Genomes and Genes
pregnancy associated plasma protein a
Summary: A product of the PLACENTA, and DECIDUA, secreted into the maternal circulation during PREGNANCY. It has been identified as an IGF binding protein (IGFBP)-4 protease that proteolyzes IGFBP-4 and thus increases IGF bioavailability. It is found also in human FIBROBLASTS, ovarian FOLLICULAR FLUID, and GRANULOSA CELLS. The enzyme is a heterotetramer of about 500-kDa.
- Stulc T, Malbohan I, Malik J, Fialova L, Soukupova J, Ceska R. Increased levels of pregnancy-associated plasma protein-A in patients with hypercholesterolemia: the effect of atorvastatin treatment. Am Heart J. 2003;146:E21 pubmed..PAPP-A may therefore not only reflect plaque instability but also serve as a marker of total atherosclerotic burden in asymptomatic subjects with hyperlipidemia. However, PAPP-A levels are not influenced by atorvastatin treatment. ..
- Spencer K, Cowans N, Chefetz I, Tal J, Meiri H. First-trimester maternal serum PP-13, PAPP-A and second-trimester uterine artery Doppler pulsatility index as markers of pre-eclampsia. Ultrasound Obstet Gynecol. 2007;29:128-34 pubmed..Further studies are required to establish the real value of PP-13 in first-trimester screening for pre-eclampsia. ..
- Cowans N, Spencer K. First-trimester ADAM12 and PAPP-A as markers for intrauterine fetal growth restriction through their roles in the insulin-like growth factor system. Prenat Diagn. 2007;27:264-71 pubmed..Further studies may elucidate if screening using such modalities can lead to new potential treatments for poorly growing fetuses. ..
- Iversen K, Teisner A, Teisner B, Kliem A, Thanning P, Grande P, et al. Pregnancy associated plasma protein A, a novel, quick, and sensitive marker in ST-elevation myocardial infarction. Am J Cardiol. 2008;101:1389-94 pubmed publisher..In the early stages of STEMI, PAPP-A seems to be a more sensitive marker of myocardial infarction than CKMB and troponin T. ..
- Miedema M, Conover C, MacDonald H, Harrington S, Oberg D, Wilson D, et al. Pregnancy-associated plasma protein-A elevation in patients with acute coronary syndrome and subsequent atorvastatin therapy. Am J Cardiol. 2008;101:35-9 pubmed..High-dose atorvastatin significantly decreased PAPP-A at 1 month and hs-CRP at 6 months in patients with verified CAD. Low-dose atorvastatin did not produce this effect. ..
- Spencer K, Yu C, Cowans N, Otigbah C, Nicolaides K. Prediction of pregnancy complications by first-trimester maternal serum PAPP-A and free beta-hCG and with second-trimester uterine artery Doppler. Prenat Diagn. 2005;25:949-53 pubmed..The combination of first trimester serum PAPP-A and uterine artery mean PI at 22-24 weeks improves the screening efficacy for the prediction of pre-eclampsia. ..
- Iversen K, Teisner A, Teisner B, Kliem A, Thanning P, Nielsen H, et al. Pregnancy associated plasma protein A, a potential marker for vulnerable plaque in patients with non-ST-segment elevation acute coronary syndrome. Clin Biochem. 2009;42:828-34 pubmed publisherTo describe the presence and time-related pattern of circulating pregnancy associated plasma protein A (PAPP-A) levels in patients with non ST-segment elevation acute coronary syndrome (NSTE-ACS)...
- Kwik M, Morris J. Association between first trimester maternal serum pregnancy associated plasma protein-A and adverse pregnancy outcome. Aust N Z J Obstet Gynaecol. 2003;43:438-42 pubmed..First trimester PAPP-A may be a useful tool for identifying pregnancies at risk of adverse fetal outcomes. ..
- Laigaard J, Sørensen T, Fröhlich C, Pedersen B, Christiansen M, Schiøtt K, et al. ADAM12: a novel first-trimester maternal serum marker for Down syndrome. Prenat Diagn. 2003;23:1086-91 pubmed..2% and a 1:400 risk cut-off was found by Monte Carlo estimation using ADAM12 and maternal age as screening markers. ADAM12 is a promising marker for Down syndrome. ..
- Tul N, Pusenjak S, Osredkar J, Spencer K, Novak Antolic Z. Predicting complications of pregnancy with first-trimester maternal serum free-betahCG, PAPP-A and inhibin-A. Prenat Diagn. 2003;23:990-6 pubmed..High inhibin-A is associated with preterm delivery before 34 weeks. Feto-placental products in the first trimester do not prove to be useful as a screening tool for predicting pregnancy complications. ..
- Spencer K, Cowans N, Chefetz I, Tal J, Kuhnreich I, Meiri H. Second-trimester uterine artery Doppler pulsatility index and maternal serum PP13 as markers of pre-eclampsia. Prenat Diagn. 2007;27:258-63 pubmed..Measuring between-trimester temporal changes may be worthy of further investigation. ..
- Miller B, Bronk J, Nishiyama T, Yamagiwa H, Srivastava A, Bolander M, et al. Pregnancy associated plasma protein-A is necessary for expeditious fracture healing in mice. J Endocrinol. 2007;192:505-13 pubmed..The ability of PAPP-A to enhance local IGF action may be an important mechanism for optimizing the fracture repair response. ..
- Smith G, Shah I, Crossley J, Aitken D, Pell J, Nelson S, et al. Pregnancy-associated plasma protein A and alpha-fetoprotein and prediction of adverse perinatal outcome. Obstet Gynecol. 2006;107:161-6 pubmedTo describe the association between pregnancy associated plasma protein A (PAPP-A), alpha-fetoprotein (AFP) and adverse perinatal outcome...
- Kavak Z, Basgul A, Elter K, Uygur M, Gokaslan H. The efficacy of first-trimester PAPP-A and free beta hCG levels for predicting adverse pregnancy outcome. J Perinat Med. 2006;34:145-8 pubmed..Even after optimization of cut-off values, these markers do not appear to be clinically acceptable as an effective tool for screening for adverse pregnancy outcomes. ..
- Goetzl L, Krantz D, Simpson J, Silver R, Zachary J, Pergament E, et al. Pregnancy-associated plasma protein A, free beta-hCG, nuchal translucency, and risk of pregnancy loss. Obstet Gynecol. 2004;104:30-6 pubmed..Normal values of PAPP-A, free beta-hCG, and nuchal translucency are associated with a very low risk of pregnancy loss at less than 20 weeks. ..
- Daponte A, Pournaras S, Zintzaras E, Kallitsaris A, Lialios G, Maniatis A, et al. The value of a single combined measurement of VEGF, glycodelin, progesterone, PAPP-A, HPL and LIF for differentiating between ectopic and abnormal intrauterine pregnancy. Hum Reprod. 2005;20:3163-6 pubmed..LIF, P, PAPP-A, HPL and GLY serum measurements did not differ significantly between EP and aIUP. VEGF serum levels might be a useful marker in differentiating between EPs and aIUPs. ..
- Jadlowiec J, Dongell D, Smith J, Conover C, Campbell P. Pregnancy-associated plasma protein-a is involved in matrix mineralization of human adult mesenchymal stem cells and angiogenesis in the chick chorioallontoic membrane. Endocrinology. 2005;146:3765-72 pubmed..Furthermore, PAPP-A is involved in the formation of new blood vessels, which is essential for proper bone regeneration. ..
- Barrett S, Bower C, Hadlow N. Use of the combined first-trimester screen result and low PAPP-A to predict risk of adverse fetal outcomes. Prenat Diagn. 2008;28:28-35 pubmed publisher..To investigate associations between combined first-trimester screen result, pregnancy associated plasma protein-A (PAPP-A) level and adverse fetal outcomes in women...
- Spencer K, Cowans N, Avgidou K, Nicolaides K. First-trimester ultrasound and biochemical markers of aneuploidy and the prediction of impending fetal death. Ultrasound Obstet Gynecol. 2006;28:637-43 pubmed..The likelihood ratio profiles provided at various levels of PAPP-A or free beta-hCG may be of some help in counseling women with such results and raise awareness among health-care professionals for increased surveillance in such cases. ..
- Canini S, Prefumo F, Pastorino D, Crocetti L, Afflitto C, Venturini P, et al. Association between birth weight and first-trimester free beta-human chorionic gonadotropin and pregnancy-associated plasma protein A. Fertil Steril. 2008;89:174-8 pubmed
- Dugoff L, Hobbins J, Malone F, Porter T, Luthy D, Comstock C, et al. First-trimester maternal serum PAPP-A and free-beta subunit human chorionic gonadotropin concentrations and nuchal translucency are associated with obstetric complications: a population-based screening study (the FASTER Trial). Am J Obstet Gynecol. 2004;191:1446-51 pubmed..Low free-beta subunit human chorionic gonadotropin levels and large nuchal translucency were both associated with early fetal loss. ..
- Gerton G, Fan X, Chittams J, Sammel M, Hummel A, Strauss J, et al. A serum proteomics approach to the diagnosis of ectopic pregnancy. Ann N Y Acad Sci. 2004;1022:306-16 pubmed
- Overgaard M, Haaning J, Boldt H, Olsen I, Laursen L, Christiansen M, et al. Expression of recombinant human pregnancy-associated plasma protein-A and identification of the proform of eosinophil major basic protein as its physiological inhibitor. J Biol Chem. 2000;275:31128-33 pubmed..Inhibition of PAPP-A by proMBP represents a novel inhibitory mechanism with the enzyme irreversibly bound to its inhibitor by disulfide bonds. ..
- Bersinger N, Smarason A, Muttukrishna S, Groome N, Redman C. Women with preeclampsia have increased serum levels of pregnancy-associated plasma protein A (PAPP-A), inhibin A, activin A and soluble E-selectin. Hypertens Pregnancy. 2003;22:45-55 pubmed..Raised levels of PAPP-A in preeclampsia confirm earlier reports. Activin A showed the highest increase over the controls and is thus likely to be a better serum marker for this pathology than the other markers that were tested. ..
- Qin Q, Laitinen P, Majamaa Voltti K, Eriksson S, Kumpula E, Pettersson K. Release patterns of pregnancy associated plasma protein A (PAPP-A) in patients with acute coronary syndromes. Scand Cardiovasc J. 2002;36:358-61 pubmedb>Pregnancy associated plasma protein A (PAPP-A) has recently been shown to be associated with acute coronary syndromes (ACS). The goal of this study was to investigate its release patterns in patients with ACS...
- Smith G, Stenhouse E, Crossley J, Aitken D, Cameron A, Connor J. Early pregnancy levels of pregnancy-associated plasma protein a and the risk of intrauterine growth restriction, premature birth, preeclampsia, and stillbirth. J Clin Endocrinol Metab. 2002;87:1762-7 pubmed..PAPP-A has been identified as a protease specific for IGF binding proteins. We conclude that control of the IGF system in the first and early second trimester trophoblast may have a key role in determining subsequent pregnancy outcome. ..
- Laursen L, Overgaard M, Søe R, Boldt H, Sottrup Jensen L, Giudice L, et al. Pregnancy-associated plasma protein-A (PAPP-A) cleaves insulin-like growth factor binding protein (IGFBP)-5 independent of IGF: implications for the mechanism of IGFBP-4 proteolysis by PAPP-A. FEBS Lett. 2001;504:36-40 pubmed..We thus conclude that IGF enhances proteolysis by binding to IGFBP-4, not by interaction with PAPP-A, which could not previously be ruled out. ..
- Lawrence J, Oxvig C, Overgaard M, Sottrup Jensen L, Gleich G, Hays L, et al. The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A. Proc Natl Acad Sci U S A. 1999;96:3149-53 pubmed..In conclusion, we have identified an IGF-dependent IGFBP protease and at the same time assigned a function to PAPP-A. This represents an unanticipated union of two areas of research that were not linked in any way before this report. ..
- Yaron Y, Heifetz S, Ochshorn Y, Lehavi O, Orr Urtreger A. Decreased first trimester PAPP-A is a predictor of adverse pregnancy outcome. Prenat Diagn. 2002;22:778-82 pubmed..30) and spontaneous miscarriage (RR = 3.78). We conclude that decreased levels of first trimester maternal serum PAPP-A are predictive not only of chromosome anomalies but also of adverse pregnancy outcome. ..
- Chen B, Overgaard M, Bale L, Resch Z, Christiansen M, Oxvig C, et al. Molecular regulation of the IGF-binding protein-4 protease system in human fibroblasts: identification of a novel inducible inhibitor. Endocrinology. 2002;143:1199-205 pubmed..These findings expand our understanding of the IGFBP-4 protease system and suggest an additional level of local cell growth control. ..
- Miyakoshi N, Qin X, Kasukawa Y, Richman C, Srivastava A, Baylink D, et al. Systemic administration of insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4) increases bone formation parameters in mice by increasing IGF bioavailability via an IGFBP-4 protease-dependent mechanism. Endocrinology. 2001;142:2641-8 pubmed..This study demonstrates that systemic administration of IGFBP-4 increases bone formation parameters in mice by increasing IGF bioavailability in the circulation via an IGFBP-4 protease-dependent mechanism. ..
- Heeschen C, Dimmeler S, Hamm C, Fichtlscherer S, Simoons M, Zeiher A. Pregnancy-associated plasma protein-A levels in patients with acute coronary syndromes: comparison with markers of systemic inflammation, platelet activation, and myocardial necrosis. J Am Coll Cardiol. 2005;45:229-37 pubmed..Simultaneous determination of biomarkers with distinct pathophysiological profiles appears to remarkably improve risk stratification in patients with ACS. ..
- Kagan K, Wright D, Baker A, Sahota D, Nicolaides K. Screening for trisomy 21 by maternal age, fetal nuchal translucency thickness, free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A. Ultrasound Obstet Gynecol. 2008;31:618-24 pubmed publisher..However, the cost of two-stage screening would be higher and, in addition, the potential advantage in terms of detection rate may be eroded by the likely increased non-compliance with the additional step. ..
- Morris R, Cnossen J, Langejans M, Robson S, Kleijnen J, Ter Riet G, et al. Serum screening with Down's syndrome markers to predict pre-eclampsia and small for gestational age: systematic review and meta-analysis. BMC Pregnancy Childbirth. 2008;8:33 pubmed publisher..Down's serum screening analytes have low predictive accuracy for pre-eclampsia and small for gestational age. They may be a useful means of risk assessment or of use in prediction when combined with other tests. ..
- Montanari L, Alfei A, Albonico G, Moratti R, Arossa A, Beneventi F, et al. The impact of first-trimester serum free beta-human chorionic gonadotropin and pregnancy-associated plasma protein A on the diagnosis of fetal growth restriction and small for gestational age infant. Fetal Diagn Ther. 2009;25:130-5 pubmed publisher..33) and 0.26 (95% CI 0.17-0.36), respectively. Low first-trimester maternal serum PAPP-A concentrations are significantly associated with reduced fetal size and increased risk of FGR with Doppler signs of impaired placental perfusion. ..
- Meloni P, D Angeli I, Piazze J, Cerekya A, Simari T, Pala A, et al. First trimester PAPP-A levels associated with early prediction of pregnancy induced hypertension. Hypertens Pregnancy. 2009;28:361-8 pubmed publisher..The purpose of this study was to determine the predictive value of maternal PAPP-A levels in the identification of women at risk of PIH...
- Cleary Goldman J, Berkowitz R. First trimester screening for Down syndrome in multiple pregnancy. Semin Perinatol. 2005;29:395-400 pubmed..Options for screening tests are limited. First trimester screening for Down syndrome in patients with multiples appears promising. This paper will review the advantages of first trimester screening in this high-risk patient population. ..
- Johns J, Muttukrishna S, Lygnos M, Groome N, Jauniaux E. Maternal serum hormone concentrations for prediction of adverse outcome in threatened miscarriage. Reprod Biomed Online. 2007;15:413-21 pubmed..Inhibin A was best at predicting the likelihood of subsequent miscarriage in this group. ..
- Body R, Ferguson C. Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. Pregnancy-associated plasma protein A: a novel cardiac marker with promise. Emerg Med J. 2006;23:875-7 pubmed
- Farina A, Sekizawa A, Purwosunu Y, Rizzo N, Banzola I, Concu M, et al. Quantitative distribution of a panel of circulating mRNA in preeclampsia versus controls. Prenat Diagn. 2006;26:1115-20 pubmed
- Hallahan T, Krantz D, Macri V, Shine T. First-trimester Down syndrome screening. Clin Chem. 2006;52:160-1; author reply 161 pubmed
- Lauzurica R, Pastor C, Bayes B, Hernandez J, Romero R. Pretransplant pregnancy-associated plasma protein-a as a predictor of chronic allograft nephropathy and posttransplant cardiovascular events. Transplantation. 2005;80:1441-6 pubmed..43-21.83; P=0.013) to be predictors of CAN. PAPP-A correlated with the inflammatory markers studied (CRP, IL-6 and TNF-alpha). Pretransplant serum concentration of PAPP-A is a predictor of posttransplant cardiovascular events and CAN. ..
- Thorn E, Khan I. Pregnancy-associated plasma protein-A: an emerging cardiac biomarker. Int J Cardiol. 2007;117:370-2 pubmed..The clinical validation will require a large and diverse patient population, a clearly defined and uniform diagnostic strategy, incorporation of multiple biomarkers in addition to PAPP-A, and measurement of outcomes data. ..
- Christians J, Hoeflich A, Keightley P. PAPPA2, an enzyme that cleaves an insulin-like growth-factor-binding protein, is a candidate gene for a quantitative trait locus affecting body size in mice. Genetics. 2006;173:1547-53 pubmed
- Liu S, Lee F, Lee J, Tsai M, Cheong M, She B, et al. Pregnancy outcomes in unselected singleton pregnant women with an increased risk of first-trimester Down's syndrome. Acta Obstet Gynecol Scand. 2004;83:1130-4 pubmed..05). Besides fetal chromosomal abnormalities and structural abnormalities, pregnancies with a positive screen for Down's syndrome in the first-trimester had a significantly higher incidence of subsequent adverse obstetric outcomes. ..
- Kavsak P, Wang X, Henderson M, Ko D, MacRae A, Jaffe A. PAPP-A as a marker of increased long-term risk in patients with chest pain. Clin Biochem. 2009;42:1012-8 pubmed publisher..02). Early measurement of PAPP-A may identify chest pain patients at higher risk for long-term death. Additional prospective ACS studies are required to fully elucidate PAPP-A's role. ..
- Spencer K, Staboulidou I, De Jesus Cruz J, Karagiannis G, Nicolaides K. Maternal serum screening marker levels in women with a previous aneuploidy pregnancy. Prenat Diagn. 2009;29:1242-3 pubmed publisher..Risk calculation algorithms may need to take account of the increased PAPP-A levels in women with a previous trisomy 21 or trisomy 13. ..
- Weyer K, Overgaard M, Laursen L, Nielsen C, Schmitz A, Christiansen M, et al. Cell surface adhesion of pregnancy-associated plasma protein-A is mediated by four clusters of basic residues located in its third and fourth CCP module. Eur J Biochem. 2004;271:1525-35 pubmed..This explains, at least in part, why PAPP-A2 lacks the ability of cell surface adhesion, and further emphasizes the role of the basic clusters defined in PAPP-A. ..
- Qin X, Wergedal J, Rehage M, Tran K, Newton J, Lam P, et al. Pregnancy-associated plasma protein-A increases osteoblast proliferation in vitro and bone formation in vivo. Endocrinology. 2006;147:5653-61 pubmed..Thus, enhancing IGF bioavailability by PAPP-A can be a powerful strategy in the treatment of certain metabolic diseases such as osteoporosis. ..
- Choi Y, Ku S, Jee B, Suh C, Choi Y, Kim J, et al. Comparison of follicular fluid IGF-I, IGF-II, IGFBP-3, IGFBP-4 and PAPP-A concentrations and their ratios between GnRH agonist and GnRH antagonist protocols for controlled ovarian stimulation in IVF-embryo transfer patients. Hum Reprod. 2006;21:2015-21 pubmed..However, the difference in microenvironment does not appear to result in a difference in clinical outcome. ..
- Boulvain M, Billieux M, Irion O. [Antenatal screening for Down syndrome: a smattering of epidemiology]. Rev Med Suisse. 2008;4:2276-8, 2280 pubmed..For women with an intermediate risk (1/380 to 1/1000), a genetic son gram allows a reassessement of the risk and may help couples to make a decision of invasive sampling. ..
- Krantz D, Hallahan T, James Macri V, Macri J. Statistical flaw in SURUSS model. Prenat Diagn. 2004;24:753-4 pubmed