Thrombolytic therapy, also known as clot busting drug, is a breakthrough treatment which has saved untold lives. It has been used in the clinical area to treat venous and arterial thromboembolic complaints which are a foremost cause of death. In 1761, Morgagni lead the way of thrombolytic therapy. Now day’s different types of thrombolytic drugs are currently available in market: alteplase, anistreplase, urokinase, streptokinase, tenecteplase, and so forth. Thrombolytic therapy should be given with maintaining proper care in order to minimize the risk of clinically important bleeding as well as enhance the chances of successfully thrombolysis of clot. These cares include preinfusion care, during the infusion care, and postinfusion care. Besides proper knowledge of contraindication, evolutionary factor, and combination of drug is essential for successful thrombolytic therapy. In these review we discussed about these aspect of thrombolytic therapy.
A blood clot (thrombus) develops in the circulatory system which consolidates a mechanism in human body to repair the injured blood vessel [
Thrombolytic therapy is a treatment to get rid of problems raised due to blood clot or thrombus to renovate function to the affected area [ venous thrombosis, pulmonary embolism, myocardial infarction, arterial thromboembolism, acute ischemic stroke [
Thrombolytic agents can be classified according to their generation as shown in Table
Generation of thrombolytic drug | Fibrin specific | Nonfibrin specific |
---|---|---|
First |
|
Urokinase* |
|
Streptokinase* | |
|
||
Second | Recombinant tissue |
Prourokinase |
Alteplase | Sk-plasminogen | |
|
||
Third | Tenecteplase* (TNK-tPA) |
|
Reteplase* |
|
|
Monteplase |
|
|
Lanoteplase |
|
|
Pamiteplase |
|
Thrombolytic drugs rapidly lyse thrombi by catalyzing the formation of the serine protease plasmin. Schematic representation of fibrinolysis is shown in Figure
Schematic representation of fibrinolysis.
Tissue plasminoogen activator is a serine protease consisting of a single chain of 527 amino acids. Its molecular weight is about 70,000 daltons [
Reteplase is another recombinant t-PA from which several amino acid sequences have been removed. Due to lack of fibrin binding domain and less fibrin specificity, reteplase is cheaper to produce than t-PA. Tenecteplase (TNK-tPA) is a mutant form of t-PA that has a longer half-life. Tenecteplase is slightly more fibrin-specific than t-PA [
Streptokinase is a protein (but not an enzyme in itself) produced by various strains of h-hemolytic streptococci having a molar mass of 47 kDa and is made up of 414 amino acid residues. The protein exhibits its maximum activity at a pH of approximately 7.5 and its isoelectric pH is 4.7 [
Urokinase is a human enzyme synthesized by the kidney that directly converts plasminogen to active plasmin [
Anistreplase (anisoylated plasminogen streptokinase activator complex; APSAC) consists of a complex of purified human plasminogen and bacterial streptokinase that has been acylated to protect the enzyme’s active site. When administered, the acyl group spontaneously hydrolyzes, freeing the activated streptokinase-proactivator complex. This product (recently discontinued in the USA) allows for rapid intravenous injection, greater clot selectivity (i.e., more activity on plasminogen associated with clots than on free plasminogen in the blood), and more thrombolytic activity [
Perhaps the field of fibrinolysis originated with Morgagni in 1761 [
The streptokinase era dates back to 1933, while Tillett and Garner [
In 1980s, there has been an explosion of works in thrombolytics therapy where melanoma tPA was first demonstrated in rabbits with experimental pulmonary embolus in vivo. Tissue plasminogen activator (tPA) originally developed in the mid 1981s for acute coronary artery occlusion [
The fibrinolytic potential of human urine was first described by Macfarlane and Pilling in 1947 [
Thrombolytic drugs are administered intravenously and are necessary to give as soon as possible after the patient progresses the signs and symptoms of STEMI; the earlier they are given the better will be noticed. The American College of Cardiology and the American Heart Association suggest that in order for the thrombolytic drugs to be most successful, they should be administered in 30 minutes of the patient’s entrance at the hospital [
The steps included during nursing care are shown in Table
Preinfusion care | During the infusion | Postinfusion care |
---|---|---|
(a) Obtain a whole health history together with recent surgeries or trauma, allergies, drug history, and possible drug interactions. |
(a) Assess and record very important signs and the infusion site for hematoma or hemorrhage every 15 minutes for the first hour, every 30 minutes for the subsequent 2 hours, and then hourly until the intravenous catheter is terminated. Evaluate pulses, sensation, color, and temperature of both extremities with each vital sign test. Vital signs and the site are commonly evaluated to find possible complications. |
(a) Evaluate important signs, distal pulses, and infusion site regularly as required. |
Thrombolytics are predominantly safe; complications related with bleeding are the major problem. Study revealed that 11% of all patients who receive thrombolytics have reasonable bleeding. Among them 0.3%–1.3% experience intracranial hemorrhage. Contraindications for using thrombolytic can be classified into two ways—absolute contraindications and relative contraindications.
Absolute contraindications are vascular lesions, severe, uncontrolled hypertension, recent cranial surgery or trauma, brain tumor, ischemic stroke in two to three months, active bleeding (except for normal menstrual bleeding).
Relative contraindications can be included: ischemic stroke > three months prior, active peptic ulcer, current use of anticoagulant drugs, pregnancy, prolonged/traumatic CPR ≤ three weeks prior, major surgery ≤ three weeks prior, internal bleeding in two to four weeks [
There is indomitable evidence that exact treatment such as thrombolytic develops the chances of an amicable outcome when administered within a suitable time-window [
The effectiveness and safety of prehospital thrombolysis is relying on several prerequisites [ Prehospital personnel should be trained to identify symptoms and management of STEMI and its earlier complexities (pain, bradycardic arrhythmias, and ventricular fibrillation/ventricular tachycardia). Diagnoses of STEMI by a 12 lead ECG with or without computer help for diagnosis and/or data transmission. Intravenous access to be conventional and the administration of reperfusion therapy to be pioneered within a treatment procedure/clinical principle and affirmed by a thrombolysis checklist. During transportation rhythm observation, availability of a defibrillator and modern cardiac life support are required. Precaution receiving hospital of imminent arrival of the patient supported by (if available) electronic transmission of the 12 lead ECG. On-going quality promise.
Patient’s education plays vital role for proper implementation of thrombolytic therapy which are followed [ Instruct patient about procedures and their necessity prior to beginning thrombolytic therapy. Instruct patient that frequent vital signs must be taken. Instruct patient that activity will be limited during infusion and that pressure dressing may be needed to prevent any active bleeding. Advise patient about assessments and why they are necessary. Advise patient that cardiac rhythm will be observed during therapy. Instruct patient about increased risk for bleeding, activity restriction, and frequent monitoring during this time.
Oxygen is commonly administered during the management of patients during thrombolysis. Its routine use in patient with pulse oximetry above 95% has been questioned primarily due to the possibility of vasoconstriction and limited evidence of benefit [
All patients with suspected acute coronary syndrome (unstable angina, non-STEMI, and acute STEMI) should be considered for prehospital aspirin treatment. It blocks prostaglandin formation which in turn leads to a decrease in the synthesis of thromboxane A2. Thromboxane A2 results platelets to adhere to each other. Despite this, aspirin is often withheld either due to concerns over allergy, adverse drug interactions (e.g., Warfarin), confusion due to chronic ongoing use of aspirin, or uncertainty of diagnosis [
Clopidogrel is a strong platelet inhibitor and the antiplatelet benefits of clopidogrel in combination with aspirin are to lessen ischaemic events in non ST-elevation acute coronary syndromes (PCI) [
New developed oral antiplatelets such Prasugrel and Ticagrelor are now existing with potentially developed antiplatelet as Ticagrelor produces a more profound and reliable antiplatelet effect than that of clopidogrel [
Heparin is considered to be effectual and is regularly given as an adjunct for PCI and thrombolytic therapy although it is frequently withheld in the first 24 hours in those patients receiving Streptokinase. The role of heparin is mainly to decrease reinfarction but the combination of dual antiplatelet therapy, thrombolysis, and heparin may amplify the risk of bleeding. The American Heart Association strategies call for careful weight based dosing of heparin with thrombolytic therapy in STEMI [
The regular administration of steroids and antihistamines to prevent hypotension/bradycardia specially in association with Streptokinase complicates the administration procedures and is improbable to avert hypotension as the cause of Streptokinase induced hypotension is principally due to speed of administration [
Some selected pharmacokinetic and pharmacodynamics parameters of thrombolytic agents are given in Table
Features | Thrombolytics | |||||
---|---|---|---|---|---|---|
Streptokinase | Urokinase | Anistreplase | Alteplase | Reteplase | Tenecteplase | |
Plasma half-life (min) | 18 | 15 | 90–112 | 4–8 | 11–14 | 20 |
Plasma clearance (mL/min) |
|
NR |
|
|
|
105 |
Volume of distribution (L/kg) | 5.68 | 0.04 | NR | 0.07 | NR | NR |
Peak plasma level (ng/mL) | NR | 2200–2400 | NR | 1000–4000 | 4000 | >1000 |
Route of excretion | Renal | Hepatic and renal | NR | Hepatic | Hepatic and renal | Hepatic |
Elimination half-life (Alpha phase) (min) | 18 | NR | 70–120 | 5–10 | 13–16 | 11–20 |
Elimination half-life (Beta phase) (min) | 83 | NR | NR | 72 | 98–135 | 41–138 |
Active metabolite | Unknown | NR | None | None | None | None |
Sezer and his colleagues studied to investigate the reflections of the progress in microvascular perfusion provided by adjuvant intracoronary streptokinase (ICSK) on late-phase infarct size and left ventricular volumes and functions. In this study, it had been demonstrated that low-dose ICSK given immediately after primary percutaneous coronary intervention significantly limits long-term infarct size and preserves left ventricular volumes and functions [
Gupta and his colleagues hypothesized throughout their clinical trial that streptokinase can be a useful adjunct in expanding nonoperative management of infected walled off pancreatic necrosis while not responding to pigtail catheter drainage and saline irrigation [
Sugimoto and his colleagues studied 93 patients and finally revealed that low-dose t-PA combined with subtherapeutic heparin is equally efficacious and safe compared with urokinase. Infusions with t-PA were significantly shorter and less expensive than those with urokinase [
Roth conducted a double-blind, multicenter, parallel-group trial for four years included patients from 18 to 80 years. He provided sufficient data that recombinant tissue plasminogen activator is useful in treatment of acute ischemic stroke [
Wang and his colleagues compared urokinase 2 h and urokinase 12 h regimen in treating acute pulmonary embolism in a randomized, controlled, multicenter trial. This study demonstrated that urokinase h (20 000 IU/Kg) regimen displayed similar efficacy and safety as the urokinase 12 h regimen in treating acute pulmonary embolism with either hemodynamic instability or massive pulmonary artery obstruction. Given the convenience, lower cost and the similar efficacy and safety as the urokinase 12 h regime, they suggested that body weight adjusted urokinase 2 h regimen could be used for pulmonary embolism treatment [
Wang and his colleagues hypothesized that among patients with transient ischemic attack or minor stroke that can be treated within 24 hours after the onset of symptoms. He with his colleagues observed that combination of clopidogrel and aspirin is superior to aspirin alone for reducing the risk of stroke in the first 90 days and does not increase the risk of hemorrhage [
Morrow and his colleagues revealed that prehospital administration of reteplase is a feasible approach to accelerating reperfusion in patients with STEMI. Valuable time savings can be achieved in the setting of contemporary transport and door-to-drug times and may translate into an improvement in clinical outcomes [
Oldgren and his colleagues demonstrate that in patients with a recent acute coronary syndrome, the addition of a new oral anticoagulant to antiplatelet therapy leads to a modest reduction in cardiovascular events but a substantial increase in bleeding. These results are most pronounced when oral anticoagulants are combined with dual antiplatelet therapy with aspirin and clopidogrel [
Understanding of thrombolytic therapy is needed for development in pharmacological reperfusion. Chronicle history of thrombolytic therapy was recorded since 1761 and till now it saved untold lives. But it is conspicuous that failure of thrombolytic therapy due to some barrier. It is not inexplicable to overcome this barrier. Proper decision making, trained personnel and equipment, and patients education could be impetus for effective thrombolytic therapy.
The authors declare that there is no conflict of interests regarding the publication of this paper.