeding incidence with low-molecular-weight heparin for equivalent antithrombotic efficacy has yet to be established in man.

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Time courses of the antithrombotic effects, bleeding enhancing effects and interactions with factors Xa and thrombin after administration of iow molecular weight heparinoid Org 10172 or heparin to rats

Hobbelen¹,

Vogel²,

Meuleman³

1987

Thrombosis Research

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Are molecular weight and anti-Xa activity sufficient to predict the antithrombotic power of heparin fractions

Cited by 7 publications

References 4 publications

Laboratory Control of Heparin and Heparin Fragment Treatment: An Experimental Study

Laboratory Control of Heparin and Heparin Fragment Treatment: An Experimental Study

Heparin and Thrombosis: A Seventy Year Long Story

Time courses of the antithrombotic effects, bleeding enhancing effects and interactions with factors Xa and thrombin after administration of iow molecular weight heparinoid Org 10172 or heparin to rats

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