Anticoagulant, antiplatelet, and thrombolytic drugs

The drugs discussed in this chapter are used to prevent formation of thrombi (intravascular blood clots) and dissolve thrombi that have already formed. These drugs act in several ways: some suppress coagulation, some inhibit platelet aggregation, and some promote clot degradation. They all interfere with normal hemostasis. As a result, they all carry a significant risk of bleeding.

Coagulation: physiology and pathophysiology

Hemostasis

Hemostasis is the physiologic process by which bleeding is stopped. Hemostasis occurs in two stages: (1) formation of a platelet plug, followed by (2) reinforcement of the platelet plug with fibrin. Both processes are set in motion by blood vessel injury.

Stage one: formation of a platelet plug.

Platelet aggregation is initiated when platelets come in contact with collagen on the exposed surface of a damaged blood vessel. In response to contact with collagen, platelets adhere to the site of vessel injury. Adhesion initiates platelet activation, which in turn leads to massive platelet aggregation.

Platelet aggregation is a complex process that ends with formation of fibrinogen bridges between glycoprotein IIb/IIIa (GP IIb/IIIa) receptors on adjacent platelets (Fig. 52–1). In order for these bridges to form, GP IIb/IIIa receptors must first undergo activation—that is, they must undergo a configurational change that allows them to bind with fibrinogen. As indicated in Figure 52–1A, activation of GP IIb/IIIa can be stimulated by multiple factors, including thromboxane A₂ (TXA₂), thrombin, collagen, platelet activation factor, and ADP. Under the influence of these factors, GP IIb/IIIa changes its shape, binds with fibrinogen, and thereby causes aggregation (see Fig. 52–1B). The aggregated platelets constitute a plug that stops bleeding. This plug is unstable, however, and must be reinforced with fibrin if protection is to last.

Figure 52–1 Mechanism of platelet aggregation and actions of antiplatelet drugs.
A, Multiple factors—TXA₂, thrombin, collagen, PAF, and ADP—promote activation of the GP IIb/IIIa receptor. Each platelet has 50,000 to 80,000 GP IIb/IIIa receptors, although only one is shown. B, Activation of the GP IIb/IIIa receptor permits binding of fibrinogen, which then causes aggregation by forming cross-links between platelets. After aggregation occurs, the platelet plug is reinforced with fibrin (not shown). (AA = arachidonic acid, ADP = adenosine diphosphate, GP IIb/IIIa = glycoprotein IIb/IIIa receptor, PAF = platelet activation factor, P2Y₁₂ = P2Y₁₂ ADP receptor, TXA₂ = thromboxane A₂.)

Stage two: coagulation.

Coagulation is defined as production of fibrin, a thread-like protein that reinforces the platelet plug. Fibrin is produced by two convergent pathways (Fig. 52–2), referred to as the contact activation pathway (also known as the intrinsic pathway) and the tissue factor pathway (also known as the extrinsic pathway). As shown in Figure 52–2, the two pathways converge at factor Xa, after which they employ the same final series of reactions. In both pathways, each reaction in the sequence amplifies the reaction that follows. Hence, once this sequence is initiated, it becomes self-sustaining and self-reinforcing.

Figure 52–2 Outline of coagulation pathways showing factors affected by warfarin and heparin.
TF = tissue factor. Common names for factors shown in roman numerals: V = proaccelerin, VII = proconvertin, VIII = antihemophilic factor, IX = Christmas factor, X = Stuart factor, XI = plasma thromboplastin antecedent, and XII = Hageman factor. The letter “a” after a factor’s name (eg, factor VIIIa) indicates the active form of the factor.

The tissue factor pathway is turned on by trauma to the vascular wall, which triggers release of tissue factor,* also known as tissue thromboplastin. Tissue factor then combines with and thereby activates factor VII, which in turn activates factor X, which then catalyzes the conversion of prothrombin (factor II) into thrombin (factor IIa). As shown in Figure 52–2, thrombin then does three things. First, it catalyzes the conversion of fibrinogen into fibrin. Second, it catalyzes the conversion of factor V into its active form (Va), a compound that greatly increases the activity of factor Xa, even though it has no direct catalytic activity of its own. Third, thrombin catalyzes the conversion of factor VIII into its active form (VIIIa), a compound that greatly increases the activity of factor IXa in the contact activation pathway.

The contact activation pathway is turned on when blood makes contact with collagen that has been exposed as a result of trauma to a blood vessel wall. Collagen contact stimulates conversion of factor XII into its active form, XIIa (see Figure 52–2). Factor XIIa then activates factor XI, which activates factor IX, which activates factor X. After this, the contact activation pathway is the same as the tissue factor pathway. As noted, factor VIIIa, which is produced under the influence of thrombin, greatly increases the activity of factor IXa, even though it has no direct catalytic activity of its own.

Important to our understanding of anticoagulant drugs is the fact that four coagulation factors—factors VII, IX, X, and II (prothrombin)—require vitamin K for their synthesis. These factors appear in green boxes in Figure 52–2. The significance of the vitamin K–dependent factors will become apparent when we discuss warfarin, an oral anticoagulant.

Overview of drugs for thromboembolic disorders

The drugs considered in this chapter fall into three major groups: (1) anticoagulants, (2) antiplatelet drugs, and (3) thrombolytic drugs, also known as fibrinolytic drugs. Anticoagulants (eg, heparin, warfarin, dabigatran) disrupt the coagulation cascade, and thereby suppress production of fibrin. Antiplatelet drugs (eg, aspirin, clopidogrel) inhibit platelet aggregation. Thrombolytic drugs (eg, alteplase) promote lysis of fibrin, and thereby cause dissolution of thrombi. Drugs that belong to these groups are listed in Table 52–1.

TABLE 52–1

Overview of Drugs for Thromboembolic Disorders

Generic Name	Trade Name	Route	Action	Therapeutic Use
ANTICOAGULANTS	Anticoagulants decrease formation of fibrin	Used primarily to prevent thrombosis in veins and the atria of the heart
Vitamin K Antagonist
Warfarin			Coumadin	PO
Heparin and Its Derivatives: Drugs That Activate Antithrombin
Heparin (unfractionated)				subQ, IV
LMW heparins
Dalteparin			Fragmin	subQ
Enoxaparin			Lovenox	subQ
Tinzaparin			Innohep	subQ
Fondaparinux			Arixtra	subQ
Direct Thrombin Inhibitors
Hirudin Analogs
Bivalirudin			Angiomax	IV
Desirudin			Iprivask	subQ
Lepirudin			Refludan	IV
Other Direct Thrombin Inhibitors
Apixaban*			Eliquis	PO
Argatroban			Acova	IV
Dabigatran			Pradaxa, Pradax	PO
Direct Factor Xa Inhibitor
Rivaroxaban			Xarelto	PO
Antithrombin (AT)
Recombinant human AT			ATryn	IV
Plasma-derived AT			Thrombate III	IV
ANTIPLATELET DRUGS	Antiplatelet drugs suppress platelet aggregation	Used primarily to prevent thrombosis in arteries
Cyclooxygenase Inhibitor
Aspirin				PO
P2Y₁₂ Adenosine Diphosphate Receptor Antagonists
Clopidogrel			Plavix	PO
Prasugrel			Effient	PO
Ticagrelor			Brilinta	PO
Ticlopidine			Ticlid	PO
Glycoprotein IIb/IIIa Receptor Antagonists
Abciximab			ReoPro	IV
Eptifibatide			Integrilin	IV
Tirofiban			Aggrastat	IV
Other Antiplatelet Drugs
Dipyridamole			Persantine	PO
Cilostazol			Pletal	PO
THROMBOLYTIC (FIBRINOLYTIC) DRUGS	Thrombolytic drugs promote breakdown of fibrin in thrombi	Used to dissolve newly formed thrombi
Alteplase			Activase	IV
Reteplase			Retavase	IV
Tenecteplase			TNKase	IV

LMW = low molecular weight.

^*Investigational in the United States.

Although the anticoagulants and the antiplatelet drugs both suppress thrombosis, they do so by different mechanisms. As a result, they differ in their effects and applications. The antiplatelet drugs are most effective at preventing arterial thrombosis, whereas anticoagulants are most effective against venous thrombosis.

Anticoagulants

By definition, anticoagulants are drugs that reduce formation of fibrin. Two basic mechanisms are involved. One anticoagulant—warfarin—inhibits the synthesis of clotting factors, including factor X and thrombin. All other anticoagulants inhibit the activity of clotting factors: either factor Xa, thrombin, or both.

Traditionally, anticoagulants have been grouped into two major classes: oral anticoagulants and parenteral anticoagulants. This scheme was reasonable because, until recently, all oral anticoagulants belonged to just one pharmacologic class: the vitamin K antagonists, of which warfarin is the principal member. Today, however, anticoagulants in two other pharmacologic classes—direct factor Xa inhibitors and direct thrombin inhibitors—can also be administered by mouth (see Table 52–1). Hence, grouping the anticoagulants by route of administration makes less sense than in the past. Accordingly, in this chapter, these drugs are grouped only by pharmacologic class, and not by whether they are given orally or by injection.

Heparin and its derivatives: drugs that activate antithrombin

All drugs in this section share the same mechanism of action. Specifically, they greatly enhance the activity of antithrombin, a protein that inactivates two major clotting factors: thrombin and factor Xa. In the absence of thrombin and factor Xa, production of fibrin is reduced, and hence clotting is suppressed.

Our discussion focuses on three preparations: unfractionated heparin, the low-molecular-weight (LMW) heparins, and fondaparinux. Although all three activate antithrombin, they do not have equal effects on thrombin and factor Xa. Specifically, heparin reduces the activity of thrombin and factor Xa more or less equally; the LMW heparins reduce the activity of factor Xa more than they reduce the activity of thrombin; and fondaparinux causes selective inhibition of factor Xa, having no effect on thrombin. Properties of the three preparations are summarized in Table 52–2.

TABLE 52–2

Comparison of Drugs That Activate Antithrombin

Property	Unfractionated Heparin	Low-Molecular-Weight Heparins	Fondaparinux
Molecular weight range	3000–30,000	1000–9000	1728
Mean molecular weight	12,000–15,000	4000–5000	1728
Mechanism of action	Activation of antithrombin, resulting in the inactivation of factor Xa and thrombin	Activation of antithrombin, resulting in preferential inactivation of factor Xa, plus some inactivation of thrombin	Activation of antithrombin, resulting in selective inactivation of factor Xa
Routes	IV, subQ	subQ only	subQ only
Nonspecific binding	Widespread	Minimal	Minimal
Laboratory monitoring	aPTT monitoring is essential	No aPTT monitoring required	No aPTT monitoring required
Dosage	Dosage must be adjusted on the basis of aPTT	Dosage is fixed	Dosage is fixed
Setting for use	Hospital	Hospital or home	Hospital or home
Cost	$3/day for heparin itself, but hospitalization and aPTT monitoring greatly increase the real cost	$35/day for LMW heparin (enoxaparin [Lovenox]), but home use and absence of aPTT monitoring greatly reduce the real cost	$59/day for fondaparinux, but home use and absence of aPTT monitoring greatly reduce the real cost

aPTT = activated partial thromboplastin time, LMW = low molecular weight.

Heparin (unfractionated)

Heparin is a rapid-acting anticoagulant administered only by injection. Heparin differs from warfarin (an oral anticoagulant) in several respects, including mechanism, time course, indications, and management of overdose.

Source

Heparin is present in various mammalian tissues. The heparin employed clinically is prepared from two sources: lungs of cattle and intestines of pigs. The anticoagulant activity of heparin from either source is equivalent. Although heparin occurs naturally, its physiologic role is unknown.

Chemistry

Heparin is not a single molecule, but rather a mixture of long polysaccharide chains, with molecular weights that range from 3000 to 30,000. The active region is a unique pentasaccharide (five-sugar) sequence found randomly along the chain. An important feature of heparin’s structure is the presence of many negatively charged groups. Because of these negative charges, heparin is highly polar, and hence cannot readily cross membranes.

Mechanism of anticoagulant action

Heparin suppresses coagulation by helping antithrombin inactivate clotting factors, primarily thrombin and factor Xa. As shown in Figure 52–3, binding of heparin to antithrombin produces a conformational change in antithrombin that greatly enhances its ability to inactivate both thrombin and factor Xa. However, the process of inactivating these two clotting factors is not identical. In order to inactivate thrombin, heparin must simultaneously bind with both thrombin and antithrombin, thereby forming a ternary complex (see Fig. 52–3). In contrast, in order to inactivate factor Xa, heparin binds only with antithrombin; heparin itself does not bind with factor Xa.

Figure 52–3 Mechanism of action of heparin, LMW heparins, and fondaparinux.
All three drugs share a pentasaccharide sequence that allows them to bind with—and thereby activate—antithrombin, a protein that inactivates two major clotting factors: thrombin and factor Xa. All three drugs enable antithrombin to inactivate factor Xa, but only heparin also facilitates inactivation of thrombin.
*Upper Panel:* Unfractionated heparin binds with antithrombin, thereby causing a conformational change in antithrombin that greatly increases its ability to interact with factor Xa and thrombin. As shown, when the heparin-antithrombin complex binds with thrombin, heparin changes its conformation such that both heparin and antithrombin come in contact with thrombin. Formation of this ternary complex is necessary for thrombin inactivation. Inactivation of factor Xa is different: It only requires contact between activated antithrombin and factor Xa; contact between heparin and factor Xa is unnecessary.
*Middle Panel:* Low-molecular-weight (LMW) heparins have the same pentasaccharide sequence as unfractionated heparin, and hence can bind with and thereby activate antithrombin. However, in contrast to unfractionated heparin, which promotes inactivation of both thrombin and factor Xa, most molecules of LMW heparin can only inactivate factor Xa; they are unable to inactivate thrombin. Why? Because most molecules of LMW heparin are too small to form a ternary complex with thrombin and antithrombin.
*Lower Panel:* Fondaparinux is a synthetic pentasaccharide identical in structure to the antithrombin binding sequence found in unfractionated heparin and LMW heparins. Being even smaller than LMW heparins, fondaparinux is too small to form a ternary complex with thrombin, and hence can only inactivate factor Xa.

By activating antithrombin, and thereby promoting the inactivation of thrombin and factor Xa, heparin ultimately suppresses formation of fibrin. Since fibrin forms the framework of thrombi in veins, heparin is especially useful for prophylaxis of venous thrombosis. Because thrombin and factor Xa are inhibited as soon as they bind with the heparin-antithrombin complex, the anticoagulant effects of heparin develop quickly (within minutes of IV administration). This contrasts with warfarin, whose full effects are not seen for days.

Pharmacokinetics

Absorption and distribution.

Because of its polarity and large size, heparin is unable to cross membranes, including those of the GI tract. Consequently, heparin cannot be absorbed if given orally, and therefore must be given by injection (IV or subQ). Since it cannot cross membranes, heparin does not traverse the placenta and does not enter breast milk.

Protein and tissue binding.

Heparin binds nonspecifically to plasma proteins, mononuclear cells, and endothelial cells. As a result, plasma levels of free heparin can be highly variable. Because of this variability, intensive monitoring is required (see below).

Metabolism and excretion.

Heparin undergoes hepatic metabolism followed by renal excretion. Under normal conditions, the half-life is short (about 1.5 hours). However, in patients with hepatic or renal impairment, the half-life is increased.

Time course.

Therapy is initiated with a bolus IV injection, and effects begin immediately. Duration of action is brief (hours) and varies with dosage. Effects are prolonged in patients with hepatic or renal impairment.

Therapeutic uses

Heparin is a preferred anticoagulant for use during pregnancy (because it doesn’t cross the placenta) and in situations that require rapid onset of anticoagulant effects, including pulmonary embolism (PE), evolving stroke, and massive deep vein thrombosis (DVT). In addition, heparin is used for patients undergoing open heart surgery and renal dialysis; during these procedures, heparin serves to prevent coagulation in devices of extracorporeal circulation (heart-lung machines, dialyzers). Low-dose therapy is used to prevent postoperative venous thrombosis. Heparin may also be useful for treating disseminated intravascular coagulation, a complex disorder in which fibrin clots form throughout the vascular system and in which bleeding tendencies may be present; bleeding can occur because massive fibrin production consumes available supplies of clotting factors. Heparin is also used as an adjunct to thrombolytic therapy of acute myocardial infarction (MI).

Adverse effects

Hemorrhage.

Bleeding develops in about 10% of patients and is the principal complication of treatment. Hemorrhage can occur at any site and may be fatal. Patients should be monitored closely for signs of blood loss. These include reduced blood pressure, increased heart rate, bruises, petechiae, hematomas, red or black stools, cloudy or discolored urine, pelvic pain (suggesting ovarian hemorrhage), headache or faintness (suggesting cerebral hemorrhage), and lumbar pain (suggesting adrenal hemorrhage). If bleeding develops, heparin should be withdrawn. Severe overdose can be treated with protamine sulfate (see below).

The risk of hemorrhage can be decreased in several ways. First, dosage should be carefully controlled so that the activated partial thromboplastin time (see below) does not exceed 2 times the control value. In addition, candidates for heparin therapy should be screened for risk factors (see Warnings and Contraindications). Finally, antiplatelet drugs (eg, aspirin, clopidogrel) should be avoided.

Spinal/epidural hematoma.

Heparin and all other anticoagulants pose a risk of spinal or epidural hematoma in patients undergoing spinal puncture or spinal/epidural anesthesia. Pressure on the spinal cord caused by the bleed can result in prolonged or permanent paralysis. Risk of hematoma is increased by

• Use of an indwelling epidural catheter

• Use of other anticoagulants (eg, warfarin, dabigatran)

• Use of antiplatelet drugs (eg, aspirin, clopidogrel)

• History of traumatic or repeated epidural or spinal puncture

• History of spinal deformity, spinal injury, or spinal surgery

Patients should be monitored for signs and symptoms of neurologic impairment. If impairment develops, immediate intervention is needed.

Heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a potentially fatal immune-mediated disorder characterized by reduced platelet counts (thrombocytopenia) and a seemingly paradoxical increase in thrombotic events. The underlying cause is development of antibodies against heparin–platelet protein complexes. These antibodies activate platelets and damage the vascular endothelium, thereby promoting both thrombosis and a rapid loss of circulating platelets. Thrombus formation poses a risk of DVT, PE, cerebral thrombosis, and MI. Ischemic injury secondary to thrombosis in the limbs may require amputation of an arm or leg. Coronary thrombosis can be fatal. The primary treatment for HIT is discontinuation of heparin and, if anticoagulation is still needed, substitution of a nonheparin anticoagulant (eg, lepirudin, argatroban). The incidence of HIT is between 1% and 3% among patients who receive heparin for more than 4 days.

HIT should be suspected whenever platelet counts fall significantly or when thrombosis develops despite adequate anticoagulation. Accordingly, to reduce the risk of HIT, patients should be monitored for signs of thrombosis and for reductions in platelets. Platelet counts should be determined frequently (2 to 3 times a week) during the first 3 weeks of heparin use, and monthly thereafter. If severe thrombocytopenia develops (platelet count below 100,000/mm³), heparin should be discontinued.

Hypersensitivity reactions.

Because commercial heparin is extracted from animal tissues, these preparations may be contaminated with antigens that can promote allergy. Possible allergic responses include chills, fever, and urticaria. Anaphylactic reactions are rare. To minimize the risk of severe reactions, patients should receive a small test dose of heparin prior to the full therapeutic dose.

Other adverse effects.

Subcutaneous dosing may produce local irritation and hematoma. Vasospastic reactions that persist for several hours may develop after 1 or more weeks of treatment. Long-term, high-dose therapy may cause osteoporosis.

Warnings and contraindications

Warnings.

Heparin must be used with extreme caution in all patients who have a high likelihood of bleeding. Among these are individuals with hemophilia, increased capillary permeability, dissecting aneurysm, peptic ulcer disease, severe hypertension, or threatened abortion. Heparin must also be used cautiously in patients with severe disease of the liver or kidneys.

Contraindications.

Heparin is contraindicated for patients with thrombocytopenia and uncontrollable bleeding. In addition, heparin should be avoided both during and immediately after surgery of the eye, brain, or spinal cord. Lumbar puncture and regional anesthesia are additional contraindications.

Drug interactions

In heparin-treated patients, platelet aggregation is the major remaining defense against hemorrhage. Aspirin and other drugs that depress platelet function will weaken this defense, and hence must be employed with caution.

Protamine sulfate for heparin overdose

Protamine sulfate is an antidote to severe heparin overdose. Protamine is a small protein that has multiple positively charged groups. These groups bond ionically with the negative groups on heparin, thereby forming a heparin-protamine complex that is devoid of anticoagulant activity. Neutralization of heparin occurs immediately and lasts for 2 hours, after which additional protamine may be needed. Protamine is administered by slow IV injection (no faster than 20 mg/min or 50 mg in 10 minutes). Dosage is based on the fact that 1 mg of protamine will inactivate 100 units of heparin. Hence, for each 100 units of heparin in the body, 1 mg of protamine should be injected.

Laboratory monitoring

The objective of anticoagulant therapy is to reduce blood coagulability to a level that is low enough to prevent thrombosis but not so low as to promote spontaneous bleeding. Because heparin levels can be highly variable, achieving this goal is difficult, and requires careful control of dosage based on frequent tests of coagulation. The laboratory test employed most commonly is the activated partial thromboplastin time (aPTT). The normal value for the aPTT is 40 seconds. At therapeutic levels, heparin increases the aPTT by a factor of 1.5 to 2, making the aPTT 60 to 80 seconds. Since heparin has a rapid onset and brief duration, if an aPTT value should fall outside the therapeutic range, coagulability can be quickly corrected through an adjustment in dosage: if the aPTT is too long (more than 80 seconds), the dosage should be lowered; conversely, if the aPTT is too short (less than 60 seconds), the dosage should be increased. Measurements of aPTTs should be made frequently (every 4 to 6 hours) during the initial phase of therapy. Once an effective dosage has been established, measuring aPTT once a day will suffice.

Unitage and preparations

Unitage.

Heparin is prescribed in units, not in milligrams. The heparin unit is an index of anticoagulant activity. In 2009, the method used in the United States to measure heparin’s anticoagulant activity was changed, and now matches the method used in Canada and Europe. Because the new method employs a new reference standard for anticoagulant activity, heparin preparations available now have about 10% less activity per unit than preparations made in the past. Nonetheless, the Food and Drug Administration (FDA) did not change dosing recommendations. Why? First, the potency of the old preparations varied by plus or minus 10% from batch to batch anyway. And second, heparin dosage is titrated on the basis of laboratory monitoring, and hence, even if there is a small decrease in activity per heparin unit, dosage can be adjusted as needed when the test results come in.

Preparations.

Heparin sodium is supplied in single-dose vials; multidose vials; and unit-dose, preloaded syringes that have their own needles. Concentrations range from 1000 to 40,000 units/mL. Heparin sodium for use in heparin locks [Hep-Lock, HepFlush-10] is supplied in dilute solutions (10 and 100 units/mL) that are too weak to produce systemic anticoagulant effects.

Dosage and administration

General considerations.

Heparin is administered by injection only. Two routes are employed: intravenous (either intermittent or continuous) and subcutaneous. Intramuscular injection causes hematoma and must not be done. Heparin is not administered orally. Why? Because heparin is too large and too polar to permit intestinal absorption.

Dosage varies with the application. Postoperative prophylaxis of thrombosis, for example, requires relatively small doses. In other situations, such as open heart surgery, much larger doses are needed. The dosages given below are for “general anticoagulant therapy.” As a rule, the aPTT should be employed as a guideline for dosage titration; increases in the aPTT of 1.5- to 2-fold are therapeutic. Since heparin is formulated in widely varying concentrations, you must read the label carefully to ensure that dosing is correct.

Intermittent IV therapy.

Intermittent IV heparin is administered via an indwelling needle with a rubber-capped port (heparin lock). Therapy is initiated with a dose of 10,000 units. Subsequent doses of 5000 to 10,000 units are given every 4 to 6 hours. The aPTT should be taken 1 hour before each injection until dosage is stabilized. To avoid venous injury, the site of the heparin lock should be moved every 2 or 3 days. When heparin is administered intermittently, plasma levels of the drug will fluctuate, possibly causing alternating periods of excessive and insufficient anticoagulation.

Continuous IV infusion.

Intravenous infusion provides steady levels of heparin, and therefore is preferred to intermittent injections. Dosing consists of a bolus (5000 units), followed by infusion of 20,000 to 40,000 units over 24 hours. During the initial phase of treatment, the aPTT should be measured once every 4 hours and the infusion rate adjusted accordingly. To decrease the risk of overdose, when heparin solutions are prepared, the amount made up should be sufficient for no more than a 6-hour infusion. Heparin should be infused using an electric pump, and the rate should be checked every 30 to 60 minutes.

Deep subq injection.

Subcutaneous injections are made deep into the fatty layer of the abdomen (but not within 2 inches of the umbilicus). The heparin solution should be drawn up using a 20- to 22-gauge needle. This needle is then discarded and replaced with a small needle (¹/₂ to ⁵/₈ inch, 25 or 26 gauge) to make the injection. Following administration, firm but gentle pressure should be applied to the injection site for 1 to 2 minutes. The initial subQ dose is 10,000 to 20,000 units (preceded immediately by an IV loading dose of 5000 units). The initial subQ dose is followed by either (1) 8000 to 10,000 units every 8 hours or (2) 15,000 to 20,000 units every 12 hours. Dosage is adjusted on the basis of aPTTs taken 4 to 6 hours after each injection. The injection site should be rotated.

Low-dose therapy.

Heparin in low doses is given for prophylaxis against postoperative thromboembolism. The initial dose (5000 units subQ) is given 2 hours prior to surgery. Additional doses of 5000 units are given every 8 to 12 hours for 7 days (or until the patient is ambulatory). Low-dose heparin is also employed as adjunctive therapy for patients with MI. During low-dose therapy, monitoring of the aPTT is not usually required.

Low-molecular-weight heparins

Group properties

Low-molecular-weight (LMW) heparins are simply heparin preparations composed of molecules that are shorter than those found in unfractionated heparin. LMW heparins are as effective as unfractionated heparin and are easier to use. Why? Because LMW heparins can be given using a fixed dosage and don’t require aPTT monitoring. As a result, LMW heparins can be used at home, whereas unfractionated heparin must be given in a hospital. Because of these advantages, LMW heparins are now considered first-line therapy for prevention and treatment of DVT. In the United States, three LMW heparins are available: enoxaparin [Lovenox], dalteparin [Fragmin], and tinzaparin [Innohep]. Differences between LMW heparins and unfractionated heparin are summarized in Table 52–2.

Production.

LMW heparins are made by depolymerizing unfractionated heparin (ie, breaking unfractionated heparin into smaller pieces). Molecular weights in LMW preparations range between 1000 and 9000, with a mean of 4000 to 5000. In comparison, molecular weights in unfractionated heparin range between 3000 and 30,000, with a mean of 12,000 to 15,000.

Mechanism of action.

Anticoagulant activity of LMW heparin is mediated by the same active pentasaccharide sequence that mediates anticoagulant action of unfractionated heparin. However, because LMW heparin molecules are short, they do not have quite the same effect as unfractionated heparin. Specifically, whereas unfractionated heparin is equally good at inactivating factor Xa and thrombin, LMW heparins preferentially inactivate factor Xa, being much less able to inactivate thrombin. Why the difference? In order to inactivate thrombin, a heparin chain must not only contain the pentasaccharide sequence that activates antithrombin, it must also be long enough to provide a binding site for thrombin. This binding site is necessary because inactivation of thrombin requires simultaneous binding of thrombin with heparin and antithrombin (see Fig. 52–3). In contrast to unfractionated heparin chains, most (but not all) LMW heparin chains are too short to allow thrombin binding, and hence LMW heparins are less able to inactivate thrombin.

Therapeutic use.

LMW heparins are approved for (1) prevention of DVT following abdominal surgery, hip replacement surgery, or knee replacement surgery; (2) treatment of established DVT, with or without PE; and (3) prevention of ischemic complications in patients with unstable angina, non–Q-wave MI, and ST-elevation MI (STEMI). In addition, these drugs have been used extensively off label to prevent DVT after general surgery and in patients with multiple trauma and acute spinal injury. When used for prophylaxis or treatment of DVT, LMW heparins are at least as effective as unfractionated heparin, and possibly more effective.

Pharmacokinetics.

Compared with unfractionated heparin, LMW heparins have higher bioavailability and longer half-lives. Bioavailability is higher because LMW heparins do not undergo nonspecific binding to proteins and tissues, and hence are more available for anticoagulant effects. Half-lives are prolonged (up to 6 times longer than that of unfractionated heparin) because LMW heparins undergo less binding to macrophages, and hence undergo slower clearance by the liver. Because of increased bioavailability, plasma levels of LMW heparin are highly predictable. As a result, these drugs can be given using a fixed dosage, with no need for routine monitoring of coagulation. Because of their long half-lives, LMW heparins can be given just once or twice a day.

Administration, dosing, and monitoring.

All LMW heparins are administered subQ. Dosage is based on body weight. Because plasma levels of LMW heparins are predictable for any given dose, these drugs can be employed using a fixed dosage without laboratory monitoring. This contrasts with unfractionated heparin, which requires dosage adjustments on the basis of aPTT measurements. Because LMW heparins have an extended half-life, dosing can be done once or twice daily. For prophylaxis of DVT, dosing is begun in the perioperative period and continued 5 to 10 days.

Adverse effects and interactions.

Bleeding is the major adverse effect. However, the incidence of bleeding complications is less than with unfractionated heparin. Despite the potential for bleeding, LMW heparins are considered safe for outpatient use. Like unfractionated heparin, LMW heparins can cause immune-mediated thrombocytopenia. As with unfractionated heparin, overdose with LMW heparins can be treated with protamine sulfate.

Like unfractionated heparin, LMW heparins can cause severe neurologic injury, including permanent paralysis, when given to patients undergoing spinal puncture or spinal or epidural anesthesia. The risk of serious harm is increased by concurrent use of antiplatelet drugs (eg, aspirin, clopidogrel) or anticoagulants (eg, warfarin, dabigatran). Patients should be monitored closely for signs of neurologic impairment.

Cost.

LMW heparins cost more than unfractionated heparin (eg, about $63/day for dalteparin vs. $8/day for unfractionated heparin). However, since LMW heparins can be used at home and don’t require aPTT monitoring, the overall cost of treatment is lower than with unfractionated heparin.

Individual preparations

In the United States, three LMW heparins are available: enoxaparin, dalteparin, and tinzaparin. Additional LMW heparins are available in other countries. Each preparation is unique. Hence clinical experience with one may not apply fully to the others.

Enoxaparin.

Enoxaparin [Lovenox] was the first LMW heparin available in the United States. The drug is prepared by depolymerization of unfractionated porcine heparin. Molecular weights range between 2000 and 8000. Enoxaparin is used widely: In the United States, hospitals spend more money on Lovenox than any other drug.

Enoxaparin is approved for prevention of DVT following hip and knee replacement surgery or abdominal surgery in patients considered at high risk of thromboembolic complications (eg, obese patients, those over age 40, and those with malignancy or a history of DVT or pulmonary embolism). The drug is also approved for preventing ischemic complications in patients with unstable angina, non–Q-wave MI, or STEMI.

In the event of overdose, hemorrhage can be controlled with protamine sulfate. The dosage is 1 mg of protamine sulfate for each milligram of enoxaparin administered.

Administration and dosage.

Enoxaparin is administered by deep subQ injection. For patients with normal renal function (or moderate renal impairment), dosages are as follows:

• Prevention of DVT after hip or knee replacement surgery—30 mg every 12 hours starting 12 to 24 hours after surgery and continuing 7 to 10 days.

• Prevention of DVT after abdominal surgery—40 mg once daily, beginning 2 hours before surgery and continuing 7 to 10 days.

• Treatment of established DVT—1 mg every 12 hours for 7 days.

• Patients with unstable angina or non–Q-wave MI—1 mg/kg every 12 hours (in conjunction with oral aspirin, 100 to 325 mg once daily) for 2 to 8 days.

• Patients with acute STEMI—30 mg/kg by IV bolus plus 1 mg/kg subQ, followed by 1 mg/kg subQ every 12 hours for up to 8 days.

For patients with severe renal impairment, dosage should be reduced.

Dalteparin.

Dalteparin [Fragmin] was the second LMW heparin approved in the United States. The drug is prepared by depolymerization of porcine heparin. Molecular weights range between 2000 and 9000, the mean being 5000. Approved indications are prevention of DVT following hip replacement surgery or abdominal surgery in patients considered at high risk of thromboembolic complications, prevention of ischemic complications in patients with unstable angina or non–Q-wave MI, and management of symptomatic venous thromboembolism (VTE). Administration is by deep subQ injection. Dosages are as follows:

• Prevention of DVT after hip replacement surgery—2500 units 1 or 2 hours before surgery, 2500 units that evening (at least 6 hours after the first dose), and then 5000 units once daily for 5 to 10 days.

• Prevention of DVT after abdominal surgery—2500 units once daily for 5 to 10 days, starting 1 to 2 hours before surgery.

• Patients with unstable angina or non–Q-wave MI—120 units /kg (but not more than 10,000 units total) every 12 hours for 5 to 8 days. Concurrent therapy with aspirin (75 to 165 mg/day) is required.

• Patients with symptomatic VTE—200 units/kg (but not more than 18,000 units total) once daily for 1 month, then 150 units/kg (but not more than 18,000 IU total) once daily for months 2 through 6.

Overdose is treated with 1 mg of protamine sulfate for every 100 units of dalteparin administered.

Tinzaparin.

Tinzaparin [Innohep] is indicated for acute symptomatic DVT (with or without PE) and should be used in conjunction with warfarin. Tinzaparin has a mean molecular weight of 6500 and a half-life of 3 to 4 hours. Excretion is renal. In clinical trials, bleeding developed in 0.8% of patients and thrombocytopenia in 1%. Eight men experienced priapism (persistent erection). In elderly patients with renal impairment, tinzaparin increases the risk of death, and hence should not be used in this population. Tinzaparin is supplied in 2-mL vials containing 20,000 units/mL. Administration is by subQ injection in the abdominal region. The recommended dosage is 175 units/kg once daily for 6 or more days. Warfarin should be initiated when appropriate, usually 1 to 3 days after starting tinzaparin. When warfarin has taken effect, tinzaparin can be discontinued. Overdose is treated with 1 mg of protamine sulfate for every 100 units of dalteparin administered.

Fondaparinux

Actions.

Fondaparinux [Arixtra], approved in 2001, is a synthetic, subQ anticoagulant that enhances the activity of antithrombin, to cause selective inhibition of factor Xa. The result is reduced production of thrombin, and hence reduced coagulation. Note that fondaparinux differs from the heparin preparations, which cause inactivation of thrombin as well as factor Xa.

Fondaparinux is closely related in structure and function to heparin and the LMW heparins. Structurally, fondaparinux is a pentasaccharide identical to the antithrombin-binding region of the heparins. Hence, like the heparins, fondaparinux is able to induce a conformational change in antithrombin, thereby increasing antithrombin’s activity—but only against factor Xa, not against thrombin. Why is fondaparinux selective for factor Xa? Because the drug is quite small—even smaller than the LMW heparins. As a result, it is too small to form a complex with both antithrombin and thrombin, and hence cannot reduce thrombin activity (see Fig. 52–3).

Fondaparinux has no effect on prothrombin time, aPTT, bleeding time, or platelet aggregation.

Therapeutic use.

Fondaparinux is approved for (1) preventing DVT following hip fracture surgery, hip replacement surgery, knee replacement surgery, or abdominal surgery; (2) treating acute PE (in conjunction with warfarin); and (3) treating acute DVT (in conjunction with warfarin). The drug is somewhat more effective than enoxaparin (an LMW heparin) at preventing DVT, but may cause slightly more bleeding. Anticoagulation may persist for 2 to 4 days after the last dose. Like the LMW heparins, fondaparinux is administered using a fixed dosage, and does not require routine laboratory monitoring.

Pharmacokinetics.

Fondaparinux is administered subQ. Bioavailability is 100%. Plasma levels peak 2 hours after dosing. The drug is eliminated by the kidneys with a half-life of 17 to 21 hours. The half-life is increased in patients with renal impairment.

Adverse effects.

As with other anticoagulants, bleeding is the biggest concern. The risk is increased by advancing age and renal impairment. Fondaparinux should be used with caution in patients with moderate renal impairment, defined as creatinine clearance (CrCl) of 30 to 50 mL/min, and avoided in patients with severe renal impairment, defined as CrCl below 30 mL/min. The drug should also be avoided in patients weighing less than 50 kg. Why? Because low body weight increases bleeding risk. Following surgery, at least 6 hours should elapse before starting fondaparinux. Aspirin and other drugs that interfere with hemostasis should be used with caution. In contrast to overdose with heparin or LMW heparins, overdose with fondaparinux cannot be treated with protamine sulfate.

Fondaparinux does not promote immune-mediated HIT, although it still can lower platelet counts. During clinical trials, thrombocytopenia developed in 3% of patients. Platelet counts should be monitored and, if they fall below 100,000/mm³, fondaparinux should be discontinued.

In patients undergoing anesthesia using an epidural or spinal catheter, fondaparinux (as well as other anticoagulants) can cause spinal or epidural hematoma, which can result in permanent paralysis. However, in clinical trials, when fondaparinux was administered no sooner than 2 hours after catheter removal, no hematomas were reported.

Preparations, dosage, and administration.

Fondaparinux [Arixtra] is available in single-dose, pre-filled syringes (2.5, 5, 7.5, and 10 mg). Dosing is done once a day by subQ injection.

For prevention of DVT, the recommended dosage is 2.5 mg once a day, starting 6 to 8 hours after surgery. The usual duration is 5 to 9 days.

For treatment of acute DVT or acute PE, dosage is based on body weight as follows: for patients under 50 kg, 5 mg once daily; for patients 50 to 100 kg, 7.5 mg once daily, and for patients over 100 kg, 10 mg once daily. The usual duration is 5 to 9 days.

Warfarin, a Vitamin K antagonist

Warfarin [Coumadin, Jantoven], a vitamin K antagonist, is our oldest oral anticoagulant. The drug is similar to heparin in some respects and quite different in others. Like heparin, warfarin is used to prevent thrombosis. In contrast to heparin, warfarin has a delayed onset, which makes it inappropriate for emergencies. However, because it doesn’t require injection, warfarin is well suited for long-term prophylaxis. Like heparin, warfarin carries a significant risk of hemorrhage, which is amplified by the many drug interactions to which warfarin is subject.

History

The history of warfarin underscores its potential for harm. Warfarin was discovered after a farmer noticed that his cattle bled after eating spoiled clover silage. The causative agent was identified as bishydroxycoumarin (dicumarol). Research into derivatives of dicumarol led to the synthesis of warfarin. When warfarin was first developed, clinical use was ruled out owing to concerns about hemorrhage. So, instead of becoming a medicine, warfarin was used to kill rats. The drug proved especially effective in this application and remains one of our most widely used rodenticides. Clinical interest in warfarin was renewed following the report of a failed suicide attempt using huge doses of a warfarin-based rat poison. The clinical trials triggered by that event soon demonstrated that warfarin could be employed safely to treat humans.

Mechanism of action

Warfarin suppresses coagulation by decreasing production of four clotting factors, namely, factors VII, IX, X, and prothrombin. These factors are known as vitamin K–dependent clotting factors, because an active form of vitamin K is needed to make them. Warfarin works by inhibiting vitamin K epoxide reductase complex 1 (VKORC1), the enzyme needed to convert vitamin K to the required active form. Because of its mechanism, warfarin is referred to as a vitamin K antagonist, a term that is somewhat misleading. Why? Because the term implies antagonism of vitamin K actions, not antagonism of vitamin K activation. In therapeutic doses, warfarin reduces production of vitamin K–dependent clotting factors by 30% to 50%.

Pharmacokinetics

Absorption, distribution, and elimination.

Warfarin is readily absorbed after oral dosing. Once in the blood, about 99% of warfarin binds to albumin. Warfarin molecules that remain free (unbound) can readily cross membranes, including those of the placenta and milk-producing glands. Warfarin is inactivated in the liver, mainly by CYP2C9, the 2C9 isozyme of cytochrome P450. Metabolites are excreted in the urine and feces.

Time course.

Although warfarin acts quickly to inhibit clotting factor synthesis, noticeable anticoagulant effects are delayed. Why? Because warfarin has no effect on clotting factors already in circulation. Hence, until these clotting factors decay, coagulation remains unaffected. Since decay of clotting factors occurs with a half-life of 6 hours to 2.5 days (depending on the clotting factor under consideration), initial responses may not be evident until 8 to 12 hours after the first dose. Peak effects take several days to develop.

After warfarin is discontinued, coagulation remains inhibited for 2 to 5 days. Why? Because warfarin has a long half-life (1.5 to 2 days), and hence synthesis of new clotting factors remains suppressed, despite stopping dosing.

Therapeutic uses

Overview of uses.

Warfarin is employed most frequently for long-term prophylaxis of thrombosis. Specific indications are (1) prevention of venous thrombosis and associated PE, (2) prevention of thromboembolism in patients with prosthetic heart valves, and (3) prevention of thrombosis in patients with atrial fibrillation. The drug has also been used to reduce the risk of recurrent transient ischemic attacks (TIAs) and recurrent MI. Because onset of effects is delayed, warfarin is not useful in emergencies. When rapid action is needed, anticoagulant therapy can be initiated with heparin.

Atrial fibrillation.

Use in atrial fibrillation requires comment. As discussed in Chapter 49 (Antidysrhythmic Drugs), atrial fibrillation carries a high risk of stroke secondary to clot formation in the atrium. (If the clot becomes dislodged, it can travel to the brain and block an artery, thereby causing ischemic stroke.) So, when people have atrial fibrillation, anticoagulant therapy is given long term to prevent clot formation. Until recently, warfarin was the only oral anticoagulant available, and hence has been the reference standard for stroke prevention. However, two new oral anticoagulants—dabigatran [Pradaxa, Pradax] and rivaroxaban [Xarelto]—which are much easier to use than warfarin, are likely to displace warfarin as the treatment of choice for many patients.

Monitoring treatment

The anticoagulant effects of warfarin are evaluated by monitoring prothrombin time (PT)—a coagulation test that is especially sensitive to alterations in vitamin K–dependent factors. The average pretreatment value for PT is 12 seconds. Treatment with warfarin prolongs PT.

Traditionally, PT test results had been reported as a PT ratio, which is simply the ratio of the patient’s PT to a control PT. However, there is a serious problem with this form of reporting: Test results can vary widely among laboratories. The underlying cause of variability is thromboplastin, a critical reagent employed in the PT test. To ensure that test results from different laboratories are comparable, results are now reported in terms of an international normalized ratio (INR). The INR is determined by multiplying the observed PT ratio by a correction factor specific to the particular thromboplastin preparation employed for the test.

The objective of treatment is to raise the INR to an appropriate value. Recommended INR ranges are summarized in Table 52–3. As indicated, an INR of 2 to 3 is appropriate for most patients—although for some patients the target INR is 3 to 4.5. If the INR is below the recommended range, warfarin dosage should be increased. Conversely, if the INR is above the recommended range, dosage should be reduced. Unfortunately, since warfarin has a delayed onset and prolonged duration of action, the INR cannot be altered quickly: Once the dosage has been changed, it may take a week or more to reach the desired INR.

TABLE 52–3

Monitoring Warfarin Therapy: Recommended Ranges of Prothrombin Time–Derived Values

	Recommended Ranges
Condition Being Treated	Observed PT Ratio*	INR^†
Acute myocardial infarction^‡	1.3–1.5	2–3
Atrial fibrillation^‡	1.3–1.5	2–3
Valvular heart disease^‡	1.3–1.5	2–3
Pulmonary embolism	1.3–1.5	2–3
Venous thrombosis^§	1.3–1.5	2–3
Tissue heart valves^‡	1.3–1.5	2–3
Mechanical heart valves	1.5–2	3–4.5
Systemic embolism
Prevention	1.3–1.5	2–3
Recurrent	1.5–2	3–4.5

^*Observed PT ratio = ratio of patient’s PT to a control PT value. In this table, the reagent used to determine the control PT value is one of the preparations of rabbit brain thromboplastin employed in the United States. Had a different preparation of thromboplastin been used, the observed PT ratio could be very different.

^†INR = international normalized ratio. This value is calculated from the observed PT ratio. The INR is equivalent to the PT ratio that would have been obtained if the patient’s PT has been compared to a PT value obtained using the International Reference Preparation, a standardized human brain thromboplastin prepared by the World Health Organization. In contrast to PT ratios, INR values are comparable from one laboratory to the next throughout the United States and the rest of the world.

^‡For prevention of ischemic stroke and systemic embolism.

^§Prophylaxis in high-risk surgery; treatment.

PT must be determined frequently during warfarin therapy. PT should be measured daily during the first 5 days of treatment, twice a week for the next 1 to 2 weeks, once a week for the next 1 to 2 months, and every 2 to 4 weeks thereafter. In addition, PT should be determined whenever a drug that interacts with warfarin is added to or deleted from the regimen.

Concurrent therapy with heparin can influence PT values. To minimize this influence, blood for PT determinations should be drawn no sooner than 5 hours after an IV injection of heparin, and no sooner than 24 hours after a subQ injection.

PT can now be monitored at home. Several devices are available, including CoaguChek and the ProTime Microcoagulation System. These small, hand-held machines are easy to use, provide reliable results, and determine PT and INR values. In addition, the ProTime meter can be programmed by the prescriber with upper and lower INR values appropriate for the individual patient. When this is done, the meter will display either In Range, INR High, or INR Low, depending on the degree of anticoagulation. Home monitoring is more convenient than laboratory monitoring and gives patients a sense of empowerment. In addition, it improves anticoagulation control. In theory, home monitoring should help reduce bleeding (from excessive anticoagulation) and thrombosis (from insufficient anticoagulation). The CoaguChek meter costs about $1300 and the ProTime meter costs about $2000. Each test costs about $10.

Adverse effects

Hemorrhage.

Bleeding is the major complication of warfarin therapy. Hemorrhage can occur at any site. Patients should be monitored closely for signs of bleeding (reduced blood pressure, increased heart rate, bruises, petechiae, hematomas, red or black stools, cloudy or discolored urine, pelvic pain, headache, and lumbar pain). If bleeding develops, warfarin should be discontinued. Severe overdose can be treated with vitamin K (see below). Patients should be encouraged to carry identification (eg, Medic Alert bracelet) to inform emergency personnel of warfarin use. Of note, compared with warfarin, the newer oral anticoagulants—rivaroxaban and dabigatran—pose a significantly lower risk of serious bleeds.

Several measures can reduce the risk of bleeding. Candidates for treatment must be carefully screened for risk factors (see Warnings and Contraindications below). Prothrombin time must be measured frequently. A variety of drugs can potentiate warfarin’s effects (see below), and hence must be used with care. Patients should be given detailed verbal and written instructions regarding signs of bleeding, dosage size and timing, and scheduling of PT tests. When a patient is incapable of accurate self-medication, a responsible individual must supervise treatment. Patients should be advised to make a record of each dose, rather than relying on memory. A soft toothbrush can reduce gingival bleeding. An electric razor can reduce cuts from shaving.

Warfarin intensifies bleeding during surgery. Accordingly, surgeons must be informed of warfarin use. Patients anticipating elective procedures should discontinue warfarin several days prior to the appointment. If an emergency procedure must be performed, injection of vitamin K can help suppress bleeding.

Does warfarin increase bleeding during dental surgery? Yes, but not that much. Accordingly, most patients needn’t interrupt warfarin for dental procedures, including dental surgery. However, it is important that the INR be in the target range.