Modulation of fibrinolysis by thrombospondin.
Thrombospondin is a large, trimeric glycoprotein secreted by activated platelets and growing cells. Thrombospondin copolymerizes with fibrin during blood coagulation and deposits in extracellular matrix. We found that thrombospondin is a slow (rate constant approximately 6.3 x 10(3) M-1 sec-1), tight-binding (Kd < 10(-9) M) inhibitor of plasmin as determined by loss of amidolytic activity, loss of ability to degrade fibrinogen, and decreased lysis zones in fibrin plate assays (Biochemistry 31: 265-269, 1992). Thrombospondin also slowly inhibits urokinase plasminogen activator. The lysis zone when urokinase is put on fibrin plates made from whole plasma is less if thrombospondin is present. The stoichiometry of inhibition is approximately one mole plasmin:one mole thrombospondin trimer, a somewhat surprising result considering the trimeric nature of thrombospondin. These results indicate that thrombospondin is an important regulator of fibrinolysis and degradation of extracellular matrix, particularly when these processes are initiated by urokinase and even when other inhibitors of fibrinolysis are present.
Mosher
D F
DF
Department of Medicine, University of Wisconsin, Madison 53706.
Misenheimer
T M
TM
Stenflo
J
J
Hogg
P J
PJ
D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D019699:Thrombospondins; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D015815:Cell Adhesion Molecules; D008562:Membrane Glycoproteins; D019699:Thrombospondins; D014568:Urokinase-Type Plasminogen Activator