HEPARIN was discovered in 1916 by McLean,1 who as a medical student was looking for a coagulant in the liver. In 1939, Brinkhous and associates2 demonstrated that the anticoagulant activity of heparin requires a plasma cofactor (that they called heparin cofactor). In 1968, Abildgaard3 renamed the substance antithrombin III, and the mechanism of interaction between antithrombin III and heparin was elucidated in the 1970s.4 5 6 7 The active center serine of thrombin and other coagulation enzymes is inhibited by an arginine reactive center of the antithrombin III molecule. Heparin binds to lysine sites on antithrombin III and produces a conformational change at the arginine reactive center, thereby converting antithrombin III from a progressive, slow inhibitor to a very rapid inhibitor5; heparin then dissociates from the complex and can be reused.5 The site on the heparin molecule that binds to antithrombin III and potentiates its activity was subsequently found to contain a unique glucosamine unit4 5 6 , 8 and to have a pentasaccharide sequence.9 The structure of the high-affinity pentasaccharide has been confirmed by chemical synthesis.10

Commercial preparations of heparin are heterogeneous, their components having molecular weights ranging from 3000 to 30,000 (mean, 15,000). Only about one third of the heparin binds to antithrombin III, and this fraction is responsible for most of its anticoagulant effect.11 , 12 The remaining two thirds has minimal anticoagulant activity at therapeutic concentrations, but high concentrations (greater than those usually obtained clinically) catalyze the antithrombin effect of a second plasma protein cofactor, heparin cofactor II.13

In addition to its anticoagulant effects, heparin inhibits platelet function14 and increases the permeability of vessel walls.15 Heparin also inhibits the proliferation of vascular smooth-muscle cells16 (an effect that is independent of its anticoagulant activity17) and delayed hypersensitivity reactions,18 and it is involved in the regulation of angiogenesis.19 This review will focus on the effects of heparin on hemostasis.

The heparin—antithrombin III complex inactivates a number of coagulation enzymes, including thrombin and activated factors X, XII, XI, and IX.5 Thrombin and activated factor X (factor Xa) are the most sensitive to inactivation5; of the two, thrombin is the more sensitive to inhibition by about one order of magnitude.5 , 13 The inhibition of thrombin requires that both antithrombin III and the enzyme bind to heparin, but the inhibition of factor Xa requires that heparin only bind to antithrombin III.8 Heparin molecules with fewer than 18 saccharide residues are unable to bind to thrombin and antithrombin III simultaneously and thus cannot catalyze the inhibition of thrombin. In contrast, even smaller heparin fragments that contain the high-affinity pentasaccharide sequence are able to catalyze the inhibition of factor Xa by antithrombin III.20 21 22 23 There is increasing evidence that heparin's principal inhibitory effect on coagulation is through the inhibition of thrombin-induced activation of factor V and factor VIII.24 25 26

Heparin is poorly absorbed from the gastrointestinal tract and is usually administered by intravenous or subcutaneous injection. After injection, heparin circulates bound to many plasma proteins.27 The pharmacokinetics of heparin are complicated and incompletely understood. There is no suitable chemical assay for heparin, so the investigation of its kinetics has depended on measurements of its biologic activity.28 , 29 After intravenous injection into normal subjects, there is a phase of rapid elimination due to equilibration, followed by more gradual disappearance that can best be explained as a combination of mechanisms of clearance involving saturable and first-order processes.28 Over the range of heparin concentrations used clinically, the practical implication of these kinetics is that the dose–response relation is not linear; instead, the anticoagulant response increases

disproportionately in intensity and duration as the dose increases.28 Olsson and associates29 reported that heparin had an apparent plasma biologic half-life of 56 minutes after an intravenous bolus dose of 100 U per kilogram of body weight and of 152 minutes after a bolus dose of 400 U per kilogram. Bjornsson et al.30 confirmed the dose-dependent increase in the apparent biologic half-life of heparin and reported an apparent half-life of approximately 30 minutes after an intravenous bolus dose of 25 U per kilogram and approximately 60 minutes after a bolus dose of 75 U per kilogram. The apparent volume of distribution was between 40 and 60 ml per kilogram.

Heparin binds to saturable sites on endothelial cells,31 , 32 after which it is internalized and depolymerized.32 The interaction of heparin with endothelial cells in vivo results in the displacement of platelet factor 4, a protein that neutralizes heparin.33 Heparin is also taken up by mononuclear phagocytes, in which it is desulfated.34 After intravenous bolus doses of 5000 U, a fraction of the drug is eliminated in the urine as a depolymerized35 and less sulfated molecule35 , 36 that retains about 50 percent of its original activity.36 The precise pathway (or pathways) of heparin elimination is uncertain, and reports of the influence of renal and hepatic disease on its pharmacokinetics have been inconsistent. The elimination of heparin from plasma is accelerated in clinical and experimental acute pulmonary embolism37 , 38 by a mechanism that is poorly understood.

There is no evidence that the pharmacokinetics or anticoagulant properties of the forms of heparin derived from porcine or bovine sources or prepared as sodium or calcium salts are different. There are reports of physical interactions between heparin and other drugs,39 but until recently there has been no convincing evidence that drugs alter the anticoagulant effect of heparin.40 Recent case reports have suggested that intravenous nitroglycerin may increase the required dose of heparin41 , 42; the observation was not confirmed, however, in a randomized crossover study using relatively low doses of nitroglycerin.43 The mechanism of this possible interaction is unknown; an alteration in the antithrombin III molecule has been suggested.44

The anticoagulant effect of heparin is modified by platelets, fibrin, vascular surfaces, and plasma proteins. Platelets inhibit the anticoagulant effect of heparin by binding factor Xa and protecting it from inactivation by the heparin—antithrombin III complex45 , 46 and by secreting the heparin-neutralizing protein platelet factor 4.47 Fibrin binds thrombin and protects it from inactivation by the heparin—antithrombin III complex.48 , 49 In plasma, approximately 20 times more heparin is needed to inactivate fibrin-bound thrombin than to inactivate free thrombin.48 In contrast, fibrin-bound thrombin is not protected from inactivation by antithrombin III—independent thrombin inhibitors, such as hirudin or hirudin fragments.48 This observation may explain why heparin is less effective in experimental models than hirudin in preventing the formation of arterial thrombosis50 and the growth of venous thrombi.51 The relative resistance of fibrin-bound thrombin to inhibition by heparin may also explain why preventing the extension of venous thrombosis requires higher concentrations of heparin than preventing its formation,52 as well as why heparin fails to inhibit thrombin activity after successful coronary thrombolysis in some patients.53 54 55 Thrombin bound to subendothelial surfaces is also protected from inactivation by heparin,56 possibly through mechanisms similar to those that protect fibrin-bound thrombin.

Heparin binds to many proteins, of which three —histidine-rich glycoprotein,57 platelet factor 4,47 and vitronectin58 — also neutralize its anticoagulant activity. Elevated levels of

these proteins may contribute to heparin resistance in patients with inflammatory and malignant disorders.

Heparin interacts with fibrinolytic components in plasma-free systems and inhibits plasmin,59 enhances the conversion of plasminogen to plasmin,60 and impairs the activation of plasminogen by tissue plasminogen activator on a fibrin surface.61 , 62 Heparin has been reported to increase fibrinolytic activity in vivo in some studies,63 but the effects have been small and inconsistent. Heparin does not enhance or inhibit thrombolysis induced by tissue plasminogen activator in vivo.64 , 65 It does, however, prevent experimental and clinical rethrombosis after thrombolysis.65 66 67 68

Heparin binds to platelets in vitro and, depending on the experimental conditions, can either induce or inhibit platelet aggregation.69 , 70 High-molecular-weight heparin fractions with low affinity for antithrombin III have a greater effect on platelet function than low-molecular-weight fractions with high affinity for antithrombin III.71 Heparin prolongs the bleeding time in humans72 and enhances blood loss from the microcirculation in rabbits.14 , 15 , 73 The interaction of heparin with platelets14 and endothelial cells15 may contribute to heparin-induced bleeding by a mechanism that is independent of its anticoagulant effect.73

Clinical Use of Heparin

Heparin is effective in the prevention and treatment of venous thrombosis and pulmonary embolism, in the prevention of mural thrombosis after myocardial infarction, in the treatment of patients with unstable angina and acute myocardial infarction, and in the prevention of coronary-artery rethrombosis after thrombolysis. Although not discussed here, heparin is also used to prevent thrombosis in extracorporeal devices in cardiovascular surgery and hemodialysis, to treat selected cases of disseminated intravascular coagulation, and to treat fetal growth retardation in pregnant women.

The anticoagulant response to heparin varies widely among patients with thromboembolic disease,37 possibly because of variations in the plasma concentrations of heparin-binding proteins. There is evidence that the clinical efficacy of heparin is optimized if the anticoagulant effect is maintained above a defined minimal level (Table 1Table 1

Relation between the Failure to Reach the Lower Limit of the Therapeutic APTT Range and the Occurrence of Thromboembolic Events, from a Subgroup Analysis of Five Prospective Studies.) and that the risk of bleeding is increased as the dose of heparin increases79 (see below). For these reasons, heparin treatment is usually monitored to maintain the ratio of the patient's activated partial-thromboplastin time (APTT) to the mean control APTT within a defined range of approximately 1.5 to 2.5 (see below), referred to as the therapeutic range. It should be noted that the responsiveness of the reagents used in APTT tests can vary widely80; this recommendation is based on laboratory81 and clinical74 studies in which the therapeutic range was equivalent to a heparin level of 0.2 to

0.4 U per milliliter by protamine titration, or 0.35 to 0.7 U per milliliter according to the level of anti—factor Xa activity. This difference in responsiveness between thromboplastins makes comparisons of anticoagulant effects difficult between studies and is responsible for variations in the relation between the APTT and plasma heparin levels. Because the slopes of the lines describing the relation between the APTT and heparin levels with different reagents may not be parallel, responsiveness may not be standardized by expressing the APTT result as a ratio. Until alternative methods are developed, the therapeutic range for any given APTT reagent should therefore be established in the clinical laboratory to correspond to a heparin level of 0.2 to 0.4 U per milliliter by protamine titration.

Treatment of Venous Thromboembolism

The evidence that heparin is effective for the treatment of pulmonary embolism comes from an open, randomized study that reported a significant reduction in mortality with heparin plus oral anticoagulants as compared with no treatment,82 and from a descriptive study.83 The evidence that heparin is effective in the treatment of venous thrombosis is based on two randomized studies demonstrating that recurrent thrombosis is very uncommon during the initial course of intravenous heparin (occurring in less than 5 percent of patients),84 , 85 but that it is common (occurring in 29 percent85 and 47 percent84 of patients, respectively) unless treatment with either adjusted-dose heparin or oral anticoagulants is continued.

A continuous intravenous infusion of heparin has been compared for effectiveness and safety with heparin administered by intermittent intravenous injection in six studies86 87 88 90 91 and with high-dose subcutaneous heparin in six studies.74 , 92 93 94 95 96 It is not possible to determine the optimal route of administration from these studies, because different 24-hour doses of heparin were used in the different groups. Furthermore, most of the studies were small, lacked the power to demonstrate clinically important differences, and used different criteria to assess both efficacy and safety (extent of bleeding). In general, the incidence of recurrent venous thromboembolism was low with all three methods, provided that adequate doses of heparin were used.

In most of the contemporary studies in which objective tests were used to assess outcomes, the mean daily dose of heparin was considerably higher than the standard 24,000 U per 24 hours used in the past. The mean maintenance dose in 11 studies using continuous intravenous heparin was 30,516 U per 24 hours, in 5 studies using subcutaneous heparin it was 33,459 U per 24 hours, and in 6 studies using intermittent intravenous heparin it was 36,062 U per 24 hours. With all three methods of administration the initial dose of heparin is critical, but it is especially so if the drug is administered by subcutaneous injection, since an adequate anticoagulant response is not achieved in the first 24 hours unless a starting dose of at least 17,500 U every 12 hours (35,000 U per 24 hours) is used.74 , 96 The most reliable estimates of the incidence of recurrence and bleeding during adequate heparin therapy and during the subsequent three months of less-intense warfarin therapy come from three contemporary prospective studies in which heparin was administered by continuous infusion. The three studies included a total of 523 patients. Heparin was administered as a bolus intravenous dose of 5000 U, followed by approximately 28,000 to 40,000 U per 24 hours. The dose was adjusted to maintain the APTT in the therapeutic range, follow-up was prospective, and the diagnosis of recurrence was based on reliable objective tests (Table

2Table 2 Confirmed Recurrences, Episodes of Major Bleeding, and Fatal Pulmonary Embolism in Patients with Venous Thromboembolism Who Received Treatment with Heparin Administered as a Continuous Intravenous Infusion, Followed by Less—Intense Oral Anticoagulants.*).74 , 97 , 98 The three-month incidence of recurrent venous thromboembolism, as confirmed by objective tests, varied from 4.7 to 7.1 percent during the combined period of initial heparin treatment and subsequent oral anticoagulant therapy. The incidence of major bleeding during heparin treatment varied from 1.6 to 7.1 percent (mean, 3.8 percent), and the incidence of fatal pulmonary embolism was zero.

A recent study (which included 271 patients with proved deep venous thrombosis) that compared continuous intravenous infusion with subcutaneous injection is particularly instructive because it illustrates the difference in anticoagulant response between continuous intravenous and subcutaneous heparin.96 The mean starting dose was approximately 36,000 U per 24 hours in both groups. The dose of heparin was adjusted with use of the APTT; after adjustment the mean dose during the seven days of heparin treatment was higher in the subcutaneous-injection group (33,800 vs. 31,700 U per 24 hours, P = 0.01), whereas the APTT response was lower, especially on the day after treatment began. The incidence of clinically important outcomes was low and similar in both groups. Thus, clinically evident pulmonary embolism was diagnosed in 1.5 percent of the patients in the subcutaneous-injection group and in 2.8 percent of those in the intravenous-infusion group, and major bleeding occurred in 3.8 percent of those in the subcutaneous-injection group and 6.5 percent of those in the intravenous-infusion group.

Informal audits of routine hospital practice indicate that dose-adjustment practices for heparin are often inadequate.99 , 100 Dosing practices can be improved with a standardized approach, as demonstrated by a recent prospective study in patients with venous thromboembolism.101 In this study heparin was given as a continuous infusion, starting with a dose of approximately 31,000 U per 24 hours after an intravenous bolus dose of 5000 U, and the dose was adjusted according to a protocol developed through an iterative process (Table 3Table 3

Protocol for Adjustment of the Dose of Heparin.*). With this protocol an APTT above the lower limit of the therapeutic range was reached in 82 percent of the patients after 24 hours and in 91 percent after 48 hours.101 The mean heparin dose required to produce an APTT in the therapeutic range was 32,903 U per 24 hours. The proportion of APTTs in the therapeutic range was significantly higher in the group for whom the standardized protocol was used to adjust the heparin dose than in a historical control group (P<0.05).

Two randomized studies in patients with proximal venous thrombosis have demonstrated that a short course of heparin therapy (4 to 5 days) is associated with a recurrence rate similar to that of a longer course (9 to 10 days)97 , 98 (Table 2). The short course is appealing because it reduces the length of hospital stay and is likely to reduce the incidence of heparin-associated thrombocytopenia. It would be premature to recommend the short course of

treatment for patients with massive iliofemoral venous thrombosis or major pulmonary embolism, however, since such patients were excluded from one study97 and represented only a small proportion of the patients in the second.98

Prophylaxis of Venous Thromboembolism

Heparin is an effective and safe form of prophylaxis in medical and surgical patients who are at risk for venous thromboembolism. It is usually administered subcutaneously in a fixed, low dose of 5000 U every 8 or 12 hours. Independent overview analyses of all clinical trials of elective surgery in which a group receiving prophylactic lowdose heparin was compared with a control group identified a 60 to 70 percent reduction in the frequency of venous thrombosis and fatal pulmonary embolism in the heparin group.102 , 103 The postoperative incidence of fatal pulmonary embolism was reduced from 0.7 percent in the control patients to 0.2 percent in the treated patients in one analysis (P<0.001),102 and from 0.8 to 0.26 percent (P<0.001) in a larger analysis that included orthopedic surgical patients.103 There was also a small but statistically significant decrease in mortality, from 3.3 to 2.4 percent (P<0.02).103 These findings are consistent with the results of a large international trial demonstrating that low-dose heparin reduced the incidence of fatal and nonfatal pulmonary embolism identified at autopsy.104 The use of low-dose heparin is associated with an increased incidence of wound hematomas,102 103 104 but no increase in major bleeding or fatal bleeding. Low-dose heparin has also been shown to be effective in reducing venous thromboembolism after myocardial infarction and other serious medical disorders105; and it reduced in-hospital mortality by 31 percent (P<0.05) among 1358 patients over 40 years of age who were admitted to general medical wards.106

Although low-dose heparin is effective in reducing deep venous thrombosis after hip surgery,103 the risk of thrombosis remains substantial (25 to 30 percent). Recent randomized studies comparing a fixed low dose of heparin with either an adjusted low dose107 or a fixed dose of low-molecular-weight heparin52 have shown that the incidence of venous thrombosis can be reduced by an additional 40 to 50 percent (to 12 to 15 percent) with these new regimens. Although direct comparisons have not been performed in randomized studies, it is likely that low-dose warfarin is more effective than a fixed low dose of heparin in patients undergoing major orthopedic surgical procedures.108 , 109

Coronary Artery Disease

Aspirin is effective in both short-term and long-term treatment of coronary heart disease. Many studies evaluating heparin have not used aspirin in the comparison group, and the relative effectiveness and safety of heparin and aspirin in coronary artery disease are uncertain.

Mortality and Reinfarction

A meta-analysis of 20 trials of acute myocardial infarction in the era before thrombolytic therapy in patients who were not treated with aspirin found a reduction in mortality of 17 percent in the heparin group and a reduction in reinfarction of 22 percent.110 Two recent open, randomized trials compared a group receiving heparin with an untreated control group.111 , 112 In one study there was a statistically significant reduction (61 percent) in reinfarction after daily treatment with 12,500 U of heparin subcutaneously in patients who had had a myocardial infarction 6 to 18 months before recruitment,111 and in the other there

was a significant reduction (44 percent) in mortality among patients with acute myocardial infarction after treatment with 12,500 U of heparin subcutaneously every 12 hours.112 There was also a reduction in mortality in a subgroup of patients who were treated initially with streptokinase.112

Left Ventricular Mural Thrombosis

Early studies found that left ventricular mural thrombosis discovered at autopsy was reduced by approximately 50 percent in patients treated with anticoagulants.113 In two randomized trials76 , 112 in which heparin in a fixed dose of 12,500 U given subcutaneously every 12 hours was compared with either no treatment112 or low-dose heparin (5000 U subcutaneously every 12 hours),76 high-dose heparin reduced the incidence of mural thrombosis, as detected on two-dimensional echocardiography, by 72 and 58 percent, respectively (P<0.05 for each study). Subgroup analysis in one study76 suggested that the incidence of thrombosis might have been lowered further if the dose of heparin had been adjusted to maintain the APTT above 1.5 times the control value (i.e., to maintain the heparin level above 0.2 U per milliliter).

Unstable Angina

In three large trials aspirin has been shown to reduce mortality in unstable angina.114 115 116 Heparin (5000 U as an intravenous bolus dose, followed by 24,000 U per 24 hours) was more effective than aspirin in relieving acute ischemic symptoms in patients with unstable angina117 , 118 and more effective than placebo in preventing acute myocardial infarction.117 The relative merits of aspirin, heparin, and their combination in reducing acute myocardial infarction and mortality in unstable angina are uncertain, however, and should be addressed in an appropriately designed randomized trial.

Patency after Thrombolytic Therapy

Five studies have investigated the effect of heparin on coronary-artery patency after thrombolytic therapy with tissue plasminogen activator. In the first study,119 a single intravenous bolus dose of 10,000 U did not appear to influence coronary-artery patency after 90 minutes. In the other four studies, heparin was administered either during or at the end of the infusion of tissue plasminogen activator as an intravenous bolus dose of 5000 U, followed by 1000 U per hour as a continuous infusion.67 , 68 , 120 , 121 The dose of heparin was adjusted to maintain the APTT at 1.5 to 2.0 times the control value. In the Heparin—Aspirin Reperfusion Trial,68 involving 205 patients, the comparison group received 80 mg of aspirin per day. After 18 hours coronary-artery patency was 82 percent in the heparin group and 52 percent in the aspirin group (P<0.0002). In the study of 83 patients reported by Bleich and associates,67 the comparison group received no treatment. Patency after two days was 71 percent in the heparin group and 44 percent in the control group (P<0.023). In the European Coronary Study Group 6 trial,120 all 687 patients received aspirin and were randomly assigned to receive either heparin or no heparin. Patency after a mean of 81 hours was 80 percent in the heparin group and 75 percent in the comparison group (P<0.01). In the Australian National Heart Study,121 all 202 patients received heparin for 24 hours. They were then randomly assigned to receive either continuous intravenous heparin or a combination of aspirin (300 mg a day) and dipyridamole (300 mg a day). After one week, patency was 80 percent in both groups. The results of these studies suggest that heparin in an initial intravenous dose of 5000 U, followed by 1000 U per hour given by continuous

infusion, increases patency during the first few days after coronary thrombolysis with tissue plasminogen activator, probably by preventing rethrombosis.

Mortality after Thrombolytic Therapy

The effect of heparin on reinfarction or death after thrombolytic therapy for acute myocardial infarction is uncertain. In the International Studies of Infarct Survival Pilot Study,122 half the patients were assigned to receive intravenous heparin for 48 hours in a two-by-two factorial design that included streptokinase and aspirin; heparin treatment was associated with a nonsignificant decrease in the rate of infarction. In the Studio sulla Calciparina nell'Angina e nella Trombosi Ventricolare nell'Infarto (SCATI) trial,112 in which the control group received no treatment, the mortality rate was significantly lower in the patients randomly assigned to receive heparin (2000 U intravenously, followed by 12,500 U subcutaneously every 12 hours) after thrombolytic therapy for acute myocardial infarction.112 The mortality rate was also lower in patients treated with heparin after receiving streptokinase but not tissue plasminogen activator in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2)—International Study Group trial.123 Among the patients who received streptokinase and heparin (90 percent of whom also received aspirin), the mortality rate was 7.9 percent (408 of 5191), whereas it was 9.2 percent (479 of 5205) among the patients who received streptokinase alone (P<0.02). When patients who died before heparin was started were excluded from the analysis, the same trend was still apparent: the mortality rates were 5.0 percent (254 of 5037) and 6.2 percent (311 of 5037), respectively (P<0.02). These results indicate that 12,500 U of heparin administered subcutaneously twice daily starting 9 to 12 hours after treatment with streptokinase, with or without an intravenous bolus dose of heparin after the streptokinase, is a useful adjuvant to streptokinase treatment in patients with acute myocardial infarction. In the GISSI-2—International Study Group trial, the mortality rate among the patients who received recombinant tissue plasminogen activator and heparin was 9.2 percent (476 of 5170), and among those who received tissue plasminogen activator but not heparin it was 8.7 percent (453 of 5202) (P = 0.393). After excluding the patients who died before heparin was started, the mortality rates were 5.9 percent (294 of 4988) among those who received heparin and 5.9 percent (298 of 5047) among those who did not (P = 0.984).

This difference in response to the heparin regimen between the patients treated with streptokinase and those treated with tissue plasminogen activator, as well as the effectiveness of heparin in the SCATI study, may be explained by the greater systemic anticoagulant effect produced by streptokinase, which, when augmented by the moderate anticoagulant effect of the relatively low dose of subcutaneous heparin, resulted in an antithrombotic effect. Since tissue plasminogen activator has a less marked systemic anticoagulant effect, the additional influence of the moderate anticoagulant effect of the relatively low dose of heparin used in the GISSI-2—International Study Group trial may have been insufficient to prevent reocclusion, particularly during the critical period soon after thrombolysis.

Recommendations for the Use of Heparin

Firm recommendations can be made for the use of heparin in the prevention and treatment of venous thromboembolism and in the treatment of unstable angina (Table 4Table 4

Clinical Uses of Heparin.). The evidence supporting specific regimens for the treatment of acute myocardial infarction is less conclusive and subject to revision. In all uses, the dose of heparin should be adjusted to maintain the APTT in the therapeutic range.

Treatment of Venous Thromboembolism

Patients with venous thromboembolism should be treated with an intravenous bolus dose of 5000 U of heparin, followed by 30,000 U per 24 hours given by continuous infusion. If subcutaneous heparin is used, the starting dose should be 17,500 U every 12 hours, and the dose should be adjusted so that after 6 hours the APTT ratio is equivalent to a heparin level of 0.2 to 0.4 U per milliliter by protamine titration. For many APTT reagents, this ratio is between 1.5 and 2.5 times the laboratory control value.

Prevention of Venous Thromboembolism

General surgical and medical patients should receive 5000 U subcutaneously every 12 hours to prevent venous thromboembolism. Patients undergoing major orthopedic surgery or patients at very high risk (those with previous recurrent venous thrombosis, for example) should receive an adjusted low dose of heparin (adjusted to the upper normal range of the APTT)107 or less-intense warfarin therapy.108 , 109

Treatment of Unstable Angina and Acute Myocardial Infarction

Patients with unstable angina or acute myocardial infarction should receive 5000 U of heparin as an intravenous bolus dose, followed by 24,000 U per 24 hours. Concomitant aspirin therapy is optional in patients with unstable angina and is recommended in those with acute myocardial infarction. Heparin treatment can be delayed until the end of thrombolytic therapy with tissue plasminogen activator, and for an additional period after streptokinase.

Side Effects of Heparin

The most common side effect of heparin is hemorrhage.79 Other complications include thrombocytopenia with or without thrombosis,124 , 125 osteoporosis,126 , 127 skin necrosis,128 alopecia,129 hypersensitivity reactions,130 and hypoaldosteronism.131 Four variables have been reported to influence bleeding during treatment with heparin: the dose of heparin, the patient's anticoagulant response, the method of administration, and other patient-related factors. There is indirect evidence that the frequency of bleeding increases with the dose of heparin and therefore its anticoagulant effect.132 , 133 Pooled analysis of randomized trials comparing different methods of heparin administration revealed an average incidence of major bleeding of 6.8 percent among patients given continuous infusions and 14.2 percent among those given intermittent intravenous injections (odds ratio, 0.42; P = 0.01). The comparison is confounded, however, by the larger 24-hour dose of heparin in the groups receiving intermittent intravenous injections in five of the six studies. The increase in bleeding could thus be attributed to the higher dose of heparin in the group given intermittent intravenous injections. For studies comparing continuous intravenous heparin with subcutaneous heparin, the average incidence of bleeding was 5.2 and 4.1 percent, respectively (odds ratio, 1.1).132 The mean 24-hour dose of heparin in the intravenous-heparin group

ranged from 29,260 to 36,814 U (mean, 31,790), and in the subcutaneous-heparin group from 29,180 to 36,998 U (mean, 33,459). Other factors that predispose patients to heparin-induced bleeding are a serious concurrent illness132 , 134 and chronic heavy consumption of alcohol.135

The concomitant use of aspirin has long been identified as a risk factor for heparin-induced bleeding.132 , 135 , 136 This observation bears close examination, because heparin and aspirin are frequently used in combination in the initial treatment of acute coronary artery syndromes. Aspirin increases operative and postoperative bleeding in patients who receive the very high doses of heparin required during open-heart surgery.137 The risk of adding aspirin to a short course of regular therapeutic doses of heparin is much lower, however, and is acceptable in patients with ischemic heart disease.

Renal failure and the age and sex of the patient have also been implicated as risk factors for heparin-induced bleeding.132 , 138 An association with female sex has not been consistently reported and remains in question. The influence of patient-related factors on heparin-associated bleeding is illustrated by a recent study of patients with proximal venous thrombosis.97 The patients received an initial intravenous bolus dose of 5000 U of heparin, followed by a continuous infusion of 30,000 U per 24 hours if they had clinical risk factors for bleeding, or 40,000 U per 24 hours if they had no risk factors. The incidence of major bleeding was 11 percent in the high-risk patients (who received the lower starting dose) and 1 percent in the low-risk patients (who received the higher starting dose) (P = 0.007).

Thrombocytopenia is a well-recognized, usually asymptomatic complication of heparin therapy.124 , 125 The reported incidence of heparin-associated thrombocytopenia varies widely. It is more common with heparin derived from bovine lung than with that from porcine gut.124 Pooled analysis of studies in which patients were randomly assigned to receive heparin derived from one source or the other revealed an overall incidence of thrombocytopenia of 15.6 percent in the 173 patients who received bovine heparin and 5.8 percent in the 223 patients who received porcine heparin.124 Analysis of all prospective studies of porcine heparin revealed that the mean incidence of thrombocytopenia was 2.4 percent for therapeutic heparin and 0.3 percent for prophylactic heparin. The incidence of arterial or venous thrombosis in patients with heparin-associated thrombocytopenia is approximately 0.4 percent.125 Arterial thrombosis occurs as a consequence of platelet aggregation in vivo, but venous thrombosis may result from heparin resistance caused by the neutralizing effect of the heparin-induced release of platelet factor 4. Thrombocytopenia usually begins between 3 and 15 days after the initiation of heparin therapy (median, 10),125 but it has been reported to begin within hours in patients previously exposed to the drug.125 The platelet count usually returns to base-line levels within four days after heparin is discontinued.125 Heparin-associated thrombocytopenia is thought to be caused by an IgG—heparin immune complex involving both the Fab and Fc portions of the IgG molecule.125 Low-molecular-weight heparins can have immunologic cross-reactivity with heparin,139 but the heparinoid ORG 10172 has minimal cross-reactivity with heparin140 and has been used successfully in a small number of patients with heparin-associated thrombocytopenia.140

Heparin in Pregnancy

Heparin is the anticoagulant of choice in pregnancy because it does not cross the placenta and it does not produce untoward effects in the fetus or newborn when administered to the mother during pregnancy. The drug should be given in therapeutic doses (approximately 15,000 U

given subcutaneously every 12 hours) when used to treat pregnant women with prosthetic heart valves or venous thromboembolism. The use of heparin in doses of more than 20,000 U per 24 hours for more than five months is problematic, because it can cause osteoporosis.126 ,

127

The Future

Two interesting new approaches are being evaluated to improve the safety and efficacy of standard anticoagulant therapy. The first is the development of low-molecular-weight

heparins, and the second is the development of thrombin inhibitors that are not antithrombin III—dependent. At doses producing an equivalent antithrombotic effect, low-molecular-weight heparins have been reported to cause less hemorrhage than standard heparin in laboratory animals14 , 15 , 52 and humans141 and to be effective and safe for the prevention of venous thromboembolism in surgical and medical patients who are at high risk.52 , 141 Because of their relatively long plasma half-life, low-molecular-weight heparins are effective when administered once daily by subcutaneous injection.52 A number of low-molecular-weight heparins have been approved for use in Europe, and they are currently being evaluated in North America.

Clinical evaluation of antithrombin III—independent thrombin inhibitors, such as hirudin or hirudin fragments, is just beginning. These agents are more effective than heparin in inactivating thrombin bound to fibrin48 and in preventing experimental arterial thrombosis50 and the extension of experimental venous thrombosis.51

References

1. 1

McLean J. The thromboplastic action of cephalin . Am J Physiol 1916; 41:250–7.

2. 2

Brinkhous KM, Smith HP, Warner ED, Seegers WH. The inhibition of blood clotting: an unidentitied substance which acts in conjunction with heparin to prevent the conversion of prothrombin into thrombin . Am J Physiol 1939; 125:683–7.Web of Science

3. 3

Abildgaard U. Highly purified antithrombin 3 with heparin cofactor activity prepared by disc electrophoresis . Scand J Clin Lab Invest 1968; 21:89–91.CrossRef | Web of Science | Medline

4. 4

Rosenberg RD, Lam L. Correlation between structure and function of heparin . Proc Natl Acad Sci U S A 1979; 76:1218–22.CrossRef | Web of Science | Medline

5. 5

Rosenberg RD. The heparin-antithrombin system: a natural anticoagulant mechanism. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Hemostasis and thrombosis: basic principles and clinical practice. 2nd ed. Philadelphia: J.B. Lippincott, 1987:1373–92.

6. 6

Lindahl U, Backstrom G, Hook M, Thunberg L, Fransson L-A, Linker A. Structure of the antithrombin-binding site of heparin . Proc Natl Acad Sci USA 1979; 76:3198–202.CrossRef | Web of Science | Medline

7. 7

Hook M, Bjork I, Hopwood J, Lindahl U. Anticoagulant activity of heparin: separation of high-activity and low-activity heparin species by affinity chromatography on immobilized antithrombin . FEBS Lett 1976; 66:90–3.CrossRef | Web of Science | Medline

8. 8

Casu B, Oreste P, Torri G, et al. The structure of heparin oligosaccharide fragments with high anti-(factor Xa) activity containing the minimal antithrombin III-binding sequence . Biochem J 1981; 197:599–609.Web of Science | Medline

9. 9

Choay J, Lormeau JC, Petitou M, Sinay P, Fareed J. Structural studies on a biologically active hexasaccharide obtained from heparin . Ann N Y Acad Sci 1981; 370:644–9.CrossRef | Medline

10. 10

Choay J, Petitou M, Lormeau JC, Sinay P, Casu B, Gatti G. Structure-activity relationship in heparin: a synthetic pentasaccharide with high affinity for antithrombin III and eliciting high anti-factor Xa activity . Biochem Biophys Res Commun 1983; 116:492–9.CrossRef | Web of Science | Medline

11. 11

Lam LH, Silbert JE, Rosenberg RD. The separation of active and inactive forms of heparin . Biochem Biophys Res Commun 1976; 69:570–7.CrossRef | Web of Science | Medline

12. 12

Andersson LO, Barrowcliffe TW, Holmer E, Johnson EA, Sims GEC. Anticoagulant properties of heparin fractionated by affinity chromatography on matrix-bound antithrombin III and by gel filtration . Thromb Res 1976; 9:575–83.CrossRef | Web of Science | Medline

13. 13

Ofosu FA, Modi GJ, Hirsh J, Buchanan M, Blajchman MA. Mechanisms for inhibition of the generation of thrombin activity by sulfated polysaccharides . Ann N Y Acad Sci 1986; 485:41–55.CrossRef | Web of Science | Medline

14. 14

Fernandez F, Nguyen P, van Ryn J, Ofosu FA, Hirsh J, Buchanan MR. Hemorrhagic doses of heparin and other glycosaminoglycans induce a platelet defect . Thromb Res 1986; 43:491–5.CrossRef | Web of Science | Medline

15. 15

Blajchman MA, Young E, Ofosu FA. Effects of unfractionated heparin, dermatan sulfate and low molecular weight heparin on vessel wall permeability in rabbits . Ann N Y Acad Sci 1989; 556:245–54.CrossRef | Web of Science | Medline

16. 16

Clowes AW, Karnowsky MJ. Suppression by heparin of smooth muscle cell proliferation in injured arteries . Nature 1977; 265:625–6.CrossRef | Web of Science | Medline

17. 17

Castellot JJ Jr, Favreau LV, Karnovsky MJ, Rosenberg RD. Inhibition of vascular smooth muscle cell growth by endothelial cell-derived heparin: possible role of a platelet endoglycosidase . J Biol Chem 1982; 257:11256–60.Web of Science | Medline

18. 18

Sy MS, Schneeberger E, McCluskey R, Greene ML Rosenberg RD, Benacerraf B. Inhibition of delayed-type hypersensitivity by heparin depleted of anticoagulant activity . Cell Immunol 1983; 82:23–32.CrossRef | Web of Science | Medline

19. 19

Folkman J. Regulation of angiogenesis: a new function of heparin . Biochem Pharmacol 1985; 34:905–9.CrossRef | Web of Science | Medline

20. 20

Lindahl U, Thunberg L, Backstrom G, Riesenfeld J, Nordling K, Bjork I. Extension and structural variability of the antithrombin-binding sequence in heparin . J Biol Chem 1984; 259:12368–76.Web of Science | Medline

21. 21

Lane DA, Demon J, Flynn AM, Thunberg L, Lindahl U. Anticoagulant activities of heparin oligosaccharides and their neutralization by platelet factor 4 . Biochem J 1984; 218:725–32.Web of Science | Medline

22. 22

Oosta GM, Gardner WT, Beeler DL, Rosenberg RD. Multiple functional domains of the heparin molecule . Proc Natl Acad Sci U S A 1981; 78:829–33.CrossRef | Web of Science | Medline

23. 23

Nesheim ME. A simple rate law that describes the kinetics of the heparincatalyzed reaction between antithrombin III and thrombin . J Biol Chem 1983; 258:14708–17.Web of Science | Medline

24. 24

Ofosu FA, Sie P, Modi GJ, et al. The inhibition of thrombin-dependent positive-feedback reactions is critical to the expression of the anticoagulant effect of heparin . Biochem J 1987; 243:579–88.Web of Science | Medline

25. 25

Ofosu FA, Hirsh J, Esmon CT, et al. Unfractionated heparin inhibits thrombin-catalyzed amplification reactions of coagulation more efficiently than those catalyzed by factor Xa . Biochem J 1989; 257:143–50.Web of Science | Medline

26. 26

Beguin S, Lindhout T, Hemker HC. The mode of action of heparin in plasma . Thromb Haemost 1988; 60:457–62.Web of Science | Medline

27. 27

Lindahl U, Hook M. Glycosaminoglycans and their binding to biological macromolecules . Annu Rev Biochem 1978;47:385–417.CrossRef | Web of Science | Medline

28. 28

de Swart CAM, Nijmeyer B, Roelofs JMM, Sixma JJ. Kinetics of intravenously administered heparin in normal humans . Blood 1982; 60:1251–8.Web of Science | Medline

29. 29

Olsson P, Lagergren H, Ek S. The elimination from plasma of intravenous heparin: an experimental study on dogs and humans . Acta Med Scand 1963; 173:619–30.CrossRef | Web of Science | Medline

30. 30

Bjornsson TO, Wolfram BS, Kitchell BB. Heparin kinetics determined by three assay methods . Clin Pharmacol Ther 1982; 31:104–13.CrossRef | Web of Science | Medline

31. 31

Glimelius B, Busch C, Hook M. Binding of heparin on the surface of cultured human endothelial cells . Thromb Res 1978; 12:773–82.CrossRef | Web of Science | Medline

32. 32

Mahadoo J, Heibert L, Jaques LB. Vascular sequestration of heparin . Thromb Res 1977; 12:79–90.CrossRef | Web of Science

33. 33

Dawes J, Smith RC, Pepper DS. The release, distribution and clearance of human β-thromboglobulin and platelet factor 4 . Thromb Res 1978; 12:851–61.CrossRef | Web of Science | Medline

34. 34

Friedman Y, Arsenis C. Studies on the heparin sulphamidase activity from rat spleen: intracellular distribution and characterization of the enzyme . Biochem J 1974; 139:699–708.Web of Science | Medline

35. 35

Dawes J, Pepper DS. Catabolism of low-dose heparin in man . Thromb Res 1979; 14:845–60.CrossRef | Web of Science | Medline

36. 36

McAllister BM, Demis DJ. Heparin metabolism: isolation and characterization of uroheparin . Nature 1966; 212:293–4.CrossRef | Web of Science | Medline

37. 37

Hirsh J, van Aken WG, Gallus AS, Dollery CT, Cade JF, Yung WL. Heparin kinetics in venous thrombosis and pulmonary embolism . Circulation 1976;53:691–5.Web of Science | Medline

38. 38

Chiu HM, van Aken WG, Hirsh J, Regoeczi E, Horner AA. Increased heparin clearance in experimental pulmonary embolism . J Lab Clin Med 1977;90:204–15.Medline

39. 39

Colburn WA. Pharmacologic implications of heparin interactions with other drugs . Drug Metab Rev 1976; 5:281–93.CrossRef | Web of Science | Medline

40. 40

Hodby ED, Hirsh J, Adeniyi-Jones C. The influence of drugs upon the anticoagulant activity of heparin . Can Med Assoc J 1972; 106:562–4.Web of Science | Medline

41. 41

Habbab MA, Haft JI. Heparin resistance induced by intravenous nitroglycerin . Circulation 1986; 74:Suppl II:II–321. abstract.

42. 42

Pizzulli L, Nitsch J, Luderitz B. Inhibition of the heparin effect by nitroglycerin . Dtsch Med Wochenschr 1988; 133:1837–40.CrossRef | Web of Science

43. 43

Bode V, Welzel D, Franz G, Polensky U. Absence of drug interaction between heparin and nitroglycerin: randomized placebo-controlled crossover study . Arch Intern Med 1990; 150:2117–9.CrossRef | Web of Science | Medline

44. 44

Becker RC, Corrao JM, Bovill EG, et al. Intravenous nitroglycerin-induced heparin resistance: a qualitative antithrombin III abnormality . Am Heart J 1990; 119:1254–61.CrossRef | Web of Science | Medline

45. 45

Marciniak E. Factor Xa inactivation by antithrombin. 3. Evidence for biological stabilization of factor Xa by factor V-phospholipid complex . Br J Haematol 1973;24:391–400.CrossRef | Web of Science | Medline

46. 46

Walker FJ, Esmon CT. The effects of phospholipid and factor Va on the inhibition of factor Xa by antithrombin III . Biochem Biophys Res Commun 1979;90:641–7.CrossRef | Web of Science | Medline

47. 47

Holt JC, Niewiarowski S. Biochemistry of α-granule proteins . Semin Hematol 1985;22:151–63.Web of Science | Medline

48. 48

Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors . J Clin Invest 1990; 86:385–91.CrossRef | Web of Science | Medline

49. 49

Hogg PJ, Jackson CM. Fibrin monomer protects thrombin from inactivation by heparin-antithrombin III: implications for heparin efficacy . Proc Natl Acad Sci U S A 1989; 86:3619–23.CrossRef | Web of Science | Medline

50. 50

Heras M, Chesebro JH, Penny WJ. Bailey KR, Badimon L, Fuster V. 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 1989; 79:657–65.CrossRef | Web of Science | Medline

51. 51

Agnelli G, Pascucci C, Cosmi B, Nenci GG. The comparative effects of recombinant hirudin (CGP 39393) and standard heparin on thrombus growth in rabbits . Thromb Haemost 1990; 63:204–7.Web of Science | Medline

52. 52

Hirsh J. From unfractionated heparins to low molecular weight heparins . Acta Chir Scand Suppl 1990; 556:42–50.Medline

53. 53

Eisenberg PR, Sherman L, Rich M. et al. Importance of continued activation of thrombin reflected by fibrinopeptide A to the efficacy of thrombolysis . J Am Coll Cardiol 1986; 7:1255–62.CrossRef | Web of Science | Medline

54. 54

Owen J, Friedman KD, Grossman BA, Wilkins C, Berke AD, Powers ER. Thrombolytic therapy with tissue plasminogen activator or streptokinase induces transient thrombin activity . Blood 1988; 72:616–20.Web of Science | Medline

55. 55

Rapold JH, Kuemmerli H, Weiss M, Baur H, Haeberli A. Monitoring of fibrin generation during thrombolytic therapy of acute myocardial infarction with recombinant tissue-type plasminogen activator . Circulation 1989; 79:980–9.CrossRef | Web of Science | Medline

56. 56

Bar-Shavit R, Eldor A, Vlodavsky I. Binding of thrombin to subendothelial extracellular matrix: protection and expression of functional properties . J Clin Invest 1989; 84:1096–104.CrossRef | Web of Science | Medline

57. 57

Lijnen HR, Hoylaerts M, Collen D. Heparin binding properties of human histidine-rich glycoprotein: mechanism and role in the neutralization of heparin in plasma . J Biol Chem 1983; 258:3803–8.Web of Science | Medline

58. 58

Preissner KT, Muller-Berghaus G. Neutralization and binding of heparin by S-protein/vitronectin in the inhibition of factor Xa by antithrombin III . J Biol Chem 1987; 262:12247–53.Web of Science | Medline

59. 59

Highsmith RF, Rosenberg RD. The inhibition of human plasmin by human antithrombin-heparin cofactor . J Biol Chem 1974: 249:4335–8.Web of Science | Medline

60. 60

Edelberg JM, Pizzo SV. Kinetic analysis of the effects of heparin and lipoproteins on tissue plasminogen activator mediated plasminogen activation . Biochemistry 1990; 29:5906–11.CrossRef | Web of Science | Medline

61. 61

Andrade-Gordon P, Strickland S. Interaction of heparin with plasminogen activators in plasminogen: effects on the activation of plasminogen . Biochemistry 1986; 25:4033–40.CrossRef | Web of Science | Medline

62. 62

Paques EP, Stohr HA, Heimbeurger N. Study on the mechanism of action of heparin and related substances on the fibrinolytic system: relationship between plasminogen activators and heparin . Thromb Res 1986; 42:797–807.CrossRef | Web of Science | Medline

63. 63

Agnelli G, Borm J, Cosmi B, Levi M. ten Cate JW. Effects of standard heparin and a low molecular weight heparin (Kabi 2165) on fibrinolysis . Thromb Haemost 1988; 60:311–3.Web of Science | Medline

64. 64

Fry ETA, Sobel BE. Lack of interference by heparin with thrombolysis or binding of tissue-type plasminogen activator to thrombi . Blood 1988;

71:1347–52.Web of Science | Medline

65. 65

Agnelli G, Pascucci C, Cosmi B, Nenci GG. Effects of therapeutic doses of heparin on thrombolysis with tissue type plasminogen activator in rabbits . Blood 1990; 76:2030–6.Web of Science | Medline

66. 66

Cercek B, Lew AS, Hod H, Yano J, Reddy NKN, Ganz W. Enhancement of thrombolysis with tissue-type plasminogen activator by pretreatment with heparin . Circulation 1986; 74:583–7.CrossRef | Web of Science | Medline

67. 67

Bleich SD, Nichols T, Schumacher R, et al. The role of heparin following coronary thrombolysis with tissue plasminogen activator (t-PA) . Circulation 1989: 80:Suppl II:II–113. abstract.

68. 68

Hsia J, Hamilton WP, Kleiman N, Roberts R, Chaitman BR, Ross AM. A comparison between heparin and low-dose aspirin as adjunctive therapy with tissue plasminogen activator for acute myocardial infarction . N Engl J Med 1990;323:1433–7.Free Full Text | Web of Science | Medline

69. 69

Eika C. Inhibition of thrombin-induced aggregation of human platelets by heparin . Scand J Haematol 1971; 8:216–22.CrossRef | Medline

70. 70

Kelton JG, Hirsh J. Bleeding associated with antithrombotic therapy . Semin Hematol 1980; 17:259–91.Web of Science | Medline

71. 71

Salzman EW, Rosenberg RD, Smith MH, Lindon JN, Favreau L. Effect of heparin and heparin fractions on platelet aggregation . J Clin Invest 1980: 65:64–73.CrossRef | Web of Science | Medline

72. 72

Heiden D, Mielke CH Jr, Rodvien R. Impairment by heparin of primary haemostasis and platelet [14C]5-hydroxytryptamine release . Br J Haematol 1977; 36:427–36.CrossRef | Web of Science | Medline

73. 73

Ockelford PA, Carter CJ, Cerskus A, Smith CA, Hirsh J. Comparison of the in vivo hemorrhagic and antithrombotic effects of a low antithrombin-III affinity heparin fraction . Thromb Res 1982; 27:679–90.CrossRef | Web of Science | Medline

74. 74

Hull RD. Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis . N Engl J Med 1986; 315:1109–14.Full Text | Web of Science | Medline

75. 75

Basu D, Gallus A, Hirsh J, Cade J. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time . N Engl J Med 1972; 287:324–7.Full Text | Web of Science | Medline

76. 76

Turpie AGG, Robinson JG, Doyle DJ, et al. 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 1989; 320:352–7.Full Text | Web of Science | Medline

77. 77

Kaplan K, Davison R, Parker M, Mayberry B, Feiereisel P, Salinger M. Role of heparin after intravenous thrombolytic therapy for acute myocardial infarction . Am J Cardiol 1987; 59:241–4.CrossRef | Web of Science | Medline

78. 78

Camilleri JF, Bonnet JL, Bouvier JL, et al. Thrombolyse intraveineuse dans l'infarctus du myocarde: influence de la qualite de l'anticoagulation sur le taux de recidives precoces d'angor ou d'infarctus . Arch Mal Coeur 1988; 81:1037–41.Medline

79. 79

Levine M, Hirsh J. Hemorrhagic complications of anticoagulant therapy . Semin Thromb Hemost 1986; 12:39–57.CrossRef | Web of Science | Medline

80. 80

Shojania AM, Tetreault J, Turnbull G. The variations between heparin sensitivity of different lots of activated partial thromboplastin time reagent produced by the same manufacturer . Am J Clin Pathol 1988; 89:19–23.Web of Science | Medline

81. 81

Chiu HM, Hirsh J, Yung WL, Regoeczi E, Gent M. Relationship between the anticoagulant and antithrombotic effects of heparin in experimental venous thrombosis . Blood 1977; 49:171–84.Web of Science | Medline

82. 82

Barritt DW, Jordon SC Anticoagulant drugs in the treatment of pulmonary embolism: a controlled trial . Lancet 1960: 1:1309–12.CrossRef | Web of Science | Medline

83. 83

Kanis JA, Heparin in the treatment of pulmonary thromboembolism . Thromb Diath Haemorrh 1974; 32:519–27.Medline

84. 84

Hull R, Delmore T, Genton E, et al. Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis . N Engl J Med 1979;301:855–8.Full Text | Web of Science | Medline

85. 85

Lagerstedt CJ, Olsson C-G, Fagher BO, Öqvist BO, Albrechtsson U. Need for long-term anticoagulant treatment in symptomatic calf-vein thrombosis . Lancet 1985;2:515–8.CrossRef | Web of Science | Medline

86. 86

Salzman EW, Deykin D, Shapiro RM, Rosenberg R. Management of heparin therapy: controlled prospective trial . N Engl J Med 1975; 292: 1046–50.Full Text | Web of Science | Medline

87. 87

Glazier RL, Crowell EB. Randomized prospective trial of continuous vs intermittent heparin therapy . JAMA 1976; 236:1365–7.CrossRef | Web of Science | Medline

88. 88

Mant MJ, O'Brien BD, Thong KL, Hammond GW, Birtwhistle RV, Grace MG. Haemorrhagic complications of heparin therapy . Lancet 1977; 1:1133–5.CrossRef | Web of Science | Medline

89. 89

Wilson JR, Lampman J. Heparin therapy: a randomized prospective study . Am Heart J 1979;97:155–8.CrossRef | Web of Science | Medline

90. 90

Fagher B, Lundh B. Heparin treatment of deep vein thrombosis . Acta Med Scand 1981; 210:357–61.CrossRef | Web of Science | Medline

91. 91

Wilson JE III, Bynum LJ, Parkey RW. Heparin therapy in venous thromboembolism . Am J Med 1981; 70:808–16.CrossRef | Web of Science | Medline

92. 92

Doyle DJ, Turpie AGG, Hirsh J, et al. Adjusted subcutaneous heparin or continuous intravenous heparin in patients with acute deep vein thrombosis: a randomized trial . Ann Intern Med 1987; 107:441–5.Web of Science | Medline

93. 93

Bentley PG, Kakkar VV, Scully MF, et al. An objective study of alternative methods of heparin administration . Thromb Res 1980; 18:177–87.CrossRef | Web of Science | Medline

94. 94

Andersson G, Fagrell B, Holmgren K, et al. Subcutaneous administration of heparin: a randomised comparison with intravenous administration of heparin to patients with deep-vein thrombosis . Thromb Res 1982; 27:631–9.CrossRef | Web of Science | Medline

95. 95

Walker MG, Shaw JW, Thomson GJL, Cumming JGR, Thomas ML. Subcutaneous calcium heparin versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legs: a multicentre prospective randomised trial . BMJ 1987; 294:1189–92.CrossRef | Web of Science | Medline

96. 96

Pini M, Pattachini C, Quintavalla R, et al. Subcutaneous vs intravenous heparin in the treatment of deep venous thrombosis — a randomized clinical trial . Thromb Haemost 1990; 64:222–6.Web of Science | Medline

97. 97

Gallus A, Jackaman J, Tillett J, Mills W, Wycherley A. Safety and efficacy of warfarin started early after submassive venous thrombosis or pulmonary embolism . Lancet 1986; 2:1293–6.CrossRef | Web of Science | Medline

98. 98

Hull RD, Raskob GE, Rosenbloom D, et al. Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis . N Engl J Med 1990; 322:1260–4.Free Full Text | Web of Science | Medline

99. 99

Wheeler AP, Jaquiss RD, Newman JH. Physician practices in the treatment of pulmonary embolism and deep vein thrombosis . Arch Intern Med 1988; 148:1321–5.CrossRef | Web of Science | Medline

100. 100

Fennerty A, Thomas P, Backhouse G, Bentley P, Campbell IA, Routledge PA. Audit of control of heparin treatment . BMJ 1985; 290:27–8.CrossRef | Web of Science | Medline

101. 101

Cruickshank MK, Levine MN, Hirsh J, Roberts R, Siguenza M. A standard heparin nomogram for the management of heparin therapy . Arch Intern Med 1991; 151:333–7.CrossRef | Web of Science | Medline

102. 102

Clagett GP, Reisch JS. Prevention of venous thromboembolism in general surgical patients . Ann Surg 1988; 208:227–40.CrossRef | Web of Science | Medline

103. 103

Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin: overview of results of randomized trials in general, orthopedic, and urologic surgery . N Engl J Med 1988; 318:1162–73.Full Text | Web of Science | Medline

104. 104

Kakkar VV, Corrigan TP, Fossard DP. Prevention of fatal postoperative pulmonary embolism by low doses of heparin . Lancet 1975; 2:45–51.Web of Science | Medline

105. 105

Gallus AS. Overview of the management of thrombotic disorders . Semin Thromb Hemost 1989; 15:99–110.CrossRef | Web of Science | Medline

106. 106

Halkin H, Goldberg J, Modan M, Modan B. Reduction of mortality in general medical in-patients by low-dose heparin prophylaxis . Ann Intern Med 1982; 96:561–5.Web of Science | Medline

107. 107

Leyvraz PF, Richard J, Bachmann F, et al. Adjusted versus fixed-dose subcutaneous heparin in the prevention of deep-vein thrombosis after total hip replacement . N Engl J Med 1983; 309:954–8.Full Text | Web of Science | Medline

108. 108

Powers PJ, Gent M, Jay RM, et al. 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 1989;

149:771–4.CrossRef | Web of Science | Medline

109. 109

Francis CW, Marder VJ, Evarts CM, Yaukoolbodi S. Two-step warfarin therapy: prevention of postoperative venous thrombosis without excessive bleeding . JAMA 1983; 249:374–8.CrossRef | Web of Science | Medline

110. 110

MacMahon S, Collins R, Knight C, Yusuf S, Peto R. Reduction of major morbidity and mortality by heparin in acute myocardial infarction . Circulation 1988; 78:Suppl II:II–98. abstract.

111. 111

Neri Serneri GG, Rovelli F, Gensini GF, Pirelli S, Carnovali M, Fortini A. Effectiveness of low-dose heparin in prevention of myocardial reinfarction . Lancet 1987; 1:937–42.CrossRef | Web of Science | Medline

112. 112

The SCATI (Studio sulla Calciparina nell'Angina e nella Trombosi Ventricolare nell'Infarto) Group. Randomised controlled trial of subcutaneous calcium-heparin in acute myocardial infarction . Lancet 1989; 2:182–6.Web of Science | Medline

113. 113

Chesebro JH, Fuster V. Antithrombotic therapy for acute myocardial infarction: mechanisms and prevention of deep venous, left ventricular, and coronary artery thromboembolism . Circulation 1986; 74:Suppl III:III-1—III–10.Web of Science

114. 114

Cairns JA, Gent M, Singer J, et al. Aspirin, sulfinpyrazone, or both in unstable angina: results of a Canadian multicenter trial . N Engl J Med 1985; 313:1369–75.Full Text | Web of Science | Medline

115. 115

Lewis HD Jr, Davis JW, Archibald DG, et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina: results of a Veterans Administration Cooperative Study . N Engl J Med 1983;

309:396–403.Full Text | Web of Science | Medline

116. 116

The RISC Group. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease . Lancet 1990; 336:827–30.CrossRef | Web of Science | Medline

117. 117

Théroux P, Ouimet H, McCans J, et al. Aspirin, heparin, or both to treat acute unstable angina? N Engl J Med 1988; 319:1105–11.Full Text | Web of Science | Medline

118. 118

Neri Serneri GG, Gensini GR, Poggesi L, et al. Effect of heparin, aspirin, or alteplase in reduction of myocardial ischaemia in refractory unstable angina . Lancet 1990; 335:615–8.CrossRef | Web of Science | Medline

119. 119

Topol EJ, George BS, Kereiakes DJ, et al. A randomized controlled trial of intravenous tissue plasminogen activator and early intravenous heparin in acute myocardial infarction . Circulation 1989; 79:281–6.CrossRef | Web of Science | Medline

120. 120

De Bono DP, Simoons ML, Tijssen J, et al. Early intravenous heparin improves coronary patency in thrombolysis with recombinant human tissue-type plasminogen activator . Br Heart J (in press).

121. 121

National Heart Foundation of Australia Coronary Thrombolysis Study Group. A randomized comparison of oral aspirin/dipyridamole versus intravenous heparin after rtPA for acute myocardial infarction . Circulation 1989; 80:Suppl III:III–14. abstract.

122. 122

ISIS (International Studies of Infarct Survival) Pilot Study Investigators. Randomized factorial trial of high-dose streptokinase, of oral aspirin and of intravenous heparin in acute myocardial infarction . Eur Heart J 1987; 8:634–42.Web of Science | Medline

123. 123

The International Study Group. In-hospital mortality and clinical course of 20 891 patients with suspected acute myocardial infarction randomised between alteplase and streptokinase with or without heparin . Lancet 1990; 336:71–5.CrossRef | Web of Science | Medline

124. 124

King DJ, Kelton JG. Heparin-associated thrombocytopenia . Ann Intern Med 1984; 100:535–40.CrossRef | Web of Science | Medline

125. 125

Warkentin TE, Kelton JG. Heparin-induced thrombocytopenia . Annu Rev Med 1989;40:31–44.CrossRef | Web of Science | Medline

126. 126

Ginsberg JS, Hirsh J. Use of anticoagulants during pregnancy . Chest 1989; 95:Suppl 2:156S–160S.Web of Science | Medline

127. 127

Ginsberg JS, Kowalchuk G, Hirsh J, et al. Heparin effect on bone density . Thromb Haemost 1990; 64:286–9.Web of Science | Medline

128. 128

White RW, Sadd JR, Nensel RE. Thrombotic complications of heparin therapy: including six cases of heparin-induced skin necrosis . Ann Surg 1979; 190:595–608.CrossRef | Web of Science | Medline

129. 129

Jaques LB. Heparins — anionic polyelectrolyte drugs . Pharmacol Rev 1980; 31:99–166.Web of Science

130. 130

Curry N, Bandana EJ, Pirofsky B. Heparin sensitivity: report of a case . Arch Intern Med 1973; 132:744–5.CrossRef | Web of Science | Medline

131. 131

O'Kelly R, Magee F, McKenna J. Routine heparin therapy inhibits adrenal aldosterone production . J Clin Endocrinol Metab 1983; 56:108–12.CrossRef | Web of Science | Medline

132. 132

Levine MN, Hirsh J, Kelton JG. Heparin-induced bleeding. In: Lane DA, Lindahl U, eds. Heparin: chemical and biological properties clinical applications. London: Edward Arnold. 1989:517–32.

133. 133

Morabia A. Heparin doses and major bleedings . Lancet 1986; 1:1278–9.CrossRef | Web of Science | Medline

134. 134

Landefeld CS, Cook EF, Flatley M, Weisberg M, Goldman L. Identification and preliminary validation of predictors of major bleeding in hospitalized patients starting anticoagulant therapy . Am J Med 1987; 82:703–13.CrossRef | Web of Science | Medline

135. 135

Walker AM, Jick H. Predictors of bleeding during heparin therapy . JAMA 1980; 244:1209–12.CrossRef | Web of Science | Medline

136. 136

Yett HS, Skillman JJ, Salzman EW. The hazards of aspirin plus heparin . N Engl J Med 1978; 298:1092.Web of Science | Medline

137. 137

Sethi GK, Copeland JG, Goldman S, Moritz T, Zadina K, Henderson WG. Implications of preoperative administration of aspirin in patients undergoing coronary artery bypass grafting . J Am Coll Cardiol 1990; 15:15–20.CrossRef | Web of Science | Medline

138. 138

Jick H, Slone D, Borda IT, Shapiro S. Efficacy and toxicity of heparin in relation to age and sex . N Engl J Med 1968; 279:284–6.Full Text | Web of Science | Medline

139. 139

Leroy J, Leclerc MH, Delahousse B, et al. Treatment of heparin-associated thrombocytopenia and thrombosis with low molecular weight heparin (CY 216) . Semin Thromb Hemost 1985; 11:326–9.CrossRef | Web of Science | Medline

140. 140

Chong BH, Ismail F, Cade J, Gallus AS, Gordon S, Chesterman CN. Heparin-induced thrombocytopenia: studies with a new low molecular weight heparinoid, Org 10172 . Blood 1989; 73:1592–6.Web of Science | Medline

141. 141

Levine MN, Hirsh J, Gent M, et al. Prevention of deep vein thrombosis after elective hip surgery: a randomized trial comparing low molecular weight heparin with standard unfractionated heparin . Ann Intern Med 1991; 114:545–51.Web of Science | Medline