2. Academic Validation
  3. Lipoprotein(a) prolongs ex vivo plasma clot lysis times through effects on clot formation rate and fibrin structure

Lipoprotein(a) prolongs ex vivo plasma clot lysis times through effects on clot formation rate and fibrin structure

  • J Thromb Haemost. 2025 Oct 31:S1538-7836(25)00674-9. doi: 10.1016/j.jtha.2025.10.009.
Justin R Clark 1,  Frances S Sutherland 2,  Julia M Assini 3,  Luke Daichedt 1,  Robert Szabla 2,  Murray W Junop 2,  Marlys L Koschinsky 4,  Michael B Boffa 5
Affiliations

Affiliations

  • 1 Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.
  • 2 Department of Biochemistry, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.
  • 3 Department of Biochemistry, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada; Robarts Research Institute, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.
  • 4 Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada; Robarts Research Institute, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada. Electronic address: [email protected].
  • 5 Department of Biochemistry, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada; Robarts Research Institute, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada. Electronic address: [email protected].
PMID: 41177455 DOI: 10.1016/j.jtha.2025.10.009
Abstract

Background: Elevated levels of lipoprotein(a) (Lp[a]) are a causal risk factor for atherosclerotic Cardiovascular Disease. Similarities between the Apolipoprotein(a) (apo[a]) component of Lp(a) and plasminogen suggest that antifibrinolytic properties may account for the pathological effects of Lp(a). However, the antifibrinolytic effects of apo(a) do not appear to be retained by the complete Lp(a) particle.

Objectives: We evaluated the effects of Lp(a), apo(a), and various apo(a) variants on clot formation and lysis times, Thrombin generation, plasminogen activation, and fibrin architectures in ex vivo plasma clots. We also constructed predictive protein models to gain insight into the apo(a)-plasminogen interaction.

Results: Apo(a) strongly inhibited fibrinolysis, an effect dependent on the presence of the apo(a) protease domain and mediated by Lys216 in this domain. Modeling of apo(a) suggests that Lys216 is blocked from binding to plasminogen in the Lp(a) particle by the presence of the apoB-containing lipoprotein. Lp(a) and apo(a) shortened plasma clot formation times, and accounting for this revealed a small but significant prolongation of fibrinolysis by Lp(a). The procoagulant effects involved the development of lysis-resistant clot architectures and were mediated through the strong lysine-binding site in apo(a) kringle IV type 10. In addition, Lp(a) (but not apo[a]) accelerated Thrombin generation.

Conclusions: The strong antifibrinolytic effects of apo(a) do not appear to be retained in the complete Lp(a) particle. However, Lp(a) and apo(a) displayed procoagulant effects, in part dependent on the kringle 4-like lysine-binding site. Further analysis is required to determine whether these reported procoagulant effects of Lp(a) impact thrombosis in vivo.

Keywords

apolipoprotein(a); coagulation; fibrinolysis; lipoprotein(a); plasminogen.

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