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python -c "from pypdf import PdfReader; p='/tmp/workspace/attachments/1aac3fb3-c244-4396-b8ca-bb81fe095669/DOC-20260927-WA0011.pdf'; r=PdfReader(p); print('PAGES',len(r.pages)); [print('---PAGE',i+1,'---'); print((x.extract_text() or '')[:12000]) for i,x in enumerate(r.pages)]"

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python -c "from pypdf import PdfReader; p='/tmp/workspace/attachments/1aac3fb3-c244-4396-b8ca-bb81fe095669/DOC-20260927-WA0011.pdf'; r=PdfReader(p); print('PAGES',len(r.pages)); exec(\"for i,x in enumerate(r.pages):\\n print('---PAGE',i+1,'---')\\n print((x.extract_text() or '')[:12000])\")"

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thrombolytic therapy AND fibrinolysis

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site:heart.org 2025 acute ischemic stroke guideline thrombolysis alteplase tenecteplase time window

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Fibrinolytic (Thrombolytic) Drugs

1. Definition

Fibrinolytic drugs, also called thrombolytics or plasminogen activators, are drugs that dissolve an already formed blood clot (thrombus).

They act by converting inactive plasminogen into active plasmin. Plasmin breaks down the fibrin meshwork that holds the clot together.

Simple flowchart:

Plasminogen → Plasmin → Fibrin clot breaks down → Fibrin degradation products

Fibrin is like the net or framework that traps blood cells and makes a clot firm.
Plasmin cuts this fibrin net.
Therefore, the clot dissolves.

Katzung's Basic and Clinical Pharmacology, 16th Edition, p. 968.

2. Normal fibrinolytic system

The body normally has a system to remove clots after a blood vessel has healed.

Plasminogen is present in blood in inactive form.
Endothelial cells release tissue plasminogen activator (t-PA).
t-PA converts plasminogen into plasmin.
Plasmin digests fibrin and dissolves the clot.

Why is plasmin not given directly?

Plasmin cannot be used as a drug because it is rapidly inactivated in plasma by natural inhibitors called antiplasmins, especially alpha-2-antiplasmin.

Therefore, drugs are used to activate plasminogen at the site of the clot.

3. Difference between thrombolytics, anticoagulants and antiplatelet drugs

Drug group	Main action	Example
Thrombolytics / fibrinolytics	Dissolve an existing clot	Alteplase, streptokinase
Anticoagulants	Prevent extension and formation of clots	Heparin, warfarin
Antiplatelet drugs	Prevent platelet aggregation, mainly arterial thrombi	Aspirin, clopidogrel

Important exam point:
Thrombolytics are used for clot lysis. Anticoagulants and antiplatelet drugs mainly prevent new clot formation or clot extension. They do not rapidly dissolve an established clot.

4. Classification of fibrinolytic drugs

A. Non-fibrin-specific drugs

These activate plasminogen in the circulating blood as well as inside the clot. Hence, they can cause more generalized bleeding.

Streptokinase
Urokinase
Anistreplase

B. Fibrin-specific drugs: t-PA group

These act more selectively on plasminogen attached to fibrin in the clot.

Alteplase
Reteplase
Tenecteplase

5. Streptokinase

Source

It is a protein obtained from beta-hemolytic streptococci.
It is not an enzyme by itself.
Being bacterial in origin, it can produce allergy and antibody formation.

Mechanism of action

Streptokinase combines with plasminogen to form a streptokinase-plasminogen complex.

This complex then converts more plasminogen into plasmin.

Flowchart:

Streptokinase + plasminogen → active complex → plasminogen converted to plasmin → fibrin clot lysed

Important features

Not fibrin-specific.
Produces a generalized lytic state.
It can break down:
- harmful thrombi
- protective hemostatic clots
- fibrinogen and some clotting factors

Therefore, bleeding is common.

Adverse effects

Bleeding, especially intracranial hemorrhage
Allergic reactions
Fever
Rarely, anaphylaxis
Reduced efficacy in patients with previous streptococcal infection or prior streptokinase exposure due to antibodies

Clinical uses

Acute ST-elevation myocardial infarction when timely primary PCI is unavailable
Massive pulmonary embolism
Deep vein thrombosis in selected cases
Peripheral arterial thrombosis or embolism
Blocked intravenous or arteriovenous cannulae in selected settings

One-line exam answer

Streptokinase is a non-fibrin-specific thrombolytic protein of streptococcal origin that forms a complex with plasminogen and converts plasminogen to plasmin.

Katzung's Basic and Clinical Pharmacology, 16th Edition, p. 968.

6. Urokinase

Source

It is a human enzyme originally isolated from urine.
It is produced by kidney cells.
It has low antigenicity compared with streptokinase.

Mechanism

Urokinase directly converts plasminogen to plasmin.

Urokinase → plasminogen → plasmin → fibrin breakdown

Features

It is an enzyme.
It is not fibrin-specific.
It can cause generalized fibrinolysis and bleeding.
It has a short half-life.

Uses

Massive pulmonary embolism
Deep vein thrombosis
Arterial thromboembolism
Coronary thrombosis in selected settings

Why is urokinase preferred over streptokinase?

Answer:

Urokinase is of human origin, so it has less antigenicity.
It causes fewer allergic reactions.
It can be used in a person previously exposed to streptokinase.
It directly activates plasminogen.

7. Anistreplase

Anistreplase is an acylated streptokinase-plasminogen complex.

Mechanism

After intravenous injection, the acyl group is removed.
The active streptokinase-plasminogen complex is released.
This activates plasminogen to plasmin and dissolves the clot.

Advantages

Can be given as a rapid IV injection.
Has a longer duration of action than streptokinase.
Has relatively greater clot selectivity.
More convenient administration.

Disadvantage

Because it contains streptokinase, it may still cause allergy.

8. Alteplase

Definition

Alteplase is recombinant tissue plasminogen activator, abbreviated as rt-PA.

It is produced by recombinant DNA technology.

Mechanism of action

Alteplase has high affinity for fibrin in the thrombus.

It binds to fibrin in the clot.
It activates fibrin-bound plasminogen.
Plasmin is formed locally.
Plasmin breaks fibrin and lyses the thrombus.

Alteplase binds fibrin → converts clot-bound plasminogen to plasmin → local clot dissolution

Advantages

More fibrin-specific than streptokinase.
Causes less systemic fibrinolysis in comparison with non-specific drugs.
Less antigenic because it is related to human t-PA.

Adverse effects

Bleeding, including gastrointestinal and intracranial bleeding
Rare hypersensitivity reaction
Orolingual angioedema, particularly in acute ischemic stroke
Risk of angioedema may be higher in patients taking ACE inhibitors

Uses

Acute ischemic stroke in eligible patients after excluding intracranial hemorrhage
Acute myocardial infarction in selected patients
Massive pulmonary embolism with hemodynamic instability
Catheter occlusion in selected clinical settings

Important update for exams

Your PDF says alteplase should be given within 3 hours for stroke. This is an older teaching point. Current stroke guidelines endorse eligible intravenous thrombolysis with alteplase or tenecteplase within 4.5 hours from symptom onset. Selected patients with unknown or extended onset may be considered after advanced imaging. The 2026 AHA/ASA stroke guidance explains this update.

Katzung's Basic and Clinical Pharmacology, 16th Edition, pp. 968-969.

9. Reteplase and Tenecteplase

Reteplase

Recombinant modified form of t-PA.
It has a longer half-life than alteplase.
It can be administered as an IV bolus.
It is less fibrin-specific than alteplase.

Tenecteplase

Genetically modified t-PA.
Has higher fibrin specificity than alteplase.
Has longer half-life.
Can be given as a single IV bolus.
Convenient because an infusion is not needed.

Easy comparison

Feature	Alteplase	Reteplase	Tenecteplase
Type	Recombinant t-PA	Modified t-PA	Modified t-PA
Half-life	Short	Longer	Longer
Administration	Bolus plus infusion	Bolus doses	Single bolus
Fibrin specificity	High	Lower than alteplase	High, greater than alteplase
Major use	Stroke, PE, MI	MI	MI and eligible ischemic stroke

Katzung's Basic and Clinical Pharmacology, 16th Edition, pp. 968-969.

10. Clinical indications of fibrinolytic drugs

1. Acute myocardial infarction

Mainly used in ST-elevation MI when primary PCI cannot be performed rapidly.
Early treatment gives better benefit.

2. Acute ischemic stroke

Used only after brain imaging excludes intracranial hemorrhage.
Given only to eligible patients within the accepted time window.

3. Massive pulmonary embolism

Used especially when pulmonary embolism causes hypotension, shock, or hemodynamic instability.

4. Deep vein thrombosis

Used only in selected severe cases, such as extensive iliofemoral DVT.

5. Acute peripheral arterial occlusion

May be given locally through an intra-arterial catheter in selected cases.

6. Occluded catheters

Certain thrombolytics may be used to open blocked vascular catheters.

The textbook specifically notes IV use in hemodynamically unstable pulmonary embolism and severe DVT, with intra-arterial use for selected peripheral vascular disease. Katzung's Basic and Clinical Pharmacology, 16th Edition, p. 969.

11. Adverse effects of fibrinolytic drugs

Most important adverse effect: Hemorrhage

Because fibrinolytics dissolve fibrin, they may dissolve both the target clot and normal protective clots.

Adverse effects

Bleeding
- Minor bleeding from injection sites
- Gastrointestinal bleeding
- Hematuria
- Intracranial hemorrhage, the most feared complication
Allergic reactions
- More common with streptokinase
- Fever, rash, hypotension, rarely anaphylaxis
Reperfusion arrhythmias
- May occur after restoration of coronary blood flow in MI
Hypotension
- Can occur especially with streptokinase
Angioedema
- Rarely with alteplase, particularly in stroke treatment

12. Contraindications of thrombolytic therapy

Absolute contraindications

Do not give thrombolytics in the following conditions:

Active internal bleeding
Previous hemorrhagic stroke
Suspected aortic dissection
Recent significant head trauma
Intracranial tumor or arteriovenous malformation
Recent intracranial or spinal surgery
Severe uncontrolled hypertension
Known bleeding disorder

Relative contraindications

Use only after careful risk-benefit assessment:

Recent major surgery or trauma
Active peptic ulcer disease
Pregnancy
Diabetic retinopathy
Severe liver disease
Recent gastrointestinal bleeding
Anticoagulant use
Prolonged or traumatic CPR

Exam sentence:
The chief danger of thrombolytic therapy is serious bleeding; therefore, recent surgery, active bleeding, hemorrhagic stroke, and intracranial lesions are major contraindications.

13. Antifibrinolytic drugs

These drugs are used when bleeding is due to excessive fibrinolysis.

They have the opposite action of thrombolytics.

Fibrinolytics	Antifibrinolytics
Increase plasmin formation	Decrease plasmin formation or action
Dissolve clot	Prevent clot breakdown
Used in thrombosis	Used in excessive bleeding

A. Tranexamic acid and aminocaproic acid

Mechanism

Both drugs are synthetic lysine analogues. They inhibit activation of plasminogen and thus prevent formation of plasmin.

Tranexamic acid / aminocaproic acid → inhibit plasminogen activation → less plasmin → less fibrin breakdown → bleeding decreases

Features

Orally active
Excreted by kidneys
Tranexamic acid is approximately 10 times more potent than aminocaproic acid.

Uses

Bleeding due to hyperfibrinolysis
Dental extraction in hemophilia
Menorrhagia
Postoperative bleeding
Bleeding after prostate or gastrointestinal surgery
As an adjunct in selected trauma and obstetric bleeding protocols

Adverse effects

Thrombosis
Nausea and vomiting
Seizures, particularly with high-dose tranexamic acid
Renal dose adjustment may be needed

Lippincott Illustrated Reviews: Pharmacology, pp. 467-468.

B. Aprotinin

Mechanism

Aprotinin is a serine protease inhibitor. It inhibits free plasmin and other proteolytic enzymes.

Use

It was used to reduce blood loss in some major surgical procedures.

Note

Its use became limited in many settings because of safety concerns, especially thrombotic and renal risks.

14. Drugs used to reverse anticoagulant-related bleeding

This part is often asked with antifibrinolytics.

Drug	Antagonizes / reverses	Mechanism
Protamine sulfate	Heparin	Positively charged protamine binds negatively charged heparin and forms an inactive complex
Vitamin K1	Warfarin	Restores vitamin K-dependent clotting factor synthesis
Tranexamic acid / aminocaproic acid	Excess fibrinolysis	Inhibit plasminogen activation

Protamine sulfate

Mechanism

Heparin is negatively charged.
Protamine is positively charged.
Both combine to form a stable inactive complex.

Protamine (+) + Heparin (-) → inactive complex

Use

Antidote for heparin overdose.

Adverse effects

Hypersensitivity
Flushing
Dyspnea
Bradycardia
Hypotension
Anaphylaxis, particularly if injected rapidly

Lippincott Illustrated Reviews: Pharmacology, p. 467.

Vitamin K1

Use

Vitamin K1, also called phytonadione, is used to reverse warfarin-induced bleeding.

Mechanism

Warfarin blocks vitamin K-dependent synthesis of clotting factors. Vitamin K1 restores synthesis of clotting factors II, VII, IX, and X.

Important point

Its effect is slow, often taking about 24 hours, because new clotting factors have to be synthesized. In life-threatening bleeding, faster reversal methods are required along with vitamin K according to clinical protocol.

Lippincott Illustrated Reviews: Pharmacology, p. 468.

15. Short note answer: Fibrinolytics

Fibrinolytic drugs are agents that dissolve formed thrombi by converting plasminogen into plasmin. Plasmin digests fibrin, the structural framework of a clot. Important drugs are streptokinase, urokinase, anistreplase, alteplase, reteplase, and tenecteplase. Streptokinase is obtained from beta-hemolytic streptococci and forms a complex with plasminogen. Urokinase directly activates plasminogen. Alteplase, reteplase and tenecteplase are tissue plasminogen activators and are relatively fibrin-specific. They are used in selected cases of acute MI, ischemic stroke, massive pulmonary embolism, extensive DVT and acute arterial occlusion. The most serious adverse effect is bleeding, especially intracranial hemorrhage. Important contraindications are active bleeding, hemorrhagic stroke, recent major surgery, head trauma and uncontrolled hypertension.

16. Very short revision points

Fibrinolytics dissolve clots.
Plasminogen becomes plasmin.
Plasmin breaks fibrin.
Streptokinase: bacterial protein, allergy, non-specific.
Urokinase: human enzyme, directly activates plasminogen.
Alteplase: recombinant t-PA, fibrin-specific.
Tenecteplase: modified t-PA, longer acting, single bolus.
Main adverse effect: bleeding.
Antifibrinolytics: tranexamic acid and aminocaproic acid.
Heparin antidote: protamine sulfate.
Warfarin antidote: vitamin K1.

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