Chapter 36: Blood Coagulation and Anticoagulant Drugs PDF

36 Chapter Blood Coagulation and Anticoagulant, Fibrinolytic, and Antiplatelet Drugs Jeffrey I. Weitz OVERVIEW OF HEMOSTASIS: PLATELET FUNCTION, BLOOD C...

36 Chapter Blood Coagulation and Anticoagulant, Fibrinolytic, and Antiplatelet Drugs Jeffrey I. Weitz OVERVIEW OF HEMOSTASIS: PLATELET FUNCTION, BLOOD COAGULATION, AND FIBRINOLYSIS Conversion of Fibrinogen to Fibrin DIRECT ORAL ANTICOAGULANTS Direct Oral Thrombin Inhibitor Direct Oral Factor Xa Inhibitors Reversal Agents for Direct Oral Anticoagulants STRUCTURE OF COAGULATION FACTORS FIBRINOLYTIC DRUGS NONENZYMATIC PROTEIN COFACTORS Tissue Plasminogen Activator Factor VIII and Factor V Are Procofactors INHIBITORS OF FIBRINOLYSIS ACTIVATION OF PROTHROMBIN ε-Aminocaproic Acid and Tranexamic Acid Initiation of Coagulation Fibrinolysis ANTIPLATELET DRUGS Coagulation In Vitro Aspirin Natural Anticoagulant Mechanisms Dipyridamole P2Y12 Receptor Antagonists PARENTERAL ANTICOAGULANTS Thrombin Receptor Inhibitor Heparin, Low-Molecular-Weight Heparin, Fondaparinux Glycoprotein IIb/IIIa Inhibitors Other Parenteral Anticoagulants THE ROLE OF VITAMIN K VITAMIN K ANTAGONIST Physiological Functions and Pharmacological Actions Warfarin Inadequate Intake Inadequate Absorption Inadequate Utilization Blood must remain fluid within the vasculature and yet clot quickly Overview of Hemostasis: Platelet Function, when exposed to subendothelial surfaces at sites of vascular injury. Under normal circumstances, a delicate balance between coagulation Blood Coagulation, and Fibrinolysis and fibrinolysis prevents both thrombosis and hemorrhage. Alteration Hemostasis is the cessation of blood loss from a damaged vessel. Plate- of this balance in favor of coagulation results in thrombosis. Thrombi, lets first adhere to macromolecules in the subendothelial regions of the composed of platelet aggregates, fibrin, and trapped red blood cells, injured blood vessel, where they become activated. Adherent platelets can form in arteries or veins. Antithrombotic drugs used to treat release substances that activate nearby platelets, thereby recruiting them thrombosis include antiplatelet drugs, which inhibit platelet activa- to the site of injury. Activated platelets then aggregate to form the pri- tion or aggregation; anticoagulants, which attenuate fibrin formation; mary hemostatic plug. and fibrinolytic agents, which degrade fibrin. All antithrombotic drugs Vessel wall injury also exposes tissue factor (TF), which initiates the coag- increase the risk of bleeding. ulation system. Activated platelets enhance activation of the coagulation This chapter reviews the agents commonly used for controlling blood system by providing a surface onto which clotting factors assemble and fluidity, including: by releasing stored clotting factors. This results in a burst of thrombin (factor IIa) generation. Thrombin converts soluble fibrinogen to fibrin, The parenteral anticoagulant heparin and its derivatives, which acti- activates platelets, and feeds back to promote additional thrombin genera- vate antithrombin, a natural inhibitor of coagulant proteases tion. The fibrin strands tie the platelet aggregates together to form a stable clot. The coumarin anticoagulants, which lower the functional levels of The processes of platelet activation and aggregation and blood coagu- multiple coagulation factors lation are summarized in Figures 36–1 and 36–2 (see also the animation The direct oral anticoagulants, which inhibit factor Xa or thrombin on the Goodman & Gilman site on AccessMedicine.com). Coagulation Fibrinolytic agents, which degrade fibrin involves a series of zymogen activation reactions, as shown in Figure 36–2. Antiplatelet agents, which attenuate platelet activation (aspirin, At each stage, a precursor protein, or zymogen, is converted to an active clopidogrel, prasugrel, ticagrelor, and vorapaxar) or aggregation protease by cleavage of one or more peptide bonds in the precursor mol- (glycoprotein IIb/IIIa inhibitors) ecule. The final protease generated is thrombin. Later, as wound healing Vitamin K, which is required for the biosynthesis of key coagulation occurs, the fibrin clot is degraded. The pathway of clot removal, fibrinoly- factors sis, is shown in Figure 36–3, along with sites of action of fibrinolytic agents. https://ebooksmedicine.net/  710 Abbreviations that is activated by thrombin, catalyzes interchain covalent cross-links between adjacent fibrin monomers, which strengthen the clot. ACT: activated clotting time α2-AP: α2-antiplasmin Structure of Coagulation Factors aPTT: activated partial thromboplastin time In addition to factor XIII, the coagulation factors include factors II COX: cyclooxygenase (prothrombin), VII, IX, X, XI, XII, high-molecular-weight kininogen, CrCL: creatinine clearance and prekallikrein. A stretch of about 200 amino acid residues at the car- CYP: cytochrome P450 boxyl termini of each of these zymogens exhibits homology to trypsin EPCR: endothelial protein C receptor and contains the active site of the proteases. In addition, 9 to 12 Glu res- Gla: γ-carboxyglutamic acid idues near the amino termini of factors II, VII, IX, and X are converted Glu: glutamic acid to Gla (γ-carboxyglutamic acid) residues in a vitamin K–dependent post- GP: glycoprotein translational step. The Gla residues bind Ca2+ and are essential for the INR: international normalized ratio coagulant activities of these proteins by enabling their interaction with LMWH: low-molecular-weight heparin the anionic phospholipid membrane of activated platelets. PAI: plasminogen activator inhibitor PAR: protease-activated receptor PT: prothrombin time Nonenzymatic Protein Cofactors TF: tissue factor CHAPTER 36 BLOOD COAGULATION AND ANTICOAGULANT, FIBRINOLYTIC, AND ANTIPLATELET DRUGS TFPI: tissue factor pathway inhibitor TF, factor V, and factor VIII are critical cofactors in coagulation. A t-PA: tissue plasminogen activator nonenzymatic lipoprotein cofactor, TF is not normally present on TxA2: thromboxane A2 blood-contacting cells. TF is constitutively expressed on the surface of sub- u-PA: urokinase plasminogen activator endothelial smooth muscle cells and fibroblasts, which are exposed when VKOR: vitamin K epoxide reductase the vessel wall is damaged. Activated monocytes and leukocyte-derived microvesicles also express TF on their surface. TF binds factor VIIa and enhances its catalytic efficiency. The TF–factor VIIa complex initiates coagulation by activating factors IX and X. Conversion of Fibrinogen to Fibrin Fibrinogen, a 340,000-Da protein, is a dimer, each half of which consists Factor VIII and Factor V Are Procofactors of three pairs of polypeptide chains (designated Aα, Bβ, and γ). Disul- Factor VIII circulates in plasma bound to von Willebrand factor, which fide bonds covalently link the chains and the two halves of the molecule. serves to stabilize it. Factor V circulates in plasma, is stored in platelets Thrombin converts fibrinogen to fibrin monomers by releasing fibrino- in a partially activated form, and is released when platelets are activated. peptide A (a 16–amino acid fragment) and fibrinopeptide B (a 14–amino Thrombin releases von Willebrand factor from factor VIII and activates acid fragment) from the amino termini of the Aα and Bβ chains, respec- factors V and VIII to yield factors Va and VIIIa, respectively. Once acti- tively. Removal of the fibrinopeptides creates new amino termini, which vated, the cofactors bind to the surface of activated platelets and serve as form knobs that fit into preformed holes on other fibrin monomers to receptors; factor VIIIa serves as the receptor for factor IXa, while factor form a fibrin gel, which is the end point of in vitro tests of coagulation Va serves as the receptor for factor Xa. In addition to binding factors IXa (see Coagulation In Vitro). Initially, the fibrin monomers are bound to and Xa, factors VIIIa and Va bind their substrates, factors X and proth- each other noncovalently. Subsequently, factor XIII, a transglutaminase rombin (factor II), respectively. Endothelial cells Platelets + COX-1 TxA2 GPIIb/IIIa IIa P2Y1/P2Y12 PAR-1/PAR-4 COX-1 Fibrinogen GPIIb/IIIa PGI2 ADP GPVI GPIb Collagen vWF Smooth muscle cells/macrophages Figure 36–1 Platelet adhesion and aggregation. GPVI 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. PAR-1 and PAR-4 are PARs 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 COX-1 to promote platelet aggregation and secretion. TxA2 is the major product of COX-1 involved in platelet activation. Prostacyclin (PGI2), synthesized by endothelial cells, inhibits platelet activation.  711 Endothelial cells Platelets X II VIIIa X IX IXa Xa Va Fibrinogen IIa VIIa TF TF TF Fibrin TF TF TF TF TF SECTION III MODULATION OF PULMONARY, RENAL, AND CARDIOVASCULAR Smooth muscle cells/macrophages Figure 36–2 Major reactions of blood coagulation. Shown are interactions among proteins of the “extrinsic” (TF and factor VII), “intrinsic” (factors IX and VIII), and “common” (factors X, V, and II) coagulation pathways that are important in vivo. Blue rectangles enclose the coagulation factor zymogens (indicated by Roman numerals); the rounded boxes represent the active proteases. Activated coagulation factors are followed by the letter a: II, prothrombin; IIa, thrombin. The intrinsic pathway is initiated in vitro when factor XII, preka- Activation of Prothrombin llikrein, and high-molecular-weight kininogen interact with kaolin, By cleaving two peptide bonds on prothrombin, factor Xa converts it to glass, or another negatively charged surface to generate small amounts thrombin. In the presence of factor Va, a negatively charged phospholipid of factor XIIa. Factor XII can be activated in vivo by contact of the blood surface, and Ca2+ (the so-called prothrombinase complex), factor Xa acti- with medical devices, such as mechanical heart valves or extracorporeal vates prothrombin with 109-fold greater efficiency than that of factor Xa circuits, or by cell-free DNA, neutrophil extracellular traps (web-like alone. This maximal rate of activation only occurs when prothrombin structures composed of DNA and histones extruded from activated neu- and factor Xa contain Gla residues at their amino termini, which endows trophils), or inorganic polyphosphates released from activated platelets. them with the capacity to bind calcium and interact with the anionic Factor XIIa activates factor XI, and the resultant factor XIa then acti- phospholipid surface. vates factor IX. Factor IXa activates factor X in a reaction accelerated by factor VIIIa, anionic phospholipids, and Ca2+. Optimal thrombin gen- Initiation of Coagulation eration depends on the formation of this factor IXa complex (intrinsic TF exposed at sites of vessel wall injury initiates coagulation via the tenase) because it activates factor X more efficiently than the TF–factor extrinsic pathway. The small amount of factor VIIa circulating in plasma VIIa complex. binds subendothelial TF, and the TF–factor VIIa complex then activates Activation of factor XII is not essential for hemostasis, as evi- factors X and IX (see Figure 36–2). When bound to TF in the presence of denced by the fact that patients deficient in factor XII, prekallikrein, or anionic phospholipids and Ca2+ (extrinsic tenase), factor VIIa activity is high-molecular-weight kininogen do not have excessive bleeding. Factor XI increased 30,000-fold over that of factor VIIa alone. deficiency is associated with a variable and usually mild bleeding disorder. Endothelial cells PAI-1 PAI-2 Plasminogen t-PA α2-AP Plasmin Fibrin Smooth muscle cells/macrophages Figure 36–3 Fibrinolysis. Endothelial cells secrete t-PA at sites of injury. t-PA binds to fibrin and converts plasminogen to plasmin, which digests fibrin. PAI-1 and PAI-2 inactivate t-PA; α2-AP inactivates plasmin. https://ebooksmedicine.net/  712 In contrast, congenital deficiency of factor VIII or IX results in hemophilia synthesized by endothelial cells inhibit platelet activation, as does CD39, A or B, respectively, and is associated with spontaneous bleeding, which can an ADP- and ATP-degrading enzyme expressed on the surface of endo- be fatal. thelial cells. Antithrombin is a plasma protein that inhibits coagulation enzymes Fibrinolysis of the extrinsic, intrinsic, and common pathways. Heparan sulfate prote- The fibrinolysis pathway is summarized in Figure 36–3. The fibrinolytic oglycans synthesized by endothelial cells enhance the activity of antith- system dissolves intravascular fibrin through the action of plasmin. To rombin by about 1000-fold. Another regulatory system involves protein initiate fibrinolysis, plasminogen activators convert single-chain plas- C, a plasma zymogen that is homologous to factors II, VII, IX, and X; its minogen, an inactive precursor, into two-chain plasmin by cleavage of activity depends on the binding of Ca2+ to Gla residues within its amino a specific peptide bond. There are two distinct plasminogen activators: terminal domain. Protein C binds to endothelial protein C receptor t-PA and u-PA, which is also known as urokinase. Although both acti- (EPCR), which presents it to the thrombin-thrombomodulin complex vators are synthesized by endothelial cells, t-PA predominates under for activation. Activated protein C then dissociates from EPCR, and, in most conditions and drives intravascular fibrinolysis, while synthesis of combination with protein S, its nonenzymatic Gla-containing cofactor, u-PA mainly occurs in response to inflammatory stimuli and promotes activated protein C degrades factors Va and VIIIa. Without these acti- extravascular fibrinolysis. vated cofactors, the rates of activation of prothrombin and factor X are The fibrinolytic system is regulated such that unwanted fibrin thrombi greatly diminished, and thrombin generation is attenuated. Congenital are removed, while fibrin in wounds is preserved to maintain hemosta- or acquired deficiency of protein C or protein S is associated with an sis. t-PA is released from endothelial cells in response to various stimuli. increased risk of venous thrombosis. Released t-PA is rapidly cleared from blood or inhibited by plasminogen Tissue factor pathway inhibitor (TFPI) is a natural anticoagulant found activator inhibitor (PAI) type 1 and, to a lesser extent, by PAI-2. There- in the lipoprotein fraction of plasma or bound to endothelial cell sur- CHAPTER 36 BLOOD COAGULATION AND ANTICOAGULANT, FIBRINOLYTIC, AND ANTIPLATELET DRUGS fore, t-PA exerts little effect on circulating plasminogen in the absence of face. TFPI first binds and inhibits factor Xa, and this binary complex then fibrin, and circulating α2-antiplasmin rapidly inhibits any plasmin that inhibits factor VIIa bound to TF. By this mechanism, factor Xa regulates is generated. The catalytic efficiency of t-PA activation of plasminogen its own generation. increases more than 300-fold in the presence of fibrin, which promotes plasmin generation on its surface. Parenteral Anticoagulants Plasminogen and plasmin bind to lysine residues on fibrin via five loop-like regions near their amino termini, which are known as krin- Heparin, Low-Molecular-Weight Heparin, gle domains. To inactivate plasmin, α2-antiplasmin binds to the first of Fondaparinux these kringle domains and then blocks the active site of plasmin. Because the kringle domains are occupied when plasmin binds to fibrin, plas- Heparin and Its Standardization min on the fibrin surface is protected from inhibition by α2-antiplasmin Heparin, a glycosaminoglycan found in the secretory granules of mast and can digest the fibrin. Once the fibrin clot undergoes degradation, cells, is synthesized from UDP-sugar precursors as a polymer of alter- α2-antiplasmin rapidly inhibits any plasmin that escapes from this local nating d-glucuronic acid and N-acetyl-d-glucosamine residues. Heparin milieu. To prevent premature clot lysis, factor XIIIa mediates covalent is commonly extracted from porcine intestinal mucosa, which is rich in cross-linking of small amounts of α2-antiplasmin onto fibrin. mast cells, and preparations may contain small amounts of other gly- When thrombi occlude major arteries or veins, therapeutic doses of cosaminoglycans. Various commercial heparin preparations have similar plasminogen activators are sometimes administered to rapidly degrade the biological activity (~150 USP units/mg). A USP unit reflects the quantity fibrin and restore blood flow. In high doses, these plasminogen activators of heparin that prevents 1 mL of citrated sheep plasma from clotting for promote the generation of so much plasmin that the inhibitory controls are 1 h after calcium addition. European manufacturers measure potency overwhelmed. Plasmin is a relatively nonspecific protease; in addition to with an anti–factor Xa assay. To determine heparin potency, residual fac- degrading fibrin, it degrades several coagulation factors. Reduction in the tor Xa activity in the sample is compared with that detected in controls levels of these coagulation proteins impairs the capacity for thrombin gen- containing known concentrations of an international heparin standard. eration, which can contribute to bleeding. In addition, unopposed plasmin When assessed this way, heparin potency is expressed in international tends to dissolve fibrin in hemostatic plugs as well as that in pathological units per milligram. Effective October 1, 2009, the new USP unit dose thrombi, a phenomenon that also increases the risk of bleeding. Therefore, was harmonized with the international unit dose. As a result, the new hemorrhage is the major side effect of fibrinolytic drugs. USP unit dose is about 10% less potent than the old one, which results in a requirement for somewhat higher heparin doses to achieve the same level of anticoagulation. Coagulation In Vitro Whole blood normally clots in 4 to 8 min when placed in a glass tube. Heparin Derivatives Under these conditions, contact of the blood with glass activates factor Derivatives of heparin in current use include low-molecular-weight XII, thereby initiating coagulation via the intrinsic pathway. Clotting is heparin (LMWH) and fondaparinux (see their comparison in Table 36–1). prevented if a chelating agent such as ethylenediaminetetraacetic acid Mechanism of Action. Heparin, LMWH, and fondaparinux have no or citrate is added to bind Ca2+. Recalcified plasma normally clots in intrinsic anticoagulant activity; rather, these agents bind to antithrombin 2 to 4 min. The clotting time after recalcification is shortened to 26 to and accelerate the rate at which it inhibits various coagulation proteases. 33 sec by the addition of negatively charged phospholipids and particulate Synthesized in the liver, antithrombin circulates in plasma at an approx- substances, such as silica (silicon dioxide), kaolin (aluminum silicate), imate concentration of 2.5 μM. Antithrombin inhibits activated coagula- or celite (diatomaceous earth), which activate factor XII; the measure- tion factors, particularly thrombin and factor Xa, by serving as a “suicide ment of this is termed the activated partial thromboplastin time (aPTT). substrate.” Thus, inhibition occurs when the protease attacks a specific Alternatively, recalcified plasma clots in 12 to 14 sec after addition of Arg–Ser peptide bond in the reactive center loop of antithrombin and “thromboplastin” (a mixture of TF and phospholipid) and calcium; the becomes trapped as a stable 1:1 complex. Heparin binds to antithrombin measurement of this is termed the prothrombin time (PT). via a specific pentasaccharide sequence that contains a 3-O-sulfated glu- cosamine residue (Figure 36–4). Natural Anticoagulant Mechanisms Pentasaccharide binding to antithrombin induces a conformational Platelet activation and coagulation do not normally occur within an intact change in antithrombin that renders its reactive site more accessible to blood vessel. Thrombosis is prevented by several regulatory mechanisms the target protease (Figure 36–5). This conformational change accelerates that require healthy vascular endothelium. Nitric oxide and prostacyclin the rate of factor Xa inhibition by at least two orders of magnitude but  713 TABLE 36–1 COMPARISON OF THE FEATURES OF SUBCUTANEOUS HEPARIN, LOW-MOLECULAR-WEIGHT HEPARIN, AND FONDAPARINUX FEATURES HEPARIN LMWH FONDAPARINUX Source Biological Biological Synthetic Mean molecular weight (Da) 15,000 5000 1500 Target Xa and IIa Xa and IIa Xa Subcutaneous Bioavailability (%) 30 (at low doses) 90 100 t1/2 (h) 1–8 a 4 17 Renal excretion No Yes Yes Antidote effect Complete Partial None Thrombocytopenia 110 mmHg) its variants, urokinase and streptokinase. Urokinase and streptokinase are rarely used and no longer available in the U.S. Traumatic or prolonged CPR or major surgery within 3 weeks Recent (within 2–4 weeks) internal bleeding Tissue Plasminogen Activator Noncompressible vascular punctures Tissue plasminogen activator is a serine protease and a poor plasmino- For streptokinase: prior exposure (more than 5 days ago) or prior gen activator in the absence of fibrin. When bound to fibrin, t-PA acti- allergic reaction to streptokinase vates fibrin-bound plasminogen several hundred–fold more rapidly than Pregnancy it activates plasminogen in the circulation. Because it has little activity Active peptic ulcer except in the presence of fibrin, physiological t-PA concentrations of 5 to 10 ng/mL do not induce systemic plasmin generation. With therapeutic Current use of warfarin and INR >1.7 ureteral obstruction by clots may lead to renal failure after treatment with Plaque disruption 721 ε-aminocaproic acid or tranexamic acid. ε-Aminocaproic acid has been used intravenously to reduce bleeding after prostatic surgery and orally to reduce bleeding after tooth extractions in patients with hemophilia. ε-Aminocaproic acid is absorbed rapidly after oral administration, and 50% is excreted unchanged in the urine within 12 h. For intravenous use, Tissue factor Collagen vWF a loading dose of 4 to 5 g is given over 1 h, followed by an infusion of 1 to 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 is given intravenously in trauma resuscitation, in Platelet adhesion patients with massive hemorrhage, and in women with postpartum and secretion hemorrhage (Franchini and Mannucci, 2020). It is also used to reduce operative bleeding in patients undergoing hip or knee arthroplasty or cardiac surgery. There appears to be little or no increased risk of throm- Aspirin COX-1 bosis. Tranexamic acid is excreted in the urine; therefore, dose reduction is necessary in patients with renal impairment. Oral tranexamic acid is TxA2 ADP approved for treatment of heavy menstrual bleeding, usually given at a Ticlopidine dose of 1 g four times daily for 4 days. Clopidrogrel Prasugrel SECTION III MODULATION OF PULMONARY, RENAL, AND CARDIOVASCULAR Cangrelor Antiplatelet Drugs Thrombin Platelet recruitment Ticagrelor and activation Platelet aggregates form the initial hemostatic plug at sites of vascular injury. Platelets also contribute to the pathological thrombi that lead to myocardial infarction, stroke, and peripheral arterial thrombosis. Potent Vorapaxar inhibitors of platelet function have been developed in recent years. These GPIIb/IIIa activation drugs act by discrete mechanisms (Figure 36–7); thus, in combination, Abciximab their effects are additive or even synergistic. Eptifibatide Tirofiban Aspirin Platelet aggregation In platelets, the major product of metabolism by cyclooxygenase (COX) Figure 36–7 Sites of action of antiplatelet drugs. Aspirin inhibits TxA2 synthe- type1 is thromboxane A2 (TxA2), a labile inducer of platelet aggregation sis by irreversibly acetylating COX-1. Reduced TxA2 release attenuates platelet and a potent vasoconstrictor. Aspirin blocks production of TxA2 by acet- activation and recruitment to the site of vascular injury. Ticlopidine, clopido- ylating a serine residue near the active site of platelet COX-1. Because grel, and prasugrel irreversibly block P2Y12, a key ADP receptor on the platelet platelets do not synthesize new proteins, the action of aspirin on platelet surface; cangrelor and ticagrelor are reversible inhibitors of P2Y12. Abciximab, COX-1 is permanent, lasting for the lifetime of the platelet (7–10 days). eptifibatide, and tirofiban inhibit the final common pathway of platelet aggrega- Thus, repeated doses of aspirin produce a cumulative effect on platelet tion by blocking fibrinogen and von Willebrand factor (vWF) from binding to function. activated GPIIb/IIIa. Vorapaxar inhibits thrombin-mediated platelet activation Complete inactivation of platelet COX-1 is achieved with a daily by targeting PAR-1, the major thrombin receptor on platelets. aspirin dose of 75 mg. Therefore, aspirin is maximally effective as an antithrombotic agent at doses much lower than those required for protein-coupled receptors for ADP. The ADP-activated platelet P2Y1 other actions of the drug. Numerous trials indicated that aspirin, when receptor couples to the Gq-PLC-IP3–Ca2+ pathway and induces platelet used as an antithrombotic drug, is maximally effective at doses of 50 to shape change and aggregation. The P2Y12 receptor couples to Gi and, 325 mg/day. Higher doses do not improve efficacy and potentially are when activated by ADP, inhibits adenylyl cyclase, resulting in lower levels less efficacious because of inhibition of prostacyclin production, which of intracellular cyclic AMP and thereby less cyclic AMP–dependent inhi- can be largely spared by using lower doses of aspirin. Higher doses also bition of platelet activation. Both receptors must be stimulated to result increase toxicity, especially bleeding. Therefore, daily aspirin doses of in maximal platelet activation. 100 mg or less are used for most indications (Arnett et al., 2019). Non- Clopidogrel is an irreversible inhibitor of P2Y12. It has largely replaced steroidal anti-inflammatory drugs that are reversible inhibitors of COX-1 ticlopidine because clopidogrel is more potent and less toxic, with throm- have not been shown to have antithrombotic efficacy and, in fact, may bocytopenia and leukopenia occurring only rarely. Clopidogrel is a pro- even interfere with low-dose aspirin regimens (see Chapters 41 and 42). drug that requires metabolic activation in the liver. Therefore, it has a slow onset of action. It also has a slow offset of action because of its irreversible effect on P2Y12. Metabolic activation of clopidogrel can be Dipyridamole affected by polymorphisms in CYP2C19 that result in reduced or absent Dipyridamole interferes with platelet function by increasing the intracel- CYP2C19 activity. These polymorphisms contribute to the variable effect lular concentration of cyclic AMP. This effect is mediated by inhibition of clopidogrel on ADP-induced platelet aggregation. Inhibition of platelet of phosphodiesterase or by blockade of uptake of adenosine, thereby activation is seen 2 h after ingestion of a loading dose of clopidogrel, and increasing the dwell time of adenosine at cell surface adenosine A2 recep- platelets are affected for the remainder of their life span. tors that link to the stimulation of platelet adenylyl cyclase. Dipyridamole Therapeutic Uses. Clopidogrel is somewhat better than aspirin for sec- is a vasodilator that, in combination with warfarin, inhibits embolization ondary prevention of stroke, and the combination of clopidogrel plus from prosthetic heart valves. Dipyridamole is approved for secondary aspirin is superior to aspirin alone for prevention of recurrent ischemia prevention of stroke when it is combined with low-dose aspirin. in patients with unstable angina. The FDA-approved indications for clopidogrel are to reduce the rate of stroke, myocardial infarction, and P2Y12 Receptor Antagonists death in patients with recent myocardial infarction, ischemic stroke, Clopidogrel established peripheral artery disease, or acute coronary syndrome Clopidogrel is a thienopyridine prodrug that inhibits the P2Y12 receptor. (Rahmann et al., 2019). Clopidogrel is routinely used in combination with Platelets contain two purinergic receptors, P2Y1 and P2Y12; both are G aspirin after coronary stent implantation. https://ebooksmedicine.net/  722 Adverse Effects. Clopidogrel increases the risk of bleeding, particularly syndrome undergoing percutaneous intervention, ticagrelor is indicated when combined with aspirin or an anticoagulant. Thrombotic thrombo- both in those undergoing intervention and in those managed medically. cytopenic purpura can occur but is rare. Adverse Effects. Dyspnea is reported in 17% of patients. This is often Drug Interactions. CYP2C19 inhibition by proton pump inhibitors (e.g., transient and not associated with pulmonary disease. Ticagrelor is asso- omeprazole, lansoprazole, dexlansoprazole, and pantoprazole) may reduce ciated with a higher risk of intracranial bleeding than clopidogrel and is conversion to the active metabolite of clopidogrel, which may contribute to contraindicated in patients with a history of prior intracranial bleeding. the lower efficacy of clopidogrel when coadministered with proton pump Platelet transfusion is ineffective in patients taking ticagrelor who pres- inhibitors. Other clopidogrel drug interactions include CYP2C19 inducers ent with serious bleeding because the drug will bind to P2Y12 on the and opioids (decrease exposure to clopidogrel); bleeding risk is increased transfused platelets. Bentracimab (PB2452) was developed to overcome with anticoagulants, nonsteroidal anti-inflammatory drugs, and antidepres- this problem. An antibody fragment that binds ticagrelor and its active sant drugs such as selective serotonin reuptake inhibitors. Extra caution is metabolite with high affinity, bentracimab is administered as an intra- advised in patients coadministered warfarin (a CYP2C9 substrate) because venous bolus followed by an infusion for up to 24 h. In volunteers given high doses of clopidogrel inhibit CYP2C9 and the acyl-β-glucuronide ticagrelor, bentracimab rapidly and completely reversed its antiplatelet metabolite of clopidogrel is a strong inhibitor of CYP2C8, causing drug effects (Bhatt et al., 2019). Bentracimab is currently under investigation interactions with CYP2C8 substrates (e.g., repaglinide). for ticagrelor reversal in patients with life-threatening bleeding or who require urgent surgery or intervention. Prasugrel Drug Interactions. Concomitant aspirin at a dose greater than The newest member of the thienopyridine class, prasugrel, is a prodrug 100 mg daily may reduce the effectiveness of ticagrelor. Potent inhibitors that requires metabolic activation in the liver. However, because the acti- of CYP3A (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, vation of prasugrel is more efficient than that of clopidogrel, prasugrel has CHAPTER 36 BLOOD COAGULATION AND ANTICOAGULANT, FIBRINOLYTIC, AND ANTIPLATELET DRUGS nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and a more rapid onset of action, and it produces greater and more predict- telithromycin) and strong inducers of CYP3A (e.g., rifampin, phenytoin, able inhibition of ADP-induced platelet aggregation. carbamazepine, and phenobarbital) should be avoided. Opioids decrease Prasugrel is rapidly and completely absorbed from the gut. It is hydro- ticagrelor systemic exposure. Ticagrelor increases serum concentrations lyzed in the intestine to a thiolactone, which is then converted to the of simvastatin and lovastatin and may affect digoxin metabolism. active metabolite in the liver. Most of the absorbed prasugrel undergoes activation; by comparison, only 15% of absorbed clopidogrel undergoes Cangrelor metabolic activation. Because the active metabolites of prasugrel bind Cangrelor is a parenteral reversible inhibitor of P2Y12. When adminis- irreversibly to the P2Y12 receptor, its effect lasts the lifetime of the plate- tered intravenously as a bolus followed by an infusion, cangrelor inhib- lets. This slow offset of action can be problematic if patients require its ADP-induced platelet aggregation within minutes, and its effect on urgent surgery. Prasugrel is inactivated by methylation or conjugation platelet aggregation disappears within 1 h of discontinuation of the drug. with cysteine. Moderate renal or hepatic impairment does not appear to Cangrelor has a short half-life because it is rapidly dephosphorylated in change the drug pharmacodynamics. the circulation to an inactive metabolite. Therapeutic Uses. Prasugrel is indicated to reduce the rate of thrombotic Therapeutic Use. Cangrelor is indicated for reduction in the risk of cardiovascular events (including stent thrombosis) in patients with acute periprocedural myocardial infarction, repeat coronary revascularization, coronary syndrome who are managed with percutaneous coronary interven- and stent thrombosis in patients undergoing percutaneous coronary tion. The incidence of cardiovascular death, myocardial infarction, and stroke intervention who have not been treated with an oral P2Y12 inhibitor and is significantly lower with prasugrel than with clopidogrel, mainly reflecting a are not given a glycoprotein IIb/IIIa antagonist. reduction in the incidence of nonfatal myocardial infarction. The incidence Adverse Effects. The risk of bleeding with cangrelor is greater than that of stent thrombosis is also lower with prasugrel than with clopidogrel. with clopidogrel during the coronary intervention. Adverse Effects. Prasugrel is associated with higher rates of fatal and Drug Interactions. When transitioning to oral P2Y12 inhibitor therapy, life-threatening bleeding than clopidogrel. Because patients with a his- ticagrelor can be given at a loading dose of 180 mg at any time during tory of a prior stroke or transient ischemic attack are at particularly high the cangrelor infusion or immediately after discontinuation. In contrast, risk of intracranial bleeding, the drug is contraindicated in such patients. loading doses of prasugrel or clopidogrel (60 and 600 mg, respectively) Patients over 75 years of age should not be prescribed prasugrel because should only be given after cangrelor is stopped because cangrelor blocks of the increased bleeding risk. After a loading dose of 60 mg, prasugrel is the interaction of their active metabolites with P2Y12. given once daily at a dose of 10 mg. The daily dose should be reduced to 5 mg in patients weighing less than 60 kg. No dose adjustment is required in patients with hepatic or renal impairment. If patients present with seri- Thrombin Receptor Inhibitor ous bleeding, platelet transfusion may be beneficial. Prasugrel has been There are two major thrombin receptors on the platelet surface, reported to cause thrombotic thrombocytopenic purpura. protease-activated receptor (PAR) type 1 and type 4. Thrombin binds to these G protein-coupled receptors and cleaves them at their amino ter- Drug Interactions. Concomitant administration of prasugrel with anti- mini. The newly created amino termini then serve as tethered ligands coagulants, antidepressant drugs such as selective serotonin reuptake to activate the receptors. PAR-1 is activated by lower concentrations of inhibitors, or nonsteroidal anti-inflammatory drugs increases the risk of thrombin than are required to activate PAR-4. bleeding. Vorapaxar Ticagrelor Vorapaxar is a competitive antagonist of PAR-1 and inhibits Ticagrelor is an orally active, reversible inhibitor of P2Y12. The drug is given thrombin-induced platelet aggregation. The drug is 90% bioavailable twice daily and not only has a more rapid onset and offset of action than and has a rapid onset of action and a circulating half-life of 3 to 4 days. clopidogrel, but also produces greater and more predictable inhibition of However, because vorapaxar remains tightly bound to PAR-1 on plate- ADP-induced platelet aggregation. The bioavailability of ticagrelor is about lets, its effect on thrombin-induced platelet aggregation can persist for 36%. It can be given as a whole tablet or crushed in water and administered up to 4 weeks after the drug is stopped. Vorapaxar is metabolized in via a nasogastric tube. Ticagrelor is metabolized by hepatic CYP3A4. the liver by CYP3A4. Therapeutic Uses. Ticagrelor is FDA approved for reduction in the risk Therapeutic Uses. Vorapaxar is given orally in combination with either of cardiovascular death, myocardial infarction, and stroke in patients with aspirin or clopidogrel. It is indicated for the reduction of thrombotic car- acute coronary syndrome or a history of myocardial infarction. In con- diovascular events in patients with a history of myocardial infarction or trast to prasugrel, which is only indicated in patients with acute coronary peripheral artery disease. Adverse Effects. Vorapaxar increases the risk of bleeding and is con- primary percutaneous coronary intervention for acute ST-segment eleva- 723 traindicated in patients with a history of intracranial bleeding, stroke, or tion myocardial infarction, although it also can be used in patients with transient ischemic attack. unstable angina. Drug Interactions. Potent CYP3A4 inducers, such as rifampin, reduce Adverse Effects. The major side effect is bleeding. Thrombocytopenia drug exposure, while strong CYP3A4 inhibitors, such as ketoconazole, occurs in 0.5% to 1% of patients and is less frequent than with abciximab. increase drug exposure. Antacids and pantoprazole reduce drug exposure. Tirofiban Glycoprotein IIb/IIIa Inhibitors Tirofiban is an intravenously administered nonpeptide, small-molecule inhibitor of αIIbβ3. It has a short duration of action and is used for man- Glycoprotein IIb/IIIa is a platelet-surface integrin, designated αIIbβ3 by the agement of patients with non–ST-segment elevation acute coronary syn- integrin nomenclature. This dimeric glycoprotein undergoes a conforma- drome. Tirofiban is administered as an intravenously bolus of 25 μg/kg tional transformation when platelets are activated to serve as a receptor followed by an infusion of 0.15 μg/kg/min for up to 18 h. The infusion for fibrinogen and von Willebrand factor, which anchor platelets to each dose is reduced by half in patients with a creatinine clearance below other, thereby mediating aggregation (Figure 36–1). Thus, inhibitors of 60 mL/min. Like the other agents in this class, the major side effect of this receptor are potent antiplatelet agents that act by a mechanism dis- tirofiban is bleeding, and it may induce thrombocytopenia. tinct from that of aspirin or P2Y12 or PAR-1 inhibitors. Three agents are approved for use at present; their features are highlighted in Table 36–4. The use of these agents has decreased with the availability of potent P2Y12 The Role of Vitamin K inhibitors such as prasugrel and ticagrelor. Green plants are a nutritional source of vitamin K for humans, in whom Abciximab vitamin K is an essential cofactor in the γ-carboxylation of multiple glu- SECTION III MODULATION OF PULMONARY, RENAL, AND CARDIOVASCULAR Abciximab is the Fab fragment of a humanized monoclonal antibody tamate residues of several clotting factors and anticoagulant proteins. The directed against the αIIbβ3 receptor. It also binds to the vitronectin recep- vitamin K–dependent formation of Gla residues permits the appropriate tor on platelets, vascular endothelial cells, and smooth muscle cells. interactions of clotting factors, Ca2+, and membrane phospholipids and The antibody is administered to patients undergoing percutaneous modulator proteins (see Figures 36–1, 36–2, and 36–3). Vitamin K antag- coronary intervention and, when used in conjunction with aspirin and onists (coumarin derivatives) block Gla formation and thereby inhibit heparin, has been shown to prevent recurrent myocardial infarction and clotting; excess vitamin K1 can reverse the effects. death. The t1/2 of the circulating antibody is about 30 min, but antibody Vitamin K activity is associated with at least two distinct natu- remains bound to the αIIbβ3 receptor and inhibits platelet aggregation as ral substances, designated as vitamin K1 and vitamin K2. Vitamin K1, measured in vitro for 18 to 24 h after infusion. It is given as a 0.25-mg/kg or phytonadione (also referred to as phylloquinone), is 2-methyl-3- bolus followed by an infusion of 0.125 μg/kg/min (maximum 10 μg/kg/min) phytyl-1,4-naphthoquinone; it is found in plants and is the only natural for 12 to 24 h. vitamin K available for therapeutic use. Vitamin K2 is a series of com- Adverse Effects. The major side effect of abciximab is bleeding, and pounds (the menaquinones) in which the phytyl side chain of phytonadi- the contraindications to its use are similar to those for the fibrino- one has been replaced by a side chain of 2 to 13 prenyl units. Synthesis of lytic agents listed in Table 36–4. The frequency of major hemorrhage menaquinones occurs in gram-positive bacteria, and the intestinal flora in clinical trials varies from 1% to 10%, depending on the intensity of synthesizes the large amounts of vitamin K contained in human and ani- concomitant anticoagulation with heparin. Thrombocytopenia with mal feces. Menadione (no longer available in the U.S.) is at least as active a platelet count below 50,000/μL occurs in about 2% of patients and on a molar basis as phytonadione. may be due to the formation of antibodies directed against neoepitopes induced by bound antibody. Because the duration of action is long, if major bleeding occurs, platelet transfusion may reverse the aggre- gation defect because free antibody concentrations fall rapidly after cessation of infusion. Abciximab re-administration may be associated with human anti-chimeric antibodies, increased incidence and severity of thrombocytopenia, and enhanced risk of hypersensitivity reactions. PHYTONADIONE (vitamin K1, phylloquinone) Abciximab is associated with pseudothrombocytopenia (laboratory arti- fact requiring blood draws be collected in three separate tubes [ethylene- diaminetetraacetic acid, citrate, and heparin]). Physiological Functions and Pharmacological Eptifibatide Actions Eptifibatide is a cyclic peptide inhibitor of the fibrinogen binding site on Phytonadione and menaquinones promote the biosynthesis of the fac- αIIbβ3. It is administered intravenously and blocks platelet aggregation. tors II (prothrombin), VII, IX, and X, as well as the anticoagulant pro- In patients undergoing percutaneous coronary intervention, eptifibat- teins C, S, and Z. ide is typically given as a double intravenous bolus of 180 μg/kg (spaced Figure 36–6 summarizes the coupling of the vitamin K cycle with glu- 10 min apart), followed by an infusion of 2 μg/kg/min for 18 to 24 h. The tamate carboxylation. The γ-glutamyl carboxylase and epoxide reductase drug is cleared by the kidneys and has a short plasma half-life of 10 to are integral membrane proteins of the endoplasmic reticulum and func- 15 min. Like abciximab, eptifibatide is mainly used in patients undergoing tion as a multicomponent complex. With respect to proteins affecting TABLE 36–4 FEATURES OF GPIIb/IIIa ANTAGONISTS FEATURE ABCIXIMAB EPTIFIBATIDE TIROFIBAN Description Fab fragment of humanized Cyclical KGD-containing Nonpeptidic RGD-mimetic mouse mAb heptapeptide Specific for GPIIb/IIIa No Yes Yes Plasma t1/2 Short (minutes) Long (2.5 h) Long (2.0 h) Platelet-bound t1/2 Long (days) Short (seconds) Short (seconds) https://ebooksmedicine.net/ Renal clearance No Yes Yes  724 blood coagulation, these reactions occur in the liver, but γ-carboxylation that responds readily to small doses of vitamin K and reestablishment of glutamate also occurs in lung, bone, and other cell types. Mutations in of normal bowel flora. Hypoprothrombinemia can occur in patients γ-glutamyl carboxylase can cause bleeding disorders. receiving prolonged intravenous alimentation; to prevent this, it is rec- ommended that such patients receive 1 mg of phytonadione per week Human Requirements (the equivalent of about 150 μg/day). In patients rendered vitamin K deficient by a starvation diet or antibiotic therapy for 3 to 4 weeks, the minimum daily requirement is estimated to Hypoprothrombinemia of the Newborn be 0.03 μg/kg of body weight and possibly as high as 1 μg/kg, which is Healthy newborn infants have decreased plasma concentrations of approximately the recommended daily intake for adults (70 μg). vitamin K–dependent clotting factors for a few days after birth, the time Symptoms of Deficiency required for adequate dietary intake of the vitamin and for establishment The major clinical manifestation of vitamin K deficiency is bleeding. of normal intestinal flora. Measurements of non-γ-carboxylated proth- Ecchymoses, epistaxis, hematuria, GI bleeding, and postoperative hem- rombin suggest that vitamin K deficiency occurs in about 3% of live orrhage are common; intracranial hemorrhage may occur. Hemoptysis births. is uncommon. The presence of vitamin K–dependent proteins in bone Hemorrhagic disease of the newborn has been associated with breast- such as osteocalcin and matrix Gla protein may explain why fetal bone feeding; human milk has low concentrations of vitamin K. In addition, abnormalities can occur with maternal warfarin administration in the the microbiome of breast-fed infants may lack microorganisms that first trimester of pregnancy. Vitamin K plays a role in adult skeletal main- synthesize the vitamin. Commercial infant formulas are supplemented tenance and the prevention of osteoporosis. Low concentrations of the with vitamin K. In the neonate with hemorrhagic disease of the newborn, vitamin are associated with decreased bone mineral density and subse- administration of vitamin K raises the concentration of these clotting fac- quent fractures; vitamin K supplementation increases the carboxylation tors to levels normal for newborns and controls the bleeding tendency CHAPTER 36 BLOOD COAGULATION AND ANTICOAGULANT, FIBRINOLYTIC, AND ANTIPLATELET DRUGS state of osteocalcin and improves bone mineral density, but the relation- within about 6 h. Routine administration of 1 mg phytonadione intra- ship between these effects is unclear. Bone mineral density in adults does muscularly at birth is required by law in the U.S. The dose may have to not appear to be changed with long-term warfarin therapy, but new bone be increased or repeated if the mother has received warfarin or anticon- formation may be affected. vulsant drug therapy or if the infant develops a bleeding diathesis. Alter- natively, some clinicians treat mothers who are receiving anticonvulsants Toxicity with oral vitamin K prior to delivery (20 mg/day for 2 weeks). Phytonadione and the menaquinones are nontoxic. Menadione and its derivatives (synthetic forms of vitamin K) may produce hemolytic ane- Inadequate Absorption mia and kernicterus in neonates and should not be used as therapeutic Vitamin K is poorly absorbed in the absence of bile. Thus, hypoproth- forms of vitamin K. rombinemia may be associated with intrahepatic or extrahepatic biliary ADME obstruction or with defective intestinal absorption of fat from other causes. The mechanism of intestinal absorption of compounds with vitamin K Biliary Obstruction or Fistula activity varies depending on their solubility. In the presence of bile salts, Bleeding that accompanies obstructive jaundice or a biliary fistula phytonadione and the menaquinones are adequately absorbed from the responds promptly to the administration of vitamin K. Oral phytona- intestine, phytonadione by an energy-dependent, saturable process in dione administered with bile salts is both safe and effective and should proximal portions of the small intestine and menaquinones by diffusion in be used in the care of the jaundiced patient, both preoperatively and the distal small intestine and the colon. After absorption, phytonadione is postoperatively. In the absence of significant hepatocellular disease, the incorporated into chylomicrons in close association with triglycerides and prothrombin level rapidly returns to normal. If oral administration is not lipoproteins. The low phytonadione levels in newborns may partly reflect feasible, a parenteral preparation should be used. The usual daily dose of the low plasma lipoprotein concentrations at birth and may lead to an vitamin K is 10 mg. underestimation of vitamin K tissue stores. After absorption, phytonadi- one and menaquinones are concentrated in the liver, but the concentration Malabsorption Syndromes of phytonadione declines rapidly. Menaquinones, produced in the distal Among the disorders that result in inadequate absorption of vitamin K bowel, are less biologically active because of their long side chain. Very from the intestinal tract are cystic fibrosis, celiac disease, Crohn’s disease, little vitamin K accumulates in other tissues. There is only modest storage ulcerative colitis, dysentery, and extensive resection of bowel. Because of vitamin K in the body. Consequently, when lack of bile interferes with drugs that reduce the bacterial population of the bowel are used fre- absorption of vitamin K, there is progressive reduction in the levels of the quently in many of these disorders, the availability of the vitamin may be vitamin K–dependent clotting factors over the course of several weeks. further reduced. For immediate correction of the deficiency, parenteral vitamin K should be given. Therapeutic Uses Vitamin K is used therapeutically to correct the bleeding tendency or Inadequate Utilization hemorrhage associated with its deficiency. Vitamin K deficiency can Hepatocellular disease or long-standing biliary obstruction may be result from inadequate intake, absorption, or utilization of the vitamin or accompanied or followed by hypoprothrombinemia. If inadequate secre- as a consequence of the action of warfarin. tion of bile salts is contributing to the syndrome, some benefit may be Phytonadione is available in tablet form and in a dispersion with buff- obtained from the parenteral administration of 10 mg of phytonadione ered polysorbate and propylene glycol or polyoxyethylated fatty acid daily. Paradoxically, administration of large doses of vitamin K or its ana- derivatives and dextrose. Phytonadione may be given by any route; how- logues in an attempt to correct the hypoprothrombinemia can be associ- ever, the subcutaneous route should be avoided in patients with a coagu- ated with severe hepatitis or cirrhosis, which may contribute to a further lopathy because of the risk of bleeding. The oral route is preferred, but if reduction in the level of prothrombin. more rapid reversal is required, phytonadione can be given by slow intra- venous infusion; it should not be given rapidly because severe reactions Drug- and Venom-Induced Hypoprothrombinemia resembling anaphylaxis can occur. Warfarin and its congeners act as competitive antagonists of vitamin K and interfere with the hepatic biosynthesis of Gla-containing clotting Inadequate Intake factors. The treatment of bleeding caused by oral anticoagulants was After infancy, hypoprothrombinemia due to dietary deficiency of described previously. Vitamin K may be of help in combating the vitamin K is extremely rare. The vitamin is present in many foods bleeding and hypoprothrombinemia that follow the bite of the tropical and is synthesized by intestinal bacteria. Occasionally, the use of a American pit viper or other species whose venom degrades or inacti- broad-spectrum antibiotic may itself produce hypoprothrombinemia vates prothrombin.  725 Drug Facts for Your Personal Formulary: Agents That Modify Blood Coagulation Drugs Therapeutic Uses Clinical Pharmacology and Tips Unfractionated Heparin Heparin Prophylaxis/treatment of venous thromboembolism Administered SC 2–3 times daily for thromboprophylaxis Acute coronary syndrome Administered IV for immediate onset of action with aPTT monitoring Percutaneous coronary intervention Can be used in renal impairment Cardiopulmonary bypass surgery Can be used in pregnancy Disseminated intravascular coagulation Low-Molecular-Weight Heparin Enoxaparin Prophylaxis against venous thromboembolism Administered SC once or twice daily Dalteparin Initial treatment of venous thromboembolism Routine anti–factor Xa monitoring not required Tinzaparin (not in the U.S.) Maintenance treatment in patients with cancer- Dosage adjustment required when CrCL