Thrombolytics and Their Mechanisms

Thrombolytics

• Thrombolytics (clot busters) are used to dissolve existing blood clots.
• Thrombolytics are used when platelet inhibitors and anticoagulants are ineffective at breaking up clots.
• Endogenous fibrinolytic plasmin is activated from zymogen plasminogen.
• Plasminogen activators include tissue plasminogen activator (tPA), recombinant tPAs, streptokinase, and urokinase.

Thrombolytics: Mechanism of Action

• Thrombolytics activate plasminogen, which breaks down fibrin, the protein that forms blood clots.
• Plasminogen activators bind to fibrin, forming a complex that activates plasminogen.
• Once activated, plasmin breaks down fibrin, dissolving the clot.
• There are natural inhibitors for this system including plasminogen activator inhibitor 1 or 2, and α2-antiplasmin.

Streptokinase

• Streptokinase is a plasminogen activator extracted from streptococci bacteria.
• It is administered intravenously.
• It is effective in treating ST-elevation myocardial infarction (STEMI) when administered within 12 hours of symptom onset.
• Streptokinase can cause antibody formation, which can reduce its effectiveness and lead to allergic reactions.
• It is contraindicated for patients who have received it previously due to the risk of anaphylaxis.

Recombinant tPAs

• Recombinant tPAs are human-made versions of tPA.
• They are less antigenic, reducing the chance of allergic reactions.
• Examples of recombinant tPAs include alteplase (Activase®) and reteplase (Retavase®).
• Alteplase is clot-selective, meaning it targets fibrin-bound plasminogen.
• Reteplase has a longer half-life.

Urokinase

• Urokinase is a trypsin-like plasminogen activator produced by the kidneys and excreted in urine.
• It can be administered intravenously or by catheter.
• It is effective in treating deep vein thrombosis (DVT) and pulmonary embolism (PE).

Side Effects of Fibrinolytics

• Common side effects include bleeding, gastrointestinal hemorrhage, and cerebral hemorrhage.
• Fibrinolytics are contraindicated in patients with invasive procedures, hemorrhagic cerebrovascular disease, serious gastrointestinal bleeding, hemorrhagic disorders, and severe uncontrolled hypertension.

Reversal of Fibrinolytic Effects

• α2-antiplasmin, a plasma protein, rapidly inactivates plasmin.
• Aprotinin is a polypeptide that inhibits plasmin, tPA, and thrombin. It can increase the risk of postoperative acute renal failure.
• Aminocaproic acid and tranexamic acid inhibit plasminogen and plasmin but may not increase the risk of postoperative acute renal failure.
• Fresh plasma provides coagulation factors.

Fibrinolytics in Pregnancy

• Most fibrinolytics are categorized as pregnancy category C, meaning their use is difficult to recommend.
• Drugs with a molecular weight higher than 1,000 Daltons often do not cross the placental barrier.

General Drug Interactions

• Bone marrow suppressants can decrease platelet production, increasing the risk of bleeding.
• Anticoagulants, antiplatelet agents, and fibrinolytics all increase bleeding risk.
• Herbal supplements like ginkgo biloba, St. John's wort, and garlic can interact with fibrinolytics.
• Ginkgo biloba is an antiplatelet agent.
• St. John's wort increases the activity of CYP3A4, which may increase the activation of clopidogrel.
• Garlic inhibits platelet aggregation and enhances fibrinolytic activity.

Ultimate Goal of Antithrombotic Therapy

• The goal of antithrombotic therapy is to prevent thrombosis without causing excessive bleeding.