title: Zinc delays clot lysis by attenuating plasminogen activation and plasmin-mediated fibrin degradation.
abstract: Zinc circulates free in plasma at a concentration of 0.1-2 µM, but its levels increase locally when it is released from activated platelets. Although zinc influences many processes in haemostasis, its effect on fibrinolysis has not been thoroughly investigated. Using a fluorescent zinc-binding probe, we demonstrated that zinc binds tissue-type plasminogen activator (tPA) and plasmin with high affinity (Kd values of 0.2 µM), and surface plasmon resonance studies revealed that zinc binds fibrin with a Kd of 12.8 µM. Zinc had no effect on the affinity of plasminogen or plasmin for fibrin, but increased the affinity of tPA by two-fold. In the presence of 5 µM zinc, the catalytic efficiency of plasminogen activation by tPA was reduced by approximately two-fold, both in the absence or presence of fibrin. Zinc attenuated plasmin-mediated degradation of the fibrinogen alpha-chain by 43 %, but had no effect on trypsin degradation. tPA-mediated fibrin clot lysis was prolonged 2.5-fold by zinc in a concentration-dependent fashion, and tPA-mediated plasma clot lysis was attenuated by 1.5-fold. Therefore, our data indicate that zinc modulates fibrinolysis by attenuating tPA-mediated plasminogen activation and plasmin-induced fibrin degradation. These findings suggest that local release of zinc by platelets attenuates fibrinolysis.
authors: Sara J
authors: SJ
authors: Henderson
authors: Alan R
authors: AR
authors: Stafford
authors: Beverly A
authors: BA
authors: Leslie
authors: Paul Y
authors: PY
authors: Kim
authors: Nima
authors: N
authors: Vaezzadeh
authors: Ran
authors: R
authors: Ni
authors: James C
authors: JC
authors: Fredenburgh
authors: Jeffrey I. Weitz, Thrombosis and Atherosclerosis Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada, Tel.: +1 905 521 2100 ext. 40721, E-mail: weitzj@taari.ca.
authors: Jeffrey I
authors: JI
authors: Weitz
mesh_terms: D001792:Blood Platelets / Q000378:metabolism*; D002384:Catalysis; D004789:Enzyme Activation; D005337:Fibrin / Q000378:metabolism*; D005341:Fibrinolysin / Q000378:metabolism*; D005342:Fibrinolysis; D006801:Humans; D007700:Kinetics; D010958:Plasminogen / Q000378:metabolism*; D015539:Platelet Activation; D011485:Protein Binding; D059748:Proteolysis; D013050:Spectrometry, Fluorescence; D020349:Surface Plasmon Resonance; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*
chemical_list: D005337:Fibrin; D010958:Plasminogen; D014357:Trypsin; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D015032:Zinc
keywords: Zinc; fibrin; fibrinolysis; plasmin; plasminogen