Pregnancy associated plasma protein-A2 (PAPP-A2) is a novel metalloproteinase identified as a homolog of PAPP-A in the metzincin superfamily of pappalysins1-8. PAPP-A2 shares 46% sequence identity with PAPP-A3. PAPP-A2 is a noncovalently linked dimer of two 220-kDa subunits. It exhibits robust proteolytic activity against IGFBP-5 and possibly also IGFBP-3 3, 8. PAPP-A2 is expressed in a wide range of tissues and is abundant in placental syncytiotrophoblasts and the pregnant uterus3. The physiological importance of PAPP-A2 is not known.

References:
1. Bulut I, Coskun A, Ciftci A et al. Relationship between Pregnancy-associated plasma protein A and lung cancer. The American Journal of the Medical sciences. April 2009; 337 (4): 241-244
2. Schindler AM and Bischof B. Histochemical localization of pregnancy associated plasma protein-A in fetal, infant, and adult organs and camparison between sntisera. Gynecol Obstet Invest 1984; 18: 88-94.
3. Overgaard MT, Oxvig C, Christiansen M , et al. Messenger ribonucleic acid levels of pregnancy-associated plasma protein-A and the preform of eosinophil major basic protein: expression in human reproductive and nonreproductive tissue. Biol Reprod 1999; 61:1083-1089.
4. Fialova L, Kalousova M, Soukupova J, et. al. Relationship of pregnancy associated plasma protein A to renal function and dialysis modalities. Kidney Blood Press Res 2004; 27: 88-95.
5. Coskum A, Balbay O, Duran S et al. Pregnancy-associated plasma protein A and asthama. Adv Ther 2007; 24: 362-367.
6. Coskum A, Duran S, Apaydin S, et al. Pregnancy-associated plasma protein A: evaluation of a new biomarker in renal transplanted patients. Transplant Proc 2007; 39:3072-3076.
7. Bayes-Genis A, Conover CA, Overgaard MT, et al. Pregnancy-associated plasma protein A as a marker of acute coronary syndromes. N Engl J Med 2001; 345: 1022-1029.
8. Overgaard MT, Boldt HB, Laursen LS, Sottrup-Jensen L, Conover CA, Oxvig C. Pregnancy-associated plasma protein-A2 (PAPP-A2), a novel insulin-like growth factor-binding protein-5 proteinase. J Biol Chem 2001; 276:21849-21853.
9. HHS Publication, 5th ed., 2007. Biosafety in Microbiological and Biomedical Laboratories. Available http://www.cdc.gov/biosafety/publications/bmbl5/BMBL5
10. DHHS (NIOSH) Publication No. 78–127, August 1976. Current Intelligence Bulletin 13 – Explosive Azide Hazard. Available http:// www.cdc.gov/niosh.
11. Approved Guideline – Procedures for the Handling and Processing of Blood Specimens, H18-A3. 2004. Clinical and Laboratory Standards Institute.
12. Kricka L. Interferences in immunoassays – still a threat. Clin Chem 2000; 46: 1037–1038.

PAPP-A2
PAPP-A2 CLIA AL-209
Kalra B, Kumar A, Tran A, Oxvig C. Development of a well characterized PAPP-A2 chemiluminescence assay to measure PAPP-A2 in maternal biological fluids. Poster session presented at American Association for Clinical Chemistry; 2012 Jul 16-19; Los Angeles, CA.

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PAPP-A2 ELISA AL-109
Babiker A, Al Noaim K, Al Swaid A, et al. Short stature with low insulin-like growth factor 1 availability due to pregnancy-associated plasma protein A2 deficiency in a Saudi family. Clin Genet. 2021;100(5):601-606. doi: 10.1111/cge.14030.

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Cabrera-Salcedo C, Mizuno T, Tyzinski L, Andrew M, Vinks AA, Frystyk J, Wasserman H, Gordon CM, Hwa V, Backeljauw P, Dauber A. Pharmacokinetics of IGF-1 in PAPP-A2-Deficient Patients, Growth Response, and Effects on Glucose and Bone Density. J Clin Endocrinol Metab. 2017 Dec 1;102(12):4568-4577.

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Dauber A, et al. Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability. EMBO Mol Med. 2016 Mar 31;8(4):363-74.

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Dereke J, Nilsson C, Strevens H, Landin-Olsson M, Hillman M. Pregnancy-associated plasma protein-A2 levels are increased in early-pregnancy gestational diabetes: a novel biomarker for early risk estimation. Diabet Med. 2020 Jan;37(1):131-137. doi: 10.1111/dme.14088. Epub 2019 Aug 14.

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DiPrisco B, Kumar A, Kalra B, Savjani GV, Michael Z, Farr O, Papathanasiou AE, Christou H, Mantzoros C. Placental proteases PAPP-A and PAPP-A2, the binding proteins they cleave (IGFBP-4 and -5), and IGF-I and IGF-II: Levels in umbilical cord blood and associations with birth weight and length. Metabolism. 2019 Nov;100:153959. doi: 10.1016/j.metabol.2019.153959. Epub 2019 Aug 8.

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Espelund US, Bjerre M, Hjortebjerg R, Rasmussen TR, Lundby A, Hoeflich A, Folkersen BH, Oxvig C, Frystyk J. Insulin-Like Growth Factor Bioactivity, Stanniocalcin-2, Pregnancy-Associated Plasma Protein-A, and IGF-Binding Protein-4 in Pleural Fluid and Serum From Patients With Pulmonary Disease. J Clin Endocrinol Metab. 2017 Sep 1;102(9):3526-3534.

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Fought AJ, Kuhn K, Schauer IE, Zhang H, D’Alessandro A. Maternal obesity in early pregnancy is associated with decreased active IGF-I availability and increased leptin concentrations. J Endocr Soc. 2019;3(Supplement_1). doi:10.1210/js.2019-SAT-LB045.

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Frystyk J, Teran E, Gude MF, Bjerre M, Hjortebjerg R. Pregnancy-associated plasma proteins and Stanniocalcin-2 – Novel players controlling IGF-I physiology. Growth Horm IGF Res. 2020 Aug-Oct;53-54:101330. doi: 10.1016/j.ghir.2020.101330. Epub 2020 Jul 4. PMID: 32693362.

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Fujimoto M, Khoury JC, Khoury PR, Kalra B, Kumar A, Sluss P, Oxvig C, Hwa V, Dauber A. Anthropometric and biochemical correlates of PAPP-A2, free IGF-I, and IGFBP-3 in childhood. European journal of endocrinology, 182(3), 363–374. https://doi.org/10.1530/EJE-19-0859

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Hansen YB, Myrhøj V, Jørgensen FS, Oxvig C, Sørensen S. First trimester PAPP-A2, PAPP-A and hCGβ in small-for-gestational-age pregnancies. Clin Chem Lab Med. 2016 Jan;54(1):117-23. doi: 10.1515/cclm-2015-0230. PMID: 26544105.

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Hjortebjerg R, Espelund U, Rasmussen TR, Folkersen B, Steiniche T, Georgsen JB, Oxvig C, Frystyk J. Pregnancy-Associated Plasma Protein-A2 Is Associated With Mortality in Patients With Lung Cancer. Front Endocrinol (Lausanne). 2020 Sep 2;11:614. doi: 10.3389/fendo.2020.00614. PMCID: PMC7492290.

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Hjortebjerg R, Høgdall C, Hansen KH, Høgdall E, Frystyk J. The IGF–PAPP-A–Stanniocalcin axis in serum and ascites associates with prognosis in patients with ovarian cancer. Int J Mol Sci. 2024;25(2014):1-16. doi:10.3390/ijms25042014.

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Kalra B, Kumar A, Tran A, Oxvig C, Shah S. Development of a well characterized PAPP-A2 ELISA to measure PAPP-A2 in maternal biological fluids. Poster session presented at the 94th Annual Endocrine Society Meeting; 2012 Jun 23-26; Houston, TX.

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Keikkala E, Forstén J, Ritvos O, Stenman UH, Kajantie E, Hämäläinen E, Räikkönen K, Villa PM, Laivuori H. Serum Inhibin-A and PAPP-A2 in the prediction of pre-eclampsia during the first and second trimesters in high-risk women. Pregnancy Hypertens: . 2021 Aug;25:116-122.doi: 10.1016/j.preghy.2021.05.024. Epub 2021 Jun 2.

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Kloverpris S, Gaidamauskas E, Rasmussen LCV, Overgaard MT, Kronborg C, Knudsen UB, Christiansen M, Kumar A, Oxvig C. A robust immunoassay for pregnancy-associated plasma protein-A2 based on analysis of circulating antigen: Establishment of normal ranges in pregnancy. Mol. Hum. Reprod. first published online June 25, 2013.

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Kumar A, Kalra B, Patel AS, Kommareddy V, Savjani G, Nagalla S. Novel Biochemical Markers Help Aid in Stratifying Patients at Risk of Preeclampsia and Adverse Events. Poster presented at AACC Meeting; 2018 July 30-Aug 2; Chicago, IL

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Munnangi S, Gross S, Madankumar R, Salcedo G, Reznik S. Pregnancy associated plasma protein-A2: A novel biomarker for down syndrome. Placenta. 35 (2014): 900-906.

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Neuman RI, Alblas van der Meer MM, Nieboer D, Saleh L, Verdonk K, Kalra B, Kumar A, Alpadi K, van den Meiracker AH, Visser W, Danser AHJ. PAPP-A2 and Inhibin A as Novel Predictors for Pregnancy Complications in Women With Suspected or Confirmed Preeclampsia. J Am Heart Assoc. 2020 Oct 20;9(19):e018219. doi: 10.1161/JAHA.120.018219. Epub 2020 Sep 29. PMID: 32990126.

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Neuman RI, Alblas van der Meer MM, Nieboer D, Saleh L, Verdonk K, Kalra B, Kumar A, Alpadi K, van den Meiracker AH, Visser W, Danser AHJ. PAPP-A2 and Inhibin A as Novel Predictors for Pregnancy Complications in Women With Suspected or Confirmed Preeclampsia. J Am Heart Assoc. 2020 Oct 20;9(19):e018219. doi: 10.1161/JAHA.120.018219. Epub 2020 Sep 29. PMID: 32990126.

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Nimptsch K, Aydin EE, Chavarria RFR, Janke J, Poy MN, Oxvig C, Steinbrecher A, Pischon T. Pregnancy-associated plasma protein-A2 (PAPP-A2) and stanniocalcin-2 (STC2), but not PAPP-A, are associated with circulating total IGF-1 in a human adult population. Sci Rep. 2024;14:1770. doi:10.1038/s41598-024-52074-8.

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Parry S, McCarthy C, Devine A, Leite R. Markers of placental dysfunction and spontaneous preterm birth. Amer Jour Obst Gyne, January 2020, Volume 222, Issue 1, Supplement S1-S760 (SMFM 40th Annual Meeting–The Pregnancy Meeting)

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Steinbrecher A, Janke J, Poy MN, Oxvig C, Pischon T. Pregnancy-Associated Plasma Protein-A2 and Anthropometry, Lifestyle, and Biochemical Factors in a Human Adult Population. Sci Rep. 2017 Sep 5;7(1):10455.

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Wang J, Hu H, Liu X, Zhao S, Zheng Y, Jia Z, Chen L, Zhang C, Xie X, Zhong J, Dong Y, Liu J, Lu Y, Zhao Z, Zhai Y, Zhao J, Cao Z. Predictive values of various serum biomarkers in women with suspected preeclampsia: A prospective study. J Clin Lab Anal. 2021 May;35(5):e23740. doi: 10.1002/jcla.23740. Epub 2021 Feb 22

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