Indications

Thrombolytic treatment is also known as fibrinolytic or thrombolysis, to dissolve dangerous intravascular clots to prevent ischemic damage by improving blood flow. Thrombosis is a significant physiological response that limits hemorrhage caused by large or tiny vascular injury. The physiological hemostatic response is well-controlled by intrinsic antithrombotic properties and fibrinolysis. Thrombus formation is supposed to be confined to localized areas of tissue injury. Any intravascular thrombus without damage that impedes the blood flow is considered abnormal. Any form of inherited or acquired hypercoagulable state may give rise to intravascular thrombus formation. Upon formation, an abnormal thrombus may propagate until complete blockage of the arterial lumen or may detach and travel to block downstream vascular lumen. Thromboembolism has the following clinical outcomes where a thrombolytic therapy can be used.

• Acute myocardial infarction (AMI)
• Deep vein thrombosis (DVT)
• Pulmonary embolism (PE)
• Acute ischemic stroke (AIS)
• Acute peripheral arterial occlusion
• Occlusion of indwelling catheters
• Intracardiac thrombus formation.

There are two ways thrombolytic agents can be given: systemic administration through a peripheral IV  or local release by a catheter after navigating to the site of the clot. Thrombolytic or fibrinolytic agents are often referred to as plasminogen activators. All of the available thrombolytic agents are serine proteases that cleave plasminogen into active plasmin. Currently, available thrombolytic agents include the following:

• Streptokinase
• Alteplase
• Reteplase
• Tenecteplase
• Urokinase
• Prourokinase
• Anistreplase(APSAC)

Streptokinase

Due to its relatively low cost with reasonable efficacy and safety, it is the most widely used fibrinolytic agent across the world. While it has lower efficacy than alteplase, the risk of intracranial hemorrhage is less.   Re-administration of streptokinase within six months is not considered as safe due to its high antigenicity and associated high antistreptococcal antibody titer.  It is not a plasminogen activator. However, after binding with free circulating plasminogen, it forms a complex that converts additional plasminogen to active plasmin. As it produced from streptococcus, it often exerts febrile reactions and other allergic reactions. Dose dependant hypotension is another potential caution for this drug.[1]

Alteplase

Alteplase is the recombinant plasminogen activator and identical to native tPA, which is more fibrin­specific with a plasma half­life of 4­6 minutes. It is the most often used fibrinolytic in the treatment of acute cardiovascular events (STEMI), pulmonary embolism(PE), and acute ischemic stroke(AIS). By theory, alteplase should only be active on the surface of a fibrin clot. In reality, however, systemic fibrinolysis, thus a substantial amount of circulating fibrin degradation products, has observed with a moderate risk of bleeding. Alteplase is not antigenic and, therefore, seldom associated with any allergic manifestations.[2][3]

Tenecteplase (TNK-tPA)

It is a commonly used fibrinolytic agent across the USA (except ischemic stroke), Canada, and many European countries. It is as efficient as alteplase while exerting a lower risk of non-cerebral bleeding. Tenecteplase has higher fibrin specificity and longer plasma half-life with final clearance, mostly through hepatic metabolism. Furthermore, it lacks antigenicity and more comfortable to administer.[4]

Reteplase

It is a second ­generation recombinant plasminogen activator that works more rapidly with lower bleeding tendency than the first ­generation agent alteplase. It's weaker binding with fibrin than native tPA does, allows more free diffusion through the clot rather than binding only to the surface as tPA does. Additionally, reteplase does not show competitive inhibition of plasminogen, therefore allows plasminogen to transform into clot­dissolving plasmin. These characteristics, in sum, explain its faster clot resolution than other agents. FDA­ approved reteplase administration two boluses of 10U in 30 minutes apart for AMI management. Each of these bolus administered over 2 minutes. Like alteplase, reteplase can be readministered when necessary and is not antigenic.[5]

Urokinase

Urokinase has been used most often for occluded catheters and peripheral vascular thrombus. It is considered a physiologic thrombolytic that usually produced by renal parenchyma, thus purified from human urine. However, recombinant urokinase is also commercially available. In contrast to streptokinase, urokinase directly cleaves plasminogen into plasmin. Its low antigenicity allows repeated dosing without antigenic problems.[6]

Prourokinase

Prourokinase is a relatively inactive precursor that necessitates the conversion to urokinase to become active. The need for such conversion provides the fibrin specific physiologic properties of prourokinase. It is a newer agent that already in clinical trials.[7]

Anistreplase

Anisoylated purified streptokinase activator complex(APSAC) or anistreplase is a complex mixture of streptokinase and plasminogen that does not depend on circulating plasminogen to be effective. Despite its many theoretical benefits over streptokinase, it exerts high antigenicity. Similarly, with streptokinase anistreplase does not distinguish between circulating vs. fibrin­bound plasminogen; subsequent production of it is the systemic lytic state. 

Mechanism of Action

Hemostasis and thrombosis are a result of an integrated and interactive response of the coagulation factors, blood vessels, and platelets. During thrombosis, circulating prothrombin is converted to its active form thrombin by activated platelets. Active thrombin then converts the fibrinogen into fibrin with eventual formation of a fibrin matrix. This process is counterbalanced by plasmin derived from plasminogen, which gathers in the fibrin matrix. Tissue plasminogen activator (tPA) is a natural fibrinolytic found in endothelial cells. It shows fibrin specificity and affinity. The end goal of this therapy is to convert plasminogen into plasmin which is accomplished at the location of thrombus and on the surface of fibrin by the binding of tPA to plasminogen. This binding helps the conversion. They can subdivide into two categories which are as follows:

1. Fibrin specific agents= mostly need the presence of fibrin for the conversion, but on a minimal scale can do so in the absence of fibrin too. e.g. alteplase (tPA), reteplase (recombinant plasminogen activator [r-PA]), and tenecteplase

2. Non-fibrin specific agents= do not need fibrin presence for conversion; that's why they can do this systematically. e.g., streptokinase

 Streptokinase is the first historical thrombolytic agent extracted from certain streptococcal strains. Researchers found another potential fibrinolytic agent in human urine named urokinase.  In contrast to streptokinase, urokinase lacks antigenicity and directly converts plasminogen to plasmin. These two substances catalyze the formation plasmin from plasminogen and are affected slightly by the local fibrin clot, thus have a higher systemic effect. Streptokinase and urokinase are not used widely in the United States but used elsewhere because of its lower cost.[8]

Administration

Acute Ischemic Stroke

Fibrinolytic therapy in acute ischemic stroke is used to break up blood clots prevenitng blood flow to the brain with a hope to restore blood flow to the areas of the brain that are not yet infarcted. Intravenous alteplase (tPA) is the mainstay of thrombolysis in acute ischemic stroke that improves functional outcome significantly when administered within 4.5 hours of stroke onset. All patients with acute ischemic stroke who present within a 4.5-hour window from their last known well time and without any absolute contraindication should receive treatment with intravenous alteplase (tPA). Mechanical thrombectomy is beneficial when an acute ischemic stroke results from a proximal intracranial arterial occlusion.[3] 

Acute Myocardial Infarction

Fibrinolytic therapy remains vital as a treatment for ST-elevation myocardial infarctions in many places where acute percutaneous coronary intervention cant be an offer and as the transport length to hospitals with this facility. Fibrinolytic therapy is a proven therapy in the treatment of AMI. It is widely available and can be administered by qualified health care professionals even in the prehospital setting. The more time taken to deliver the therapy after AMI lesser is its efficacy. A useful way of quantifying the time window is the "door to needle time," which should be kept under 30 minutes to get the maximum results.[9][10]

Acute Limb Ischemia

Primary fibrinolysis is the treatment of choice for non–life-threatening limb ischemia from in-situ thrombosis of fewer than 14 days of duration. Local fibrinolysis usually takes 6 to 72 hours to achieve clot lysis, thus not suitable for patients with limb-threatening ischemia.[11][12] Pulmonary Embolism (PE)

Following thrombolytic agents are approved by the FDA for use in acute PE, alteplase, urokinase, and streptokinase. Tenecteplase is currently under study but not yet recommended. Clinicians should avoid simultaneous administration of unfractionated heparin (UFH) in acute massive PE, and it should only be started for prophylaxis of recurrent thrombosis following fibrinolytic therapy has been given and when the activated partial thromboplastin time (aPTT) has come down to a value lower than two times the normal value. 

Deep Vein Thrombosis

Anticoagulation is the mainstay of initial treatment for DVT. However, certain patients with extensive acute  DVT with low risk of bleeding can undergo catheter­directed thrombolysis to lyse the intravenous clot. Patient criteria include symptoms of less than 14 days (acute DVT),upper-extremity DVT or proximal DVT, and good functional status.[13][14]

Combination therapy with different fibrinolytic agents and glycoprotein inhibitors is not generally a recommendation due to the increased risk of bleeding and lack of any mortality benefit.

Adverse Effects

Adverse effects of any fibrinolytic agents are almost similar, which include, but are not limited to, bleeding, hypotension, allergic reactions, angioedema, and reperfusion arrhythmias (when used in acute MI). Among all of the fibrinolytic agents, streptokinase is the most antigenic, thus most frequently complicated by allergic reaction and hypotension. 

Bleeding is the most frequent complication of thrombolytic therapy and can occur in puncture site or spontaneously anywhere inside the body. Intracranial hemorrhage or hemorrhagic stroke is the greatest concern. Risk factors associated with hemorrhagic complications include elderly patient, uncontrolled hypertension, recent stroke or surgery, presence of bleeding diathesis, and concurrent use of anticoagulants.[15][16] Overdose most often occurs when administered in a non-body-weight adjusted manner and can cause severe hemorrhagic complications. 

Contraindications

Absolute Contraindications for Thrombolytic Treatment

• Recent intracranial hemorrhage (ICH)
• Structural cerebral vascular lesion
• Intracranial neoplasm
• Ischemic stroke within three months
• Possible aortic dissection
• Active bleeding or bleeding diathesis (excluding menses)
• Significant head injury or facial trauma within three months
• Recent Intracranial or spinal surgery 
• Severe uncontrolled hypertension
• For streptokinase, previous treatment within six months[17]

Relative Contraindications for Thrombolytic Treatment 

• History of severe and poorly controlled hypertension
• Severe hypertension at presentation (systolic blood pressure >180 mmHg or diastolic blood pressure >110mmHg)
• Prolonged (>10 minutes) cardiopulmonary resuscitation (CPR) or major surgery within three weeks.
• History of ischemic stroke.
• Dementia
• Internal bleeding within 2 to 4 weeks
• Noncompressible vascular punctures
• Pregnancy
• Active peptic ulcer
• Current therapy of anticoagulant associated with an elevated international normalized ratio (INR) higher than 1.7 or a prothrombin time (PT) longer than 15 seconds[17]

Monitoring

Patients receiving thrombolytic therapy must undergo a constant neurologic and cardiovascular evaluation with blood pressure monitoring every 15 minutes during and after tPA infusion at least for 2 hours, then half-hourly for 6 hours and hourly for the next 16 hours after injection. Strict BP monitoring is essential to prevent complications. Thrombolytic therapy should be stopped urgently with any signs of neurologic deterioration, and the patient should receive an emergency computed tomography (CT).

Fibrinolytic agents or any anticoagulants must be stopped immediately with any evidence of bleeding complications in a patient with ongoing fibrinolytic therapy. In the next step, supportive measures should be instituted, including volume correction and blood factor transfusion.

If the patient also has been on concomitant heparin, protamine sulfate can reverse the heparin effect.[18]

Toxicity

Fresh frozen plasma (FFP), cryoprecipitate, can help refurbish the clotting factors and fibrin, depending upon availability and patient comorbidities. For the fibrinolytic agents' reversal of action, aminocaproic acid is useful because of its specific action. Aminocaproic acid should not be introduced unless life-threatening hemorrhage as it inhibits intrinsic physiologic fibrinolytic activity, which in turn may precipitate widespread thrombosis with potential end-organ damage at many sites. The drug may worsen disseminated intravascular coagulation (DIC) and heparin-induced thrombocytopenia.[19]

Enhancing Healthcare Team Outcomes

Pre-hospital thrombolytic therapy is a new treatment paradigm that can dramatically change patient outcomes. Several studies have shown that trained pre-hospital professionals may identify ST-segment elevation with 12­ lead ECGs, thereby, may play a role in pre-hospital administration of thrombolytic or advance notification to the coronary care facility. However, pre-hospital fibrinolysis is safe and reasonable when administered by skilled and first responders. Tissue plasminogen activator, alteplase, or modified forms of it reteplase or tenecteplase are commonly used fibrinolytic agents in pre-hospital settings. Reteplase or Tenecteplase is preferable for their convenient single­ or double­bolus dosing. Besides, to ensure standard out­ of ­hospital thrombolytic treatment, appropriate protocols with checklists, interpretation, and transmission of 12 lead ECG, advanced cardiac life support (ACLS) training, and uninterrupted availability of medical direction is mandatory.

When fibrinolytic used in acute ischemic stroke, strict blood pressure monitoring and control are essential to prevent hemorrhagic complications with goal blood pressure less than 180/110 mmHg. Adjunctive therapies with anticoagulants and antiplatelet should be avoided within 24 hours of thrombolytic treatment for acute ischemic stroke. An emergent CT scan of the brain is necessary if there is a change in neurologic examination during or after thrombolytic administration in the setting of acute ischemic stroke.