Fixed dosage of low‐molecular‐weight heparins causes large individual variation in coagulability, only partly correlated to body weight

Summary.  Backgrounds: Low‐molecular‐weight heparins (LMWHs) are routinely given without the control of their effect on coagulation. The endogenous thrombin potential (ETP) is a sensitive detector of the heparin effect. Question: What is the interindividual variation in TG after a fixed dose of LMWH in normal volunteers, is it explained by variation in weight? Methods: Subcutaneous (s.c.) injection, in 12 healthy volunteers, of 9000 aXa‐units of unfractionated heparin (UFH) and of three heparins with narrow MW distribution around 10.5, 6.0 and 4.5 kD. Measurement of anti‐thrombin (aIIa) and antifactor Xa (aXa)‐activities and ETP at 11 time points over 24 h. Results: The coefficient of variation (CV) of the AUCs of aXa‐ and aIIa‐activities is 50% for UFH and 22–37% for LMWHs. Because of the hyperbolic form of the dose–response curve, the CV of the inhibition of the ETP is lower: 32% for UFH and 13–21% for the LMWHs. Fixed dosage of LMWH caused under‐dosage in 10–13% of the samples and over‐dosage in 5–11%. High or low response is an individual property independent of the type of heparin injected and only partially explained by variation in body weight. Conclusion: Optimized individual dosage of LMWH is possible through recognition of high and low responders, which requires one measurement of the heparin concentration or, preferably, the heparin effect on the ETP, 2–5 h after a first injection.

[1]  S. Béguin,et al.  Thrombin generation for the control of heparin treatment, comparison with the activated partial thromboplastin time , 2004, Journal of thrombosis and haemostasis : JTH.

[2]  M. Kovacs,et al.  Body weight does not predict for anti-Xa levels after fixed dose prophylaxis with enoxaparin after orthopedic surgery. , 1998, Thrombosis research.

[3]  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.

[4]  H. Hemker,et al.  The inhibition of blood coagulation by heparins of different molecular weight is caused by a common functional motif—the C‐domain , 2003, Journal of thrombosis and haemostasis : JTH.

[5]  Georgios Nakos,et al.  Monitoring , 1976, Encyclopedia of the UN Sustainable Development Goals.

[6]  P. de Moerloose,et al.  Is laboratory monitoring of low‐molecular‐weight heparin therapy necessary? No , 2004, Journal of thrombosis and haemostasis : JTH.

[7]  I. Gouin-Thibault,et al.  Safety Profile of Different Low-Molecular Weight Heparins Used at Therapeutic Dose , 2005, Drug safety.

[8]  D. Anderson,et al.  Comparing the quality of oral anticoagulant management by anticoagulation clinics and by family physicians: a randomized controlled trial. , 2003, CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne.

[9]  J. Ennker,et al.  INR Self-Management Permits Lower Anticoagulation Levels After Mechanical Heart Valve Replacement , 2003, Circulation.

[10]  M. Wolzt,et al.  The inhibitory effect of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, compared with enoxaparin and r-hirudin on ex vivo thrombin generation in human plasma. , 2004, Thrombosis research.

[11]  M. Samama,et al.  Correlation between anti-Xa and occurrence of thrombosis and haemorrhage in post-surgical patients treated with either Logiparin (LMWH) or unfractionated heparin. Post-surgery Logiparin Study Group. , 1992, Thrombosis research.

[12]  E. Ohman,et al.  Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. , 1998, Chest.

[13]  H. Hemker,et al.  Phenotyping the Clotting System , 2002, Thrombosis and Haemostasis.

[14]  R. al Dieri,et al.  Laboratory assessment of antithrombotic therapy: what tests and if so why? , 1997, Haemostasis.

[15]  By,et al.  A THROMBIN GENERATION TEST THE APPLICATION IN HAEMOPHILIA AND THROMBOCYTOPENIA , 2022 .

[16]  H. Hemker,et al.  Mode of action of enoxaparin in plasma. , 1990, Acta chirurgica Scandinavica. Supplementum.

[17]  A. Fung,et al.  A randomized trial of patient self-managed versus physician-managed oral anticoagulation. , 2004, The Canadian journal of cardiology.

[18]  D. Fitzmaurice,et al.  Patient self‐management of oral anticoagulation and external quality assessment procedures , 2003, British journal of haematology.

[19]  G. L. Reijnierse,et al.  Monitoring of unfractionated heparin with the activated partial thromboplastin time: determination of therapeutic ranges. , 2002, Thrombosis research.

[20]  T. Baglin,et al.  Clinical measurement of thrombin generation by calibrated automated thrombography requires contact factor inhibition , 2004, Journal of thrombosis and haemostasis : JTH.

[21]  F. Depasse,et al.  Comparison of the effect of fondaparinux and enoxaparin on thrombin generation during in-vitro clotting of whole blood and platelet-rich plasma , 2004, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[22]  J. Harenberg.  Is laboratory monitoring of low‐molecular‐weight heparin therapy necessary? Yes , 2004, Journal of thrombosis and haemostasis : JTH.

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

[24]  Stig L Boström,et al.  Effects of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, and dalteparin on the endogenous thrombin potential in venous blood from healthy male subjects , 2003, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[25]  R. White,et al.  Low‐Molecular‐Weight Heparins: Are they all the Same? , 2003, British journal of haematology.

[26]  E. Ohman,et al.  Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. , 2001, Chest.

[27]  P. Ockelford,et al.  Audit of community‐based anticoagulant monitoring in patients with thromboembolic disease: is frequent testing necessary? , 2004, Internal medicine journal.

[28]  H. Hemker,et al.  Pharmacokinetic and Pharmacodynamic Characterization of a Medium-Molecular-Weight Heparin in Comparison with UFH and LMWH , 2002, Seminars in thrombosis and hemostasis.

[29]  T. Barrowcliffe.  Monitoring haemophilia severity and treatment: new or old laboratory tests? , 2004, Haemophilia : the official journal of the World Federation of Hemophilia.

[30]  S. Alban,et al.  Plasma Levels of Total and Free Tissue Factor Pathway Inhibitor (TFPI) as Individual Pharmacological Parameters of Various Heparins , 2001, Thrombosis and Haemostasis.

[31]  M. Alhenc-Gelas,et al.  Adjusted Versus Fixed Doses of the Low-Molecular-Weight Heparin Fragmin in the Treatment of Deep Vein Thrombosis , 1994, Thrombosis and Haemostasis.

[32]  J. Hirsh,et al.  Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. , 2004, Chest.

[33]  T. Lindahl,et al.  A Critical Evaluation of the Prothrombin Time for Monitoring Oral Anticoagulant Therapy , 2003, Pathophysiology of Haemostasis and Thrombosis.

[34]  T. Morris,et al.  Pharmacokinetics of UH and LMWH are similar with respect to antithrombin activity. , 2005, Thrombosis research.

[35]  J. Sixma,et al.  Identification of risk factors for bleeding during treatment of acute venous thromboembolism with heparin or low molecular weight heparin. , 1991, Blood.

[36]  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.

[37]  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.

[38]  Flora Peyvandi,et al.  The Thrombogram in Rare Inherited Coagulation Disorders: Its Relation to Clinical Bleeding , 2002, Thrombosis and Haemostasis.

[39]  M. Laposata,et al.  College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy: the clinical use and laboratory monitoring of low-molecular-weight heparin, danaparoid, hirudin and related compounds, and argatroban. , 1998, Archives of pathology & laboratory medicine.

[40]  L. Norgren,et al.  Enoxaparin effect depends on body‐weight and current doses may be inadequate in obese patients , 2003, The British journal of surgery.

[41]  J. Renberg.  Is laboratory monitoring of low-molecular-weight heparin therapy necessary ? , 2004 .

[42]  J. Herbert,et al.  New synthetic heparin mimetics able to inhibit thrombin and factor Xa. , 1999, Bioorganic & medicinal chemistry letters.

[43]  E. Nutescu,et al.  Dosing and Monitoring of Low‐Molecular‐Weight Heparins in Special Populations , 2001, Pharmacotherapy.

[44]  S. Béguin,et al.  Clinical studies and thrombin generation in patients homozygous or heterozygous for the G20210A mutation in the prothrombin gene. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[45]  H C Hemker,et al.  Thrombin Generation in Plasma: Its Assessment Via the Endogenous Thrombin Potential , 1995, Thrombosis and Haemostasis.

[46]  M. Haugh,et al.  Factor Xa inhibition: correlation between the plasma levels of anti-Xa activity and occurrence of thrombosis and haemorrhage. , 1993, Haemostasis.