PLASMINOGEN-ACTIVATOR INHIBITOR-1 RELEASED FROM ACTIVATED PLATELETS PLAYS A KEY ROLE IN THROMBOLYSIS RESISTANCE - STUDIES WITH THROMBI GENERATED IN THE CHANDLER LOOP

To investigate the potential role of plasminogen activator inhibitor-1 (PAI-1), which is released from the alpha-granules of activated plate lets, in thrombolysis resistance, we employed a model (the ''Chandler loop'') that mimics the formation of arterial thrombi in vivo and that can be manipulated in terms of theological parameters and composition of blood cells. Light and electron microscopy revealed that the distr ibution of blood cells in Chandler thrombi is polarized, as it is in a rterial thrombi, resulting in platelet-rich ''white heads'' and red bl ood cell-rich ''red tails.'' Resistance toward tissue-type plasminogen activator (TPA)-mediated thrombolysis parallels the presence of plate lets that are fully activated in this system. We demonstrate that the PAI-1 released by the alpha-granules is preferentially retained within the thrombus and that the concentration of PAI-1 antigen is higher in the head than in the tail of the thrombus. The relative thrombolysis resistance of the heads of Chandler thrombi can be largely abolished b y inclusion of an anti-PAI-1 monoclonal antibody that blacks that inhi bitory activity of PAI-1 toward TPA. We propose that PAI-1, released f rom activated platelets, plays a key role thrombolysis resistance and/ or reocclusion after thrombolytic therapy. This is due to binding of P AI-1 to polymerized fibrin within the thrombus, followed by inhibition of TPA-mediated fibrinolysis.