24A06: Exam Report
(a) Outline the process of fibrinolysis including how it interacts with the coagulation system (80% of marks).
(b) Describe the mechanism of action and adverse effects of alteplase (20% of marks).
3% of candidates passed this question.
- This part required candidates to demonstrate their knowledge of the fibrinolytic pathway with details of the relevant mediators and inhibitors. Candidates where then required to apply their knowledge of both the coagulation cascade and fibrinolysis, with detail of how the pathways are simultaneously activated by the same stimuli to ensure balance between bleeding and clotting. An example would be endothelial damage stimulating both the clotting cascade through collagen exposure and thromboplastin activation (faster response) as well as fibrinolysis through t-PA activation (slower response).
- This section of the question required a detailed description of the mechanism of action of alteplase, recombinant t-PA. A comparison to endogenous t-PA helped illustrate this action and the subsequent bleeding and the non-bleeding effects.
Q1v / 24A06: Outline the process of fibrinolysis including how it interacts with the coagulation system
Part A
Definition
Fibrinolysis is a delayed and naturally occurring process following the initiation of the coagulation cascade, where fibrin and fibrinogen are cleared by plasmin and a clot is broken down.
Fibrinolysis is required to achieve homeostatic balance and maintain small vessel patency.
Both coagulation and fibrinolysis are activated by similar stimuli to ensure balance between bleeding and clotting.
Example 1
Endothelial damage stimulating both the clotting cascade through collagen exposure and thromboplastin activation (faster response) as well as fibrinolysis through t-PA activation (slower response) ie Intrinsic activation.
Example 2
Extrinsic activation via tissue activators eg Factor XIa, XIIa (Intrinsic pathway) and tissue Kallikrein activate both Plasminogen pro enzyme and Intrinsic pathway of coagulation cascade model.
Fibrinolytic Pathway
- Endothelial cells release t-Pa (tissue plasminogen activator), a potent enzyme
- T-Pa cleaves: the pro enzyme plasminogen -> plasmin
- Plasmin degrades fibrin clots from the endothelial cell surface into “fibrin degradation products” via hydrolysis of arginine and lysine bonds.
Plasminogen is a b- globulin synthesized in the liver; fibrin (Ia) is a serine protease.
D- dimer is an example of an FDP, and laboratory testing of its concentration can correlate clinically with recent presence of venous thromboembolic disease.
Mediators – of fibrinolysis
- tPa (endogenous tissue plasminogen activator); alteplase is recombinant (exogenous) tPa.
- Streptokinase – A purified fibrinolytic bacterial protein naturally produced by Streptococci spp
- Urokinase – endogenous peptide (serine protease) present in humans to stimulate plasminogen activation. Can be synthesized via recombinant technology from renal cell cultures.
Inhibitors – of fibrinolysis
- Plasminogen activator inhibitor (PAI 1 & 2): endogenous inhibitors of protease activity ie will inhibit the formation of tPa and urokinase. Elevated endothelial PAIs can lead to increased clot formation. PAI-1 (also known as serpin) is found within endothelium, and PAI-2 is secreted by the placenta during pregnancy.
- Anti fibrinolytic drugs prolong clot stability and/ or limit bleeding risk eg Tranexamic acid (competitive plasminogen inhibitor, and at high enough concentration non competitively blocks plasmin).
Part B
Alteplase (Class: Thrombolytics)
Mechanism of Action
Tissue- type plasminogen activator, a glycoprotein synthesized via recombinant DNA technology from human tPa.
Due to its high alteplase—fibrin affinity for lysine residues, Alteplase only becomes active when bound to fibrin (ie in presence of formed clot). Alteplase can then induce the conversion of naturally occurring plasminogen into plasmin to promote clot lysis (fibrinolysis) at a local level, with limited systemic proteolysis.
In the absence of fibrin, the alteplase- mediated conversion of plasminogen is limited.
Dose
- 0.9mg/kg IV (max dose 90mg)
- Over 60 mins (with initial 10% dose bolus within 1 min) for acute stroke
- 50mg vials (1 mg/mL)
Use
- Acute STEMI
- massive PE
- acute ischaemic stroke
- venous catheter related occlusion
Adverse effects
Bleeding is main risk – there is no antidote/ reversal agent, supportive care only
Absolute contra indications
- Include recent intra cranial haemorrhage
- SAH
- Active internal bleeding; recent (last 3/12) intracranial or intraspinal surgery or serious head trauma
- Known intra cranial pathology at increased risk of bleeding (eg neoplasm)
- Bleeding diathesis
- Current severe uncontrolled hypertension.
Non bleeding related
- Hypersensitivity, including urticarial / anaphylactic reactions.
- Thromboembolism – in high VTE risk (eg AF, mechanical valves), use of alteplase can cause re- embolization if deep venous thrombosis is lysed.
- Reperfusion arrhythmia (in AMI)
References
- Principles of Physiology for the Anaesthetist
- Power/ Kam 4th edition // Peck and Harris Pharmacology
- Diagram – Chambers
Author: Ines Vaz