Thrombolytics & Fibrinolytics

Thrombolytics ("clot-busters") are drugs that dissolve an already formed thrombus by converting plasminogen into the active fibrinolytic enzyme plasmin. They are central to the early management of ST-elevation myocardial infarction (STEMI), massive pulmonary embolism, and acute ischaemic stroke, and are a perennial favourite in NEET PG pharmacology because of their crisp mechanism, sharp time windows, and a long list of contraindications.

Where they sit in haemostasis

To understand thrombolytics you must separate three pharmacological roles that are constantly confused in MCQs:

• Antiplatelets (aspirin, clopidogrel, ticagrelor, abciximab) — prevent platelet plug formation. Used for prevention.
• Anticoagulants (heparin, warfarin, DOACs) — prevent fibrin clot extension/propagation. Cannot lyse an existing clot.
• Thrombolytics / Fibrinolytics — actively dissolve an established fibrin clot. Used for treatment of an acute occlusion.

High-yield: Only thrombolytics dissolve an existing thrombus. Heparin and warfarin merely prevent new clot/extension — they do NOT lyse a formed clot. This single distinction is repeatedly tested.

The fibrinolytic system (pathophysiology)

The endogenous fibrinolytic cascade is built around plasminogen, an inactive zymogen synthesised by the liver and incorporated into clots. Its physiological activators are tissue plasminogen activator (t-PA) and urokinase, both released from vascular endothelium.

Plasminogen → (activator) → Plasmin → degrades fibrin & fibrinogen → fibrin degradation products (FDPs, including D-dimer)

Plasmin is a non-specific serine protease: it cleaves not only fibrin but also fibrinogen, factor V and factor VIII — which is why systemic ("non–fibrin-specific") agents produce a systemic lytic state and bleeding.

Endogenous brakes on the system:

• PAI-1 (plasminogen activator inhibitor-1) — inhibits t-PA/urokinase.
• α2-antiplasmin — the principal circulating inhibitor of free plasmin.
• TAFI (thrombin-activatable fibrinolysis inhibitor).

High-yield: Tranexamic acid and ε-aminocaproic acid (EACA) are antifibrinolytics — they block the lysine-binding sites on plasminogen, preventing its activation. They are the antidotes / reversal agents for thrombolytic overdose and are used in hyperfibrinolytic bleeding (menorrhagia, trauma, post-tonsillectomy).

Classification of thrombolytic agents

Thrombolytics are best classified by fibrin specificity — i.e., whether they preferentially activate clot-bound plasminogen (fibrin-specific) or activate circulating plasminogen indiscriminately (non-specific).

Generation	Agent	Fibrin specificity	Antigenic / allergenic	Source
First	Streptokinase	Non-specific	Yes (antigenic)	β-haemolytic Streptococci
First	Urokinase	Non-specific	No	Human renal cells / urine
Second	Alteplase (rt-PA)	Fibrin-specific	No	Recombinant DNA
Third	Reteplase (r-PA)	Fibrin-specific	No	Recombinant (deletion mutant)
Third	Tenecteplase (TNK-tPA)	Most fibrin-specific	No	Recombinant (point mutations)
Third	Staphylokinase / Lanoteplase	Fibrin-specific	Staphylokinase antigenic	Recombinant

High-yield: Streptokinase is the only commonly tested antigenic thrombolytic. It can cause allergic reactions, hypotension, and — because of pre-formed/neutralising antibodies — it should not be re-administered between 5 days and ~12 months after a prior dose or a recent streptococcal infection. Repeat dosing reduces efficacy and risks anaphylaxis.

Individual agents — must-know points

Streptokinase

• A protein (not an enzyme itself). It forms a 1:1 activator complex with plasminogen, and this complex then activates other plasminogen molecules to plasmin.
• Non–fibrin-specific → produces a systemic lytic state, depletes fibrinogen.
• Cheap → still widely used in resource-limited settings (and in Indian practice) for STEMI.
• Adverse effects: hypotension during infusion, allergic/anaphylactoid reactions, bleeding.

Urokinase

• Directly converts plasminogen to plasmin; non-antigenic. Mainly used for catheter clearance, PE, and clotted arteriovenous access.

Alteplase (recombinant t-PA, rt-PA)

• Fibrin-specific: activates plasminogen preferentially on the fibrin surface. Short half-life (~4–6 min) → requires bolus + infusion.
• The only thrombolytic approved for acute ischaemic stroke.

Reteplase

• Deletion mutant with longer half-life; given as two boluses 30 min apart. Less fibrin-specific than alteplase.

Tenecteplase (TNK)

• Bioengineered alteplase with three mutations (T, N, K) giving: longer half-life, highest fibrin specificity, and resistance to PAI-1.
• Single weight-based IV bolus → ideal for pre-hospital / ambulance thrombolysis and now the preferred fibrinolytic in STEMI where PCI is unavailable.

High-yield mnemonic — "TNK is the King": Tenecteplase = single bolus, highest fibrin specificity, PAI-1 resistant, longest half-life among the lytics. These four facts are the most asked features.

Pharmacokinetic / dosing comparison

Feature	Streptokinase	Alteplase	Reteplase	Tenecteplase
Fibrin specificity	None	++	+	+++
Plasma half-life	~20 min	4–6 min	13–16 min	20–24 min
Administration	Infusion (1 h)	Bolus + infusion (90 min)	Double bolus	Single bolus
Antigenicity	Yes	No	No	No
Risk of hypotension/allergy	High	Low	Low	Low
Relative cost	Lowest	High	High	High

Clinical indications

1. ST-elevation MI (STEMI) — when primary PCI cannot be delivered within 120 minutes of first medical contact. Fibrinolysis should ideally be given within 30 minutes (door-to-needle).
2. Acute massive / high-risk pulmonary embolism — with haemodynamic instability (hypotension, shock).
3. Acute ischaemic stroke — alteplase within the time window (see below).
4. Acute peripheral arterial occlusion / limb ischaemia (often catheter-directed).
5. Occluded central venous catheters / AV shunts / dialysis grafts (urokinase, alteplase).
6. Selected DVT (extensive iliofemoral / phlegmasia) — catheter-directed.

STEMI — the time windows (most tested)

• Greatest benefit when given within the first 1–3 hours of symptom onset ("golden hour" of myocardial salvage).
• Generally indicated up to 12 hours from symptom onset (benefit declines steeply with time — "time is muscle").
• Primary PCI is preferred over fibrinolysis if it can be performed within 90–120 min.
• After successful lysis, transfer for early angiography (pharmaco-invasive strategy) is recommended.

Approach to a STEMI presenting to a non-PCI centre:

Confirm STEMI on ECG → check onset time (<12 h) → screen contraindications → if PCI not available within 120 min → give fibrinolytic (TNK/SK) within 30 min + aspirin + clopidogrel + anticoagulant → assess reperfusion at 60–90 min → transfer for angiography

High-yield: Markers of successful reperfusion after fibrinolysis: ≥50% resolution of ST elevation at 60–90 min, relief of chest pain, reperfusion arrhythmias (classically accelerated idioventricular rhythm — AIVR), and an early peak of cardiac biomarkers ("washout" of CK-MB/troponin).

Acute ischaemic stroke — alteplase windows

• IV alteplase (0.9 mg/kg, max 90 mg; 10% bolus, rest over 60 min) within 4.5 hours of symptom onset (extended from the original 3-hour window).
• A non-contrast CT must exclude haemorrhage before giving the drug.
• Blood pressure must be < 185/110 mmHg before lysis.
• Beyond the window or large-vessel occlusion → mechanical thrombectomy (up to 24 h in selected patients).

High-yield: Alteplase is the only thrombolytic licensed for acute ischaemic stroke. Streptokinase is contraindicated in stroke (unacceptably high intracranial haemorrhage rates in trials).

Contraindications

The single most examined table in this topic. Contraindications exist because the dominant adverse effect is bleeding, especially intracranial haemorrhage (ICH).

Absolute contraindications	Relative contraindications
Any prior intracranial haemorrhage	Severe uncontrolled hypertension (>180/110) on presentation
Known structural cerebral vascular lesion (AVM)	History of chronic, poorly controlled HTN
Known intracranial malignancy	Ischaemic stroke >3 months ago, dementia
Ischaemic stroke within 3 months	Traumatic/prolonged CPR (>10 min); major surgery <3 weeks
Suspected aortic dissection	Recent internal bleeding (2–4 weeks)
Active bleeding / bleeding diathesis (excl. menses)	Non-compressible vascular punctures
Significant closed head / facial trauma <3 months	Pregnancy
Intracranial/spinal surgery within 2 months	Active peptic ulcer; current anticoagulant use
Severe uncontrolled HTN unresponsive to therapy	For streptokinase: prior exposure (5 days–12 months) / allergy

High-yield: Aortic dissection and previous haemorrhagic stroke (ever) are classic absolute contraindications. Menstruation, controlled hypertension, and pregnancy are relative, not absolute. Diabetic retinopathy is a relative (not absolute) contraindication — a frequent distractor.

Mnemonic for absolute contraindications — "HEAD STAB":

• H — Haemorrhagic stroke ever / Head trauma <3 months
• E — Endocranial (intracranial) neoplasm / vascular lesion
• A — Aortic dissection (suspected)
• D — Diathesis (active bleeding / bleeding disorder)
• S — Stroke (ischaemic) within 3 months
• TAB — recent intracranial/spinal surgery

Adverse effects

1. Bleeding — commonest. Ranges from oozing at puncture sites to intracranial haemorrhage (the most feared, ~0.5–1% in STEMI, higher in stroke patients).
2. Hypotension — particularly with streptokinase infusion (rate-related; slow the infusion).
3. Allergic / anaphylactoid reactions, fever, rash — streptokinase (antigenic).
4. Reperfusion arrhythmias — AIVR, VPCs, transient bradycardia/heart block (especially inferior MI).
5. Cholesterol embolisation / orolingual angioedema — angioedema notably with alteplase (more in patients on ACE inhibitors).
6. Reocclusion — fibrin-specific agents have higher early reocclusion rates → adjunct anticoagulation needed.

Management of thrombolytic-induced bleeding

Stop infusion → give cryoprecipitate (replaces fibrinogen & factor VIII) and fresh frozen plasma → administer antifibrinolytic (tranexamic acid / aminocaproic acid) → reverse heparin with protamine → platelet transfusion if needed → CT head if neurological deterioration

High-yield: For a fibrinogen-depleting lytic bleed (streptokinase), cryoprecipitate is the key replacement product; tranexamic acid / aminocaproic acid is the pharmacological reversal agent. Protamine reverses heparin, not the thrombolytic itself.

Fibrin-specific vs non-specific — the conceptual table

Property	Non-specific (Streptokinase, Urokinase)	Fibrin-specific (Alteplase, TNK, Reteplase)
Plasminogen activation	Systemic (circulating + clot-bound)	Preferentially clot-bound
Systemic lytic state	Marked (fibrinogen depleted)	Minimal
Systemic bleeding tendency	Higher systemic depletion	More localised clot lysis
Intracranial haemorrhage risk	Lower (paradoxically) for SK in some MI data	Slightly higher with rt-PA
Early reocclusion	Lower	Higher → needs heparin
Antigenic	SK yes	No

High-yield: A classic trick: fibrin-specific agents do not abolish bleeding risk. In fact, intracranial haemorrhage may be marginally higher with rt-PA than streptokinase in MI trials, even though they spare systemic fibrinogen. Fibrin specificity ≠ "safer for the brain".

Adjuncts given alongside fibrinolysis in STEMI

• Aspirin (loading 162–325 mg) + clopidogrel (loading) — dual antiplatelet.
• Anticoagulant — enoxaparin / unfractionated heparin (or fondaparinux) to prevent reocclusion.
• These are co-administered, not alternatives, to lytic therapy.

Key differentials / "compare and contrast" traps

• Thrombolytic vs antiplatelet vs anticoagulant — see opening section; the most frequent conceptual MCQ.
• Streptokinase vs Tenecteplase — antigenic + infusion + hypotension vs non-antigenic + single bolus + PAI-1 resistant.
• Alteplase vs Tenecteplase — both fibrin-specific recombinant t-PA; TNK is longer-acting, more fibrin-specific, single bolus; alteplase is the stroke drug.
• Tranexamic acid vs aprotinin — both antifibrinolytics; aprotinin (a serine protease inhibitor) was withdrawn for increased mortality in cardiac surgery (BART trial).
• D-dimer — a fibrin degradation product; raised whenever fibrinolysis is active (PE/DVT screen). Distinguish endogenous lysis marker from therapeutic agents.

Recently asked / exam angle

• "Which thrombolytic is fibrin-specific AND resistant to PAI-1 and given as a single bolus?" → Tenecteplase.
• "Antigenic thrombolytic that should not be repeated within 1 year?" → Streptokinase.
• "Only thrombolytic approved for acute ischaemic stroke?" → Alteplase, within 4.5 h.
• "Antidote / reversal for thrombolytic-induced fibrinolysis?" → Tranexamic acid / ε-aminocaproic acid (± cryoprecipitate).
• "Absolute contraindication to thrombolysis?" → Suspected aortic dissection / prior intracranial haemorrhage / recent ischaemic stroke (<3 months).
• "Best ECG marker of successful reperfusion?" → ≥50% ST resolution at 60–90 min and AIVR.
• "Mechanism of streptokinase?" → Forms an activator complex with plasminogen (it is not itself an enzyme).
• "Time window for fibrinolysis in STEMI?" → up to 12 h, best <3 h; PCI preferred if available within 120 min.
• Match-the-following on fibrin specificity and antigenicity of the five main agents is a recurring format.

Rapid revision

1. Thrombolytics convert plasminogen → plasmin, which degrades fibrin; only they dissolve an existing clot.
2. Streptokinase = antigenic, non-specific, causes hypotension, do not repeat 5 days–12 months.
3. Alteplase = recombinant t-PA, fibrin-specific, only drug for ischaemic stroke (window 4.5 h).
4. Tenecteplase = highest fibrin specificity, PAI-1 resistant, longest half-life, single bolus — ideal pre-hospital.
5. Reteplase = double bolus, 30 min apart.
6. STEMI fibrinolysis window up to 12 h; door-to-needle ≤30 min; PCI preferred if ≤120 min.
7. Successful reperfusion → ≥50% ST resolution, pain relief, AIVR, early biomarker peak.
8. Absolute contraindications: prior ICH, ischaemic stroke <3 months, aortic dissection, active bleeding, intracranial tumour/AVM.
9. Tranexamic acid / aminocaproic acid = antifibrinolytics → reversal of lytic bleeding; cryoprecipitate replaces fibrinogen.
10. Fibrin specificity does not lower intracranial haemorrhage risk — rt-PA may even be slightly higher than SK in MI.
11. Adjuncts in STEMI lysis: aspirin + clopidogrel + heparin/enoxaparin.
12. Streptokinase is contraindicated in stroke; protamine reverses heparin, not the thrombolytic.