Thrombolytic Agents

Chapter 188 Thrombolytic Agents

Daniel F. Hogan, DVM, DACVIM (Cardiology)

• Thrombolytic agents are used to return patency to obstructed blood vessels and improve blood flow to infarcted organs.

• The thrombolytic process occurs primarily on recently formed thrombi because older thrombi have extensive fibrin polymerization that makes them more resistant to thrombolysis. Therefore the use of thrombolytic agents carries the greatest chance for success if these agents are administered as early as possible following identification of a thrombus.

• Thrombolytic agents are used frequently in emergency situations and are commonly associated with complications such as bleeding and reperfusion injury.

• The thrombolytic agents most commonly used in veterinary medicine include tissue plasminogen activator, streptokinase and urokinase.

• There is very little clinical experience with these agents in veterinary medicine. Additionally, these agents are quite expensive, which may limit their clinical usefulness.

INTRODUCTION

Thrombolysis is the dissolution of thrombi within the cardiovascular system through the enzymatic breakdown of fibrin (fibrinolysis) by the serine protease plasmin. Endogenous thrombolysis is mediated by tissue plasminogen factor (t-PA), which is synthesized in the vascular endothelial cells and facilitates the conversion of plasminogen to active plasmin. Plasmin formation takes place in an intimate association among t-PA, plasminogen, and fibrin. Endogenous thrombolysis via t-PA is modulated by multiple substances, of which plasminogen activator inhibitor and thrombin-activatable fibrinolysis inhibitor are the most notable.

Therapeutic thrombolysis is used for conditions including venous thrombosis, pulmonary embolism, systemic arterial occlusive disease, ischemic stroke, and acute myocardial infarction (Box 188-1). Supraphysiologic levels of exogenous plasminogen activators are administered intravenously to cause thrombus dissolution. The thrombolytic process works primarily on recently formed clots; older thrombi have extensive fibrin polymerization that makes them more resistant to thrombolysis. Therefore the use of thrombolytic agents carries the greatest chance for success if administered as early as possible following identification of a thrombus.

Box 188-1 Recommendations for Thrombolytic Therapy

Clinical Scenarios in Which Thrombolytic Therapy Could Be Considered

Incomplete infarction of pelvic or thoracic limbs

Symptomatic but static (nonprogressive) pulmonary embolism

^* Some thrombotic states may require surgical intervention instead of thrombolytic therapy.

Multiple agents have been approved for use in people for treatment of pathologic thromboses, including streptokinase, urokinase, anisoylated plasminogen streptokinase, t-PA, and modified forms of t-PA (reteplase and tenecteplase). These agents vary with respect to pharmacokinetics, fibrin specificity, thrombolytic activity, and clinical response. However, there is not a tremendous amount of experience with these agents in veterinary medicine, and scientific reports are limited to streptokinase, urokinase, and t-PA.

SPECIFIC THROMBOLYTIC AGENTS

Streptokinase

Streptokinase combines with plasminogen to form an activator complex that converts plasminogen to the proteolytic enzyme plasmin. Plasmin degrades fibrin, fibrinogen, plasminogen, coagulation factors, and streptokinase. The streptokinase-plasminogen complex converts circulating and fibrin-bound plasminogen and is therefore considered a nonspecific activator of plasmin. This results in a systemic proteolytic state that may predispose to bleeding from loss of coagulation factors and fibrinogen and increase in fibrin degradation products. Although the half-life of streptokinase is relatively short (30 minutes), hypofibrinogenemia can persist for 24 hours.¹

Streptokinase is produced by streptococci, which can lead to antigenic stimulation within the patient, especially with repeated administrations. Anisoylated purified streptokinase activator complex is a combination of streptokinase and plasminogen that does not require free circulating plasminogen to be effective. Although it does have many theoretic benefits over streptokinase, antigenic stimulation may still occur. This product has not been investigated in clinical veterinary patients.

Streptokinase is typically administered by giving 90,000 IU IV over 1 hour followed by an infusion of 45,000 IU/hr for up to 12 hours (dogs and cats). Currently, the smallest amount of streptokinase that can be purchased is 750,000 IU (estimated cost of $300), which would provide over 15 hours of infusion time. Once reconstituted, it must be used within 8 hours if stored at 2° to 8° C (35.6° to 46.4° F).

Urokinase

The renal tubular epithelium, not endothelium, appears to be the primary in vivo source of the proteolytic enzyme urokinase or urokinase plasminogen activator (u-PA). Urokinase is similar in activity to streptokinase but is considered more fibrin specific because of the physical characteristics of the compound. Commercial preparations, derived from human fetal cell cultures, consist of both high-molecular-weight (HMW) and low-molecular-weight (LMW) fractions. Although the HMW fraction predominates, it is converted quickly and continuously within the circulation to the LMW form, which exhibits greater binding characteristics to the lysine-plasminogen form of plasminogen.^2,3

Lysine-plasminogen, in contrast to the glutamate-plasminogen form, differentially accumulates within thrombi, thereby conferring fibrin specificity to the u-PA. Additionally, glutamate-plasminogen is converted to lysine-plasminogen during thrombolysis, thereby increasing the binding of u-PA to plasminogen within the thrombus. It is interesting to note that for u-PA to interact with many cell types, including epithelial cells, the high-affinity u-PA receptor (u-PAR) is required.^4,5 HMW u-PA, but not LMW u-PA, binds to u-PAR, and u-PA associated with the u-PAR is susceptible to the physiologic inhibitor plasminogen activator inhibitor, suggesting a possible clearance mechanism.^6,7

It also appears that u-PA associated with u-PAR is mostly involved in nonproteolytic activities such as cellular adhesion and migration.⁸ Prourokinase, a relatively inactive precursor that must be converted to urokinase before it becomes active in vivo, is under investigation in humans. It is inactive in plasma and does not bind to or consume circulating inhibitors. As with tissue-type plasminogen activator (t-PA), prourokinase is somewhat thrombus specific, because the presence of fibrin enhances the conversion of prourokinase to active urokinase by an unknown mechanism. This fibrinolytic agent has not yet been studied in clinical veterinary patients.

Urokinase is available as a lyophilized product in 250,000-IU vials. The manufacturer recommends reconstituting with 5 ml of sterile water and then further diluting the stock solution with 0.9% sodium chloride to a volume of 195 ml. This contains the total dosage for humans. A loading dose is given over 10 minutes, followed by a 12-hour infusion period. Urokinase has been administered to cats and dogs using a protocol of 4400 IU/kg loading dose given over 10 minutes, followed by 4400 IU/kg/hr for 12 hours.^9,10 The average sized cat (4.54 kg) would require approximately one 250,000-IU vial, and a 20-kg dog would require approximately five vials. With a cost of approximately $500 per vial, this translates into an approximate cost of $500 per cat and $2500 per dog for a 12-hour infusion period, respectively.

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Tags: Small Animal Critical Care Medicine

Sep 10, 2016 | Posted by admin in SMALL ANIMAL | Comments Off

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