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Anticoagulants: Assessment, Analysis, and Associated Dental Management Guidelines

ANTICOAGULATION THERAPY OVERVIEW

Anticoagulation therapy is indicated in the presence of thrombosis formation or when there is a risk of thrombosis. Because of its immediate action, intravenous (IV) heparin (standard heparin/unfractionated heparin) is the anticoagulant of choice, and it is used in a hospitalized setting to stabilize a patient experiencing an acute thrombotic episode. Once the acute state is brought under control, warfarin (Coumadin) is started orally. Coumadin cannot be used at the start of an acute thrombotic episode because of its slow onset of action and slow achievement of optimal action. IV heparin is withdrawn when the therapeutic level of Coumadin is reached and blood thinning can be completely maintained using warfarin (Coumadin). At the time of discharge, the patient is sent home taking only warfarin (Coumadin) to continue with the blood-thinning process.

Common indications for anticoagulation: Anticoagulation is needed to prevent pathologic clot formation or thrombus, which may lead to stroke or death. It is also needed in conditions in which you want to inhibit clotting, as in the case of protein defects that compromise hemostasis. The most common indications for anticoagulation include transient ischemic attacks (TIAs) or strokes, atrial fibrillation, low ejection fraction causing stasis/pooling of blood, which promotes thrombus formation, pulmonary embolism, deep vein thrombosis (DVT), and hypercoagulation states: proteins C/S deficiency, Factor V Lieden mutation, lupus anticoagulant, antiphospholipid antibody syndrome, and antithrombin III deficiency.

WARFARIN (COUMADIN)

Warfarin (Coumadin) antagonizes the synthesis of the vitamin K–dependent clotting factors II, VII, IX, and X. Deficiency of vitamin K can thus affect the intrinsic and extrinsic clotting pathways causing a prolongation of the activated partial thromboplastin time (APTT) and the prothrombin time (PT), respectively.

Coumadin is given PO (oral) and it peaks in 60–90 minutes after oral administration. Once ingested, Coumadin gets highly bound to albumin. It takes 9–16 hours for Coumadin to be effective and 36–48 hours for therapeutic levels to be established. The plasma half-life of warfarin (Coumadin) is about 37 hours. Warfarin is a racemic mixture of R- and S-warfarin, with the S-form being two-to-five times more potent. Both forms are metabolized by cytochrome P450 with predominant involvement of CYP1A1, CYP1A2, CYP2C9, CYP2C19, and CYP3A4. S-warfarin is metabolized primarily by CYP2C9, whereas CYP1A2 and CYP3A4 account for most of the metabolism of R-warfarin.

At the therapeutic level, Coumadin affects only Factor VII, which is part of the extrinsic pathway. This accounts for why PT/INR is the only test monitored to assess warfarin (Coumadin) response. The half-life of Factor VII is eight hours, so when the Coumadin intake is temporarily stopped prior to major dental surgery, it takes 48 hours (six half-lives) for the PT/INR to normalize.

The warfarin (Coumadin) level can be affected by certain dietary foods that are high in vitamin K. Dark green leafy vegetables, avocados, turnips, beets, and liver are the food items that decrease the effectiveness of warfarin (Coumadin), thus increasing the risk for thrombosis.

Warfarin (Coumadin) Reversal

During dire situations when emergency dental surgery is needed in a patient on Coumadin, the effect of Coumadin can immediately be reversed with Fresh Frozen Plasma (FFP). The PT/INR is always checked post FFP transfusion to confirm the reversal. Post-surgery FFP transfusion does not negatively affect the future doses of Coumadin. Vitamin K can also be used to reverse the effects of Coumadin. However, a significantly large dose of vitamin K is needed for the reversal process to be quick. Large doses of vitamin K (oral or IV) used for reversal have a negative impact on the future doses of Coumadin. Higher doses of Coumadin will be needed, post emergency surgery. Therefore, as a preventive measure, only low-dose vitamin K is used to reverse the effects of Coumadin in semi-urgent situations. It can take almost 24 hours for Coumadin action reversal to occur. Low-dose vitamin K, as stated previously, does not affect the future doses of Coumadin. In most patients with a history of Coumadin intake, the INR is maintained at a therapeutic range of 2.0–3.0. Patients maintained at this range can tolerate a physician-approved, temporary interruption of Coumadin for major surgical procedures, as they are not at high risk for thrombosis. It is always best to communicate with the patient’s M.D. for advice when the patient is on Coumadin. Indicate the type of major and/or minor procedures planned and the amount of bleeding expected.

Patients with a high risk for thrombosis need higher doses of Coumadin. The PT/INR in such cases is maintained between 3.0–4.5 or greater. In the presence of higher Coumadin doses, the PTT will also be affected. Nevertheless, the PT/INR is the only test evaluated when monitoring even the high-risk patients.

Conditions Associated with Increased Risk of Thrombosis

The following are conditions associated with increased risk of thrombosis:

Presence of any documented end-organ thrombosis-associated condition with AF places the patient at a high risk for thrombosis. The end-organ conditions can be TIA/CVA/MI. Therefore, high-risk patients cannot afford to have their blood-thinning process stopped at any time, and for all surgical procedures these patients will have to be switched from Coumadin to heparin. Depending upon the dental procedure planned, the patient’s M.D. could switch the patient to either low molecular weight heparin (LMWH) or standard/unfractionated/IV heparin.

The PT/INR is monitored every 4–6 weeks when the patient is on Coumadin. The dentist must always request and evaluate the latest PT/INR from the physician’s office before starting any dental treatment. In a patient who has always been in the therapeutic range, a PT/INR done no earlier than one week prior is most reliable and helpful.

STANDARD/UNFRACTIONATED HEPARIN (UFH)/INTRAVENOUS HEPARIN AND LOW MOLECULAR WEIGHT HEPARINS (LMWHS)

Mechanism of Action of IV and Low Molecular Weight Heparins

The anticoagulant effect of heparin is directly related to its activation of antithrombin III, which rapidly inactivates thrombin and Factor Xa in the coagulation process. Unfractionated heparin (UFH) or IV heparin potentiates the action of antithrombin III, and this rapidly inactivates thrombin and Factor Xa in the coagulation process. Intravenous (IV) heparin also inactivates Factors IX, X, XI, XII, and plasmin, plus IV heparin inhibits the conversion of fibrinogen to fibrin. LMWHs have less anti–Factor IIa activity and more Factor Xa activity. LMWHs bind to antithrombin III and this instantly inactivates Factor Xa and Factor II (prothrombin).

IV or standard heparin inhibits thrombin-induced platelet activation, thus causing IV heparin-induced thrombocytopenia. This effect is more pronounced if the patient has had several past exposures to IV heparin. This accounts for why it is important to check the platelet count at one, three, and seven days postoperatively after the use of IV heparin. LMWHs have decreased platelet-activation action and affinity and are less likely to cause thrombocytopenia.

IV heparin is extensively bound to plasma proteins and has a short half-life (60–90 minutes). LMWHs have a longer plasma half-life. LMWHs are minimally bound to plasma proteins and the proteins released from activated platelets and endothelial cells. Thus the anticoagulation action of LMWH is more consistent and predictable.

IV heparin does not cross the placental barrier, so it can be safely given to pregnant patients when needed. Heparin clearance from the plasma is reduced in patients with cirrhosis or severe kidney disease.

The plasma half-life of IV heparin or unfractionated heparin is approximately one hour. It is injected intravenously (IV). The onset of action is immediate following an IV injection and the total clearance time is six hours.

Standard heparin effectiveness is judged by monitoring the PTT. Standard heparin is the drug used in the hospitalized setting when any acute thromboembolic state needs immediate attention. Once stable, warfarin (Coumadin) is added orally. When the anticoagulation is completely supported by Coumadin in about 2–4 days, standard heparin is then totally withdrawn.

Massive myocardial infarction (MI), stroke, atrial fibrillation (AF) associated with stroke/MI (end-organ problems), heart valve surgery, deep vein thrombosis (DVT), or pulmonary embolism (PE) are examples of acute thromboembolic states. LMWHs are prepared by depolymerization of unfractionated heparin chains. They are injected subcutaneously (SC) by the patient. This is a huge advantage because the patient can be ambulatory and does not need hospitalization. LMWHs are widely used in pregnant patients. They do not cross the placenta and have a fetal safety profile similar to UFH.

The onset of action of LMWH occurs in 30–60 minutes. The plasma half-life of LMWHs is 2–4 hours. The amount of LMWH given is determined by the patient’s height and weight. LMWH is usually given q12h.

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LMWHs, as previously discussed, have better bioavailability, longer half-lives, more predictable dose response, and less negative effect on the platelets, compared to standard heparin. LMWHs are the preferred choice in the dental setting when blood thinning has to be continued for high-risk patients (after Coumadin withdrawal) for major procedures.

LMWH Preparations

The LMWHs preparations available />