Download PDF
Thromb Haemost 2025; 125(02): 120-129
DOI: 10.1055/a-2365-8601
Coagulation and Fibrinolysis

Serum Leucine Aminopeptidase Activity Patterns Across Various Disease States: Potential Implications for Bleeding and Thrombosis Risk

Sha Yu
1   Department of Obstetrics, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
2   Systems Biology and Medicine Center for Complex Diseases, The Affiliated Hospital of Qingdao University, Qingdao, China
,
Meng Zhang
2   Systems Biology and Medicine Center for Complex Diseases, The Affiliated Hospital of Qingdao University, Qingdao, China
3   Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Xi'an, China
,
Yachong Guo
4   Nanjing Drum Tower Hospital, Kuang Yaming Honors School, Nanjing University, Nanjing, China
,
Lijuan Zhang 
2   Systems Biology and Medicine Center for Complex Diseases, The Affiliated Hospital of Qingdao University, Qingdao, China
5   Department of Diagnosis, American Institute of Translational Medicine and Therapeutics, Missouri, United States
› Author Affiliations Funding This study was funded by the Ministry of Science and Technology of the People's Republic of China (2021ZD0201301, 11804151), Natural Science Foundation of Jiangsu Province BK20221437 and National Natural Science Foundation of China, (81672585).
› Further Information
Also available at
    Permissions and Reprints


Abstract

Background Disruptions in the pathways for activating and deactivating proteases in the bloodstream can lead to thrombosis and bleeding issues. Leucine aminopeptidases (LAPs), which are exopeptidases essential for regulating protein and peptide activities, are recognized as clinical biomarkers for liver diseases. However, the relationship between serum LAP activity and the risks of bleeding or thrombosis, as well as the identification of the specific tissues or organs that control LAP levels, is not well understood.

Methods We performed a retrospective study to evaluate serum LAP activities in 149,360 patients with 47 different diseases and 9,449 healthy individuals. The analysis was conducted using SPSS V2.6, RStudio V.1.3.1073, and libraries in Python 3.8.

Results Our research revealed that 21 of the 47 diseases studied showed increased median serum LAP activities, while 26 diseases were associated with significantly lower activities, especially those related to thrombosis. Furthermore, most diseases were found to have an increased risk of bleeding and thrombosis, indicated by higher Q25 and lower Q75 LAP activities compared to the control group. Receiver operating characteristic curve analysis confirmed the effectiveness of LAP activities as biomarkers for specific conditions like hepatic encephalopathy, liver cancer, pancreatitis, and pancreatic cancer. Diseases were categorized into clusters with similar bleeding or thrombotic tendencies through principal component analysis.

Conclusion This study highlighted regulatory influence of the liver and pancreas on LAP levels. The established link between serum LAP concentrations and the risk of bleeding or thrombosis paved the way for the development of diagnostic and preventative approaches for various medical conditions.

Keywords

biomarkers - leucine aminopeptidase (LAP) - area under the curve (AUC) - receiving operating characteristic (ROC) - principal component analysis

Supplementary Material



Publication History

Received: 27 February 2024

Accepted: 14 July 2024

Accepted Manuscript online:
15 July 2024

Article published online:
06 August 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Tsao CW, Aday AW, Almarzooq ZI. et al; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2023 Update: a report from the American Heart Association. Circulation 2023; 147 (08) e93-e621
    CrossrefPubMedSearch in Google Scholar
  • 2 Pan N, Wu Y, Yang B. et al. The liver and blood cells are responsible for creatine kinase clearance in blood Circulation: a retrospective study among different human diseases. Clin Chim Acta 2023; 544: 117335
    CrossrefPubMedSearch in Google Scholar
  • 3 Wu Y, Lu C, Pan N. et al. Serum lactate dehydrogenase activities as systems biomarkers for 48 types of human diseases. Sci Rep 2021; 11 (01) 12997
    CrossrefPubMedSearch in Google Scholar
  • 4 Bai C, Zhang M, Zhang Y. et al. Gamma-glutamyltransferase activity (GGT) is a long-sought biomarker of redox status in blood circulation: a retrospective clinical study of 44 types of human diseases. Oxid Med Cell Longev 2022; 2022: 8494076
    PubMedSearch in Google Scholar
  • 5 Wu Y, Pan N, An Y, Xu M, Tan L, Zhang L. Diagnostic and prognostic biomarkers for myocardial infarction. Front Cardiovasc Med 2021; 7: 617277
    CrossrefPubMedSearch in Google Scholar
  • 6 Tsujimoto M, Goto Y, Maruyama M, Hattori A. Biochemical and enzymatic properties of the M1 family of aminopeptidases involved in the regulation of blood pressure. Heart Fail Rev 2008; 13 (03) 285-291
    CrossrefPubMedSearch in Google Scholar
  • 7 Goto Y, Hattori A, Ishii Y, Tsujimoto M. Reduced activity of the hypertension-associated Lys528Arg mutant of human adipocyte-derived leucine aminopeptidase (A-LAP)/ER-aminopeptidase-1. FEBS Lett 2006; 580 (07) 1833-1838
    CrossrefPubMedSearch in Google Scholar
  • 8 Taylor A. Aminopeptidases: structure and function. FASEB J 1993; 7 (02) 290-298
    CrossrefPubMedSearch in Google Scholar
  • 9 Long AT, Kenne E, Jung R, Fuchs TA, Renné T. Contact system revisited: an interface between inflammation, coagulation, and innate immunity. J Thromb Haemost 2016; 14 (03) 427-437
    CrossrefPubMedSearch in Google Scholar
  • 10 Puy C, Pang J, Reitsma SE. et al. Cross-talk between the complement pathway and the contact activation system of coagulation: activated factor XI neutralizes complement factor H. J Immunol 2021; 206 (08) 1784-1792
    CrossrefPubMedSearch in Google Scholar
  • 11 Strukova S. Blood coagulation-dependent inflammation. Coagulation-dependent inflammation and inflammation-dependent thrombosis. Front Biosci 2006; 11: 59-80
    CrossrefPubMedSearch in Google Scholar
  • 12 Pan J, Qian Y, Weiser P. et al. Glycosaminoglycans and activated contact system in cancer patient plasmas. Prog Mol Biol Transl Sci 2010; 93: 473-495
    CrossrefPubMedSearch in Google Scholar
  • 13 Su M, Wei M, Zhou Z, Liu S. Application of capillary electrophoresis coupling with electrochemiluminescence detection to estimate activity of leucine aminopeptidas. Biomed Chromatogr 2013; 27 (07) 946-952
    CrossrefPubMedSearch in Google Scholar
  • 14 Xu S, Liu HW, Hu XX. et al. Visualization of endoplasmic reticulum aminopeptidase 1 under different redox conditions with a two-photon fluorescent probe. Anal Chem 2017; 89 (14) 7641-7648
    CrossrefPubMedSearch in Google Scholar
  • 15 Zhang W, Liu F, Zhang C. et al. Near-infrared fluorescent probe with remarkable large stokes shift and favorable water solubility for real-time tracking leucine aminopeptidase in living cells and in vivo. Anal Chem 2017; 89 (22) 12319-12326
    CrossrefPubMedSearch in Google Scholar
  • 16 Balamurugan TST, Chen GZ, Kumaravel S. et al. Electrochemical substrate for active profiling of cellular surface leucine aminopeptidase activity and drug resistance in cancer cells. Biosens Bioelectron 2020; 150: 111948
    CrossrefPubMedSearch in Google Scholar
  • 17 Sturgeon CM, Viljoen A. Analytical error and interference in immunoassay: minimizing risk. Ann Clin Biochem 2011; 48 (Pt 5): 418-432
    CrossrefPubMedSearch in Google Scholar
  • 18 Tate J, Ward G. Interferences in immunoassay. Clin Biochem Rev 2004; 25 (02) 105-120
    PubMedSearch in Google Scholar
  • 19 Huang S, Wu Y, Zeng F, Chen J, Wu S. A turn-on fluorescence probe based on aggregation-induced emission for leucine aminopeptidase in living cells and tumor tissue. Anal Chim Acta 2018; 1031: 169-177
    CrossrefPubMedSearch in Google Scholar
  • 20 Huang Y, Qi Y, Zhan C, Zeng F, Wu S. Diagnosing drug-induced liver injury by multispectral optoacoustic tomography and fluorescence imaging using a leucine-aminopeptidase-activated probe. Anal Chem 2019; 91 (13) 8085-8092
    CrossrefPubMedSearch in Google Scholar
  • 21 Milligan GW, Cooper MC. A study of standardization of variables in cluster analysis. J Classif 1988; 5: 181-204
    CrossrefPubMedSearch in Google Scholar
  • 22 Alter O, Brown PO, Botstein D. Singular value decomposition for genome-wide expression data processing and modeling. Proc Natl Acad Sci U S A 2000; 97 (18) 10101-10106
    CrossrefPubMedSearch in Google Scholar
  • 23 Gupta SK, Aziz M, Khan AA, Siddiqui MA, Ajmal MR. Prognostic significance of serum leucine aminopeptidase in myocardial infarction with left ventricular failure. J Assoc Physicians India 1987; 35 (11) 760-762
    PubMedSearch in Google Scholar
  • 24 Gupta SK, Aziz M, Khan AA, Mohsin S. Significance of serum leucine aminopeptidase in tumours of female genital tract. J Indian Med Assoc 1989; 87 (03) 68-70
    PubMedSearch in Google Scholar
  • 25 Aziz M, Gupta SK, Khan AA. Serum leucine aminopeptidase profile in cancers of gastro-intestinal tract with special reference to hepatic metastasis. J Indian Med Assoc 1990; 88 (06) 160-163
    PubMedSearch in Google Scholar
  • 26 Inokuma S, Setoguchi K, Ohta T, Matsuzaki Y, Yoshida A. Serum leucine aminopeptidase as an activity indicator in systemic lupus erythematosus: a study of 46 consecutive cases. Rheumatology (Oxford) 1999; 38 (08) 705-708
    CrossrefPubMedSearch in Google Scholar
  • 27 Garg LN, Yadav SP, Lal H. Serum leucine aminopeptidase in head and neck cancer. J Laryngol Otol 1994; 108 (08) 660-662
    CrossrefPubMedSearch in Google Scholar
  • 28 Zhang M, Liu Y, Zhang Y. et al. Fasting blood glucose to mannose ratio: a glycan-based systems biomarker differentiating health from 39 human diseases. Nat Med 2024
    PubMedSearch in Google Scholar
  • 29 Jarocki VM, Tacchi JL, Djordjevic SP. Non-proteolytic functions of microbial proteases increase pathological complexity. Proteomics 2015; 15 (5–6): 1075-1088
    CrossrefPubMedSearch in Google Scholar
  • 30 Cahan R, Axelrad I, Safrin M, Ohman DE, Kessler E. A secreted aminopeptidase of Pseudomonas aeruginosa. Identification, primary structure, and relationship to other aminopeptidases. J Biol Chem 2001; 276 (47) 43645-43652
    CrossrefPubMedSearch in Google Scholar
  • 31 Matsui M, Fowler JH, Walling LL. Leucine aminopeptidases: diversity in structure and function. Biol Chem 2006; 387 (12) 1535-1544
    CrossrefPubMedSearch in Google Scholar
  • 32 Hara M, Matsuura T, Kojima S. TGF-β LAP degradation products, a novel biomarker and promising therapeutic target for liver fibrogenesis. In: Nakao K, Minato N, Uemoto S. eds. Innovative Medicine: Basic Research and Development. Tokyo: Springer; 2015: 317-325 2015
    Search in Google Scholar
  • 33 Gong Q, Shi W, Li L, Ma H. Leucine aminopeptidase may contribute to the intrinsic resistance of cancer cells toward cisplatin as revealed by an ultrasensitive fluorescent probe. Chem Sci (Camb) 2016; 7 (01) 788-792
    CrossrefPubMedSearch in Google Scholar
  • 34 Dumnicka P, Maduzia D, Ceranowicz P, Olszanecki R, Drożdż R, Kuśnierz-Cabala B. The interplay between inflammation, coagulation and endothelial injury in the early phase of acute pancreatitis: clinical implications. Int J Mol Sci 2017; 18 (02) 354
    CrossrefPubMedSearch in Google Scholar
  • 35 Roullet S, Freyburger G, Labrouche S. et al. Hyperfibrinolysis during liver transplantation is associated with bleeding. Thromb Haemost 2015; 113 (05) 1145-1148
    Thieme ConnectPubMedSearch in Google Scholar
  • 36 Lisman T, Porte RJ. Pathogenesis, prevention, and management of bleeding and thrombosis in patients with liver diseases. Res Pract Thromb Haemost 2017; 1 (02) 150-161
    CrossrefPubMedSearch in Google Scholar
  • 37 Longstaff C, Kolev K. Basic mechanisms and regulation of fibrinolysis. J Thromb Haemost 2015; 13 (Suppl. 01) S98-S105
    CrossrefPubMedSearch in Google Scholar
  • 38 Sumaya W, Wallentin L, James SK. et al. Fibrin clot properties independently predict adverse clinical outcome following acute coronary syndrome: a PLATO substudy. Eur Heart J 2018; 39 (13) 1078-1085
    CrossrefPubMedSearch in Google Scholar
  • 39 Undas A, Ariëns RA. Fibrin clot structure and function: a role in the pathophysiology of arterial and venous thromboembolic diseases. Arterioscler Thromb Vasc Biol 2011; 31 (12) e88-e99
    CrossrefPubMedSearch in Google Scholar