Antithrombotics: new drugs, new doses? (Proceedings)
Thromboembolic agents are indicated for a variety of conditions, ranging from disseminated intravascular coagulation to pulmonary thromboembolism in both dogs and cats. The selection of appropriate thromboembolic therapy will depend on the underlying condition and the goal of treatment. For example, if a thromboembolic obstruction has been diagnosed, then the goal of therapy is generally dissolution of the thrombus. However, a second goal of therapy for a primary thrombus is the prevention of additional thromboembolism due to fragmentation of the original lesion with subsequent blockage of the smaller, down-stream vessels. Similarly, prophylaxis of thromboembolic disease is frequently the primary goal of anticoagulant therapy in patients that are predisposed to thrombus formation, such as cats with hypertrophic cardiomyopathy. Thromboembolic agents can be broadly classified into agents that are thrombolytic and those that are anticoagulant. It is important to recognize that while anticoagulant therapy can indirectly support the lysis of pre-existing thrombi, anticoagulants cannot directly lyse a clot.
Thrombolytic agents include urokinase, streptokinase, and recombinant tissue plasminogen activators (rt-PA). The present thrombolytic agents share a common mechanism of action, serving to stimulate the endogenous system of thrombus removal. Normally, the initiation of thrombus degradation is by release of t-PA from endothelial cells that respond to signals such as vessel occlusion. The t-PA first binds to fibrin in the clot, than converts free plasminogen to the enzyme plasmin, which in turn will digest fibrin. The action of the thrombolytic agents tends to be nonspecific, such that both pathological fibrin clots and those at the sites of vascular injury are lysed. In addition, plasmin can degrade other plasma proteins, including coagulation cofactors, worsening the possibility of hemorrhage. As a consequence, hemorrhage is the most worrisome side effect associated with the use of thrombolytic agents and can occur at sites of catheter placement and trauma. For this reason, recent surgery, gastrointestinal bleeding, and hemorrhagic disorders are all contraindications for thrombolytic therapy. However, the thrombolytic agents do differ with respect to their specificity for fibrin. Streptokinase is the oldest member of this class of drugs and is produced from beta-hemolytic Streptococcus. Streptokinase facilitates the cleavage of plasminogen to plasmin. Because Streptococcus spp. exposure generally produces antibodies to streptokinase, streptokinase is immunogenic. High doses may be necessary to bind streptokinase antibody and allow high enough circulating concentrations of streptokinase for drug efficacy. In addition to the risk of hemorrhage due to the lack of specificity for fibrin degradation, streptokinase may also be associated with hypersensitivity reactions. Only the low molecular weight form of urokinase is presently available in the U.S., as an injectable drug approved for the treatment of pulmonary emboli in humans. Urokinase is derived from human donor neonatal kidney cells, making it an expensive preparation with major supply issues. Like streptokinase, urokinase is also not selective for fibrin, making it unattractive from the standpoint of both side effects and cost. The use of t-PA has largely supplanted that of streptokinase and urokinase in human medicine. By acting similarly to endogenous t-PA, rt-PA products (such as alteplase and reteplase) provide a greater measure of safety as compared to the streptokinase and urokinase. Because endogenous t-PA only converts plasminogen to plasmin in the presence of fibrin, systemic lysis of proteins does not occur. However, physiological thrombi at the site of vascular injury will still be affected by low concentrations of t-PA. In addition, supra-physiological concentrations of rt-PA occur during drug therapy, such that hemorrhage is still the major side effect associated with the administration of rt-PA. Therapy with rt-PA is also very expensive. Alteplase has been used in companion animals with thromboembolic disease,1,2 although evidence for its safety and efficacy in presently incomplete.3 Similarly, retrospective studies of streptokinase administration in companion animals with arterial thromboembolic disease have not provided strong evidence of increase survival.3,4 Overall, clinical evidence for the efficacy of thrombolytic therapy for the treatment of thromboembolic disease in veterinary species is primarily retrospective and inconclusive, but does not support a robust treatment effect.