Abstract—Thrombolytic therapy has been a major advance in the management of acute myocardial infarction. Unfortunately, it continues to be underused or is administered later than is optimal. Thrombolytic therapy works by lysing infarct artery thrombi and achieving reperfusion, thereby reducing infarct size, preserving left ventricular
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When should thrombolytic therapy be used in the treatment of acute MI?
Thrombolytic therapy in acute myocardial infarction Recombinant tissue-type plasminogen activator (rt-PA), streptokinase (SK), and anisoylated plasminogen-streptokinase activator complex (APSAC) have salutary effects on mortality when administered to patients with evolving acute myocardial infarction (MI).
Are enzymes effective as thrombolytic drugs?
Early thrombolytic therapy has been shown to reduce hospital mortality after myocardial infarction by 20-50%. This is achieved through reperfusion of the ischemic myocardium, which leads to limitation of infarct size by 15-30% and preservation of regional and global left ventricular function. Thromb …
What are thrombolytics used for?
· Several thrombolytic enzymes have been reported to be isolated from microbial sources with therapeutic application in vascular diseases and have been shown to possess the following advantages over currently available treatment strategies: (i) extended plasma half-life, (ii) increased fibrin specificity, (iii) high therapeutic index, (iv) lower allergic response, and (v) …
When is thrombolysis indicated in the treatment of hemophilia A?
· This activity will highlight the mechanism of action and adverse event profile pertinent for members of the interprofessional team in the treatment of patients with intravascular clots such as Acute myocardial infarction, acute ischemic stroke, and related conditions. Thrombolytics or fibrinolytics are a group of medications used in the management …
Why are thrombolytics used to treat MI?
A blood clot can block the arteries to the heart. This can cause a heart attack, when part of the heart muscle dies due to a lack of oxygen being delivered by the blood. Thrombolytics work by dissolving a major clot quickly. This helps restart blood flow to the heart and helps prevent damage to the heart muscle.
What is used as an thrombolytic therapy for the treatment of myocardial infarction?
Alteplase is FDA-approved for treatment of ST-elevation myocardial infarction (STEMI), AIS, acute massive PE, and occluded CVADs. At present, it is the only thrombolytic drug approved for AIS. In theory, alteplase should be effective only at the surface of fibrin clot.
What do thrombolytic enzymes do?
Fibrinolytic enzymes are involved in the degradation of fibrin clots, by either catalyzing fibrin degradation process or by transforming the inactive plasminogen into active plasmin, thus re-establishing the normal blood vascular architecture (Krishnamurthy et al., 2018).
What is an indication for thrombolytic therapy for acute MI?
Current indications for thrombolytic therapy include ischemic chest pain of at least 30 min duration that is unrelieved by nitroglycerin and is associated with ST-segment elevations of at least 0.1 mV in two contiguous electrocardiographic leads.
What is thrombolysis in myocardial infarction?
Thrombolytic therapy works by lysing infarct artery thrombi and achieving reperfusion, thereby reducing infarct size, preserving left ventricular function, and improving survival. The most effective thrombolytic regimens achieve angiographic epicardial infarct-artery patency in only ≈50% of patients within 90 minutes.
Which condition is a contraindication for thrombolytic therapy in the treatment of an acute MI?
However, limitations to the use of thrombolytic therapy include perceived or definite contraindications, intracranial bleeding, inability to establish Thrombosis In Myocardial Infarction (TIMI-3) flow in many patients, and high rates of recurrent ischemia and reocclusion.
How do thrombolytics dissolve clots?
Thrombolytic agents are proteases that break down clots formed through the body's normal clotting cascade. Thrombolytics primarily work by activating a substance known as plasminogen. Plasminogen is then converted to plasmin, an enzyme that breaks down strands of a protein called fibrin.
How does thrombolysis treatment cause arrhythmias?
When high-grade ventricular arrhythmias occur after thrombolytic therapy for acute myocardial infarction, they are often attributed to successful reperfusion of the infarcted myocardium. This analysis of data from 2546 patients in the Thrombolysis in Myocardial Infarction (TIMI) Phase II study suggests the opposite.
What is the meaning of thrombolytic?
Listen to pronunciation. (throm-BOL-ih-sis) The process of breaking up a thrombus (blood clot) that is blocking blood flow. The blood clot may be dissolved using drugs delivered through a catheter (tube) into the clot.
What is the standard treatment for an acute myocardial infarction?
1. A patient with a large acute myocardial infarction may be concurrently treated with aspirin, streptokinase, heparin and an ACE inhibitor. 2. Streptokinase is preferred to tissue plasminogen activator as it has a greater effect on cardiovascular mortality.
What drugs are used in thrombolytic therapy?
List of Thrombolytics:Drug NameAvg. RatingReviewsActivase (Pro) Generic name: alteplase101 reviewTNKase (Pro) Generic name: tenecteplaseNo reviewsRetavase Half-Kit Generic name: reteplaseNo reviewsRetavase (Pro) Generic name: reteplaseNo reviews5 more rows
What is streptokinase enzyme?
Streptokinase is an enzyme produced by many strains of β-haemolytic streptococci isolated naturally from upper respiratory tract and is used to dissolve the fibrin matrix of blood clots, especially those in the arteries of the heart and lungs.
What is the half life of t-PA?
Recombinant t-PA (rt-PA) is produced in pharmacologic quantities by recombinant DNA technology. The plasma half-life of rt-PA is 5 to 10 min.
What is a rt-PA?
Recombinant tissue-type plasminogen activator (rt-PA), streptokinase (SK), and anisoylated plasminogen-streptokinase activator complex (APSAC) have salutary effects on mortality when administered to patients with evolving acute myocardial infarction (MI). Studies suggest that intravenous rt-PA is more effective in reperfusing occluded infarct-related arteries than SK, and the results of ongoing studies directly comparing the influence of SK and rt-PA on mortality are awaited. The clinical role of agents such as APSAC, urokinase, and pro-urokinase, used alone or in combination, remains to be determined. It is evident that a variety of thrombolytic agents will be effective, and variables such as ease of administration, pharmacokinetics, fibrin specificity, effects on blood viscosity, and incidence of adverse effects need to be assessed to determine which agents are the most suitable for clinical use. There is an increased risk of bleeding at vascular puncture sites with all thrombolytic agents. Current indications for thrombolytic therapy include ischemic chest pain of at least 30 min duration that is unrelieved by nitroglycerin and is associated with ST-segment elevations of at least 0.1 mV in two contiguous electrocardiographic leads. Such therapy is usually reserved for patients less than 75 years old who are not at increased risk for bleeding and whose chest pain began less than 4-6 h prior to treatment. Trials are under way to determine whether patients with shorter pain duration, transient ST-segment changes ( ie, unstable angina patients), chest pain associated with ST-segment depressions or T-wave inversions ( ie, non-Q-wave infarction patients), or patients whose pain began more than 4 to 6 h earlier will benefit from early thrombolytic therapy. Other factors such as patient age, the likelihood of the diagnosis of MI, and the estimated risk of bleeding should also be considered. The findings of available major randomized trials indicate that early invasive procedures are generally unnecessary and that meticulous care must be exercised in the selection and management of patients subjected to thrombolytic therapy.
How long is the follow up on streptokinase?
The Western Washington randomized trial of intracoronary streptokinase in acute myocardial infarction: a 12-month follow-up report.
How many randomized controlled trials are there for fibrinolytic therapy?
Intravenous and intracoronary fibrinolytic therapy in acute myocardial infarction: overview of results on mortality, reinfarction, and side effects from 33 randomized controlled trials.
Is streptokinase an antigen?
Streptokinase, a protein produced from ultrafiltrates of group C streptococci, may be antigenic. Consequently, allergic or anaphylactic reactions can occur in 1 percent of patients receiving short-term high-dose therapy. Previous streptococcal infection, and previous treatment with SK, can lead to the development of neutralizing antibodies. Streptokinase is also acted upon by plasmin inactivators; it has a plasma half-life of 10 to 18 min.
Does thrombolysis reduce MI size?
This has led to a resurgence of interest in thrombolytic therapy, and it has now been established that thrombolysis, initiated early after coronary thrombosis, may restore coronary blood flow, reverse myocardial ischemia, reduce MI size, limit left ventricular (LV) dysfunction, and reduce mortality.
Is thrombus occluding an atherosclerotic epicardial artery
Coronary arteriography in patients with acute MI has revealed that a thrombus occluding an atherosclerotic epicardial coronary artery is almost always present early in the course of Q-wave acute MI.
Why are enzymes used in thrombolytic therapy?
Enzyme therapies are attracting significant attention as thrombolytic drugs during the current scenario owing to their great affinity, specificity, catalytic activity, and stability. Among various sources, the application of microbial-derived thrombolytic and fibrinolytic enzymes to prevent and treat vascular occlusion is promising due to their advantageous cost–benefit ratio and large-scale production. Thrombotic complications such as stroke, myocardial infarction, pulmonary embolism, deep venous thrombosis, and peripheral occlusive diseases resulting from blood vessel blockage are the major cause of poor prognosis and mortality. Given the ability of microbial thrombolytic enzymes to dissolve blood clots and prevent any adverse effects, their use as a potential thrombolytic therapy has attracted great interest. A better understanding of the hemostasis and fibrinolytic system may aid in improving the efficacy and safety of this treatment approach over classical thrombolytic agents. Here, we concisely discuss the physiological mechanism of thrombus formation, thrombo-, and fibrinolysis, thrombolytic and fibrinolytic agents isolated from bacteria, fungi, and algae along with their mode of action and the potential application of microbial enzymes in thrombosis therapy.
What are the producers of thrombolytic enzymes?
The known microbial producers of thrombolytic enzymes include bacteria, fungi, and algae.
Why are bacteria the first line source of protein?
Bacteria are the first-line sources because bacterial proteins are suitable for oral administration and facilitate large-scale production. (a) Bacillussp. are among the most preferred sources; various strains have been reported to have fibrinolytic activity (Figure 3A). In addition, several other strains with fibrinolytic properties have been reported, although their mode of action is yet to be elucidated, such as Bacillussp. DJ–2 [44], B. subtilisA26-derived subtilisin BSF1 and BAF1 obtained from B. amyloliquefaciensAn6 [45,46], enzyme URAK produced by B. cereusNK1 [47], B. cereusGD 55-derived protease [48], B. cereusIND1 [49] and B. haloduransIND18 [50] are the sources of proteolytic enzymes that exhibit both thrombolytic activity and PLG activation properties, while a fibrinolytic protease with absolute clot dissolution ability in a short span of time (within 4 h) in in vitro conditions was obtained from Bacillussp. IND12 [51], B. pseudomycoidesstrain MA02 [52], and B. cereusRSA1 [53]; (b) Streptomycessp. are the largest fibrinolytic enzyme-producing genus. Figure 3B summarizes the fibrinolytic agents derived from different strains of Streptomycessp.; (c) other bacterial sp. that have been reported to produce fibrinolytic enzymes are summarized in Figure 3C. Additionally, a proteolytic enzyme of ~50 kDa serrapeptase (SP) or serralysin derived from enterobacterium SerratiaE–15 [54] was noted to have fibrinolytic potential [55] along with the ability to distinguish and dissolve only dead and damaged tissue without harming the living tissue [55], Treponema denticolawas used to produce thrombolytic enzymes [56], proteases of 44 kDa and 64 kDa obtained from Shewanellasp. IND20 and Psuedoalteromonassp. IND11, respectively, showed direct clot lysis activity as well as PLG activation ability [57,58], Paenibacillussp. IND8 [59], and Stenotrophomonas maltophiliaGd2 were shown to possess robust fibrinolytic activity [30].
What are the in vivo assays for thrombolytic agents?
The in vivo assays include: (i) Carrageenan-induced thrombosis model —helps assessment of clinically relevant anti-thrombus and thrombolytic agents by demonstrating disappearance of wine-colored thrombus [40]; (ii) D—Dimer test—fibrin derivatives containing cross-linked D—dimer (XDP) domains help monitor fibrinolysis [41]; (iii) Ferric chloride-induced thrombosis model—aids in assessing anti-platelet and anticoagulant drugs [42]; and (iv) Rat groin flap model—an important tool in comparative analysis of various anticoagulants and vasomotor drugs [43]. In addition to promising a better understanding of the role of the drug candidate in alleviating disease pathophysiology and determining its therapeutic potential, the combination of in vitro and in vivo assays also provides propitious translational application of microbial-derived novel thrombolytic agents.
What is the protein that forms a blood clot?
Fibrin is a primary protein component of a blood clot that is formed from fibrinogen (340 kDa glycoprotein) by thrombin-mediated proteolysis and elimination of N-terminal fibrinopeptides from the Aα and Bβ chains. A serine protease, plasmin, is an activated form of inert plasma precursor, plasminogen (PLG). PLG is a 791-AA-long glycoprotein that circulates in blood plasma as an inactive zymogen. The plasmin is a crucial enzyme in the dissolution of fibrin clots. There exist two major glycoforms of human plasminogen, namely, type I (consists of two molecules of glycosylation) and type II (consists of one molecule of glycosylation) [8,22]. The binding of circulating PLG to the cell surface or blood clot acquires an open conformation, which aids in the formation of catalytically active plasmin by the Arg561-Val562 bond cleavage via a direct PLG activator [23]. Direct PA includes tissue plasminogen activator (tPA), streptokinase and urokinase or their variants [3,24]. Plasmin formation leads to fibrin lysis, giving soluble fibrin degradation products (FDPs) [22,25]. Therefore, the process of fibrinolysis involves two phases: (i) PLG activation on the surface of the fibrin clot to forms plasmin, which dissolves fibrin—i.e., a physiological process; and (ii) amplification of plasmin-induced clot breakdown by exposing the additional binding sites of degraded fibrin—i.e., pharmacologically mediated processes such as fibrinolytic and thrombolytics.
What are the two stages of hemostasis?
The process of hemostasis is divided into two stages: (1) primary (involves rapid platelet activation) and (2) secondary (requires additional coagulation pathways to form polymeric fibrin) processes (Table 1) .
What are the processes of hemostasis and thrombosis?
Hemostasis and thrombosis are intricate, multifactorial processes. Platelets, in conjugation with endothelial cells and coagulation proteins, are the crucial mediator of vascular hemostasis and thrombosis. Disruption to any of these processes could result in atherosclerotic plaque formation [9,10,11] (Figure 2, leading to variety of thrombotic diseases including CVDs (cardiovascular diseases) [12,13], abdominal aortic aneurysms (AAAs) [14,15], pulmonary embolism (PE) [16], and stroke [17,18].
What is thrombolytic treatment?
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.
How are thrombolytic agents given?
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:
What is a fibrolytic thrombolytic therapy?
Fibrinolytic therapy in acute ischemic stroke is used to break up blood clots preventing blood flow to the brain with the hope of restoring blood flow to the areas of the brain that have not yet suffered infarct. 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]
What agents need fibrin?
e.g. alteplase (tPA), reteplase (recombinant plasminogen activator [r-PA]), and tenecteplase
What is the process of thrombosis?
During thrombosis, circulating prothrombin is converted to its active form thrombin by activated platelets. Active thrombin then converts the fibrinogen into fibrin with the 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 the thrombus and on the surface of fibrin by the binding of tPA to plasminogen. This binding helps the conversion.
What is anisoylated purified streptokinase activator complex?
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. Similar to streptokinase, anistreplase does not distinguish between circulating vs. fibrin-bound plasminogen; subsequently, it produces the systemic lytic state.
Is Reteplase a plasminogen activator?
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, 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 clot dissolving plasmin. These characteristics, in sum, explain its faster clot resolution than other agents. The FDA approved reteplase administration of two boluses of 10U 30 minutes apart for AMI management. Each of these boluses is administered over 2 minutes. Like alteplase, reteplase can be readministered when necessary and is not antigenic. [5]
How does thrombolytic therapy work?
Thrombolytic therapy works by lysing infarct artery thrombi and achieving reperfusion, thereby reducing infarct size , preserving left ventricular function, and improving survival.
Why are diabetics less likely to be treated with thrombolytic agents?
Diabetic patients have been less frequently treated with thrombolytic agents because of concerns about the increased risk of bleeding complications. The 1990 American College of Cardiology/American Heart Association guidelines for the management of acute myocardial infarction classified diabetic hemorrhagic retinopathy as an absolute contraindication against the use of thrombolytic therapy. 71 In the FTT analysis, however, the incidence of stroke and major bleeding complications after thrombolytic therapy was only slightly higher in diabetic patients (stroke, 1.9% versus 1.0%; major bleeding, 1.3% versus 1.0%), 38 and in the GISSI-2/International Study Group trial, the incidence of these complications was similar among diabetic and nondiabetic patients. 72 Intraocular hemorrhage and, more specifically, retinal bleeding are extremely uncommon complications of thrombolytic therapy. In the GUSTO-I study, 300 of the 6011 diabetic patients were estimated to have proliferative retinopathy, but none had intraocular hemorrhages, and the calculated upper 95% confidence limit of the possible occurrence of intraocular hemorrhage was only 0.05%. 73 It is unlikely that thrombolytic therapy would increase vitreous hemorrhage, which is due to vitreous detachment, in patients with diabetic retinopathy. Also, the few nondiabetic patients reported have shown no limitation of visual acuity at follow-up. 7475 Thus, the concerns many clinicians have about bleeding complications after thrombolysis in diabetic patients are not supported by the results of large-scale clinical trials.
What are the amino acids in TNK-TPA?
TNK-tPA is a genetically engineered triple-combination mutant of native tissue plasminogen activator with amino acid substitutions at the following sites: a threonine (T) is replaced by an asparagine, which adds a glycosylation site to position 103; an asparagine (N) is replaced by a glutamine, thereby removing a glycosylation site from site 117; and four amino acids, lysine (K), histidene (H), and arginine (R), are replaced by four alanines (A) at sites 296–299. (Fig 4 ). These substitutions result in reduced plasma clearance, increased fibrin specificity, and resistance to plasminogen activator inhibitor-1. 116 In the TIMI-10B study, a large, phase II efficacy trial in 886 patients, a single 40-mg bolus of TNK-tPA produced TIMI grade 3 flow rates at 90 minutes that were identical to those seen with accelerated alteplase (63% in both groups). 117 Furthermore, TIMI frame counting in TIMI-10B suggested faster and more complete reperfusion with 40 mg of TNK-tPA than with accelerated alteplase. The best angiographic results were obtained with a dose/weight ratio of ±0.5 mg/kg. In the ASSENT-1 trial in 3325 patients, an intracranial hemorrhage rate of 0.76% was observed with the 40-mg dose of TNK-tPA. This incidence was considered acceptable, because 14.6% of the patients in ASSENT-1 were >75 years old. On the basis of the results of TIMI-10B and ASSENT-1, 16 500 patients with acute myocardial infarction are being randomized in a double-blind manner to receive weight-adjusted TNK-tPA or alteplase in the ASSENT-2 phase III mortality trial. The results are expected in early 1999.
Is Streptokinase more expensive than alteplase?
97 An international issue is the appropriate allocation of scarce healthcare resources, and many hospitals worldwide use streptokinase because it is 7 to 8 times cheaper than alteplase. The GUSTO-I study prospectively gathered details of hospital and medical charges in a subgroup of US patients. 98 Compared with streptokinase therapy, the additional cost of accelerated alteplase per extra life-year saved was US $27 382 (in 1992 dollars). The cost-effectiveness of preferentially using alteplase varied according to the age of the patients and the site of infarction (Table 2 ).
Is thrombolysis a treatment for myocardial infarction?
Although thrombolysis has become the mainstay of acute treatment in the majority of patients with suspected acute myocardial infarction, uncertainties still remain with regard to the clinical benefit of this therapy in certain subgroups of patients.
Is thrombolytic therapy effective for diabetics?
With regard to efficacy, the GUSTO-I angiography substudy showed that thrombolytic therapy is equally efficacious in restoring early coronary artery patency in patients with and without diabetes. 61 In the FTT analysis, diabetics had a 21% reduction in 35-day mortality with thrombolytic therapy compared with control therapy, which corresponds to 37 lives saved per 1000 patients treated versus 15 lives in nondiabetic patients. Thus, diabetic patients with acute myocardial infarction are just as eligible for thrombolytic therapy as nondiabetics, but their early mortality rates remain high even after adjustment for both clinical and angiographic variables. 61 A higher reocclusion rate and reduced compensatory hyperkinesis of the noninfarct zones have been proposed as explanations for this excess in early mortality. 61
Is oral anticoagulant a contraindication for thrombolytic therapy?
Some authorities and most recent trials have considered oral anticoagulants to be an absolute contraindication against the use of thrombolytic therapy. In a multivariate logistic regression analysis of 2469 patients with acute myocardial infarction, those on oral anticoagulants before admission had a significantly higher risk of intracranial hemorrhage after thrombolysis. 59 Theoretically, these patients would be at increased risk of bleeding because of depletion of the vitamin K–dependent clotting factors (factors II, VII, IX, and X). However, if the international normalized ratio is subtherapeutic, it may be reasonable to administer thrombolytic therapy as indicated and to delay or reduce the first dose of heparin. If the international normalized ratio is in the therapeutic range, one approach would be to administer thrombolytic therapy simultaneously with fresh frozen plasma to replenish the clotting factors. It should be acknowledged, however, that these approaches have not been formally evaluated.
When did the patient attribute myo-?
patient in his seminal paper in 1912, ' attributing myo-
When did DeWood and colleagues find thrombus?
1980, DeWood and colleagues2reported finding thrombus in
Is thrombolytic therapy underused?
Unfortunately, it continues to be underused or is administered later than is optimal. Thrombolytic therapy works by
Who reported acute myocardial infarction?
acute myocardial infarction was reported by Fletcher and
Do patients receive thrombolytic therapy?
patients do not receive thrombolytic therapy, and countless