• Intravascular clots dissolve via plasmin by digesting fibrin
• Plasminogen is an inactive precursor that is converted to plasmin via a single peptide cleavage by tissue plasminogen-activator (t-PA) released by endothelial cells 
• Normally the fibrinolytic system removes unwanted fibrin thrombi while leaving wound fibrin intact to maintain hemostasis 
• Mechanisms of control:  1)  Greater activity of plasmin bound to clot fibrin than when bound to fibrinogen in circulation. 2)  t-PA is rapidly cleared from the blood by inhibitors (alpha-2-antiplasmin) so it doesn't affect circulating plasminogen normally 

Alteplase 

Reteplase

Tenecteplase

Streptokinase

Urokinase 

Streptokinase-plasminogen complex (APSAC)

• Recombinant t-PA:

          Alteplase

          Reteplase

          Tenecteplase 

• Recombinant proteolytic enzymes:

          Streptokinase

          Urokinase

          Streptokinase-plasminogen complex (APSAC) 

• They are used to dissolve pathologic thrombi by injecting the enzyme to stimulate endogenous fibrinolytic activity

1. Acute MI (these are the MAIN ones)
2. Pulmonary embolism (these are the MAIN ones)
3. DVT (but they are not used for these usually)
4. Ischemic stroke (only in special circumstances) 

• These agents tend to dissolve BOTH pathological thrombi and physiological clots due to vascular injury 
• So these often cause hemorrhage as a major side effect

• As before, since hemorrhage is a major concern, do not give to people where chances of hemorrhaging are increased
• Recent surgery
• Severe HTN
• GI bleeding
• Urinary bleeding 

• Alteplase (rt-PA):  Full-length recombinant form of t-PA.  Binds to fibrin in thrombus and converts the entrapped plasminogen to plasmin.  This initiates a LOCAL fibrinolysis w/limited systemic proteolysis.  This acts petty much like the physiologic system does.  When bound to fibrin, it is 100X more efficient at stimulating plasminogen vs when it is in free solution. This is why normal fibrinolytic activity is limited. But this is at much HIGHER levels than in-vivo to achieve its therapeutic effects. Since this needs to bind to the fibrin, it does not really diffuse into clots, instead it stays on the top of the clot typically.. 

Alteplase (rt-PA) clearance?

Half-life?

Cleared by the liver 

Very short half-life of a few minutes

• Reteplase (r-PA):  Shorter genetically engineered form of t-PA.  It does NOT bind to fibrin so tightly which allows the drug to diffuse through the clot rather than stay on the surface as t-PA usually does.  
• In high concentrations, does NOT compete with plasminogen for fibrin-binding sites (because t-PA and rt-PA need to bind to fibrin in order to be more effective at converting plasminogen to plasmin), so this can allow plasminogen to clot-dissolve once it is covereted to plasmin. 

Reteplase clearance? 

Half-life?

• Clearance = live
• Half-life = shorter half-life than alteplase 

1. Percutaneous coronary interventino w/stent (PCI-stent) is SUPERIOR in outcome vs the use of fibrinolytics
2. When PCI is NOT availbe, then you should use a fibrinolytic. However the efficacy of these drugs decline after time since the infart (they have very little efficacy after 90 minutes from the onset of the event) 

1. In ONLY low risk cerebral hemorrhage patients w/CT-scan can you administer fibrinolytic agents as a treatment. Give this patient an IV-bolus followed by an IV-infusion over the next hour.  This is ONLY recommended if treatment is initiated w/in 3 horus of the onset of ischemic stroke! This is because if there is significant ischemia, revascularization by dissolving the clot can lead to an emboli stroke which will now cause a hemorrhagic stroke

• Non-enzymatic activator of plasminogen
• Extracted from beta-hemolytic streptococci 
• Forms complex w/plasminogen and accelerates its converstion to plasmin.  

Streptokinase ROA

Importance of dose?

• ROA = IV
• Dose is important because most people have Ab to streptokinase b/c previous expsoure to streptococci. So need to give a loading dose that saturates these Ab 

• Dissolution of MI thrombi:  Most beneficial when instituted early (w/in 90 minutes) after the onset of symtpoms. Do you give a stent or these?
• Pulmonary embolism
• Deep venous thrombosis 
• Peripheral vascular disease 

• Anistreplase = Anisoylated Plasminogen Streptokinase Activator Complex (APSAC)
• MOA:  Inactive form of plasminogen-streptokinase-complex that becomes activated when in the blood.  Has greater selectivity for plasminogen assocaited w/clots (so it does NOT react with free plasminogen in the plasma very well so it has less of a propensity to cause a systemic fibrinolytic state)

Anistreplase ROA

Use?

• ROA:  Rapid IV injection 
• Use:  Shown to be useful in early administration after ischemic attack in an MI