Heparin is commonly extracted from porcine intestinal mucosa or bovine lung. Despite the heterogeneity in composition among different commercial preparations of heparin, their biological activities are similar (~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 (~ 4500 Da, or 15 monosaccharide units) are isolated from standard heparin by gel filtration chromatography, precipitation with ethanol, or partial depoly-merization 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.
mechanism of action Heparin catalyzes the inhibition of several coagulation proteases by antithrombin, a glycosylated, single-chain polypeptide (432 amino acids). Antithrombin is synthesized in the liver and circulates in plasma at an approximate concentration of 2.6 ¡M. It inhibits activated coagulation factors of the intrinsic and common pathways, including thrombin, Xa, and IXa; however, it has relatively little activity against factor Vila. 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 1000-fold 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 (Figure 54-4). This structure occurs in ~30% of heparin molecules and less abundantly in heparan sulfate. Heparin molecules containing fewer than 18 monosaccharide units (<5400 Da) do not catalyze inhibition of thrombin by antithrombin, since they cannot bind thrombin and antithrombin simultaneously. In contrast, the pentasaccharide shown in Figure 54-4 catalyzes inhibition of factor Xa by antithrombin. 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.
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.
clinical use Heparin is used to initiate treatment of venous thrombosis and pulmonary embolism because of its rapid onset of action. An oral anticoagulant usually is started concurrently, and heparin is continued for at least 4-5 days to allow the oral anticoagulant to achieve its full therapeutic effect. 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.
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. Their principal advantage of 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 is not 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. 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 (GI) mucosa and must be given by continuous intravenous infusion or subcutaneous injection. Heparin has an immediate onset of action when given intravenously; there is considerable variation in the bioavailability of heparin given subcutaneously, and the onset of action is delayed 1-2 hours. Low-molecular-weight heparins are absorbed more uniformly.
The t1/2 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 ~1, 2.5, and 5 hours. Heparin appears to be cleared and degraded primarily by the reticuloendothe-lial system; a small amount of undegraded heparin appears in the urine. The t1/2 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 1200-1600 units/h delivered by an infusion pump. Therapy routinely is monitored by the aPTT; the target is an elevation to 1.8-2.5 times the normal value. 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. Once a steady dosage schedule has been established, daily monitoring is sufficient.
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 ~35,000 units administered as divided doses every 8-12 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, to whom it should be administered every 8 hours in a hospital setting; laboratory monitoring is unnecessary in this setting.
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 with similar anti-factor Xa activity will produce equivalent antithrombotic effects. The more predictable pharmacokinetic properties of low-molecular-weight heparins permit subcutaneous administration in a fixed or weight-adjusted dosage regimen 1-2 times daily. 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 t1/2 of low-molecular-weight heparin. Specific dosage recommendations for various low-molecular-weight heparins may be obtained from the manufacturers' literature. Nadroparin and reviparin are not available in the U.S.
synthetic heparin derivatives Fondaparinux (arixtra) is a synthetic pentasac-charide 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 t1/2 of 17-21 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 and for the therapy of pulmonary embolism and deep venous thrombosis.
Bleeding Bleeding is the primary untoward effect of heparin. Major bleeding occurs in 1-5% of patients treated with intravenous heparin for venous thromboembolism, somewhat less in patients treated with low-molecular-weight heparin for this indication. 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 drug discontinuation. 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 that bind tightly to heparin and thereby neutralize its anticoagulant effect. Use the minimal amount of protamine required to neutralize the heparin present in the plasma, ~1 mg of protamine for every 100 units of heparin remaining in the patient, giving it intravenously at a slow rate (up to 50 mg over 10 minutes).
Anaphylactic reactions occur in ~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/^L or a 50% decrease from pretreatment value) occurs in ~0.5% of medical patients, typically 5-10 days after initiation of therapy with standard heparin. The incidence of thrombocy-topenia 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 throm-bocytopenia 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 3-4 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 throm-bocytopenia has resolved and the patient is adequately anticoagulated with another agent.
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 protein that binds tightly to both the catalytic site and the extended substrate recognition site of thrombin. Lepirudin is approved in the U.S. for treatment of patients with heparin-induced thrombocytopenia. It is administered intravenously at a dose adjusted to maintain the aPTT at 1.5-2.5 times the median of the laboratory's normal range. The drug is excreted by the kidneys with a t1/2 of ~1.3 hours. Lepirudin should be used cautiously in patients with renal failure, since it can accumulate and cause bleeding. Occasionally, patients may develop antihirudin antibodies that paradoxically increase 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. Bivalirudin contains the sequence Phe1-Pro2-Arg3-Pro4, which occupies the catalytic site of thrombin, followed by a polyGly 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 t1/2 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-Arg, binds reversibly to the catalytic site of thrombin. Administered intravenously, it has an immediate onset of action and a t1/2 of 40-50 minutes. Argatroban is metabolized by hepatic CYPs 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 1.5-3 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 Da. Danaparoid is used 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 t1/2 is ~24 hours. Patients with renal failure may require monitoring with an anti-factor xa assay because of a prolonged t1/2 of the drug. No antidote is available. Danaparoid is no longer available in the U.S.
drotrecogin alfa Drotrecogin alfa (xigris) is a recombinant form of human activated protein C that inhibits coagulation by proteolytic inactivation of factors Va and Villa. It also has anti-inflammatory effects. A 96-hour continuous infusion of drotrecogin alfa decreases mortality in adult patients 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.
ORAL ANTICOAGULANTS Warfarin
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