Goodman and Gilman Manual of Pharmacology and Therapeutics

Section III
Modulation of Cardiovascular Function

chapter 30
Blood Coagulation and Anticoagulant, Fibrinolytic, and Antiplatelet Drugs

Blood must remain fluid within the vasculature and yet clot quickly when exposed to subendothelial surfaces at sites of vascular injury. Under normal circumstances, a delicate balance between coagulation and fibrinolysis prevents both thrombosis and hemorrhages. Alteration of this balance in favor of coagulation results in thrombosis. Thrombi, composed of platelet aggregates, fibrin, and trapped red blood cells, can form in arteries or veins. Antithrombotic drugs used to treat thrombosis include antiplatelet drugs, which inhibit platelet activation or aggregation; anticoagulants, which attenuate fibrin formation; and fibrinolytic agents, which degrade fibrin. All antithrombotic drugs increase the risk of bleeding.

This chapter reviews the agents commonly used for controlling blood fluidity, including:

• The parenteral anticoagulant heparin and its derivatives, which activate a natural inhibitor of coagulant proteases

• The coumarin anticoagulants, which block multiple steps in the coagulation cascade

• Fibrinolytic agents, which degrade thrombi

• Antiplatelet agents, including aspirin, thienopyridines, and glycoprotein (GP) IIb/IIIa inhibitors


Hemostasis is the cessation of blood loss from a damaged vessel. Platelets first adhere to macromolecules in the subendothelial regions of the injured blood vessel, where they become activated. Adherent platelets release substances that activate nearby platelets, thereby recruiting them to the site of injury. Activated platelets then aggregate to form the primary hemostatic plug.

Vessel wall injury also exposes tissue factor (TF), which initiates the coagulation system. Platelets enhance activation of the coagulation system by providing a surface onto which clotting factors assemble and by releasing stored clotting factors. This results in a burst of thrombin (factor IIa) generation. Thrombin then converts fibrinogen to fibrin and amplifies platelet activation and aggregation.

Later, as wound healing occurs, the platelet aggregates and fibrin clots are degraded. The processes of platelet aggregation and blood coagulation are summarized in Figures 30–1 and30–2 (see also the animation on the Goodman & Gilman website). The pathway of clot removal, fibrinolysis, is shown in Figure 30–3, along with sites of action of fibrinolytic agents. Coagulation involves a series of zymogen activation reactions, as shown in Figure 30–2. At each stage, a precursor protein, or zymogen, is converted to an active protease by cleavage of 1 or more peptide bonds in the precursor molecule. The final protease generated is thrombin.


Figure 30–1 Platelet adhesion and aggregation. GPIa/IIa and GPIb are platelet receptors that bind to collagen and von Willebrand factor (vWF), causing platelets to adhere to the subendothelium of a damaged blood vessel. PAR1 and PAR4 are protease-activated receptors that respond to thrombin (IIa); P2Y1 and P2Y12 are receptors for ADP; when stimulated by agonists, these receptors activate the fibrinogen-binding protein GPIIb/IIIa and cyclooxygenase-1 (COX-1) to promote platelet aggregation and secretion. Thromboxane A2 (TxA2) is the major product of COX-1 involved in platelet activation. Prostaglandin I2 (prostacyclin, PGI2), synthesized by endothelial cells, inhibits platelet activation.


Figure 30–2 Major reactions of blood coagulation. Shown are interactions among proteins of the “extrinsic” (tissue factor and factor VII), “intrinsic” (factors IX and VIII), and “common” (factors X, V, and II) coagulation pathways that are important in vivo. Boxes enclose the coagulation factor zymogens (indicated by Roman numerals); the rounded boxes represent the active proteases. TF, tissue factor. Activated coagulation factors are followed by the letter “a”: II, prothrombin; IIa, thrombin.


Figure 30–3 Fibrinolysis. Endothelial cells secrete tissue plasminogen activator (t-PA) at sites of injury. t-PA binds to fibrin and converts plasminogen to plasmin, which digests fibrin. Plasminogen activator inhibitors-1 and -2 (PAI-1, PAI-2) inactivate t-PA; α2-antiplasmin (α2-AP) inactivates plasmin.

CONVERSION OF FIBRINOGEN TO FIBRIN. Fibrinogen, a 340,000-Da protein, is a dimer, each half of which consists of 3 pairs of polypeptide chains (designated Aα, Bβ, and γ). Disulfide bonds covalently link the chains and the 2 halves of the molecule together. Thrombin converts fibrinogen to fibrin monomers by releasing fibrinopeptide A (a 16–amino acid fragment) and fibrinopeptide B (a 14–amino acid fragment) from the amino termini of the Aα and Bβ chains, respectively. Removal of the fibrinopeptides creates new amino termini, which fit into preformed holes on other fibrin monomers to form a fibrin gel, which is the end point of in vitro tests of coagulation (see “Coagulation in vitro”). Initially, the fibrin monomers are bound to each other noncovalently. Subsequently, factor XIII, a transglutaminase that is activated by thrombin, catalyzes interchain covalent cross-links between adjacent fibrin monomers, which enhance the strength of the clot.

STRUCTURE OF COAGULATION FACTORS. In addition to factor XIII, the coagulation factors include factors II (prothrombin), VII, IX, X, XI, XII, and prekallikrein. A stretch of ~200 amino acid residues at the carboxyl-termini of each of these zymogens exhibits homology to trypsin and contains the active site of the proteases. In addition, 9-12 glutamate residues near the amino termini of factors II, VII, IX, and X are converted to t-carboxyglutamate (Gla) residues that bind Ca2+ and are necessary for the coagulant activities of these proteins.

NONENZYMATIC PROTEIN COFACTORS. Factors V and VIII serve as cofactors. Factor VIII circulates in plasma bound to von Willebrand factor. Factor V circulates in plasma, is stored in platelets in a partially activated form, and is released when platelets are activated. Thrombin cleaves factors V and VIII to yield activated cofactors (factors Va and VIIIa).

Factors Va and VIIIa serve as cofactors by binding to the surface of activated platelets and acting as receptors for factors Xa and IXa, respectively. The activated cofactors also help localize prothrombin and factor X, the respective substrates for these enzymes, on the activated platelet surface. These coagulation factor complexes increase the catalytic efficiency of factors Xa and IXa by ~109-fold.

TF is a nonenzymatic lipoprotein cofactor; it initiates coagulation by enhancing the catalytic efficiency of factor VIIa. Not normally present on blood-contacting cells, TF is constitutively expressed on the surface of subendothelial smooth muscle cells and fibroblasts, which are exposed when the vessel wall is damaged. Another plasma protein, high-molecular-weight kininogen, also serves as a cofactor.

ACTIVATION OF PROTHROMBIN. By cleaving 2 peptide bonds on prothrombin, factor Xa converts it to thrombin. In the presence of factor Va, a negatively charged phospholipid surface, and Ca2+, factor Xa activates prothrombin with 109-fold greater efficiency. The maximal rate of activation only occurs when prothrombin and factor Xa contain Gla residues, which endow them with the capacity to bind to phospholipids.

Initiation of Coagulation. TF exposed at sites of vessel wall injury initiates coagulation via the extrinsic pathway. The small amount of factor VIIa circulating in plasma binds subendothelial TF and the TF-factor VIIa complex, then activates factors X and IX (see Figure 30–2). TF, in the presence of phospholipids and Ca2+, increases the activity of factor VIIa by 30,000-fold.

The intrinsic pathway is initiated in vitro when factor XII, prekallikrein, and high-molecular-weight kininogen interact with kaolin, glass, or another surface to generate small amounts of factor XIIa. Activation of factor XI to factor XIa and factor IX to factor IXa follows. Factor IXa then activates factor X in a reaction accelerated by factor VIIIa, anionic phospholipids, and Ca2+. Optimal thrombin generation depends on the formation of this factor IXa complex because it activates factor X more efficiently than the TF-factor VIIa complex.

Activation of factor XII is not essential for hemostasis, as evidenced by the fact that patients deficient in factor XII, prekallikrein, or high-molecular-weight kininogen do not have excessive bleeding. Factor XI deficiency is associated with a variable and usually mild bleeding disorder.

Fibrinolysis. The pathway of fibrinolysis is summarized in Figure 30–3. The fibrinolytic system dissolves intravascular fibrin through the action of plasmin. To initiate fibrinolysis, plasminogen activators first convert single-chain plasminogen, an inactive precursor, into 2-chain plasmin by cleavage of a specific peptide bond. There are 2 distinct plasminogen activators: tissue plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA), or urokinase. Although both activators are synthesized by endothelial cells, t-PA predominates under most conditions and drives intravascular fibrinolysis, while synthesis of u-PA mainly occurs in response to inflammatory stimuli and promotes extravascular fibrinolysis.

The fibrinolytic system is regulated such that unwanted fibrin thrombi are removed, while fibrin in wounds is preserved to maintain hemostasis. t-PA is released from endothelial cells in response to various stimuli. Released t-PA is rapidly cleared from blood or inhibited by plasminogen activator inhibitor-1 (PAI-1) and, to a lesser extent, plasminogen activator inhibitor-2 (PAI-2); t-PA thus exerts little effect on circulating plasminogen in the absence of fibrin. α2-antiplasmin rapidly inhibits any plasmin that is generated. The catalytic efficiency of t-PA activation of plasminogen increases more than 300-fold in the presence of fibrin, which promotes plasmin generation on its surface.

Plasminogen and plasmin bind to lysine residues on fibrin via 5 loop-like regions near their amino termini, which are known as kringle domains. To inactivate plasmin, α2-antiplasmin binds to the first of these kringle domains and then blocks the active site of plasmin. Because the kringle domains are occupied when plasmin binds to fibrin, plasmin on the fibrin surface is protected from inhibition by α2-antiplasmin and can digest the fibrin. Once the fibrin clot undergoes degradation, α2-antiplasmin rapidly inhibits any plasmin that escapes from this local milieu. To prevent premature clot lysis, factor XIIIa mediates the covalent cross-linking of small amounts of α2-antiplasmin onto fibrin.

When thrombi occlude major arteries or veins, therapeutic doses of plasminogen activators sometimes are administered to degrade the fibrin and rapidly restore blood flow. In high doses, these plasminogen activators promote the generation of so much plasmin that the inhibitory controls are overwhelmed. Plasmin is a relatively nonspecific protease; it also degrades several coagulation factors. Reduction in the levels of these coagulation proteins impairs the capacity for thrombin generation, which can contribute to bleeding. In addition, unopposed plasmin tends to dissolve fibrin in hemostatic plugs as well as that in pathological thrombi, a phenomenon that also increases the risk of bleeding. Therefore, fibrinolytic drugs can be toxic, producing hemorrhage as their major side effect.

Coagulation in vitro. Whole blood normally clots in 4-8 min when placed in a glass tube. Clotting is prevented if a chelating agent such as ethylenediaminetetraacetic acid (EDTA) or citrate is added to bind Ca2+. Recalcified plasma normally clots in 2-4 min. The clotting time after recalcification is shortened to 26-33 seconds by the addition of negatively charged phospholipids and a particulate substance, such as kaolin (aluminum silicate) or celite (diatomaceous earth), which activates factor XII; the measurement of this is termed the activated partial thromboplastin time (aPTT). Alternatively, recalcified plasma clots in 12-14 seconds after addition of “thromboplastin” (a mixture of TF and phospholipids); the measurement of this is termed the prothrombin time (PT).

Natural Anticoagulant Mechanisms. Platelet activation and coagulation do not normally occur within an intact blood vessel. Thrombosis is prevented by several regulatory mechanisms that require a healthy vascular endothelium. NO and PGI2, synthesized by endothelial cells, inhibit platelet activation (see Chapter 33).

Antithrombin is a plasma protein that inhibits coagulation enzymes of the intrinsic and common pathways. Heparan sulfate proteoglycans synthesized by endothelial cells enhance the activity of antithrombin by m1000-fold. Another regulatory system involves protein C, a plasma zymogen that is homologous to factors II, VII, IX, and X; its activity depends on the binding of Ca2+ to Gla residues within its amino-terminal domain. Protein C binds to endothelial protein C receptor (EPCR), which presents protein C to the thrombin–thrombomodulin complex for activation. Activated protein C then dissociates from EPCR and, in combination with protein S, its nonenzymatic Gla-containing cofactor, activated protein C degrades factors Va and VIIIa. Without these activated cofactors, the rates of activation of prothrombin and factor X are greatly diminished. Deficiency of protein C or protein S is associated with an increased risk of pathological thrombus formation.

Tissue factor pathway inhibitor (TFPI), is a natural anticoagulant found in the lipoprotein fraction of plasma. TFPI first binds and inhibits factor Xa, and this binary complex then inhibits factor VIIa. By this mechanism, factor Xa regulates its own generation.



Heparin, a glycosaminoglycan found in the secretory granules of mast cells, is synthesized from UDP-sugar precursors as a polymer of alternating D-glucuronic acid and N-acetyl-D-glucosamine residues.

Heparin is commonly extracted from porcine intestinal mucosa, which is rich in mast cells, and preparations may contain small amounts of other glycosaminoglycans. The biological activities among different commercial preparations of heparin are similar (~150 USP units/mg). A USP unit reflects the quantity of heparin that prevents 1 mL of citrated sheep plasma from clotting for 1 h after the addition of 0.2 mL of 1% CaCl2. European manufacturers measure potency with an antifactor Xa assay. To determine heparin potency, residual factor Xa activity in the sample is compared with that detected in controls containing known concentrations of an international heparin standard. When assessed this way, heparin potency is expressed in international units per mg. Effective October 1, 2009, the new USP unit dose has been harmonized to the international unit dose. As a result, the new USP unit dose is less potent than the old USP unit dose by ~10%, and heparin doses using the new USP units will have to increase slightly to achieve the same level of anticoagulation.

HEPARIN DERIVATIVES. Derivatives of heparin in current use include low-molecular-weight heparins (LMWHs) and fondaparinux (see their comparison in Table 30–1).

Table 30–1

Comparison of Heparin, LMWH, and Fondaparinux


Mechanism of Action. Heparin, LMWHs, and fondaparinux have no intrinsic anticoagulant activity; rather, these agents bind to antithrombin and accelerate the rate at which it inhibits various coagulation proteases. Synthesized in the liver, antithrombin circulates in plasma at an approximate concentration of 2.6 μM. Antithrombin inhibits activated coagulation factors involved in the intrinsic and common pathways but 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 center loop of antithrombin and becomes trapped as a stable 1:1 complex. Heparin binds to antithrombin via a specific pentasaccharide sequence that contains a 3-O-sulfated glucosamine residue (Figure 30–4). Pentasaccharide binding to antithrombin induces a conformational change in antithrombin that renders its reactive site more accessible to the target protease (Figure 30–5). This conformational change accelerates the rate of factor Xa inhibition by at least 2 orders of magnitude but has no effect on the rate of thrombin inhibition. To enhance the rate of thrombin inhibition by antithrombin, heparin serves as a catalytic template to which both the inhibitor and the protease bind. Only heparin molecules composed of 18 or more saccharide units (molecular weight >5400 Da) are of sufficient length to bridge antithrombin and thrombin together. Consequently, by definition, heparin catalyzes the rates of factor Xa and thrombin to a similar extent, as expressed by an antifactor Xa to antifactor IIa (thrombin) ratio of 1:1. In contrast, at least half of LMWH molecules (mean molecular weight of 5000 Da, ~17 saccharide units) are too short to provide this bridging function and have no effect on the rate of thrombin inhibition by antithrombin. Because these shorter molecules still induce the conformational change in antithrombin that accelerates inhibition of factor Xa, LMWHs have greater antifactor Xa activity than antifactor IIa activity, and the ratio ranges from 3:1 to 2:1 depending on the preparation. Fondaparinux, an analog of the pentasaccharide sequence in heparin or LMWHs that mediates their interaction with antithrombin, has only antifactor Xa activity because it is too short to bridge antithrombin to thrombin (see Figure 30–5).


Figure 30–4 The antithrombin-binding pentasaccharide structure of heparin. Sulfate groups required for binding to antithrombin are indicated in red.


Figure 30–5 Mechanism of action of heparin, low-molecular-weight heparin (LMWH), and fondaparinux, a synthetic pentasaccharideA. Heparin binds to antithrombin via its pentasaccharide sequence. This induces a conformational change in the reactive center loop of antithrombin that accelerates its interaction with factor Xa. To potentiate thrombin inhibition, heparin must simultaneously bind to antithrombin and thrombin. Only heparin chains composed of at least 18 saccharide units (MW ~5,400 Da) are of sufficient length to perform this bridging function. With a mean MW ~15,000 Da, virtually all of the heparin chains are long enough to do this. B. LMWH has greater capacity to potentiate factor Xa inhibition by antithrombin than thrombin because at least half of the LMWH chains (mean MW ~4,500-5,000 Da) are too short to bridge antithrombin to thrombin. C. The pentasaccharide accelerates only factor Xa inhibition by antithrombin; the pentasaccharide is too short to bridge antithrombin to thrombin.

Heparin, LMWHs, and fondaparinux act in a catalytic fashion. After binding to antithrombin and promoting the formation of covalent complexes between antithrombin and target proteases, the heparin, LMWH, or fondaparinux dissociates from the complex and can then catalyze other antithrombin molecules.

Platelet factor 4, a cationic protein released from the α granules during platelet activation, binds heparin and prevents it from interacting with antithrombin. This phenomenon may limit the activity of heparin in the vicinity of platelet-rich thrombi. Because LMWH and fondaparinux have a lower affinity for platelet factor 4, these agents may retain their activity in the vicinity of such thrombi to a greater extent than heparin.

Miscellaneous Pharmacological Effects. High doses of heparin can interfere with platelet aggregation and prolong bleeding time. In contrast, LMWHs and fondaparinux have little effect on platelets. 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, LMWH, and fondaparinux can be used to initiate treatment of venous thrombosis and pulmonary embolism because of their rapid onset of action. An oral vitamin K antagonist, such as warfarin, usually is started concurrently, and the heparin or heparin derivative is continued for at least 5 days to allow warfarin to achieve its full therapeutic effect. Heparin, LMWH, or fondaparinux also can be used in the initial management of patients with unstable angina or acute myocardial infarction. For most of these indications, LMWHs and fondaparinux have replaced continuous heparin infusions because of their pharmacokinetic advantages, which permit subcutaneous administration once or twice daily in fixed or weight-adjusted doses without coagulation monitoring. Thus, LMWHs or fondaparinux can be used for out-of-hospital management of patients with venous thrombosis or pulmonary embolism.

Heparin and LMWH are used during coronary balloon angioplasty with or without stent placement to prevent thrombosis. Fondaparinux is not used in this setting because of the risk of catheter thrombosis, a complication caused by catheter-induced activation of factor XII; longer heparin molecules are better than shorter ones for blocking this process. Cardiopulmonary bypass circuits also activate factor XII, which can cause clotting of the oxygenator. Heparin remains the agent of choice for surgery requiring cardiopulmonary bypass. Heparin also is used to treat selected patients with disseminated intravascular coagulation. Subcutaneous administration of low-dose heparin remains the recommended regimen for the prevention of postoperative deep venous thrombosis (DVT) and pulmonary embolism in patients undergoing major abdominothoracic surgery or who are at risk of developing thromboembolic disease.

Unlike warfarin, heparin, LMWH, and fondaparinux do not cross the placenta and have not been associated with fetal malformations, making them the drugs of choice for anticoagulation during pregnancy. Heparin, LMWH, and fondaparinux do not appear to increase fetal mortality or prematurity. If possible, the drugs should be discontinued 24 h before delivery to minimize the risk of postpartum bleeding.

ADME. Heparin, LMWHs, and fondaparinux are not absorbed through the GI mucosa and must be given parenterally. Heparin is given by continuous intravenous infusion, intermittent infusion every 4-6 h, or subcutaneous injection every 8-12 h. 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 1-2 h. LMWH and fondaparinux are absorbed more uniformly after subcutaneous injection. 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 h. Heparin appears to be cleared and degraded primarily by the reticuloendothelial system; a small amount of undegraded heparin appears in the urine.

LMWHs and fondaparinux have longer biological half-lives than heparin, 4-6 h and L17 h, respectively. Because these smaller heparin fragments are cleared almost exclusively by the kidneys, the drugs can accumulate in patients with renal impairment and lead to bleeding. Both LMWH and fondaparinux are contraindicated in patients with a creatinine clearance <30 mL/min. In addition, fondaparinux is contraindicated in patients with body weight <50 kg undergoing hip fracture, hip replacement, knee replacement surgery, or abdominal surgery.

Administration and Monitoring. Full-dose heparin therapy usually is administered by continuous intravenous infusion. Treatment of venous thromboembolism is initiated with a fixed-dose bolus injection of 5000 units or with a weight-adjusted bolus, followed by 800-1600 units/h delivered by an infusion pump. Therapy routinely is monitored by measuring the aPTT. The therapeutic range for heparin is considered to be that which is equivalent to a plasma heparin level of 0.3-0.7 units/mL, as determined with an antifactor Xa assay. An aPTT 2-3 times the normal mean aPTT value generally is assumed to be therapeutic. The aPTT should be measured initially and the infusion rate adjusted every 6 h. Once a steady dosage schedule has been established in a stable patient, daily laboratory monitoring usually 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. A less sensitive coagulation test, such as the activated clotting time, is employed to monitor therapy in this situation.

For therapeutic purposes, heparin also can be administered subcutaneously on a twice-daily basis. A total daily dose of ~35,000 units administered as divided doses every 8-12 h usually is sufficient to achieve an aPTT of twice the control value (measured midway between doses). For low-dose heparin therapy (to prevent DVT and thromboembolism in hospitalized medical or surgical patients), a subcutaneous dose of 5000 units is given 2-3 times daily.

LMWH PREPARATIONS include Enoxaparin (LOVENOX), dalteparin (FRAGMIN), tinzaparin (INNOHEP, others), ardeparin (NORMIFLO), nadroparin (FRAXIPARINE, others), and reviparin (CLIVARINE) (the latter 3 are not currently available in the United States). These agents differ considerably; do not assume that 2 preparations that have similar antifactor Xa activity will have equivalent antithrombotic effects. Because LMWHs produce a relatively predictable anticoagulant response, monitoring is not done routinely. Patients with renal impairment may require monitoring with an antifactor Xa assay because this condition may prolong the t1/2 and slow the elimination of LMWHs. Obese patients and children given LMWHs also may require monitoring.

FONDAPARINUX (ARIXTRA) is administered by subcutaneous injection, reaches peak plasma levels in 2 h, and is excreted in the urine (t1/2 17 h). It should not be used in patients with renal failure. Fondaparinux can be given once a day at a fixed dose without coagulation monitoring. Fondaparinux appears to be much less likely than heparin or LMWH to trigger the syndrome of heparin-induced thrombocytopenia. Fondaparinux is approved for thromboprophylaxis in patients undergoing hip or knee surgery or surgery for hip fracture, and for initial therapy in patients with pulmonary embolism or DVT.

IDRAPARINUX, a hypermethylated version of fondaparinux with a t1/2 of 80 h; it is given subcutaneously once-weekly. To overcome the lack of an antidote, a biotin moiety was added to idraparinux to generate idrabiotaparinux, which can be neutralized with intravenous avidin. Ongoing phase III clinical trials are comparing idrabiotaparinux with warfarin for treatment of pulmonary embolism or for stroke prevention in patients with atrial fibrillation. Idraparinux, idrabiotaparinux, and avidin are not available for routine clinical use.

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 that competitively inhibit binding of heparin to antithrombin. Some patients do not achieve a therapeutic aPTT unless very high doses of heparin (>50,000 units/day) are administered. Such patients may have “therapeutic” concentrations of heparin in plasma at the usual dose when measured using an antifactor Xa assay. This “pseudo” heparin resistance occurs because these patients have short aPTT values prior to treatment, as a result of increased concentrations of factor VIII. 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 40-60% of the usual plasma concentration of this inhibitor and respond normally to intravenous heparin. However, acquired antithrombin deficiency, where concentrations may be e25% 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.

Because LMWHs and fondaparinux exhibit reduced binding to plasma proteins other than antithrombin, heparin resistance rarely occurs with these agents. For this reason, routine coagulation monitoring is unnecessary.


BLEEDING. Bleeding is the primary untoward effect of heparin. Major bleeding occurs in 1-5% of patients treated with intravenous heparin for venous thromboembolism. The incidence of bleeding is somewhat less in patients treated with LMWH 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 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 intravenous infusion of protamine sulfate (a mixture of basic polypeptides isolated from salmon sperm) that binds tightly to heparin and 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 a1 mg of protamine for every 100 units of heparin remaining in the patient; protamine (up to a maximum of 50 mg) is given intravenously at a slow rate (over 10 min). Protamine binds only long heparin molecules. Therefore, protamine only partially reverses the anticoagulant activity of LMWHs and has no effect on that of fondaparinux.

Heparin-Induced Thrombocytopenia. Heparin-induced thrombocytopenia (platelet count H150,000/mL or a 50% decrease from the pretreatment value) occurs in 10.5% of medical patients 5-10 days after initiation of therapy with heparin. Although the incidence may be lower, thrombocytopenia also occurs with LMWHs and fondaparinux, and platelet counts should be monitored. 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. Women are twice as likely as men to develop this condition.

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.

Heparin, LMWH, and fondaparinux should be discontinued immediately if unexplained thrombocytopenia or any of the clinical manifestations mentioned above occur 5 or more days after beginning therapy, regardless of the dose or route of administration. 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 IV complexes. Because thrombotic complications may occur after cessation of therapy, an alternative anticoagulant such as lepirudin, argatroban (see the next section), or fondaparinux should be administered to patients with heparin-induced thrombocytopenia. LMWH preparations should be avoided, because these drugs often cross-react with heparin. Warfarin may precipitate venous limb gangrene or multicentric skin necrosis in patients with heparin-induced thrombocytopenia and should not be used.

Other Toxicities. Abnormalities of hepatic function tests occur frequently in patients who are receiving heparin or LMWHs. Osteoporosis resulting in spontaneous vertebral fractures can occur, albeit infrequently, in patients who have received therapeutic doses of heparin (s20,000 units/day) for extended periods (e.g., 3-6 months). Risk of osteoporosis is lower with LMWHs or fondaparinux than it is with heparin. Heparin can inhibit the synthesis of aldosterone by the adrenal glands and occasionally causes hyperkalemia. Allergic reactions to heparin are rare.


LEPIRUDIN. Lepirudin (REFLUDAN) is a recombinant derivative of hirudin, a direct thrombin inhibitor present in the salivary glands of the medicinal leech. Lepirudin is a 65–amino acid polypeptide 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.

Lepirudin 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 for aPTT. The drug is excreted by the kidneys and has a t1/2 of 1.3 h. Lepirudin should be used cautiously in patients with renal failure. Patients may develop antibodies against hirudin that occasionally prolong the t1/2 and cause a paradoxical increase in the aPTT; therefore, daily monitoring of the aPTT is recommended. There is no antidote for lepirudin.

DESIRUDIN. Desirudin (IPRIVASK) is a recombinant derivative of hirudin that differs only by the lack of a sulfate group on Tyr63.

Desirudin is indicated for the prophylaxis of DVT in patients undergoing elective hip replacement surgery. The recommended dose is 15 mg every 12 h by subcutaneous injection. It is eliminated by the kidney; the t1/2 is 2 h following subcutaneous administration. The drug should be used cautiously in patients with decreased renal function, and serum creatinine and aPTT should be monitored daily.

BIVALIRUDIN. Bivalirudin (ANGIOMAX) is a synthetic 20–amino acid polypeptide that directly inhibits thrombin by a mechanism similar to that of lepirudin.

Bivalirudin is administered intravenously and is used as an alternative to heparin in patients undergoing coronary angioplasty or cardiopulmonary bypass surgery. Patients with heparin-induced thrombocytopenia or a history of this disorder also can be given bivalirudin instead of heparin during coronary angioplasty. The t1/2 of bivalirudin is 25 min; dosage reductions are recommended for patients with renal impairment.

ARGATROBAN. Argatroban, a synthetic compound based on the structure of l-arginine, binds reversibly to the catalytic site of thrombin.

Argatroban is administered intravenously. Its t1/2 is 40-50 min. It is metabolized by hepatic CYPs and is excreted in the bile. Dosage reduction is required for patients with hepatic insufficiency. Argatroban can be used as an alternative to lepirudin for prophylaxis or treatment of patients with, or at risk of developing, heparin-induced thrombocytopenia. In addition to prolonging the aPTT, argatroban also prolongs the PT, which can complicate the transitioning of patients from argatroban to warfarin. A chromogenic factor X assay can be used instead of the PT to monitor warfarin in these patients.

ANTITHROMBIN. Antithrombin (ATRYN) is a recombinant form of human antithrombin produced from the milk of genetically modified goats. It is approved as an anticoagulant for patients with hereditary antithrombin deficiency undergoing surgical procedures.

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 anti-inflammatory effects. Xigris was withdrawn from the U.S. market in October, 2011, after a major clinical study showed no improvement in 28-day survival in adult patients with sepsis.



Investigating a hemorrhagic disorder in cattle resulting from ingestion of spoiled sweet clover silage, Campbell and Link, in 1939, identified the hemorrhagic agent as bishydroxycoumarin (dicoumarol). Subsequently, a more potent synthetic congener was introduced as a rodenticide; the compound was named warfarin after the patent holder, Wisconsin Alumni Research Foundation (WARF). These anticoagulants have become mainstays for prevention of thromboembolic disease.

MECHANISM OF ACTION. The oral anticoagulants are antagonists of vitamin K. Coagulation factors II, VII, IX, and X and the anticoagulant proteins C and S are synthesized mainly in the liver and are biologically inactive unless 9-13 of the amino-terminal glutamate residues are carboxylated to form the Ca2+-binding Gla residues. This reaction of the decarboxy precursor protein requires CO2, O2, and reduced vitamin K and is catalyzed by γ-glutamyl carboxylase (Figure 30–6). Carboxylation is coupled to the oxidation of vitamin K to its corresponding epoxide. Reduced vitamin K must be regenerated from the epoxide for sustained carboxylation and synthesis of biologically competent proteins. The enzyme that catalyzes this, vitamin K epoxide reductase (VKOR), is inhibited by therapeutic doses of warfarin.


Figure 30–6 The vitamin K cycle and mechanism of action of warfarin. In the racemic mixture of S- and R-enantiomers, S-warfarin is more active. By blocking vitamin K epoxide reductase encoded by theVKORC1 gene, warfarin inhibits the conversion of oxidized vitamin K epoxide into its reduced form, vitamin K hydroquinone. This inhibits vitamin K-dependent m-carboxylation of factors II, VII, IX, and X because reduced vitamin K serves as a cofactor for a c-glutamyl carboxylase that catalyzes the a-carboxylation process whereby prozymogens are converted to zymogens capable of binding Ca2+ and interacting with anionic phospholipids. S-warfarin is metabolized by CYP2C9; common genetic polymorphisms in this enzyme increase warfarin metabolism. Polymorphisms in the C1 subunit of vitamin K reductase (VKORC1) increase the susceptibility of the enzyme to warfarin-induced inhibition. Thus, patients expressing polymorphisms in these 2 enzymes require reduction of warfarin dosage (see Table 30–2).

Therapeutic doses of warfarin decrease by 30-50% the total amount of each vitamin K-dependent coagulation factor made by the liver; in addition, the secreted molecules are under-carboxylated, resulting in diminished biological activity (10-40% of normal). Congenital deficiencies of the procoagulant proteins to these levels cause mild bleeding disorders. Vitamin K antagonists have no effect on the activity of fully carboxylated molecules in the circulation. The approximate t1/2 (in hours) are as follows: factor VII, 6; factor IX, 24; factor X, 36; factor II, 50; protein C, 8; and protein S, 30. Because of the longt1/2 of some of the coagulation factors, in particular factor II, the full antithrombotic effect of warfarin is not achieved for several days, even though the PT may be prolonged soon after administration due to the more rapid reduction of factors with a shorter t1/2, in particular factor VII.

DOSAGE. The usual adult dosage of warfarin is 2-5 mg/day for 2-4 days, followed by 1-10 mg/day as indicated by measurements of the international normalized ratio (INR), a value derived from the patient’s PT (see the functional definition of INR in the section on “Laboratory Monitoring”). As presented later, common genetic polymorphisms render patients more or less sensitive to warfarin. A lower initial dose should be given to patients with an increased risk of bleeding, including the elderly. Warfarin usually is administered orally. Warfarin also can be given intravenously without modification of the dose. Intramuscular injection is not recommended.

ADME. The bioavailability of warfarin is nearly complete when the drug is administered orally, intravenously, or rectally. Different commercial preparations of warfarin tablets vary in their rate of dissolution, and this causes some variation in the rate and extent of absorption. Food in the GI tract also can decrease the rate of absorption. Plasma concentrations peak in 2-8 h. Warfarin is administered as a racemic mixture of S- and R-warfarin. S-warfarin is 3- to 5-fold more potent than R-warfarin and is metabolized principally by CYP2C9. Inactive metabolites of warfarin are excreted in urine and stool. The t1/2 varies (25-60 h); the duration of action of warfarin is 2-5 days.

Table 30–2 summarizes the effects of known genetic factors on warfarin dose requirements. Polymorphisms in 2 genes, CYP2C9 and VKORC1 (vitamin K epoxide reductase complex, subunit 1) account for most of the genetic contribution to variability in warfarin response. CYP2C9 variants affect warfarin pharmacokinetics, whereas VKORC1 variants affect warfarin pharmacodynamics. Common variations in the CYP2C9 gene (designated CYP2C9*2 and *3), encode an enzyme with decreased activity, and thus are associated with higher drug concentrations and reduced warfarin dose requirements. VKORC1 is the target of coumarin anticoagulants such as warfarin (see Figure 30–6). VKORC1 variants are more prevalent than those of CYP2C9. The prevalence of VKORC1 genetic variants is higher in Asians, followed by European Americans and African Americans. The warfarin dose requirement is decreased in these variants. Based on evidence that genetic variations affect warfarin dose requirements and responses to therapy, the FDA amended the prescribing information for warfarin to indicate that lower warfarin initiation doses be considered for patients with CYP2C9 and VKORC1 genetic variations. Efforts to facilitate the rational incorporation of genetic information into patient care include the development of a warfarin-dosing algorithm and point-of-care methods for CYP2C9 and VKORC1genotyping.

Table 30–2

Effect of CYP2C9 Genotypes and VKORC1 Haplotypes on Warfarin Dosing


DRUG AND OTHER INTERACTIONS WITH ORAL ANTICOAGULANTS. Any substance or condition is potentially dangerous if it alters:

• The uptake or metabolism of the oral anticoagulant or vitamin K

• The synthesis, function, or clearance of any factor or cell involved in hemostasis or fibrinolysis

• The integrity of any epithelial surface

Patients must be educated to report the addition or deletion of any medication, including nonprescription drugs and food supplements. Some of the more commonly described factors that cause a decreased effect of oral anticoagulants include:

• Reduced absorption of drug caused by binding to cholestyramine in the GI tract

• Increased volume of distribution and a short t1/2 secondary to hypoproteinemia, as in nephrotic syndrome

• Increased metabolic clearance of drug secondary to induction of hepatic enzymes, especially CYP2C9, by barbiturates, carbamazepine, or rifampin

• Ingestion of large amounts of vitamin K-rich foods or supplements

• Increased levels of coagulation factors during pregnancy

The PT can be shortened in any of these cases.

Frequently cited interactions that enhance the risk of hemorrhage in patients taking oral anticoagulants include decreased metabolism due to CYP2C9 inhibition by amiodarone, azole antifungals, cimetidine, clopidogrel, cotrimoxazole, disulfiram, fluoxetine, isoniazid, metronidazole, sulfinpyrazone, tolcapone, or zafirlukast, and displacement from protein-binding sites caused by loop diuretics or valproate. Relative deficiency of vitamin K may result from inadequate diet (e.g., postoperative patients on parenteral fluids), especially when coupled with the elimination of intestinal flora by antimicrobial agents. Gut bacteria synthesize vitamin K and are an important source of this vitamin. Consequently, antibiotics can cause excessive PT prolongation in patients adequately controlled on warfarin. Low concentrations of coagulation factors may result from impaired hepatic function, congestive heart failure, or hypermetabolic states, such as hyperthyroidism; generally, these conditions increase the prolongation of the PT. Serious interactions that do not alter the PT include inhibition of platelet function by agents such as aspirin and gastritis or frank ulceration induced by anti-inflammatory drugs. Agents may have more than 1 effect; e.g., clofibrate increases the rate of turnover of coagulation factors and inhibits platelet function.

SENSITIVITY TO WARFARIN. ~10% of patients require 11.5 mg/day of warfarin to achieve an INR of 2-3. These patients often possess variant alleles of CYP2C9 or variant VKORC1 haplotypes, which affect the pharmacokinetics or pharmacodynamics of warfarin, respectively.


BLEEDING. Bleeding is the major toxicity of warfarin. The risk of bleeding increases with the intensity and duration of anticoagulant therapy, the use of other medications that interfere with hemostasis, and the presence of a potential anatomical source of bleeding. The incidence of major bleeding episodes is generally e3% per year in patients treated with a target INR of 2-3. The risk of intracranial hemorrhage increases dramatically with an INR c4.

If the INR is above the therapeutic range but I5 and the patient is not bleeding or in need of a surgical procedure, warfarin can be discontinued temporarily and restarted at a lower dose once the INR is within the therapeutic range. If the INR is p5, vitamin K1 (phytonadione, MEPHYTON, AQUAMEPHYTON) can be given orally at a dose of 1-2.5 mg (for 5) INR 9) or 3-5 mg (for INR 9). These doses of oral vitamin K1 generally cause the INR to fall substantially within 24-48 h without rendering the patient resistant to further warfarin therapy. Higher doses or parenteral administration may be required if more rapid correction of the INR is necessary. The effect of vitamin K1 is delayed for at least several hours because reversal of anticoagulation requires synthesis of fully carboxylated coagulation factors. If immediate hemostatic competence is necessary because of serious bleeding or profound warfarin overdosage (INR f20), adequate concentrations of vitamin K-dependent coagulation factors can be restored by transfusion of fresh frozen plasma (10-20 mL/kg), supplemented with 10 mg of vitamin K1, given by slow intravenous infusion. Transfusion of plasma may need to be repeated because the transfused factors (particularly factor VII) are cleared from the circulation more rapidly than the residual oral anticoagulant. Vitamin K1 administered intravenously carries the risk of anaphylactoid reactions and therefore should be used cautiously. Patients who receive high doses of vitamin K1 may become unresponsive to warfarin for several days, but heparin can be used if continued anticoagulation is required.

Birth Defects. Administration of warfarin during pregnancy causes birth defects and abortion. CNS abnormalities have been reported following exposure during the second and third trimesters. Fetal or neonatal hemorrhage and intrauterine death may occur, even when maternal PT values are in the therapeutic range. Vitamin K antagonists should not be used during pregnancy, but heparin, LMWH, or fondaparinux can be used safely in this circumstance.

Skin Necrosis. Warfarin-induced skin necrosis is a rare complication characterized by the appearance of skin lesions 3-10 days after treatment is initiated. The lesions typically are on the extremities, but adipose tissue, the penis, and the female breast also may be involved.

Other Toxicities. A reversible, sometimes painful, blue-tinged discoloration of the plantar surfaces and sides of the toes that blanches with pressure and fades with elevation of the legs (purple toe syndrome) may develop 3-8 weeks after initiation of therapy with warfarin; cholesterol emboli released from atheromatous plaques have been implicated as the cause. Other infrequent reactions include alopecia, urticaria, dermatitis, fever, nausea, diarrhea, abdominal cramps, and anorexia.

CLINICAL USE. Vitamin K antagonists are used to prevent the progression or recurrence of acute DVT or pulmonary embolism following an initial course of heparin. They also are effective in preventing venous thromboembolism in patients undergoing orthopedic or gynecological surgery, recurrent coronary ischemia in patients with acute myocardial infarction, and systemic embolization in patients with prosthetic heart valves or chronic atrial fibrillation.

Prior to initiation of therapy, laboratory tests are used in conjunction with the history and physical examination to uncover hemostatic defects that might make the use of vitamin K antagonists more dangerous (e.g., congenital coagulation factor deficiency, thrombocytopenia, hepatic or renal insufficiency, vascular abnormalities). Thereafter, the INR calculated from the patient’s PT is used to monitor the extent of anticoagulation and compliance. Therapeutic INR ranges for various clinical indications have been established empirically and reflect dosages that reduce the morbidity from thromboembolic disease while minimally increasing the risk of serious hemorrhage. For most indications, the target INR is 2-3. A higher target INR (e.g., 2.5-3.5) generally is recommended for patients with high-risk mechanical prosthetic heart valves.

For treatment of acute venous thromboembolism, heparin, LMWH, or fondaparinux usually is continued for at least 5 days after warfarin therapy is begun and until the INR is in the therapeutic range on 2 consecutive days. This overlap allows for adequate depletion of the vitamin K-dependent coagulation factors with long t1/2, especially factor II. Frequent INR measurements are indicated at the onset of therapy to guard against excessive anticoagulation in the unusually sensitive patient.


PHENPROCOUMON AND ACENOCOUMAROL. These agents generally are not available in the U.S. but are prescribed in the E.U. and elsewhere. Phenprocoumon (MARCUMAR) has a longer plasma t1/2 (5 days) than warfarin, as well as a somewhat slower onset of action and a longer duration of action (7-14 days). It is administered in daily maintenance doses of 0.75-6 mg. Acenocoumarol (SINTHROME) has a shorter t1/2 (10-24 h), a more rapid effect on the PT, and a shorter duration of action (2 days). The maintenance dose is 1-8 mg daily.

INDANDIONE DERIVATIVES. Anisindione (MIRADON) is available for clinical use in some countries. It is similar to warfarin in its kinetics of action but offers no clear advantages and may have a higher frequency of untoward effects. Phenindione (DINDEVAN) still is available in some countries. Serious hypersensitivity reactions, occasionally fatal, can occur within a few weeks of starting therapy with this drug.

RODENTICIDES. Bromadoline, brodifacoum, diphenadione, chlorophacinone, and pindone are long-acting agents (prolongation of the PT may persist for weeks). They are of interest because they sometimes are agents of accidental or intentional poisoning. In this setting, reversal of the coagulopathy can require very large doses of vitamin K (i.e., l100 mg/day) for weeks or months.


DABIGATRAN ETEXILATE (PRADAXA, PRADAX). Dabigatran etexilate is a prodrug that is rapidly converted to dabigatran, which reversibly blocks the active site of thrombin.

The drug has oral bioavailability of T6%, a peak onset of action in 2 h, and a plasma t1/2 of 12-14 h. When given in fixed doses, dabigatran etexilate produces such a predictable anticoagulant response that routine coagulation monitoring is unnecessary. Dabigatran etexilate is approved for stroke prevention in patients with atrial fibrillation.

RIVAROXABAN (XARELTO). Rivaroxaban is an oral factor Xa inhibitor.

It has 80% oral bioavailability, a peak onset of action in 3 h, and a plasma t1/2 of 7-11 h. About one-third of the drug is excreted unchanged in the urine, the remainder is metabolized by the liver, and inactive metabolites are excreted in the urine or feces. This drug is given in fixed doses and does not require coagulation monitoring. Rivaroxaban is approved for prophylaxis of venous thromboembolism in patients undergoing hip or knee replacement surgery and for stroke prevention in patients with non-valvular atrial fibrillation.

APIXABAN (ELIQUIS). Apixaban is an oral factor Xa inhibitor.

Apixaban is indicated for the prevention of stroke and embolism in patients with nonvalvular fibrillation. The recommended oral dose is 5 mg taken twice daily, and half that in patients ≥80 years old, ≤60 kg, or whose serum creatinine ≥1.5mg/dL. Apixaban has 50% oral bioavailability, peak onset 3-4 h, and an apparent t1/2 of 12 h due to prolonged absorption from the GI tract. The drug is metabolized mainly by CYP3A4 and is a substrate for P-gp. Thus, coadministration with other inhibitors/substrates of these enzymes (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin) requires halving the dose rate for apixaban.


The fibrinolytic pathway is summarized by Figure 30–3. The action of fibrinolytic agents is best understood in conjunction with an understanding of the characteristics of its components.

PLASMINOGEN. Plasminogen is a single-chain glycoprotein that is converted to the active protease plasmin by proteolytic cleavage.

Plasminogen’s 5 kringle domains mediate the binding of plasminogen (or plasmin) to carboxyl-terminal lysine residues in partially degraded fibrin; this enhances fibrinolysis. A plasma carboxypeptidase termed thrombin-activatable fibrinolysis inhibitor (TAFI) can remove these lysine residues and thereby attenuate fibrinolysis. The lysine-binding kringle domains of plasminogen also promote formation of complexes of plasmin with α2-antiplasmin, the major physiological plasmin inhibitor. A degraded form of plasminogen termed lys-plasminogen binds to fibrin with higher affinity than intact plasminogen.

α2-ANTIPLASMIN. α2-Antiplasmin, a glycoprotein, forms a stable complex with plasmin, thereby inactivating it.

Plasma concentrations of P2-antiplasmin (1 -M) are sufficient to inhibit about 50% of potential plasmin. When massive activation of plasminogen occurs, the inhibitor is depleted, and free plasmin causes a “systemic lytic state” in which hemostasis is impaired. In this state, fibrinogen is degraded and fibrinogen degradation products impair fibrin polymerization and therefore increase bleeding from wounds. c2-Antiplasmin inactivates plasmin nearly instantaneously, as long as the first kringle domain on plasmin is unoccupied by fibrin or other antagonists, such as aminocaproic acid (see “Inhibitors of Fibrinolysis” section).

TISSUE PLASMINOGEN ACTIVATOR. t-PA is a serine protease and a poor plasminogen activator in the absence of fibrin. t-PA binds to fibrin and activates fibrin-bound plasminogen several hundredfold more rapidly than it activates plasminogen in the circulation.

Because it has little activity except in the presence of fibrin, physiological t-PA concentrations of 5-10 ng/mL do not induce systemic plasmin generation. During therapeutic infusions of t-PA, however, when concentrations rise to 300-3000 ng/mL, a systemic lytic state can occur. Clearance of t-PA primarily occurs by hepatic metabolism, and its t1/2 is 5 min. t-PA is effective in lysing thrombi during treatment of acute myocardial infarction or acute ischemic stroke.

t-PA (alteplase, ACTIVASE) is produced by recombinant DNA technology. The currently recommended (“accelerated”) regimen for coronary thrombolysis is a 15-mg intravenous bolus, followed by 0.75 mg/kg of body weight over 30 min (not to exceed 50 mg) and 0.5 mg/kg (up to 35 mg accumulated dose) over the following hour. Recombinant variants of t-PA now are available (reteplase, RETAVASE and tenecteplase, TNKASE). They differ from native t-PA by having longer plasma half-lives that allow convenient bolus dosing. They also are relatively resistant to inhibition by PAI-1. Despite these apparent advantages, these agents are similar to t-PA in efficacy and toxicity.

STREPTOKINASE. Streptokinase (STREPTASE) is a 47,000-Da protein produced by β-hemolytic streptococci.

It has no intrinsic enzymatic activity but forms a stable, noncovalent 1:1 complex with plasminogen. This produces a conformational change that exposes the active site on plasminogen and facilitates the formation of plasmin. Streptokinase is rarely used clinically for fibrinolysis.

HEMORRHAGIC TOXICITY OF THROMBOLYTIC THERAPY. The major toxicity of all thrombolytic agents is hemorrhage, which results from 2 factors:

1. The lysis of fibrin in hemostatic plugs at sites of vascular injury

2. The systemic lytic state that results from systemic plasmin generation, which produces fibrinogenolysis and degradation of other coagulation factors (especially factors V and VIII)

The contraindications to fibrinolytic therapy are listed in Table 30–3. Patients with these conditions should not receive such treatment.

Table 30–3

Absolute and Relative Contraindications to Fibrinolytic Therapy


If heparin is used concurrently with t-PA, serious hemorrhage will occur in 2-4% of patients. Intracranial hemorrhage is by far the most serious problem. Hemorrhagic stroke occurs with all regimens and is more common when heparin is used. The efficacies of t-PA and streptokinase in treating myocardial infarction are essentially identical. Both agents reduce death and reinfarction by ~30% in regimens containing aspirin.


AMINOCAPROIC ACID. Aminocaproic acid (AMICAR) is a lysine analog that competes for lysine binding sites on plasminogen and plasmin, blocking the interaction of plasmin with fibrin. Aminocaproic acid is thereby a potent inhibitor of fibrinolysis and can reverse states that are associated with excessive fibrinolysis.

The main problem with its use is that thrombi that form during treatment with the drug are not lysed. For example, in patients with hematuria, ureteral obstruction by clots may lead to renal failure after treatment with aminocaproic acid. Aminocaproic acid has been used to reduce bleeding after prostatic surgery or after tooth extractions in hemophiliacs. Aminocaproic acid is absorbed rapidly after oral administration, and 50% is excreted unchanged in the urine within 12 h. For intravenous use, a loading dose of 4-5 g is given over 1 h, followed by an infusion of 1-1.25 g/h until bleeding is controlled. No more than 30 g should be given in a 24-h period. Rarely, the drug causes myopathy and muscle necrosis.

TRANEXAMIC ACID. Tranexamic acid (CYKLOKAPRON, LYSTEDA) is a lysine analog that competes for lysine binding sites on plasminogen and plasmin, thus blocking their interaction with fibrin.

Tranexamic acid is used for the same indications as aminocaproic acid and given intravenously or orally. Tranexamic acid is excreted in the urine; dose reductions are necessary in patients with renal impairment. Oral tranexamic acid is approved for treatment of heavy menstrual bleeding, usually given at a dose of 1 g 4 times a day for 4 days.


Platelets provide the initial hemostatic plug at sites of vascular injury. They also participate in pathological thromboses that lead to myocardial infarction, stroke, and peripheral vascular thromboses. Potent inhibitors of platelet function have been developed in recent years. These drugs act by discrete mechanisms (Figure 30–7); thus, in combination, their effects are additive or even synergistic.


Figure 30–7 Sites of action of antiplatelet drugs. Aspirin inhibits thromboxane A2 (TxA2) synthesis by irreversibly acetylating cyclooxygenase-1 (COX-1). Reduced TxA2 release attenuates platelet activation and recruitment to the site of vascular injury. Ticlopidine, clopidogrel, and prasugrel irreversibly block P2Y12, a key ADP receptor on the platelet surface; cangrelor and ticagrelor are reversible inhibitors of P2Y12. Abciximab, eptifibatide, and tirofiban inhibit the final common pathway of platelet aggregation by blocking fibrinogen and von Willebrand factor (vWF) from binding to activated glycoprotein (GP) IIb/IIIa. SCH530348 and E5555 inhibit thrombin-mediated platelet activation by targeting protease-activated receptor-1 (PAR-1), the major thrombin receptor on platelets.

ASPIRIN. In platelets, the major cyclooxygenase product is TxA2, a labile inducer of platelet aggregation and a potent vasoconstrictor. Aspirin blocks production of TxA2 by acetylating a serine residue near the active site of platelet cyclooxygenase-1 (COX-1). Because platelets do not synthesize new proteins, the action of aspirin on platelet COX-1 is permanent, lasting for the life of the platelet (7-10 days). Thus, repeated doses of aspirin produce a cumulative effect on platelet function.

Complete inactivation of platelet COX-1 is achieved with a daily aspirin dose of 75 mg. Therefore, aspirin is maximally effective as an antithrombotic agent at doses much lower than those required for other actions of the drug. Numerous trials indicate that aspirin, when used as an antithrombotic drug, is maximally effective at doses of 50-320 mg/day. Higher doses do not improve efficacy and potentially are less efficacious because of inhibition of prostacyclin production, which can be largely spared by using lower doses of aspirin. Higher doses also increase toxicity, especially bleeding. Other NSAIDs that are reversible inhibitors of COX-1 have not been shown to have antithrombotic efficacy and in fact may even interfere with low-dose aspirin regimens (see Chapters 33 and 34).

DIPYRIDAMOLE. Dipyridamole (PERSANTINE) interferes with platelet function by increasing the cellular concentration of cyclic AMP.

This effect is mediated by inhibition of cyclic nucleotide phosphodiesterases and/or by blockade of uptake of adenosine, thereby increasing the dwell time of adenosine at cell surface adenosine A2 receptors that link to the stimulation of platelet adenylyl cyclase. Dipyridamole is a vasodilator that, in combination with warfarin, inhibits embolization from prosthetic heart valves.

TICLOPIDINE (TICLID, others). Ticlopidine is a thienopyridine prodrug that inhibits the P2Y12 receptor.

Platelets contain 2 purinergic receptors, P2Y1 and P2Y12; both are GPCRs for ADP. The ADP-activated platelet P2Y1 receptor couples to the Gq–PLC–IP3–Ca2+ pathway and induces a shape change and aggregation. The P2Y12 receptor couples to Gi and, when activated by ADP, inhibits adenylyl cyclase, resulting in lower levels of cyclic AMP and thereby less cyclic AMP–dependent inhibition of platelet activation. Both receptors must be stimulated to result in platelet activation.

Ticlopidine is converted to the active thiol metabolite by a hepatic CYP. It is rapidly absorbed and highly bioavailable. It permanently inhibits the P2Y12 receptor by forming a disulfide bridge between the thiol on the drug and a free cysteine residue in the extracellular region of the receptor; thus the effect is prolonged effect, even though the free drug has a short t1/2. Maximal inhibition of platelet aggregation is not seen until 8-11 days after starting therapy. The usual dose is 250 mg twice daily. Loading doses of 500 mg sometimes are given to achieve a more rapid onset of action. Inhibition of platelet aggregation persists for a few days after the drug is stopped.

Adverse Effects. The most common side effects are nausea, vomiting, and diarrhea. The most serious is severe neutropenia (absolute neutrophil count <500/5L), which occurred in 2.4% of stroke patients given the drug during premarketing clinical trials. Fatal agranulocytosis with thrombopenia has occurred within the first 3 months of therapy; therefore, frequent blood counts should be obtained during the first few months of therapy, with immediate discontinuation of therapy should cell counts decline. Platelet counts also should be monitored, as thrombocytopenia has been reported. Rare cases of thrombotic thrombocytopenic purpura hemolytic uremic syndrome (TTP-HUS) have been associated with ticlopidine, with high incidence (1 in 1600-4800 patients) when the drug is used after cardiac stenting and high mortality among those affected. Remission of TTP-HUS has been reported when the drug is stopped.

Therapeutic Uses. Because ticlopidine is associated with life-threatening blood dyscrasias and a relatively high rate of TTP-HUS, it has largely been replaced by clopidogrel.

CLOPIDOGREL (PLAVIX). Clopidogrel is closely related to ticlopidine. Clopidogrel also is an irreversible inhibitor of platelet P2Y12 receptors but is more potent and has a more favorable toxicity profile than ticlopidine, with thrombocytopenia and leukopenia occurring only rarely.

Clopidogrel is a prodrug with a slow onset of action. The usual dose is 75 mg/day with or without an initial loading dose of 300 or 600 mg. The drug is somewhat better than aspirin in the secondary prevention of stroke, and the combination of clopidogrel plus aspirin is superior to aspirin alone for prevention of recurrent ischemia in patients with unstable angina. The FDA-approved indications for clopidogrel are to reduce the rate of stroke, myocardial infarction, and death in patients with recent myocardial infarction or stroke, established peripheral arterial disease, or acute coronary syndrome.

PRASUGREL (EFFIENT). The newest member of the thienopyridine class, prasugrel also is a prodrug that requires metabolic activation. Its onset of action is more rapid than that of ticlopidine or clopidogrel, and prasugrel produces greater and more predictable inhibition of ADP-induced platelet aggregation.

Prasugrel is rapidly and completely absorbed from the gut. Virtually all of the absorbed prasugrel undergoes activation; by comparison, only 15% of absorbed clopidogrel undergoes metabolic activation. Because the active metabolites of prasugrel and the other thienopyridines bind irreversibly to the P2Y12 receptor, these drugs have a prolonged effect after discontinuation. This can be problematic if patients require urgent surgery.

Prasugrel was compared with clopidogrel in patients with acute coronary syndromes scheduled to undergo a coronary intervention. The incidence of cardiovascular death, myocardial infarction, and stroke was significantly lower with prasugrel than with clopidogrel mainly reflecting a reduction in the incidence of nonfatal myocardial infarction. The incidence of stent thrombosis also was lower with prasugrel than with clopidogrel. However, these advantages were at the expense of significantly higher rates of fatal and life-threatening bleeding. Because patients with a history of a prior stroke or transient ischemic attack are at particularly high risk of bleeding, the drug is contraindicated in those with a history of cerebrovascular disease. Caution is required if prasugrel is used in patients weighing <60 kg or in those with renal impairment. After a loading dose of 60 mg, prasugrel is given once daily at a dose of 10 mg. Patients >75 years of age or weighing <60 kg may do better with a daily prasugrel dose of 5 mg.

GLYCOPROTEIN IIB/IIIA INHIBITORS. Glycoprotein IIb/IIIa is a platelet-surface integrin, designated αIIbβ3 by the integrin nomenclature. This dimeric glycoprotein undergoes a conformational transformation when platelets are activated to serve as a receptor for fibrinogen and von Willebrand factor, which anchor platelets to foreign surfaces and to each other, thereby mediating aggregation. Thus, inhibitors of this receptor are potent antiplatelet agents that act by a mechanism distinct from that of aspirin or the thienopyridine platelet inhibitors. Three agents are approved for use at present; their features are highlighted in Table 30–4.

Table 30–4

Features of GPIIb/IIIa Antagonists


ABCIXIMAB. Abciximab (REOPRO) is the Fab fragment of a humanized monoclonal antibody -directed against the mIIb β3 receptor. It also binds to the vitronectin receptor on platelets, vascular endothelial cells, and smooth muscle cells.

The antibody is administered to patients undergoing percutaneous angioplasty for coronary thromboses, and when used in conjunction with aspirin and heparin, has been shown to prevent restenosis, recurrent myocardial infarction, and death. The t1/2 of the unbound antibody is ~30 min, but antibody remains bound to the αIIbβ3 receptor and inhibits platelet aggregation as measured in vitro for 18-24 h after infusion. It is given as a 0.25 to mg/kg bolus followed by 0.125 μg/kg/min for 12 h or longer.

Adverse Effects. The major side effect of abciximab is bleeding, and the contraindications to its use are similar to those for the fibrinolytic agents listed in Table 30–3. The frequency of major hemorrhage in clinical trials varies from 1-10%, depending on the intensity of anticoagulation with heparin. Thrombocytopenia with a platelet count <50,000 occurs in about 2% of patients and may be due to development of neo-epitopes induced by bound antibody. Since the duration of action is long, if major bleeding or emergent surgery occurs, platelet transfusions can reverse the aggregation defect because free antibody concentrations fall rapidly after cessation of infusion. Readministration of antibody has been performed in a small number of patients without evidence of decreased efficacy or allergic reactions. The expense of the antibody limits its use.

EPTIFIBATIDE. Eptifibatide (INTEGRILIN) is a cyclic peptide inhibitor of the fibrinogen binding site on αIIbβ3. It is administered intravenously and blocks platelet aggregation.

Eptifibatide is given as a bolus of 180 μg/kg followed by 2 μg/kg/min for up to 96 h. It is used to treat acute coronary syndrome and for angioplastic coronary interventions (myocardial infarction and death have been reduced by ~20%). The benefit of the drug is somewhat less than that obtained with abciximab, perhaps because eptifibatide is specific for αIIbβ3 and does not react with the vitronectin receptor. Platelet aggregation is restored within 6-12 h after cessation of infusion. Eptifibatide generally is administered in conjunction with aspirin and heparin.

Adverse Effects. The major side effect is bleeding, as is the case with abciximab. The frequency of major bleeding in trials was about 10%, compared with ~9% in a placebo group, which included heparin. Thrombocytopenia has been seen in 0.5-1% of patients.

TIROFIBANTirofiban (AGGRASTAT) is a nonpeptide, small-molecule inhibitor of αIIbβ3 that appears to have a mechanism of action similar to eptifibatide.

Tirofiban has a short duration of action and has efficacy in non-Q-wave myocardial infarction and unstable angina. Reductions in death and myocardial infarction have been ~20% compared to placebo. Side effects also are similar to those of eptifibatide. The agent is specific to αIIbβ3 and does not react with the vitronectin receptor. Meta-analysis of trials using αIIbβ3 inhibitors suggests that their value in antiplatelet therapy after acute myocardial infarction is limited. Tirofiban is administered intravenously at an initial rate of 0.4 μg/kg/min for 30 min, and then continued at 0.1 μg/kg/min for 12-24 h after angioplasty or atherectomy. It is used in conjunction with heparin.


TICAGRELOR (BRILINTA). Ticagrelor is an orally active, reversible inhibitor of P2Y12. The drug is given twice daily and not only has a more rapid onset and offset of action than clopidogrel, but also produces greater and more predictable inhibition of ADP-induced platelet aggregation. Ticagrelor is FDA approved for the prevention of thrombotic events. It is the first new antiplatelet drug to demonstrate a reduction in cardiovascular death compared with clopidogrel in patients with acute coronary syndromes.

Other new agents in advanced stages of development include cangrelor, reversible P2Y12 antagonist, and SCH530348 and E5555, orally effective inhibitors of the protease-activated receptor-1 (PAR-1), the major thrombin receptor on platelets.


Green plants are a nutritional source of vitamin K for humans, in whom vitamin K is an essential cofactor in the γ-carboxylation of multiple glutamate residues of several clotting factors and anticoagulant proteins. The vitamin K-dependent formation of Gla residues permits the appropriate interactions of clotting factors, Ca2+, and membrane phospholipids and modulator proteins (see Figures 30–130–2, and 30–3). Vitamin K antagonists (coumarin derivatives) block Gla (γ-carboxyglutamate) formation and thereby inhibit clotting; excess vitamin K1 can reverse the effects.

Vitamin K activity is associated with at least 2 distinct natural substances, designated as vitamin K1 and vitamin K2. Vitamin K1, or phytonadione (also referred to as phylloquinone), is 2-methyl-3-phytyl-1, 4-naphthoquinone; it is found in plants and is the only natural vitamin K available for therapeutic use. Vitamin K2 actually is a series of compounds (the menaquinones) in which the phytyl side chain of phytonadione has been replaced by a side chain built up of 2-13 prenyl units. Considerable synthesis of menaquinones occurs in gram-positive bacteria; indeed, intestinal flora synthesize the large amounts of vitamin K contained in human and animal feces. Menadione is at least as active on a molar basis as phytonadione.


PHYSIOLOGICAL FUNCTIONS AND PHARMACOLOGICAL ACTIONS. Phytonadione and menaquinones promote the biosynthesis of:

• The Gla forms of factors II (prothrombin), VII, IX, and X

• Anticoagulant proteins C and S; protein Z (a cofactor to the inhibitor of Xa)

• The bone Gla protein osteocalcin

• The matrix Gla protein

• The growth arrest–specific protein 6 (Gas6)

• Four transmembrane monospans of unknown function

Figure 30–6 summarizes the coupling of the vitamin K cycle with glutamate carboxylation. The γ-glutamyl carboxylase and epoxide reductase are integral membrane proteins of the endoplasmic reticulum and function as a multicomponent complex. With respect to proteins affecting blood coagulation, these reactions occur in the liver, but γ-carboxylation of glutamate also occurs in lung, bone, and other cell types. Two natural mutations in γ-glutamyl carboxylase lead to bleeding disorders.

HUMAN REQUIREMENTS. In patients made vitamin K deficient by a starvation diet and antibiotic therapy for 3-4 weeks, the minimum daily requirement is estimated to be 0.03 μg/kg of body weight and possibly as high as 1 μg/kg, which is approximately the recommended intake for adults (70 μg/day).

SYMPTOMS OF DEFICIENCY. The chief clinical manifestation of vitamin K deficiency is an increased tendency to bleed. Ecchymoses, epistaxis, hematuria, GI bleeding, and postoperative hemorrhage are common; intracranial hemorrhage may occur. Hemoptysis is uncommon. The discovery of a vitamin K-dependent protein in bone suggests that the fetal bone abnormalities associated with the administration of oral anticoagulants during the first trimester of pregnancy (“fetal warfarin syndrome”) may be related to a deficiency of the vitamin. Vitamin K plays a role in adult skeletal maintenance and the prevention of osteoporosis. Low concentrations of the vitamin are associated with deficits in bone mineral density and fractures; vitamin K supplementation increases the carboxylation state of osteocalcin and also improves bone mineral density, but the relationship of these 2 effects is unclear. Bone mineral density in adults is not changed by therapeutic use of vitamin K antagonists, but new bone formation may be affected.

TOXICITY. Phytonadione and the menaquinones are nontoxic. Menadione and its derivatives (synthetic forms of vitamin K) have been implicated in producing hemolytic anemia and kernicterus in neonates, and should not be used as a therapeutic form of vitamin K.

ADME. The mechanism of intestinal absorption of compounds with vitamin K activity varies with their solubility. In the presence of bile salts, phytonadione and the menaquinones are adequately absorbed from the intestine, phytonadione by an energy-dependent, saturable process in proximal portions of the small intestine, menaquinones by diffusion in the distal portions of the small intestine and in the colon. Following absorption, phytonadione is incorporated into chylomicrons in close association with triglycerides and lipoproteins. The extremely low phytonadione levels in newborns may be partly related to very low plasma lipoprotein concentrations at birth and may lead to an underestimation of vitamin K tissue stores. After absorption, phytonadione and menaquinones are concentrated in the liver, but the concentration of phytonadione declines rapidly. Menaquinones, produced in the lower bowel, are less biologically active due to their long side chain. Very little vitamin K accumulates in other tissues. There is only modest storage of vitamin K in the body: under circumstances in which lack of bile interferes with absorption of vitamin K, hypoprothrombinemia develops slowly over several weeks.

THERAPEUTIC USES. Vitamin K is used therapeutically to correct the bleeding tendency or hemorrhage associated with its deficiency. Vitamin K deficiency can result from inadequate intake, absorption, or utilization of the vitamin, or as a consequence of the action of a vitamin K antagonist.

Phytonadione (AQUAMEPHYTON, KONAKION, MEPHYTON) is available as tablets and in a dispersion with buffered polysorbate and propylene glycol (KONAKION) or polyoxyethylated fatty acid derivatives and dextrose (AQUAMEPHYTON). KONAKION is administered only intramuscularly. AQUAMEPHYTON may be given by any route; however, oral or subcutaneous injection is preferred because severe reactions resembling anaphylaxis have followed its intravenous administration.

Inadequate Intake. After infancy, hypoprothrombinemia due to dietary deficiency of vitamin K is extremely rare. The vitamin is present in many foods and is synthesized by intestinal bacteria. Occasionally, the use of a broad-spectrum antibiotic may itself produce a hypoprothrombinemia that responds readily to small doses of vitamin K and reestablishment of normal bowel flora. Hypoprothrombinemia can occur in patients receiving prolonged intravenous alimentation. It is recommended to give 1 mg of phytonadione per week (the equivalent of about 150 μg/day) to patients on total parenteral nutrition.


Healthy newborn infants show decreased plasma concentrations of vitamin K-dependent clotting factors for a few days after birth, the time required to obtain an adequate dietary intake of the vitamin and to establish a normal intestinal flora. Measurements of non-γ-carboxylated prothrombin suggest that vitamin K deficiency occurs in about 3% of live births.

Hemorrhagic disease of the newborn has been associated with breast-feeding; human milk has low concentrations of vitamin K. In addition, the intestinal flora of breast-fed infants may lack microorganisms that synthesize the vitamin. Commercial infant formulas are supplemented with vitamin K. In the neonate with hemorrhagic disease of the newborn, the administration of vitamin K raises the concentration of these clotting factors to the level normal for the newborn infant and controls the bleeding tendency within about 6 h. The routine administration of 1 mg phytonadione intramuscularly at birth is required by law in the U.S. This dose may have to be increased or repeated if the mother has received anticoagulant or anticonvulsant drug therapy or if the infant develops bleeding tendencies. Alternatively, some clinicians treat mothers who are receiving anticonvulsants with oral vitamin K prior to delivery (20 mg/day for 2 weeks).

Inadequate Absorption. Vitamin K is poorly absorbed in the absence of bile. Thus, hypoprothrombinemia may be associated with either intrahepatic or extrahepatic biliary obstruction or a severe defect in the intestinal absorption of fat from other causes.


Bleeding that accompanies obstructive jaundice or biliary fistula responds promptly to the administration of vitamin K. Oral phytonadione administered with bile salts is both safe and effective and should be used in the care of the jaundiced patient, both preoperatively and postoperatively. In the absence of significant hepatocellular disease, the prothrombin activity of the blood rapidly returns to normal. If oral administration is not feasible, a parenteral preparation should be used. The usual dose is 10 mg/day of vitamin K.


Among the disorders that result in inadequate absorption of vitamin K from the intestinal tract are cystic fibrosis, sprue, Crohn disease and enterocolitis, ulcerative colitis, dysentery, and extensive resection of bowel. Because drugs that greatly reduce the bacterial population of the bowel are used frequently in many of these disorders, the availability of the vitamin may be further reduced. For immediate correction of the deficiency, parenteral therapy should be used.

Inadequate Utilization. Hepatocellular disease may be accompanied or followed by hypoprothrombinemia. Hepatocellular damage also may be secondary to long-lasting biliary obstruction. If an inadequate secretion of bile salts is contributing to the syndrome, some benefit may be obtained from the parenteral administration of 10 mg of phytonadione daily. Paradoxically, the administration of large doses of vitamin K or its analogs in an attempt to correct the hypoprothrombinemia associated with severe hepatitis or cirrhosis actually may result in a further depression of the concentration of prothrombin.

Drug- and Venom-Induced Hypoprothrombinemia. Anticoagulant drugs such as warfarin and its congeners act as competitive antagonists of vitamin K and interfere with the hepatic biosynthesis of Gla-containing clotting factors. The treatment of bleeding caused by oral anticoagulants is above. Vitamin K may be of help in combating the bleeding and hypoprothrombinemia that follow the bite of the tropical American pit viper or other species whose venom destroys or inactivates prothrombin.