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Antithrombotic Drugs: Part I

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Summary

There are three categories of antithrombotic agents: drugs which prevent fibrin formation (the anticoagulants and defibrinating enzymes), drugs which prevent platelet adhesion or aggregation (the antiplatelet drugs), and thrombolytic drugs which induce fibrin degradation. Clinical studies have now led to a better understanding of the relative value of these drugs in different thrombotic disorders. In addition, knowledge of the mechanism of action of some of these drugs has recently been much advanced.

The anticoagulant drugs in clinical use are heparin and the oral anticoagulants. Heparin is a potent inhibitor of several steps of the intrinsic coagulation pathway through its effect on a plasma cofactor, antithrombin III. Its action is immediate, but heparin must be given parenterally. Oral anticoagulants act more slowly, by reducing the hepatic synthesis of biologically active factors II, VII, IX and X, but can be given by mouth. Heparin is therefore most suitable for starting anticoagulant treatment, while oral anticoagulants are generally used for prolonged therapy.

The value of the anticoagulants as antithrombotic agents has been best assessed by studying their effectiveness in preventing and treating venous thromboembolic disease. Oral anticoagulants have been repeatedly shown to prevent venous thrombosis and pulmonary embolism in patients at high risk of developing these complications. However, the increased risk of postoperative bleeding has prevented their widespread use for this purpose in surgical patients. Recently, the use of low doses of heparin, given subcutaneously before and after surgery, has been shown to markedly reduce the incidence of venous thrombosis and pulmonary embolism (including fatal pulmonary embolism) after major elective abdominal surgery, and to produce only a slight increase of postoperative bleeding. This represents a major advance in anticoagulant prophylaxis of venous thromboembolism in surgical patients. However, low dose heparin prophylaxis is relatively ineffective in patients having hip surgery, and has not been evaluated in patients having other types of orthopaedic surgery.

There is direct evidence that anticoagulant therapy prevents death and recurrent embolism in patients who have developed pulmonary embolism, and considerable indirect evidence that it prevents pulmonary embolism (and death from pulmonary embolism) in patients who have venous thrombosis. The incidence of further venous thromboembolism or bleeding during treatment appears to be minimised when heparin is given by continuous intravenous infusion in a dose sufficient to produce a moderate, but not excessive, prolongation of a heparin-sensitive, in vitro coagulation test. The tests most commonly used to monitor heparin therapy was based on either the whole blood clotting time or the activated partial thromboplastin time. There is evidence that 3 to 6 months of oral anticoagulant treatment after initial heparin therapy results in a significantly reduced frequency of further thromboembolism, but that longer treatment is of little benefit except in patients with recurrent disease.

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References

  • Abernethy, E.E. and Hartsuck, J.M.: Postoperative pulmonary embolism. A prospective study utilizing low dose heparin. American Journal of Surgery 128: 739–742 (1974).

    CAS  Google Scholar 

  • Abildgaard, U.: Heparin cofactor and antithrombin. Thrombosis et Diathesis Haemorrhagica 33: 38–42 (1974).

    Google Scholar 

  • Anderson, G.M. and Hull, E.: The effect of dicumarol upon the mortality and incidence of thromboembolic complications in congestive heart failure. American Heart Journal 39: 697–702 (1950).

    Article  PubMed  CAS  Google Scholar 

  • Babb, R.R.; Spittell, J.A. and Bartholomew, L.G.: Gastrointestinal complications of anticoagulant therapy. Mayo Clinical Proceedings 43: 738–751 (1968).

    CAS  Google Scholar 

  • Baden, J.P.; Sonnenfeld, M.; Ferlic, R.M. and Sellers, R.D.: The precise management of heparin therapy. American Journal of Surgery 124: 777–779 (1972).

    Article  PubMed  CAS  Google Scholar 

  • Ballard, R.M.; Bradley-Watson, P.J.; Johnstone, F.D.; Kenney, A.; McCarthy, T.G.; Campbell, S. and Weston, J.: Low dose of subcutaneous heparin in the prevention of deep vein thrombosis after gynecological surgery. Journal of Obstetrics and Gynaecology of the British Commonwealth 80: 469–472 (1973).

    Article  PubMed  CAS  Google Scholar 

  • Barnett, H.J.M.: Platelets, drugs and cerebral ischemia, p.233; in Hirsh, Cade, Gallus, and Schonbaum (Eds) Platelets, Drugs, and Thrombosis (Karger, Basel 1975).

    Google Scholar 

  • Barnhorst, D.A.; Oxman, H.A.; Connolly, D.C.; Pluth, J.R.; Danielson, G.K.; Wallace, R.B. and McGoon, D.C.: Long-term follow-up of isolated replacement of the aortic or mitral valve with the Starr-Edwards Prosthesis. American Journal of Cardiology 35: 228–233 (1975).

    Article  PubMed  CAS  Google Scholar 

  • Barritt, D.W. and Jordan, S.C.: Anticoagulant drugs in the treatment of pulmonary embolism. A controlled trial. Lancet 1: 1309–1312 (1960)

    CAS  Google Scholar 

  • Basu, D.; Gallus, A.; Hirsh, J. and Cade, J.: A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. New England Journal of Medicine 287: 324–327 (1972).

    Article  PubMed  CAS  Google Scholar 

  • Bauer, G.: Clinical experiences of surgeon in the use of heparin. American Journal of Cardiology 14: 29–35 (1964).

    Article  PubMed  CAS  Google Scholar 

  • Bernstein, I.L.: Anaphylaxis to heparin sodium. Journal of the American Medical Association 161: 1379–1381 (1956).

    Article  PubMed  CAS  Google Scholar 

  • Bjerkelund, C.J. and Orung, O.M.: Efficacy of anticoagulant therapy in preventing embolism related to D.C. electrical conversion of atrial fibrillation. American Journal of Cardiology 23: 208–216 (1969).

    CAS  Google Scholar 

  • Blakely, J.A.: A rapid bedside method for the control of heparin therapy. Canadian Medical Association Journal 99: 1072–1076 (1968).

    PubMed  CAS  Google Scholar 

  • Borgström, S.; Greitz, T.; Van der Linden, W.; Molin, J. and Rudics, E.: Anticoagulant prophylaxis of venous thrombosis in patients with fractured neck of the femur. A controlled clinical trial using venous phlebography. Acta Chirurgica Scandinavica 129: 500–509 (1965).

    Google Scholar 

  • Browse, N.L.; Clemenson, G. and Croft, D.N.: Fibrinogendetectable thrombosis in the legs and pulmonary embolism. British Medical Journal 1: 603–604 (1974).

    Article  PubMed  CAS  Google Scholar 

  • Chen, A.L.; Hershgold, E.J. and Wilson, D.E.: One-stage assay of heparin. Journal of Laboratory and Clinical Medicine 85: 843–854 (1975).

    PubMed  CAS  Google Scholar 

  • Chessels, J.M.; Braithwaite, T.A. and Chamberlain, D.A.: Dextrose and sorbitol as diluents for continuous intravenous heparin infusion. British Medical Journal 2: 81–82 (1972).

    Article  Google Scholar 

  • Collin, J.; Collin, C; Constable, F.L. and Johnston, I.D.A.: Infusion thrombophlebitis and infection with various cannulas. Lancet 2: 150–152 (1975).

    Article  PubMed  CAS  Google Scholar 

  • Congdon, J.E.; Kardinal, CG. and Wallin, J.D.: Monitoring heparin therapy in hemodialysis. Journal of the American Medical Association 226: 1529–1532 (1973).

    Article  PubMed  CAS  Google Scholar 

  • Coon, W.W.; Willis, P.W. and Symons, M.J.: Assessment of anticoagulant treatment of venous thromboembolism. Annals of Surgery 170: 559–568 (1969).

    Article  PubMed  CAS  Google Scholar 

  • Coon, W.W. and Willis, P.W.: Thromboembolic complications during anticoagulant therapy. Archives of Surgery 105: 209–212 (1972).

    Article  PubMed  CAS  Google Scholar 

  • Coon, W.W. and Willis, P.W.: Recurrence of venous thromboembolism. Surgery 73: 823–827 (1973).

    PubMed  CAS  Google Scholar 

  • Coon, W.W. and Willis, P.W.: Hemorrhagic complications of anticoagulant therapy. Archives of Internal Medicine 133: 386–392 (1974).

    Article  PubMed  CAS  Google Scholar 

  • Cox, J.S.T.: The maturation and canalization of thrombi. Surgery, Gynecology and Obstetrics 116: 593–599 (1963).

    PubMed  CAS  Google Scholar 

  • Crane, C.: Deep venous thrombosis and pulmonary embolism. New England Journal of Medicine 257: 147–157(1957).

    Article  PubMed  CAS  Google Scholar 

  • Curry, N.; Bardana, E.J. and Pirofsky, B.: Heparin Sensitivity. Archives of Internal Medicine 132: 744–745 (1973).

    Article  PubMed  CAS  Google Scholar 

  • Dale, W.A. and Lewis, M.R.: Heparin control of venous thromboembolism. Archives of Surgery 101: 744–755 (1970).

    Article  PubMed  CAS  Google Scholar 

  • Denson, K.W.E. and Bonnar, J.: The measurement of heparin. A ‘method based on potentiation of anti-Factor Xa. Thrombosis et Diathesis Haemorrhagica 30: 471–479 (1973).

    CAS  Google Scholar 

  • Dick, W.; Matis, P. and Mayer, W.: Results of alternating anticoagulant prophylaxis in surgery. Thrombosis et Diathesis Haemorrhagica 3: 11–19 (1959).

    PubMed  CAS  Google Scholar 

  • DiSaia, P. Pregnancy and delivery of a patient with a Starr-Edwards mitral valve prosthesis. Obstetrics and Gynecology 28: 469–472 (1966).

    Google Scholar 

  • Douglas, A.S.: Anticoagulant therapy (Blackwell, Oxford 1962).

    Google Scholar 

  • Douglas, A.S.: Anticoagulant therapy in coronary artery disease, p690; Sherry, Brinkhous, Genton and Stengle (Eds) Thrombosis (National Academy of Sciences, Washington DC (1969).

    Google Scholar 

  • Douglas, A.S. and McNicol, G.P.: Anticoagulant therapy, p497; Biggs (Ed) Human Blood Coagulation Haemostasis and Thrombosis (Blackwell, Oxford 1972).

    Google Scholar 

  • Duguid, J.B. and Robertson, W.B.: Mechanical factors in atherosclerosis. Lancet 1: 1205–1209 (1957).

    Article  Google Scholar 

  • Duma, R.J.; Warner, J.F. and Dalton, H.P.: Septicemia from intravenous infusions. New England Journal of Medicine 284: 257–260 (1971).

    Article  PubMed  CAS  Google Scholar 

  • Duvoisin, G.E.; Brandenburg, R.O. and McGoon, D.C: Factors affecting thromboembolism associated with prosthetic heart valves. Circulation 35 (Suppl. 1), 70–76 (1967).

    Article  Google Scholar 

  • Eastham, R.D.: Improved control of long-term anticoagulant therapy. British Medical Journal 2: 337–340 (1968).

    Article  PubMed  CAS  Google Scholar 

  • Editorial.: Long-term anticoagulant treatment after myocardial infarction. British Medical Journal 1: 514–515 (1970).

    Google Scholar 

  • Ehrlich, J. and Stivala, S.S.: Chemistry and pharmacology of heparin. Review Article. Journal of Pharmaceutical Sciences 62: 517–544 (1973).

    Article  CAS  Google Scholar 

  • Eiber, H.B.; Danishefsky, I. and Borrelli, F.J.: Studies made with radioactive heparin in humans. Angiology 11: 40–43 (1960).

    Article  PubMed  CAS  Google Scholar 

  • Esmon, C.T.; Suttie, J.W. and Jackson, C.M.: The functional significance of Vitamin—K action— Difference in phospholipid binding between normal and abnormal prothrombin. Journal of Biological Chemistry 250: 4095–4099 (1975).

    PubMed  CAS  Google Scholar 

  • Estes, J.W. and Poulin, P.F.: Pharmacokinetics of heparin distribution and elimination. Thrombosis et Diathesis Haemorrhagica 33: 26–37 (1974).

    Google Scholar 

  • Estes, J.W.: The fate of heparin in the body. Current Therapeutic Research 18: 45–57 (1975).

    PubMed  CAS  Google Scholar 

  • Feder, W. and Auerback, R.: ‘Purple toes’: an uncommon sequela of oral coumarin drug therapy. Annals of Internal Medicine 55: 911–917 (1961).

    PubMed  CAS  Google Scholar 

  • Feinstein, A.R.: More blood for the anticoagulant battle. New England Journal of Medicine 292: 1400–1402 (1975).

    Article  PubMed  CAS  Google Scholar 

  • Fleming, H.A. and Bailey, S.M.: Mitral valve disease, systemic embolism and anticoagulants. Postgraduate Medical Journal 47: 599–604 (1971).

    Article  PubMed  CAS  Google Scholar 

  • Fratantoni, J.C. Pollet, R. and Gralnick, H.R.: Heparin-induced thrombocytopenia: Confirmation of diagnosis with in vitro methods. Blood 45: 395–401 (1975).

    PubMed  CAS  Google Scholar 

  • Freeman, R. and King, B.: Infective complications of indwelling intravenous catheters and the monitoring of infections by the nitro blue tetrazolium test. Lancet 1: 992–993 (1972).

    Article  PubMed  CAS  Google Scholar 

  • Freiman, D.G.: Surgical conditions as risk factors in the development of venous thrombosis. Millbank Memorial Foundation Quarterly 50: 60–70 (1972).

    Article  Google Scholar 

  • French, T.E.: The fine structure of experimental thrombi; in Sherry, Brinkhous, Genton and Stengle Thrombos p300 (National Academy of Sciences, Washington DC 1969).

    Google Scholar 

  • Friedli, B.; Aerichide, N.; Grondin, P. and Campeau, L.: Thromboembolic complications of heart valve prosthesis. American Heart Journal 81: 702–708 (1971).

    Article  PubMed  CAS  Google Scholar 

  • Gadboys, H.L.; Iitwak, R.S.; Niemetz, J. and Wisch, N.: Role of anticoagulants in preventing embolization from prosthetic heart valves. Journal of the American Medical Association 202: 282–286 (1967).

    Article  PubMed  CAS  Google Scholar 

  • Gallus, A.S.; Hirsh, J. and Gent, M.: Relevance of preoperative and postoperative blood tests to postoperative leg-vein thrombosis. Lancet 2: 805–809 (1973).

    Article  PubMed  CAS  Google Scholar 

  • Gallus, A.S.; Hirsh, J.; Tuttle, R.J.; Trebilcock, R.; O’Brien, S.E.; Carroll, J.J.; Minden, J.H. and Hudecki, S.M.: Small subcutaneous doses of heparin in prevention of venous thrombosis. New England Journal of Medicine 288: 545–551 (1973).

    Article  PubMed  CAS  Google Scholar 

  • Gallus, A.S. and Hirsh, J.: 125 I-fibrinogen leg scanning in: Fratantoni, J. and Wessler, S. (Eds) Prophylactic therapy of deep vein thrombosis and pulmonary embolism, p.77 (DHEW Publication No. (NIH) 76-866, Government Printing Office, Washington DC, 1975).

    Google Scholar 

  • Gallus, A.S. and Hirsh, J.: Prevention of Venous Thromboembolism. Seminars in Thrombosis and Hemostasis 2: 232–290 (1976a).

    PubMed  CAS  Google Scholar 

  • Gallus, A.S. and Hirsh, J.: Treatment of Venous Thromboembolic Disease. Seminars in Thrombosis and Hemostasis 2: 291–331 (1976b).

    PubMed  CAS  Google Scholar 

  • Gallus, A.S.; Hirsh, J.; Tuttle, R.J.; O’Brien, S.E.; Gent, M. and McBride, J.: Prevention of Venous Thrombosis with Small Subcutaneous Doses of Heparin. Journal of the American Medical Association 235: 1980–1982 (1976b).

    Article  PubMed  CAS  Google Scholar 

  • Genton, E.: Use of anticoagulants in the prevention of embolization from prosthetic heart valves; in Sherry, Brinkhouse, Genton and Stengle (Eds) Thrombosis p.708 (National Academy of Sciences, Washington DC 1969).

    Google Scholar 

  • Genton, E. and Steele. P.: Platelets, Drugs and Heart Disease; in Hirsh, Cade, Gallus and Schonbaum (Eds) Platelets, Drugs and Thrombosis p.263 (Karger, Basel 1975).

    Google Scholar 

  • Gifford, R.H. and Feinstein, A.R.: A critique of methodology in studies of anticoagulant therapy for acute myocardial infarction. New England Journal of Medicine 280: 351–357, 1969.

    Article  PubMed  CAS  Google Scholar 

  • Goldberg, E.; O’Reilly, M. and Chaithiraphan, S.: Prevention of post-brachial arteriotomy thrombosis. Lancet 1: 789 (1972).

    Article  PubMed  CAS  Google Scholar 

  • Goodnight, S.H.; Feinstein, D.I.; Østerud, B. and Rapaport, S.I.: Factor VII antibody —neutralizing material in hereditary and acquired factor VII deficiency. Blood 38: 1–8 (1971).

    PubMed  CAS  Google Scholar 

  • Gordon-Smith, I.C.; LeQuesne, L.P.; Grundy, D.J. and Newcome, J.F.: Controlled trial of two regimens of sub-cutaneous heparin in prevention of post-operative deep-vein thrombosis. Lancet 1: 1133–1135 (1972).

    Article  PubMed  CAS  Google Scholar 

  • Griffith, G.C.; Nichols, G. and Asher, J.D.: Heparin osteoporosis. Journal of the American Medical Association 193: 85–88 (1965).

    Article  Google Scholar 

  • Griffith, J.C. and Boggs, R.B.: The clinical usage of heparin. Amer. J. Cardiol. 14: 39–46 (1964).

    Article  PubMed  CAS  Google Scholar 

  • Gross, H.; Vaid, A.K.; Levine, H.S. and Hasson, J.: Anticoagulant therapy in myocardial infarction. American Journal of Medicine 52: 421–424 (1972).

    Article  PubMed  CAS  Google Scholar 

  • Hamilton, M.W.; Crawford, J.S.; Gardiner, J.H. and Wiley, A.M.: Venous thrombosis in patients with fracture of the upper end of the femur. Journal of Bone and Joint Surgery 52B; 268–289 (1970).

    Google Scholar 

  • Hampson, W.G.J.; Harris, F.C.; Lucas, H.K.; Roberts, P.H.; McCall, I.W.; Jackson, P.S.; Powell, N.L. and Staddon, G.E.: Failure of low-dose heparin to prevent deep-vein thrombosis after hip replacement arthroplasty. Lancet 2: 795–797 (1974).

    Article  PubMed  CAS  Google Scholar 

  • Hancock, B.W. and Naysmith, A.: Hypersensitivity to cholorocresol-preserved heparin. British Medical Journal 3: 746–747 (1975).

    Article  PubMed  CAS  Google Scholar 

  • Handley, A.J.: Low-dose heparin after myocardial infarction. Lancet 2: 623–624 (1972).

    Article  PubMed  CAS  Google Scholar 

  • Handley, A.J.; Emerson, P.A. and Fleming. P.R.: Heparin in the prevention of deep vein thrombosis after myocardial infarction. British Medical Journal 2: 436–438 (1972).

    Article  PubMed  CAS  Google Scholar 

  • Handley, A.J.: Heparin therapy: A Simpler test of control. Journal of Clinical Pathology 27: 250–252 (1974).

    Article  PubMed  CAS  Google Scholar 

  • Hardisty, R.M. and Ingram, G.I.C.: Bleeding Disorders, p320 (Blackwell, Oxford 1965).

    Google Scholar 

  • Hardisty, R.M. and Hutton, R.A.: Platelet aggregation and the availability of platelet factor 3. British Journal of Haemagology 12: 764–767 (1966).

    Article  CAS  Google Scholar 

  • Harris, W.H.; Salzman, E.W. and De Sanctis, R.W.: The prevention of thromboembolic disease by prophylactic anticoagulants. A controlled study in elective hip surgery. Journal of Bone and Joint Surgery 49A: 81–89 (1967).

    Google Scholar 

  • Harris, W.H.; Salzman, E.W.; Athanasoulis, C.; Waltman, A.C.; Baum, S. and DeSanctis, R.W.: Comparison of warfarin, low-molecular-weight dextran, aspirin, and subcutaneous heparin prevention of venous thromboembolism following total hip replacement. Journal of Bone and Joint Surgery 56A: 1552–1562 (1974).

    Google Scholar 

  • Harris, W.H.; Salzman, E.W. Athanasoulis, C; Waltman, A.C.; Baum, S.; DeSanctis, R.W.; Potsaid, M.S. and Sise, H.: Comparison of 125 I-fibrinogen count scanning with phlebography for detection of venous thrombi after elective hip surgery. New England Journal of Medicine 292: 665–667 (1975).

    Article  PubMed  CAS  Google Scholar 

  • Harvey, W.P and Finch, C.A.: Dicumarol prophylaxis of thromboembolic disease in congestive heart failure. New England Journal of Medicine 242: 208–211 (1950).

    Article  PubMed  CAS  Google Scholar 

  • Hattersley, P.G.: Activated coagulation time of whole blood. Journal of the American Medical Association 196: 436–440 (1966).

    Article  PubMed  CAS  Google Scholar 

  • Hirsh, J.; Buchanan, M.; Blynn, M.F. and Mustard, J.F.: Effect of streptokinase on hemostasis. Blood 32: 726–737 (1968).

    PubMed  CAS  Google Scholar 

  • Hirsh, J.; O’Sullivan, E.F.; Gallus, A.S. and Martin, M.: Evaluation of subcutaenous calcium heparin therapy in the treatment of thrombo-embolic disease. Medical Journal of Australia 1: 15–17 (1970a).

    PubMed  CAS  Google Scholar 

  • Hirsh, J.; Cade, J.F. and Gallus, A.S.: Fetal effects of coumadin administered during pregnancy. Blood 36: 623–627 (1970c).

    PubMed  CAS  Google Scholar 

  • Hirsh, J.; Cade, J.F. and Gallus, A.S.: Anticoagulants in pregnancy: A review of indications and complications. American Heart Journal 83: 301–305 (1972).

    Article  PubMed  CAS  Google Scholar 

  • Hirsh, J. and Gallus, A.S.: The activated partial thromboplastin time. New England Journal of Medicine 288: 1410 (1973).

    Google Scholar 

  • Hirsh, J. and Genton, E.: Thrombogenesis; in Root and Berlin (Eds) Physiological Pharmacology. V. Blood, p99 (Academic Press, New York 1974).

    Google Scholar 

  • Hirsh, J.; Genton, E. and Gent, M.: Low-dose heparin prophylaxis for venous thromboembolism; in Fratantoin and Wessler (Eds) Prophylactic Therapy of Deep Vein Thrombosis and Pulmonary Embolism. DHEW Publication No. (NIH) 76–866 (Government Printing Office, Washington, DC, 1975).

    Google Scholar 

  • Hirsh, J.; Van Aken, W.G.; Gallus, A.S.; Dollery, C.T.; Cade, J.F. and Young, W.L.: Heparin Kinetics in venous thrombosis and pulmonary embolism. Circulation 53: 691–695 (1976).

    Article  PubMed  CAS  Google Scholar 

  • Hodby, E.D.; Hirsh, J. and Adeniyi-Jones, C.: The influence of drugs upon the anticoagulant activity of heparin. Canadian Medical Association Journal 106: 562–564 (1972).

    PubMed  CAS  Google Scholar 

  • Hume, M.; Kuriakose, T.; Xavier, Z.L. and Turner, R.H.: 125 I-fibrinogen and the prevention of venous thrombosis. Archives of Surgery 107: 803–806 (1973).

    Article  PubMed  CAS  Google Scholar 

  • Illingworth, R.S.: Ethyl-biscoumacetate (Tromexan) in human milk. Journal of Obstetrics and Gynaecology of the British Empire 66: 487–488 (1959).

    Article  PubMed  CAS  Google Scholar 

  • International Multicentre Trial: Prevention of fatal postoperative pulmonary embolism by low doses of heparin. Lancet 2: 45–51 (1975).

    Google Scholar 

  • Jacobs J.; Kletter, D.; Superstine, E.; Hill, K.R.; Lyne, B. and Webb, R.A.: Intravenous infusions of heparin and penicillins. Journal of Clinical Pathology 26: 742–746 (1973).

    Article  PubMed  CAS  Google Scholar 

  • Jaques, L.B.: The pharmacology of heparin and heparinoids. Progress in Medical Chemistry 5: 139–198 (1967).

    Article  CAS  Google Scholar 

  • Jick, H.; Slone, D.; Borda, I.T. and Shapiro, S.: Efficacy and toxicity of heparin in relation to age and sex. New England Journal of Medicine 279: 284–286 (1968).

    Article  PubMed  CAS  Google Scholar 

  • J/orgensen, L. and Borchgrevink, C.F.: The platelet plug in normal person. I. Histological appearance of the plug 15 and 20 minutes and 24 hours after the bleeding and its role in the capillary haemostasis. Acta Pathologica et Microbiologica Scandinavica 57: 40–56 (1963).

    Google Scholar 

  • Jørgensen, L.; Hirsh, J.; Glynn, M.F.; Buchanan, M.R. and Mustard, J.F.: Effect of streptokinase therapy on experimental fibrin-rich arterial thrombi. American Journal of Pathology 62: 7–12 (1971).

    PubMed  Google Scholar 

  • Jørgensen, L.; Rowsell, H.C.; Hovig, T.; Glynna, M.F. and Mustard, J.F.: Adenosine-diphosphate induced platelet aggregation and myocardial infarction in swine. Laboratory Investigation 17: 614–644 (1967).

    Google Scholar 

  • Josso, F.; Lavergne, J.M.; Gouault, M.; Prou-Wartelle, O. and Soulier, J.P.: Différents états moléculaires du facteur II (prothrombine). Leur étude à l’aide de la staphylocoagulase et d’anticorps antifacteur II. I. Le facteur II chez les sujets traités par les antagonistes de la vitamine K. Thrombosis et Diathesis Haemorrhagica 20: 88–98 (1969).

    Google Scholar 

  • Kakkar, V.V.; Howe, C.T.; Flanc, C. and Clarke, M.B.: Natural history of postoperative deep-vein thrombosis. Lancet 2: 230–233 (1969c).

    Article  PubMed  CAS  Google Scholar 

  • Kakkar, V.V.; Howe, C.T.; Nicolaides, A.N.; Renney, J.T.G. and Clarke, M.B.: Deep vein thrombosis of the leg. Is there a ‘high-risk’ group? American Journal of Surgery 120: 527–530 (1970).

    CAS  Google Scholar 

  • Kakkar, V.V.; Spindler, J.; Flute, P.T.; Corrigan, T.; Fossard, D.P. and Crellin, R.Q.: Efficacy of low-doses of heparin in prevention of deep-vein thrombosis after major surgery; a double-blind randomized trial. Lancet 2: 101–106 (1972).

    Article  PubMed  CAS  Google Scholar 

  • Kerber, I.J.; Warr, O.S. and Richardson, C.: Pregnancy in a patient with a prosthetic mitral valve. Associated with a fetal anomaly attributed to warfarin sodium. Journal of the American Medical Association 203: 223–225 (1968).

    CAS  Google Scholar 

  • Kernohan, R.J. and Todd, C.: Heparin therapy in thromboembolic disease. Lancet 1: 621–623 (1966).

    Article  PubMed  CAS  Google Scholar 

  • Koch-Weser, J. and Sellers, E.M.: Drug interactions with coumarin anticoagulants. New England Journal of Medicine 285: 487–498, 547–558 (1971).

    Article  CAS  Google Scholar 

  • Koch-Weser, J.: Drug interactions during oral anticoagulant therapy; in Dimitrov and Nodine (Eds) Drugs and Hematologic Reactions, p.297 (Grune & Stratton, New York 1974).

    Google Scholar 

  • Lahnborg, G.; Friman, L.; Bergstrom, K. and Lagergren, H.: Effect of low-dose heparin on incidence of postoperative pulmonary embolism detected by photoscanning. Lancet 1: 329–331 (1974).

    Article  PubMed  CAS  Google Scholar 

  • Larrieu, M.J. and Meyer, D.: Abnormal factor IX during anticoagulant treatment. Lancet 2: 1085 (1970).

    Article  PubMed  CAS  Google Scholar 

  • Lee, R.I. and White, P.D.: A clinical study of the coagulation time of blood. American Journal of the Medical Sciences 145: 495–503 (1913).

    Article  Google Scholar 

  • Lewis, R.J.; Trager, W.F.; Robinson, A.J.; Chau, K.K.: Warfarin metabolites: The anticoagulant activity and pharmacology of warfarin alcohols. Journal of Laboratory and Clinical Medicine 81: 925–931 (1973).

    PubMed  CAS  Google Scholar 

  • Mann, K.G.; and Fass, D.N.: Calcium and prothrombin activation. Mayo Clinic Proceedings 49: 929–932 (1974).

    PubMed  CAS  Google Scholar 

  • Marciniak, E.: Binding of heparin in vitro and in vivo to plasma proteins. Journal of Laboratory and Clinical Medicine 84: 344–356 (1974).

    PubMed  CAS  Google Scholar 

  • Marciniak, E.; Farley, C.H. and DeSimone, D.E.: Familial thrombosis due to antithrombin III deficiency. Blood 43: 219–231 (1974).

    PubMed  CAS  Google Scholar 

  • Millikan, C.H.: Anticoagulant or surgical treatment of cerebral ischemia; in Ingelfinger, Ebert, Finland and Relman (Eds) Controversy in Internal Medicine II, p.787 (Saunders, Philadelphia 1974).

    Google Scholar 

  • Morris, G.K.; Henry, A.P.J. and Preston, B.J.: Prevention of deep-vein thrombosis by low-dose heparin in patients undergoing total hip replacement. Lancet 2: 797–799 (1974).

    Article  PubMed  CAS  Google Scholar 

  • Moser, R.H.: Disorders produced by anticoagulants. Bibliographies on diseases of medical progress. Clinical Pharmacology and Therapeutics 9: 388–394 (1968).

    CAS  Google Scholar 

  • Murray, G. and MacKenzie, R.: Postoperative thrombosis and embolism. American Journal of Surgery 57: 414–428 (1942).

    Article  Google Scholar 

  • Murray, G.: Anticoagulants in venous thrombosis and the prevention of pulmonary embolism. Surgery, Gynecology and Obstetrics 84: 665–668 (1947).

    PubMed  CAS  Google Scholar 

  • Mustard, J.F.; Murphy, E.A.; Rowsell, H.C. and Downie, H.G.: Factors influencing thrombus formation in vivo. American Journal of Medicine 33: 621–647 (1962).

    Article  PubMed  CAS  Google Scholar 

  • Mustard, J.F.: Hemostasis and Thrombosis. Seminars in Hematology 5: 91–106 (1968).

    PubMed  CAS  Google Scholar 

  • Mustard, J.F. and Packham, M.A.: Thromboembolism: A manifestation of the response of blood to injury. Circulation 42: 1–21 (1970a).

    Article  PubMed  CAS  Google Scholar 

  • Mustard, J.F. and Packham, M.A.: Platelets thrombosis and drugs. Drugs 9: 19–76 (1975).

    Article  PubMed  CAS  Google Scholar 

  • Nader, H.B.; McDuffie, N.M. and Dietrich, C.P.: Heparin fractionation by electrofocusing: presence of 21 components of different molecular weights. Biochemical and Biophysical Research Communications 57: 488–493 (1974).

    Article  PubMed  CAS  Google Scholar 

  • Nalbandian, R.M.; Beller, F.K.: Kamp, A.K.; Henry, R.L. and Wolf, P.L.: Coumarin necrosis of skin treated successfully with heparin. Obstetrics and Gynecology 38: 395–399 (1971).

    CAS  Google Scholar 

  • Natelson, E.A.; Lynch, E.C.; Alfrey, C.R. and Gross, J.B.: Heparin-induced thrombocytopenia. Annals of Internal Medicine 71: 1121–1125(1969).

    PubMed  CAS  Google Scholar 

  • Nelsestuen, G.L.; Zytokvicz, T.H. and Howard, J.B.: α-Carboxyglutamic acid. Identification and distribution in Vitamin K-dependent proteins. Mayo Clinic Proceedings 49: 941–944 (1974).

    CAS  Google Scholar 

  • Nicolaides, A.N.; Desai, S.; Douglas, J.N.; Fourides, G.; Dupont, P.A.; Lewis, J.D.; Dodsworth, H.; Luck, K.J. and Jamieson, C.W.: Small doses of subcutaneous sodium heparin in preventing deep venous thrombosis after major surgery. Lancet 2: 890–893 (1972).

    Article  PubMed  CAS  Google Scholar 

  • O’Reilly, R.A. and Aggeler, P.M.: Studies on coumarin anticoagulant drugs: initiation of warfarin therapy without a loading dose. Circulation 38: 169–177 (1968).

    Article  PubMed  Google Scholar 

  • O’Reilly, R.A. and Aggeler, P.A.: Determinants of the response to oral anticoagulant drugs in man. Pharmacology Reviews 22: 35–96 (1970).

    Google Scholar 

  • O’Reilly, R.A.: The pharmacodynamics of the oral anticoagulant drugs. Progress in Hemostasis and Thrombosis 2: 175–213 (1974).

    PubMed  Google Scholar 

  • Orme, M.; Breckenridge, A. and Brooks, R.V.: Interactions of benzodiazepines with warfarin. British Medical Journal 3: 611–614 (1972).

    Article  PubMed  CAS  Google Scholar 

  • O’Sullivan, E.F.; Hirsh, J.; McCarthy, R.A. and de Gruchy, G.C.: Heparin in the treatment of venous thromboembolic disease. Medical Journal of Australia 2: 153–159(1968).

    PubMed  Google Scholar 

  • Paterson, J.C.: The pathology of venous thrombi; in Sherry, Brinkhous, Genton, and Stengle (Eds) Thrombo p.321 (National Academy of Sciences, Washington DC 1969).

    Google Scholar 

  • Pettifor, J.M. and Benson, R.: Congenital malformation associated with the administration of oral anticoagulants during pregnancy. Journal of Pediatrics 86: 459–462 (1975).

    Article  PubMed  CAS  Google Scholar 

  • Pitney, W.R.; Pettit, J.E. and Armstrong, L.: Control of heparin therapy. British Medical Journal 4: 139–141 (1970).

    Article  PubMed  CAS  Google Scholar 

  • Pritchard, J.: Stability of heparin solutions. Journal of Pharmaceutics and Pharmacology 16: 487–489 (1964).

    Article  CAS  Google Scholar 

  • Ratnoff, O.D.: The physiology of blood coagulation; in Root, and Berlin (Eds) Physiologic Pharmacology, V, Blood p5 (Academic Press, New York 1974).

    Google Scholar 

  • Ray, P.K. and Harper, T.A.: Comparison of activated recalcification and partial thromboplastin tests as controls of heparin therapy. Journal of Laboratory and Clinical Medicine 77: 901–907 (1971).

    PubMed  CAS  Google Scholar 

  • Rem, J.; Duckert, F.; Fridric, R. and Gruber, U.R.: Subkutane kleine Heparin dosen zur Thromboseprophylaxe in der allgemeinen Chirurgie and Urologie. Schweizerische Medizinische Wochenschrift 105: 827–835 (1975).

    PubMed  CAS  Google Scholar 

  • Report of Working Party on Anticoagulant Therapy in Coronary Thrombosis to the Medical Research Council. Assessment of short-term anti-coagulant administration after cardiac infarction. British Medical Journal 1: 335–342 (1969).

    Article  Google Scholar 

  • Rhodes, G.R.; Dixon, R.H. and Silver, D.: Heparin induced thrombocytopenia with thrombotic and hemorrhagic manifestations. Surgery, Gynecology and Obstetrics 136: 409–416 (1973).

    PubMed  CAS  Google Scholar 

  • Rodman, N.F.; Barrow, E.M. and Graham, J.B.: Diagnosis and control of the hemophilioid states with the partial thromboplastin time (PTT) test. American Journal of Clinical Pathology 29: 525–538 (1958).

    PubMed  Google Scholar 

  • Romanucci, D.; Jakovic, L.G. and Smedberg, K.: Anticoagulants and hemorrhage — Breast necrosis: A case report. Angiology 25: 612–616 (1974).

    Article  PubMed  CAS  Google Scholar 

  • Rosenberg, I.L.; Evans, M. and Pollock, A.V.: Prophylaxis of postoperative leg vein thrombosis by low dose subcutaneous heparin or preoperative calf muscle stimulation: A controlled clinical trial. British Medical Journal 1: 649–651 (1975).

    Article  PubMed  CAS  Google Scholar 

  • Rosenberg, R.D. and Damus, P.S.: The purification and mechanism of action of human antithrombin-heparin cofactor. Journal of Biological Chemistry 248: 6490–6505 (1973).

    PubMed  CAS  Google Scholar 

  • Rosenberg, R.D.: Heparin action. Circulation 49: 603–605 (194a).

  • Rosenberg, R.D.: The effect of heparin on factor XIa and plasmin. Thrombosis et Diathesis Haemorrhagica 33: 51–62 (1974b).

    Google Scholar 

  • Rosenberg, R.D.: Actions and interactions of antithrombin and heparin. New England Journal of Medicine 292: 146–151(1975).

    Article  PubMed  CAS  Google Scholar 

  • Sackler, J.P. and Lin, L.: Heparin-induced osteoporosis. British Journal of Radiology 46: 548–550 (1973).

    Article  PubMed  CAS  Google Scholar 

  • Salzman, E.W.; Harris, W.H. and DeSanctis, R.W.: Anti-coagulation for prevention of thromboembolism following fractures of the hip. New England Journal of Medicine 275: 122–130 (1966).

    Article  PubMed  CAS  Google Scholar 

  • Salzman, E.W.; Deykin, D.; Shapiro, R.M. and Rosenberg, R.: Management of heparin therapy. Controlled prospective trial. New England Journal of Medicine 292: 1046–1050 (1975).

    CAS  Google Scholar 

  • Scottish Study: A multi-unit controlled trial: Heparin versus dextran in the prevention of deep-vein thrombosis. Lancet 2: 118–120 (1974).

    Google Scholar 

  • Sevitt, S. and Gallagher, N.G.: Prevention of venous thrombosis and pulmonary embolism in injured patients. Trial of anticoagulant prophylaxis in middleaged and elderly patients with fractured necks of femur. Lancet 2: 981–989 (1959).

    CAS  Google Scholar 

  • Sevitt, S. and Gallagher, N.: Venous thrombosis and pulmonary embolism: A clinico-pathological study in injured and burned patients. British Journal of Surgery 48: 475–489 (1961).

    Article  PubMed  CAS  Google Scholar 

  • Sevitt, S. and Innes, D.; Prothrombin-time and thrombotest in injured patients on prophylactic anticoagulant therapy. Lancet 1: 124–129 (1964).

    Article  PubMed  CAS  Google Scholar 

  • Sevitt, S.: Venous thrombosis in injured patients (with some observations on pathogenesis); in Sherry, Brinkhous, Genton and Stengle (Eds) Thrombosis, p29 (National Academy of Sciences, Washington DC 1969).

    Google Scholar 

  • Sevitt, S.: Organization of valve pocket thrombi and the anomalies of double thrombi and valve cusp involvement. British Journal of Surgery 61: 641–649 (1974).

    Article  PubMed  CAS  Google Scholar 

  • Sherry, S.: Low-dose heparin prophylaxis for postoperative venous thromboembolism. New England Journal of Medicine 293: 300–302 (1975).

    Article  PubMed  CAS  Google Scholar 

  • Silverglade, A.: Biological equivalence of beef lung and hog mucosal heparin. Current Therapeutic Research 18: 91–103 (1975).

    PubMed  CAS  Google Scholar 

  • Soloway, H.B.; Cornett, B.M. and Grayson, J.W.: Comparison of various activited partial thromboplastin reagents in the laboratory control of heparin therapy. American Journal of Clinical Pathology 59: 587–590 (1973a).

    PubMed  CAS  Google Scholar 

  • Soloway, H.B.; Cornett, B.M. and Grayson, J.W.: Comparison of various activated partial thromboplastin reagents in the laboratory control of heparin therapy. American Journal of Clinical Pathology 59: 760–762 (1973b).

    PubMed  CAS  Google Scholar 

  • Spaet, R.H. and Zucker, M.B.: Mechanism of platelet plug formation and role of adenosine diphosphate. American Journal of Physiology 206: 1267–1274 (1964).

    PubMed  CAS  Google Scholar 

  • Spaet, T.H.: Hemostatic homeostasis. Blood 28: 112–123 (1966).

    PubMed  CAS  Google Scholar 

  • Spaet, T.H. and Erickson, R.B.: The vascular wall in the pathogenesis of thrombosis. Thrombosis et Diathesis Haemorrhagica 21 (Suppl.): 67–86 (1966).

    CAS  Google Scholar 

  • Spector, I. and Corn, M.: Control of heparin therapy with activated partial thromboplastin times. Journal of the American Medical Association 201: 157–159 (1967).

    Article  Google Scholar 

  • Steele, P.P.; Weily, H.S. and Genton, E.: Platelet survival and adhesiveness in recurrent venous thrombosis. New England Journal of Medicine 288: 1148–1152 (1973).

    Article  PubMed  CAS  Google Scholar 

  • Stemerman, M.B.: Vascular Intimai Components: Precursors of thrombosis: in Spaet (Ed) Progress in Hemostasis and Thrombosis, 2, p1 (Grune & Stratton, New York 1974).

    Google Scholar 

  • Stock, S.L. and Warner, N.: Heparin in acid solutions. British Medical Journal 3: 307 (1971).

    Article  PubMed  CAS  Google Scholar 

  • Storm, O.: Anticoagulant protection in surgery. Thrombosis et Diathesis Haemorrhagica 2: 484–491 (1958).

    PubMed  CAS  Google Scholar 

  • Stuart, R.K. and Michel, A.: Monitoring heparin therapy with the activated partial thromboplastin time. Canadian Medical Association Journal 104: 385–388 (1971).

    PubMed  CAS  Google Scholar 

  • Suttie, J.W.; Grant, G.A.; Esmon, C.T. and Shah, D.V.: Postribosomal function of Vitamin K in prothrombin synthesis. Mayo Clinic Proceedings 49: 933–940 (1974).

    PubMed  CAS  Google Scholar 

  • Thompson, R.C.: Heparin osteoporosis. An experimental model using rats. Journal of Bone and Joint Surgery 55A: 606–612 (1973).

    Google Scholar 

  • Udall, J.A.: Warfarin therapy not influenced by meprobamate. A controlled study in nine men. Current Therapeutic Research 12: 724–728 (1970).

    CAS  Google Scholar 

  • Udall, J.A.: Warfarin-chloral hydrate interaction. Pharmacological activity and clinical significance. Annals of Internal Medicine 81: 341–344 (1974).

    CAS  Google Scholar 

  • Urokinase Pulmonary Embolism Trial. A national cooperative study. Circulation 47: (Suppl. 11) 1–108 (1973).

    Google Scholar 

  • Venous Thrombosis Clinical Study Group: Small doses of subcutaneous sodium heparin in the prevention of deep vein thrombosis after elective hip operations. British Journal of Surgery 62: 348–350 (1975).

    Article  Google Scholar 

  • Verstraete, M. and Verwilghen, R.L.: Haematological disorders. Drug interactions with oral anticoagulants; in Avery (Ed) Drug Treatment: Principles and Practice of Clinical Pharmacology and Therapeutics, p681 (ADIS Press, Sydney/Auckland 1976).

    Google Scholar 

  • Vessel, E.S.; Passananti, G.T. and Johnson, A.O.: Failure of indomethacin and warfarin to interact in normal human volunteers. The Journal of Clinical Pharmacology 15: 486–495 (1975).

    Google Scholar 

  • Vieweg, W.V.R.; Piscatelli, P.L.; Houser, J.J. and Proulx, R.A.: Complications of intravenous administration of heparin in elderly women. Journal of the American Medical Association 213: 1303–1306 (1970).

    Article  PubMed  CAS  Google Scholar 

  • Warlow, C.; Terry, G.; Kenmure, A.C.F.; Beattie, A.G.; Ogston, D. and Douglas, A.S.: A double-blind trial of low doses of subcutaneous heparin in the prevention of deep-vein thrombosis after myocardial infarction. Lancet 2: 934–936 (1973).

    Article  PubMed  CAS  Google Scholar 

  • Wessler, S.; Morris, L.E.; Ho, C. and Moran, J.: Studies in intravascular coagulation IV. The effect of heparin and dicoumarol on serum-induced venous thrombosis. Circulation 12: 553–556 (1955).

    CAS  Google Scholar 

  • Wessler, S.: Thrombosis in the presence of vascular stasis. American Journal of Medicine 33: 648–666 (1962).

    Article  PubMed  CAS  Google Scholar 

  • Wessler, S. and Yin, E.T.: On the mechanism of thrombosis; in Brown and Moore (Eds) Progress in Hematology, p.1201 (Grune and Stratton, New York 1969).

    Google Scholar 

  • Williams, H.T.: Prevention of postoperative deep vein thrombosis with perioperative subcutaneous heparin. Lancet 2: 950–952 (1971).

    Article  PubMed  CAS  Google Scholar 

  • Wray, R.; Maurer, B. and Shillingford, J.: Prophylactic anticoagulant therapy in the prevention of calf-vein thrombosis after myocardial infarction. New England Journal of Medicine 288: 815–817 (1973).

    Article  PubMed  CAS  Google Scholar 

  • Wright, I.S.; Marple, CD. and Beck, D.F.: Report of the committee for the evaluation of anticoagulants in the treatment of coronary thrombosis with myocardial infarction. American Heart Journal 36: 801–815 (1948).

    Article  PubMed  CAS  Google Scholar 

  • Yin, E.T.; Wessler, S. and Stoll, P.J.: Biological properties of the naturally occurring plasma inhibitor to activated Factor X. Journal of Biological Chemistry 246: 3703–3711(1971).

    PubMed  CAS  Google Scholar 

  • Yin, E.T.; Wessler, S.; Butler, J.V. and Cole, J.: Plasma heparin: a unique, practical, submicrogram-sensitive assay. Journal of Laboratory and Clinical Medicine 81: 298–310 (1973).

    PubMed  CAS  Google Scholar 

  • Yin, E.T.: Effect of heparin on the neutralization of Factor Xa and thrombin by the plasma alpha-2-globulin inhibitor. Thrombosis et Diathesis Haemorrhagica 33: 43–50 (1974). auZilliacus, H.: On the specific treatment of thrombosis and pulmonary embolism with anticoagulants, with particular reference to the post-thrombotic sequelae. Acta Medica Scandinavica (Suppl. 171): 1–200 (1946).

    Google Scholar 

  • Zucker, S.; Cathey, M.H. and Wylie, R.L.: Control of heparin therapy. Sensitivity of the activated partial thromboplastin time for monitoring the antithrombotic effect of heparin. Journal of Laboratory and Clinical Medicine 73: 320–326 (1969).

    CAS  Google Scholar 

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    A. S. Gallus &  J. Hirsh

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First of a 2-part review. Part II will appear in the next issue

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Gallus, A.S., Hirsh, J. Antithrombotic Drugs: Part I. Drugs 12, 41–68 (1976). https://doi.org/10.2165/00003495-197612010-00002

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