Conjectures and Refutations on the Mode of Action of Heparins

Low-molecular-weight heparins (LMWHs), like unfractionated heparin (UFH), exert their action primarily by accelerating the interaction between antithrombin (AT) and thrombin. At the levels of aXa activity that are attained in human pharmacology, it does not cause significant (>15%) inhibition of the clotting system. The essential differences between LMWHs and UFH are: (a) LMWHs attain higher plasma concentrations after subcutaneous injection (high bioavailability), and (b) in contrast to LMWHs, UFH contains very large heparin molecules with a putative hemorrhagic action. The reputedly higher aXa activity of LMWH can be shown to be largely due to the absence of Ca2+ using the current laboratory methods to estimate this activity. Via this artifact the apparently high aXa activity of LMWHs is correlated but not related to their favorable pharmacokinetic properties. Consequently dosage guidelines for the use of different LMWHs cannot be based upon their aXa activity. Until better laboratory methods are available, clinical results are the only reliable guideline to heparin dosage.

[1]  H. Hemker,et al.  The Activity of Heparin in the Presence and Absence of Ca2+ Ions; why the Anti-Xa Activity of LMW Heparins Is about two Times Overestimated , 1993, Thrombosis and Haemostasis.

[2]  H. Hemker,et al.  Inhibition of Prothrombinase by Antithrombin-Heparin at a Macroscopic Surface , 1995, Thrombosis and Haemostasis.

[3]  H. Hemker,et al.  Pharmacokinetics and Pharmacodynamics of a Low Molecular Weight Heparin (Enoxaparin) after Subcutaneous Injection, Comparison with Unfractionated Heparin – A Three Way Cross Over Study in Human Volunteers , 1994, Thrombosis and Haemostasis.

[4]  L. Verschoor,et al.  Elimination of high affinity heparin fractions and their anticoagulant and lipase activity. , 1984, Blood.

[5]  S. Béguin,et al.  Changes In The Antithrombin III Activity At The Interface Plasma-Phospholipids , 1981, Thrombosis and Haemostasis.

[6]  K. F. Yee,et al.  Heparin and Partial Thromboplastin Time: an International Survey , 1980, British journal of haematology.

[7]  J. Hirsh,et al.  The disappearance of a low molecular weight heparin fraction (CY 216) differs from standard heparin in rabbits. , 1987, Thrombosis research.

[8]  T. Barrowcliffe,et al.  Low-affinity heparin potentiates the action of high-affinity heparin oligosaccharides. , 1984, Thrombosis research.

[9]  H. Hemker,et al.  The Mode of Action of CY 216 and CY 222 in Plasma , 2022 .

[10]  M. Samama,et al.  ANTITHROMBOTIC ACTIVITY OF A SYNTHETIC HEPARIN PENTASACCHARIDE IN A RABBIT STASIS THROMBOSIS MODEL USING DIFFERENT THROMBOGENIC CHALLENGES , 1987, Thrombosis and Haemostasis.

[11]  J. Dawes,et al.  Low-Affinity Material Does not Contribute to the Antithrombotic Activity of Orgaran (Org 10172) in Human Plasma , 1994, Thrombosis and Haemostasis.

[12]  H. Hemker,et al.  The Effect of Trace Amounts of Tissue Factor on Thrombin Generation in Platelet Rich Plasma, its Inhibition by Heparin , 1989, Thrombosis and Haemostasis.

[13]  T. Barrowcliffe,et al.  High and Low Affinity Heparin Compared with Unfractionated Heparin as Antithrombotic Drugs , 1984, Thrombosis and Haemostasis.

[14]  M. Lie,et al.  Assay of heparin in plasma using a chromogenic substrate for activated factor X. , 1976, Thrombosis research.

[15]  T. Barrowcliffe,et al.  The Relative Antithrombotic Effectiveness of Heparin, a Low Molecular Weight Heparin, and a Pentasaccharide Fragment in an Animal Model , 1989, Thrombosis and Haemostasis.

[16]  H. Hemker,et al.  The Mode of Action of Heparin in Plasma , 1988, Thrombosis and Haemostasis.

[17]  Low molecular weight heparin. , 1992 .

[18]  H. Hemker,et al.  The Action of a Synthetic Pentasaccharide on Thrombin Generation in Whole Plasma , 1989, Thrombosis and Haemostasis.

[19]  H. Hemker,et al.  The Mode of Action of CY216 and CY222 in Plasma , 1992, Thrombosis and Haemostasis.

[20]  S. Wessler,et al.  Identity of plasma-activated factor X inhibitor with antithrombin 3 and heparin cofactor. , 1971, The Journal of biological chemistry.

[21]  H. Hemker,et al.  Factor IXa Inhibition Contributes to the Heparin Effect , 1991, Thrombosis and Haemostasis.

[22]  V. Kakkar,et al.  Can the haemorrhagic component of heparin be identified? Or an attempt at clean thinking on a dirty drug. , 1996, Haemostasis.

[23]  J. Hirsh,et al.  The inhibition of thrombin-dependent positive-feedback reactions is critical to the expression of the anticoagulant effect of heparin. , 1987, The Biochemical journal.

[24]  V. Kakkar,et al.  The Routine Determination of the Endogenous Thrombin Potential, First Results in Different Forms of Hyper- and Hypocoagulability , 1997, Thrombosis and Haemostasis.

[25]  R. Bertina,et al.  Monitoring Heparin Therapy: Relationships between the Activated Partial Thromboplastin Time and Heparin Assays Based on Ex-Vivo Heparin Samples , 1990, Thrombosis and Haemostasis.

[26]  H. Hemker,et al.  Continuous Registration of Thrombin Generation in Plasma, Its Use for the Determination of the Thrombin Potential , 1993, Thrombosis and Haemostasis.

[27]  T. Seya,et al.  Assay of Heparin in Plasma Using a Chromogenic Substrate and It’s Clinical Applications , 1979 .

[28]  M. Petitou,et al.  Structure-activity relationship in heparin: a synthetic pentasaccharide with high affinity for antithrombin III and eliciting high anti-factor Xa activity. , 1983, Biochemical and biophysical research communications.

[29]  V. Kakkar,et al.  Molecular weight dependence of the anticoagulant properties of heparin: intravenous and subcutaneous administration of fractionated heparins to man. , 1979, Thrombosis research.

[30]  J. Hirsh,et al.  Comparison of the in vivo hemorrhagic and antithrombotic effects of a low antithrombin-III affinity heparin fraction. , 1982, Thrombosis research.

[31]  L. Verschoor,et al.  Elimination of high affinity heparin fractions and their anticoagulant and lipase activity , 1984 .

[32]  S. Wessler,et al.  Biological properties of the naturally occurring plasma inhibitor to activated factor X. , 1971, The Journal of biological chemistry.

[33]  H. Hemker,et al.  The thrombin potential a Parameter to Assess the effect of antithrombotic drugs on thrombin generation , 1990 .

[34]  H. Hemker,et al.  The Mode of Action of Low Molecular Weight Heparin Preparation (PK10169) and Two of its Major Components on Thrombin Generation in Plasma , 1989, Thrombosis and Haemostasis.

[35]  V. Kakkar,et al.  Low molecular weight versus standard heparin for prevention of venous thromboembolism after major abdominal surgery , 1993, The Lancet.

[36]  H. Hemker,et al.  Standard and Method Independent Units for Heparin Anticoagulant Activities , 1993, Thrombosis and Haemostasis.

[37]  D. Lane,et al.  Anticoagulant activities of heparin oligosaccharides and their neutralization by platelet factor 4. , 1984, The Biochemical journal.

[38]  J. Weitz.  Low-molecular-weight heparins. , 1997, The New England journal of medicine.

[39]  H. Hemker,et al.  Interindividual variation in relationships between plasma heparin concentration and the results of five heparin assays. , 1982, Clinica chimica acta; international journal of clinical chemistry.

[40]  O. Odegård,et al.  Heparin cofactor activity measured with an amidolytic method. , 1975, Thrombosis research.