TBBP_Plasminogen^J Plasmin

extrinsic pathway: fibrin clot formation in response to tissue injury. Intrinsic pathway: fibrin clot formation in response to an abnormal vessel wall (f.e. by contact with lipoprotein particles or bacteria)

activation plasminogen to plasmin with tPA by cleavage of N-terminal peptide (nicking Arg 561 at activation side), plasmin degrades fibrin clot unless it gets repressed by Alpha2-Antiplasmin (control)

zymogen, inactive form of the enzyme and conversion to plasmin, single chain glycoprotein, 92 kD, 0.2 g/L, synthesis in liver

serine protease (homology to trypsin), 24 disulfide bridges, nonspecific protease, degrades fibrin clots to maintain clot hemostasis, plasmin is rapidly inactivated

purify plasminogen, then activate using a plasmin activator (tPA). Affinity chr. Leveraging the kringle regions. Critical to stabilize plasmin under conditions to avoid autodegradation, viral inactivation must be present. 1. Purification of plasminogen (DF/viral reduction --> AFC --> freeze. 2. purification of plasmin and removal of impurities (viral inactivation, AFC, hydrophobic chr., UF/DF, nanofiltration), 3. formulation, fill and freeze-dry

plasmin degrades clots by splitting fibrin into fragments, plasmin itself can't be used: inhibitors in plasma prevent its effects, fibrinolytic drugs catalyze activation to plasmin, rapidly lyse or break down thrombi, some drugs more clot specific (act on fibrin bound plasminogen)

congenital deficiencies (Type 1: autosomal recessive, formation of fibrous depositions throughout the body, plasminogen unavailable for clot dissolution. Type 2: only a polymorphic variation of population, no specific clinical manifestation), wound healing. direct dissolution of clots: locally delivering of the drug maintaining its activity, safe and quickly inactivated drug. today delivering plasminogen activators systemically

lysis of fresh clots: plasmin and tPA lyse clots, lysis of retracted clots: plasmin lyses clots, tPA is ineffective, clots are poor in plasminogen

peripheral arterial disease (PAD), deep vein thrombosis (DVT), Ischemic stroke, pulmonary embolism