Tissue plasminogen activator (tPA) and urokinase (uPA) differ in their modes of action. Efficient tPA-mediated plasminogen activation requires binding to fibrin. In contrast, uPA is fibrin independent and activates plasminogen in solution or when associated with its cellular receptor uPAR. We have previously shown that polyphosphate (polyP), alters fibrin structure and attenuates tPA and plasminogen binding to fibrin, thereby down-regulating fibrinolysis. Here we investigate the impact of polyP on uPA-mediated fibrinolysis. As previously reported polyP of an average chain length of 65 (polyP65) delays tPA-mediated fibrinolysis. The rate of plasmin generation was also delayed and reduced 1.6-fold in polyP65-containing clots (0.74 ± 0.06 vs. 1.17 ± 0.14 pM/s in P < 0.05). Analysis of tPA-mediated fibrinolysis in real-time by confocal microscopy was significantly slower in polyP65-containing clots. In marked contrast, polyP65 augmented the rate of uPA-mediated plasmin generation 4.7-fold (3.96 ± 0.34 vs. 0.84 ± 0.08 pM/s; P < 0.001) and accelerated fibrinolysis (t1/2 64.5 ± 1.7 min vs. 108.2 ± 3.8 min; P < 0.001). Analysis of lysis in real-time confirmed that polyP65 enhanced uPA-mediated fibrinolysis. Varying the plasminogen concentration (0.125 to 1 μM) in clots dose-dependently enhanced uPA-mediated fibrinolysis, while negligible changes were observed on tPA-mediated fibrinolysis. The accelerating effect of polyP65 on uPA-mediated fibrinolysis was overcome by additional plasminogen, while the down-regulation of tPA-mediated lysis and plasmin generation was largely unaffected. PolyP65 exerts opposing effects on tPA- and uPA-mediated fibrinolysis, attenuating the fibrin cofactor function in tPA-mediated plasminogen activation. In contrast, polyP may facilitate the interaction between fibrin-independent uPA and plasminogen thereby accelerating plasmin generation and downstream fibrinolysis.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849561 | PMC |
| http://dx.doi.org/10.3324/haematol.2019.237966 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Regulation of macrophage fibrinolysis during venous thrombus resolution.
Thromb Res
November 2024
Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Research & Development Service, VA Maryland Health Care System, Baltimore, MD, 21201, USA. Electronic address:
Background: Venous thromboembolism (VTE), which includes pulmonary embolism (PE) and deep vein thrombosis (DVT), is a serious cardiovascular disease with significant mortality and morbidity. Clinically, patients with faster resolution of a venous thrombi have improved prognosis. Urokinase-plasminogen activator (uPA), produced by macrophages, is a key mediator of fibrinolysis required for resolving venous thrombi and restoring vascular integrity.
View Article and Find Full Text PDFTissue plasminogen activator (tPA) and urokinase (uPA) differ in their modes of action. Efficient tPA-mediated plasminogen activation requires binding to fibrin. In contrast, uPA is fibrin independent and activates plasminogen in solution or when associated with its cellular receptor uPAR.
View Article and Find Full Text PDFTAFI deficiency causes maladaptive vascular remodeling after hemophilic joint bleeding.
JCI Insight
October 2019
Deptartment of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA.
Excessive vascular remodeling is characteristic of hemophilic arthropathy (HA) and may contribute to joint bleeding and the progression of HA. Mechanisms for pathological vascular remodeling after hemophilic joint bleeding are unknown. In hemophilia, activation of thrombin-activatable fibrinolysis inhibitor (TAFI) is impaired, which contributes to joint bleeding and may also underlie the aberrant vascular remodeling.
View Article and Find Full Text PDFTranexamic acid mediates proinflammatory and anti-inflammatory signaling via complement C5a regulation in a plasminogen activator-dependent manner.
J Trauma Acute Care Surg
January 2019
From the Koch Institute for Integrative Cancer Research, Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts (C.D.B, Y-W.K, G.S., D.L., M.B.Y.); Division of Acute Care Surgery and Critical Care, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (C.D.B., M.B.Y.); Department of Surgery, University of Colorado Denver, Denver, Colorado (H.B.M., E.E.M.); Department of Radiology, University of Colorado Denver, Denver, Colorado (M.P.C.); and Department of Surgery, Denver Health Medical Center, Denver, Colorado (E.E.M.).
Background: Both tissue plasminogen activator (tPA) in the circulation and urokinase (uPA) in tissues cleave plasminogen (PLG) to plasmin to promote clot lysis. Tranexamic acid (TXA) blocks both the tPA-dependent generation of plasmin on blood clots as well as active plasmin binding to polymerized fibrin, and is commonly administered for bleeding in trauma to limit fibrinolysis. In addition to lysing clots, however, active plasmin also cleaves complement proteins, potentially enhancing inflammation.
View Article and Find Full Text PDFDefective TAFI activation in hemophilia A mice is a major contributor to joint bleeding.
Blood
October 2018
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA.
Joint bleeds are common in congenital hemophilia but rare in acquired hemophilia A (aHA) for reasons unknown. To identify key mechanisms responsible for joint-specific bleeding in congenital hemophilia, bleeding phenotypes after joint injury and tail transection were compared in aHA wild-type (WT) mice (receiving an anti-factor VIII [FVIII] antibody) and congenital HA (FVIII) mice. Both aHA and FVIII mice bled severely after tail transection, but consistent with clinical findings, joint bleeding was notably milder in aHA compared with FVIII mice.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!