Procoagulant, Anticoagulant, and Thrombolytic Drugs

26 Procoagulant, Anticoagulant, and Thrombolytic Drugs Barton S. Johnson

K E Y I N F O R M AT I O N Overview • The three aspects of the coagulation cascade are: • Vascular constriction • Platelet adhesion/aggregation/activation • Fibrin formation • Clot remodeling is via plasmin. • Clot control is designed to prevent extension beyond the site of injury. Procoagulant drugs • Medications that can be used to improve hemostasis include: • Systemic antihemophilic factors • Astringents/styptics • Vasoconstrictors • Topically applied agents • Intrasocket preparations Fibrin-modulating drugs • Antifibrinolytic agents such as tranexamic acid and aminocaproic acid slow clot degradation.

• Fibrinolytic agents such as tPA degrade clots rapidly in settings such as stroke and myocardial infarction. Anticoagulant drugs • Major antiplatelet agents are: • Aspirin • Ibuprofen and related drugs • Thienopyridines (Clopidogrel and related drugs) • GP IIb/IIIa inhibitors • The indirect thrombin inhibitors are warfarin and warfarin-like drugs. • The direct thrombin inhibitors are drugs such as dabigatran. • The factor Xa inhibitors belong to the xaban family. • Heparin drugs are classified as: • Low-molecular-weight heparins • Unfractionated heparin

 

CASE STUDY Mr. J is a 72-year-old gentleman who presents for care, stating that he wants his remaining teeth removed and replaced with implant-supported removable dentures. Your examination shows that he has 24 remaining teeth, all of which are very carious and effectively non-salvageable. He has a cardiac history that includes a two-vessel coronary artery bypass graft 15 years ago and a balloon angioplasty 2 years ago. He used to take warfarin on a daily basis, but he has recently been switched to dabigatran. He also takes a baby aspirin every day. It is within your skill set to remove the teeth and do the eventual implants, but what considerations should you take with the anticoagulant drugs in preparation for the surgery? Should an intraoperative bleed occur, what options do you have?

INTRODUCTION The practice of dentistry frequently involves procedures that cause bleeding, and the dentist is often confronted with the need to achieve and maintain hemostasis. The dental practitioner must be familiar with the physiologic processes of hemostasis and the myriad conditions that cause abnormalities of these processes. Complicating matters, modern medicine has developed several therapies for systemic disease that use medications that purposefully alter normal hemostasis. When appropriate, the dentist needs to make alterations in the dosage or scheduling of these compounds before surgery. Only with a clear

understanding of the complex process of hemostasis and the various drugs that affect it can the clinician manage patients with inherited or acquired bleeding disabilities safely.

HEMOSTASIS PHYSIOLOGY REVIEW To understand how the various procoagulant/anticoagulant pharmaceutical drugs interact with the clotting system, it is critical that the dentist have a basic understanding of the physiology of hemostasis. Our surgical approaches constantly cause vascular injury, whether by needle, scalpel, forcep, or bur. Unlike the trauma setting, in the dental surgical setting, large or intermediate arteries and veins are generally not severed intentionally without prior ligation, but it is common during the extraction of teeth and other oral surgical procedures to sever small arteriolar, venous, and capillary vessels. Extensive blood loss may occur if hemostasis is delayed. The immediate formation of a patent clot requires four distinct yet interdependent steps: (1) vessel constriction; (2) platelet adhesion, activation, and aggregation; (3) cross-linking of fibrin by the coagulation cascade; and (4) limitation of the blood clot to the area of damage only. Later, a fifth step becomes necessary: the controlled breakdown of the clot so that repair and remodeling can occur.

Vascular Constriction Transection of small arteries and arterioles generally shows a rapid moderate–severe reduction in flow, apparently caused by contraction

371

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CHAPTER 26  Procoagulant, Anticoagulant, and Thrombolytic Drugs

of vascular smooth muscle initiated directly by the trauma. This initial hemostasis is independent of blood coagulation and platelet agglutination, and it is maintained only for a short period (5 to 20 minutes). Physiologically, the uninjured vessel wall is lined with endothelial cells that constitutively secrete nitric oxide and prostacyclin, both of which are potent smooth muscle relaxing agents. Nitric oxide and prostacyclin diffuse to the nearby vascular smooth muscle, effect relaxation, and maintain luminal patency. On injury, this secretion is disrupted, and the now unopposed muscle layer reflexively and rapidly constricts, greatly narrowing the lumen. After a few minutes the constriction wanes, and the muscle layers begin to relax again. This brief period of constriction provides a healthy individual sufficient time for the platelets and coagulation cascade to seal the injured site.

Platelet Adhesion, Activation, and Aggregation Adhesion

The next major event is the adhesion of platelets at the severed edges of the vessel. In normal un-traumatized blood vessels, platelets show little tendency to adhere to the endothelium, partly because prostacyclin, again elaborated by the endothelial cells, induces cyclic adenosine 3′,5′-monophosphate (cAMP) synthesis in platelets and inhibits platelet adhesion. Endothelium-derived relaxing factor (nitric oxide), also normally secreted by the endothelial cells, is another natural inhibitor of platelet adhesion. Injury to the endothelium, even if the vessel wall remains intact, however, leads to exposure of subendothelial extracellular matrix proteins such as collagen, fibronectin, von Willebrand factor (vWF), thrombospondin, and laminin.

The presence of these proteins, particularly vWF, stimulates a “catch and grab” response in the platelets, causing them to leave the laminar flow of the blood and adhere to the injured area. Platelets have a high density of surface receptors that respond to these proteins, and they undergo an extremely rapid localization to the site of injury, beginning the formation of a thrombus. Two main receptors are involved in adhesion: the glycoprotein (GP) Ia/IIa heterodimer, which binds to collagen directly but weakly, and the GP Ib/IX/V heterotrimer, which binds with high shear strength to connective tissue vWF associated with the collagen surface (Fig. 26-1). The GP Ib/IX/V–vWF linkage is more of a “tethering” of the platelet to the substrate; later, the adhesion is firmed up by GP IIb/IIIa activation. If vessels without a muscular sheath are severed, the immediate hemostatic action of platelet aggregation is especially important. The true significance of platelets in hemostasis is most evident in the management of patients with thrombocytopenia.

Activation Activation of platelets is a crucial step in forming a proper thrombus. Activation can occur from various agonists, some of which are strong and others that are weak. Examples include thrombin, adenosine diphosphate (ADP), thromboxane A2 (TXA2), 5-hydroxytryptamine (serotonin), epinephrine, vasopressin, fibrinogen, immune complexes, plasmin, and platelet-activating factor. Most plasma-derived agonists exert their effect by numerous G protein–linked membrane receptors. The strongest agonist for platelet activation is binding of vWF to the GP Ib/IX/V heterotrimeric receptors. When one of these receptors is bound by its specific agonist, an intraplatelet protein cascade begins

Platelet Aggregation vWF

Fibrinogen→Fibrin

GP IIb/IIIa GP IIb/IIIa

Collagen

Platelet GP Ia/IIa

GP Ib/IX/V Platelet Adhesion vWF

FIG 26-1  Platelet adhesion and aggregation. Exposed collagen at the site of injury stimulates initial weak platelet adhesion by the glycoprotein (GP) Ia/IIa receptors. Stronger adhesion follows by the GP Ib/IX/V/vWF complex. Platelet activation is triggered, which leads to initial aggregation by the GP IIb/IIIa receptors binding the GP Ib/IX/V complex. This low-shear bond is later supplanted by a pair of GP IIb/IIIa receptors interacting with fibrinogen to create high-strength mature fibrin “ropes” interconnecting the two, then cross-linking to others. vWF, von Willebrand factor.

CHAPTER 26  Procoagulant, Anticoagulant, and Thrombolytic Drugs that ultimately causes activation of Ca2+ transporters and movement of Ca2+ from stores in the platelet’s dense tubular system to the general intracellular matrix. The intracellular increase in Ca2+ begins several other changes. Platelets in the resting state have internal cytoskeletal actin that provides them with a smooth shape; as Ca2+ increases, the actin is fragmented into smaller subunits, transforming the normal discoid shape of the platelet to a spherical conformation. These smaller actin subunits are then rapidly reassembled into very-long-chain actin monomers, which cause the platelet to sprout filopods. The filopods are important in ultimate clot retraction. Meanwhile, as the filopods are developing, the increasing intracellular Ca2+ concentrations act on cytoplasmic vesicles known as α and dense (or δ) granules (Fig. 26-2), prompting them to rise to the cell surface and degranulate. The dense granules release ADP, adenosine triphosphate (ATP), the vasoconstrictor 5-hydroxytryptamine, Ca2+, and inorganic pyrophosphate. The α granules contain numerous proteins involved in coagulation, adhesion, cellular mitogenicity, protease inhibition, and other functions (Box 26-1). Major proteins released include fibrinogen, coagulation factors, vWF, fibronectin, high-molecular-weight kininogen, plasminogen, plasminogen activator inhibitor-1 (PAI-1), platelet-derived growth factor, additional GP IIb/IIIa, and thrombospondin.

Release of the dense granule ADP into the extracellular milieu has an autocatalytic effect on the platelet from which it came while also stimulating nearby platelets. The ADP binds to its own purinergic receptors, most notably P2Y1 and P2Y12. Activation of both of these receptors is required for maximal aggregation of the platelets to one another. P2Y1 stimulation acts to mobilize Ca2+ further (an autocatalytic effect), which leads to further shape change and transient aggregation. P2Y12 activation causes inhibition of adenylyl cyclase (blocking conversion of ATP to cAMP), potentiation of secretion by the α and dense granules, and sustained aggregation. ADP also binds the transmembrane protein P2X1, an ion channel receptor linked to influx of extracellular Ca2+ into the platelet.

Aggregation As the activated platelets interact with one another, they begin to aggregate. Aggregation is initiated by the Ca2+-mediated conformational activation of GP IIb/IIIa, a heterodimeric transmembrane protein. GP IIb/IIIa is a protein receptor complex unique to platelets and is expressed at extraordinarily high density on the surface of the platelets—some 80,000 to 100,000 per platelet—at an average distance of only 20 nm from one another. Another 20,000 to 40,000 proteins are stored in the α granules and are released onto the surface or within

ATP 5-HT Ca2+ PPi Active GP IIb/IIIa

ADP

Ca2+

P2Y12

P2Y1 Ca2+

Dense Granule

Actin De-assembly/ Re-assembly Ca2+

Fibrinogen PAI-1 vWF PDGF Fibronectin GP IIb/IIIa HMWK Others Plasminogen

2+

Ca2+ Ca2+ Ca Ca2+ Ca2+ Ca2+

Filopod formation Adhesion via GP Ia/IIa and GP Ib/XI/v

373

Ca2+

Alpha Granule

PGH2 PGG2 TS

COX AA

TxA2

FIG 26-2  Platelet activation. Lower left, moving clockwise: contact with the compromised vessel wall by platelet membrane GPs Ia/IIa and Ib/XI/V, stabilized by von Willebrand factor (vWF), causes the platelets to become activated and begin moving Ca2+ out of their tubular stores. The increased intracellular Ca2+ causes actin to break down and reassemble in long chains, resulting in filopod formation. The increase in Ca2+ causes conversion of the GP IIb/IIIa from its inactive form to the active form. The dense granules move to the surface and release many activating substances, one of which is adenosine diphosphate (ADP). ADP stimulates purinergic receptors P2Y1 and P2Y12, both of which accelerate the activation process. The increase in Ca2+ also causes a degranulation, resulting in the release of many substances important for further aggregation. Finally, platelet membrane phospholipids yield arachidonic acid (AA), which is converted by cyclooxygenase (COX) to prostaglandins G2 (PGG2) and H2 (PGH2). Thromboxane synthase (TS) converts these to thromboxane A2 (TXA2), which, acting on a G protein–linked receptor, is a potent catalyst of platelet aggregation by accelerating further release of stored platelet Ca2+. 5-HT, 5-hydroxytryptamine; HMWK, high-molecular-weight kininogen; PAI-1, plasminogen activator inhibitor-1; PDGF, platelet-derived growth factor; PPi, pyrophosphate.

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CHAPTER 26  Procoagulant, Anticoagulant, and Thrombolytic Drugs

BOX 26-1  Contents of Platelet α Granules α2-Antiplasmin α2-Macroglobulin Albumin β-Thromboglobulin CD63 C1-inhibitor Endothelial cell growth factor Epidermal growth factor Factors V, XI, XIII Fibrinogen Fibronectin GMP 33 High-molecular-weight kininogen IgA, IgG, IgM Interleukin-1B Multimerin P-selectin Plasminogen activator inhibitor 1 Platelet factor Platelet-derived growth factor Protein S Thrombospondin Tissue factor pathway inhibitor Transforming growth factor-β Vascular endothelial growth factor Vitronectin von Willebrand factor

the local plasma milieu during degranulation. In the circulating platelet, the resting GP IIb/IIIa receptor has little affinity for its ligands (primarily fibrinogen), so intravascular thrombus formation is minimized. Upon activation, this GP undergoes a conformational change that imparts new high affinity for its ligands. Several proteins have the specific amino acid sequence necessary for binding to the GP IIb/IIIa receptor, including fibrinogen, fibronectin, vitronectin, and vWF. As the α and dense granule contents are released extracellularly, nearby platelets become activated. The ligand proteins bind to the surface-associated GP IIb/IIIa of these adjacent platelets, forming bridges. At low shear rates, fibronectin and fibrinogen (stabilized by thrombospondin) serve as the main adhesive proteins, whereas vWF is necessary for proper adhesion in areas of high shear. Microvascular video imaging studies show that thrombus formation initially is inefficient. Platelets bind quickly, but a significant percentage of them break free and float away. As a result, thrombus formation is much slower than would be the case if all the platelets that physically aggregate remained bound. Several other events occur simultaneously with activation and aggregation, but the two most important are generation of TXA2 and platelet-assisted generation of thrombin. Both of these agents accelerate the platelet-activation response. TXA2 is generated when platelet phospholipases are activated during platelet aggregation, which release arachidonic acid from glycerophospholipids of the platelet membrane. Arachidonic acid is a substrate for cyclooxygenase (COX), yielding the prostaglandin endoperoxides PGH2 and PGG2. These prostaglandins are modified by thromboxane synthase to produce TXA2, which acts at its own protein-linked receptor. Perhaps the most remarkable effect of platelet activation is the procoagulant activity the platelets impart. In the normally resting platelet, the plasma membrane has negatively charged phospholipids, including phosphatidylserine, sequestered almost exclusively on the inner

surface by processes that are not fully understood. When activating ligands bind to the platelet, the resultant increase in intracellular Ca2+ causes a membrane enzyme termed scramblase to evert the phosphatidylserine to the outer surface, while simultaneously prompting the membrane to form small evaginated microvesicles. Factors Va and VIIIa (discussed subsequently) bind to the phosphatidylserine moieties and recruit factors Xa and IXa. The interaction of these complexes accelerates the conversion of prothrombin to thrombin by a factor of 2.4 × 106. In addition, the binding of activated coagulation factors to the platelets seems to protect the factors from plasma inhibitors, while directing the bulk of the coagulation cascade to the site of injury. The α granules contain factors V and IX; factor V is apparently complexed with multimerin, a carrier protein. As the thrombin is generated, it activates other platelets by stimulating G protein–linked receptors. The thrombin receptors seem to be unique “suicide” receptors, requiring proteolytic cleavage to transmit an activating signal. Thrombin is a serine protease, and it acts on the receptors by cleaving the protein at a serine residue near the amino terminus. The new amino terminus acts as a “tethered ligand” to double back and stimulate the transmembrane protein to activate—hence this receptor has been named a protease-activated receptor (PAR). There are four such thrombin receptors, PAR-1 through PAR-4; only PAR-1 and PAR-4 are expressed by human platelets. Thrombin-induced activation seems to upregulate GP IIb/IIIa activation while downregulating GP Ib/IX/V activity. The platelets effectively are converted from an adhesive role to an aggregate role when thrombin is present. Two other important activities of platelets warrant mention. First, the α granules contain P-selectin, a membrane protein that helps recruit and tether neutrophils and monocytes into the local area. This activity is believed to be crucial for generating a local inflammatory response at the site of injury, while promoting yet limiting thrombosis. Second, platelets are also essential in clot retraction, an event that facilitates wound healing by bringing the severed ends of small blood vessels into closer apposition. Clot retraction, or syneresis, occurs when the filopodia expressed by platelets during activation attach to fibrin strands and contract. A number of actin-binding proteins are present in platelets. On activation, phosphorylated myosin monomers polymerize into filaments next to the long-chain actin filaments, which slide past one another to generate a contractile force in the presence of ATP.

Coagulation Cascade Although it is possible to separate the numerous events of hemostasis (e.g., platelet aggregation, formation of fibrin, retraction of the blood clot), the whole process occurs synergistically. Many of the factors involved are enzymatic cofactors, and most of the reaction occurs on cell and platelet membranes (Fig. 26-3). Many refinements in the understanding of blood coagulation have come about through study of “experiments of nature,” in which discrete defects of the clotting process have been identified in patients with bleeding diatheses, as illustrated by the factors and deficiency states listed in Table 26-1. Initiation of coagulation after injury is a complex process involving an initial pathway of thrombin generation, which autocatalyzes a subsequent burst of additional thrombin generation sufficient to convert fibrinogen to fibrin (see Fig. 26-3). Before the process is described, a brief review of the crucial factors and cofactors and how they function is warranted.

Vitamin K–dependent clotting factors Synthesized in the liver, the vitamin K–dependent clotting factors comprise factors II (prothrombin), VII, IX, and X, and protein C. These five proteins are serine proteases and have similar structural elements. Molecular genetic evidence suggests they all are derived from

CHAPTER 26  Procoagulant, Anticoagulant, and Thrombolytic Drugs

375

Platelet Activation Degranulation

Alpha granule

PAR IXa

Fibrinogen Fibrin

Evagination

X

GP IIb/IIIa

VIIIa

Cross-link via XIII

V IIa

VIII

GP IIb/IIIa

II IIa

VII

II

vWF

XIa Xa

Va

IX

VIIa

IIa or XIIa

Platelet

V

XI

VIIa TF

TF

Extravascular cell FIG 26-3  Blood coagulation cascade. Tissue factor (TF) (factor III) on cell membranes of exposed subendothelial matrix cells combines with circulating factor VIIa (activated by Ca2+) to form an activating complex for factor X and factor IX. Factor Xa, locally bound to the membrane by factor Va, converts prothrombin (factor II) to thrombin (factor IIa). Meanwhile, converted factor IXa diffuses to adjacent platelets, where it is bound to the platelet membrane by factor VIIIa. The complex acts to accelerate factor Xa conversion, leading to additional factor Va binding and ultimately vastly increased thrombin formation. Fibrin, after it is formed from fibrinogen by the proteolytic action of thrombin, is cross-linked and stabilized by factor XIIIa. Thrombin, a serine protease, accelerates the entire cascade by catalyzing cleavage of factor XI to factor XIa, stimulating platelets to activate by the transmembrane protease-activated receptor (PAR), and it stimulates conversion of factor XIII to factor XIIIa (not shown). GP, Glycoprotein; vWF, von Willebrand factor.

a common ancestral precursor gene. They all have a preprotein leader that is cleaved away posttranslationally, leaving an amino-terminal γ-carboxyglutamic acid (Gla) domain with 9 to 12 Gla residues. The amino terminus Gla domain is crucial for the protein to settle into the lipid membrane and exert its effects locally rather than systemically. To function, the Gla residues must be carboxylated, which requires oxygen, carbon dioxide, and vitamin K (see Fig. 26-7). For every glutamate residue carboxylated, one molecule of reduced vitamin K is converted to its epoxide form. A separate enzyme, vitamin K epoxide reductase, converts the vitamin K back to the reduced form. This reductase is the target of the warfarin-like anticoagulants and is discussed in greater detail later. Each of the clotting factors mentioned is a protease that dimerizes with its specific cofactor to allosterically bring out its activity. Tissue factor (TF) dimerizes with VIIa (a for activated), VIIIa with IXa, and Va with Xa.

Enzymatic cofactors TF is a protein normally constitutively expressed on the cell surfaces of many extravascular cell types. In contrast to the other coagulation cofactors, it is a transmembrane protein homologous to the receptors for interleukin-10 and interferons α, β, and γ. It seems to have procoagulant and signal transduction functions. When injury occurs and the vasculature gains exposure to cells with TF on their surface, circulating factor VII rapidly binds to TF and undergoes proteolytic cleavage to factor VIIa. The TF/VIIa complex serves two crucial functions: it cleaves factor X to Xa and factor IX to IXa.

Newly formed factor Xa rapidly binds to circulating factor V and activates it to Va. The factor Xa/Va dimer settles into the adjacent cellular membrane (via the hydrophobic Gla domain), where it cleaves circulating prothrombin to generate a very small amount of thrombin. This tiny amount of thrombin is insufficient to cleave fibrinogen significantly but, instead, serves four crucial functions that set up the area for a much larger burst of thrombin formation: (1) nearby platelets are activated by their PAR receptors, which causes degranulation; (2) additional factor V is liberated from the platelet α granules and activated; (3) factor VIII is activated and dissociated from vWF; and (4) factor XI is activated. Factor Xa inhibitors are the newest form of anticoagulant medications. In contrast to the factor Xa/Va complex, activation of factor IXa by TF/VIIa results in an enzyme that is not restricted to the nearby cell surface. As a result, factor IXa diffuses among nearby activated platelets that have placed factors Va and VIIIa on their cell surfaces. The diffusing factor IXa binds tightly to the factor VIIIa cofactor, and this IXa/ VIIIa complex efficiently activates additional factor X to Xa. As before, factor Xa then binds to adjacent factor Va, and this time a much larger burst of prothrombin converts to thrombin. This burst is sufficient to begin cleaving fibrinogen and start clot formation.

Fibrinogen and factor XIII The final phase of blood clotting consists of the thrombinmediated proteolytic cleavage of fibrinogen to fibrin. Fibrinogen consists of a mirror-image dimer in which each monomer is composed of three intertwined and disulfide bond–linked polypeptide chains.

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CHAPTER 26  Procoagulant, Anticoagulant, and Thrombolytic Drugs

TABLE 26-1  Blood Clotting Factors Cause or Description of Deficiency

Factor*

Alternative Names

I II

Fibrinogen Prothrombin

III IV V VI VII

TF, thromboplastin Ca2+ Never deficient without tetany Proaccelerin Parahemophilia, rare (Abandoned; see note below) Proconvertin Liver disease or vitamin K deficiency Antihemophilic factor A Hemophilia A, 80% of hemophiliacs Christmas factor, AHF B Hemophilia B (Christmas disease), depressed with vitamin K deficiency Stuart-Prower factor Liver disease or vitamin K deficiency Plasma thromboplastin Factor XI hemophilia antecedent, AHF C (hemophilia C) Hageman factor Generally no clinical symptoms but may have thromboses, rare Fibrin-stabilizing factor, Delayed bleeding, defective Laki-Lorand factor, fibrinase healing, rare Platelet factor 3 Thrombocytopenia Protein C Liver disease or vitamin K deficiency Protein S Liver disease or vitamin K deficiency von Willebrand factor vWD types I, IIa, IIb, IIc, III Prekallikrein, Fletcher factor High-molecular-weight kininogen

VIII IX

X XI XII XIII PF3 ~ ~ vWF Pre-K HMWK

Liver disease Liver disease or vitamin K deficiency

AHF, Antihemophilic factor; TF, tissue factor. *Roman numerals were assigned in 1958 by the International Committee on Blood Clotting Factors. Factor VI, originally assigned to prothrombin converting principle (prothrombinase) has since been abandoned.

In the dimer, the amino terminus of all six polypeptides meet in the middle of the linear molecule to form the N-terminal disulfide knot, or E domain. The carboxy termini of the three polypeptides at each opposite end form a globular protein cluster known as the D domain. Between the E and D domains, the polypeptide chains form a helical structure (Fig. 26-4). Thrombin binds to the central E domain and cleaves off peptides from the knot to expose binding sites in the E domain that match the corresponding D domains of two neighboring fibrinogen molecules. The monomers begin to form a staggered “ladder” protofibril. As the monomers continue to associate, branch points occur that allow the fibrin meshwork to become more like a net and thicken. The initial clot is unstable, being held together primarily by hydrogen bonds. With time, however, the fibrin strands stabilize by becoming covalently bonded by factor XIII. This factor cross-links proteins between the γ-carbon of glutamine in one fibrin strand and the ε-amino group of lysine in the other. Entrapped in this coagulum “net” are red and white blood cells and intact platelets; the latter promote clot retraction as previously described. These events are followed by the inflammatory processes of organization and wound healing, which require, among other things,

an effective proteolytic (fibrinolytic) mechanism described later in this chapter.

Other coagulation cascade proteins It has long been known that patients with factor XI deficiency do not have severe bleeding profiles. Activated by thrombin, factor XIa cleaves factor IX to IXa. It is thought that this factor boosts the levels of factor IXa, but it is not crucial to its function. Factor XII, prekallikrein, and high-molecular-weight kininogen all have been implicated in the activation of platelets when exposed to a negatively charged surface such as glass or kaolin. It is believed that these proteins work together to yield factor XIIa, which activates factor XI to XIa and ultimately factor IX to IXa. This method of “surface activation” is used to initiate the activated partial thromboplastin time (aPTT) test to determine how well the factor IXa system is functioning.

Regulation of Coagulation When discussing hemostatic mechanisms, consideration should be given to the natural inhibitors of blood clotting. As important as the procoagulant process is, it is equally important to ensure that inappropriate clotting does not occur. The intent of the clotting system is to seal a site of vascular compromise; powerful antithrombotic mechanisms must come into play to ensure that clotting remains limited to the injured area. Several mechanisms of antithrombosis have been elucidated; they are discussed in detail subsequently and summarized in Figure 26-5. Strict control of the extremely efficient coagulation cascade is mediated by several proteins that act as natural anticoagulants, all of which rely on the first traces of thrombin from the nearby wound site to activate them. In general, the theory is simple: bind or degrade any activated procoagulant proteins if they escape the site of injury. At the same time, the site of injury must be protected from invasion or inclusion of these same inhibitory proteins. Because thrombin is the major procoagulant protein, it makes sense that inactivation of it is a high priority. An elegant mechanism exists that, instead of destroying thrombin, uses thrombin to catalyze an important set of anticoagulant proteins, the protein C/protein S system. In the microcirculation, where there is a high cell surface-to-volume ratio, the protein C/protein S system predominates. Vascular endothelial cells normally express thrombomodulin on their membranes. Thrombomodulin is a transmembrane cofactor protein with no known enzymatic activity. It binds the thrombin that escapes from the surface of nearby platelets but is not carried off in the vascular flow. Thrombomodulin, as the name implies, alters the conformation of the thrombin and effectively removes its ability to cleave fibrinogen, activate platelets, and activate factors V and VIII. Instead, the new conformation of thrombin imparts a two-thousandfold greater affinity for activation of the vitamin K–dependent protein C. Activated protein C (aPC) has considerable homologous characteristics with the other vitamin K–dependent factors, complete with a Gla domain, hydrophobic domain, and active serine protease domain. The cofactor for aPC is protein S, a membrane-bound protein that has no inherent activity. When aPC is bound, the complex efficiently cleaves and destroys any factors Va and VIIIa that might have been liberated from the platelet surfaces. Another protein, antithrombin III (ATIII), is a serine protease inhibitor (“serpin”) found in the plasma. It inhibits clotting by covalently binding to the active sites of thrombin and certain other serine proteases (factors IXa, Xa, and XIIa). This reaction is normally slow but is accelerated one-thousandfold in the presence of heparan sulfate, a proteoglycan synthesized on the surfaces by endothelial cells. (A similar effect is achieved therapeutically by administration of the closely related pharmaceutical agent heparin sulfate.) Although ATIII binds

CHAPTER 26  Procoagulant, Anticoagulant, and Thrombolytic Drugs

377

Fibrin Monomer Streptokinase + Plasminogen

FDPs

K

Plasminogen

K

K

K

D-dimer

K

VIII

Plasmin

K

K

K

K

K

Activated Plasmin

V

Plasminogen

Inhibitors: α2-AP vs. Plasmin PAI-1 vs. t-PA PAI-2 vs. u-PA

K

K

K

t-PA

K

Cross-linked Fibrin Polymer

u-PA

t-PA

O

H2N Lysine

NH3

H2N OH

GP IIb/IIIa

O OH

Aminocaproic acid

FIG 26-4  Fibrinolysis. Thrombin formation causes adjacent endothelial cells to release tissue plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA). t-PA adheres to lysine residues on the fibrin molecules and adsorbs plasminogen onto it, also by lysine binding. The proteolytic action of t-PA converts the plasminogen to plasmin at the wound site, whereas u-PA converts it in the free circulation. Plasmin acts to degrade factors V and VIII and proteolytically cleave the fibrin. Various fibrin degradation products (FDPs) are liberated, including the D-dimer formed from two fibrin molecule “ends” linked to one fibrin molecule “middle.” Aminocaproic acid interferes with plasminogen conversion by occupying lysine-binding sites on t-PA and plasminogen, resulting in antifibrinolysis. The endothelial cells also release several inhibitors: plasminogen activator inhibitor-1 (PAI-1), which destroys any free circulating t-PA, and plasminogen activator inhibitor-2 (PAI-2), which inhibits u-PA. Both serve to limit the plasminogen activation primarily to the clot site. Another protein, circulating α2-antiplasmin (α2-AP), neutralizes any free plasmin in the bloodstream, also restricting activity of plasmin to the wound site. Exogenous t-PA functions similarly to endogenous t-PA. Streptokinase combines with plasminogen to create a complex that cleaves other plasminogen molecules to free circulating plasmin. As a result, systemic fibrinolysis is more common with this medication. Not shown is streptokinase formulated with exogenous acylated plasminogen, which spontaneously deacylates on mixing with the plasma to form the same streptokinase–plasminogen complex. GP, Glycoprotein.

to these factors without destroying them, reactivation by unbinding probably does not occur physiologically. The ATIII-protease complexes are cleared in the liver. It is believed that ATIII is responsible for complexing with proteases that escape into the circulation. Finally, tissue factor pathway inhibitor (TFPI) (see Fig. 26-5) is a protease inhibitor found in low concentrations in the plasma, mostly bound to circulating lipoproteins or to endothelial cell membrane heparans. It is capable of inactivating factor Xa and the TF/VIIa complex; it must first bind factor Xa before it can bind to the TF/VIIa complex. TFPI seems to be the major inhibitor of free-floating factor Xa, and it may be responsible for shifting the activation of factor IX from the TF/

VIIa complex to thrombin-activated factor XI. The inhibitor is found in high concentrations in patients with hemophilia A and B, presumably because fewer substrates are available for TFPI binding. This finding offers one explanation for why hemophiliacs bleed despite normal concentrations of TF, factor VIIa, and factor Xa at the site of injury. TFPI is synthesized in liver and endothelial cells.

PROCOAGULANT AGENTS In medical and dental practice, it is essential to take appropriate precautions to avoid serious hemorrhage. This admonition is particularly

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CHAPTER 26  Procoagulant, Anticoagulant, and Thrombolytic Drugs

Heparan/ Heparin

IIa

Hepatic Clearance

IXa

Activated TFPI:Xa

TFPI

Xa

XIIa

Antithrombin III (ATIII)

VIIIa Protein C

Xa

Va

Quaternary Complex

IIa Xa

VIIa

Modified IIa TF

aPC

Protein S

Thrombomodulin Clotting Factors That Escape Site of Injury

FIG 26-5  The clotting inhibition system: examples of proteins that help limit fibrin formation to the site of the vascular injury by inactivating clotting factors. Antithrombin III (ATIII) undergoes conformational change in the presence of heparin/heparan, which allows it to bind and sequester factors IIa (thrombin), IXa, Xa, and XIIa. It is later cleared in the liver. When trace amounts of thrombin bind to thrombomodulin on intact endothelial cell membranes, the thrombin-thrombomodulin dimer undergoes a conformational change that allows it to activate protein C, which is bound to the membrane by protein S to form a protease complex specific for factors Va and VIIIa. Loss of these two factors disrupts the coagulation cascade sufficiently to prevent disseminated intravascular coagulation. A final inhibitor, tissue factor pathway inhibitor (TFPI), is first activated by factor Xa and then binds to the tissue factor (TF)/VIIa complex to interrupt conversion of additional factor X. aPC, Activated protein C.

true for patients with hemophilia, patients with hematopoietic disease, and patients receiving therapies known to affect hemostasis. Precautions, which may include the administration of clotting factors or hospitalization or both, are prudent in these cases. In contrast, normal patients usually require no more than temporary hemostatic assistance (e.g., pressure packs, hemostatic forceps, ligation, or other locally active measures) to facilitate normal hemostasis and allow clotting to occur.

Local Measures A perplexing hemostatic problem may arise from continued, slow oozing of blood from small arterioles, veins, and capillaries. These vessels cannot be ligated, and measures such as pressure packs and intrasocket preparations, vasoconstrictor agents, and procoagulants must be used. Styptics or astringents, extensively used in the past, are no longer viewed as rational procedures for routine hemostasis in most applications; however, some astringents are commonly used during gingival retraction to aid in controlling the tissue for impressions.

Bleeding caused by dentoalveolar surgery is most often controlled by applying direct pressure with sterile cotton gauze. If this treatment is inadequate, the clinician must localize the source of bleeding as originating either within the soft tissues or within the bony structures. Soft tissue bleeding may be controlled by hemostats, ligation, electrocautery, or application of microfibrillar collagen or collagen sheets (on broad bleeding surfaces). Microfibrillar collagen, made from purified bovine skin collagen, is used topically to arrest certain hemorrhagic conditions that do not respond to conventional methods of hemostasis. Collagen accelerates the aggregation of platelets and may have limited effectiveness in patients with platelet disorders or hemophilia.

Intrasocket Preparations Bleeding from bony structures, especially from extraction sockets, can be controlled by various means. If initial attempts to achieve hemostasis with sterile cotton gauze and pressure do not succeed, a gelatin

CHAPTER 26  Procoagulant, Anticoagulant, and Thrombolytic Drugs sponge, denatured cellulose sponge, or collagen plug may be inserted within the bony crypt. Gelatin sponges are intended to be a matrix in which platelets and red blood cells can be trapped. In so doing, the sponges facilitate platelet disruption and can absorb 40 to 50 times their own weight in blood, both of which aid in coagulation. They typically resorb in 4 to 6 weeks. Because they are made of gelatin, they must be applied dry; when moistened, they become difficult to handle. For this reason, many practitioners prefer to use either denatured cellulose preparations or collagen sponge. Denatured cellulose sponge or gauze serves as a physical plug and a chemical hemostatic. The apparent coagulation-promoting action stems from the release of cellulosic acid, which denatures hemoglobin, and these breakdown products help plug the site of injury. However, cellulosic acid, similar to tannic acid, inactivates thrombin; the use of cellulose sponge in conjunction with this procoagulant is ineffective. Two forms of cellulose sponge, oxidized cellulose and oxidized regenerated cellulose, are available. Both these materials cause delayed healing, particularly oxidized cellulose, which notably interferes with bone regeneration and epithelialization. Although regenerated cellulose is said to have less inhibitory action, neither dressing should be left permanently in the wound if it can be removed. The collagen plug, similar to microfibrillar collagen, serves to accelerate the aggregation of platelets and form a physical barrier. Because it also is usually made from bovine collagen sources, occasional foreign body responses can occur. Overall, the collagen plug generally activates platelets more completely and is the preferred intrasocket product.

Topically Applied Clotting Factors The most physiologic hemostatic aids are the blood clotting factors themselves. Assuming an otherwise normal clotting system, topical thrombin is often used clinically. It must remain topically applied; if given intravenously, thrombin causes extensive thrombosis and possibly death. Topically applied thrombin (particularly in conjunction with a compatible matrix such as gelatin sponge) operates as a hemostatic, particularly if the patient has a coagulation deficiency or is receiving oral anticoagulants, because all that is required for clotting is a normal supply of platelets, fibrinogen, and factor XIII in the plasma. If blood flows too freely, temporary physical hemostasis must be attained before topical thrombin can be of practical value. Recombinant human thrombin is currently available for this purpose. Fibrin sealant, also sometimes referred to as fibrin glue, takes the concept of the application of topical thrombin one step further. Bovine or human thrombin and calcium chloride are mixed in one of two syringes; purified human fibrinogen with factor XIII, aprotinin, and other plasma proteins (fibronectin and plasminogen) are in the second syringe. The two solutions are mixed in a single delivery barrel, where the thrombin cleaves the fibrinogen to fibrin monomers. Initially, they are gelled by hydrogen bond formation, but in 3 to 5 minutes the factor XIII in the presence of Ca2+ initiates cross-linking and increases the tensile strength of the clot. As the clot solidifies, the sealant becomes milky white. The rate of fibrin clot formation depends on the concentration of the thrombin; 4 IU/mL produces a clot in approximately 1 minute, whereas 500 IU/mL requires only a few seconds. The strength of the clot depends on the concentration of the fibrinogen. If used in an area where the clot is likely to break down too soon, or in patients with compromised hemostasis, a protease inhibitor such as aprotinin can be added to delay fibrinolysis. Aprotinin functions by inhibiting plasmin, which is generally carried along with the thrombin. The term glue arises from the fact that in many medical applications this material has been literally used to adhere tissues together naturally.

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Fibrin sealant is commercially available in the United States. The protein fractions are lyophilized and require careful reconstitution at 37° C under sterile conditions; proper mixing of the materials requires approximately 30 minutes to perform. As a result, the emergent use of this material is difficult; typically, it is used more in planned surgeries in patients with known bleeding disorders. It is also an expensive medication; 1 mL of the material costs several hundred dollars. Fibrin sealant works well in stopping the microbleeding and oozing that often accompany dental procedures.

Astringents and Styptics The terms astringents and styptics are interchangeable, referring to different concentrations of the same drugs. Many chemicals have vasoconstrictive or protein-denaturing ability, but relatively few are appropriate for dentistry. The suitable preparations are primarily salts of several metals, particularly zinc, silver, iron, and aluminum. Aluminum and iron salts are quite acidic (pH 1.3 to 3.1) and irritating. Iron causes annoying, although temporary, surface staining of the enamel, whereas silver stains may be permanent. Currently, astringents are generally used in dentistry only to aid hemostasis while retracting gingival tissue. Aluminum and iron salts function by denaturing blood and tissue proteins, which agglutinate and form plugs that occlude the capillary orifices. In a rabbit mandible model, when ferric sulfate salts were left in an osseous wound, there was an intense foreign body reaction and delayed healing in many of the experimental sites compared with the control sites. Therefore, it is imperative that if these compounds are used in dentistry, they are used briefly and with copious irrigation and debridement to remove the breakdown products. They should not be applied to areas of exposed osseous material so as to avoid inflammation or complications of retarded healing such as the distressful dry socket. Tannic acid (0.5% to 1%) is an effective astringent; it also precipitates proteins, including thrombin, but is often incompatible with other drugs and metal salts used therapeutically. Finally, the use of an astringent in a patient with even a mild bleeding tendency may provide temporary hemostasis but subsequently lead to a larger area of delayed oozing after the chemically affected tissue sloughs.

Vasoconstrictors Temporary hemostasis may be obtained with adrenergic vasoconstrictor agents, generally epinephrine. Such vasoconstrictors should be applied topically or just under the mucosa only for restricted local effects and for very short periods to avoid prolonged ischemia and tissue necrosis. Because some of the drug is absorbed systemically, particularly in inflamed and abraded tissue, cardiovascular responses may occur. Epinephrine solutions and dry cotton pellets impregnated with racemic epinephrine are available for topical application, but other methods to control bleeding are generally preferred.

Systemic Measures Patients with acquired or genetic bleeding disorders usually have deficiencies in platelet number, platelet function, or faulty or missing clotting factors. Bleeding may develop several hours after trauma or surgery. Uncontrolled bleeding does not generally appear with superficial abrasions, but hemarthrosis and hemorrhage are common with deeper injuries. Thrombocytopenia is frequently drug-induced or associated with other myelogenous diseases; hemophilia disorders are generally inherited. With proper evaluation and supportive therapy (Table 26-2), extensive surgery can usually be accomplished without serious incident.

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CHAPTER 26  Procoagulant, Anticoagulant, and Thrombolytic Drugs

TABLE 26-2  Procoagulant Preparations Used in the Management of Bleeding Disorders Nonproprietary (Generic) Name

Proprietary (Trade) Names

Content

Therapeutic Use

Humate-P

250, 500, and 1000 IU/vial; contains albumin vWF and small amounts of other proteins 250, 500, 1000, and 1500 IU/vial; contains albumin 250, 500, and 1000 IU/vial; contains albumin and trace amounts of animal protein

Hemophilia A, vWD

500, 1000, and 1500 IU/vial; also contains significant amounts of factors II, VII, and X 500, 1000, and 1500 IU/vial; contains small amounts of factors II, VII, and X Varies per manufacturer

Hemophilia B

NovoSeven RT

1, 2, and 5 mg/vial

Hemophilia A or B; patients with inhibitors for factors VIII or IX

Autoplex T, FEIBA VH

≥80 IU/bag; contains other clotting factors; prepared from single donors

Hemophilia A, vWD, hypofibrinogenemia, DIC, Kasabach-Merritt syndrome

–

≥80 IU/bag; contains other clotting factors; prepared from single donors

Hemophilia A, vWD, hypofibrinogenemia, DIC, Kasabach-Merritt syndrome

Factor VIII Products Antihemophilic factor, plasma derived Antihemophilic factor, plasma derived, purified Antihemophilic factor, recombinant Antihemophilic factor, recombinant, albumin-free

Alphanate, Hemofil M, Koate DVI, Monarc-M, Monoclate-P Bioclate, Helixate, FS, Recombinate

Hemophilia A Hemophilia A; patients without HIV or viral hepatitis

Advate, Kogenate FS, ReFacto, Xyntha

Factor IX Products Factor IX complex

Bebulin VH, Profilnine SD, Proplex T

Factor IX human complex, purified Factor IX, recombinant

AlphaNine SD, Mononine BeneFIX Rixubis Alprolix (Fc Fusion) Ixinity

Hemophilia B Hemophilia B; patients without HIV or viral hepatitis Formulations vary to prolong activity

Factor VIIa Product Factor VIIa, recombinant Mixed Factor Products Anti-inhibitor coagulant complex (factor VIII inhibitor bypassing activity) Antihemophilic factor, cryoprecipitated

Unless otherwise noted, all products are derived from human plasma or, in the case of recombinant products, based on human genes. DIC, Disseminated intravascular coagulopathy; HIV, human immunodeficiency virus; IU, international units; vWD, von Willebrand disease; vWF, von Willebrand factor.

Platelet disorders Patients with a platelet count of less than 50,000/mm3 are at risk for surgical or other trauma, but they generally do not exhibit spontaneous hemorrhage until the count becomes less than 20,000/mm3. Platelet transfusion should be reserved for acute situations because alloimmunization to injected platelets can occur. One unit of platelet concentrate (equal to the platelets derived from 1 U of whole blood) increases the platelet count in adults from 4000/mm3 to 10,000/mm3. Platelet recovery is low in patients with hypersplenism and may be undetectable in patients with immune thrombocytopenia. Idiopathic forms may benefit from corticosteroid administration, splenectomy, use of immunosuppressive agents, or (acutely) high doses of intravenous immunoglobulin. Drug-induced disease generally is alleviated by withdrawal of the offending drug. In the case of aspirin or a thienopyridine such as clopidogrel prescribed deliberately to alter platelet function, the relative risks of hemorrhage versus thromboembolism must be considered in relation to the planned procedure.

Hemophilia All forms of hemophilia are genetically based disorders of coagulation. They may range in severity from mild to moderate to severe; this designation greatly affects what dental interventions can occur. The most common forms of hemophilia result from deficiencies in factors VIII and IX (hemophilia A and B). Although the transmission of both

hemophilia A or B is hereditary and X-linked, nearly half of all cases arise spontaneously as new mutations. Any child or adult with newly discovered hemophilia should have counseling with the family as provided by hemophilia treatment centers. Bleeding disorders (especially of the mild variety) are often first discovered after dental procedures, such as extractions or periodontal surgery. Hemophilia A occurs when there is a deficiency in circulating factor VIII activity. Factor VIII accelerates blood coagulation by serving as a cofactor in the platelet membrane in the enzymatic activation of factor X by the factor IXa/VIIIa complex (see Fig. 26-3). The normal amount of factor VIII antigen averages 100 U/dL. Mild hemophilia occurs when the patient’s blood has 5% to 30% of normal factor VIII activity. Moderate disease is defined as showing 1% to 4% factor VIII, and severe hemophilia shows less than 1% factor VIII. Individuals with more than 40% normal factor VIII antigen clot normally. The gene for factor VIII resides on the long arm of the X chromosome (Xq28), resulting in an X-linked pattern of inheritance. In severe factor VIII hemophilia, gene inversions account for 45% of mutations, whereas other patients have point mutations that often cause a premature stop codon to be inserted, resulting in incomplete mRNA transcription. In general, only males with a faulty factor VIII gene on their only X chromosome show phenotypic expression of severe disease, at a rate of 1 in 10,000. Females who carry an affected X chromosome typically do not show phenotypic disease because the unaffected factor VIII gene

CHAPTER 26  Procoagulant, Anticoagulant, and Thrombolytic Drugs on the other X chromosome provides sufficient protein to allow normal clotting. Expression of the normal gene may become depressed during development, however, if key progenitor cells favor the chromosome with the defective gene. The result is that some carrier females are phenotypically mild (or, rarely, moderate) hemophiliacs, with factor VIII concentrations 15% to 25% of normal. Referred to as symptomatic carriers, their bleeding tendency is often not discovered until they encounter a significant insult, such as extraction of teeth, orthognathic surgery, or extensive periodontal surgery. For this reason, female relatives of hemophiliacs should have interviews, and possibly blood tests, to determine their carrier status and their factor VIII activity. Hemophilia B was discovered when it was noted that combining plasma from different hemophiliacs sometimes allowed normal clotting; it was deduced that the second sample corrected the defect in the first. It was later determined that deficiencies in factor IX were responsible for approximately one-fifth of the forms of hemophilia. Older literature refers to factor IX deficiency as Christmas disease, named after the surname of the first family studied with this variant of hemophilia. Similar to hemophilia A, the gene for factor IX is on the X chromosome (Xq27.3) and shows the same familial pattern of expression: affected males and carrier females. Similar to factor VIII deficiency, partial or whole gene deletions or insertions lead to severe hemophilia B, as do nonsense point and some missense mutations. Also similar to hemophilia A, there are mild, moderate, and severe forms of the disease, and female symptomatic carriers occur. Hemophilia A and B are clinically indistinguishable.

Von Willebrand disease Originally described by von Willebrand in 1926, von Willebrand disease (vWD) is an autosomal dominant hemorrhagic disorder resulting from a quantitative or qualitative deficiency of the vWF GP. Males and females are affected equally; the defect is in an autosomal dominant gene located on chromosome 12. vWD may be the most common inherited bleeding disorder, with many cases remaining undiagnosed. The vWF GP is produced in vascular endothelial cells and megakaryocytes and is stored intracellularly in the α granules of platelets and circulated in the plasma as multimeric polymers. The high-molecular-weight multimers are necessary for normal biologic activity, presumably because of their greater number of ligand-binding domains. vWF has three important functions. The first is to form a tight but noncovalent complex with factor VIII protein, stabilizing and slowing its clearance from the circulation. Second, vWF promotes normal, highshear platelet adhesion to the subendothelium on injury and exposure of subendothelial matrix proteins. Third, vWF is one of the proteins that binds to the multiple platelet membrane GP IIb/IIIa receptors, along with fibrinogen, to help stabilize the aggregating platelets. As an aside, ristocetin, one of the first antistaphylococcal antibiotics, was found to cause thrombocytopenia by binding to the platelet membrane and catalyzing the binding of vWF. This resulted in platelet aggregation, thrombus formation, and depletion thrombocytopenia. The antibiotic was removed from clinical use as a result, but is now used as an assay for vWD. By mixing ristocetin, washed platelets, and plasma from the affected patient, an inverse correlation occurs between the amount of functional vWF present in the plasma (originally called ristocetin cofactor) and the amount of ristocetin necessary to induce platelet aggregation. The hematologic disorder in vWD can manifest as either structural or quantitative changes in vWF. Three basic types of disease exist. Type 1 vWD is associated with a mild quantitative defect in the amount of vWF produced. Titers of vWF antigen (total vWF protein) and ristocetin cofactor activity (functional vWF protein) are comparable. This is the most common type (80%) and is most often manifested by mucocutaneous bleeding. Type 2 vWD is a defect in the amount

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of high-molecular-weight multimers present in the plasma, causing a marked decrease in platelet adhesion but little change in total vWF antigen. There is a high ratio of antigen to ristocetin cofactor activity. Type 3 vWD is characterized by severe bleeding disorders from an essential lack of any vWF, with concomitantly low concentrations of factor VIII and decreased platelet adhesion. This third type is rare, mostly occurring in homozygous or compound heterozygous offspring of parents with mild or asymptomatic variants of vWD.

Treatment Treatment of either variety of hemophilia or vWD requires the restoration of the appropriate factor so that factor complex IXa/VIIIa activity is sufficient. For the treatment of hemophilia A, various factor VIII replacement products are available (see Table 26-2). Because the half-life of factor VIII is 8 to 12 hours, the patient must be reinfused with at least half the original dose at approximately 12-hour intervals to prevent late bleeding from surgical wounds. Until more recently, the only way to obtain factor VIII was by pooled human blood products. Initially, the most common method was to use cryoprecipitate. Cryoprecipitate is the cold-insoluble (precipitated) protein fraction derived when fresh frozen plasma is thawed at 4° C. It is primarily composed of factor VIII, fibrinogen, and vWF. Classically, it was one of the mainstays of factor VIII hemophilia treatment, but it has virtually disappeared from this use with the development of methods to manufacture recombinant factor VIII. Similar to plasma, cryoprecipitate is not virally inactivated. The most common current use of cryoprecipitate is as a source of fibrinogen for the treatment of disseminated intravascular coagulopathy. Cryoprecipitate is still occasionally used for the treatment of vWD, particularly if it is obtained from a single donor after desmopressin stimulation, but this use is waning. Modern plasma-derived factor VIII products have greatly reduced the risk of viral transmission by donor screening and viral inactivation protocols. Two methods are currently being used to inactivate viruses: heat and solvent detergent. All viruses that have lipid envelopes are readily destroyed, including HIV, hepatitis B, and hepatitis C. Viruses that do not have lipid envelopes, such as the B19 parvovirus and hepatitis A, can still be transmitted in the solvent detergent or heat-inactivated products. A vaccination for hepatitis A is now available, and patients with hemophilia or vWD are encouraged to receive it early in life. Some manufacturers additionally purify their factor VIII protein products from the pooled factor VIII proteins on affinity columns, increasing the specific activity of the preparation and decreasing further the risk of viral transmission. Those products are more expensive. One of the factor VIII products, Humate-P, is purified with a process that retains a considerable amount of vWF. Although still occasionally used for factor VIII hemophiliacs, this product has become the favored way to treat bleeds or potential bleeds in patients with moderate–severe vWD and is used mostly for this reason. It has the advantage that it can be manufactured on a large scale, lyophilized for stability and storage, and reconstituted when necessary. It is considered very safe from viral contamination. Most factor VIII hemophiliacs are now receiving recombinant factor VIII products, particularly if they are HIV and hepatitis virus negative. These proteins are derived from stable transfection of the human factor VIII cDNA into Chinese hamster ovary (CHO) or baby hamster kidney cells, with resultant transcription and protein production. The first-generation products required human albumin to be added to provide stabilization through the purification process; the second-generation and third-generation products are now being made albumin-free. The distinction is important because the albumin adds a small risk for viral contamination. The new products are considered virus-free, have high specific activities, and have been successful in transiently

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correcting the bleeding disorder. The main difficulty is that in a patient with severe hemophilia with essentially no endogenous protein, the use of this “foreign antigen” product may cause the development of anti-factor VIII antibodies, known in hematology as inhibitors and discussed in greater detail subsequently. In most patients who develop them, the inhibitors are low titer and controllable with low-dose daily infusions of factor VIII protein to build immune tolerance over time. Another approach to the treatment of mild hemophilia A and type 1 vWD was introduced when it was discovered that desmopressin, the synthetic 1-desamino-8-d-arginine analogue of vasopressin (antidiuretic hormone), could prevent bleeding in many of these patients. This medication causes endogenous factor VIII, vWF, and plasminogen activator to be released from storage sites on the vascular endothelium. In many patients with mild hemophilia or type 1 vWD, the protein structures are normal, but concentrations are low. With desmopressin, transient increases of two to three times the patient’s baseline concentrations can be achieved, which may be sufficient to allow adequate hemostasis during minor surgery. For hemophiliacs who use single donors (usually a parent or sibling) as their sole source of factor product, desmopressin can be given to the donor before donation to double or triple the amount of factor VIII recovered. The advantage of desmopressin over vasopressin is that it retains the factor VIII–releasing activity but has diminished vasoconstrictor action. Most importantly, desmopressin is devoid of the risk of viral transmission inherent in the blood-derived products. Desmopressin is subject to peptic hydrolysis and is injected or insufflated intranasally. Mild facial flushing is normal during the infusion, with headache, nausea, and lightheadedness as common side effects. Because of its antidiuretic properties, water intake must be restricted for 12 hours to avoid volume overload. (The drug is also used in lower doses as an aid for children with bed-wetting difficulties.) Historically, factor IX concentrates have been difficult to purify. The most common factor IX preparations are known as factor IX complex because, although they have high amounts of factor IX protein, they also contain factors II and X and some factor VII (see Table 26-2). Because of the presence of the excessive extra clotting factors (some partially activated), disseminated intravascular coagulopathy is occasionally a problem. Similar to factor VIII concentrates, they are subjected to various forms of viral inactivation to reduce the transmission of HIV, hepatitis B, and hepatitis C. Several recombinant factor IX preparations are currently available. Similar to all recombinant products, they are essentially virus-free because they are produced in CHO cells. They vary in how the factor is stabilized, whether by human albumin, the Fc portion of IgG immunoglobulin, or other proprietary methods. The major difficulties in developing these products are the extensive posttranslational modifications the natural protein undergoes. As a result, the manufactured factor IX protein is not as efficacious as the natural factor, so patients often require more protein than the highly purified plasma-derived protein to get sufficient increases in plasma factor IX. One aspect of blood product replacement therapy that is often overlooked is cost. On average, a patient with severe hemophilia A uses $10,000 to $100,000 worth of factor per year depending on the type of product used and the dose required. Younger hemophiliacs, to avoid potential viral exposure, generally use the recombinant products. As a hope for the future, correction of hemophilia by gene transfer is being pursued. Gene therapy is in its infancy, but hemophilia is considered one of the more ideal targets for early trials because the active proteins are found in the bloodstream and can be made in just about any tissue as long as they can be released to the blood. It will be interesting to see which hemophilia gene transfer succeeds first. The factor VIII gene is larger and more difficult to transfer, but the

resultant protein undergoes much less posttranslational modification than occurs with factor IX.

Inhibitors and ways to circumvent them A confounding problem in treating hemophiliacs is the development of antibody inhibitors against the deficient factor. Approximately 5% of patients with severe hemophilia A express a high titer of inhibitor, usually within the first few years of being treated with factor VIII concentrates. Multiple approaches must be used to protect these patients against bleeding crises. The most crucial task is to determine whether the patient carries low-titer or high-titer antibodies. Patients with low-titer antibodies can often be given excessive amounts of factor replacement, depleting the inhibitor antibody sufficiently to allow the remaining factor to promote hemostasis. Although low-titer inhibitors may persist for years, they do not show the typical alloantibody boost response after exposure to human factor VIII concentrates. In patients with high-titer inhibitors, preventing or reducing hemorrhage risk is crucial. Daily infusion of high-dose, medium-dose, or lowdose factor replacement to induce immune tolerance can be successful. Concomitant administration of immunosuppressant medications may depress antibody formation further. This approach is much more effective with autoantibody inhibitors than with alloimmune responses. A short course of daily intravenous infusion of IgG has sometimes reduced titers as well. After immune tolerance is achieved, most patients require continued low-dose prophylactic factor infusions at least weekly. When hemophiliacs with high-titer inhibitors require coagulation support, but factor VIII replacement therapy cannot be used, two products may be effective. Factor VIIa is a recombinant protein that functions similar to its endogenous counterpart: it combines with TF at the site of injury to stimulate conversion of factors IX and X to their respective activated analogues. Because TF is found only at the site of injury, disseminated coagulation has not been a problem. Also, factor VIIa is not rapidly inactivated by ATIII, giving it a sufficient half-life to allow hemostasis. Because it has a much shorter half-life than either factor VIII or factor IX, it requires high doses every 2 hours in the dental setting. The drug has the limitation that its mechanism is to achieve sufficient thrombin formation via the part of the coagulation cascade that is intended for only small amounts of thrombin generation. It seems to work well for initial hemostasis, but there have been difficulties with breakthrough bleeding 48 hours or so after surgery. Concomitant use of local control measures (suturing/collagen) is wise. The current cost of this medication is several thousand dollars per dose. The other medication that can be used is a procoagulant complex known as FEIBA VH (factor eight inhibitor bypassing activity). The VH form is a vapor-heated concentrate of plasma-derived factors II, VII, IX, and X (the vitamin K–dependent clotting factors) in their inactive and active forms. How this medication corrects the bleeding disorder is unknown, but it is believed the extra factors II and X complex with endogenous factor V and reconstruct the common pathway, eliminating the need for factor VIII. The main difficulty with this medication is that the extra clotting factors can overshoot and cause thrombosis elsewhere in the body. Which product, FEIBA versus factor VIIa, works best in any given patient is unpredictable. Some patients clearly do better with one over the other, but the reason for this is elusive.

AGENTS THAT PROMOTE OR INHIBIT FIBRINOLYSIS Physiology of Clot Remodeling Achieving hemostasis is a crucial aspect of the coagulation system, and limiting its spread is another. Remodeling or breaking down clots when they are no longer necessary is a third crucial facet of vascular repair. As healing occurs, it is necessary to remove part or all of

CHAPTER 26  Procoagulant, Anticoagulant, and Thrombolytic Drugs

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Fibrin monomers

Branch point to allow net formation

Fibrin chain ˝under construction˝

FIG 26-6  Fibrin formation. After conversion of fibrinogen to fibrin, the monomers begin to link together as shown to create staggered “ropes” with branch points. The branch points go on to form the “net,” which will be used to capture red blood cells and bring about eventual hemostasis.

the fibrin that has been deposited so that normal blood flow can be restored to the affected tissue. This process is mediated by the protease, plasmin. When fibrin is initially deposited (Fig. 26-6), thrombin stimulates adjacent endothelial cells to release tissue plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA). t-PA is a serine protease that must adhere to the fibrin molecules to function. This binding occurs on lysine residues of the fibrin. When adhered, t-PA binds plasminogen (also at a lysine residue) and cleaves it to liberate plasmin, another serine protease. Plasmin has the ability to bind directly to fibrin. u-PA acts independently of fibrin and instead activates plasminogen to plasmin in the circulation. Plasmin associated with t-PA lyses the fibrin, releasing fibrin degradation products, and degrades factors V and VIII, inhibiting further clotting. As expected, strict control mechanisms for plasmin activity exist. Without such control, circulating plasmin would cause systemic fibrinolysis and oozing of previously clotted sites. Three proteins are intimately involved. The first, α2-antiplasmin (α2-AP), is synthesized in the liver and is efficient at neutralizing any free plasmin circulating in the blood. Binding plasmin to fibrin protects it from attack by α2-AP, which restricts the activity of plasmin to the wound site. The second control protein, plasminogen activator inhibitor-1 (PAI-1), is synthesized by the endothelial cells in response to thrombin stimulation, with specificity for t-PA. PAI-1 effectively inhibits conversion of plasminogen to plasmin by t-PA, unless the t-PA can “hide” from it by binding to fibrin. The third control protein is PAI-2, which functions similarly to PAI-1, only with specificity for u-PA. The liver also functions to clear the bloodstream of any free active plasmin, further helping to prevent systemic fibrinolysis.

Fibrinolytics Therapeutic measures designed to induce or facilitate fibrinolysis are available for use in relieving certain types of thromboses, most notably in the event of acute myocardial infarction. These agents may also be valuable in patients with a life-threatening pulmonary embolus, infarctive stroke, or deep venous thrombosis. All these agents function by activating the conversion of plasminogen to plasmin with subsequent natural fibrinolysis. t-PA (alteplase) is produced by recombinant DNA techniques. Because t-PA is naturally more fibrin specific than other preparations, it is the first thrombolytic agent recommended by the American Heart Association in the management of myocardial thrombosis. At pharmacologic doses, it imparts some circulating plasminogen conversion, however. A deletion mutation variant of t-PA is

available by the nonproprietary name of reteplase. It is similar in activity and side effects to t-PA. Streptokinase, an exotoxin from certain β-hemolytic streptococci, also serves as an activator of plasminogen. It is different from t-PA and u-PA because it is not an enzyme and does not proteolytically cleave plasminogen to plasmin. Instead, it binds noncovalently to plasminogen and confers plasmin-like proteolytic activity on the plasminogen–streptokinase complex. The complex cleaves other molecules of plasminogen, liberating active plasmin. Because streptokinase is an exogenous protein originating in bacteria, there is a higher incidence of adverse and allergic reactions with this medication. A similar medication, anistreplase (anisoylated streptokinase plasminogen activator complex), is a combination of streptokinase with an acylated plasminogen, forming an inactive complex that spontaneously deacylates in plasma. The deacylated form is the same as the streptokinase–plasminogen complex previously discussed. The many available plasminogen activators have made effective treatment possible in reducing ischemic myocardial necrosis if given within 30 to 60 minutes after the onset of chest pain. There is a 47% success rate in thrombolysis if the products are given 1 hour from onset of symptoms. Results are poor if given after a 3- to 6-hour delay.

Antifibrinolytics In some circumstances, it is advantageous to limit fibrinolytic activity (e.g., after surgery in a hemophilic who may be prone to breakthrough bleeding as the wound heals). Two drugs used for this purpose are aminocaproic acid (sometimes referred to as ε-aminocaproic acid) and tranexamic acid. Both competitively inhibit plasminogen and plasminogen activators from binding to fibrin. The usual dose of aminocaproic acid is 50 mg/kg every 6 hours for 10 days. In its tablet forms (500 mg or 1000 mg), this dosage requires the average adult patient to take several tablets every 6 hours. As a result, compliance can be difficult. A concentrated syrup form exists for pediatric use (250 mg/mL), and experience indicates that adult patients generally are more compliant with taking the liquid form of the medication, especially after oral surgical procedures. Tranexamic acid is roughly eight times more efficient at antifibrinolysis as aminocaproic acid. It is available as an injectable form (Cyklokapron) or as oral tablets (Lysteda). Because the usual dosing is two tablets (650 mg × 2 = 1300 mg) TID, compliance is much better. As a result, it has overtaken aminocaproic acid as the drug of choice in dentistry.

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CHAPTER 26  Procoagulant, Anticoagulant, and Thrombolytic Drugs

Note that oral rinses of both medications will penetrate several millimeters into an oozing socket, and they may provide hemostatic relief for patients with oozing after extractions. Rare side effects of these medications include unwanted thrombosis in patients who are prone to deep venous thrombosis and cardiovascular disease. Careful consideration and consultation with the physician is important before using either medication in such patients.

ANTICOAGULANTS Although dentists are unlikely ever to prescribe an anticoagulant, it is essential that they be aware of any hemostatic deficiency in their patient, whether pathologic or therapeutic in origin. Anticoagulants are being prescribed with ever-increasing frequency by physicians, and dentists commonly encounter patients who are taking these medications. There are now three classes of anticoagulants in clinical use: directly acting agents; indirectly acting agents, which interfere with the synthesis of coagulation proteins; and platelet inhibitors, of which three subclasses exist: COX inhibitors, GP IIb/IIIa antagonists, and ADP receptor antagonists. Dentists should be familiar with the pharmacologic features of each class and understand if, how, and when their effects should be modified.

Directly Acting Anticoagulants: Heparins First extracted by McLean in 1916, heparin is a powerful, systemically effective direct-acting anticoagulant. Heparin is a linear mucopolysaccharide primarily composed of repeating units of d-glucosamine in 1,4 glucosidic linkage with d-glucuronic and l-iduronic acids. These disaccharide residues, which are partially esterified (≤40%) with sulfuric acid, make heparin the strongest organic acid normally occurring in the body. About 10 to 15 of these chains, each with 200 to 300 monosaccharide units, are attached to a core protein to give the final proteoglycan as the storage form of heparin in mast cells. Because the polysaccharide chains differ in length, and the sulfation reactions vary, endogenous heparin is a heterogeneous mixture of molecules, with molecular weights ranging from 4000 to 40,000, none of which has been completely characterized. Commercial preparations are made primarily from recombinant DNA techniques. Heparin is produced endogenously in mast cells, where it is stored in a large macromolecular form complexed with histamine. Heparin and histamine are released together, providing a physiologic example of a fixed-drug combination, the significance of which is not yet fully understood. It has been proposed that adsorbed heparin-like mucopolysaccharides (termed heparans) are major contributors to the normally strong electronegative charge maintained by the vascular epithelium. This property is made use of in the manufacture of prosthetic devices such as heart valves, in which ionizable heparin is incorporated into the surface material to inhibit thrombus generation.

Mechanism of action Heparin interferes with blood coagulation in several ways. Heparin functions by binding tightly to the plasma protease inhibitor ATIII, causing a conformational change in the inhibitor that exposes its active site and accelerates its activity a thousandfold. ATIII is a “suicide” protein that covalently binds to several proteases (factors IXa, Xa, and XIIa), resulting in the permanent inactivation of the protease and the ATIII protein. As a true catalyst, heparin is not destroyed in this process. The heparin–ATIII complex dissociates on binding of a protease to ATIII, releasing intact heparin for renewed binding to another ATIII molecule.

With higher molecular-weight heparins, the heparin–ATIII complex binds to and inactivates thrombin itself (also a serine protease), inhibiting its proteolytic action on fibrinogen. This occurs when the heparin-ATIII dimer forms a ternary complex with thrombin by the heparin binding to one site on the thrombin protein and ATIII binding the active site on the other side. These two sites are a significant distance from one another, which is why only the higher molecular-weight moieties of heparin are capable of producing the effect. Molecules of less than 18 monosaccharides are incapable of reaching far enough across the protein to allow ATIII to bind and inhibit thrombin. The effects of heparin on platelets are complex. When thrombin is rendered inactive, platelet activation is usually reduced. More troubling, heparin may also sometimes induce independently of other aggregating agents a transient, anomalous platelet aggregation and significant thrombocytopenia in 1% to 5% of patients. Two varieties of heparin-induced thrombocytopenia (HIT) exist: a relatively benign nonimmune process and an immune-mediated process. The latter, known as type II, can be fatal in 30% of cases. It is believed that complexing of the heparin to platelet factor 4 results in antibody formation and subsequent activation of platelets. In this syndrome, the difficulty is not with bleeding, but with runaway thrombosis. As the platelets activate, they form thrombi, which account for much of the clinical presentation. As the platelets are used up, thrombocytopenia and bleeding occur. Patients with a history of type II HIT are far more likely to have a repeat problem, as would be expected with immunologic phenomena.

Low-molecular-weight heparins Much research activity has focused on the use of low-molecular-weight heparin (LMWH) fractions for the prevention of thrombosis. Unfractionated heparin consists of heterogeneous combinations of various-sized sulfated mucopolysaccharides. Because only high-molecular-weight heparins (heparins with ≥18 specific saccharide sequences) can bind thrombin and inactivate it, attention has turned to LMWHs. They are poor inhibitors of thrombin, but they retain the ability to catalyze ATIII to inhibit other serine proteases, most notably factor Xa. As a result, they have at least some advantage in that they exert antithrombotic activity without completely destroying the coagulant activity thrombin imparts on factors V, VIII, XII, and XIII. A problem with LMWHs is that they all are prepared by fractionating heparin, and different methods impart different ratios of anticoagulant and antithrombotic activity. Enoxaparin and dalteparin currently are the most commonly used medications in this class; the one selected by the physician depends on the degree of anticoagulation desired for the patient. A synthetic pentasaccharide, fondaparinux, similar to LMWHs, has been marketed. This medication is a selective factor Xa inhibitor, and studies have shown that it is more effective than enoxaparin in preventing deep venous thrombosis after hip and knee surgery.

Absorption, fate, and excretion All available forms of heparin must be administered parenterally because they are highly charged and rapidly hydrolyzed in the gastrointestinal tract. Unfractionated heparin is infused intravenously but may be given by deep subcutaneous or fat depot injection. It should not be injected intramuscularly because of the risk of deep muscle hematoma. Heparin has a dose-dependent biologic half-life of 1 to 5 hours when given intravenously, and it is removed primarily by the liver. When injected subcutaneously, it is absorbed into the systemic circulation so slowly that it rarely is a problem for any kind of dental treatment. LMWHs are generally administered subcutaneously with once-daily or twice-daily dosing.

CHAPTER 26  Procoagulant, Anticoagulant, and Thrombolytic Drugs Heparin activity is best monitored by the partial thromboplastin time or the aPTT, both of which measure drug effects on the intrinsic pathway and are sensitive to low doses of heparin. The partial thromboplastin time is much less sensitive (and often completely normal) to LMWHs. Standardized doses of LMWHs achieve a more consistent anticoagulant effect, reducing the need for monitoring. The prothrombin time (PT), routinely used to monitor oral (indirect-acting) anticoagulants, is also of little value because it does not respond to inhibition of the thrombin-catalyzed part of the coagulation cascade, and heparin is diluted out in the procedure.

Other Directly Acting Anticoagulants Direct thrombin inhibitors

It has long been known that leeches secrete a potent anticoagulant in their saliva. In many centers, medicinal leeches (Hirudo medicinalis) are still used to help patients combat venous thromboembolic events. The active component has been isolated and identified as hirudin, a 65-amino acid polypeptide chain that is a specific direct thrombin inhibitor. It works by stoichiometrically binding to thrombin at two sites: the fibrinogen-binding site and the active protease site. It is the most powerful naturally occurring anticoagulant known. Hirudin has many advantages over heparin. As a direct thrombin inhibitor, it is able to inhibit clot-bound thrombin that the heparin-ATIII complex cannot reach. As would be expected with a direct inhibitor, it also has caused severe bleeds. A recombinant analogue, lepirudin, has been approved for the treatment of thrombosis associated with HIT. Because 50% of patients develop IgG antibodies against the hirudins, aPTT must be monitored closely. Perhaps the most widely used direct thrombin inhibitor is bivalirudin, a semisynthetic analogue of hirudin consisting of 20 amino acids. It competes for the fibrinogen-binding site and the proteolytic site, effectively stopping all cleavage of fibrinogen to fibrin. Bivalirudin differs from hirudin in that it produces only transient inactivation of the thrombin protease site because the thrombin itself slowly acts on the bivalirudin to cleave it, and when cleaved, it “falls off” the thrombin molecule, allowing fibrinogen to bind. This net effect means that it has a relatively short clinical half-life of 1 to 2 hours, but that is advantageous because it can be infused to prevent thrombosis before cardiac surgery and turned off shortly before the case to allow full clotting to occur in a predictable fashion. Bivalirudin was shown more recently to prevent blood clots better than heparin in patients undergoing angioplasty. The drug is primarily cleared via intravascular proteolysis and renal elimination in the urine; it has a significantly longer clinical halflife in patients with moderate–severe renal failure. Dabigatran (Pradaxa) is a direct thrombin inhibitor available in an oral tablet formulation. It is being used instead of warfarin in many patients due to more consistent anticoagulation, but it has yet to have data on exactly how to manage it in the dental setting. The bleeding risk would, in part, depend on the extent of the dental procedure. A reversal drug for dabigatran, idarucizumab (Praxbind), is now available. Monitoring is generally done with the aPTT.

Factor Xa inhibitors The newest group of anticoagulants are the factor Xa (FXa) inhibitors. Rivaroxaban (Xarelto), Apixaban (Eliquis), edoxaban (Savaysa), and Betrixaban stop the coagulation cascade by binding to FXa and inhibiting the resultant cleavage of prothrombin to thrombin. They have the advantage of rapid onset and relatively short half-lives, which reduces need for “bridging” near surgery. They are generally unmonitored on a routine basis, but the PT and the aPTT will show some effect. Evidence-based guidelines are not available on whether or not discontinuing care prior to dental surgery is necessary, particularly with regard

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to the extent of the planned surgery and the availability of local control measures (collagen, suturing, etc.), This topic will be discussed in greater detail under dental considerations later in the chapter.

Indirectly Acting Anticoagulants: Warfarin Discovery of the prothrombin-depressant action of spoiled sweet clover by Roderick in 1929 led to the isolation and synthesis of dicumarol (bishydroxycoumarin) by Campbell and Link in the 1940s. These advances introduced a new era of relatively inexpensive, self-­ administered oral anticoagulant therapy. Since then, several other coumarin compounds (and the similar indanediones) have been introduced, but warfarin is the only significant medication in current use.

Mechanism of action Warfarin acts by competitively inhibiting vitamin K epoxide reductase, an enzyme essential for the synthesis of many coagulation factors by the liver. Vitamin K serves as a cofactor in the γ-carboxylation of glutamic acid residues of several proteins, including the clotting factors II, VII, IX, and X and proteins C and S. The carboxyglutamic acid moieties formed are able to chelate Ca2+, which promotes conformational change and eversion of hydrophobic domains, allowing the factors to settle into the platelet or endothelial cell membrane and bind cofactors. Vitamin K is oxidized in the carboxylation process and must be reduced enzymatically to regain cofactor activity. Warfarin inhibits this reduction (Fig. 26-7). The most sensitive indicator of vitamin K deficiency or warfarin anticoagulation is the depression of factor VII. The PT test best shows factor VII activity and is therefore the monitoring test of choice. Of the four vitamin K–dependent clotting factors, factor VII shows depression first because its half-life is only 4 to 8 hours. Prothrombin, with a half-life of 2 to 3 days, is the last to be diminished.

Adverse effects Indirect anticoagulants notably produce adverse reactions in the presence of certain drugs and medical conditions. These effects most often arise from interference with vitamin K absorption or metabolism, competition for the drug-binding sites of proteins, or competition for or activation of the hepatic microsomal enzymes responsible for biotransformation. The most important toxic effect of warfarin is unexpected hemorrhage. Any change in the absorption or availability of vitamin K from the intestine affects the balance between the anticoagulant and vitamin K in the liver and is reflected in the PT. In patients with marginal amounts of vitamin K in the diet, depressed bacterial synthesis (such as after antibiotic therapy) of vitamin K in the intestine may affect anticoagulation. Some oral contraceptive agents greatly increase vitamin K1 absorption in experimental animals. Warfarin is highly plasma protein bound (approximately 99%). This association creates a tremendous reserve of drug in the bloodstream, a very small displacement of which could easily double the concentration of active free drug. Many unrelated compounds that are also highly plasma protein bound theoretically can displace this protein binding and potentiate warfarin’s action. Clinically, this effect is thankfully generally mild. Warfarin is a racemic mixture of an R-enantiomer and S-enantiomer. The R-enantiomer, a weak anticoagulant, is metabolized primarily by hepatic biotransformation using CYP1A2, with CYP2C19 and CYP3A4 providing minor pathways. The S-enantiomer, a potent anticoagulant, is metabolized by CYP2C9. Medications that either inhibit or induce these various hepatic microsomal enzymes may affect the patient’s response to warfarin. Only trace amounts (approximately 1%) of warfarin are excreted unchanged.

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CHAPTER 26  Procoagulant, Anticoagulant, and Thrombolytic Drugs

Vitamin K hydroquinone

Glutamic acid O C O HC CH2 CH2 C O– H N C O

OH

O2 CO2

OH

CH3

NAD+

R

Vitamin K Epoxide Reductase

γ-Glutamylcarboxylase O O C O C O– HC CH2 CH2 C O– H N O C O

CH3 O R

O Vitamin K epoxide

NADH

Coumarins Indanediones Vitamin K Epoxide Reductase

Coumarins Indanediones

γ-Carboxyglutamic acid

FIG 26-7  Inhibition of synthesis of vitamin K–dependent clotting factors by coumarin and indanedione anticoagulants. In the final posttranslational modification of prothrombin (factor II), factor VII, factor IX, factor X, protein C, and protein S, vitamin K is oxidized to the epoxide in the process of carboxylating glutamic acid residues on the amino end of each protein. The resultant γ-carboxyglutamic acid groups serve to chelate Ca2+ ions and conformationally change to expose a hydrophobic domain that settles into phospholipid membranes, anchoring the factors for normal hemostasis. The indirect-acting anticoagulants prevent the restoration of vitamin K by competitively inhibiting vitamin K epoxide reductase, the enzyme responsible for reducing vitamin K epoxide by nicotinamide adenine dinucleotide (NADH). R, Hydrocarbon side chain of vitamin K.

Many other drug interactions regarding oral anticoagulant agents do not involve vitamin K absorption, carrier protein displacement, or biotransformation. Aspirin, ibuprofen, and clopidogrel are representative drugs that inhibit platelet function. When administered concurrently with warfarin, their combined influences on the coagulation cascade may result in uncontrolled bleeding.

Antidotes Except in situations in which an emergency demands the replacement of whole blood or plasma, the usual antidote for warfarin ­toxicity is vitamin K administered parenterally in high concentrations. Because warfarin inhibits recycling of vitamin K, simple administration of more “fresh” vitamin K obviates the need for recycling the epoxide form immediately. Subcutaneous or intramuscular administration provides obvious improvement in coagulation in 1 to 3 hours, but normal hemostasis may not be achieved for 24 hours. Similarly, minor correction in an anticoagulated PT is seen if patients ingest significant amounts of vitamin K via their diet. Liver, broccoli, brussels sprouts, spinach, Swiss chard, collards, and other green leafy vegetables that are high in vitamin K can add enough vitamin K to shift the patient’s anticoagulation profile in a few hours after ingestion. This technique is often used by anticoagulation clinics to “fine-tune” a patient before dental surgery if he or she is close to, but not quite under, his or her target PT international normalized ratio (INR). Kcentra (prothrombin complex concentrate, human) has been recently introduced to more quickly control major bleeding due to vitamin K antagonist therapy. Kcentra contains factors II, VII, IX, and X. The product contains a black box warning about thromboembolic

complications. Because of its risks, need for close monitoring, and intravenous use, it is unlikely to be of general use in dentistry.

Anticoagulants: General Pharmacological Characteristics and Therapeutic Uses The principal pharmacologic actions of directly acting and indirectly acting anticoagulants interfere with some steps in the blood coagulation process. Beyond this, neither directly acting nor indirectly acting anticoagulants have outstanding effects on the cardiovascular, respiratory, or other systems except in the case of warfarin through competition with other drugs for protein binding sites and drug-metabolizing enzymes. There are many indications in medicine for the use of anticoagulants, including prevention of myocardial infarction, cerebrovascular thrombosis, pulmonary embolism, and venous thrombosis. Clotting protection is necessary for mechanical cardiac valves and during renal dialysis. Cardiovascular compromise, such as that seen in atrial fibrillation or congestive heart failure, causes decreased flow of blood and presents a greater risk for thrombosis in areas of stasis. Atherosclerotic plaques, especially in hypertensive patients, are risks for intimal tears, with resultant thrombus formation. Heparin and oral anticoagulants are useful in the prevention and treatment of these disorders. Oral anticoagulants, classically warfarin but now also with the direct thrombin and FXa inhibitors, provide sustained forms of therapy. It has become commonplace to see patients treated with anticoagulants for long periods for these various reasons, and anticoagulation clinics are a staple in most medical centers. The dentist must be able to manage such patients appropriately without causing undue harm either from excessive bleeding or from increased thrombosis risk.

CHAPTER 26  Procoagulant, Anticoagulant, and Thrombolytic Drugs Platelet Inhibitors As is discussed in Chapter 17, drugs that interfere with platelet function are increasingly being recommended for prophylaxis of arterial and venous thrombosis. In recent years, many different agents have been developed and marketed successfully. These agents can be divided into three essential groups: COX inhibitors, ADP receptor inhibitors, and GP IIb/IIIa inhibitors. Each has unique characteristics in managing thrombosis via platelet inhibition, and the dentist is likely to find patients with one or more of these medications in their drug profiles.

Cyclooxygenase inhibitors Aspirin (acetylsalicylic acid) is the prototypic and most commonly recognized COX inhibitor. Inexpensive and readily available, it is prescribed in doses of 81 to 325 mg/day to reduce the risk of myocardial infarction, ischemic stroke, or both. The antihemostatic effect of aspirin is ascribed to irreversible acetylation of COX-1 isozyme. COX-1 is required to synthesize platelet TXA2 from arachidonic acid. Disruption of this pathway results in decreased platelet aggregation and decreased ADP release. Because platelets are incapable of synthesizing new COX, the inhibition by aspirin lasts for the life of the platelet. When aspirin therapy is used in combination with thrombolytic therapy after acute myocardial infarction, there are significant reductions in mortality and the incidence of major complications.

Adenosine diphosphate receptor inhibitors As described earlier, ADP binds to its own receptor proteins P2Y1 and P2Y12, which results in maximal platelet aggregation. The thienopyridine compounds clopidogrel and prasugrel irreversibly inhibit the P2Y12 receptor by what is believed to be a covalent bond to the receptor. Both are inactive until metabolized in the liver to their active forms. Because they bind only to the P2Y12 receptor, the P2Y1-­mediated ADP effects still occur. This results in the platelets still undergoing shape change and transient aggregation, but sustained aggregation and potentiation of granule secretion are impaired. Clinically, patients generally do not have significant hemorrhage from oral surgery if the extent of the surgery is limited and local control measures are used. In more extensive surgeries, stopping the use of these drugs for 24 to 72 hours prior may be advisable. Note that a newer drug, cangrelor, is a non-thienopyridine drug that also inhibits the P2Y12 receptor in a similar manner to the thienopyridines but has a much shorter half-life.

Glycoprotein IIb/IIIa receptor inhibitors Activation of GP IIb/IIIa receptors is a crucial near-final step in platelet aggregation, and platelets genetically deficient in these receptors (i.e., Glanzmann thrombasthenia) display a much more profound inhibition of aggregation than platelets altered by the limited effects of aspirin or thienopyridines. As a result, attention has been focused on developing agents that can antagonize the GP IIb/IIIa receptors. The first agent, abciximab, is a mouse-human chimeric monoclonal antibody protein. The highly variable region of the antibody is from the mouse and is directed against the human GP IIb/IIIa protein complex. The Fc region is human, however, so as to not engender an immunogenic response. No allergic or anaphylactic reactions have been reported, but the medication can result in severe thrombocytopenia. Molecular analysis of the GP IIb/IIIa receptors indicates that they recognize a specific arginine-glycine-aspartic acid (RGD) sequence found in many of the adhesive molecules to which they bind (e.g., vWF). As a result, peptide analogues have been developed to bind at this RGD sequence and compete for the active sites. (Similarly, the venom of several species of viper contains peptides with similar RGD homologic features; these peptides bind to the GP IIb/IIIa receptors in an antagonistic fashion.) Eptifibatide is a currently available example

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from this group. Rather than an RGD sequence, it has a lysine-glycine-aspartic acid (KGD) sequence that imparts improved specificity for the GP IIb/IIIa receptor. Other nonpeptide agents that can compete for binding with the GP IIb/IIIa receptor have been developed. Similar to eptifibatide, they have structure and charge characteristics that mimic the RGD sequence and compete for the receptor’s docking. Tirofiban (a tyrosine derivative) is an example of this kind of medication.

Herbal and Dietary Supplements There is great academic interest in the surging herbal and dietary supplement use in current society and whether these agents may have pharmacologic action. Many of these agents have been implicated in directly modifying the coagulation status of patients or indirectly interacting with Western medications to increase or decrease their pharmacokinetic profiles. Appendix 2 lists many of these compounds. As more data become available, it will be necessary for the dentist to be knowledgeable about what these medications might do in a patient who requires dentoalveolar or other oral surgery.

IMPLICATIONS FOR DENTISTRY Surgical Pharmacologic Adjuncts “Local control measures” is a term often used in the literature to describe non-pharmacologic methods of obtaining or hastening hemostasis. Examples include direct pressure, suturing with or without primary closure, intrasocket sponges of one variety or another, injection of local anesthetic with epinephrine for capillary vasoconstriction, and clotting agents such as fibrin sealants. In the non-complicated surgical scenario, the best approach by far is to allow a normal, natural blood clot to form without additional intervention. Direct, firm, sustained gauze pressure, maintained without “peeking” for 15 to 20 minutes, is generally all that is necessary to successfully stop bleeding in the intraoral environment. If gingival tissues are loose and can be better approximated by suturing, this serves to decrease the socket size and will likely improve the speed of hemostasis. When a patient has excessive bleeding, the practicing dentist has several options from which to select. While all intrasocket preparations (oxidated cellulose, gelatin, collagen) can help, collagen is generally best. Platelets activate with collagen exposure, and the material is considered to be much more natural and therefore kinder to the inflammatory and reparative processes than cellulose or gelatin. As a result, the healing is usually smoother and faster as the body can break down the collagen easily over time. Another option to consider is topical thrombin or fibrin sealants. The latter has the disadvantage that it takes 30 to 60 minutes to prepare and so is generally used in the practice of medical surgery for planned events rather than unplanned, urgent bleeding problems. Topical thrombin, on the other hand, can be quickly reconstituted with a sterile solution (usually local anesthetic) and soaked into a collagen plug and placed tightly into the socket in a matter of minutes. This generally stops the bleeding. If the use of suturing, collagen, and thrombin fail to adequately control the bleeding, the dentist must consider two other possibilities. The first is that the platelets are sluggish and failing to activate appropriately; transfusion of a “six pack” (six units) of platelets may be necessary. The other option is that the plasmin in the local area is outrunning the clot formation, effectively breaking up the clot as quickly as it is trying to form. In this instance, application of an oral rinse of tranexamic acid or aminocaproic acid may be helpful. This scenario is particularly common if the patient presents several hours after the surgery with complaints of excessive oozing from the surgical site.

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Of course, if all of these methods fail to control the bleeding, emergent care in a hospital setting may become necessary for both transfusion support and possibly additional surgical intervention to ligate feeder vessels. It must be remembered that many cases of mild hemophilia remain undiagnosed during childhood and only present at the time of the patient’s first significant surgical experience, such as removal of teeth for orthodontic reasons or removal of wisdom teeth. Thankfully, in modern dental/medical practice, it is extremely rare to have to deal with true uncontrolled bleeding, and permanent morbidity or mortality is almost unheard of.

Patients Using Anticoagulants There are no accepted indications for the use of anticoagulants in the practice of dentistry. Many patients requiring dental treatment receive some form of medical anticoagulation therapy, however, for the reasons previously cited. These patients present three kinds of problems to the dentist: (1) without possible modification, their therapeutic regimen may result in excessive bleeding after oral or periodontal surgery; (2) modification of their therapeutic regimen in preparation for surgery may predispose them to thromboembolic events; and (3) they may present a real danger of drug interaction between their anticoagulants and agents commonly used in dental practice, such as some analgesics, antibiotics, and sedatives. It is essential for the dentist to have a complete and thorough knowledge of the patient’s drug history and what options are available when treating patients in whom anticoagulant therapy is involved. Any intended oral surgical therapy in anticoagulated patients requires preliminary planning and consultation with the patient’s physician or anticoagulation clinic. Warfarin is monitored by the INR. The INR test is performed by adding a source of TF and Ca2+ to a patient’s citrated blood sample and measuring the time necessary to coagulate the sample. Because various laboratories use TF from different sources (human, rabbit, recombinant), there have been wide variations in the reported values and the resulting amount of anticoagulation. In an effort to normalize the activity of the various forms of TF, a formula has been developed that accounts for the inherent sensitivities of TF and individual laboratory methods. The resultant ratio, the INR, can be compared with any other INR value with high accuracy. Because the INR is derived from an exponential formula, small changes in anticoagulation result in large changes in the INR value as the anticoagulation progresses. It is generally agreed that for warfarin a INR value of 2.5 to 3.0 is considered ideal for most medical conditions. Prosthetic heart valves and other instances in which more anticoagulation is required generally have a target value of 2.5 to 3.5. Although there are no official recommendations from the American Dental Association on the topic of INR and dental treatment, one report recommends that a INR of 4.0 be used as the upper limit for simple oral surgical procedures and that a maximum of 3.0 be targeted for procedures likely to result in significant blood loss, such as multiple extractions with alveoloplasty. Others have agreed that it is unusual to have significant clinical bleeding when the INR is less than 3.0. If a patient is anticoagulated to a high INR value, the dentist should consult with the physician about the possibility of reducing the anticoagulation to an acceptable INR, as shown in Figure 26-8. A unilateral decision by a dentist to have his or her patient discontinue or decrease coumarin without consulting the physician is at best poor medical practice because medicolegally, even if the warfarin is ultimately decreased, the physician is the appropriate individual to alter and follow the dosages perioperatively. This adjustment may take several days to accomplish. Current medical practice often places the responsibility of the anticoagulation management with an anticoagulation clinic that tracks

the INR on a consistent basis, and such a clinic is a reliable resource to help guide the dentist and patient in making therapeutic decisions. Some patients have erratic responses to warfarin, with unpredictable highs and lows in the INR despite the best efforts of the medical team to stabilize it. In these patients, the prudent dentist will obtain a INR on the day of surgery and is prepared to reschedule the appointment if the value is too high to be safe. In the emergent patient, reversal with vitamin K and use of local hemostatic measures (collagen plugs, suturing, topical thrombin, fibrin sealant) may be indicated; in severe cases, the administration of fresh frozen plasma may be necessary. If the anticoagulant is intravenous heparin, the drug may be withheld by the physician for 1 to 6 hours. This time interval is dose dependent. If the heparin is to be restarted after surgery, typically waiting at least 1 hour is advisable to allow time for the clot to form fully. The use of local hemostatic agents may be considered for further hemorrhage control. Note that subcutaneous “maintenance” heparin absorbs into the bloodstream at such a slow rate that it can be effectively ignored in terms of dental bleeding issues. Patients who are taking an LMWH such as enoxaparin present a dilemma. Because LMWHs stimulate ATIII to be active against factor Xa but are not very effective against thrombin (factor IIa), the INR and aPTT in these patients are usually normal. A special factor Xa assay (costly and not always available) can be used to monitor these medications. The question arises as to what a dentist should do when patients are using these agents on a daily basis. Data are limited; however, it has been suggested that the LMWH should be discontinued for 12 hours before the surgical event. It can be argued, however, that for simple surgical procedures (e.g., dentoalveolar surgery, periodontal surgery), if there is sufficient thrombin generation to maintain the aPTT at a normal value, perhaps no adjustment to the regimen needs to be made. Anecdotal evidence supports this latter concept. Several studies have shown that postoperative bleeding after minor oral surgery, including tooth extraction, is not significantly affected by long-term aspirin therapy. Although such studies are not currently available with respect to thienopyridines such as clopidogrel—either taken alone or with aspirin—an advisory report regarding patients with coronary artery stents states “there is little or no indication to interrupt antiplatelet drugs for dental procedures.” (See Grines et al., 2007.) This conclusion is based on a paucity of reported bleeding problems after dental procedures, easy access to the affected tissues, and the high effectiveness of local measures in controlling oral bleeding. Should unusual circumstances dictate the need to restore platelet function to normal before treatment, withholding antiplatelet drugs for 3 to 7 days may be necessary because of the irreversible nature of the antiplatelet actions of aspirin and clopidogrel. The patient’s physician should be involved in any plan to limit antiplatelet therapy. Local measures coupled with platelet transfusion as required may be necessary if the clinical situation is emergent or too risky to have the patient off these medications for several days. The direct thrombin and factor Xa inhibitors currently have no data to suggest how to guide the dentist/oral surgeon in managing patients prior to surgery. Generally if the aPTT is normal, it can be argued that it is safer to leave the patients on these medications rather than discontinue them for a period of time, particularly if the extent of planned surgery is minor. If more extensive bleeding is expected, or if the aPTT is elevated, consultation with the physician becomes necessary. Generally they will remove the patient from these medications for 2 to 3 days prior to surgery and restart the following day after surgery.

Hemophiliacs Managing a patient with hemophilia and other coagulopathies has become significantly easier in recent years, but many issues require

CHAPTER 26  Procoagulant, Anticoagulant, and Thrombolytic Drugs

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INR

<4.0

Extent of surgery?

Minimal bleeding expected (minor surgical procedure)

No modifications required; use local measures

Moderate bleeding expected (multiple extractions, third molars)

Consider reducing INR; use local measures

>4.0

No surgical treatment until INR is reduced

Significant bleeding expected (full mouth clearance)

Modify anticoagulation to achieve an INR of <3.0; use local measures

FIG 26-8  Flow chart for determining the appropriateness of dental therapy based on the prothrombin time. INR, International normalized ratio. (From Beirne OR, Koehler JR: Surgical management of patients on warfarin sodium. J Oral Maxillofac Surg 54:1115–1118, 1996.)

careful consideration before proceeding. The most difficult problem a hemophilic faces outside of dentistry is not the threat of exsanguination from a small laceration but rather the problems encountered from a massive muscle bleed or chronic joint disease resulting from hemarthroses. In dentistry, surgical procedures must be planned so that replacement factor can be given preoperatively and postoperatively. Most patients can now be treated routinely in either the hospital or dental office. An important issue involves prediction of where an uncontrolled hematoma might develop in the head and neck region. Any potential space that might support the movement of blood through fascial planes toward crucial structures (e.g., the airway or major blood vessels) needs to be considered for “vented” wound management. In these areas, suturing to a tight, primary closure may be contraindicated so as to allow any accumulation of blood to drain preferentially into the oral cavity rather than fill crucial spaces. Conversely, whenever the wound site is sufficiently removed from worrisome dissection paths (e.g., an anterior frenectomy), closure should be sutured tightly to help control localized bleeding. For similar reasons, the dentist must take care that inferior alveolar or posterior superior alveolar nerve block injections of local anesthetic are adequately covered by factor replacement to reduce the risk of hemorrhage into muscle or one of the parapharyngeal areas or both. The use of a commercial intraosseous anesthetic delivery system (Stabident, X-Tip) is indicated for patients in whom block anesthesia is contraindicated. Profound anesthesia usually can be easily obtained with minimal hemorrhage risk when these systems are used in hemophiliacs. Associated disorders that commonly occur with hemophiliacs also may affect the delivery of dental care. Hemophiliacs often have joint disorders resulting from hemarthrosis. Any spontaneous or trauma-induced bleeding into the synovial space of a joint may cause

permanent damage if inflammatory by-products, produced as the blood breaks down, damage the surrounding cartilaginous and bony structures. Knees, ankles, and elbows are most commonly affected, and many hemophiliacs have permanent limitation of motion in their joints by the time they reach adulthood. Joint replacement surgery is common in patients with severe hemophilia. As a result, mobility in and out of the operatory and positioning in the chair itself may be compromised. Because of the historic necessity of transfusing hemophiliacs with pooled human blood products before recombinant factor replacements were available or the products were treated with heat or solvent detergent to inactivate viruses, many hemophilic patients were infected with HIV, hepatitis B virus, and hepatitis C virus. Seroconversion to HIV began around 1979 and accelerated rapidly until the mid-1980s. Many of these patients have since died. Screening donors began in the 1970s for hepatitis B, in 1985 for HIV, and in 1990 for hepatitis C. This screening has significantly reduced, but not eliminated, the viral risk. Noninfected hemophiliacs (primarily children and teens) are now being given recombinant factor replacements, whereas infected hemophiliacs more often select pooled human-­ derived, virally inactivated products. In uninfected patients for whom no recombinant factor replacement is available, and especially in families with vWD that is not responsive to desmopressin, the use of single-donor cryoprecipitate (usually a family member) for all necessary transfusions has proved effective in reducing the risk for viral transmission. When surgical procedures are required in hemophiliacs, it is imperative that the dentist work closely with a hematologist well versed in the care of these patients. The dentist should describe the nature of the proposed surgery, the expected amount of bleeding, and the normal postoperative course after the procedure. In this way, the hemophilia treatment center can best plan how much and

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CHAPTER 26  Procoagulant, Anticoagulant, and Thrombolytic Drugs

which kinds of factor replacement (or other pharmacologic intervention, such as desmopressin) are most appropriate. Depending on the training, location (office versus hospital), and experience of the treating dentist, the blood product or factor replacement may be given in the dental office, the medical office, or perhaps at home by the patient. Most of the products have an in vivo half-life of several hours, allowing the patient to receive the product at another site and go to the dental office for treatment with no reduction in hemostatic ability. The normal healing mechanism of a wound site involves breakdown and reestablishment of newer fibrin matrices as the tissue



heals. In a patient with a coagulopathy, the normal breakdown of fibrin can result in a rebleeding episode a few days later. Stabilization of the clot with an antifibrinolytic medication such as tranexamic or aminocaproic acid helps reduce the incidence of bleeding episodes for several days postoperatively. In many cases, the use of these antifibrinolytics can greatly reduce or eliminate the need for additional blood or factor replacement. Adjunctive measures, such as the use of local hemostatic agents (microfibrillar collagen, suturing, thrombin, or fibrin sealant), may also be helpful.

AGENTS THAT AFFECT COAGULATION AND HEMOSTASIS Nonproprietary (Generic) Name Proprietary (Trade) Name

Nonproprietary (Generic) Name Proprietary (Trade) Name

Astringents-Styptics Aluminum chloride Tannic acid

Hemodent In tea bags

Enoxaparin Fondaparinux Tinzaparin

Vasoconstrictor Epinephrine

Adrenalin

Topical Procoagulants Absorbable gelatin film Absorbable gelatin powder Absorbable gelatin sponge Absorbable gelatin sponge with thrombin (human) Fibrin sealant (human) Gelatin matrix with thrombin (human) Microfibrillar collagen Oxidized cellulose Oxidized regenerated cellulose Thrombin (bovine) Thrombin (recombinant)

Direct Thrombin Inhibitors

Gelfilm Gelfoam Gelfoam, Surgifoam Gelfoam Plus

See Table 26-2

Fibrinolytics Alteplase (t-PA) Anistreplase Reteplase Streptokinase Tenecteplase Urokinase (u-PA)

Activase Eminase Retavase Streptase TNKase Abbokinase Amicar Cyklokapron (IV) Lysteda (tablets)

Directly Acting Anticoagulants Unfractionated Heparin

Heparin†

—

Low-Molecular-Weight Heparins

Ardeparin* Dalteparin

Argatroban Bivalirudin Dabigatran Desirudin Hirudin Lepirudin

Novastan Angiomax Pradaxa Iprivask Hirudo medicinalis‡ Refludan

Factor Xa Inhibitors

Artiss, Tisseel FloSeal Avitene Oxycel Surgicel Thrombin-JMI RECOTHROM

Systemic Procoagulants

Fibrinolysis Inhibitors Aminocaproic acid Tranexamic acid

Lovenox Arixtra Innohep

Normiflo Fragmin

*Not currently available in the United States. †Available in calcium and sodium salts. ‡Organism of origin.

Apixaban Betrixaban Edoxaban Rivaroxaban Indirectly Acting Anticoagulants Warfarin

Eliquis Savaysa Xarelto Coumadin

Antidotes for Anticoagulants Idarucizumab Praxbind Menadiol* (vitamin K4) Synkayvite Menadione (vitamin K3) — Phytonadione (vitamin K1) Mephyton Prothrombin complex concentrate (human) Kcentra Protamine sulfate — Platelet Inhibitors Abciximab Aspirin Cangrelor Clopidogrel Dipyridamole Prasugrel Eptifibatide Ticlopidine Tirofiban

ReoPro — Kengreal Plavix Persantine Effient Integrilin Ticlid Aggrastat

Coagulation Factors

Listed in chapter

CHAPTER 26  Procoagulant, Anticoagulant, and Thrombolytic Drugs

CASE DISCUSSION Given Mr. J’s history of ongoing cardiac issues, it is recommended that you consult with his medical doctor to confirm that his overall health can handle the stress of multiple extractions in the outpatient office setting. If not, then referral to an oral surgeon or hospital dentist who performs the procedure in an operating room with a cardiac anesthesiologist is best. Assuming that he can be managed conservatively, then ordering INR and aPTT tests is indicated. If both of these tests come back within therapeutic limits (INR < 3.0 and aPTT normal), then no alteration to his anticoagulation may be necessary. If the managing MD is comfortable stopping the dabigatran for 2 to 3 days prior to the procedure, this will gain you an extra margin of safety. However, if not, then it may be best to keep the patient on the anticoagulant and plan to treat in a controlled hospital setting. It may also be wise to consider phased extractions (a few teeth at a time) rather than attempting to remove all of the teeth in one visit. Should intraoperative hemorrhage become greater than expected, use of suturing (ideally primary closure) and collagen plugs (+/− reconstituted thrombin) is recommended. Of course, direct firm sustained gauze pressure is always required. This will be effective the vast majority of the time. If this fails to adequately control the bleeding, stop the procedure, and prepare the patient for transport to your local hospital for additional expert management.

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GENERAL REFERENCES 1. AHFS drug information 2015, Bethesda, MD, 2015, American Society of Health-System Pharmacists. 2. Grines CL, Bonow RO, Casey Jr DE: Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians, J Am Dent Assoc 138:652–655, 2007. 3. Hillman RS, Ault KA, Leporrier M, Rinder H: Hematology in clinical practice, ed 5, New York, 2010, McGraw-Hill. 4. Kaushansky K, Lichtman MA, Beutler E, et al.: Williams hematology, ed 8, New York, 2010, McGraw-Hill. 5. Papadakis MA, McPhee SJ, Rabow MW, editors: Current medical diagnosis and treatment 2015, Stamford, CT, 2015, Lange Medical Books/ McGraw-Hill. 6. Weitz J: Blood coagulation and anticoagulant, fibrinolytic, and antiplatelet drugs. In Brunton LL, Chabner B, Knollman B, editors: Goodman & Gillman’s the pharmacological basis of therapeutics, ed 12, New York, 2010, McGraw-Hill.