Heparin and Low-Molecular-Weight Heparin Mechanisms of Action, Pharmacokinetics, Dosing, Monitoring, Efficacy, and Safety

Chest - Tập 119 Số 1 - Trang 64S-94S - 2001
Jack Hirsh1, Theodore E. Warkentin, Stephen G. Shaughnessy, Sridhar Anand, Jonathan L. Halperin, Robert Raschke, Christopher B. Granger, E. Magnus Ohman, James E. Dalen
1Hamilton Civics Hospitals Research Centre, ON, Canada.

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Tài liệu tham khảo

Rosenberg, 1979, Correlation between structure and function of heparin, Proc Natl Acad Sci USA, 76, 1218, 10.1073/pnas.76.3.1218

McLean, 1916, The thromboplastic action of cephalin, Am J Physiol, 41, 250, 10.1152/ajplegacy.1916.41.2.250

Brinkhous, 1939, The inhibition of blood clotting: an unidentified substance which acts in conjunction with heparin to prevent the conversion of prothrombin into thrombin, Am J Physiol, 125, 683, 10.1152/ajplegacy.1939.125.4.683

Abildgaard, 1968, Highly purified antithrombin III with heparin cofactor activity prepared by disc electrophoresis, Scand J Clin Lab Invest, 21, 89, 10.3109/00365516809076981

Rosenberg, 1994, The heparin-antithrombin system: a natural anticoagulant mechanism, 837

Lindahl, 1979, Structure of the antithrombin-binding site of heparin, Proc Natl Acad Sci U S A, 76, 3198, 10.1073/pnas.76.7.3198

Casu, 1981, The structure of heparin oligosaccharide fragments with high anti-(factor Xa) activity containing the minimal antithrombin III-binding sequence, Biochem J, 97, 599, 10.1042/bj1970599

Choay, 1981, Structural studies on a biologically active hexasaccharide obtained from heparin, Ann NY Acad Sci, 370, 644, 10.1111/j.1749-6632.1981.tb29770.x

Vuillemenot, 1999, Efficacy of a synthetic pentasaccharide, a pure factor Xa inhibitor, as an antithrombotic agent: a pilot study in the setting of coronary angioplasty, Thromb Haemost, 81, 214, 10.1055/s-0037-1614445

Herbert, 1998, Biochemical and pharmacological properties of SANORG 34006, a potent and long-acting synthetic pentasaccharide, Blood, 91, 4197, 10.1182/blood.V91.11.4197

Lam, 1976, The separation of active and inactive forms of heparin, Biochem Biophys Res Commun, 69, 570, 10.1016/0006-291X(76)90558-1

Andersson, 1976, Anticoagulant properties of heparin fractionated by affinity chromatography on matrix-bound antithrombin III and by gel filtration, Thromb Res, 9, 575, 10.1016/0049-3848(76)90105-5

Tollefsen, 1982, Heparin cofactor II: purification and properties of a heparin-dependent inhibitor of thrombin in human plasma, J Biol Chem, 257, 2162, 10.1016/S0021-9258(18)34900-7

Lindahl, 1984, Extension and structural variability of the antithrombin-binding sequence in heparin, J Biol Chem, 259, 12368, 10.1016/S0021-9258(18)90755-6

Lane, 1984, Anticoagulant activities of heparin oligosaccharides and their neutralization by platelet factor 4, Biochem J, 218, 725, 10.1042/bj2180725

Oosta, 1981, Multiple functional domains of the heparin molecule, Proc Natl Acad Sci U S A, 78, 829, 10.1073/pnas.78.2.829

Nesheim, 1983, A simple rate law that describes the kinetics of the heparin-catalyzed reaction between antithrombin III and thrombin, J Biol Chem, 258, 14708, 10.1016/S0021-9258(17)43920-2

Ofosu, 1987, The inhibition of thrombin-dependent feedback reactions is critical to the expression of anticoagulant effects of heparin, Biochem J, 243, 579, 10.1042/bj2430579

Ofosu, 1989, Unfractionated heparin inhibits thrombin-catalyzed amplification reactions of coagulation more efficiently than those catalyzed by factor Xa, Biochem J, 257, 143, 10.1042/bj2570143

Beguin, 1988, The mode of action of heparin in plasma, Thromb Haemost, 60, 457, 10.1055/s-0038-1646990

Lupu, 1999, Cellular effects of heparin on the production and release of tissue factor pathway inhibitor in human endothelial cells, Arterioscler Thromb Vasc Biol, 19, 2251, 10.1161/01.ATV.19.9.2251

Altman, 1998, Efficacy of unfractionated heparin, low molecular weight heparin, and both combined for releasing total and free tissue factor pathway inhibitor, Haemostasis, 28, 229

Gori, 1999, Tissue factor reduction and tissue factor pathway inhibitor release after heparin administration, Thromb Haemost, 81, 589, 10.1055/s-0037-1614530

Andersson, 1979, Molecular weight dependency of the heparin potentiated inhibition of thrombin and activated factor X: effect of heparin neutralization in plasma, Thromb Res, 5, 531, 10.1016/0049-3848(79)90159-2

Harenberg, 1990, Pharmacology of low molecular weight heparins, Semin Thromb Hemost, 16, 12

Johnson, 1976, The molecular weight range of commercial heparin preparations, Carbohydr Res, 51, 119, 10.1016/S0008-6215(00)84041-0

Sobel, 1991, Heparin inhibition of von Willebrand factor-dependent platelet function in vitro and in vivo, J Clin Invest, 87, 1787, 10.1172/JCI115198

Eika, 1971, Inhibition of thrombin-induced aggregation of human platelets in heparin, Scand J Hematol, 8, 216, 10.1111/j.1600-0609.1971.tb01976.x

Kelton, 1980, Bleeding associated with antithrombotic therapy, Semin Hematol, 17, 259

Heiden, 1977, Impairment by heparin of primary hemostasis and platelet (14C)5-hydroxytryptamine release, Br J Hematol, 36, 427, 10.1111/j.1365-2141.1977.tb00666.x

Fernandez, 1986, Hemorrhagic doses of heparin and other glycosaminoglycans induce a platelet defect, Thromb Res, 43, 491, 10.1016/0049-3848(86)90094-0

Blajchman, 1989, Effects of unfractionated heparin, dermatan sulfate and low molecular weight heparin on vessel wall permeability in rabbits, Ann NY Acad Sci, 556, 245, 10.1111/j.1749-6632.1989.tb22507.x

Ockelford, 1982, Comparison of the in vivo hemorrhagic and antithrombotic effects of a low antithrombin III affinity heparin fraction, Thromb Res, 27, 679, 10.1016/0049-3848(82)90006-8

Clowes, 1977, Suppression by heparin of smooth muscle cell proliferation in injured arteries, Nature, 265, 625, 10.1038/265625a0

Shaughnessy, 1995, The effects of low molecular weight and standard heparin on calcium loss from the fetal rat calvaria, Blood, 86, 1368, 10.1182/blood.V86.4.1368.bloodjournal8641368

Bhandari, 1998, The effects of standard and low molecular weight heparin on bone nodule formation in vitro, Thromb Haemost, 80, 413, 10.1055/s-0037-1615222

Castellot, 1982, Inhibition of vascular smooth muscle cell growth by endothelial cell-derived heparin: possible role of a platelet endoglycosidase, J Biol Chem, 257, 11256, 10.1016/S0021-9258(18)33750-5

Hull, 1986, Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis, N Engl J Med, 315, 1109, 10.1056/NEJM198610303151801

Hirsh, 1976, Heparin kinetics in venous thrombosis and pulmonary embolism, Circulation, 53, 691, 10.1161/01.CIR.53.4.691

Young, 1992, Heparin binding to plasma proteins, an important mechanism for heparin resistance, Thromb Haemost, 67, 639, 10.1055/s-0038-1648515

Barzu, 1985, Binding and endocytosis of heparin by human endothelial cells in culture, Biochem Biophys Acta, 845, 196, 10.1016/0167-4889(85)90177-6

de Swart, 1982, Kinetics of intravenously administered heparin in normal humans, Blood, 60, 1251, 10.1182/blood.V60.6.1251.1251

Olsson, 1963, The elimination from plasma of intravenous heparin: an experimental study on dogs and humans, Acta Med Scand, 173, 619, 10.1111/j.0954-6820.1963.tb17446.x

Bjornsson, 1982, Heparin kinetics determined by three assay methods, Clin Pharmacol Ther, 31, 104, 10.1038/clpt.1982.16

Glimelius, 1978, Binding of heparin on the surface of cultured human endothelial cells, Thromb Res, 12, 773, 10.1016/0049-3848(78)90271-2

Mahadoo, 1977, Vascular sequestration of heparin, Thromb Res, 12, 79, 10.1016/0049-3848(78)90087-7

Friedman, 1974, Studies on the heparin sulphamidase activity from rat spleen: intracellular distribution and characterization of the enzyme, Biochem J, 139, 699, 10.1042/bj1390699

Dawes, 1979, Catabolism of low-dose heparin in man, Thromb Res, 14, 845, 10.1016/0049-3848(79)90004-5

McAllister, 1966, Heparin metabolism: isolation and characterization of uroheparin, Nature, 212, 293, 10.1038/212293a0

Bara, 1985, Comparative pharmacokinetics of low molecular weight heparin (PK 10169) and unfractionated heparin after intravenous and subcutaneous administration, Thromb Res, 39, 631, 10.1016/0049-3848(85)90244-0

Turpie, 1989, Comparison of high-dose with low-dose subcutaneous heparin to prevent left ventricular mural thrombosis in patients with acute transmural anterior myocardial infarction, N Engl J Med, 320, 352, 10.1056/NEJM198902093200604

Pini, 1990, Subcutaneous vs intravenous heparin in the treatment of deep venous thrombosis: a randomized clinical trial, Thromb Haemost, 64, 222, 10.1055/s-0038-1647289

Raschke, 1996, The effectiveness of implementing the weight-based heparin nomogram as a practice guideline, Arch Intern Med, 156, 1645, 10.1001/archinte.1996.00440140067006

EPIC Investigators, 1994, Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty, N Engl J Med, 330, 956, 10.1056/NEJM199404073301402

EPILOG Investigators, 1997, Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization, N Engl J Med, 336, 1689, 10.1056/NEJM199706123362401

Cruickshank, 1991, A standard heparin nomogram for the management of heparin therapy, Arch Intern Med, 151, 333, 10.1001/archinte.1991.00400020085018

Camilleri, 1988, Thrombolyse intraveineuse dans l'infarctus du myocarde. Influence de la qualite de l'antiocoagulation sur le taux de recidives precoces d'angor ou d'infarctus, Arch Mal Coeur, 81, 1037

Kaplan, 1987, Role of heparin after intravenous thrombolytic therapy for acute myocardial infarction, Am J Cardiol, 59, 241, 10.1016/0002-9149(87)90792-2

de Bono, 1992, Early intravenous heparin improves coronary patency in thrombolysis with recombinant human tissue-type plasminogen activator: European Cooperative Study Group, Br Heart J, 67, 122, 10.1136/hrt.67.2.122

Arnout, 1992, Correlation between the intensity of heparinization and patency of the infarct-related coronary artery after treatment of acute myocardial infarction with alteplase (rt-PA), J Am Coll Cardiol, 20, 513, 10.1016/0735-1097(92)90001-4

Basu, 1972, A prospective study of value of monitoring heparin treatment with the activated partial thromboplastin time, N Engl J Med, 287, 324, 10.1056/NEJM197208172870703

Levine, 1994, A randomized trial comparing activated thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin, Arch Intern Med, 154, 49, 10.1001/archinte.1994.00420010073009

Anand, 1996, The relation between the activated partial thromboplastin time response and recurrence in patients with venous thrombosis treated with continuous intravenous heparin, Arch Intern Med, 156, 1677, 10.1001/archinte.1996.00440140107010

Anand, 1999, Recurrent venous thrombosis and heparin therapy: an evaluation of the importance of early activated partial thromboplastin times, Arch Intern Med, 159, 2029, 10.1001/archinte.159.17.2029

GUSTO Investigators, 1993, An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction, N Engl J Med, 329, 673, 10.1056/NEJM199309023291001

Brill-Edwards, 1993, Establishing a therapeutic range for heparin therapy, Ann Intern Med, 119, 104, 10.7326/0003-4819-119-2-199307150-00002

Levine, 1989, Heparin-induced bleeding, 517

Morabia, 1986, Heparin doses and major bleedings, Lancet, 1, 1278, 10.1016/S0140-6736(86)91421-2

GUSTO IIA Investigators, 1994, Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes, Circulation, 90, 1631, 10.1161/01.CIR.90.4.1631

Antman, 1994, Hirudin in acute myocardial infarction: safety report from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A Trial, Circulation, 90, 1624, 10.1161/01.CIR.90.4.1624

The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb investigators, 1996, A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes, N Engl J Med, 335, 775, 10.1056/NEJM199609123351103

Antman, 1996, Hirudin in acute myocardial infarction: Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B trial, Circulation, 94, 911, 10.1161/01.CIR.94.5.911

Landefeld, 1987, Identification and preliminary validation of predictors of major bleeding in hospitalized patients starting anticoagulant therapy, Am J Med, 82, 703, 10.1016/0002-9343(87)90004-0

Fennerty, 1985, Audit of control of heparin treatment, BMJ, 290, 27, 10.1136/bmj.290.6461.27-a

Reilly, 1993, Intravenous heparin dosing: patterns and variations in internist's practices, J Gen Intern Med, 8, 536, 10.1007/BF02599634

Wheeler, 1988, Physician practices in the treatment of pulmonary embolism and deep venous thrombosis, Arch Intern Med, 148, 1321, 10.1001/archinte.1988.00380060085018

LeBras, 1992, Standardization of heparin therapy improves efficacy [letter], Arch Intern Med, 152, 2140, 10.1001/archinte.152.10.2140

Raschke, 1993, The weight-based heparin dosing nomogram compared with a “standard care” nomogram, Ann Intern Med, 119, 874, 10.7326/0003-4819-119-9-199311010-00002

Hull, 1992, Optimal therapeutic level of heparin therapy in patients with venous thrombosis, Arch Intern Med, 152, 1589, 10.1001/archinte.1992.00400200027006

Elliot, 1994, Physician-guided treatment compared with a heparin protocol for deep vein thrombosis, Arch Intern Med, 154, 999, 10.1001/archinte.1994.00420090081008

Flaker, 1994, Use of a standardized heparin nomogram to achieve therapeutic anticoagulation after thrombolytic therapy in myocardial infarction, Arch Intern Med, 154, 1492, 10.1001/archinte.1994.00420130084011

Gunnarsson, 1995, Appropriate use of heparin: empiric vs nomogram-based dosing, Arch Intern Med, 155, 526, 10.1001/archinte.1995.00430050104011

Schaefer, 1996, Rapid heparin anticoagulation: use of a weight-based nomogram, Am Fam Physician, 54, 2517

Kershaw, 1994, Computer-assisted dosing of heparin, Arch Intern Med, 154, 1005, 10.1001/archinte.1994.00420090089009

Mungall, 1994, A prospective randomized comparison of the accuracy of computer-assisted versus GUSTO nomogram-directed heparin therapy, Clin Pharmacol Ther, 55, 591, 10.1038/clpt.1994.73

Braunwald, 1994, Diagnosing and managing unstable angina: Agency for Health Care Policy and Research, Circulation, 90, 613, 10.1161/01.CIR.90.1.613

US Agency for Health Care Policy and Research. Unstable angina: diagnosis and management; clinical practice guideline No. 10. May 1994 (amended). Bethesda, MD: National Library of Medicine. DOCLINE Information: CAT/9422862. AHCPR Publication No. 94–0602

Berry, 1998, A model for collaboration in quality improvement projects: implementing a weight-based heparin dosing nomogram across an integrated health care delivery system, Joint Comm J Qual Improv, 24, 459

Hochman, 1999, A new regimen for heparin use in acute coronary syndromes, Am Heart J, 138, 313, 10.1016/S0002-8703(99)70118-3

Schlicht, 1997, Reevaluation of a weight-based heparin dosing nomogram: is institution-specific modification necessary?, Ann Pharmacother, 31, 1454, 10.1177/106002809703101202

Olson, 1998, College of American Pathologists Conference XXXI on Laboratory Monitoring of Anticoagulant Therapy: laboratory monitoring of unfractionated heparin therapy, Arch Pathol Lab Med, 122, 782

Hollingsworth, 1995, The successful application of a heparin nomogram in a community hospital, Arch Intern Med, 155, 2095, 10.1001/archinte.1995.00430190089012

Brown, 1997, An evaluation of empiric vs nomogram-based dosing of heparin in an intensive care unit, Crit Care Med, 25, 1534, 10.1097/00003246-199709000-00021

Raschke, 1996, The effectiveness of implementing the weight-based heparin nomogram as a practice guideline, Arch Intern Med, 156, 1645, 10.1001/archinte.1996.00440140067006

OASIS-2 Investigators, 1999, Effect of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularisation procedures in patients with acute myocardial ischemia without ST elevation: a randomised trial, Lancet, 353, 429, 10.1016/S0140-6736(98)07332-2

Antman, 1999, Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q wave myocardial infarction, Circulation, 100, 1593, 10.1161/01.CIR.100.15.1593

Raschke, 1991, Clinical use of the heparin nomogram [letter], Arch Intern Med, 151, 2318, 10.1001/archinte.1991.00400110144033

Levine, 1991, Clinical use of the heparin nomogram [letter], Arch Intern Med, 151, 2321, 10.1001/archinte.1991.00400110144034

Anand, 1997, Management of iliofemoral thrombosis in a pregnant patient with heparin resistance, Arch Intern Med, 157, 815, 10.1001/archinte.1997.00440280157015

Hirsh, 1994, Treatment of venous thromboembolism, 1346

Doyle, 1987, Adjusted subcutaneous heparin or continuous intravenous heparin in patients with acute deep venous thrombosis: a randomized trial, Ann Intern Med, 107, 441, 10.7326/0003-4819-107-4-441

Prandoni, 1992, Comparison of subcutaneous low molecular weight heparin with intravenous standard heparin in proximal deep vein thrombosis, Lancet, 339, 441, 10.1016/0140-6736(92)91054-C

Hull, 1990, Heparin for five days as compared with ten days in the initial treatment of proximal venous thrombosis, N Engl J Med, 322, 1260, 10.1056/NEJM199005033221802

Whitfield, 1983, Effect of pregnancy on the relationship between concentration and anticoagulant action of heparin, Clin Pharmacol Ther, 34, 23, 10.1038/clpt.1983.123

Lijnen, 1983, Heparin binding properties of human histidine-rich glycoprotein: mechanism and role in the neutralization of heparin in plasma, J Biol Chem, 258, 3803, 10.1016/S0021-9258(18)32737-6

Marci, 1993, A review of the clinical indications for the plasma heparin assay, Am J Clin Pathol, 99, 546, 10.1093/ajcp/99.5.546

Edson, 1967, Kaolin partial thromboplastin time: high levels of procoagulants producing short clotting times or masking deficiencies of other procoagulants or low concentrations of anticoagulants, J Lab Clin Med, 70, 463

Levine, 1984, The effect of platelet factor 4 on assays of plasma heparin, Br J Hematol, 57, 585, 10.1111/j.1365-2141.1984.tb02936.x

Fisher, 1992, Heparin resistance after aprotinin, Lancet, 340, 1230, 10.1016/0140-6736(92)92935-9

Becker, 1990, Intravenous nitroglycerin-induced heparin resistance: a qualitative antithrombin III abnormality, Am Heart J, 119, 1254, 10.1016/S0002-8703(05)80172-3

Raschke, 1991, Heparin-nitroglycerin interaction [letter], Am Heart J, 121, 1849

Cirisano, 1996, Apparent heparin resistance from elevated factor VIII in a patient with postoperative deep venous thrombosis: a case report, J Reprod Med, 41, 191

Stirling, 1984, Haemostasis in normal pregnancy, Thromb Haemost, 52, 176, 10.1055/s-0038-1661167

Chiu, 1977, Relationship between the anticoagulant and antithrombotic effects of heparin in experimental venous thrombosis, Blood, 49, 171, 10.1182/blood.V49.2.171.171

Gallus, 1987, The relative contributions of antithrombin III during heparin treatment and of clinically recognizable risk factors to early recurrence of venous thromboembolism, Thromb Res, 46, 539, 10.1016/0049-3848(87)90155-1

Marciniak, 1977, Heparin-induced decrease in circulating antithrombin III, Lancet, 2, 581, 10.1016/S0140-6736(77)91429-5

Hirsh, 1998, Heparin and low-molecular weight heparin: mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy and safety, Chest, 114, 489S, 10.1378/chest.114.5_Supplement.489S

Young, 1994, Ex-vivo and in-vitro evidence that low molecular weight heparins exhibit less binding to plasma proteins than unfractionated heparin, Thromb Haemost, 71, 300, 10.1055/s-0038-1642434

Lane, 1989, Heparin binding and neutralizing protein, 363

Visentin, 1994, Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells, J Clin Invest, 93, 81, 10.1172/JCI116987

Greinacher, 1994, Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4-heparin complex as the major antigen, Thromb Haemost, 71, 247

Hirsh, 1992, Low molecular weight heparin, Blood, 79, 1, 10.1182/blood.V79.1.1.1

Hirsh, 1999, New antithrombotic agents, Lancet, 353, 1431, 10.1016/S0140-6736(98)09233-2

Marciniak, 1973, Factor Xa inactivation by antithrombin III: Evidence for biological stabilization of factor Xa by factor V-phospholipid complex, Br J Haematol, 24, 391, 10.1111/j.1365-2141.1973.tb01662.x

Walker, 1979, The effects of phospholipid and factor Va on the inhibition of factor Xa by antithrombin III, Biochem Biophys Res Commun, 90, 641, 10.1016/0006-291X(79)91283-X

Lane, 1986, Neutralization of heparin-related saccharides by histidine-rich glycoprotein and platelet factor 4, J Biol Chem, 261, 3980, 10.1016/S0021-9258(17)35610-7

Weitz, 1990, Clot-bound thrombin is protected from inhibition by heparin-antithrombin but is susceptible to inactivation by antithrombin III-independent inhibitors, J Clin Invest, 86, 385, 10.1172/JCI114723

Hogg, 1989, Fibrin monomer protects thrombin from inactivation by heparin-antithrombin III: implications for heparin efficacy, Proc Natl Acad Sci U S A, 86, 3619, 10.1073/pnas.86.10.3619

Becker, 1999, Exosites 1 and 2 are essential for protection of fibrin-bound thrombin from heparin-catalyst inhibition by antithrombin and heparin cofactor II, J Biol Chem, 274, 6226, 10.1074/jbc.274.10.6226

Bar-Shavit, 1989, Binding of thrombin to subendothelial extracellular matrix: protection and expression of functional properties, J Clin Invest, 84, 1096, 10.1172/JCI114272

Heras, 1989, Effects of thrombin inhibition on the development of acute platelet-thrombus deposition during angioplasty in pigs: heparin versus recombinant hirudin, a specific thrombin inhibitor, Circulation, 79, 657, 10.1161/01.CIR.79.3.657

Agnelli, 1990, The comparative effects of recombinant hirudin (CGP 39393) and standard heparin on thrombus growth in rabbits, Thromb Haemost, 63, 204, 10.1055/s-0038-1645195

Salzman, 1975, Management of heparin therapy, N Engl J Med, 292, 1046, 10.1056/NEJM197505152922002

Glazier, 1976, Randomized prospective trial of continuous vs intermittent heparin therapy, JAMA, 236, 1365, 10.1001/jama.1976.03270130027021

Mant, 1977, Haemorrhagic complications of heparin therapy, Lancet, 1, 1133, 10.1016/S0140-6736(77)92388-1

Wilson, 1979, Heparin therapy: a randomized prospective study, Am Heart J, 97, 155, 10.1016/0002-8703(79)90349-1

Fagher, 1981, Heparin treatment of deep vein thrombosis, Acta Med Scand, 210, 357, 10.1111/j.0954-6820.1981.tb09831.x

Wilson, 1981, Heparin therapy in venous thromboembolism, Am J Med, 70, 808, 10.1016/0002-9343(81)90537-4

Krahenbuehl, 1979, Traitement heparinique: comparaison entre les voies d'admistration intraveineuse et souscutanee, Schweiz Med Wochenschr, 109, 1322

Bentley, 1980, An objective study of alternative methods of heparin administration, Thromb Res, 18, 1771, 10.1016/0049-3848(80)90182-6

Andersson, 1982, Subcutaneous administration of heparin: a randomised comparison with intravenous administration of heparin to patients with deep vein thrombosis, Thromb Res, 27, 631, 10.1016/0049-3848(82)90001-9

Walker, 1987, Subcutaneous calcium heparin versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legs: a multicenter prospective randomized trial, Br J Med, 294, 1189, 10.1136/bmj.294.6581.1189

Gould, 1999, Low molecular weight heparins compared with unfractionated heparin for the treatment of acute deep venous thrombosis: a meta-analysis of randomized controlled trials, Ann Intern Med, 130, 800, 10.7326/0003-4819-130-10-199905180-00003

Gallus, 1986, Safety and efficacy of warfarin started early after submassive venous thrombosis or pulmonary embolism, Lancet, 2, 1293, 10.1016/S0140-6736(86)91431-5

Clagett, 1988, Prevention of venous thromboembolism in general surgical patients, Ann Surg, 208, 227, 10.1097/00000658-198808000-00016

Collins, 1988, Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin, N Engl J Med, 318, 1162, 10.1056/NEJM198805053181805

Kakkar, 1975, Prevention of fatal postoperative pulmonary embolism by low doses of heparin, Lancet, 2, 45

Gallus, 1989, Overview of the management of thrombotic disorders, Semin Thromb Hemost, 15, 99, 10.1055/s-2007-1002692

Halkin, 1982, Reduction of mortality in general medical inpatients by low-dose heparin prophylaxis, Ann Intern Med, 96, 561, 10.7326/0003-4819-96-5-561

Leyvraz, 1983, Adjusted versus fixed dose subcutaneous heparin in the prevention of deep vein thrombosis after total hip replacement, N Engl J Med, 309, 154, 10.1056/NEJM198310203091605

Powers, 1989, A randomized trial of less intense postoperative warfarin or aspirin therapy in the prevention of venous thromboembolism after surgery for fractured hip, Arch Intern Med, 149, 771, 10.1001/archinte.1989.00390040013003

Francis, 1983, Two-step warfarin therapy: prevention of postoperative venous thrombosis without excessive bleeding, JAMA, 249, 374, 10.1001/jama.1983.03330270038029

Oler, 1996, Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina: a meta-analysis, JAMA, 276, 811, 10.1001/jama.1996.03540100055028

PRISM PLUS Study Investigators, 1998, Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-q-wave myocardial infarction, N Engl J Med, 338, 1488, 10.1056/NEJM199805213382102

CAPTURE Investigators, 1997, Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE Study, Lancet, 349, 1429, 10.1016/S0140-6736(96)10452-9

Collins, 1997, Aspirin, heparin, and fibrinolytic therapy in suspected acute myocardial infarction, N Engl J Med, 336, 847, 10.1056/NEJM199703203361207

The RISC Group, 1990, Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease, Lancet, 336, 827, 10.1016/0140-6736(90)92336-G

Theroux, 1988, Aspirin, heparin, or both to treat acute unstable angina, N Engl J Med, 319, 1105, 10.1056/NEJM198810273191701

Theroux, 1992, Reactivation of unstable angina after the discontinuation of heparin, N Engl J Med, 327, 141, 10.1056/NEJM199207163270301

Serneri, 1990, Effect of heparin, aspirin, or alteplase in reduction of myocardial ischemia in refractory unstable angina, Lancet, 335, 615, 10.1016/0140-6736(90)90407-V

Theroux, 1993, Aspirin versus heparin to prevent myocardial infarction during the acute phase of unstable angina, Circulation, 99, 2045, 10.1161/01.CIR.88.5.2045

MacMahon, 1988, Reduction in major morbidity and mortality by heparin in acute myocardial infarction [abstract], Circulation, 78, 98

Serneri, 1987, Effectiveness of low-dose heparin in prevention of myocardial reinfarction, Lancet, 1, 937, 10.1016/S0140-6736(87)90291-1

The SCATI (Studio sulla Calciparina nell'Angina e nella Thrombosi Ventricolare nell'Infarto) Group, 1989, randomised controlled trial of subcutaneous calcium-heparin in acute myocardial infarction, Lancet, 2, 182

Folts, 1976, Platelet aggregation in partially obstructed vessels and its elimination with aspirin, Circulation, 54, 365, 10.1161/01.CIR.54.3.365

1992, ISIS-3: a randomized comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial infarction, Lancet, 339, 753, 10.1016/0140-6736(92)91893-D

O'Connor, 1994, A randomized trial of intravenous heparin in conjunction with anistreplase (anisolyated plasminogen streptokinase activator complex) in acute myocardial infarction: the Duke University Clinical Cardiology Study (DUCCS), J Am Coll Cardiol, 29, 11, 10.1016/0735-1097(94)90496-0

Collins, 1996, Clinical effects of anticoagulant therapy in suspected acute myocardial infarction: systematic overview of randomized trials, BMJ, 313, 652, 10.1136/bmj.313.7058.652

Kruse, 1996, 459

Mahaffey, 1996, Overview of randomized trials of intravenous heparin in patients with acute myocardial infarction treated with thrombolytic therapy, Am J Cardiol, 77, 551, 10.1016/S0002-9149(97)89305-8

Ryan, 1996, ACC/AHA guidelines for the management of patients with acute myocardial infarction, J Am Coll Cardiol, 28, 1328, 10.1016/S0735-1097(96)00392-0

Nairns, 1996, Relation between activated clotting time during angioplasty and abrupt closure, Circulation, 93, 667, 10.1161/01.CIR.93.4.667

Johnson, 1976, Four heparin preparations: anti-Xa potentiating effect of heparin after subcutaneous injection, Thromb Haemost, 35, 586, 10.1055/s-0038-1648001

Carter, 1982, The relationship between the hemorrhagic and antithrombotic properties of low molecular weight heparins and heparin, Blood, 59, 1239, 10.1182/blood.V59.6.1239.1239

Esquivel, 1982, Comparison between commercial heparin, low-molecular weight heparin and pentosan polysulphate on hemostasis and platelets in vivo, Thromb Res, 28, 389, 10.1016/0049-3848(82)90120-7

Cade, 1984, A comparison of the antithrombotic and hemorrhagic effects of low molecular weight heparin fractions: the influence of the method of preparation, Thromb Res, 35, 613, 10.1016/0049-3848(84)90265-2

Holmer, 1982, Anticoagulant and antithrombotic effects of low molecular weight heparin fragments in rabbits, Thromb Res, 25, 475, 10.1016/0049-3848(82)90089-5

Andriuoli, 1985, Comparison of the antithrombotic and hemorrhagic effects of heparin and a new low molecular weight heparin in the rat, Haemostasis, 15, 324

Bergqvist, 1985, The effects of heparin fragments of different molecular weight in experimental thrombosis and hemostasis, Thromb Res, 38, 589, 10.1016/0049-3848(85)90202-6

Frydman, 1988, The antithrombotic activity and pharmacokinetics of enoxaparin, a low molecular weight heparin, in man given single subcutaneous doses of 20 up to 80 mg, J Clin Pharmacol, 28, 609, 10.1002/j.1552-4604.1988.tb03184.x

Briant, 1989, Unfractionated heparin and CY216: pharmacokinetics and bioavailabilities of the anti-factor Xa and IIa; effects of intravenous and subcutaneous injection in rabbits, Thromb Haemost, 61, 348, 10.1055/s-0038-1646593

Bratt, 1986, Low molecular weight heparin (KABI 2165, Fragmin): pharmacokinetics after intravenous and subcutaneous administration in human volunteers, Thromb Res, 42, 613, 10.1016/0049-3848(86)90340-3

Matzsch, 1987, Effect of an enzymatically depolymerized heparin as compared with conventional heparin in healthy volunteers, Thromb Haemost, 57, 97, 10.1055/s-0038-1651070

Bara, 1988, Pharmacokinetics of low molecular weight heparins, Acta Chir Scand, 543, 65

Bradbrook, 1987, ORG 10172: a low molecular weight heparinoid anticoagulant with a long half life in man, Br J Clin Pharmacol, 23, 667, 10.1111/j.1365-2125.1987.tb03100.x

Weitz, 1997, Low-molecular-weight heparins, N Engl J Med, 337, 688, 10.1056/NEJM199709043371007

Jordan, 1980, The kinetics of hemostatic enzyme-antithrombin interactions in the presence of low molecular weight heparin, J Biol Chem, 255, 10081, 10.1016/S0021-9258(19)70431-1

Holmer, 1981, The molecular-weight dependence of the rate-enhancing effect of heparin on the inhibition of thrombin, factor Xa, factor IXa, factor XIa, factor XIIa and kallikrein by antithrombin, Biochem J, 193, 395, 10.1042/bj1930395

Holmer, 1986, Heparin and its low molecular weight derivatives: anticoagulant and antithrombotic properties, Haemostasis, 16, 1

Griffith, 1983, Heparin-catalyzed inhibitor/protease reactions: kinetic evidence for a common mechanism of action of heparin, Proc Natl Acad Sci U S A, 80, 5460, 10.1073/pnas.80.18.5460

Pletcher, 1983, Two-substrate reaction models for the heparin-catalyzed bovine antithrombin/protease reaction, J Biol Chem, 258, 1086, 10.1016/S0021-9258(18)33162-4

Rosenberg, 1979, Highly active heparin species with multiple binding sites for antithrombin, Biochem Biophys Res Commun, 86, 1319, 10.1016/0006-291X(79)90260-2

Danielsson, 1986, Role of ternary complexes in which heparin binds both antithrombin and proteinase, in the acceleration of the reactions between antithrombin and thrombin or factor Xa, J Biol Chem, 261, 15467, 10.1016/S0021-9258(18)66735-3

Jordan, 1982, Heparin with two binding sites for antithrombin or platelet factor 4, J Biol Chem, 257, 400, 10.1016/S0021-9258(19)68378-X

Boneu, 1988, Pharmacokinetic studies of standard UFH, and low molecular weight heparins in the rabbit, Semin Thromb Hemost, 14, 18, 10.1055/s-2007-1002751

Caranobe, 1985, Disappearance of circulating anti-Xa activity after intravenous injection of unfractionated heparin and of low molecular weight heparin (CY216) in normal and nephrectomized rabbits, Thromb Res, 40, 129, 10.1016/0049-3848(85)90357-3

Palm, 1987, Pharmacokinetics of heparin and low molecular weight heparin fragment (Fragmin) in rabbits with impaired renal or metabolic clearance, Thromb Haemost, 58, 932, 10.1055/s-0038-1646018

Handeland, 1990, Dose adjusted heparin treatment of deep venous thrombosis: a comparison of unfractionated and low molecular weight heparin, Eur J Clin Pharmacol, 39, 107, 10.1007/BF00280041

Choay, 1983, Structure-activity relationship in heparin: a synthetic pentasaccharide with high affinity for antithrombin and eliciting high anti-factor Xa activity, Biochem Biophys Res Commun, 116, 492, 10.1016/0006-291X(83)90550-8

Litin, 1998, Use of low-molecular-weight heparin in the treatment of venous thromboembolic disease: answers to frequently asked questions, Mayo Clin Proc, 73, 545, 10.4065/73.6.545

Kessler, 1997, Low molecular weight heparins: practical considerations, Semin Hematol, 34, 35

Abbate, 1998, Monitoring of low-molecular-weight heparins, Am J Cardiol, 82, 33L, 10.1016/S0002-9149(98)00111-8

Samama, 1995, Contemporary laboratory monitoring of low molecular weight heparins, Clin Lab Med, 15, 119, 10.1016/S0272-2712(18)30347-0

College of American Pathologists, 1999

Kessler, 1995, Monitoring the anticoagulant effects of a low molecular weight heparin preparation, Am J Clin Pathol, 103, 642, 10.1093/ajcp/103.5.642

Laposata, 1998, The clinical use and laboratory monitoring of low-molecular-weight heparin, danaparoid, hirudin and related compounds, and argatroban: College of American Pathologists Conference XXXI on Laboratory Monitoring of Anticoagulant Therapy, Arch Pathol Lab Med, 122, 799

Alhenc-Gelas, 1994, Adjusted versus fixed doses of the low-molecular-weight heparin Fragmin in the treatment of deep vein thrombosis, Thromb Haemost, 71, 698, 10.1055/s-0038-1642507

Levine, 1989, The relationship between antifactor Xa level and clinical outcome in patients receiving enoxaparin low molecular weight heparin to prevent deep vein thrombosis after hip replacement, Thromb Haemost, 62, 940, 10.1055/s-0038-1651032

Hettiarachchi, 1999, Do heparins do more than just treat thrombosis? The influence of heparins on cancer spread, Thromb Haemost, 82, 947, 10.1055/s-0037-1615937

Scuimbatta, 1996, Treatment with modified heparins inhibits experimental metastasis formation and leads, in some animals, to long term survival, Invasion Metastasis, 16, 132

Vlodavsky, 1994, Inhibition of tumour metastasis by heparanase inhibiting species of heparin, Invasion Metastasis, 14, 290

Albada, 1989, Treatment of acute venous thromboembolism with low molecular weight heparin (Fragmin), Circulation, 80, 935, 10.1161/01.CIR.80.4.935

Nieuwenhuis, 1991, Identification of risk factors for bleeding during treatment of acute venous thromboembolism with heparin or low molecular weight heparin, Blood, 78, 2337, 10.1182/blood.V78.9.2337.2337

Boneu, 1994, Low molecular weight heparin therapy: is monitoring needed?, Thromb Haemost, 72, 330, 10.1055/s-0038-1648866

Simonneau, 1997, A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism, N Engl J Med, 337, 663, 10.1056/NEJM199709043371002

Levine, 1996, A comparison of low molecular weight heparin administered primarily at home with UFH administered in the hospital for proximal deep vein thrombosis, N Engl J Med, 334, 677, 10.1056/NEJM199603143341101

Decousus, 1998, A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis: Prevention du Risque d'Embolie Pulmonaire par Interruption Ca e Study Group, N Engl J Med, 338, 409, 10.1056/NEJM199802123380701

Hull, 1992, Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis, N Engl J Med, 326, 975, 10.1056/NEJM199204093261502

Spiro, 1997, Multicenter clinical trial comparing once daily and twice daily subcutaneous enoxaparin and intravenous heparin in the treatment of acute deep vein thrombosis, Thromb Haemost, 373

Gurfinkel, 1995, Low molecular weight heparin versus regular heparin or aspirin in the treatment of unstable angina and silent ischemia, J Am Coll Cardiol, 26, 313, 10.1016/0735-1097(95)80001-W

Klein, 1997, Comparison of low molecular weight heparin with UFH acutely and with placebo for 6 weeks in the management of unstable coronary artery disease: the Fragmin in Unstable Coronary Artery Disease study (FRIC), Circulation, 96, 61, 10.1161/01.CIR.96.1.61

Cohen, 1997, A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease, N Engl J Med, 337, 447, 10.1056/NEJM199708143370702

Koopman, 1996, Treatment of venous thrombosis with intravenous UFH administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home, N Engl J Med, 334, 682, 10.1056/NEJM199603143341102

The COLUMBUS Investigators, 1997, Low-molecular-weight heparin in the treatment of patients with venous thromboembolism, N Engl J Med, 337, 657, 10.1056/NEJM199709043371001

Charbonier, 1998, Comparison of a once daily with a twice daily subcutaneous low molecular weight heparin regimen in the treatment of deep vein thrombosis, Thromb Haemost, 79, 897, 10.1055/s-0037-1615089

FRISC Study Group, 1996, Low-molecular-weight heparin during instability in coronary artery disease: Fragmin During Instability in Coronary Artery Disease (FRISC) Study Group, Lancet, 347, 561, 10.1016/S0140-6736(96)91270-2

Dalpozzo, 1989, New heparin complexes active by intestinal absorption: I. Multiple ion pairs with basic organic compounds, Thromb Res, 56, 119, 10.1016/0049-3848(89)90014-5

Brayden, 1997, Heparin absorption across the intestine: effects of sodium N-8-(2-hydroxybenzoyl)amino caprylate in rat in situ intestinal installations and in caco-2 monolayers, Pharm Res, 14, 1772, 10.1023/A:1012192115828

Leone-Bay, 1998, Acylated non-α-amino acids as novel agents for the oral delivery of heparin sodium, USP, J Control Release, 50, 41, 10.1016/S0168-3659(97)00101-6

Salartash, 1999, Oral low-molecular weight heparin and delivery agent prevent jugular venous thrombosis in the rat, J Vasc Surg, 30, 526, 10.1016/S0741-5214(99)70080-7

Baughman, 1998, Oral delivery of anticoagulant doses of heparin: a randomized, double-blind, controlled study in humans, Circulation, 98, 1610, 10.1161/01.CIR.98.16.1610

Norrby, 1993, Heparin and angiogenesis: a low molecular weight fraction inhibits and a high molecular weight fraction stimulates angiogenesis systemically, Haemostasis, 23, 141

Lepri, 1994, Effect of low molecular weight heparin sulphate on angiogenesis in the rat cornea after chemical cauterization, J Ocul Pharmacol, 10, 273, 10.1089/jop.1994.10.273

Pezzuoli, 1989, Prophylaxis of fatal pulmonary embolism in general surgery using low molecular weight heparin Cy216: a multicenter double-blind randomized controlled clinical trial versus placebo, Int Surg, 74, 205

Nurmohamed, 1992, Low-molecular-weight heparin versus standard heparin in general and orthopedic surgery: a meta-analysis, Lancet, 340, 152, 10.1016/0140-6736(92)93223-A

Leclerc, 1992, Prevention of deep vein thrombosis after major knee surgery: a randomized, double-blind trial comparing a low molecular weight heparin fragment (enoxaparin) to placebo, Thromb Haemost, 67, 417, 10.1055/s-0038-1648463

Turpie, 1986, A randomized controlled trial of a low molecular weight heparin (enoxaparin) to prevent deep vein thrombosis in patients undergoing elective hip surgery, N Engl J Med, 315, 925, 10.1056/NEJM198610093151503

Hoek, 1992, Prevention of deep vein thrombosis (DVT) following total hip replacement by a low molecular weight heparinoid, Thromb Haemost, 67, 28, 10.1055/s-0038-1648374

Levine, 1991, Prevention of deep vein thrombosis after elective hip surgery: a randomized trial comparing low molecular weight heparin with standard unfractionated heparin, Ann Intern Med, 114, 545, 10.7326/0003-4819-114-7-545

Planes, 1988, Prevention of postoperative venous thrombosis: a randomized trial comparing unfractionated heparin with low molecular weight heparin in patients undergoing total hip replacement, Thromb Haemost, 60, 407, 10.1055/s-0038-1646980

Eriksson, 1991, Prevention of deep vein thrombosis and pulmonary embolism after total hip replacement: comparison of low-molecular-weight heparin and unfractionated heparin, J Bone Joint Surg Am, 73, 484, 10.2106/00004623-199173040-00002

Leyvraz, 1991, Prevention of deep vein thrombosis after hip replacement: randomized comparison between unfractionated heparin and low molecular weight heparin, BMJ, 303, 543, 10.1136/bmj.303.6802.543

Dechavanne, 1989, Randomized trial of low molecular weight heparin (Kabi 2165) versus adjusted dose subcutaneous standard heparin in the prophylaxis of deep vein thrombosis after elective hip surgery, Haemostasis, 1, 5

Bergqvist, 1991, Thromboprophylaxis in hip fracture patients: a prospective randomised comparative study between ORG 10172 and dextran, Surgery, 109, 617

Borris, 1991, Low-molecular-weight heparin (enoxaparin) vs dextran 70: the prevention of postoperative deep vein thrombosis after total hip replacement, Arch Intern Med, 151, 1621, 10.1001/archinte.1991.00400080105020

Heit, 1991, Efficacy of RD heparin (a LMWH) and warfarin for prevention of deep-vein thrombosis after hip or knee replacement [abstract], Blood, 778, 187A

Anderson, 1993, Efficacy and cost of low-molecular-weight heparin compared with standard heparin for the prevention of deep vein thrombosis after total hip arthroplasty, Ann Intern Med, 119, 1105, 10.7326/0003-4819-119-11-199312010-00008

Colwell, 1995, Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep venous thrombosis after elective knee arthroplasty, Clin Orthop, 321, 19

Fauno, 1994, Prophylaxis for the prevention of venous thromboembolism after total knee arthroplasty: a comparison between unfractionated and low-molecular-weight heparin, J Bone Joint Surg Am, 76, 1814, 10.2106/00004623-199412000-00007

RD Heparin Arthroplasty Group, 1994, RD heparin compared with warfarin for prevention of venous thromboembolic disease following total hip or knee arthroplasty, J Bone Joint Surg Am, 76, 1174, 10.2106/00004623-199408000-00008

Spiro, 1994, Efficacy and safety of enoxaparin to prevent deep venous thrombosis after hip replacement surgery, Ann Intern Med, 121, 81, 10.7326/0003-4819-121-2-199407150-00001

Heit, 1997, Efficacy and safety of low molecular weight heparin (ardeparin sodium) compared to warfarin for the prevention of venous thromboembolism after total knee replacement surgery: a double-blind dose-ranging study, Thromb Haemost, 77, 32, 10.1055/s-0038-1655902

Hull, 1993, A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation, N Engl J Med, 19, 1370, 10.1056/NEJM199311043291902

Leclerc, 1996, Prevention of venous thromboembolism (VTE) after knee arthroplasty: a randomized double-blind trial comparing enoxaparin with warfarin sodium, Ann Intern Med, 124, 619, 10.7326/0003-4819-124-7-199604010-00001

Leclerc, 1994, Prevention of venous thromboembolism (VTE) after knee arthroplasty: a randomized, double-blind trial, comparing enoxaparin to warfarin sodium [abstract], Haemostasis, 24, 232

Deleted in proof

Hamulyak, 1994, Subcutaneous low-molecular weight heparin or oral anticoagulants for the prevention of deep-vein thrombosis in elective hip and knee replacement?, Thromb Haemost, 74, 1428

Gent, 1996, Low molecular weight heparinoid orgaran is more effective than aspirin in the prevention of venous thromboembolism after surgery for hip fracture, Circulation, 93, 80, 10.1161/01.CIR.93.1.80

Geerts, 1996, A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxes against venous thromboembolism after major trauma, N Engl J Med, 335, 701, 10.1056/NEJM199609053351003

Agnelli, 1998, Enoxaparin plus compression after elective neurosurgery, N Engl J Med, 339, 80, 10.1056/NEJM199807093390204

Prins, 1987, Deep vein thrombosis prophylaxis with a low molecular weight heparin (Kabi 2165) in stroke patients [abstract], Thromb Haemost, 58, 117

Turpie, 1987, A double-blind randomized trial of ORG 10172 low molecular weight heparinoid in the prevention of deep vein thrombosis in thrombotic stroke, Lancet, 1, 523, 10.1016/S0140-6736(87)90173-5

Green, 1990, Prevention of thromboembolism after spinal cord injury using low molecular weight heparin, Ann Intern Med, 113, 571, 10.7326/0003-4819-113-8-571

Turpie, 1992, A low molecular weight heparinoid compared with unfractionated heparin in the prevention of deep vein thrombosis in patients with acute ischemic stroke, Ann Intern Med, 117, 353, 10.7326/0003-4819-117-5-353

Kuijer, 1997, Low-molecular-weight heparins: treatment of venous thromboembolism, 129

Patrono, 1998, Platelet-active drugs: the relationships among dose, effectiveness, and side effects, Chest, 114, 470S, 10.1378/chest.114.5_Supplement.470S

Goodman, 2000, Randomized trial of low molecular weight heparin (enoxaparin) versus unfractionated heparin for unstable coronary artery disease: one year results of the ESSENCE study, J Am Coll Cardiol, 36, 693, 10.1016/S0735-1097(00)00808-1

Leizorivicz A. The FRAXIS Investigators. XXth Congress of the European Society of Cardiology; August 22–26, 1998; Vienna, Austria

FRISC II Investigators, 2000, Long-term low-molecular-mass heparin in unstable coronary-artery disease: FRISC II prospective randomised multicentre study: Fragmin and fast revascularisation during instability in coronary artery disease, Lancet, 356, 9

Kontny, 1997, Randomized trial of low molecular weight heparin (dalteparin) in prevention of left ventricular thrombus formation and arterial embolism after acute anterior myocardial infarction: the Fragmin in Acute Myocardial Infarction (FRAMI) Study, J Am Coll Cardiol, 39, 962, 10.1016/S0735-1097(97)00258-1

Glick, 1996, Reduction of reinfarction and angina with use of low-molecular-weight heparin therapy after streptokinase (and heparin) in acute myocardial infarction, Am J Cardiol, 77, 1145, 10.1016/S0002-9149(96)00152-X

Hanke, 1992, Inhibition of cellular proliferation after experimental balloon angioplasty by low-molecular-weight heparin, Circulation, 85, 1548, 10.1161/01.CIR.85.4.1548

Buchwald, 1992, Low-molecular-weight heparin reduces neointimal proliferation after coronary stent implantaton in hypercholesterolemic minipigs, Circulation, 86, 531, 10.1161/01.CIR.86.2.531

Faxon, 1994, Low molecular weight heparin in prevention of restenosis after angioplasty, Circulation, 90, 908, 10.1161/01.CIR.90.2.908

Cairns, 1996, Fish oils and low-molecular-weight heparin for the reduction of restenosis after percutaneous transluminal coronary angioplasty, Circulation, 94, 1553, 10.1161/01.CIR.94.7.1553

1999, Protamine sulfate antiheparin agents 20:12.08, 1265

Horrow, 1985, Protamine: a review of its toxicity, Anesth Analg, 64, 348, 10.1213/00000539-198503000-00008

Caplan, 1976, Protamine sulfate and fish allergy [letter], N Engl J Med, 295, 172, 10.1056/NEJM197607152950318

Stewart, 1984, Increased risk of severe protamine reactions in NPH insulin-dependent diabetics undergoing cardiac catheterization, Circulation, 70, 788, 10.1161/01.CIR.70.5.788

Cooney, 1999, Recent experiences with hexadimethrine for neutralizing heparin after cardiopulmonary bypass, Anesth Intensive Care Med, 27, 298, 10.1177/0310057X9902700314

Kikura, 1996, Heparin neutralization with methylene blue, hexadimethrine, or vancomycin after cardiopulmonary bypass, Anesth Analg, 83, 223, 10.1213/00000539-199608000-00004

Despotis, 1994, In vitro reversal of heparin effect with heparinase: evaluation with whole blood prothrombin time and activated partial thromboplastin time in cardiac surgical patients, Anesth Analg, 79, 670

Dehmer, 1995, Reversal of heparin anticoagulation by recombinant platelet factor 4 in humans, Circulation, 91, 2188, 10.1161/01.CIR.91.8.2188

D'Ambra, 1996, Restoration of the normal coagulation process: advances in therapies to antagonize heparin, J Cardiovasc Pharmacol, 27, S58, 10.1097/00005344-199600001-00012

Hendrikx, 1997, The use of a heparin removal device: a valid alternative to protamine, Int J Artif Organs, 20, 166, 10.1177/039139889702000308

Tao, 1998, Extracorporeal heparin adsorption following cardiopulmonary bypass with a heparin removal device: an alternative to protamine, Crit Care Med, 26, 1096, 10.1097/00003246-199806000-00035

Hulin, 1997, A novel protamine variant reversal of heparin anticoagulation in human blood in vitro, J Vasc Surg, 26, 1043, 10.1016/S0741-5214(97)70018-1

Racanelli, 1985, Biochemical and pharmacologic studies on the protamine interactions with heparin: its fractions and fragments, Semin Thromb Hemost, 11, 176, 10.1055/s-2007-1004373

Lindblad, 1987, Protamine reversal of anticoagulation achieved with a low molecular weight heparin: the effects on eicosanoids, clotting and complement factors, Thromb Res, 48, 31, 10.1016/0049-3848(87)90343-4

Massonnet-Castel, 1986, Partial reversal of low molecular weight heparin (PK 10169) anti-Xa activity by protamine sulfate: in vitro and in vivo study during cardiac surgery with extracorporeal circulation, Haemostasis, 16, 139

Hirsh, 1991, Comparative effects of heparin and LMW heparin on hemostasis, Thromb Res, 14, 11, 10.1016/0049-3848(91)90399-H

Woltz, 1995, Studies on the neutralizing effects of protamine on unfractionated and low molecular weight heparin (Fragmin) at the site of activation of the coagulation system in man, Thromb Haemost, 73, 439, 10.1055/s-0038-1653794

Gram, 1988, Does protamine chloride neutralize low molecular weight heparin sufficiently?, Thromb Res, 52, 353, 10.1016/0049-3848(88)90019-9

Sugiyama, 1992, Study on neutralization of low molecular weight heparin by protamine sulfate and its neutralization characteristics, Thromb Res, 68, 119, 10.1016/0049-3848(92)90027-8

Harenberg, 1985, Inhibition of low molecular weight heparin by protamine chloride in vivo, Thromb Res, 38, 11, 10.1016/0049-3848(85)90003-9

Racanelli, 1988, Low molecular weight heparin induced bleeding can be neutralized by protamine, Haemostasis, 18, 163

Van Ryn-McKenna, 1990, Neutralization of enoxaparine-induced bleeding by protamine sulfate, Thromb Haemost, 63, 271, 10.1055/s-0038-1645207

Doutremepuich, 1985, In vivo neutralization of low-molecular weight heparin fraction CY 216 by protamine, Semin Thromb Hemost, 11, 318, 10.1055/s-2007-1004385

Wakefield, 1995, Effective and less toxic reversal of low-molecular weight heparin anticoagulation by a designer variant of protamine, J Vasc Surg, 21, 839, 10.1016/S0741-5214(05)80016-3

Byun, 1999, Low molecular weight protamine: a potential nontoxic heparin antagonist, Thromb Res, 94, 53, 10.1016/S0049-3848(98)00201-1

Hulin, 1997, Comparison of the hemodynamic and hematologic toxicity of a protamine variant after reversal of low-molecular-weight heparin anticoagulation in a canine model, Lab Animal Sci, 47, 153

Wakefield, 1996, A [+18RGD] protamine variant for nontoxic and effective reversal of conventional heparin and low-molecular-weight heparin anticoagulation, J Surg Res, 63, 280, 10.1006/jsre.1996.0261

Dietrich, 1999, Structural features and bleeding activity of commercial low molecular weight heparins: neutralization by ATP and protamine, Semin Thromb Hemost, 25, 43

Shenoy, 1999, Development of heparin antagonists with focused biological activity, Curr Pharm Design, 5, 965

Warkentin, 1998, Heparin-induced thrombocytopenia: towards consensus, Thromb Haemost, 79, 1, 10.1055/s-0037-1614206

Warkentin, 1999, Heparin-induced thrombocytopenia: a clinicopathologic syndrome, Thromb Haemost, 82, 439

Warkentin, 1995, Formation of heparin-induced thrombocytopenia IgG without thrombocytopenia: analysis of a clinical trial [abstract], Blood, 86, 537a

Warkentin, 1996, Heparin-induced skin lesions, Br J Haematol, 92, 494, 10.1046/j.1365-2141.1996.d01-1481.x

Amiral, 1992, Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia [letter], Thromb Haemost, 68, 95, 10.1055/s-0038-1656329

Amiral, 2000, Heparin-dependent antigens in heparin-induced thrombocytopenia, 127

Visentin, 2000, Molecular immunopathogenesis of heparin-induced thrombocytopenia, 139

Greinacher, 1992, Heparin-associated thrombocytopenia in a patient treated with polysulphated chondroitin sulphate: evidence for immunological crossreactivity between heparin and polysulphated glycosaminoglycan, Br J Haematol, 81, 252, 10.1111/j.1365-2141.1992.tb08216.x

Tardy-Poncet, 1994, Pentosan polysulfate-induced thrombocytopenia and thrombosis, Am J Hematol, 45, 252, 10.1002/ajh.2830450312

Collins, 1997, Diagnostic testing for heparin-induced thrombocytopenia (HIT): an enhanced platelet factor 4 complex enzyme linked immunosorbent assay (PF ELISA) [abstract], Blood, 90, 461a

Funk, 2000, Heparin-induced thrombocytopenia (HIT) in orthopedic patients: a prospective cohort trial comparing UFH and LMWH [abstract], Ann Hematol, 79, A92

Warkentin, 1995, Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin, N Engl J Med, 332, 1330, 10.1056/NEJM199505183322003

Amiral, 1997, Absence of cross-reactivity of SR90107A/ORG31540 pentasaccharide with antibodies to heparin-PF4 complexes developed in heparin-induced thrombocytopenia, Blood Coagul Fibrinolysis, 8, 114, 10.1097/00001721-199703000-00005

Petitou, 1999, Synthesis of thrombin-inhibiting heparin mimetics without side effects, Nature, 398, 417, 10.1038/18877

Warkentin, 1999, Thrombocytopenia due to platelet destruction and hypersplenism, 2138

Chong, 1994, Plasma P-selectin is increased in thrombotic consumptive platelet disorders, Blood, 83, 1535, 10.1182/blood.V83.6.1535.1535

Warkentin, 1994, Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin- induced thrombocytopenia, Blood, 84, 3691, 10.1182/blood.V84.11.3691.bloodjournal84113691

Kelton, 1988, Heparin-induced thrombocytopenia: laboratory studies, Blood, 72, 925, 10.1182/blood.V72.3.925.bloodjournal723925

Warkentin, 1997, The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia, Ann Intern Med, 127, 804, 10.7326/0003-4819-127-9-199711010-00005

Greinacher, 2000, Heparin-induced thrombocytopenia with thromboembolic complications: meta-analysis of two prospective trials to assess the value of parenteral treatment with lepirudin and its therapeutic aPTT range, Blood, 96, 846, 10.1182/blood.V96.3.846

Warkentin, 1999, Generation of platelet-derived microparticles and procoagulant activity by heparin-induced thrombocytopenia IgG/serum and other IgG platelet agonists: a comparison with standard platelet agonists, Platelets, 10, 319, 10.1080/09537109975960

Warkentin, 2000, Clinical picture of heparin-induced thrombocytopenia, 43

Warkentin, 1999, Multicentric warfarin-induced skin necrosis complicating heparin-induced thrombocytopenia, Am J Hematol, 62, 44, 10.1002/(SICI)1096-8652(199909)62:1<44::AID-AJH7>3.0.CO;2-F

Warkentin, 1996, Heparin-induced thrombocytopenia: IgG-mediated platelet activation, platelet microparticle generation, and altered procoagulant/anticoagulant balance in the pathogenesis of thrombosis and venous limb gangrene complicating heparin-induced thrombocytopenia, Transfus Med Rev, 10, 249, 10.1016/S0887-7963(96)80001-0

Warkentin, 1999, Venous limb gangrene (VLG) complicating warfarin treatment of deep-vein thrombosis (DVT) in metastatic carcinoma [abstract], Blood, 94, 114b

Warkentin, 2000, The impact of the patient population on the risk of heparin-induced thrombocytopenia, Blood, 96, 1703, 10.1182/blood.V96.5.1703

Lee, 2000, Frequency of heparin-induced thrombocytopenia, 81

Warkentin, 2000, Laboratory testing for heparin-induced thrombocytopenia, 211

Griffiths, 1997, Assays for heparin-induced thrombocytopenia, Transfus Med, 7, 1, 10.1046/j.1365-3148.1997.d01-77.x

Warkentin, 1992, Determinants of donor platelet variability when testing for heparin-induced thrombocytopenia, J Lab Clin Med, 120, 371

Greinacher, 1994, Laboratory diagnosis of heparin-associated thrombocytopenia and comparison of platelet aggregation test, heparin-induced platelet activation test, and platelet factor 4/heparin enzyme-linked immunosorbent assay, Transfusion, 34, 381, 10.1046/j.1537-2995.1994.34594249047.x

Eichler, 1999, First workshop for detection of heparin-induced antibodies: validation of the heparin-induced platelet-activation test (HIPA) in comparison with a PF4/heparin ELISA, Thromb Haemost, 81, 625, 10.1055/s-0037-1614536

Warkentin, 1996, A 14-year study of heparin-induced thrombocytopenia, Am J Med, 101, 502, 10.1016/S0002-9343(96)00258-6

Chong, 1996, Low molecular weight heparinoid and heparin-induced thrombocytopenia [abstract], Aust NZ J Med, 26, 331

Chong, 2000, Danaparoid for the treatment of heparin-induced thrombocytopenia, 291

Newman, 1998, Heparin-induced thrombocytopenia: IgG binding to PF4-heparin complexes in the fluid phase and cross-reactivity with low molecular weight heparin and heparinoid, Thromb Haemost, 80, 292, 10.1055/s-0037-1615190

Warkentin, 1996, Blood, 88, 626a

Greinacher, 2000, Recombinant hirudin for the treatment of heparin-induced thrombocytopenia, 313

Greinacher, 1999, Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study, Circulation, 99, 73, 10.1161/01.CIR.99.1.73

Greinacher, 1999, Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia, Circulation, 100, 587, 10.1161/01.CIR.100.6.587

Song, 1999, Generation of anti-hirudin antibodies in heparin-induced thrombocytopenic patients treated with r-hirudin, Circulation, 100, 1528, 10.1161/01.CIR.100.14.1528

Lewis BE. Preliminary results of a prospective randomized controlled trial of argatroban versus conventional therapy for heparin-induced thrombocytopenia. Presented at XVI International Congress of the International Society on Thrombosis and Haemostasis. Florence, Italy. June 12, 1997

Warkentin, 1998, Limitations of conventional treatment options for heparin-induced thrombocytopenia, Semin Hematol, 35, 17

Thomas, 1992, Thrombocytopenia, cutaneous necrosis, and gangrene of the upper and lower extremities in a 35-year-old man, Chest, 102, 1578, 10.1378/chest.102.5.1578-b

Gupta, 1998, Heparin-induced thrombocytopenia, Ann Pharmacother, 32, 55, 10.1345/aph.16388

Battey, 1985, Venous gangrene associated with heparin-induced thrombocytopenia, Surgery, 97, 618

Wallis, 1999, Safety of warfarin anticoagulation in patients with heparin-induced thrombocytopenia, Chest, 116, 1333, 10.1378/chest.116.5.1333

Greinacher, 1992, Heparin-associated thrombocytopenia: antibody is not heparin-specific, Thromb Haemost, 67, 545, 10.1055/s-0038-1648491

Ranze, 2000, The use of low-molecular-weight heparins in heparin-induced thrombocytopenia (HIT): a cohort study [abstract], Ann Hematol, 79, 198

Contreras, 1998, The appropriate use of platelets: an update from the Edinburgh Consensus Conference, Br J Hematol, 101, 10

Babcock, 1976, Heparin-induced thrombocytopenia, N Engl J Med, 295, 237, 10.1056/NEJM197607292950501

Cimo, 1979, Heparin-induced thrombocytopenia: association with a platelet aggregating factor and arterial thromboses, Am J Hematol, 6, 125, 10.1002/ajh.2830060204

Boon, 1994, Heparin-induced thrombocytopenia and antithrombotic therapy [letter], Lancet, 344, 1296, 10.1016/S0140-6736(94)90781-1

Wallis, 1999, Failure of early heparin cessation as treatment for heparin-induced thrombocytopenia, Am J Med, 106, 629, 10.1016/S0002-9343(99)00124-2

Tardy, 1999, Lower limb veins should be systematically explored in patients with isolated heparin-induced thrombocytopenia [letter], Thromb Haemost, 82, 1199, 10.1055/s-0037-1614355

Griffith, 1965, Heparin osteoporosis, JAMA, 193, 85, 10.1001/jama.1965.03090020005001

Jaffe, 1965, Multiple fractures associated with long term sodium heparin therapy, JAMA, 193, 152, 10.1001/jama.1965.03090020072024

Miller, 1966, Osteoporosis resulting from heparin therapy, Cleve Clin Q, 33, 31, 10.3949/ccjm.33.1.31

Avioli, 1975, Heparin induced osteoporosis: an appraisal, Adv Exp Med Biol, 52, 375, 10.1007/978-1-4684-0946-8_33

Squires, 1979, Heparin-induced spinal fractures, JAMA, 241, 2417, 10.1001/jama.1979.03290480051024

Rupp, 1982, Risk of osteoporosis in patients treated with long-term intravenous heparin, Curr Probl Surg, 39, 419

Monreal, 1991, Heparins, coumarin, and bone density [letter], Lancet, 338, 706, 10.1016/0140-6736(91)91292-3

Murphy, 1992, Heparin therapy and bone fractures [letter], Lancet, 340, 1098, 10.1016/0140-6736(92)93118-7

Dahlman, 1993, Osteoporotic fractures and the recurrence of thromboembolism during pregnancy and the puerperium in 184 women undergoing thromboprophylaxis with heparin, Am J Obstet Gynecol, 168, 1265, 10.1016/0002-9378(93)90378-V

Barbour, 1994, A prospective study of heparin-induced osteoporosis in pregnancy using bone densitometry, Am J Obstet Gynecol, 170, 862, 10.1016/S0002-9378(94)70299-3

Dahlman, 1994, Bone mineral density during long-term prophylaxis with heparin in pregnancy, Am J Obstet Gynecol, 170, 1315, 10.1016/S0002-9378(13)90457-9

Monreal, 1994, Comparison of subcutaneous unfractionated heparin with a low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contraindications to coumarin, Thromb Haemost, 71, 7, 10.1055/s-0038-1642376

Muir, 1996, Histomorphometric analysis of the effects of standard heparin on trabecular bone in vivo, Blood, 88, 1314, 10.1182/blood.V88.4.1314.bloodjournal8841314

Shaughnessy, 1999, A histomorphometric evaluation of heparin-induced bone loss after discontinuation of heparin treatment in rats, Blood, 93, 1231, 10.1182/blood.V93.4.1231

Muir, 1997, A histomorphometric comparison of the effects of heparin and low molecular-weight heparin on cancellous bone in rats, Blood, 89, 3236, 10.1182/blood.V89.9.3236

Bhandari, 1998, The effect of heparin and low molecular weight heparin on osteoblastogenesis in vitro[abstract], Blood, 92, 1474

Barritt, 1960, Anticoagulant drugs in the treatment of pulmonary embolism: a controlled trial, Lancet, 1, 1309, 10.1016/S0140-6736(60)92299-6

Brandjes, 1992, Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal vein thrombosis, N Engl J Med, 327, 1485, 10.1056/NEJM199211193272103