Parenteral Anticoagulants

Heparin

Heparin is an endogenous substance produced by many cells in the body, but is primarily made by mast cells found in the connective tissue surrounding capillaries in the body. These mast cells continuously produce small quantities of heparin that diffuses into the circulation. Basophils in the blood also release heparin into the plasma. The concentration of heparin in the blood is normally very low, and only produces significant anticoagulant effects under specific circumstances. It is used medically in much higher concentrations to prevent intravascular clotting.26

Heparin itself is not an anticoagulant; however, by binding to antithrombin III, it serves as a catalyst to enhance the inactivation of multiple coagulation factors, including thrombin. Heparin also prevents the conversion of fibrinogen to fibrin, thus inhibiting clot formation.5,26 Unfractionated heparin (Hep-Lock®, heparin sodium, heparin calcium) has been used in medicine since the 1920s, and is used primarily in hospitalized patients to treat thromboembolism and PE.27 High-dose therapy is used for DVT and PE, while low-dose therapy is used preventively.5

Both warfarin (Coumadin®) and heparin therapy are started on the first day of treatment, and the overlap allows for the 4 days to 5 days needed for warfarin to take effect. Heparin inactivates existing coagulation factors relatively quickly, while warfarin therapy blocks the synthesis of new clotting factors by the liver. In older adults undergoing general surgery, prophylaxis with low-dose unfractionated heparin (LDUH) or an intermittent pneumatic compression device, such as compression elastic stockings, is recommended to prevent DVT and venous thromboembolism (VTE).28 Heparin is also used to prevent clot formation in catheters, shunts, pumps, and infusion machines (eg. dialysis machines).6

Standard heparin is comprised of an unfractionated heterogeneous mixture of polysaccharide chains with mean molecular weights ranging from 12 000 to 16 000 daltons. Heparin is administered parenterally, usually by intravenous injection, which results in an immediate anticoagulant effect.5,27,29 When administered by intravenous infusion or as a deep subcutaneous injection, onset of action occurs anywhere from 20 minutes to 30 minutes.27,29 Response to heparin is varied and unpredictable; therefore, patients receiving heparin are monitored with an aPTT (activated partial thromboplastin time) test.5,27

Most patients receiving heparin will be treated in the hospital setting, and invasive dental procedures should be avoided during active treatment. Dental emergencies in these hospitalized patients must be treated carefully and conservatively 5 The most common dental patients taking heparin seen outside of the hospital setting are those who are undergoing hemodialysis, who receive heparin on an outpatient basis. As heparin has a half-life of 1 hour to 2 hours, its effects last for only a few hours after dialysis has been completed. It is safe for these patients to receive invasive dental procedures on the day following dialysis.5

Heparin may induce thrombocytopenia in up to 30% of users; however, for most affected patients, this adverse event is not clinically significant. However, heparin may induce an immunologically-mediated thrombocytopenia in 1% to 2 % of users that causes a marked decrease in platelet count, leading to thromboembolic complications, such as PE, skin necrosis, and gangrene.29 Daily platelet counts for the first week following the initiation of drug therapy can help to detect this condition.

Hemorrhage, including gingival hemorrhage, is another risk associated with heparin. This risk is increased by the use of other anticoagulant medications, thrombolytic agents and drugs that alter platelet function (see below). It is important to note that heparin is often used in conjunction with thrombolytics and during the initiation of warfarin therapy to assure adequate anticoagulation. Certain cephalosporins and parenterally administered penicillins may also increase risk for hemorrhage in heparinized patients.29

Low Molecular Weight Heparins

Low molecular weight heparins (LMWHs) are the preferred method for prophylaxis for elective hip replacement surgery, started preoperatively or immediately after surgery, as these drugs have been found to be very effective in preventing asymptomatic VTE.30 For elective knee replacement or hip fracture surgery, LMWH or adjusted-dose warfarin may be used.28 Routine prophylaxis for VTE with LDUH or LMWH is recommended for patients with ischemic stroke and impaired mobility. These agents are also recommended for patients with other risk factors for VTE including immobility, cancer, heart failure, and severe lung disease.28

LMWHs act in a similar manner to standard heparin, by inhibiting activated factor X and thrombin; however, they produce a lesser effect on the inhibition of thrombin.31,32,33 LMWHs are formed by depolymerization of unfractionated heparin side chains, producing “smaller” heparin fragments, with mean molecular weights ranging from 1000 daltons to 10 000 daltons.27

LMWHs are administered subcutaneously, and exhibit a better bioavailability than standard heparin, as they are less bound to plasma proteins, endothelial cells and macrophages. They also have a longer half-life (2 hours to 4 hours) than heparin, and dosage is based upon body weight. Because LMWHs produce a more predictable anticoagulant response, laboratory monitoring during treatment is generally not necessary.5,27 Dental professionals do not need to order laboratory testing for patients taking these drugs for routine dental care.

For patients undergoing orthopedic surgery to the lower extremities, the optimal duration of prophylaxis is unknown.28 Risk for DVT following surgery is related to the length of time that the patient remains immobile and other risk factors; risk persists for up to 2 months following total hip replacement surgery.28,34,35,36,37 Six randomized double-blind controlled clinical trials demonstrated reduced risk of total and proximal DVT by at least 50% for patients with total hip replacement who received prophylaxis with either LDUH or LMWH for 5 weeks beyond the hospital stay.30

LMWHs can be provided on an outpatient basis, and patients taking these drugs have lower risks for hemorrhage and heparin-induced thrombocytopenia, as compared to patients taking heparin. Risks for bleeding increase when the LMWHs are used with thrombolytic agents, oral anticoagulants, and drugs that alter platelet function, although they are frequently used during initial therapy with oral anticoagulants to ensure proper anticoagulation. There are 3 FDA approved LMWHs in the United States: dalteparin (Fragmin®), enoxaparin (Lovenox®), and tinzaparin (Innohep®).27,29 Enoxaparin is the most widely used LMWH, and has been shown to prevent ischemic complications associated with unstable angina and non-Q wave myocardial infarction (MI).5,29,38

Patients on LMWHs who present to the dental office can usually receive invasive dental treatment without any modifications necessary to their medication regimen. Should excessive bleeding be anticipated, as with oral or periodontal surgery, a physician consultation is warranted to determine whether the medication should be temporarily discontinued prior to performing the dental procedure. Given the short half-life of these drugs, high dose LMWH can be stopped for one day on the day before the surgery; then, therapy is resumed following hemostasis on the day of surgery. However, the best option is to wait until LMWH therapy has been completed before attempting any elective dental surgery.5

Antithrombotic Agents

There are 3 FDA approved antithrombotics that are used for the prevention of postoperative deep vein thrombosis (DVT), and for the treatment of heparin-induced thrombocytopenia and related thromboembolic complications. These drugs are argatroban (no brand name), danaparoid (Orgaran®), and lepirudin (Refludan®).

Argatroban is indicated for the prevention and treatment of thromboembolic complications in patients with heparin-induced thrombocytopenia. This drug is a highly selective thrombin inhibitor and binds reversibly to the active thrombin site of free and clot-associated thrombin. Drug administration is by IV, which produces an immediate onset of action. The drug inhibits fibrin formation, the activation of numerous clotting factors, and platelet aggregation.27,29

Danaparoid (Orgaran®) is indicated for the postoperative prevention of DVT following elective hip replacement surgery. This drug prevents fibrin formation by inhibiting activated factor X by antithrombin. It is administered subcutaneously, with maximum effect occurring within 2 hours to 5 hours.27,29

Lepirudin (Refludan®) is indicated for anticoagulation in patients with heparin-induced thrombocytopenia and related thromboembolic complications, and has investigational use for the prevention of ischemic complications associated with unstable angina. This drug is a highly specific inhibitor of thrombin, and is administered by IV. All antithrombotic agents have a risk for hemorrhage, which is increased with concurrent use of oral anticoagulants and drugs that alter platelet function.27,29

Factor Xa Inhibitor

There is 1 antithrombotic agent in this new class of medications called fondaparinux (Arixtra®). This drug is indicated for prevention of deep vein thrombosis (DVT) in patients undergoing hip or knee replacement or hip fracture surgery. It may also be used for the treatment of acute pulmonary embolism (PE) or for treatment of acute DVT without PE. Fondaparinux is a synthetic pentasaccharide that inhibits activated factor X, which inhibits thrombin formation. It is administered subcutaneously, once daily. Risk for hemorrhage is increased when this drug is taken concurrently with oral anticoagulants, antiplatelet drugs, non-steroidal anti-inflammatory drugs (NSAIDS), salicylates, and thrombolytics.27,29