Determinants of Fibrinolysis in Single Fibrin Fibers

Blood clot contraction differentially modulates internal and external fibrinolysis

“…There are several plausible mechanistic explanations for the impairment of external lysis (Fig. ): (i) the clot is less permeable to t‐PA and plasminogen and, perhaps less likely, to fibrin degradation products extruded during the contraction process; (ii) reduced surface area accessible to t‐PA; (iii) formation of dense unstructured fibrin–platelet aggregates ; (iv) increased fibrin network density ; (v) increased mechanical tension on individual fibrin fibers leading to greater stability ; (vi) t‐PA binding to fibrin outcompeting plasmin binding ; (vii) activation within the contracted clot of antifibrinolytic enzymes such as carboxypeptidases‐B and ‐N, which cleave off C‐terminal lysines from fibrin and thus limit the binding sites for t‐PA and plasminogen, preventing plasmin formation and fibrinolysis ; and (viii) depletion of t‐PA near the clot surface because of the lack of flow .…”

“…(v) increased mechanical tension on individual fibrin fibers leading to greater stability [17,60]; (vi) t-PA binding The parameters were determined from a fitting analysis using an exponential decay (see Methods for details). Statistical analysis of uncontracted compared to contracted clots was completed using a one-way ANOVA, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.…”

“…Lysis is also modulated by the inherent strain that develops during formation of the fibrin network, which augments the lysis of individual fibrin fibers . However, the application of strain to a preformed fibrin clot impedes lysis . The application of strain may also affect plasminogen binding and/or the propensity of fibers to elongate .…”