The previous dogmas regarding heparin therapy are currently being challenged. It is apparent that the experimental work on which guidelines for heparin therapy are based do not necessarily have any relevance clinically. Once clotting has been initiated, there are multiple factors that result in a relative refractory response to heparin anticoagulation. In addition, it is now apparent that heparin's effect cannot be accurately monitored with current tests of anticoagulation. Most importantly, the risk of bleeding does not correlate with heparin levels but with clinical risk factors and to the presence or absence of functioning platelets. For this reason, sufficient heparin should be given initially to ensure that clotting is under control. If this is not done, all of the risk of heparin anticoagulation is assumed with none of the benefit. Life-threatening clotting conditions require high doses of heparin, equivalent to those required for cardiopulmonary bypass. Even though there is no good laboratory test available to ascertain the adequacy of anticoagulation, assessment of the clinical response is sufficient. When heparin levels are adequate, clinical improvement is evident as manifest by decreased pain and improvement in well-being, cardiac function, and/or collateral flow.
BairdRJ. The story of heparin — As told by sketches from the lives of William Howell, Jay McLean, Charles Best, and Gordon Murray. J Vasc Surg1990; 11: 4–18.
2.
MajerusPWBrozeGJJrMiletichJPTollefsenDM. Anticoagulant, thrombolytic and antiplatelet drugs. In: Goodman and Gilman's The Pharmacological Basis sof Therapeutics, 8th ed.New York: Pergamon Press, 1990: 1313–17.
3.
FarcedJ.Heparin, its fractions, fragments and derivatives. Semin Thromb Hemost1985; 11: 1–9.
4.
FarcedJHoppensteadtDWalengaJM. Low molecular weight heparins in the management of thrombotic disorders. In: FareedJ. ed. Low Molecular Weight Heparin in the Prophylaxis and Treatment of Thrombosis.Chicago: Loyola University Press, 1994: 233–41.
5.
VairelEGBoury-BoyeHToulemondeFDoutremepuichCMarshNAGaffneyPJ. Heparin and a low molecular weight fraction enhances thrombolysis and by this pathway exercises a protective effect against thrombosis. Thromb Res1983; 30: 219–24.
6.
BarrowcliffeTW. LMWH: Relationship between antithrombotic and anticoagulant effects. In: LaneDABjorkILindahlU, eds. Heparin and Related Polysaccharides.New York: Plenum Press, 1992: 205–20.
7.
AbildgaardU.Tissue factor pathway inhibitor and heparin. In: LaneDABjorkILindahlU, eds. Heparin and Related Polysaccharides.New York: Plenum Press, 1992: 199–204.
BithellTC. Thrombosis and antithrombotic therapy. In: LeeGRBithellTCFoersterJAthensJWLukensJN, eds. Wintrobe's Clinical Hematology, 9th ed. Philadelphia: Lee and Febiger, 1993: 1515–28.
10.
DietrichWSpannaglMSchrammWThe influence of preoperative anticoagulation on heparin response during cardiopulmonary bypass. J Thorac Cardiovasc Surg1991; 102: 505–14.
11.
FernandezFN'guyenPVan RynJOfosuFAHirshJBuchananMR. Hemorrhagic dose of heparin and other glycosaminoglycans. Thromb Res1986; 43: 491–5.
12.
ZuckerMB. Heparin and platelet function. Fed Proc1977; 36: 47–9.
13.
Grulich-HennJPreissnerKTMuller-BerghausG.Heparin stimulates fibrinolysis in mesothelial cells by selective induction of tissue-plasminogen activator but not plasminogen activator inhibitor-1 synthesis. Thromb Haemost1990; 64: 420–5.
14.
EkreH-PNaparastekYLiderOAnti-inflammatory effects of heparin and its derivatives. Inhibition of complement and of lymphocyte migration. In: LaneDABjorkILindahlU, eds. Heparin and Related Polysaccharides.New York: Plenum Press, 1992: 329–40.
15.
SalibaMJSalibaSJ. Heparin in burns: Dose related and dose dependent effects. Thrombosis et Diathesis Haemorrhagica1974; 33: 113–23.
16.
FioreLDeykinD.Anticoagulant therapy. In: BeutlerELichtmanMACollerBSKippsTJ, eds. Williams Hematology, 5th ed. New York: McGraw-Hill Inc., 1995: 1562–80.
17.
DeykinD.Current concepts: The use of heparin. N Engl J Med1982; 280: 937–8.
18.
HolmHAKalvenesSAbildgaardU.Changes in plasma antithrombin during intravenous heparin therapy. Scand J Haematol1985; 35: 564–9.
19.
HemkerHCBeguinS.The mode of action of heparins in vitro and in vivo. In: LaneDABjorkILindahlU, eds. Heparin and Related Polysaccharides.New York: Plenum Press, 1992: 221–30.
20.
HowellWHHoltE.Two new factors in blood coagulation — Heparin and pro-antithrombin. Am J Physiol1918; 47: 328–41.
21.
BestCH. Heparin and thrombosis. J Physiol1938; 92: 20–31.
22.
BestCH. Preparation of heparin and its use in the first clinical cases. Circulation1959; 19: 79–86.
23.
MurrayDWGJaquesLBPerrettTSBestCH. Heparin and vascular occlusion. Can Med Assoc J1936; 35: 621–2.
24.
CrafoordC.Preliminary report on post-operative treatment with heparin as a preventive of thrombosis. Acta Chir Scand1937; 79: 407–26.
25.
JorpesJE. Heparin in the Treatment of Thrombosis, 2nd ed. London: Oxford University Press, 1946.
26.
MurrayDWGJaquesLBPerrettTSBestCH. Heparin and the thrombosis of veins following injury. Surgery1937; 2: 163–87.
27.
MurrayGDW. Experimental surgery: Heparin in thrombosis and embolism. Br J Surg1939; 27: 567–98.
28.
MurrayG.Anticoagulants in venous thrombosis and the prevention of pulmonary embolism. Surg Gynecol Obstet1947; 84: 665–8.
29.
MurrayGWDBestCH. The use of heparin in thrombosis. Ann Surg1938; 108: 163–77.
30.
MurrayGWD. Heparin in surgical treatment of blood vessels. Arch Surg1940; 40: 307–25.
31.
JaquesLBRickerAG. The relationship between heparin dosage and clotting. Blood1948; 3: 1197–212.
32.
JaquesLB. A fundamental consideration of anticoagulant therapy. N Engl J Med1950; 243: 395–401.
33.
WesslerS.Studies in intravascular coagulation. I. Coagulation changes in isolated venous segments. J Clin Invest1952; 31: 1011–114.
34.
WesslerS.Studies in intravascular coagulation. II. A comparison of the effect of dicoumarol and heparin on clot formation in isolated venous segments. J Clin Invest1953; 32: 650–3.
35.
WesslerS.Studies in intravascular coagulation. III. The pathogenesis of serum-induced venous thrombosis. J Clin Invest1955; 34: 647–51.
36.
WesslerS.Studies in intravascular coagulation. IV. The effect of heparin and dicoumarol on serum-induced venous thrombosis. Circulation1955; 12: 553–6.
37.
SalzmanEWDeykinDShapiroRMRosenbergR.Management of heparin therapy. N Engl J Med1975; 292: 1046–50.
38.
PennerJA. Managing the hemorrhagic complications of heparin therapy. Hematol Oncol Clin North Am1994; 7: 1281–9.
39.
ChiuHMHirshJYungWLRegoecziEGentM.Relationship between the anticoagulant and antithrombotic effects of heparin in experimental venous thrombosis. Blood1977; 49: 171–84.
40.
MarderVJ. Variations of heparin therapy for thromboembolic disease. Med Clin North Am1974; 58: 1121–8.
41.
HirshJ.Treatment of venous thrombosis with heparin. In: KakkarWThomasDP, eds. Heparin: Chemistry and Clinical Usage.New York: Academic Press, 1992: 175–88.
42.
HyersTMHullRDWegJG. Antithrombotic therapy for venous thromboembolic disease. Chest1986; 89: S26–35.
43.
MoserKM. Pulmonary thromboembolism. In: IsselbacherKJBraunwaldEWilsonJDMartinJBFauciASKasperDL, eds. Harrison's Principles of Internal Medicine, 13th ed. New York: McGraw Hill Inc., 1994: 1218–20.
44.
SchrieverHGEpsteinSEMintzMD. Statistical correlation and heparin sensitivity of activated partial thromboplastin time, whole blood coagulation time, and an automated coagulation time. Am J Clin Pathol1973; 60: 323–9.
45.
WesslerS.Current dilemmas in the clinical use of heparin. Fed Proc1977; 36: 66–9.
46.
ConlanMGFolsomARFinchAAntithrombin III: Associations with age, race, sex and cardiovascular disease risk factors. Thromb Haemost1994; 72: 551–6.
47.
WhitfieldLRSchentagJJLevyGL. Relationship between concentration and anticoagulant effect of heparin in plasma of hospitalized patients. Clin Pharmacol Ther1982; 32: 503–16.
48.
DamusPSWallaceGA. Immunologic measurement of antithrombin III. Thromb Res1975; 6: 27–38.
49.
OdegardORLieMAbildgaardU.Heparin cofactor activity measured with an amidolytic method. Thromb Res1975; 6: 287–94.
50.
WeitzJIHudobaMMasselDMaraganoreJHirshJ.Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-dependent inhibitors. J Clin Invest1990; 86: 385–91.
51.
WalzDAHungG-L.In vivo studies on the binding of heparin and its fractions with platelet factor 4. Semin Thromb Hemost1985; 11: 40–7.
52.
HirshJ.Relationship between dose, anticoagulant effect and the clinical efficacy and safety of heparin. In: LaneDABjorkILindahlU, eds. Heparin and Related Polysaccharides.New York: Plenum Press, 1992: 283–95.
53.
ToffefsenDM. Interaction of glycosaminoglycans with heparin cofactor II. In: LaneDABjorkILindahlU, eds. Heparin and Related Polysaccharides.New York: Plenum Press, 1992: 167–75.
54.
WesslerSGitelSN. Heparin: New concepts relevant to clinical use. Blood1970; 53: 525–44.
55.
BlaisdellFWGrazianoCJEffeneyDJ. In vivo assessment of anticoagulation. Surgery1977; 82: 827–39.
56.
BlaisdellFWGrazianoCJ. Assessment of clotting by the determination of fibrogen catabolism. Am J Surg1978; 135: 436–43.
57.
MooreFDOsteenRTKarpDDAnticoagulants, venous thromboembolism, and the cancer patient. Arch Surg1981; 116: 405–7.
FedulloPFHartmanMTKonopkaRGEffect of heparin on indium-111 platelet and I-125 fibrinogen uptake by venous thrombi. Circulation1983; 68(IIIs): 106.
60.
HolmHAAbildgaardUKalvenesSThe antithrombotic effect of heparin in deep venous thrombosis: Relation to four heparin assays. Acta Med Scand1984; 216: 287–93.
61.
GravleeGPHaddonWSRothbergerHKHeparin dosing and monitoring for cardiopulmonary bypass. J Thorac Cardiovasc Surg1990; 99: 518–27.
62.
GurewichV.Guidelines for the management of anticoagulant therapy. Semin Thromb Hemost1976; 2: 176–96.
63.
ClagettGPReischJS. Prevention of venous thromboembolism in general surgical patients. Ann Surg1988; 208: 227–40.
64.
WeberEWalterEHarengergJ.Side effects of heparin: In: WittI, ed. Heparin: New Biochemical and Medical Aspects.Berlin: Walter de Gruyter, 1983: 241–59.
65.
Michel-MeyerS.Treatment of deep vein thrombosis (DVT) with low molecular weight heparins (LMWH). In: LaneDABjorkILindahlU, eds. Heparin and Related Polysaccharides.New York: Plenum Press, 1992: 275–81.
66.
NieuwenhuisHKAlbadaJBangaJDSixmaJJ. Identification of risk factors for bleeding during treatment of acute venous thromboembolism with heparin or low molecular weight heparin. Blood1991; 78: 2337–43.
DeykinD.The risks and benefits of heparin therapy (Editorial). West J Med1982; 136: 241–2.
69.
BasuDGallusAHirshJCadeJ.A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med1972; 287: 324–7.
70.
JickHSloneDBordaITShapiroS.Efficacy and toxicity of heparin in relation to age and sex. N Engl J Med1968; 279: 284–6.
71.
HullRDRaskobGERosenbloomDHeparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis. N Engl J Med1990; 322: 1260–4.
BlaisdellFW. Thromboembolic problems, Sect VII. In: BrennanMRHarkenAHHolcroftJWMeakinsJL, eds. Care of the Surgical Patient.New York: Scientific American, 1992: 2–32.
74.
MantMJO'BrienBDThongKLHammondGWBirtwhistleRVGraceMG. Hemorrhagic complications of heparin therapy. Lancet1977; 1: 1133–5.
75.
PitneyWRPettitJEArmstrongL.Control of heparin therapy. Br Med J1970; 2: 139–41.
76.
WilsonJRLampmanJ.Heparin therapy: A randomized prospective study. Am Heart J1979; 97: 155–8.
77.
ContiSDaschbachMBlaisdellEW. A comparison of high-dose versus conventional dose heparin therapy for deep vein thrombosis. Surgery1982; 92: 972–80.
78.
KashtanJWContiSBlaisdellFW. Heparin therapy for deep venous thrombosis. Am J Surg1980; 104: 837–42.
79.
HunterGCarsonSWongH.Low versus high-dose heparin in the treatment of pulmonary embolism. Vasc Surg1980; 14: 238–42.
80.
NelsonPHMoserKMStonerCMoserKS. Risk of complications during intravenous heparin therapy. West J Med1982; 136: 189–97.
81.
LandefeldCSCookEEFlatleyMWeisbergMGoldmanL.Identification and preliminary validation of predictors of major bleeding in hospitalized patients starting anticoagulant therapy. Am J Med1987; 82: 703–13.
82.
WalkerAMJickH.Predictors of bleeding during heparin therapy. JAMA1980; 244: 1209–12.
83.
ThomasDP. Heparin and pulmonary embolism. In: KakkarVVThomasDP, eds. Heparin: Chemistry and Clinical Usage.New York: Academic press, 1976: 189–99.
84.
FagherBLundhB.Heparin treatment of deep vein thrombosis. Acta Med Scand1984; 210: 357–61.
85.
EngelbergH.Adverse reactions to heparin. In: EngelbergH, ed. Heparin and the Prevention of Atherosclerosis.New York: Wiley-Liss, 1990: 191–7.
86.
deTakatsG.Heparin: The need for a flexible protocol (Editorial). Am J Surg1976; 132: 1–3.
87.
AdamsJGHumphreyLJZhangXSilverD.Heparin specific antibodies in patients with heparin induced thrombocytopenia. J Vasc Surg1995; 21: 247–54.
88.
GreinacherAMichelsIKiefelVMueller-EckhardtC.A rapid and sensitive test for diagnosing heparin-associated thrombocytopenia. Thromb Haemost1991; 66: 734–6.
89.
BoldtJSchindlerEOsmerCWittstockMStertmannWAHempelmannG.Influence of different anticoagulation regimens on platelet function during cardiac surgery. Br J Anaesth1994; 73: 639–44.
90.
Ryn-McKennaJVOfosuFAHirshJBuchananMR. Antithrombotic and bleeding effects of glycosaminoglycans with different degrees of sulphation. Br J Haematol1989; 71: 265–9.
91.
HashimotoKYamagishiMSasakiTNakanoMKurosawaH.Heparin and antithrombin III levels during cardiopulmonary bypass: Correlation with subclinical plasma coagulation. Ann Thorac Surg1994; 58: 799–805.
92.
HolmerESoderstromGAnderssonL-O.Effect of heparin in antithrombin III depleted plasma. International Congress on Thrombosis and Haemorrhage1979; VII, 9.
93.
MillerRSWeatherfordDASteinDCraneMMSteinM.Antithrombin III and trauma patients: Factors that determine low levels. J Trauma1994; 37: 442–5.
94.
BlaisdellFWSteeleMAllenRE. Management of acute arterial ischemia due to embolism and thrombosis. Surgery1978; 84: 822–34.
95.
QuickAJ. On the action of heparin and its relation to thromboplastin. Am J Physiol1936; 115: 317–33.
96.
FennertyAThomasPBackhouseGAudit of control of heparin treatment. Br Med J Clin Res1985; 290: 27–8.
97.
GansHKrivitW.Problems in hemostasis during open heart surgery. IV. On the changes in the blood clotting mechanism during cardiopulmonary bypass surgery. Ann Surg1961; 155: 353–9.
98.
GentonE.Guidelines for heparin therapy. Ann Intern Med1974; 80: 77–82.
