Perioperative Management of Oral Antithrombotics in Dentistry and Oral Surgery: Part 1
Increasing numbers of patients seeking dental care are at heightened thrombotic or thromboembolic risk and are therefore taking either oral antiplatelet (OAP) or oral anticoagulant (OAC) agents that disrupt the coagulation process. In addition, the arsenal of OAP and OAC agents in use has continued to expand as new drug development persists. The impairment of functional coagulation by these agents can lead to prolonged and/or major blood loss from surgical sites during invasive dental procedures. To properly manage these patients perioperatively, sedation and anesthesia providers for dentistry and oral surgery must understand the pharmacokinetics and pharmacodynamics of these agents as well as the factors that influence and augment bleeding and thrombotic risk. Part 1 of this review will present a summary of the coagulation processes and discuss the pharmacokinetic and pharmacodynamic properties of oral antithrombotics currently approved for use in the United States. Part 2 will focus on factors that affect perioperative management of antithrombotic agents with special consideration given to procedures typically encountered when providing sedation and anesthesia in the dental setting.
HEMOSTASIS AND COAGULATION
Hemostasis is the body's normal response to stop bleeding and involves the processes of forming and ultimately degrading a fibrin clot at the site of a vessel injury. It involves the complex coordination of 4 components: (1) vascular endothelium, (2) platelet aggregation, (3) coagulation factor activation, and (4) fibrinolysis.1 Upon damage or disruption to the vascular endothelium, primary hemostasis occurs within seconds, consisting of vasoconstriction of the damaged vessels and initiation of platelet aggregation forming a platelet plug. Vasoconstriction of the injured vessel occurs via release of humoral factors from activated platelets in smaller blood vessels and via sympathetic-mediated vasoconstriction in larger vessels.2 To form the platelet plug, inactive circulating platelets initially adhere to subendothelial collagen stabilized by von Willebrand factor (vWF). Activation and binding of platelets to the exposed collagen leads to subsequent formation of thromboxane A2 (TXA2). Platelet degranulation also occurs, which releases a number of substances including vWF, adenosine diphosphate (ADP), factor V, and other substances that attract and activate additional platelets.2,3
Platelet aggregation is also augmented by the activation of ADP-bound P2Y12 receptors located in the platelet membrane. Once activated by ADP, these G-inhibitory protein receptors inhibit adenylyl cyclase and thus promote more platelet aggregation. In addition, P2Y12 receptor activation antagonizes the action of the antiplatelet eicosanoid prostacyclin, promoting further aggregation.4
Coagulation is the next stage of hemostasis and involves the activation of protein precursors to form a fibrin clot, which binds and strengthens the platelet plug. The clotting cascade has classically been described as 2 distinct pathways, the extrinsic and intrinsic, that converge to a common pathway with the activation of factor X (factor Xa; Figure 1).
Citation: Anesthesia Progress 69, 3; 10.2344/anpr-69-03-05
However, coagulation in vivo occurs via a more complex process. A more contemporary coagulation model was developed to better describe in vivo clotting that involves 3 phases: the initiation phase with activation of small quantities of clotting factors, the amplification phase of clotting factors, and the propagation phase of clot formation by thrombin. Tissue factor exposure following vascular injury activates factor VII (factor VIIa; Figure 2A), which activates small amounts of factors X and IX (Figure 2B). Factor Xa both activates and forms complexes with factor V to form the prothrombinase complex, which converts a small amount of prothrombin (factor II) into thrombin (factor IIa; Figure 2C). The process is then amplified both by the thrombin itself, activating larger amounts of factors V, VIII, and XI and platelets, as well as by a high-efficiency tenase-complex composed of factors VIIIa and IXa, which generates large amounts of factor Xa (Figure 2D-F). In addition to amplification of the clotting cascade, thrombin also further propagates clot formation by converting fibrinogen (factor I) into fibrin (factor Ia), which binds to other fibrin monomers and to platelets via glycoprotein IIb/IIIa (GP IIb/IIIa) to form a strong and insoluble blood clot (Figure 2G).
Citation: Anesthesia Progress 69, 3; 10.2344/anpr-69-03-05
Fibrinolysis is required for breakdown of the fibrin clot. Tissue plasminogen activator is released by endothelial cells in response to thrombin and converts plasminogen into plasmin on the fibrin clot surface. Eventually, plasmin degrades fibrin and fibrinogen along with other clotting factors to break down the formed clot.2
ORAL ANTIPLATELET AGENTS
It is estimated that 9.3% (26.1 million) of the adult population in the United States suffers from cardiovascular disease, including atherosclerosis.5 Such conditions commonly include acute coronary syndrome (ACS), coronary artery disease, peripheral arterial disease, ischemic cerebrovascular accidents, and transient ischemic attacks.6 Oral antiplatelet (OAP) agents are the cornerstone of pharmacologic management for these atherothrombotic conditions, helping prevent disease progression and related complications by disrupting normal platelet function (Table 1). Broadly speaking, all of the current OAPs target either the activation or aggregation of platelets.
Cyclo-oxygenase Inhibitors
Acetylsalicylic acid (ASA; aspirin) is the most common OAP used globally. ASA acts within the arachidonic acid cascade to decrease prostanoid production via inhibition of cyclo-oxygenase (COX)–1 and 2. It irreversibly acetylates a serine residue on COX-1 enzymes, ultimately preventing TXA2 generation. Without TXA2, vasoconstriction and platelet aggregation are impaired.9,10 Although other nonsteroidal anti-inflammatory drugs such as ibuprofen and naproxen act similarly, their respective COX inhibition is reversibly transient and lasts only while the drug is present.
ASA is rapidly absorbed in the upper gastrointestinal (GI) tract, resulting in measurable platelet function inhibition within 60 minutes. The plasma half-life of ASA is only 20 minutes, with 90% being metabolized in the liver and 10% renally excreted. Although its plasma half-life is short, the antiplatelet action of ASA is permanent and endures for the life span of a given platelet (7-10 days). Doses of ASA >100 mg will effectively cease production of TXA2 in platelets, while lower doses have a dose-dependent inhibitory effect on TXA2 production.9
A notable side effect of ASA's COX-1 inhibition stems from the diminished production of PGE2, a cytoprotective prostaglandin in the gastric mucosa. This can lead to GI symptoms such as nausea or, in some cases, significant GI bleeding.
P2Y12 Receptor Antagonists
The P2Y12 receptor antagonists can be used in combination with ASA for patients requiring dual antiplatelet therapy. In addition, these agents are now being used in single antiplatelet regimens for secondary prevention of atherosclerotic cardiovascular disease. These agents prevent the binding of ADP to the P2Y12 receptor, which impairs the aggregation of platelets and binding of fibrinogen to platelets via GPIIb/IIIa indirectly. The 2 classes of P2Y12 receptor antagonists are thienopyridine derivatives and direct-acting nucleoside derivatives.
Thienopyridine Derivatives
Clopidogrel (Plavix), the first US Food and Drug Administration (US FDA) approved irreversible P2Y12 antagonist, is a thienopyridine derivative. It is a prodrug that undergoes 2 sequential oxidative reactions involving several cytochrome P450 (CYP) enzymes, mainly CYP2C19, to generate an active metabolite.6 Drug-to-drug interactions (DDIs) involving CYP2C19 activity can affect metabolite formation. Proton pump inhibitors used for gastroesophageal reflux disease can attenuate clopidogrel activation via this mechanism.11
Prasugrel (Effient), a newer irreversible P2Y12 antagonist, is a prodrug similar to clopidogrel. It is hepatically activated via both CYP3A4 and CYP2B6, resulting in fewer DDIs when compared with clopidogrel. Prasugrel exhibits a higher degree of P2Y12 antagonism achieved more rapidly and more consistently than clopidogrel does.12 Because of this, prasugrel is often recommended over clopidogrel for patients with ACS undergoing percutaneous coronary intervention.6
Both clopidogrel and prasugrel are irreversible P2Y12 antagonists. Therefore, like ASA, their antiplatelet effects last for the lifetime of the platelets (7-10 days), even though their plasma half-life is less than 1 hour.
Direct-Acting Nucleoside Derivatives
Ticagrelor (Brilinta) is an adenosine triphosphate analog that binds reversibly to the P2Y12 receptor at a site separate from where ADP binds to the receptor. Unlike the thienopyridine derivatives, ticagrelor requires no metabolic activation. It is metabolized mostly by CYP3A4 to a secondary active metabolite that makes up 30% to 40% of the pharmacologically active circulating drug.6 Ticagrelor provides a more rapid onset and offset of antiplatelet action than the thienopyridine derivatives, with peak inhibition 2 to 4 hours after administration and nearly normal platelet function after 5 days.
Other OAP Agents
PAR-1 Antagonists
Vorapaxar (Zontivity), which was approved by the US FDA in 2014, is an oral reversible protease-activated receptor-1 (PAR-1) antagonist that inhibits thrombin-related platelet aggregation. PARs are G protein–coupled receptors highly expressed on platelets and endothelium. Under normal conditions, thrombin (Xa) cleaves the silencing domain (ie, the exterior amino terminal) of the PAR complex, leading to activation of GPIIb/IIIa, which binds platelets with fibrinogen. Vorapaxar disrupts this pathway and can be prescribed in combination with standard antiplatelet therapies for secondary thrombosis prevention in patients with a history of myocardial infarction.6
Cyclic Adenosine Monophosphate–Related Agents
Agents that increase cyclic adenosine monophosphate (cAMP) concentration inhibit platelet activation, although the specific mechanism is unclear.13 Increased intracellular cAMP production can be stimulated by the intravenous agent iloprost, a synthetic prostacyclin analog, while decreased degradation of cAMP occurs with phosphodiesterase inhibitors such as dipyridamole (Persantine) and cilostazol.6
ORAL ANTICOAGULATION
Anticoagulation with oral agents is an essential component when treating patients with active thromboses or to prevent thromboembolic complications in patients with atrial fibrillation, mechanical heart valves, venous thromboembolism (VTE), pulmonary embolism, or elevated VTE risk. About 6 million patients are on long-term anticoagulation in the United States.14 This number is rising due to an aging population, higher age-adjusted incidence of chronic illness, and advances in early detection of elevated thromboembolic risk. Since the 1950s, vitamin K antagonists (VKAs) such as warfarin have been the principle oral anticoagulant (OAC) agents in use.15 However, since 2010, a number of direct-acting OACs (DOACs) received US FDA approval and are gaining traction due to a more favorable pharmacologic profile than VKAs with equivalent risk reduction of thromboembolic events for many conditions.14,16
Vitamin K Antagonists
Warfarin (Coumadin) has been safely used for anticoagulation for decades. It exerts its anticoagulant action by interfering with the posttranslational modifications of several coagulation factors (II, VII, IX, X) as well as the naturally occurring endogenous anticoagulant factors (proteins C and S). This occurs indirectly via inhibition of the vitamin K oxide reductase (VKOR), which prevents the carboxylation of glutamate in factors II, VII, IX, and X.15,17 Without the carboxylation of glutamate, the activity of these factors is severely reduced.
Warfarin is formulated as a racemic mixture of R and S enantiomers. The S enantiomer is 2 to 3 times more potent than the R enantiomer and undergoes oxidative metabolism almost exclusively with CYP2C9 as the primary enzyme. The R enantiomer undergoes oxidative metabolism via CYP1A2 and CYP3A4.17
Warfarin does not inhibit coagulation factors that have already undergone their posttranslational modification, so its onset of action will be dependent on the half-life of these activated factors. Initiation of warfarin therapy often leads to a transient procoagulant state because of the shorter half-life of regulatory anticoagulant proteins C and S (8 and 30 hours, respectively) when compared with the half-lives of factors II and X (60 and 72 hours, respectively). Therapeutic anticoagulation typically becomes clinically relevant within 4 to 6 days.18,19 The return of normal coagulation after cessation of warfarin therapy takes ∼5 days due to its long half-life of 36 to 42 hours.17
Several agents exist for warfarin reversal depending on the urgency of the situation. These agents include vitamin K, 4-factor prothrombin complex concentrate (with factors II, VII, IX, and X), 3-factor prothrombin complex concentrate (with factors II, IX, and X), and fresh frozen plasma.14
Genetic polymorphisms in genes that encode VKOR and CYP2C9 as well as hundreds of DDIs and drug-food interactions can cause significant variation in the anticoagulant effects of warfarin between individuals and within the same individual at different times.17 For this reason, frequent monitoring of anticoagulation status is warranted in patients on warfarin using prothrombin time and international normalized ratio (INR). The therapeutic INR for warfarin generally ranges from 2.0 to 3.0 with select patients at higher thromboembolic risk (eg, patients with a mechanical heart valve or recurrent systemic emboli) requiring higher INR values (2.5-3.5).19
Although warfarin has a well-established track record for treating and preventing thromboembolic complications, its use is hampered by several drawbacks including a delayed onset and offset of action, a narrow therapeutic range for clinical effectiveness, genetic variations of metabolism, and numerous food and drug interactions as well as a need for frequent monitoring and dose adjustments.15
DOACs
Due to the suboptimal pharmacokinetics and pharmacodynamics of the VKAs, there was motivation to develop OACs that act directly upon specific clotting factors. The first DOAC, dabigatran (Pradaxa), received US FDA approval in 2010. All of the current DOACs have faster onset and offset times than warfarin, less genetic variation, and fewer food and drug interactions and do not require frequent monitoring (Table 2). These features, in addition to a better risk-benefit profile, have led to the rapid adoption of DOACs for the anticoagulation of patients with nonvalvular atrial fibrillation or elevated risk of VTE.21–25 Two features of DOACs that have limited their widespread use were cost and lack of direct reversal agents. The DOACs have all existed as brand-name medications, leading to higher costs than VKAs. In 2019, apixaban (Eliquis) was granted generic approval, and although immediate product availability is limited, it is a promising development to reduce the cost of DOACs.26 In addition, new direct reversal agents idarucizumab (Praxbind) and andexanet alfa (Andexxa) now exist for direct thrombin inhibitors and factor Xa inhibitors, respectively.14 However, reversal agents are extremely expensive, with andexanet alfa costing between $25,000 and $50,000 for a single dose, limiting their utility to emergent situations.27
Currently, US FDA-approved DOACs work by 1 of 2 mechanisms: direct thrombin inhibition (dabigatran) or factor Xa inhibition (apixaban, edoxaban, rivaroxaban).26
Direct Thrombin Inhibitors
Dabigatran (Pradaxa). Dabigatran is a selective reversible direct thrombin inhibitor that is commercially produced as dabigatran etexilate to allow for enteral absorption. Plasma levels of dabigatran peak within 2 to 3 hours of a single dose, and with repeated dosing, the terminal half-life is 12 to 17 hours. About 15% of dabigatran is conjugated to pharmacologically active but unstable glucuronides, while nearly 85% is renally excreted unchanged. Because of the significant renal excretion, patients with creatinine clearances less than 30 mL/min may need to adjust dosage, and the duration of action will be extended.17
Factor Xa Inhibitors
Apixaban (Eliquis). Apixaban is a highly selective reversible factor Xa inhibitor. Peak plasma levels occur 3 hours after oral administration, and the terminal half-life is 8 to 15 hours. Roughly 75% of circulating apixaban undergoes oxidative metabolism in the liver via CYP3A4, and the other 25% is renally excreted unchanged.20
Rivaroxaban (Xarelto). Like apixaban, rivaroxaban is a selective reversible factor Xa inhibitor. Plasma levels of rivaroxaban similarly peak 3 hours after a dose, and the terminal half-life is 5 to 13 hours. Approximately 66% of rivaroxaban undergoes oxidative metabolism by CYP3A4 and CYP2J2 prior to excretion, while the remaining third is renally excreted unchanged.17
CONCLUSION
During the perioperative milieu, patients on OAP and OAC agents are at an elevated risk of significant bleeding due to impaired hemostasis. With these patients presenting in the dental setting more frequently, it is critical for sedation and anesthesia providers to understand the indications for these drugs as well as their pharmacokinetic and pharmacodynamic characteristics to minimize excessive blood loss as well as thrombotic or thromboembolic complications. Part 2 of this review will discuss the factors involved in determining if the hemostatic benefits of stopping these antithrombotic agents outweigh the thrombotic and thromboembolic risks associated with their cessation. If it is determined that cessation is necessary, the pharmacologic features outlined above will guide the optimal timing of discontinuing and restarting these agents.
Classic coagulation cascade model featuring the extrinsic, intrinsic, and common coagulation pathways.
Contemporary coagulation model demonstrating the 3 phases: activation (A-C), amplification (D-F), and clot propagation (G).3
Contributor Notes