PARENTERAL ANTICOAGULANTS

Heparin
Biochemistry. Heparin is a glycosaminoglycan found in the secretory granules of mast cells. It is synthesized from UDP-sugar precursors as a polymer of alternating D-glucuronic acid and N-acetyl-D-glucosamine residues (Sugahara and Kitagawa, 2002). About 10 to 15 glycosaminoglycan chains, each containing 200 to 300 monosaccharide units, are attached to a core protein and yield a proteoglycan with a molecular mass of 750,000 to 1,000,000 daltons. The glycosaminoglycan then undergoes a series of modifications, which include the following: N-deacetylation and N-sulfation of glucosamine residues, epimerization of D-glucuronic acid to L-iduronic acid, O-sulfation of iduronic and glucuronic acid residues at the C2 position, and O-sulfation of glucosamine residues at the C3 and C6 positions. Each of these modifications is incomplete, yielding a variety of oligosaccharide structures. After the heparin proteoglycan has been transported to the mast cell granule, an endo-b-D-glucuronidase degrades the glycosaminoglycan chains to fragments of 5000 to 30,000 daltons (mean, about 12,000 daltons or 40 monosaccharide units) over a period of hours.
Heparan Sulfate. Heparan sulfate is synthesized from the same repeating disaccharide precursor (D-glucuronic acid linked to N-acetyl-D-glucosamine) as is heparin. However, heparan sulfate undergoes less modification of the polymer than does heparin and therefore contains higher proportions of glucuronic acid and N-acetylglucosamine and fewer sulfate groups. Heparan sulfate on the surface of vascular endothelial cells or in the subendothelial extracellular matrix interacts with circulating antithrombin (see below) to provide a natural antithrombotic mechanism. Patients with malignancies may experience bleeding related to circulating heparan sulfate or related glycosaminoglycans that probably originate from lysis of the tumor cells.
Source. Heparin is commonly extracted from porcine intestinal mucosa or bovine lung, and preparations may contain small amounts of other glycosaminoglycans. Despite the heterogeneity in composition among different commercial preparations of heparin, their biological activities are similar (about 150 USP units/mg). The USP unit is the quantity of heparin that prevents 1 ml of citrated sheep plasma from clotting for 1 hour after the addition of 0.2 ml of 1% CaCl2.
Low-molecular-weight heparins (1000 to 10,000 daltons; mean, 4500 daltons, or 15 monosaccharide units) are isolated from standard heparin by gel filtration chromatography, precipitation with ethanol, or partial depolymerization with nitrous acid and other chemical or enzymatic reagents. Low-molecular-weight heparins differ from standard heparin and from each other in their pharmacokinetic properties and mechanism of action (see below). The biological activity of low-molecular-weight heparin is generally measured with a factor Xa inhibition assay, which is mediated by antithrombin (see below).
Mechanism of Action. Heparin catalyzes the inhibition of several coagulation proteases by antithrombin, a glycosylated, single-chain polypeptide composed of 432 amino acid residues (Olson and Chuang, 2002). Antithrombin is synthesized in the liver and circulates in plasma at an approximate concentration of 2.6 mM. It inhibits activated coagulation factors of the intrinsic and common pathways, including thrombin, Xa, and IXa; however, it has relatively little activity against factor VIIa. Antithrombin is a "suicide substrate" for these proteases; inhibition occurs when the protease attacks a specific Arg-Ser peptide bond in the reactive site of antithrombin and becomes trapped as a stable 1:1 complex.
Heparin increases the rate of the thrombin-antithrombin reaction at least a thousandfold by serving as a catalytic template to which both the inhibitor and the protease bind. Binding of heparin also induces a conformational change in antithrombin that makes the reactive site more accessible to the protease. Once thrombin has become bound to antithrombin, the heparin molecule is released from the complex. The binding site for antithrombin on heparin is a specific pentasaccharide sequence that contains a 3-O-sulfated glucosamine residue. This structure occurs in about 30% of heparin molecules and less abundantly in heparan sulfate. Other glycosaminoglycans (e.g., dermatan sulfate, chondroitin-4-sulfate, and chondroitin-6-sulfate) lack the antithrombin-binding structure and do not stimulate antithrombin. Heparin molecules containing fewer than 18 monosaccharide units (<5400 daltons) also do not catalyze inhibition of thrombin by antithrombin. Molecules of 18 monosaccharides or greater are required to bind thrombin and antithrombin simultaneously. In this case, catalysis may occur solely by induction of a conformational change in antithrombin that facilitates reaction with the protease. Low-molecular-weight heparin preparations produce an anticoagulant effect mainly through inhibition of Xa by antithrombin, because the majority of molecules are of insufficient length to catalyze inhibition of thrombin.
When the concentration of heparin in plasma is 0.1 to 1 units/ml, thrombin, factor IXa, and factor Xa are inhibited rapidly (half-lives less than 0.1 second) by antithrombin. This effect prolongs both the aPTT and the thrombin time (i.e., the time required for plasma to clot when exogenous thrombin is added); the PT is affected to a lesser degree. Factor Xa bound to platelets in the prothrombinase complex and thrombin bound to fibrin are both protected from inhibition by antithrombin in the presence of heparin. Thus, heparin may promote inhibition of factor Xa and thrombin only after they have diffused away from these binding sites. Platelet factor 4, released from the a-granules during platelet aggregation, blocks binding of antithrombin to heparin or heparan sulfate and may promote local clot formation at the site of hemostasis.
Miscellaneous Pharmacological Effects. High doses of heparin can interfere with platelet aggregation and thereby prolong bleeding time. It is unclear to what extent the antiplatelet effect of heparin contributes to the hemorrhagic complications of treatment with the drug. Heparin "clears" lipemic plasma in vivo by causing the release of lipoprotein lipase into the circulation. Lipoprotein lipase hydrolyzes triglycerides to glycerol and free fatty acids. The clearing of lipemic plasma may occur at concentrations of heparin below those necessary to produce an anticoagulant effect. Rebound hyperlipemia may occur after heparin administration is stopped.
Clinical Use. Heparin is used to initiate treatment of venous thrombosis and pulmonary embolism because of its rapid onset of action (Hirsh et al., 2001). An oral anticoagulant usually is started concurrently, and heparin is continued for at least 4 to 5 days to allow the oral anticoagulant to achieve its full therapeutic effect (see Clinical Use and Monitoring Anticoagulant Therapy). Patients who experience recurrent thromboembolism despite adequate oral anticoagulation (e.g., patients with Trousseau's syndrome) may benefit from long-term heparin administration. Heparin is used in the initial management of patients with unstable angina or acute myocardial infarction, during and after coronary angioplasty or stent placement, and during surgery requiring cardiopulmonary bypass. Heparin also is used to treat selected patients with disseminated intravascular coagulation. Low-dose heparin regimens are effective in preventing venous thromboembolism in certain high-risk patients. Specific recommendations for heparin use have been reviewed (Hirsh et al., 2001).
Low-molecular-weight heparin preparations were first approved for prevention of venous thromboembolism. They are also effective in the treatment of venous thrombosis, pulmonary embolism, and unstable angina (Hirsh et al., 2001). The principal advantage of low-molecular-weight heparin over standard heparin is a more predictable pharmacokinetic profile, which allows weight-adjusted subcutaneous administration without laboratory monitoring. Thus, therapy of many patients with acute venous thromboembolism can be provided in the outpatient setting. Other advantages of low-molecular-weight heparin include a lower incidence of heparin-induced thrombocytopenia and possibly lower risks of bleeding and osteopenia.
In contrast to warfarin, heparin does not cross the placenta and has not been associated with fetal malformations; therefore it is the drug of choice for anticoagulation during pregnancy. Heparin does not appear to increase the incidence of fetal mortality or prematurity. If possible, the drug should be discontinued 24 hours before delivery to minimize the risk of postpartum bleeding. The safety and efficacy of low-molecular-weight heparin use during pregnancy have not been adequately evaluated.
Absorption and Pharmacokinetics. Heparin is not absorbed through the gastrointestinal mucosa and therefore is given by continuous intravenous infusion or subcutaneous injection. Heparin has an immediate onset of action when given intravenously. In contrast, there is considerable variation in the bioavailability of heparin given subcutaneously, and the onset of action is delayed 1 to 2 hours; low-molecular-weight heparins are absorbed more uniformly.
The half-life of heparin in plasma depends on the dose administered. When doses of 100, 400, or 800 units/kg of heparin are injected intravenously, the half-lives of the anticoagulant activities are approximately 1, 2.5, and 5 hours, respectively (see Appendix II for pharmacokinetic data). Heparin appears to be cleared and degraded primarily by the reticuloendothelial system; a small amount of undegraded heparin also appears in the urine. The half-life of heparin may be shortened in patients with pulmonary embolism and prolonged in patients with hepatic cirrhosis or end-stage renal disease. Low-molecular-weight heparins have longer biological half-lives than do standard preparations of the drug.
Administration and Monitoring. Full-dose heparin therapy usually is administered by continuous intravenous infusion. Treatment of venous thromboembolism is initiated with a bolus injection of 5000 units, followed by 1200 to 1600 units per hour delivered by an infusion pump. Therapy routinely is monitored by the aPTT. The therapeutic range for standard heparin is considered to be that which is equivalent to a plasma heparin level of 0.3 to 0.7 units/ml as determined with an anti-factor Xa assay (Hirsh et al., 2001). The aPTT value that corresponds to this range varies depending on the reagent and instrument used to perform the assay. A clotting time of 1.8 to 2.5 times the normal mean aPTT value generally is assumed to be therapeutic; however, values in this range obtained with some aPTT assays may overestimate the amount of circulating heparin, and therefore be subtherapeutic. The risk of recurrence of thromboembolism is greater in patients who do not achieve a therapeutic level of anticoagulation within the first 24 hours. Initially, the aPTT should be measured and the infusion rate adjusted every 6 hours; dose adjustments may be aided by use of a nomogram (Hirsh et al., 2001). Once a steady dosage schedule has been established, daily monitoring is sufficient.
Very high doses of heparin are required to prevent coagulation during cardiopulmonary bypass. The aPTT is infinitely prolonged over the dosage range used. Another coagulation test, such as the activated clotting time, is employed to monitor therapy in this situation.
Subcutaneous administration of heparin can be used for the long-term management of patients in whom warfarin is contraindicated (e.g., during pregnancy). A total daily dose of about 35,000 units administered as divided doses every 8 to 12 hours usually is sufficient to achieve an aPTT of 1.5 times the control value (measured midway between doses). Monitoring generally is unnecessary once a steady dosage schedule is established.
Low-dose heparin therapy is used prophylactically to prevent deep venous thrombosis and thromboembolism in susceptible patients. (Until recently a suggested regimen for such treatment was 5000 units of heparin given every 8 to 12 hours.) The body of evidence now suggests that this regimen is clinically less effective than giving heparin every 8 hours in hospitalized medical and surgical patients at high risk for venous thromboembolism (Cade, 1982; Gardlund, 1996; Belch et al., 1981). Laboratory monitoring is unnecessary, since this regimen does not prolong the aPTT.
Low-Molecular-Weight Heparin Preparations. Enoxaparin (LOVENOX), dalteparin (FRAGMIN), tinzaparin (INNOHEP, others), ardeparin (NORMIFLO), nadroparin (FRAXIPARINE, others), and reviparin (CLIVARINE) differ considerably in composition, and it cannot be assumed that two preparations that have similar anti-factor Xa activity will produce equivalent antithrombotic effects. The more predictable pharmacokinetic properties of low-molecular-weight heparins, however, permit administration in a fixed or weight-adjusted dosage regimen once or twice daily by subcutaneous injection. Since they have a minimal effect on tests of clotting in vitro, monitoring is not done routinely. Patients with end-stage renal failure may require monitoring with an anti-factor Xa assay because this condition may prolong the half-life of low-molecular-weight heparin. Specific dosage recommendations for various low-molecular-weight heparins may be obtained from the manufacturer's literature. Nadroparin and reviparin are not currently available in the United States.
Synthetic Heparin Derivatives. Fondaparinux (ARIXTRA) is a synthetic pentasaccharide based on the structure of the antithrombin binding region of heparin. It mediates inhibition of factor Xa by antithrombin but does not cause thrombin inhibition due to its short polymer length. Fondaparinux is administered by subcutaneous injection, reaches peak plasma levels in 2 hours, and is excreted in the urine with a half-life of 17 to 21 hours. It should not be used in patients with renal failure. Because it does not interact significantly with blood cells or plasma proteins other than antithrombin, fondaparinux can be given once a day at a fixed dose without coagulation monitoring. Fondaparinux appears to be much less likely than heparin or low-molecular-weight heparin to trigger the syndrome of heparin-induced thrombocytopenia (see below). Fondaparinux is approved for thromboprophylaxis of patients undergoing hip or knee surgery (Buller et al., 2003) and for the therapy of pulmonary embolism and deep venous thrombosis. Idraparinux (undergoing phase III clinical testing as of 2004) is a more highly sulfated derivative of fondaparinux that has a half-life of 5 to 6 days; the lack of a suitable antidote may limit its clinical application.
Heparin Resistance. The dose of heparin required to produce a therapeutic aPTT varies due to differences in the concentrations of heparin-binding proteins in plasma, such as histidine-rich glycoprotein, vitronectin, and platelet factor 4; these proteins competitively inhibit binding of heparin to antithrombin. Occasionally a patient's aPTT will not be prolonged unless very high doses of heparin (>50,000 units per day) are administered. Such patients may have "therapeutic" concentrations of heparin in plasma at the usual dose when values are measured by other tests (e.g., anti-factor Xa activity or protamine sulfate titration). These patients may have very short aPTT values prior to treatment because of the presence of an increased concentration of factor VIII and may not be truly resistant to heparin. Other patients may require large doses of heparin because of accelerated clearance of the drug, as may occur with massive pulmonary embolism. Patients with inherited antithrombin deficiency ordinarily have 40% to 60% of the normal plasma concentration of this inhibitor and respond normally to intravenous heparin. However, acquired antithrombin deficiency (concentration less than 25% of normal) may occur in patients with hepatic cirrhosis, nephrotic syndrome, or disseminated intravascular coagulation; large doses of heparin may not prolong the aPTT in these individuals.
Toxicities. Bleeding. Bleeding is the primary untoward effect of heparin. Major bleeding occurs in 1% to 5% of patients treated with intravenous heparin for venous thromboembolism (Hirsh et al., 2001). The incidence of bleeding is somewhat less in patients treated with low-molecular-weight heparin for this indication. Although the number of bleeding episodes appears to increase with the total daily dose of heparin and with the degree of prolongation of the aPTT, these correlations are weak, and patients can bleed with aPTT values that are within the therapeutic range. Often an underlying cause for bleeding is present, such as recent surgery, trauma, peptic ulcer disease, or platelet dysfunction.
The anticoagulant effect of heparin disappears within hours of discontinuation of the drug. Mild bleeding due to heparin usually can be controlled without the administration of an antagonist. If life-threatening hemorrhage occurs, the effect of heparin can be reversed quickly by the slow intravenous infusion of protamine sulfate, a mixture of basic polypeptides isolated from salmon sperm. Protamine binds tightly to heparin and thereby neutralizes its anticoagulant effect. Protamine also interacts with platelets, fibrinogen, and other plasma proteins and may cause an anticoagulant effect of its own. Therefore, one should give the minimal amount of protamine required to neutralize the heparin present in the plasma. This amount is approximately 1 mg of protamine for every 100 units of heparin remaining in the patient; it is given intravenously at a slow rate (up to 50 mg over 10 minutes).
Protamine is used routinely to reverse the anticoagulant effect of heparin following cardiac surgery and other vascular procedures. Anaphylactic reactions occur in about 1% of patients with diabetes mellitus who have received protamine-containing insulin (NPH insulin or protamine zinc insulin) but are not limited to this group. A less common reaction consisting of pulmonary vasoconstriction, right ventricular dysfunction, systemic hypotension, and transient neutropenia also may occur after protamine administration.
Heparin-Induced Thrombocytopenia. Heparin-induced thrombocytopenia (platelet count <150,000/ml or a 50% decrease from the pretreatment value) occurs in about 0.5% of medical patients 5 to 10 days after initiation of therapy with standard heparin (Warkentin, 2003). The incidence of thrombocytopenia is lower with low-molecular-weight heparin. Thrombotic complications that can be life-threatening or lead to amputation occur in about one-half of the affected heparin-treated patients and may precede the onset of thrombocytopenia. The incidence of heparin-induced thrombocytopenia and thrombosis is higher in surgical patients. Venous thromboembolism occurs most commonly, but arterial thromboses causing limb ischemia, myocardial infarction, and stroke also occur. Bilateral adrenal hemorrhage, skin lesions at the site of subcutaneous heparin injection, and a variety of systemic reactions may accompany heparin-induced thrombocytopenia. The development of IgG antibodies against complexes of heparin with platelet factor 4 (or, rarely, other chemokines) appears to cause all of these reactions. These complexes activate platelets by binding to FcgIIa receptors, which results in platelet aggregation, release of more platelet factor 4, and thrombin generation. The antibodies also may trigger vascular injury by binding to platelet factor 4 attached to heparan sulfate on the endothelium.
Heparin should be discontinued immediately if unexplained thrombocytopenia or any of the clinical manifestations mentioned above occur 5 or more days after beginning heparin therapy, regardless of the dose or route of administration. The onset of heparin-induced thrombocytopenia may occur earlier in patients who have received heparin within the previous 3 to 4 months and have residual circulating antibodies. The diagnosis of heparin-induced thrombocytopenia can be confirmed by a heparin-dependent platelet activation assay or an assay for antibodies that react with heparin/platelet factor 4 complexes. Since thrombotic complications may occur after cessation of therapy, an alternative anticoagulant such as lepirudin, argatroban, or danaparoid (see below) should be administered to patients with heparin-induced thrombocytopenia. Low-molecular-weight heparins should be avoided, because these drugs often cross-react with standard heparin in heparin-dependent antibody assays. Warfarin may precipitate venous limb gangrene or multicentric skin necrosis in patients with heparin-induced thrombocytopenia and should not be used until the thrombocytopenia has resolved and the patient is adequately anticoagulated with another agent.
Other Toxicities. Abnormalities of hepatic function tests occur frequently in patients who are receiving heparin intravenously or subcutaneously. Mild elevations of the activities of hepatic transaminases in plasma occur without an increase in bilirubin levels or alkaline phosphatase activity. Osteoporosis resulting in spontaneous vertebral fractures can occur, albeit infrequently, in patients who have received full therapeutic doses of heparin (greater than 20,000 units per day) for extended periods of time (e.g., 3 to 6 months). Heparin can inhibit the synthesis of aldosterone by the adrenal glands and occasionally causes hyperkalemia, even when low doses are given. Allergic reactions to heparin (other than thrombocytopenia) are rare.
Other Parenteral Anticoagulants
Lepirudin. Lepirudin (REFLUDAN) is a recombinant derivative (Leu1-Thr2-63-desulfohirudin) of hirudin, a direct thrombin inhibitor present in the salivary glands of the medicinal leech. It is a 65-amino-acid polypeptide that binds tightly to both the catalytic site and the extended substrate recognition site (exosite I) of thrombin. Lepirudin is approved in the United States for treatment of patients with heparin-induced thrombocytopenia. It is administered intravenously at a dose adjusted to maintain the aPTT at 1.5 to 2.5 times the median of the laboratory's normal range for aPTT. The drug is excreted by the kidneys and has a half-life of about 1.3 hours. Lepirudin should be used cautiously in patients with renal failure, since it can accumulate and cause bleeding in these patients. Patients may develop antihirudin antibodies that occasionally cause a paradoxical increase in the aPTT; therefore, daily monitoring of the aPTT is recommended. There is no antidote for lepirudin.
Bivalirudin. Bivalirudin (ANGIOMAX) is a synthetic, 20-amino-acid polypeptide that directly inhibits thrombin by a mechanism similar to that of lepirudin. Bivalirudin contains the sequence Phe1-Pro2-Arg3-Pro4, which occupies the catalytic site of thrombin, followed by a polyglycine linker and a hirudin-like sequence that binds to exosite I. Thrombin slowly cleaves the Arg3-Pro4 peptide bond and thus regains activity. Bivalirudin is administered intravenously and is used as an alternative to heparin in patients undergoing coronary angioplasty. The half-life of bivalirudin in patients with normal renal function is 25 minutes; dosage reductions are recommended for patients with moderate or severe renal impairment.
Argatroban. Argatroban, a synthetic compound based on the structure of L-arginine, binds reversibly to the catalytic site of thrombin. It is administered intravenously and has an immediate onset of action. Its half-life is 40 to 50 minutes. Argatroban is metabolized by cytochrome P450 enzymes in the liver and is excreted in the bile; therefore dosage reduction is required for patients with hepatic insufficiency. The dosage is adjusted to maintain an aPTT of 1.5 to 3 times the baseline value. Argatroban can be used as an alternative to lepirudin for prophylaxis or treatment of patients with or at risk of developing heparin-induced thrombocytopenia.
Danaparoid. Danaparoid (ORGARAN) is a mixture of nonheparin glycosaminoglycans isolated from porcine intestinal mucosa (84% heparan sulfate, 12% dermatan sulfate, 4% chondroitin sulfate) with a mean mass of 5500 daltons. Danaparoid is approved in the United States for prophylaxis of deep venous thrombosis. It also is an effective anticoagulant for patients with heparin-induced thrombocytopenia and has a low rate of cross-reactivity with heparin in platelet-activation assays. Danaparoid mainly promotes inhibition of factor Xa by antithrombin, but it does not prolong the PT or aPTT at the recommended dosage. Danaparoid is administered subcutaneously at a fixed dose for prophylactic use and intravenously at a higher, weight-adjusted dose for full anticoagulation. Its half-life is about 24 hours. Patients with renal failure may require monitoring with an anti-factor Xa assay because of a prolonged half-life of the drug. No antidote is available. Danaparoid is no longer available in the United States.
Drotrecogin Alfa. Drotrecogin alfa (XIGRIS) is a recombinant form of human activated protein C that inhibits coagulation by proteolytic inactivation of factors Va and VIIIa. It also has antiinflammatory effects (Esmon, 2003). A 96-hour continuous infusion of drotrecogin alfa decreases mortality in adult patients who are at high risk for death from severe sepsis if given within 48 hours of the onset of organ dysfunction (e.g., shock, hypoxemia, oliguria). The major adverse effect is bleeding.
Philip W. Majerus and Douglas M. Tollefsen
key words: blood, Parenteral Anticoagulants, heparin