Thrombolytic Agents - Clinical Tree

Introduction

Embolic and thrombotic events in the arterial and venous systems lead to end-organ malperfusion and dysfunction. In the past, open surgical procedures were used to restore vessel patency and organ function; however, with the advent of thrombolytic agents and endovascular techniques, intravenous thrombolysis (IVT) and catheter-directed thrombolysis (CDT) have become essential components in the contemporary management of acute arterial and venous thromboembolic conditions.

Thrombolytic agents have evolved over time, with many of the original agents (streptokinase [SK] and urokinase [UK]) no longer manufactured in the United States, even while still holding Food and Drug Administration (FDA) labels for use. In current practice, alteplase (recombinant tissue plasminogen activator [rt-PA]) is the agent most commonly used. Current FDA indications for thrombolysis include acute myocardial infarction (AMI), pulmonary embolism (PE), ^, ^, acute ischemic stroke (AIS), arterial thrombosis and embolization, deep venous thrombosis (DVT), and central venous catheter occlusion ( Table 43.1 ).

TABLE 43.1

Thrombolytic Agents and Indications Approved by the US Food and Drug Administration

Generic Name	Trade Name	Manufacturer	FDA Indication
Streptokinase ^a	Streptase	CSL Behring (King of Prussia, Pennsylvania)	AMI, PE, DVT, peripheral arterial thrombosis or embolism
Streptokinase ^a	Kabikinase	Pharmacia & Upjohn AB	AMI, PE, DVT, peripheral arterial thrombosis or embolism
Urokinase ^a	Kinlytic	Microbix Biosystems (Ontario, Canada)	PE
Alteplase	Activase	Genentech (South San Francisco, California)	AMI, PE, stroke
Alteplase	CathFlo Activase	Genentech	Central venous catheter occlusion
Reteplase	Retavase	Cornerstone Therapeutics (Cary, North Carolina)	AMI
Tenecteplase	TNKase	Genentech	AMI

a Though still FDA approved, no longer available in the United States. AMI , acute myocardial infarction; DVT , deep venous thrombosis; FDA , US Food and Drug Administration; PE , pulmonary embolism.

History

Early theories on the method of clot lysis arose from observations of postmortem blood, which was found to exist in both liquid and coagulated forms. In 1769, Morgagni noted this phenomenon occurred after traumatic death, and in 1906 Morawitz found that postmortem liquid blood contained no fibrinogen and could liquefy coagulated blood. It was postulated that an “inactive component” of blood, controlled by a “regulator,” could be converted into a “fibrin-degrading agent.”

The “inactive component” was first described by Milstone in 1941 as “lytic factor,” now known as plasminogen. Subsequently, Kaplan and Christensen separately identified the “fibrin-degrading agent” as plasmin. The “regulator,” or tissue plasminogen activator (t-PA), was the last to be isolated in 1957 by Albrechtsen (see Ch. 38 , Normal Coagulation).

The discovery of the first thrombolytic agent, SK, came by chance at Johns Hopkins University in 1933 by Tillett. He observed that streptococcus in human plasma would agglutinate, whereas streptococcus in human serum did not. He hypothesized that fibrinogen, present in plasma but not in serum, bound to the bacteria and caused agglutination. To test this hypothesis, he compared human plasma in test tubes as a control to human plasma in which streptococci were added. After addition of calcium, both tubes demonstrated clot formation. However, after the test tubes sat overnight, he noted the clot had liquefied in the streptococcus-containing tube. He attributed this finding to the production of “fibrinolysin” by streptococci. ^, A year later he isolated “fibrinolysin,” which is now known as SK.

In 1949, Tillett and Sherry reported the first clinical uses of SK in the thoracic cavity to treat empyema and retained hemothorax. ^, They reported the first human intravascular experience with SK in 1954. ^, Urokinase was the second thrombolytic agent discovered in 1946, with clinical application in 1961. As experience with these two early agents grew and additional agents developed, large clinical trials encompassing many vascular applications soon followed, expanding the use of thrombolytic agents in clinical practice ( Fig. 43.1 ).

Figure 43.1, Timeline of Key Moments in Thrombolytic History.

Thrombolytic Drug AdministrAtion

Systemic/Intravenous Thrombolysis

When thrombolysis was first introduced, systemic delivery via a peripheral intravenous catheter was the only method of administration. Although this was effective in certain clinical scenarios, it required large doses of thrombolytic agents with an increased risk of hemorrhagic complications. The development of CDT has allowed a more targeted delivery of thrombolytic agents in smaller doses. However, IVT still remains a common mode of delivery in applications in which preservation of end organ function requires rapid delivery (AMI, AIS).

Catheter-Directed Thrombolysis

CDT provides direct delivery of the thrombolytic agent into the thrombus. ^, It is the preferred method of delivery for acute limb ischemia, ^, DVT, and arteriovenous graft (AVG) occlusion. The endovascular techniques used for CDT also permit concomitant percutaneous treatment of the underlying culprit lesions responsible for vessel or graft occlusion.

CDT requires traversal of the occluded arterial or venous thrombosis with a guidewire, followed by placement of a multiple side-hole infusion catheter. An initial bolus is delivered via pulse spray technique. Depending on the particular vessel and end organ being treated, a continuous infusion for a specified period of time follows. To maximize the effectiveness and minimize systemic delivery of the thrombolytic agents, the infusion catheter side holes should be placed within the thrombus. Heparin is used as an ancillary drug during CDT and commonly infused through the indwelling arterial sheath. Administration of heparin is crucial to prevent propagation of thrombus around the indwelling catheter. ^, ^, Full anticoagulation with heparin with an activated partial thromboplastin time (aPTT) of 60 to 80 seconds should be achieved before thrombolysis, but once CDT has begun, the heparin dose should be decreased to 500 to 1000 U/h. The heparin drip should be adjusted to maintain an aPTT no more than 1.5 times control. Full anticoagulation with larger doses of heparin during CDT does not improve outcomes, and evidence suggests that excessive anticoagulation can potentiate bleeding complications.

Catheter-Directed Thrombolysis with Mechanical Thrombectomy

Percutaneous mechanical thrombectomy is a catheter-based therapy that disrupts the thrombus and allows better penetration of the clot by the thrombolytic agent. Its putative advantages include decreased thrombolytic dosing and shortened therapy time. Most mechanical devices were originally used for the treatment of AVG thrombosis, but their use has been expanded to the peripheral vasculature (discussed in greater detail in Ch. 104 , Acute Limb Ischemia: Surgical and Endovascular Treatment; Ch. 161 , Iliocaval Venous Obstruction: Endovascular Treatment; and Ch. 162 , Superior Vena Cava Obstruction and its Management). A number of methodologies and devices exist for mechanical thrombectomy, each with advantages and disadvantages:

1.
Hydrodynamic: Saline is infused and aspirated to create a local reduction in pressure (the Venturi effect).
2.
Rotational recirculation: Rotating blades or propellers macerate the thrombus.
3.
Mixing: Devices with a double-balloon catheter system confine the thrombolytic agent within a vessel, whereas a rotating, sinusoidal wire disrupts the clot.
4.
Ultrasound: High-frequency, low-power ultrasound energy is delivered to loosen and separate fibrin strands to permit better penetration of the thrombolytic agent.
5.
Aspiration: Aspiration of thrombus by a large suction catheter and syringe.
6.
Magnetic targeting: External magnetic field is used to localize magnetic carriers within the administered drug and guide therapy to the thrombus.

Biological Targeting

Biological targeting most frequently involves binding the thrombolytic agent to red blood cells (RBCs). The abundancy, large size of RBCs, and high fibrin content provide beneficial characteristics as a drug delivery system. A study using in vivo animal models by Murciano demonstrated that t-PA bound to RBCs was much more selective in lysing nascent thrombus than free t-PA in the lungs and other arteries. , Advantages include the potential for increased bioavailability and longer circulation. Disadvantages also include prolonged circulation, and the inability to lyse preexisting clot. Therefore, at present RBC target therapy may serve as a prophylactic rather than a therapeutic agent. Further studies and trials are warranted to better evaluate these effects on other in vivo models and in humans.

Monitoring

No existing laboratory test directly monitors the degree and effectiveness of thrombolysis. D-dimer and fibrin degradation products are elevated by thrombolysis, but levels do not correlate with the degree of thrombolysis. Thrombolytic therapy creates a dynamic fibrinolytic state consisting of both thrombus dissolution and thrombus formation. Formation occurs in an attempt to replace lysed clot, consuming coagulation factors and fibrinogen in the process. If fibrinogen levels drop below 100 mg/dL (2.9 μmol/L) or the aPTT increases above 100 seconds, excessive consumption of coagulation factors is present and an increased risk of hemorrhagic complications exists. In these circumstances, it is prudent to reduce or temporarily stop the lytic infusion until fibrinogen levels increase or the aPTT decreases, or both.

Other laboratory tests for indirect monitoring of the thrombolytic state include hemoglobin, platelet count, and creatinine, primarily to evaluate for signs of ensuing hemorrhagic complications. Patients treated by thrombolysis should be monitored in the intensive care unit or intermediate unit, where laboratory tests can be drawn at 4- to 6-hour intervals and patients assessed on an hourly basis. ^,

With CDT, serial angiography is performed through the indwelling catheter to assess the results of thrombolysis at 6- to 12-hour intervals over a 24- to 48-hour period. Restored pulse, Doppler signal, or improved symptoms can be surrogates for successful treatment. CDT should be discontinued once organ perfusion has been adequately restored, with subsequent transition to full anticoagulation with heparin. ^, ^, Thrombolysis beyond the 48-hour window increases the risk of complications with little to no additional benefit.

Complications

Complications of thrombolytic therapy can be classified as hemorrhagic, antigenicity-related, catheter-related, or embolic.

Hemorrhagic

Bleeding is always a risk when thrombolysis is used. Major versus minor bleeding correlates with the degree of bleeding and resultant clinical consequences, but in general, major bleeding includes intracerebral, retroperitoneal, or gastrointestinal hemorrhage. Minor bleeding is usually at the CDT puncture site and managed with local measures. ^, Puncture-site bleeding can evolve into major bleeding if a large hematoma develops or if blood tracks into potential spaces such as the retroperitoneum. Ultrasound guidance can minimize multiple needle passes for vascular access and thus minimize this bleeding risk.

The risk of remote-site bleeding increases as more thrombolytic drug is administered leading to clotting factors and fibrinogen depletion. In general, patients treated for pathologies that require longer infusions have a higher bleeding risk. Acute limb ischemia, PE, and DVT use more total thrombolytic compared to AMI and AIS; AVG and catheter occlusion use the smallest doses.

Intracerebral hemorrhage (ICH) is the most dreaded complication. AIS is associated with the greatest incidence of ICH (6.4% to 8.8%). Thrombolysis provides reperfusion of a stunned penumbra, but also lyses hemostatic plugs, leading to hemorrhagic reperfusion. For other thrombolytic indications, the incidence of ICH varies depending on the thrombotic process: PE (0% to 4.5%), AMI (0.3% to 1.8%), and peripheral artery occlusion (1% to 2%). ^, The true incidence of other remote bleeding complications is difficult to determine given inconsistent definitions and reporting. When major bleeding is defined as that causing permanent disability, increased hospital stay, or a requirement for blood transfusion, rates as high as 27% have been noted. ^, Overall major bleeding after thrombolysis has been reported in 10% to 27% of patients with acute limb ischemia, 5% to 21% with PE, 0.3% to 5.9% with AMI, and 4% to 11% with DVT.

Antigenicity Related

This complication is mainly related to SK. Minor allergic reactions have been reported in 1% to 10% of cases, and life-threatening allergic reactions in less than 0.01%. Pretreatment with 100 to 250 mg of methylprednisolone, antihistamines, or acetaminophen (or any combination of these drugs) can reduce the allergic response. Other thrombolytics, such as UK and rt-PA, are naturally found in vivo , thus allergic reactions are rare. ^,

Catheter Related

Catheter insertion for CDT poses the same risks associated with any endovascular procedure, including but not limited to dissection of the artery, pseudoaneurysm, dislodgment of thrombus during wire or catheter manipulation, and bleeding around the introducer sheath.

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