Incorporation of fragment X into fibrin clots renders them more susceptible to lysis by plasmin.
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.
Schaefer
Amy V L
AV
Department of Medicine, McMaster University, Hamilton, Ontario L8V 1C3, Canada.
Leslie
Beverly A
BA
Rischke
Janice A
JA
Stafford
Alan R
AR
Fredenburgh
James C
JC
Weitz
Jeffrey I
JI
D001777:Blood Coagulation / Q000187:drug effects; D043424:Carboxypeptidase B / Q000378:metabolism; D004789:Enzyme Activation; D005337:Fibrin / Q000502:physiology; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism*; D005341:Fibrinolysin / Q000494:pharmacology*; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D010446:Peptide Fragments / Q000096:biosynthesis; D010958:Plasminogen / Q000096:biosynthesis / Q000378:metabolism
D005338:Fibrin Fibrinogen Degradation Products; D010446:Peptide Fragments; C030568:fibrinogen fragment X; C018998:lysyl-plasminogen; D005337:Fibrin; D010958:Plasminogen; D043424:Carboxypeptidase B; D005341:Fibrinolysin