Bleeding, the most serious complication of
thrombolytic therapy with
tissue-type plasminogen activator (t-PA), is thought to result from lysis of
fibrin in
hemostatic plugs and from the systemic lytic state caused by unopposed
plasmin. One mechanism by which systemic
plasmin can impair hemostasis is by partially degrading
fibrinogen to
fragment X, a product that retains clottability but forms clots with reduced tensile strength that stimulate
plasminogen activation by t-PA more than
fibrin clots. The purpose of this study was to elucidate potential mechanisms by which
fragment X accelerates t-PA-mediated fibrinolysis. In the presence of t-PA, clots containing
fragment X were degraded faster than
fibrin clots and exhibited higher rates of
plasminogen activation. Although treatment with
carboxypeptidase B, an
enzyme that reduces
plasminogen binding to
fibrin, prolonged the lysis times of
fragment X and
fibrin clots, clots containing
fragment X still were degraded more rapidly. Furthermore,
plasmin or
trypsin also degraded clots containing
fragment X more rapidly than
fibrin clots, suggesting that this effect is largely independent of
plasminogen activation.
Fragment X-derived degradation products were not preferentially released by
plasmin from clots composed of equal concentrations of
fibrinogen and
fragment X, indicating that
fragment X does not constitute a preferential site for proteolysis. These data suggest that structural changes resulting from incorporation of
fragment X into clots promote their lysis. Thus, attenuation of
thrombolytic therapy-induced
fragment X formation may reduce the risk of
bleeding.