Physiological basis of fibrinolysis
Thrombus formation in the body automatically triggers the fibrinolytic system. The central link of this process is the conversion of the inactive proenzyme plasminogen into the active enzyme plasmin (fibrinolysin). Under physiological conditions, this transition is initiated by tissue plasminogen activator (tPA), which is secreted by the vascular endothelium.
Plasmin performs the main task: it hydrolyzes fibrin (the basis of the thrombus) into soluble peptides. However, plasmin does not possess absolute specificity. It is also capable of destroying fibrinogen circulating in the blood, as well as other clotting factors. To prevent total destruction of fibrinogen (systemic fibrinogenolysis), natural inhibitors are present in the blood, primarily $\alpha_2$-antiplasmin, which rapidly inactivate free plasmin.
Mechanisms of drug action
All fibrinolytic drugs are aimed at activating plasminogen, but they do this via three different pathways:
- Indirect activation (streptokinase preparations). Streptokinase itself does not possess proteolytic activity. It binds to the plasminogen molecule, forming an equimolar complex. It is this complex that acquires the ability to convert other plasminogen molecules into active plasmin.
- Direct activation (urokinase preparations). These agents act as direct activators. They directly catalyze the transition of plasminogen to plasmin, working similarly to the body's natural enzymes.
- Fibrin-specific activation (alteplase, tenecteplase). These are recombinant analogues of endogenous tPA. Their key feature is a high affinity for fibrin. They predominantly activate plasminogen that is already adsorbed on fibrin strands within the clot. The presence of fibrin accelerates their action hundredfold, ensuring locality of action.
Characteristics of main drugs
- Streptokinase. Highly purified protein obtained from a culture of $\beta$-hemolytic streptococcus. Acts systemically: activates plasminogen both inside the thrombus and in blood plasma. Due to its bacterial origin, it has pronounced antigenic properties — can cause allergic reactions up to anaphylactic shock (especially upon repeated administration). The presence of circulating antibodies can cause resistance to therapy.
- Alteplase and tenecteplase. Administered intravenously. Due to their fibrin specificity, their action is limited to the thrombus, while in the general circulation they are bound by specific inhibitors. This reduces the effect on circulating fibrinogen.
- Urokinase. An enzyme of human origin (normally produced by kidney cells). The drug is obtained from a culture of human embryonic kidney cells. Acts systemically, but, unlike streptokinase, has absolutely no antigenic properties.
Indications and complications of therapy
The main goal of thrombolytic use is the rapid dissolution of a thrombus in life-threatening conditions. Drugs are administered intravenously (dosed in IU).
Main indications:
- Acute myocardial infarction (highest efficacy is achieved in the first 3–6 hours for streptokinase and 6–12 hours for alteplase).
- Pulmonary embolism (PE).
- Deep vein thrombosis and acute peripheral arterial thrombosis.
- Retinal vessel thrombosis (additional indication for streptokinase).
The main complication of any thrombolytic therapy is bleeding. Their pathogenesis is associated with systemic action: plasmin formed in plasma destroys fibrinogen. As a result, fibrinogen and fibrin degradation products (FDPs) are formed, which accumulate in the blood and reduce platelet aggregation. In addition to bleeding, arterial hypotension and dyspeptic disorders (nausea, vomiting) are possible.
Briefly: answers to topical questions
What are the absolute contraindications to the administration of fibrinolytic agents?
An absolute contraindication to thrombolytic therapy in massive pulmonary embolism is prior surgery within the preceding 10–14 days due to the high risk of fatal bleeding in the early postoperative period.
Which drugs are used as antidotes for bleeding caused by fibrinolytics?
Aminocaproic acid and aprotinin are used as specific agents to inactivate fibrinolytics and stop bleeding caused by them.
To remember the safety profile: Streptokinase is Systemic and Streptococcal (high risk of allergy and systemic bleeding). Alteplase is Active locally (fibrin-specific, works inside the thrombus).
Class and exam questions
Why do thrombolytics cause bleeding if their target is a thrombus?
Drugs (especially non-specific ones) activate plasminogen not only in the thrombus, but also in blood plasma. The resulting plasmin destroys circulating fibrinogen, and its breakdown products (FDPs) additionally reduce platelet aggregation.
What is the difference between streptokinase and urokinase if both act systemically?
Streptokinase is a bacterial protein that forms a complex with plasminogen and frequently causes allergies. Urokinase is an enzyme of human origin; it activates plasminogen directly and lacks antigenic properties.
How does anistreplase work?
This is a prodrug representing a complex of streptokinase and plasminogen with a blocked (acylated) active center. The drug turns into active plasmin only after the cleavage of the acyl group (deacylation), which takes from 40 minutes to several hours.
What else to study on this topic
- Mechanism of action of anistreplase as a prodrug
- Differences between saruplase (prourokinase) and standard urokinase
- The role of fibrinogen degradation products (FDPs) in hemostasis
- The problem of immunogenicity and resistance to streptokinase preparations
Master the entire topic in the «Pharmacology» course
This is a summary. The course covers everything tested in classes and exams.
- Complete study guide on "Fibrinolytic agents" and 5,304 more pages of the subject
- Assignments and quizzes after every topic — just like in a colloquium
- AI tutor answers questions on the topic anytime
- 116 video lessons on the subject
Other topics in the section "Drugs affecting hemostasis and thrombosis"
Free video lessons: pharmacologyShort lessons with study notes — no registration required.
Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.