0
Articles |

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

Jack Hirsh, MD, FCCP, Chair; Theodore E. Warkentin, MD; Stephen G. Shaughnessy, PhD; Sonia S. Anand, MD; Jonathan L. Halperin, MD; Robert Raschke, MD, MS; Christopher Granger, MD; E. Magnus Ohman, MBBCh, FCCP; James E. Dalen, MD, MPH, Master FCCP
Author and Funding Information

Correspondence to: Jack Hirsh, MD, FCCP, Director, Hamilton Civic Hospitals Research Centre, 711 Concession St, Hamilton, ON L8V 1C3, Canada



Chest. 2001;119(1_suppl):64S-94S. doi:10.1378/chest.119.1_suppl.64S
Text Size: A A A
Published online

Heparin and its derivative, low-molecular-weight heparin (LMWH), are the anticoagulants of choice when a rapid anticoagulant effect is required, because their onset of action is immediate when administered by IV injection. Both types of heparins are administered in lower doses for primary prophylaxis than for treatment of venous thrombosis or acute myocardial ischemia. Heparin has pharmacokinetic limitations1 not shared by LMWHs. Based on these pharmacokinetic limitations, heparin therapy is usually restricted to the hospital setting, where its effect can be monitored and its dosage adjusted frequently. In contrast, LMWH preparations can be administered in either the in-hospital or out-of-hospital setting because they can be administered subcutaneously (sc) without the need for laboratory monitoring. When long-term anticoagulant therapy is indicated, heparin or LMWH administration is usually followed by treatment with oral anticoagulants. However, long-term out-of-hospital treatment with heparin or LMWH is used when anticoagulant therapy is indicated in pregnancy and in patients who develop recurrent venous thromboembolism while treated with appropriate doses of oral anticoagulants.

Since our report in 1998 (Supplement to CHEST, Vol. 114, iss 5), a number of LMWH preparations have been approved for use for the treatment of venous thrombosis and for the treatment of unstable angina (UA).

Heparin is effective and indicated for the prevention of venous thromboembolism; for the treatment of venous thrombosis and pulmonary embolism (PE); for the early treatment of patients with UA and acute myocardial infarction (MI); for patients who undergo cardiac surgery using cardiac bypass, vascular surgery, and coronary angioplasty; in patients with coronary stents; and in selected patients with disseminated intravascular coagulation.

LMWHs are effective and indicated for the prevention of venous thromboembolism, for the treatment of venous thrombosis, for the treatment of acute PE, and for the early treatment of patients with UA. The levels of evidence and grading of recommendations for the clinical use of heparin and LMWHs are discussed in the chapters that consider the evidence supporting antithrombotic therapy with these agents for the various clinical indications.

This chapter will review the mechanisms of action of heparin and LMWHs, their pharmacokinetics, anticoagulant effects, side effects, and laboratory monitoring. The clinical uses of heparin and LMWHs and the results of clinical trials will also be discussed, although more details appear in other chapters.

Heparin was discovered by McLean2in 1916, and Brinkhous and associates3demonstrated that its anticoagulant effect requires a plasma cofactor later named antithrombin III (AT-III),4 but is now known simply as antithrombin (AT). Rosenberg and Lam,1 Rosenberg and Bauer,5and Lindahl et al6 elucidated the mechanisms responsible for the heparin/AT interaction. It is now known that the active center serine of thrombin and other coagulation enzymes are inhibited by an arginine-reactive site on the AT molecule and that heparin binds to lysine site on AT, producing a conformational change at the arginine-reactive site that converts AT from a slow, progressive thrombin inhibitor to a very rapid inhibitor of thrombin and factor Xa.5 AT binds covalently to the active serine centers of coagulation enzymes; heparin then dissociates from the ternary complex and can be reutilized (Fig 1 ).,5 Subsequently, it was discovered1,56 that heparin binds to and potentiates the activity of AT through a unique glucosamine unit1,57 contained within a pentasaccharide sequence,8the structure of which has been confirmed. A synthetic pentasaccharide has been developed and is undergoing clinical evaluation for prevention and treatment of venous thrombosis.910

Only about one third of an administered dose of heparin binds to AT, and this fraction is responsible for most of its anticoagulant effect.1112 The remaining two thirds has minimal anticoagulant activity at therapeutic concentrations, but at concentrations greater than usually obtained clinically, both high-affinity and low-affinity heparin catalyze the AT effect of a second plasma protein, heparin cofactor II (Table 1 ).13

The heparin-AT complex inactivates a number of coagulation enzymes, including thrombin factor (IIa), factors Xa, IXa, XIa, and XIIa.5 Of these, thrombin and factor Xa are most responsive to inhibition, and human thrombin is about 10-fold more sensitive to inhibition by the heparin-AT complex than factor Xa (Fig 2 ). To inhibit thrombin, heparin must bind to both the coagulation enzyme and AT, but binding to the enzyme is less important for the inhibition of activated factor X (factor Xa; Fig 3 ).,7 Molecules of heparin containing < 18 saccharides do not bind simultaneously to thrombin and AT and are therefore unable to catalyze thrombin inhibition. In contrast, very small heparin fragments containing the high-affinity pentasaccharide sequence catalyze inhibition of factor Xa by AT.1417 By inactivating thrombin, heparin not only prevents fibrin formation but also inhibits thrombin-induced activation of factor V and factor VIII.1820 Unfractionated heparin (UFH) and LMWH also induce secretion of tissue factor pathway inhibitor by vascular endothelial cells that reduce procoagulant activity of tissue factor VIIa complex, and this could contribute to the antithrombotic action of heparin and LMWH.2123

Heparin is heterogeneous with respect to molecular size, anticoagulant activity, and pharmacokinetic properties (Table 2 ). Its molecular weight ranges from 3,000 to 30,000 d average, with a mean molecular weight of 15,000 d (approximately 45 monosaccharide chains; Fig 4 ).2426 Its anticoagulant activity varies because only one third of heparins have anticoagulant function and because its anticoagulant profile and clearance are influenced by the chain length of the molecules, with the higher-molecular-weight species cleared from the circulation more rapidly than the lower-molecular-weight species. This differential clearance results in accumulation in vivo of the lower-molecular-weight species, which have a lower ratio of antifactor IIa to antifactor Xa activity. The lower-molecular-weight species that are retained in vivo are measured by the antifactor Xa heparin assay, but these have little effect on the activated partial thromboplastin time (APTT). Binding of heparin to von Willebrand factor also inhibits von Willebrand factor-dependent platelet function.27

Heparin binds to platelets, and depending on the experimental conditions in vitro, can either induce or inhibit platelet aggregation.2829 Heparin prolongs the bleeding time in humans30and enhances blood loss from the microvasculature in rabbits.3133 The interaction of heparin with platelets31and endothelial cells32may contribute to heparin-induced bleeding by a mechanism independent of its anticoagulant effect.33

In addition to its anticoagulant effect, heparin increases vessel wall permeability,32 inhibits the proliferation of vascular smooth muscle cells,34and suppresses osteoblast formation and activates osteoclasts that promote bone loss.3536 Each of these effects is independent of its anticoagulant activity, but only the osteopenic effect is likely to be relevant clinically.37

The preferred routes of UFH administration are continuous IV infusion and sc injection. When the sc route is selected, the initial dose must be sufficient to overcome the lower bioavailability associated with this route of administration.38 An immediate anticoagulant effect requires an IV bolus.

In the circulation, heparin binds to a number of plasma proteins (Fig 5 ), which reduces its anticoagulant activity at low concentrations, thereby contributing to the variability of the anticoagulant response to heparin among patients with thromboembolic disorders39 and to the laboratory phenomenon of heparin resistance.40 Heparin also binds to endothelial cells41 and macrophages, which further complicates its pharmacokinetics.

Heparin clearance involves a combination of a rapid saturable and a much slower first-order mechanisms (Fig 6 ).4244 The mechanism of the saturable phase of heparin clearance is through binding to receptors on endothelial cells4546 and macrophages47where it is depolymerized (Fig 5),49 while the slower unsaturable mechanism is renal (Fig 6). At therapeutic doses, heparin is cleared predominantly through the rapid saturable, dose-dependent mechanism and its anticoagulant effects are nonlinear, with both the intensity and duration of effect rising disproportionately with increasing dose. As a result, the half-life of heparin increases from approximately 30 min following an IV bolus of 25 U/kg, to 60 min with a bolus of 100 U/kg, and to 150 min with a bolus of 400 U/kg.,4244

Plasma recovery of heparin is reduced50 when administered by sc injection in low (5,000 U q12h) or moderate (12,500 to 15,000 U q12h) doses.38,51At high therapeutic doses (> 35,000 U/24 h), however, plasma recovery is almost complete.52 The difference between the bioavailability of heparin administered by sc or IV injection was demonstrated in patients with venous thrombosis38 randomized to receive either 15,000 q12h by sc injection or 30,000 U by continuous IV infusion; both regimens were preceded by a 5,000-U bolus. Therapeutic heparin levels and APTT ratios were achieved at 24 h in only 37% of patients given sc heparin, compared with 71% of those given the same total dose by continuous IV infusion.

Randomized trials show a relationship among heparin dose, efficacy,38,51,53and safety.5455 Since the anticoagulant response to heparin varies among patients with thromboembolic disorders,5660 it is standard practice to adjust the dose of heparin and monitor its effect by measurement of the APTT that is sensitive to the inhibitory effects of heparin on thrombin, factor Xa, and factor IXa. Although a relationship exists between heparin dose and therapeutic efficacy for patients with venous thromboembolism, such a relationship has not been established for patients with acute coronary ischemia, although those receiving concomitant thrombolytic therapy or glycoprotein (GP) IIb/IIIa (GPIIb/IIIa) antagonists given heparin in a dose used to treat venous thrombosis have an unacceptably high rate of bleeding.

Although a close relationship between an effect of heparin ex vivo on the APTT and its clinical effect in vivo has been assumed, the data supporting this assumption are derived from retrospective subgroup analysis of cohort studies38,51,5758,6061 (Table 3 ) and are inconsistent with the results of a randomized trial62 and meta-analyses of contemporary cohort studies.6364 Furthermore, there was no direct relationship between APTT and efficacy observed in the subgroup analysis of the GUSTO I study65in patients with acute MI who were treated with thrombolytic therapy followed by heparin. And even if the APTT were predictive of clinical efficacy, its value would be limited by the variable responsiveness of commercial APTT reagents to heparin.66

The risk of heparin-associated bleeding increases with dose6768 and with concomitant thrombolytic therapy6972 or the GPIIb/IIIa antagonist abciximab.5455 The risk of bleeding is also increased by recent surgery, trauma, invasive procedures, or concomitant hemostatic defects.73

Despite its limitations, the APTT remains the most frequently used method for monitoring the anticoagulant response to heparin. The APTT should be measured approximately 6 h after the bolus dose of heparin, and the continuous IV dose should be adjusted based on the result.

When heparin is given by sc injection in a dose of 35,000 U/24 h in two divided doses,52 the anticoagulant effect is delayed for approximately 1 h and peak plasma levels occur at approximately 3 h.

Audits of physician-directed heparin therapy have demonstrated a great deal of variability in dosing decisions.7477 A number of methods for standardizing the management of IV heparin therapy have been published, including heparin dose-adjustment nomograms56,7883 and computer algorithms.8485 Nomograms and computer-assisted dosage adjustment have also been used to manage heparin in conjunction with thrombolytic therapy for patients with MI.65,81,85The weight-adjusted nomogram has been incorporated into the Agency for Health Care Policy and Research guideline for treatment of UA.8687

A weight-based nomogram using a starting dose of 18 U/kg/h heparin infusion (1,260 U/h for a 70-kg patient; Fig 7 ) reduced recurrent thromboembolism in a randomized controlled trial (relative risk [RR] = 0.2; 95% confidence interval [CI], 0.05 to 0.91)78,88; the control group, however, received an inadequate initial heparin infusion (1,000 U/h). Several other nomograms utilize initial heparin infusion doses as low as 12 U/kg/h,8990 but the APTT was determined unconventionally91 and therefore might not be valid.

Two nomograms have been validated independently9293; both significantly reduced latency to therapeutic APTT levels. Over a 5-year period, voluntary physician use of the nomogram approached 95% at one institution and this was associated with significantly higher initial heparin dosage, shorter time to therapeutic APTT, and no increase in bleeding.94

Weight-adjusted nomograms have also been evaluated in clinical trials in patients with UA. These have used a lower initial infusion rate of 15 U/kg/h.9596 In the OASIS-2 study,95a bolus dose of 5,000 U was followed by an infusion of 15 U/kg/h. More than 80% of patients reached the therapeutic APTT range (60 s and 100 s) within 24 h. In the TIMI-11B study,96 a 70-U/kg bolus was followed by an infusion of 15 U/kg/h and the APTT reached 55 to 58 s in 42% of patients within 12 h. A weight-adjusted nomogram has been incorporated into the guidelines for treatment of UA promulgated by the Agency for Health Care Policy and Research.8687

When a nomogram is used, it is important to determine the appropriate therapeutic range based on the local laboratory reagent and to adapt the recommended dosage adjustments accordingly. For patients with venous thrombosis or PE, the targeted APTT should be equivalent to a heparin level or 0.3 to 0.7 U/mL by antifactor Xa heparin levels.9798 A lower therapeutic range is recommended for patients with acute myocardial ischemia receiving thrombolytic or GPIIb/IIIa antagonist agents, since a lower dose of heparin proved safer and no less effective in these circumstances than the higher-dose regimen established for patients with venous thrombosis. Recognizing that the traditional heparin dosing regimens cause excessive bleeding in patients with acute MI who receive thrombolytic therapy, a therapeutic range corresponding to antifactor Xa levels of 0.14 to 0.34 seems reasonable.89 Failure to adapt nomograms to the therapeutic range could result in dangerous errors in heparin therapy.

Some patients require higher-than-average doses of heparin to prolong APTT to the therapeutic range. These patients are designated heparin resistant if their daily heparin requirement is > 35,000 U/24 h,62,99100 and approximately 25% of patients with venous thromboembolism fulfill this criterion.38,52,101103 Heparin resistance has been associated with AT deficiency,5,91 increased heparin clearance,104 elevations in heparin binding proteins,40,105106 and elevations of factor VIII,62,107 fibrinogen,107and platelet factor 4 (PF4).108Aprotinin and nitroglycerin have been reported to cause drug-induced heparin resistance,109110 though the association with nitroglycerin is controversial.111 Factor VIII or fibrinogen levels are elevated in response to acute illness or pregnancy.91,112113 Elevation of the levels of factor VIII alters the response of the APTT to heparin without diminishing the antithrombotic effect,62 as the anticoagulant effect of heparin (measured by the APTT) and the antithrombotic effect measured by anti-Xa activity become dissociated.91,100 Studies in experimental animals demonstrated that the infusion of factor VIII significantly lowers APTT values without interfering with the antithrombotic effect of heparin. Under these experimental circumstances, heparin concentration was unperturbed and was a more accurate measure of thrombus inhibition than the APTT.114 A randomized, controlled trial has shown that adjusting dosage by anti-Xa heparin concentrations results in favorable clinical outcomes in heparin-resistant patients despite lower doses of heparin and subtherapeutic APTT levels.62

For patients who require > 35,000 U of UFH per 24 h, the dose should be adjusted to maintain anti-Xa heparin levels of 0.35 to 0.70 IU/mL.91,106,112 In a randomized, controlled trial in 131 patients with venous thromboembolism requiring > 35,000 U of heparin per day, monitoring the APTT was compared to anti-Xa heparin activity with no significant differences in clinical outcomes, but the group monitored using anti-Xa heparin levels required significantly less heparin with no difference in bleeding.62 This approach is especially useful for patients at high risk of bleeding when continued heparin therapy is necessary. Substitution of LMWH may be inadvisable in such patients due to its long half-life and the lack of an effective neutralizing agent. Although measurement of AT levels has also been recommended in the management of heparin resistance,91 low values are usually secondary to heparin therapy,115116 rather than the cause of heparin resistance.

The limitations of heparin are based on its pharmacokinetic, biophysical, and its nonanticoagulant biological properties.117All of these limitations are caused by the AT-independent, charge-dependent binding properties of heparin to proteins and surfaces. Pharmacokinetic limitations are caused by the following: (1) AT-independent binding of heparin to plasma proteins,118to proteins released from platelets,119 and possibly to endothelial cells, which result in the variable anticoagulant response to heparin and to the phenomenon of heparin resistance62; and (2) AT-independent binding to macrophages and endothelial cells, which result in its dose-dependent mechanism of clearance.

The biophysical limitations occur because the heparin/AT complex is unable to inactivate factor Xa in the prothrombinase complex and thrombin bound to fibrin or to subendothelial surfaces. The biological limitations of heparin include osteopenia and heparin-induced thrombocytopenia (HIT). Osteopenia is caused as a result of the binding of heparin to osteoblasts,35 which then release factors that activate osteoclasts, whereas HIT results from heparin binding to PF4 to form an epitope to which the HIT antibody binds.120121 The pharmacokinetic and nonanticoagulant biological limitations of heparin are less evident with LMWH,122while the limited ability of the heparin-AT complex to fibrin- bound thrombin and factor Xa is overcome by several new classes of AT-independent thrombin and factor Xa inhibitors.123

The anticoagulant effect of heparin is modified by platelets, fibrin, vascular surfaces, and plasma proteins. Platelets limit the anticoagulant effect of heparin by protecting surface factor Xa from inhibition by heparin/AT124125 and by secreting PF4, a heparin-neutralizing protein.126Fibrin limits the anticoagulant effect of heparin by protecting fibrin-bound thrombin from inhibition by heparin/AT.127Heparin binds to fibrin and bridges between fibrin and the heparin binding site on thrombin. As a result, heparin increases the affinity of thrombin for fibrin, and by occupying the heparin binding site on thrombin, protects fibrin-bound thrombin from inactivation by heparin/AT.128129 Thrombin also binds to subendothelial matrix proteins, where it is protected from inhibition by heparin.130These observations explain why in experimental animals131132 heparin is less effective than the AT-independent thrombin and factor Xa inhibitors123 at preventing thrombosis at sites of deep arterial injury and may explain why hirudin is more effective than heparin in UA and non-Q-wave myocardial infarction (NQMI).95

Heparin is indicated for prevention of venous thromboembolism; for treatment of venous thrombosis and PE for the early treatment of patients with UA and acute MI; for patients who undergo cardiac surgery using cardiopulmonary bypass, vascular surgery, coronary angioplasty, and stents; and in selected patients with disseminated intravascular coagulation. LMWHs are indicated for prevention of venous thromboembolism, for treatment of venous thrombosis, for treatment of acute PE, and for the early treatment of patients with UA. Levels of evidence and grading of recommendations for the clinical use of heparin and LMWHs are discussed in the chapters discussing antithrombotic therapy for the various clinical indications.

In patients with venous thromboembolism or UA, the dose of heparin is usually adjusted to maintain the APTT at an intensity equivalent to an antifactor Xa level of 0.35 to 0.7 U/mL. For many APTT reagents, this is equivalent to a ratio (patient/control APTT) of 1.5 to 2.5. This therapeutic range38,61 is recommended based on animal studies114 and subgroup analysis of prospective studies of patients with established deep vein thrombosis (DVT),38 and studies of prevention of mural thrombosis after MI51 and prevention of recurrent ischemia following coronary thrombolysis.5758 Recommended heparin regimens for venous and arterial thrombosis are summarized in Table 4 .

The efficacy and safety of continuous IV infusion of heparin has been compared with intermittent IV injection in seven studies135141 and with high-dose sc injection in five studies.52,101,142144 From these studies, it is difficult to determine the optimal route of heparin administration because most were underpowered, total doses varied, and disparate criteria were used to assess outcome. A pooled analysis of 11 clinical trials involving 15,000 patients treated with either IV UFH (administered as an initial bolus of 5,000 U followed by 30,000 to 35,000 U/24 h with APTT monitoring) or sc LMWH145 found the mean incidence of recurrent venous thromboembolism 5.4% (fatal in 0.7%) and major bleeding 1.9% (fatal in 0.2%).

A 5-day course of heparin therapy appears as effective as a 10-day course for the treatment of DVT (Table 5 ),103,146 and brevity has obvious appeal, reducing both hospital stay and the risk of HIT. While adequate for most patients with venous thromboembolism, a 5-day course of heparin therapy may not be sufficient for those with extensive iliofemoral venous thrombosis or PE who were underrepresented in these studies.103,146

Heparin in a fixed low dose of 5,000 U sc every 8 to 12 h results in 60 to 70% risk reduction for venous thrombosis and fatal PE.147148 The incidence of fatal PE in general surgical patients was reduced from 0.7% in control subjects to 0.2% in one analysis (p < 0.001),147and from 0.8 to 0.3% (p < 0.001) in a larger analysis that included orthopedic surgical patients.148 There was also a statistically significant decrease in mortality, from 3.3 to 2.4% (p < 0.02).148 The use of low-dose heparin was associated with a small excess of wound hematoma,147149 but there was no statistically significant increase in major bleeding. Low-dose heparin therapy is also effective for prevention of venous thromboembolism in patients with MI and other serious medical disorders,150reducing in-hospital mortality by 31% (p < 0.05) in a study of 1,358 general medical patients > 40 years old.151 The incidence of DVT remains substantial (20 to 30%) after hip surgery,148 despite low-fixed-dose heparin prophylaxis, and risk can be reduced further by administering either adjusted-dose heparin152 or fixed-dose LMWH.122 Moderate-dose warfarin therapy is also effective in patients undergoing major orthopedic surgical procedures,153154 but direct comparisons of low-dose heparin and warfarin therapy have not been performed in patients undergoing major orthopedic surgery in sufficiently powered trials.

Coronary thrombosis is important in the pathogenesis of UA, acute MI, and sudden cardiac death, and affects the outcomes of patients with acute MI treated with thrombolytic therapy or percutaneous transluminal coronary angioplasty (PTCA). Heparin is no longer used as the sole antithrombotic drug in patients with acute coronary syndromes, but it is combined with aspirin in eligible patients with acute MI,155with thrombolytic therapy in patients with evolving MI, and with GPIIb/IIIa antagonists in high-risk patients with UA156157 or in those undergoing high-risk PTCA.5455,157 Heparin increases the risk of bleeding when given in full doses combined with aspirin,155,158 thrombolytic therapy, and GPIIb/IIIa antagonists, so the dose is usually reduced in these settings.55

Heparin has been evaluated in a number of randomized, double-blind, placebo-controlled clinical trials for the short-term treatment of patients with UA or NQMI.159162 When used alone in patients with UA, heparin reduces the risk of developing recurrent angina or acute MI.160162 Meta-analysis of short-term results suggests that the combination of heparin and aspirin reduces cardiovascular death and MI by about 30% over that achieved by aspirin alone.159