Anticoagulation Regimens and Associated Anesthetic Concerns
Antiplatelet therapy is indicated for patients at risk of cerebrovascular accident, myocardial infarction (MI), or other vascular thrombosis complications.
There are two forms of the COX enzyme with variable distribution throughout the body. COX-1 plays an integral part in maintaining the integrity of the gastric lining, renal blood flow, and initiating the formation of thromboxane A2, an important molecule for platelet aggregation.
Inhibition of COX-1 puts the patient at risk for bleeding as well as gastrointestinal and renal morbidity. COX-2 is primarily responsible for synthesizing the prostaglandin mediators of pain and inflammation.
The current recommendations from the American Heart Administration for the therapeutic use of COX-2 inhibitors, namely celecoxib, in patients with cardiovascular disease emphasize using the lowest effective dose in conjunction with a proton pump inhibitor and low dose aspirin.
Phosphodiesterase inhibitors are primarily used for stroke prophylaxis because they increase the production of cyclic adenosine monophosphate, which is an active inhibitor of platelet aggregation.
These drugs are used for patients with coronary artery disease to prevent MI, for stent thrombosis, and for patients with cerebrovascular or peripheral artery disease to inhibit thromboembolism.
Clopidogrel is the most commonly prescribed agent in this class and acts as a noncompetitive and irreversible antagonist. It is an inactive prodrug that requires oxidation to its active metabolite. A genetic polymorphism results in the inability to metabolize clopidogrel, making it ineffective and putting patients at risk for cardiovascular morbidity and mortality.
GP IIb/IIA receptor blockers (abciximab, tirofiban, eptifibatide) inhibit the cross-linkage of fibrinogen, the final step in the common hemostatic pathway for platelet aggregation.
These agents are administered only intravenously and primarily used for management of acute coronary syndrome.
Their effects can be monitored with activated clotting times and are reversible with clearance of the drug.
All of these drugs cause thrombocytopenia, but the effect is strongest with abciximab with an incidence of about 2.5% as opposed to 0.5% with the other receptor antagonists.
Warfarin is an oral anticoagulant therapy used as the first-line agent for management of hypercoagulable disorders, venous thromboembolism (VTE), and stroke prophylaxis for patients with atrial fibrillation or mechanical heart valves.
Warfarin therapy is monitored with the INR (therapeutic targets generally range between 2 and 3).
Emergency reversal for patients with major bleeding or those who require immediate surgery can be achieved with a 25- to 50-µg/kg dose of 4-factor prothrombin complex concentrates that contain active factors II, VII, IX, and X.
Dabigatran (Pradaxa), a DTI, and the factor Xa inhibitors (rivaroxaban and apixaban) have completed phase III trials and passed US Food and Drug Administration approval for stroke prophylaxis and therapeutic anticoagulation for patients with history of VTE.
If urgent antagonism is necessary, it makes the most sense to attempt reversal with prothrombin complex concentrates (PCCs) that contain factors II, VII, IX, and X, thereby overcoming the antagonistic effects.
These agents should be discontinued 24 hours before minor surgery or diagnostic procedures and 48 hours before major surgery or procedures involving the eye, spine, or brain.
The half-lives of these agents are about 12 hours; thus, assuming normal hepatic and renal function, more than four half-lives ensures almost 100% drug clearance.
Heparin therapy is one of the oldest and most common anticoagulation regimens. (Use as prophylaxis against VTE has decreased, but it is still used for emergent anticoagulation with acute coronary syndrome, pulmonary embolism, and during cardiopulmonary bypass or vascular surgery.)
The clinical effects of heparin therapy are monitored with the aPTT or ACT.
Patients may be resistant to unfractionated heparin if they have a hereditary insufficiency of antithrombin III (ATIII) or an acquired deficiency from prolonged heparin administration. ATIII is replenished with FFP transfusions.
The main complication of heparin is HIT.
LMWH (enoxaparin, dalteparin, reviparin) is a fractionated form of heparin that acts similarly but with more specific inhibition of factor Xa.
LMWH is preferred over unfractionated heparin for DVT prophylaxis and treatment because laboratory monitoring is unnecessary, and its longer half-life allows for once or twice daily dosing.
Treatment can be monitored with factor Xa levels, but this is only necessary for obese patients and those with renal insufficiency, which prolongs the elimination.
Reversal with protamine is unpredictable and not likely to completely resolve bleeding tendencies.
Fondaparinux is a highly specific antagonist for free factor Xa that also acts via binding with ATIII. Similar to LMWH, it is popular for DVT treatment and prophylaxis because it has a long half-life that requires only once-daily dosing and highly reliable absorption that negates the need for coagulation monitoring.
There is no available antidote in the event of bleeding or the need for emergency procedures.
The incidence of HIT is relatively low for this class of agents.
It occurs in approximately 1% to 5% of patients receiving heparin and is associated with morbidity from thromboembolic complications.
There are two types. HIT1 is mild thrombocytopenia; it is benign and does not involve immune complexes. HIT2 is an immune-mediated response and carries a significant risk of hypercoagulability.
Parenteral DTIs directly inhibit thrombin in its free and fibrin-bound states. None of them are immunogenic, so there is no risk for HIT.