Serpins in Hemostasis As Therapeutic Targets for Bleeding or Thrombotic Disorders

Overview

Journal Front Cardiovasc Med

Specialty Cardiology & Vascular Diseases

Date 2021 Jan 25

PMID 33490121

Citations 9

Authors

Elsa P Bianchini

Claire Auditeau

Mahita Razanakolona

Marc Vasse

Delphine Borgel

Affiliations

Soon will be listed here.

Abstract

Bleeding and thrombotic disorders result from imbalances in coagulation or fibrinolysis, respectively. Inhibitors from the serine protease inhibitor (serpin) family have a key role in regulating these physiological events, and thus stand out as potential therapeutic targets for modulating fibrin clot formation or dismantling. Here, we review the diversity of serpin-targeting strategies in the area of hemostasis, and detail the suggested use of modified serpins and serpin inhibitors (ranging from small-molecule drugs to antibodies) to treat or prevent bleeding or thrombosis.

Citing Articles

Multi-omic signatures of host response associated with presence, type, and outcome of enterococcal bacteremia.

Bayne C, McGrosso D, Sanchez C, Rossitto L, Patterson M, Gonzalez C mSystems. 2025; 10(2):e0147124.

PMID: 39835799 PMC: 11834471. DOI: 10.1128/msystems.01471-24.

A systematically investigation of plasma complement and coagulation-related proteins and adiponectin in gestational diabetes mellitus by multiple reaction monitoring technology.

Lin J, Liang Z, Liang Y, Cao X, Tang X, Zhuang H Acta Diabetol. 2025; .

PMID: 39821309 DOI: 10.1007/s00592-025-02451-0.

Economic Burden of Haemophilia from a Societal Perspective: A Scoping Review.

El-Sayed A, Bolous N Pharmacoecon Open. 2024; 9(2):179-205.

PMID: 39548037 PMC: 11865401. DOI: 10.1007/s41669-024-00540-4.

Molecular Characterization and Functional Analysis of a Serine Protease Inhibitor, Smserpin-p46.

Lee C, Hall B, Sanford L, Molehin A Microorganisms. 2024; 12(6).

PMID: 38930546 PMC: 11205507. DOI: 10.3390/microorganisms12061164.

Circulating Blood Prognostic Biomarker Signatures for Hemorrhagic Cerebral Cavernous Malformations (CCMs).

Croft J, Grajeda B, Aguirre L, Abou-Fadel J, Ellis C, Estevao I Int J Mol Sci. 2024; 25(9).

PMID: 38731959 PMC: 11084792. DOI: 10.3390/ijms25094740.

References

Opneja A, Kapoor S, Stavrou E . Contribution of platelets, the coagulation and fibrinolytic systems to cutaneous wound healing. Thromb Res. 2019; 179:56-63. PMC: 6556139. DOI: 10.1016/j.thromres.2019.05.001. View

Zhang J, Tu Y, Lu L, Lasky N, Broze Jr G . Protein Z-dependent protease inhibitor deficiency produces a more severe murine phenotype than protein Z deficiency. Blood. 2008; 111(10):4973-8. PMC: 2384128. DOI: 10.1182/blood-2007-12-126391. View

Polderdijk S, Adams T, Ivanciu L, Camire R, Baglin T, Huntington J . Design and characterization of an APC-specific serpin for the treatment of hemophilia. Blood. 2016; 129(1):105-113. PMC: 5305054. DOI: 10.1182/blood-2016-05-718635. View

Fortenberry Y . Plasminogen activator inhibitor-1 inhibitors: a patent review (2006-present). Expert Opin Ther Pat. 2013; 23(7):801-15. DOI: 10.1517/13543776.2013.782393. View

Al-Horani R . Serpin regulation of fibrinolytic system: implications for therapeutic applications in cardiovascular diseases. Cardiovasc Hematol Agents Med Chem. 2014; 12(2):91-125. DOI: 10.2174/1871525712666141106095927. View

Onishi A, St Ange K, Dordick J, Linhardt R . Heparin and anticoagulation. Front Biosci (Landmark Ed). 2016; 21(7):1372-92. DOI: 10.2741/4462. View

Schechter I, Berger A . On the size of the active site in proteases. I. Papain. Biochem Biophys Res Commun. 1967; 27(2):157-62. DOI: 10.1016/s0006-291x(67)80055-x. View

Quinsey N, Greedy A, Bottomley S, Whisstock J, Pike R . Antithrombin: in control of coagulation. Int J Biochem Cell Biol. 2003; 36(3):386-9. DOI: 10.1016/s1357-2725(03)00244-9. View

Hoffman M, Monroe D . Coagulation 2006: a modern view of hemostasis. Hematol Oncol Clin North Am. 2007; 21(1):1-11. DOI: 10.1016/j.hoc.2006.11.004. View

10.

Jalbert L, Rosen E, Moons L, Chan J, Carmeliet P, Collen D . Inactivation of the gene for anticoagulant protein C causes lethal perinatal consumptive coagulopathy in mice. J Clin Invest. 1998; 102(8):1481-8. PMC: 508997. DOI: 10.1172/JCI3011. View

11.

Han X, Fiehler R, Broze Jr G . Characterization of the protein Z-dependent protease inhibitor. Blood. 2000; 96(9):3049-55. View

12.

Spadarella G, Di Minno A, Milan G, Franco N, Polimeno M, Castaldo F . Paradigm shift for the treatment of hereditary haemophilia: Towards precision medicine. Blood Rev. 2019; 39:100618. DOI: 10.1016/j.blre.2019.100618. View

13.

Barbon E, Ayme G, Mohamadi A, Ottavi J, Kawecki C, Casari C . Single-domain antibodies targeting antithrombin reduce bleeding in hemophilic mice with or without inhibitors. EMBO Mol Med. 2020; 12(4):e11298. PMC: 7136963. DOI: 10.15252/emmm.201911298. View

14.

Huntington J . Mechanisms of glycosaminoglycan activation of the serpins in hemostasis. J Thromb Haemost. 2003; 1(7):1535-49. DOI: 10.1046/j.1538-7836.2003.00305.x. View

15.

Pautus S, Alami M, Adam F, Bernadat G, Lawrence D, de Carvalho A . Characterization of the Annonaceous acetogenin, annonacinone, a natural product inhibitor of plasminogen activator inhibitor-1. Sci Rep. 2016; 6:36462. PMC: 5120274. DOI: 10.1038/srep36462. View

16.

Izuhara Y, Yamaoka N, Kodama H, Dan T, Takizawa S, Hirayama N . A novel inhibitor of plasminogen activator inhibitor-1 provides antithrombotic benefits devoid of bleeding effect in nonhuman primates. J Cereb Blood Flow Metab. 2010; 30(5):904-12. PMC: 2949193. DOI: 10.1038/jcbfm.2009.272. View

17.

Van De Craen B, Declerck P, Gils A . The Biochemistry, Physiology and Pathological roles of PAI-1 and the requirements for PAI-1 inhibition in vivo. Thromb Res. 2012; 130(4):576-85. DOI: 10.1016/j.thromres.2012.06.023. View

18.

Hirsh J, Bauer K, Donati M, Gould M, Samama M, Weitz J . Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008; 133(6 Suppl):141S-159S. DOI: 10.1378/chest.08-0689. View

19.

Boulaftali Y, Adam F, Venisse L, Ollivier V, Richard B, Taieb S . Anticoagulant and antithrombotic properties of platelet protease nexin-1. Blood. 2009; 115(1):97-106. DOI: 10.1182/blood-2009-04-217240. View

20.

Bauer K, Hawkins D, Peters P, Petitou M, Herbert J, van Boeckel C . Fondaparinux, a synthetic pentasaccharide: the first in a new class of antithrombotic agents - the selective factor Xa inhibitors. Cardiovasc Drug Rev. 2002; 20(1):37-52. DOI: 10.1111/j.1527-3466.2002.tb00081.x. View