Continuing Education Activity

Thrombolytics or fibrinolytic are a group of medications used to manage and treat dissolving intravascular clots. They are in the plasminogen activator class of drugs. This class of medicine is used in acute myocardial infarction, deep vein thrombosis, pulmonary embolism, acute ischemic stroke, acute peripheral arterial occlusion, occlusion of indwelling catheters, and intracardiac thrombus formation. This activity describes the indications, action, and contraindications for thrombolytics. This activity will also highlight the mechanism of action, adverse event profile, monitoring, and toxicity pertinent for interprofessional team members in treating patients with intravascular clots such as acute myocardial infarction, acute ischemic stroke, and related conditions.

Objectives:

• Identify the mechanism of action of thrombolytics.
• Describe the potential adverse effects associated with various thrombolytic agents.
• Review the monitoring for patients on thrombolytic therapy.
• Summarize interprofessional team strategies for improving care coordination and communication to advance thrombolytics and improve outcomes.

Indications

Thrombolytic treatment, also known as fibrinolytic therapy, dissolves 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 detach and travel to block the downstream vascular lumen. Thromboembolism has the following clinical outcomes where 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.
• Severe frostbite(off-label use)[1]

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 clot site. Ultrasound-facilitated catheter-directed thrombolysis (USCDT) used in patients with acute massive and sub-massive pulmonary embolism improves the efficacy and safety of thrombolytic therapy.[2]

Thrombolytic or fibrinolytic agents are often referred to as plasminogen activators. All 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 good efficacy and safety, it is the most widely used fibrinolytic agent worldwide. While it has lower efficacy than alteplase, the risk of intracranial hemorrhage is less. Re-administration of streptokinase within six months is not considered 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 is produced from streptococcus, it often exerts febrile and other allergic reactions. Dose-dependant hypotension is another potential caution for this drug.[3]

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). Theoretically, alteplase should only be active on the surface of a fibrin clot. However, it exhibits systemic fibrinolysis; thus, a substantial amount of circulating fibrin degradation products has been observed with a moderate risk of bleeding. Alteplase is not antigenic and, therefore, seldom associated with any allergic manifestations.[4][5]

Tenecteplase (TNK-tPA)

It is a commonly used fibrinolytic agent across the USA (except for 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 a longer plasma half-life with final clearance, primarily through hepatic metabolism. Furthermore, it lacks antigenicity and is more comfortable to administer.[6]

Reteplase

It is a second ­generation recombinant plasminogen activator that works more rapidly with lower bleeding tendency than the first ­generation agent alteplase. It demonstrates weaker binding with fibrin than native tPA does and 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, thus allowing plasminogen to transform into clot­ dissolving plasmin. These characteristics, in sum, explain its faster clot resolution than other agents. The FDA­ approved reteplase administration of two boluses 10U 30 minutes apart for AMI management. Each of these boluses is administered over two minutes. Like alteplase, reteplase can be readministered when necessary and is not antigenic.[7]

Urokinase

Urokinase has been used most often for occluded catheters and peripheral vascular thrombus. It is considered a physiologic thrombolytic 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.[8]

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 pro-urokinase. It is a newer agent that is already in clinical trials.[9]

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. When administered, the acyl group spontaneously hydrolyzes, freeing the activated streptokinase-pro activator complex. Like streptokinase, anistreplase does not distinguish between circulating vs. fibrin­-bound plasminogen; subsequently, it produces the systemic lytic state.[10]

Mechanism of Action

Hemostasis and thrombosis result from an integrated and interactive response of the coagulation factors, blood vessels, and platelets. During thrombosis, activated platelets convert circulating prothrombin to its active form of thrombin. Active thrombin then converts the fibrinogen into fibrin, eventually forming 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 the thrombus and on the surface of fibrin by the binding of tPA to plasminogen. This binding helps the conversion.

They can be subdivided into two categories which are as follows:

1. Fibrin-specific agents: These 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: These do not need fibrin presence for conversion, which is why they can do this systemically. 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 plasminogen formation and are affected slightly by the local fibrin clot, thus having a higher systemic effect. Streptokinase and urokinase are not used widely in the United States but are used elsewhere because of their lower cost.[11]

Alteplase (TPA) is the recombinant tissue-type plasminogen activator and is identical to native tPA and is produced by recombinant DNA technology using complementary DNA for natural human tissue-type plasminogen activator obtained from a human melanoma cell line. Reteplase (recombinant plasminogen activator, r-PA)  is an unglycosylated single-chain t-PA deletion variant produced in E. coli. The kringle-1 domain is responsible for its rapid clearance. Tenecteplase (TNK-tPA) is a variant of t-PA with three-point mutations. Tenecteplase has a slow clearance rate; hence a simplified single bolus regimen is used.[12]

Administration

Acute Ischemic Stroke

Fibrinolytic therapy in acute ischemic stroke breaks up blood clots, preventing blood flow to the brain to restore blood flow to the brain areas that have not yet suffered an infarct. According to AHA(American heart association/ASA(American Stroke Association) guidelines, Intravenous alteplase (tPA) is the mainstay of thrombolysis in acute ischemic stroke that improves functional outcomes 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). The benefit is significant when treatment with thrombolytics occurs early after stroke onset and declines with time.[13] 

Mechanical thrombectomy is beneficial when an acute ischemic stroke results from a proximal intracranial arterial occlusion.[5] According to a recent meta-analysis, patients with acute ischemic stroke, having large vessel occlusion receiving tenecteplase have better recanalization and clinical outcomes than those receiving intravenous alteplase.[14] Alteplase is the preferred thrombolytic agent in acute ischemic stroke.[15] The recommended dose is 0.9 mg/kg (maximum 90 mg total dose), 10% of the total dose is administered as an initial IV bolus over one minute, and the remaining dose is infused over 60 minutes. 

Acute Myocardial Infarction

Fibrinolytic therapy remains vital as a treatment for ST-elevation myocardial infarctions in many places where acute percutaneous coronary intervention is not an option and during transport 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 greater the time necessary to deliver the therapy after the AMI lessens its efficacy. A useful means to quantify the time window is the "door to needle time," which should be kept under 30 minutes to get the maximum results.[16][17] 

According to the 2022 American college of cardiology(ACC)/American heart association(AHA) guidelines; rescue PCI can be recommended in patients with evidence of failed reperfusion after thrombolysis as it is associated with a decrease in cardiovascular events compared with conservative care or repeat thrombolytic therapy. In addition, risks associated with fibrinolytic therapy, i.e., increased bleeding and stroke, can be reduced by using half-dose tenecteplase in patients >75 years of age. In addition, fibrinolytic therapy is recommended only in patients in which primary PCI is not immediately available, and the delay from hospital admission to PCI is expected to be >120 minutes. Approximately 35% of patients treated with fibrinolysis do not achieve reperfusion, and 10% have ineffective reperfusion (Thrombolysis In Myocardial Infarction] flow grade <3); hence the rapid transfer of patients to centers competent for performing PCI is required.[18]

Alteplase: Accelerated and 3-hour regimens are used in acute myocardial infarction.

Accelerated alteplase infusion regimen: The recommended accelerated infusion dose regimen consists of an IV bolus followed by an IV infusion. For patients weighing> 67 kg, the bolus dose is 15 mg; 50 mg is infused in the first 30 minutes, and 35 mg is infused in 60 minutes. For patients weighing≤ 67 kg, the bolus dose is 15 mg; 0.75 mg/kg is infused in the first 30 minutes, and 0.50 mg/kg is infused in 60 minutes.

3-hour alteplase regimen: For patients weighing ≥ 65 kg, the recommended dosage is 100 mg intravenously given as 60 mg in the first hour (6-10 mg is administered as a bolus), 20 mg in the second hour, and 20 mg in the third hour. For patients weighing < 65 kg, clinicians may use a 1.25 mg/kg dose administered over 3 hours.

Tenecteplase: Tenectaplase is administered  as a single IV bolus over 5 seconds. Tenecteplase is preferred in acute MI due to the simplified single bolus regimen. The recommended daily dose should not exceed 50 mg and is based on patient weight. The dose, according to the manufacturer's labeling, is given below.

• Weight<60 kg:30 mg single IV bolus dose of tenecteplase
• Weight≥60 to <70 kg: 35 mg single IV bolus dose of tenecteplase
• Weight≥70 to <80 kg: 40 mg single IV bolus dose of tenecteplase
• Weight ≥80 to <90 kg: 45 mg single IV bolus dose of tenecteplase
• Weight≥90 kg:50 mg single IV bolus dose of tenecteplase

Reteplase: Reteplase is administered 10 units intravenously over 2 minutes and then administered the following dose of 10 units 30 minutes after the first dose. Heparin and reteplase are incompatible. Do not administer reteplase by the same IV line.  

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; therefore, it is unsuitable for patients with limb-threatening ischemia.[19][20] Intra-arterial thrombolysis is the preferred method of thrombolysis for acute limb ischemia. For alteplase (TPA) weight-adjusted doses have ranged from 0.02 to 0.1 mg/kg/h, whereas non–weight-based doses generally range from 0.25 to 1.0 mg/h. The maximum recommended dose of alteplase is 40 mg for catheter-directed therapy. For reteplase, the dose range of 0.25 to 1.0 U/h, with a maximum dose of 20 Units and a maximum infusion of 24 hours.[21][20] Pulmonary Embolism (PE)

The most commonly used thrombolytic agent used in acute massive PE  is alteplase. The recommended dose of alteplase is 100 mg administered by IV infusion over two hours. Clinicians should initiate parenteral anticoagulation immediately following the alteplase infusion when the activated partial thromboplastin time (aPTT) or thrombin time returns to twice normal or less. Tenecteplase is currently under study but not yet recommended. Clinicians should avoid simultaneous administration of unfractionated heparin (UFH) in acute massive PE. According to guidelines, thrombolytic therapy should be used only for patients with pulmonary embolism with significant hypotension(systolic BP <90 mm Hg).[22]

Anticoagulation is the mainstay of initial treatment for DVT. However, certain patients with extensive acute DVT with a 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.[23][24] Combination therapy with different fibrinolytic agents and glycoprotein inhibitors is not generally recommended due to the increased risk of bleeding and lack of any mortality benefit.

Use in Specific Patient Populations

Patients with Hepatic Impairment: Use with caution in patients with severe hepatic impairment due to the increased risk of bleeding due to coagulopathy.[25]

Patients with Renal Impairment: Use with caution in patients with end-stage renal disease(ESRD) due to the increased risk of bleeding due to hemostatic defects and bleeding tendencies.[25]

Pregnancy Considerations: Pregnancy is a relative contraindication for using thrombolytic agents due to the increased risk of bleeding. Thrombolysis in normotensive patients with pulmonary embolism was associated with increased mortality.[26] However, according to the American heart association/American stroke association guidelines, IV alteplase administration may be regarded in pregnancy when the benefits of treating stroke outweigh the increased risks of uterine bleeding.[13]

Breastfeeding Considerations: Information regarding the excretion of tenecteplase in human milk is unknown. There is no data on the presence of reteplase in human milk or the effects on the breastfed infant. Reteplase has not been studied in nursing mothers. Therefore, caution should be exercised when a nursing woman is administered tenecteplase or reteplase. Alteplase should be used cautiously during breastfeeding, especially while nursing a newborn or preterm infant.[27]

Adverse Effects

Adverse effects of any fibrinolytic agents are almost similar, including, but not limited to, bleeding, hypotension, allergic reactions, angioedema, anaphylactic shock, and reperfusion arrhythmias (when used in acute MI).[28] Among all fibrinolytic agents, streptokinase is the most antigenic; thus, it is most frequently complicated by allergic reactions and hypotension.[29]

Bleeding is the most frequent complication of thrombolytic therapy and can occur in puncture sites or spontaneously anywhere inside the body. Intracranial hemorrhage or hemorrhagic stroke is the greatest concern. Risk factors associated with hemorrhagic complications include elderly patients, uncontrolled hypertension, recent stroke or surgery, the presence of bleeding diathesis, and concurrent use of anticoagulants.[30][31] 

Overdose most often occurs when administered in a non-body-weight-adjusted manner and can cause severe hemorrhagic complications. Cholesterol embolism is reported in patients treated with thrombolytic agents. Cholesterol embolism may lead to cyanotic or "purple toe syndrome" and acute kidney injury.[32][33]

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[25]

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
• Concurrent therapy of anticoagulants is associated with an elevated international normalized ratio (INR) higher than 1.7 or a prothrombin time (PT) longer than 15 seconds.[25]

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 for at least 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. Clinicians should stop thrombolytic therapy urgently with any signs of neurologic deterioration, and the patient should receive an emergency computed tomography (CT). Cardiac monitoring is required due to the risk of reperfusion arrhythmias.[28] Clinicians should obtain the National Institutes of Health Stroke Scale (NIHSS) score to quantify stroke severity and assess whether the patient is a potential candidate to receive fibrinolytic therapy.[34]

Fibrinolytic agents or 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 is also on concomitant heparin, protamine sulfate can reverse the heparin effect.[35]

Toxicity

Fresh frozen plasma (FFP) cryoprecipitate can help refurbish 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 there is a life-threatening hemorrhage. It inhibits intrinsic physiologic fibrinolytic activity, which may precipitate widespread thrombosis with potential end-organ damage at many sites. The drug may worsen disseminated intravascular coagulation (DIC) and heparin-induced thrombocytopenia. Platelet transfusion is indicated if the platelet count is <100,000/microL.[36]

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 EKGs, thereby playing a role in pre-hospital administration of thrombolytic or advance notification to the coronary care facility. However, when administered by skilled first responders, pre-hospital fibrinolysis is safe and reasonable. Therefore, 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 EKG, advanced cardiac life support (ACLS) training, and uninterrupted availability of medical direction are mandatory.

When fibrinolytic is used in acute ischemic stroke, strict blood pressure monitoring and control are essential to prevent hemorrhagic complications with a goal blood pressure of less than 180/110 mmHg. Clinicians should avoid adjunctive therapies with anticoagulants and antiplatelets 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. A pharmacy consult is crucial to ensure proper dosing and prevent interactions.

Thrombolytic therapy is a crucial tool in treating conditions where it is indicated (e.g., AMI, occlusive stroke). It requires the coordinated efforts of an entire interprofessional team, including EMTs/paramedics, clinicians, specialists, nurses, and pharmacists. Through collaborative effort and open communication between all these disciplines, patients who require thrombolytic therapy can achieve the best possible outcomes with the fewest adverse events. The interprofessional PERT (The Pulmonary Embolism Response Team) model has been developed to manage pulmonary embolism. The PERT team consists of healthcare providers from critical care, pulmonary medicine, vascular medicine, emergency medicine, interventional and noninterventional cardiology, interventional radiology, vascular surgery, cardiac surgery, hematology, and clinical pharmacy. This multidisciplinary PERT team rapidly engages multiple experts. It provides rapid evidence-based care for patients with pulmonary embolism improving patient outcomes.[37][38] Patient outcomes improvement was evident from an observational study published in the American journal of cardiology. Implementing PERT was associated with a statistically significant reduction in mortality six months after pulmonary embolism. There was a decreased length of stay following multidisciplinary PERT implementation.[39] [Level 3]

The Heart Team relies on the principles of collaboration, respect, and commitment to excellence in patient care with CAD. Observational studies in the Multidisciplinary Heart Team have included interventional cardiology, cardiac surgery, and noninvasive cardiologists. Additional clinicians who offer input may include the patient’s primary physician and palliative care, critical care, anesthesiology, and imaging specialists. The multidisciplinary heart team (MHT) approach reduced the MACCE(major adverse cardiovascular and cerebrovascular events) treatment for CAD. Therefore, the dedicated interprofessional MHT approach can improve the outcomes for patients with CAD.[40][41] [Level 3] All team members are responsible for maintaining accurate patient records and openly communicating with other interprofessional team members as necessary.

A dedicated acute stroke team that includes physicians and other clinicians, nurses, and laboratory/radiology personnel is recommended by AHA/ASA. Multidisciplinary teams with access to neurological expertise are recommended to improve patient outcomes related to IV fibrinolytic treatment.[13] [Class I]