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11 Cards in this Set

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Explain normal fibrinolysis.
-- A thrombus is held together by a cross-linked fibrin net.
-- fibrin net is dissolved by the proteolytic enzyme plasmin when vascular repair is complete
-- Both t-PA released from vascular endothelial cells and the plasma protein plasminogen (synth by the liver) bind to fibrin
-- when bound fibrin in close proximity, t-PA activates plasminogen to plasmin
-- protease activity of the plasmin then destroys the fibrin net of the clot
-- t-PA normally causes the proteolytic activity of plasmin to be clot specific
Plasmin is not specific for fibrin. What else does plasmin's protease activity degrade?
-- it will also degrade clotting factors 5 and 8, and fibrinogen, so the body would like to keep t-PA in the circulation in check
What keeps t-PA and plasmin in check?
-- Plasma proteins (plasminogen activator inhibitors 1 and 2) keeps circulating t-PA from activating circulating plasminogen

-- a2-antiplasmin directly inhibits enzymatic activity of plasmin in circulation

-- a2 also binds to fibrin to block the binding of plasminogen, thus it protects the thrombus from degradation before vascular repair can be completed

-- all three of the above prevent the degradation of clotting factors 5 and 8 and fibrinogen

**any plasmin BOUND to fibrin cannot be inhibited by circulating a2-antiplasmin since they both bind to the same site on fibrin
Name the drugs that cause activation of plasmin.
TISSUE PLASMINOGEN ACTIVATOR (t-PA)
ALTEPASE -- unmodified human t-PA produced by recombinant technology

STREPTOKINASE -- a non-enzymatic protein produced by b-hemolytic Streptococcus
t-PA MOA?
1. t-PA is a serine protease that cleaves a single peptide bond of plasminogen to form plasmin

2. Plasminogen activator inhibitors 1 & 2 limit the activation of free plasminogen in the plasma

3. Fibrin possess binding sites for lysine residues thar are found on the amino-terminal ends of plasminogen and t-PA

4. This interaction allows plasminogen and t-PA to bind to thrombi

5. Once boud to fibrin, the enzymatic activity of t-PA is increased 200x and cleaves plasmin from plasminogen: plasmin degrades fibrin and thus lyses the thrombus
t-PA in normal physiological situations?
-- the activity of t-PA is so small that systemic fibrinolysis does not occur
Response to altepase i.v. injection?
After i.v. injection, the enzymatic activation of plasminogen to plasmin is so great that the endogenous inhibitors of t-PA and plasmin are overwhelmed

-- specificity of plasmin for the fibrin in thrombi is lost

-- systemic fibrinolytic state ensues due to the degradation of clotting factors 5 and 8 and fibrinogen

**half-life 5-10min
Streptokinase MOA?
1. Binding of streptokinase near the carboxy terminus of plasminogen induces a conformational change that exposes the protease activity near the amino terminus of plasmiinogen

2. This protease activity cleaves plasmin from another plasminogen molecule

3. The plasmin can attack firbin in thrombi or circulating clotting factors 5 and 8 and fibrinogen

4. Large doses streptokinase may be required in patients who have developed Ab against strep proteins during prior infection w/ strep

**half-life -- 40-80min
Therapeutic uses of fibrinolytic drugs?
1. Establish reperfusion of coronary vessels after MI
-- Streptokinase and t-PA induced reperfusion decreases mortality by 30% after MI, but immediate PTCA (PCI), w/ or w/out intra-arterial stents, is superior to thrombolytic therapy
-- Increased rate of survival from MI after trtmt w/ thrombolytic drug is enhanced by cotrtmt w/:
-- ASA and tirofiban
-- beta-blocker -- reduces infarct size and myocardial ischemia, prevents reinfarction, and fatal ventricular dysrhythmias
-- ACEi -- reduces preload and afterload to improve CO, reduces infarct size and prevents dysrhythmias
-- nitrate -- reduces preload and infarct size

2. Pulmonary Embolism

3. DVTs

4. Ischemic stroke
Toxicity of fibrinolytic drugs?
BLEEDING

-- results from non-selective lysis of thrombi involved in normal vascular repair and the uninhibited degradation of clotting factors 5 and 8 and fibrinogen

-- Incidence - 1%
-- Incidence w/ heparin - 2-4%
What antagonizes plasmin?
aminocaproic acid

-- lysine analog that binds to plasmin and plasminogen and thus prevents their binding to fibrin in thrombi

-- used to prevent bleeding caused by fibrinolytic therapy and the extracorporeal circulation of blood