Streptokinase
Description
Introduction to Streptokinase
Streptokinase is a thrombolytic medication that activates plasminogen through a nonenzymatic mechanism. It is a 47-kDa protein isolated and secreted by most group A, C, and G β-hemolytic streptococci . As a therapeutic agent, streptokinase is used to break down clots in various thrombotic conditions, including myocardial infarction, pulmonary embolism, and arterial thromboembolism . Its primary clinical value lies in its ability to dissolve pathological blood clots and restore blood flow in occluded vessels8.
Despite its clinical importance, streptokinase is no longer commercially available in the United States, though it remains on the World Health Organization's List of Essential Medicines as a critical thrombolytic agent . This is particularly significant for developing nations where its relatively low cost and ease of production make it a more accessible option compared to newer thrombolytic agents .
Structure and Properties
Streptokinase is a single-chain protein with a molecular weight of approximately 47,286.7 Daltons and a protein chemical formula of C₂₁₀₀H₃₂₇₈N₅₆₆O₆₆₉S₄ . Its structure consists of three distinct domains:
-
α domain (residues 1-150)
-
β domain (residues 151-287)
-
γ domain (residues 288-414)
Each of these domains can bind plasminogen, although none can independently activate it . This three-domain structure is critical to the protein's ability to form complexes with human plasminogen and catalyze its conversion to plasmin.
Structurally, streptokinase shares similarities with staphylokinase (Sak), which is found in Staphylococcus aureus. Both enzymes are carried by phages and serve similar functions in their bacterial hosts, though their clinical applications and mechanisms differ slightly .
Mechanism of Action
Streptokinase belongs to a group of medications known as fibrinolytics. Its mechanism of action is distinct from many other thrombolytic agents in that it does not directly cleave fibrin but instead works through plasminogen activation.
The mechanism involves several key steps:
-
Streptokinase binds to plasminogen to form a streptokinase-plasminogen complex
-
This complex undergoes conformational changes that create an active site
-
The active complex then converts substrate plasminogen molecules to plasmin
-
Plasmin degrades fibrin (the primary constituent of blood clots), fibrinogen, and other plasma proteins
-
This cascade results in the dissolution of blood clots
Research has revealed important details about this process. Residues 1-59 of streptokinase regulate its capacity to induce an active site in bound plasminogen by a nonproteolytic mechanism and to activate substrate plasminogen in a fibrin-independent manner .
Two candidates for this counterion have been identified:
-
Ile1 of streptokinase
-
Lys698 of plasminogen
Studies have shown that deletion of Ile1 of streptokinase significantly inhibits its capacity to induce an active site in plasminogen, supporting the hypothesis that a salt bridge between Ile1 of streptokinase and Asp740 of plasminogen is necessary for streptokinase to induce an active site in plasminogen by a nonproteolytic mechanism .
Medical Uses
Streptokinase has several established medical applications, primarily in acute cardiovascular emergencies:
ST-Elevation Myocardial Infarction (STEMI)
If percutaneous coronary intervention (PCI) is not available within 90-120 minutes of first contact, streptokinase is recommended intravenously as soon as possible after the onset of a STEMI . The goal of treatment is to restore coronary blood flow rapidly and limit myocardial damage.
Pulmonary Embolism
Streptokinase is used to break down clots in the lungs in cases of pulmonary embolism, helping to restore pulmonary circulation and prevent further complications 8.
Arterial Thromboembolism
The medication is effective in treating arterial thromboembolism by dissolving clots that obstruct arterial blood flow .
Deep Vein Thrombosis
Streptokinase can be used in the management of deep vein thrombosis to dissolve clots in the venous system8.
An important clinical consideration is that streptokinase is a bacterial product, allowing the body to develop immunity against it. Therefore, it is recommended that this medication should not be used again after four days from the first administration, as it may be less effective and can cause allergic reactions. For this reason, it is usually given only for a person's first heart attack .
Pharmacokinetics
The pharmacokinetic profile of streptokinase has several important characteristics:
Administration Route
Streptokinase is administered intravenously, typically as a 1.5 million unit infusion over 60 minutes in cases of myocardial infarction 8.
Distribution
The volume of distribution approximates plasma volume8.
Metabolism
Streptokinase is metabolized in the liver8.
Elimination
The half-life of streptokinase is approximately 20 minutes. It is excreted through both the kidneys and liver8.
Dosing Considerations
The standard dose for myocardial infarction is 1.5 million units administered over 60 minutes. In clinical trials like ISIS-2, this dose was found to be effective in reducing mortality .
Efficacy in Clinical Trials
Streptokinase has been extensively studied in multiple large-scale clinical trials, providing robust evidence for its efficacy in various conditions:
6.1.1 GISSI-1 Trial
The GISSI-1 trial was the first large thrombolytic trial that evaluated streptokinase therapy versus no treatment in acute myocardial infarction patients. The trial demonstrated significant mortality benefits of streptokinase:
-
8.2% versus 15.4% for patients who received streptokinase within 1 hour of symptom onset
-
9.2% versus 12% for those treated within three hours
6.1.2 ISIS-2 Trial
The ISIS-2 trial further confirmed the benefits of streptokinase in over 17,000 patients presenting with symptoms of acute myocardial infarction within 24 hours. This trial used a "2×2 factorial" design, with patients randomly allocated to receive:
-
1.5 MU streptokinase or matching placebo
-
Oral aspirin (162.5 mg) or matching placebo daily for 1 month
6.1.3 GUSTO-I Trial
The Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries (GUSTO-I) trial compared different thrombolytic regimens in 41,021 patients. The one-year results showed:
-
9.1% mortality rate in patients randomized to accelerated tissue plasminogen activator (TPA)
-
10.1% in those treated with streptokinase and subcutaneous heparin (P=0.011 versus TPA)
-
10.1% in those treated with streptokinase and intravenous heparin (P=0.009 versus TPA)
Long-term Outcomes
The ISIS-2 trial provided valuable data on long-term outcomes following streptokinase treatment:
-
Allocation to streptokinase was associated with 29 (95% confidence interval 20 to 38) fewer deaths per 1000 patients during days 0-35
-
This early benefit persisted (death rate ratio 0.98 for additional deaths between day 36 and end of year 10)
-
After 10 years, there were 23 (2 to 44) fewer deaths per 1000 patients treated with streptokinase
Comparative Efficacy
When compared with other thrombolytic agents, particularly tissue plasminogen activator (TPA), streptokinase has shown slightly less favorable outcomes in some studies:
| Treatment | 1-Year Mortality Rate | P-value (vs. TPA) |
|---|---|---|
| Accelerated TPA | 9.1% | - |
| Streptokinase + SC heparin | 10.1% | 0.011 |
| Streptokinase + IV heparin | 10.1% | 0.009 |
| Combination therapy | 9.9% | 0.050 |
Meta-analyses
A recent reanalysis of historical data using Trial Sequential Analysis found that conclusive evidence favoring streptokinase was established after the megatrials (GISSI and ISIS-II) were launched. This suggests that while the evidence eventually became conclusive, the large-scale trials were justified and not redundant as sometimes claimed .
Adverse Effects and Contraindications
While streptokinase is effective, it is associated with several important adverse effects and contraindications:
Common Adverse Effects
Common side effects include:
In a 14-month study of 217 patients who received streptokinase, the average number of adverse drug reactions per patient was 2.3 ± 1.7, with female patients experiencing a higher rate of adverse reactions (4.2 times more) than males .
Severe Adverse Effects
Streptokinase is a non-human protein, and its introduction into the circulatory system can lead to severe anaphylactic responses, including death in rare cases. The risk of this immune response depends on the level of anti-streptokinase antibodies in circulation .
Immunogenicity
The immunogenicity of streptokinase limits multiple treatments. After initial exposure, patients develop antibodies against the protein, making subsequent doses less effective and potentially more dangerous. For this reason, streptokinase is typically only used for a patient's first heart attack .
Contraindications
Streptokinase is contraindicated in several situations:
-
Recent stroke
-
Active or recent bleeding
-
Major coagulation abnormalities
-
Recent trauma or major surgery
-
Noncompressible vascular punctures
-
Previous treatment with streptokinase or anistreplase (particularly within the previous 4 days)
Use with Other Medications
Concomitant use of aspirin with streptokinase has been associated with increased mortality in some studies. In one analysis, excess mortality rates in streptokinase-treated patients were 17% without aspirin versus 91% with aspirin .
Production Sources
Commercial streptokinase used for thrombolytic therapy is typically derived from Streptococcus equisimilis (Lancefield Group C). This strain was identified as a suitable source because it does not produce erythrogenic toxins and has less fastidious growth requirements than most other Group A strains, allowing it to be grown on semi-synthetic media for commercial production .
Historical Development
The development of streptokinase as a therapeutic agent spans nearly a century:
Discovery
Streptokinase was discovered in 1933 by William S. Tillett, working along with his student Sol Sherry . They isolated the protein from beta-hemolytic streptococci and recognized its fibrinolytic properties.
Early Applications
Initially, streptokinase was used in the treatment of:
Its role in acute myocardial infarction was discovered serendipitously and developed later.
Evolution as a Cardiac Treatment
In 1958, Sherry and colleagues began exploring streptokinase's potential in cardiac care . Over subsequent decades, multiple clinical trials established its efficacy in treating myocardial infarction.
Landmark Studies
The publication of results from the GISSI-1 trial in 1986 and the ISIS-2 trial in the late 1980s established streptokinase as a standard treatment for acute myocardial infarction, showing significant mortality benefits compared to conventional treatment at that time .
Future Research Directions
Despite being an established medication, several areas of ongoing and potential future research for streptokinase exist:
Production Optimization
Research continues on optimizing the production and purification of streptokinase to improve its efficacy and reduce production costs. According to recent investigations, purification techniques can achieve a recovery rate of up to 75% .
Immunological Concerns
Given the immunogenic nature of streptokinase, research into reducing its antigenicity or developing modified versions with lower immunogenicity could expand its clinical utility and allow for repeated administrations when necessary .
Combination Therapies
Further research into optimal combination therapies, particularly the balance between efficacy and bleeding risk when streptokinase is combined with other antithrombotic agents, remains an important area of investigation .
Product Specs
Q&A
What is the molecular structure and mechanism of action of streptokinase?
Streptokinase is a single polypeptide chain enzyme produced by β-hemolytic streptococci with 414 amino acid residues and a molecular weight of 47 kDa . It has a pH optimum of approximately 7.5 and an isoelectric point of 4.7 . The mechanism of action differs from direct thrombolytics as streptokinase works indirectly through plasminogen activation.
Specifically, streptokinase activates the conversion of plasminogen (the inactive precursor) to plasmin (the active enzyme) . When streptokinase binds to plasminogen, it forms a complex that converts additional plasminogen molecules to plasmin, which then degrades fibrin in blood clots . This cascade mechanism explains why streptokinase is classified as an indirect plasminogen activator rather than a direct fibrinolytic agent.
How can researchers accurately measure streptokinase activity in laboratory settings?
Streptokinase activity can be measured using several validated methodologies:
-
Casein digestion assay: This involves preparing a mixture of 50 mM Tris HCl (pH 8.0), casein, and the streptokinase sample, incubating at 37°C for approximately 20 minutes, followed by reaction termination with HCl and trichloroacetic acid (TCA). The resulting solution is measured spectrophotometrically at 280 nm to determine enzyme activity .
-
Solution chromogenic method: This method has been validated in international collaborative studies and has been adopted by both British and European Pharmacopoeias for standardized assessment of streptokinase activity .
-
Fibrin-based methods: These techniques measure the time required for clot lysis and have shown equivalent results to solution-based methods when using the established International Standards for streptokinase .
For optimal reproducibility, researchers should consider standardizing their data analysis methods and using larger sample sizes, particularly as recent improvements in analytical approaches have enhanced precision in activity measurements .
What are the established animal models for testing streptokinase efficacy?
Two primary animal models are widely employed for evaluating streptokinase efficacy:
-
FeCl₃-induced arterial thrombosis model: This model is extensively used to assess the arterial effectiveness of potential antithrombotic drugs including streptokinase. It provides valuable insights into the mechanisms of thrombotic diseases and helps in developing preventive and remedial measures .
-
Rabbit jugular vein thrombosis model: This in vivo model involves artificially producing thrombus in the jugular vein of rabbits. The model allows researchers to directly observe the thrombolytic activity of streptokinase through ultrasound assessment of blood velocity before and after intervention .
The selection between these models depends on the specific research question, with the FeCl₃ model being more suitable for arterial thrombosis research and the rabbit jugular vein model providing direct visualization of thrombolytic activity in venous thrombosis.
What factors influence successful reperfusion with streptokinase in clinical trials?
Multiple factors have been identified that influence successful reperfusion with streptokinase:
-
Time to treatment: Shorter door-to-needle times correlate with higher reperfusion rates. Studies show that streptokinase had a door-to-needle time of approximately 116.75 minutes compared to 63.24 minutes for tenecteplase, which may contribute to differences in efficacy .
-
Patient characteristics: Patient-specific factors such as age, weight, and comorbidities influence response to streptokinase. Studies suggest that heavier patients may require dose adjustments from the standard 1.5 million units .
-
Concomitant medication: Research has demonstrated that concomitant aspirin use significantly increases mortality risk with streptokinase (91% with aspirin versus 17% without aspirin, P=0.005) .
-
Treatment protocols: Successful reperfusion rates vary significantly between protocols, with streptokinase achieving approximately 70.11% successful reperfusion compared to 81.90% with tenecteplase (p=0.0035) .
Researchers should carefully control for these variables in study design to ensure valid comparisons between different thrombolytic strategies.
How should researchers interpret conflicting results between earlier small trials and larger megatrials of streptokinase?
The interpretation of conflicting results between earlier small trials and larger megatrials requires sophisticated methodological assessment:
-
Statistical power considerations: Smaller trials may have been underpowered to detect clinically meaningful differences. The GISSI trial with 2,388 patients found significantly lower 6-month mortality with streptokinase (15.6%) compared to control (30.6%, P<0.01), providing more reliable estimates than smaller studies .
-
Risk of bias assessment: Recent reanalysis of historical streptokinase trials using Trial Sequential Analysis revealed that earlier trials had serious methodological differences and high risks of bias, making cumulative meta-analysis potentially invalid by today's standards .
-
Heterogeneity evaluation: Researchers should assess clinical and methodological heterogeneity across studies. The ASK, MAST-E, MAST-I, and Glasgow trials showed variable results partly due to differences in patient populations, concomitant treatments, and methodology .
-
Temporal context: The timing of trials matters. The ISAM trial showed benefit before the megatrials GISSI and ISIS-II were published, but these larger trials were initiated before ISAM results were available .
When faced with conflicting evidence, researchers should employ comprehensive meta-analytic techniques that account for heterogeneity and risk of bias rather than relying solely on statistical significance in individual trials.
What methodological approaches can improve the detection of differential treatment effects in streptokinase clinical trials?
Advanced methodological approaches that can enhance detection of differential treatment effects include:
-
Trial Sequential Analysis: This technique accounts for statistical heterogeneity and risk of bias in historical trials, providing more reliable cumulative evidence assessment than traditional meta-analysis .
-
Subgroup analysis with predefined variables: Analysis of treatment effect according to specific variables such as delay from symptom onset to treatment can identify important trends, though these may not always reach statistical significance .
-
Multivariate modeling: This approach can determine interaction between treatment effect and various factors including delay from symptom onset, baseline risk, age, concomitant medication use, and presence of early CT signs .
-
Intention-to-treat analyses: Proper implementation of ITT analyses is critical for avoiding bias in treatment effect estimation, particularly in trials with significant dropout rates or protocol violations .
-
Random-effects cumulative meta-analyses: These account for between-study variability more effectively than fixed-effect models when assessing evolving evidence bases .
These approaches should be pre-specified in research protocols to avoid post-hoc analysis bias and maximize the validity of identified treatment effect modifiers.
How does streptokinase compare with newer thrombolytics and interventional approaches in terms of research methodology challenges?
Comparative research between streptokinase and newer approaches presents several methodological challenges:
Researchers should employ propensity score matching, instrumental variable analysis, or carefully designed pragmatic trials to overcome these methodological challenges when comparing different reperfusion strategies.
What are the optimal laboratory methods for assessing streptokinase resistance and antibody development?
Streptokinase resistance assessment requires sophisticated laboratory approaches:
-
Neutralization assays: These measure the capacity of patient plasma to neutralize standardized streptokinase activity, detecting both pre-existing and treatment-induced antibodies.
-
ELISA-based antibody detection: Enzyme-linked immunosorbent assays can quantify anti-streptokinase antibodies, allowing for determination of antibody titers before and after treatment.
-
Functional clot lysis assays: These assess the ability of streptokinase to lyse standardized clots in the presence of patient plasma, providing a functional measure of resistance.
-
Standardization with International Standards: The WHO International Standards for streptokinase provide reference materials against which laboratory methods should be calibrated to ensure comparability across studies .
Researchers should be aware that streptokinase resistance mechanisms are multifactorial, including both antibody-mediated neutralization and non-antibody mechanisms such as elevated plasminogen activator inhibitor levels. Comprehensive assessment should incorporate both immunological and functional approaches.
How should researchers design studies to investigate the relationship between streptokinase dosing and safety outcomes?
Optimal study design for streptokinase dosing-safety relationships should include:
-
Dose-ranging phase: Prior evidence suggests heavier patients may have lower adverse event rates with the standard 1.5 million unit dose, indicating weight-based dosing may be preferable to fixed dosing for safety optimization .
-
Safety endpoint stratification: Categorize safety outcomes into major hemorrhagic complications, minor bleeding, allergic/pyrogenic reactions, and mortality to allow for comprehensive risk profiling.
-
Pharmacokinetic/pharmacodynamic modeling: Incorporate PK/PD modeling to establish exposure-response relationships for both efficacy and safety outcomes.
-
Concomitant medication restrictions: Carefully control antiplatelet and anticoagulant co-therapies, as research has demonstrated that concomitant aspirin significantly increases mortality risk with streptokinase (91% vs. 17%, P=0.005) .
-
Time-to-event analysis: Utilize survival analysis techniques to characterize the temporal relationship between streptokinase administration and adverse events.
Researchers should consider adaptive trial designs that allow for dose modification based on emerging safety signals while maintaining statistical integrity.
What are the key considerations when designing clinical trials comparing streptokinase to newer thrombolytics?
Clinical trial design for comparative thrombolytic studies should address:
Well-designed comparative trials should prioritize pragmatic outcomes while maintaining methodological rigor to provide clinically relevant evidence for therapeutic selection.
How can researchers effectively assess early CT signs in streptokinase trials for acute ischemic stroke?
Effective assessment of early CT signs in streptokinase stroke trials requires:
-
Standardized radiological criteria: Implement established scoring systems such as the Alberta Stroke Program Early CT Score (ASPECTS) or the Early Infarct Signs scale to ensure consistent evaluation.
-
Centralized image reading: Utilize blinded central adjudication by experienced neuroradiologists to minimize inter-observer variability and reduce site-specific biases.
-
Timing protocols: Standardize the timing of CT acquisition relative to symptom onset and streptokinase administration to enable valid comparisons across patients.
-
Advanced imaging integration: Consider supplementing conventional CT with CT perfusion or MRI diffusion-weighted imaging to better characterize the penumbra and identify patients most likely to benefit from thrombolysis.
Contrary to some hypotheses, previous research has demonstrated that the presence of early CT scan signs did not increase the detrimental effect of streptokinase, suggesting that patient selection for thrombolysis should consider multiple factors beyond radiological findings alone .
What is the optimal approach to measuring reperfusion success in streptokinase research?
Comprehensive reperfusion assessment should incorporate multiple complementary methods:
-
Electrocardiographic criteria: ST-segment resolution (>50% from baseline) provides a non-invasive measure of myocardial reperfusion, with research showing streptokinase achieves this in approximately 70.11% of cases compared to 80.40% with tenecteplase (p=0.0116) .
-
Clinical markers: Chest pain resolution serves as an important patient-centered outcome, occurring in 67.89% of streptokinase-treated patients versus 81.90% with tenecteplase (p=0.0006) .
-
Angiographic assessment: TIMI (Thrombolysis In Myocardial Infarction) flow grading provides direct visualization of epicardial coronary flow restoration.
-
Microvascular perfusion measures: Myocardial blush grade and ST-segment resolution together can identify patients with epicardial flow restoration but inadequate tissue perfusion.
-
Composite success definition: Research protocols should pre-specify a definition of successful reperfusion that integrates multiple criteria, similar to the approach used in comparative studies showing 70.11% success with streptokinase versus 81.90% with tenecteplase (p=0.0035) .
This multi-modal approach provides more comprehensive assessment than any single measure alone, enabling researchers to characterize both epicardial and microvascular reperfusion efficacy.
How should researchers address the historical context when interpreting modern streptokinase trials?
Contextualizing modern streptokinase research within historical frameworks requires:
Modern researchers should view streptokinase not simply as a historical agent but as part of the continuum of reperfusion therapy development that transformed cardiovascular care from palliation to active intervention .
Product Science Overview
Streptokinase is a potent plasminogen activator widely used as a thrombolytic agent in clinical settings. It is naturally secreted by several strains of beta-hemolytic streptococci, particularly Streptococcus equisimilis . Streptokinase works by converting plasminogen to plasmin, which then breaks down fibrin clots, making it an essential treatment for conditions such as myocardial infarction, pulmonary embolism, and deep vein thrombosis .
The natural production of streptokinase has several limitations, including low yields and the pathogenic nature of its native host. To overcome these challenges, recombinant DNA technology has been employed to produce streptokinase in various host organisms. One notable example is the expression of streptokinase in the Gram-positive bacterium Streptomyces lividans .
In this process, the structural gene encoding streptokinase is fused to signal sequences that facilitate its secretion. For instance, the Streptomyces venezuelae CBS762.70 subtilisin inhibitor (vsi) signal sequence or the Streptomyces lividans xylanase C (xlnC) signal sequence can be used . The recombinant production in Streptomyces lividans has shown higher yields when the Sec-dependent signal peptide mediates the translocation of streptokinase .
Recombinant streptokinase offers several advantages over its naturally produced counterpart:
- Higher Yields: Recombinant production methods can significantly increase the yield of streptokinase, making it more cost-effective .
- Reduced Pathogenicity: By using non-pathogenic host organisms, the risks associated with the pathogenic nature of the native host are eliminated .
- Enhanced Specificity: Recombinant techniques allow for the modification of streptokinase to enhance its specificity and reduce potential side effects .
Streptokinase is primarily used as a thrombolytic agent to dissolve blood clots in patients suffering from acute myocardial infarction, pulmonary embolism, and other thrombotic conditions . Its ability to activate plasminogen and subsequently degrade fibrin clots makes it a critical component in emergency medicine.
