Plasminogen and tissue plasminogen activator
Fibrin and control · t-PA PAI-1 Alteplase
Plasminogen circulates inertly and binds lysine residues on fibrin as the clot forms. Endothelium releases tissue plasminogen activator in response to thrombin, stasis and hypoxia; t-PA is almost inactive in free solution but hundreds of times more active once bound to fibrin, so lysis is confined to the clot itself. Plasminogen activator inhibitor-1 is the brake.
Traced from the start
- Tissue factor and the extrinsic triggerVitamin K cycle and gamma-carboxylation
- Contact activation system (factor XII, prekallikrein, high-molecular-weight kininogen)
- Subendothelial collagen and von Willebrand factor
- Tissue factor-factor VIIa complex (extrinsic tenase)Factor IXaFactor VIIIa and its von Willebrand factor carrierActivated platelet phospholipid surface
- Factor XaFactor VaProthrombin (factor II)
- Thrombin (factor IIa)
- Plasminogen and tissue plasminogen activator
Detail
- Activators
- Tissue plasminogen activator (fibrin-dependent) and urokinase; as drugs, alteplase, tenecteplase, reteplase and streptokinase
- Inhibitors
- PAI-1 from endothelium, platelets and adipose tissue; alpha-2-antiplasmin; and TAFI, activated by the thrombin-thrombomodulin complex
- Fibrin selectivity
- t-PA activity rises several hundred-fold on a fibrin surface, which keeps physiological lysis local rather than systemic
- Clinical use
- Alteplase or tenecteplase for ischaemic stroke within 4.5 hours of onset, and for massive pulmonary embolism with haemodynamic compromise
When it goes wrong
Thrombolysis given despite recent surgery, major trauma or uncontrolled hypertension
Symptomatic intracranial haemorrhage, the principal hazard of thrombolysis; blood pressure must be below 185/110 mmHg before alteplase for acute ischaemic stroke
High PAI-1 levels in obesity, metabolic syndrome and chronic inflammation
Impaired fibrinolysis contributing to both arterial and venous thrombotic risk
Practise this structure
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