Therapy Of Thromboembolic Disease

By | 2013-07-19

The management of primary diseases resulting in the development of thromboembolism is discussed in related posts throughout this textbook. Therapy of thromboembolism should be directed toward the underlying disorder whenever possible. Therapeutic strategies for managing thromboembolism include short-term systemic anticoagulation and fibrinolysis followed by long-term antiplatelet or anticoagulant therapy to reduce the risk of rethrombosis.

Supportive Care

General patient care is critical for successful management of thrombosis. Analgesic agents should be considered for acute pain management. Fluid therapy should be administered when indicated to correct acid-base abnormalities and dehydration. Dextrose-containing fluids should be avoided whenever possible because they may cause endothelial damage, further promoting thrombosis. A risk of volume overload exists with heart failure or pulmonary hypertension and fluid therapy must be carefully monitored. Strict cage rest and oxygen therapy are indicated in cases of pulmonary thromboembolism or thrombosis associated with congestive heart failure (CHF).

Acute Anticoagulation

Heparin is the mainstay of acute anticoagulation. Anticoagulants prevent additional clots from forming but do not dissolve clots (see thrombolysis). Coumadin therapy for the long-term control of thrombosis is initiated after adequate hepariniza-tion has been achieved.

Heparin functions as a cofactor with antithrombin III, and together this complex exerts its effect by neutralizing factor X and thrombin. Heparin is inactivated by gastrointestinal (GI) enzymes when given orally and therefore must be administered by injection. Heparin is administered to prolong the baseline activated partial thromboplastin time (aPTT) to 1.5 to 3.0 times the baseline value. Prolongation of the aPTT or activated coagulation time (ACT) does not correlate well with heparin levels in cats and dogs, and measurement of plasma heparin levels may be more useful in monitoring heparin therapy. Although many different heparin doses have been advocated, little clinical data exist concerning efficacy. Doses of heparin required to achieve adequate heparin levels in cats with thromboembolism ranged from 175 U/kg every 6 hours to 475 U/kg every 8 hours, subcutaneously. In normal dogs the dose of heparin required to achieve adequate heparin concentrations was 250 U/kg every 6 hours, subcutaneously. The most common side effect of heparin therapy is hemorrhage. In the event of severe hemorrhage, heparin can be neutralized by protamine sulfate administration.

Low molecular weight (LMW) heparin is being increasingly used. Its anticoagulant effect is limited to blocking the activity of factor X. Because LMW heparin has a lower antithrombin effect than unfractionated heparin, LMW heparin does not markedly influence the PT or aPlT. Measurement of factor X activity has been used to assess the effect of LMW heparin. One advantage of LMW heparin is that it has a lower risk of hemorrhage than conventional hep-arin therapy. The optimal dose of LMW heparin in dogs and cats with thromboembolic disease remains to be determined.

Chronic Anticoagulation

Warfarin (Coumadin) is a vitamin K antagonist inhibiting the synthesis of vitamin K-dependent clotting proteins (prothrom-bin and factors VII, IX and X). In addition, warfarin reduces efficacy of the vitamin K-dependent regulatory proteins C and S. Proteins C and S are anticoagulant factors, and their function is the first to be inhibited by warfarin administration. Therefore heparin and warfarin administration are generally overlapped for 2 to 4 days to prevent a transient hypercoagulable state. Some animals appear to do well with just warfarin. Starting doses for warfarin are 0.25 to 0.5 mg every 24 hours in the cat and 0.1 to 0.2 mg/kg every 24 hours in the dog. Due to the high individual patient variability, close monitoring of PT is essential. Early recommendations were to maintain PT 1.5 times the baseline value, and more recent recommendations suggest attaining an international normalized ratio (INR) of 2:3. INR is calculated by the formula (patient PT/control PT). The ISI is a value specific to the tissue thromboplastin that is used in measuring the PT Coumadin is continued on a long-term basis to prevent recurrent TE. Studies documenting the optimal dose, efficacy, and duration of Coumadin therapy for specific thromboembolic diseases in dogs and cats are unknown.

The use of Coumadin is not without risks. The major risk is fatal hemorrhage, which occurs acutely and unexpectedly. Ideally, pets maintained on Coumadin should live indoors and be well supervised to prevent trauma and to monitor for hemorrhage. Periodic measurement of the PT should be done to ensure adequate dosing. Coumadin interacts with many drugs. The addition of medications to the treatment regimen of a pet on Coumadin should be done cautiously because certain drugs will raise the activity of Coumadin and predispose patients to bleeding. Some of these drugs are phenylbutazone, metronidazole, trimethoprim sulfa, and second- and third-generation cephalosporins. Barbiturates will decrease Coumadin anticoagulant effect. If bleeding complications occur, warfarin therapy is discontinued and administration of vitamin K is recommended.

Antiplatelet Therapy

Antiplatelet drugs have been advocated for long-term management to prevent rethrombosis. These drugs inhibit platelet aggregation and adhesion, preventing the formation of the hemostatic platelet plug. Aspirin inhibits cyclooxygenase, leading to decreased thromboxane A2 synthesis. This renders platelets nonfunctional by preventing their aggregation. Cats lack the enzyme needed to metabolize aspirin (glucuronyl transferase), making them sensitive to aspirin-induced platelet dysfunction. Doses of 0.5 mg/kg every 12 hours in the dog and 25 mg/kg twice weekly in the cat may decrease platelet aggregation. However, rethrombosis generally occurs despite aspirin therapy, although it is not known whether aspirin delays recrudescence. Additional antiplatelet drugs include dipyridamole and ticlopidine. Dipyridamole is thought to inhibit platelet aggregation by inhibition of platelet phospho-diesterase, leading to increased levels of cyclic adenosine monophosphate (cAMP) within platelets. Ticlopidine impairs fibrinogen binding and inhibits platelet aggregation induced by ADP and collagen. The use of these newer compounds has been limited thus far in veterinary medicine.

Thrombolysis

Thrombolytic agents such as streptokinase, urokinase, and tissue plasminogen activator (tPA) are potent activators of fib-rinolysis. These agents have been used with variable and often limited success in veterinary medicine.

Streptokinase binds plasminogen, and the complex transforms other plasminogen molecules into plasm in. Plasmin then binds to fibrin and causes thrombolysis. Streptokinase binds both free and clot-associated plasminogen. It also degrades factors V, VIII, and prothrombin, resulting in a massive systemic coagulation defect.

Streptokinase has been used to treat aortic thromboembolism (ATE) in cats with varying degrees of success. In one study of 46 cats, 15 were discharged from the hospital after streptokinase therapy with a median survival of 51 days. Reperfusion injury occurred in approximately 35% after thrombolysis, with streptokinase often resulting in fatal hyperkalemia and metabolic acidosis- Eleven of the cats developed clinical hemorrhage after streptokinase therapy. In three cats, hemorrhage was significant enough to require transfusion. Others reported conservative management (treatment of heart failure plus Coumadin or aspirin) of thromboembolism with a hospital discharge rate of 28%, which was similar to cats treated with streptokinase. One recommended dose of streptokinase for dogs and cats with thromboembolism is 90,000 U, intravenously administered over 20 to 30 minutes, followed by a maintenance infusion of 45,000 U for 7 to 12 hours. Infusions may be repeated over a total of 3 days.

Recombinant DNA technology produces t-PA, a serine protease. A complex forms between t-PA and fibrin, and that complex preferentially activates thrombus-associated plasminogen-resulting in rapid fibrinolysis. Life-threatening hemorrhage is the number one side effect. The half-life of t-PA in dogs is 2 to 3 minutes; consequendy, if bleeding occurs, stopping the infusion will result in the drug clearance from the system in 5 to 10 minutes. Because t-PA causes rapid thrombolysis, the risk of reperfusion syndrome and lethal hyperkalemia is substantial. In one report, 50% of cats with thromboembolism died acutely during t-PA therapy, with death attributed to hyperkalemia, severe anemia, and renal hemorrhage.