Altered Platelet Function in Intrauterine Growth Restriction: A Cause or a Consequence of Uteroplacental Disease?

Abstract

Objective A limited number of platelet function studies in intrauterine growth restriction (IUGR) have yielded conflicting results. We sought to evaluate platelet reactivity in IUGR using a novel platelet aggregation assay.

Study Design Pregnancies with IUGR were recruited from 24 weeks' gestation (estimated fetal weight < 10th centile) and had platelet function testing performed after diagnosis. A modification of light transmission aggregometry created dose–response curves of platelet reactivity in response to multiple agonists at differing concentrations. Findings were compared with healthy third trimester controls. IUGR cases with a subsequent normal birth weight were analyzed separately.

Results In this study, 33 pregnancies retained their IUGR diagnosis at birth, demonstrating significantly reduced platelet reactivity in response to all agonists (arachidonic acid, adenosine diphosphate, collagen, thrombin receptor–activating peptide, and epinephrine) when compared with 36 healthy pregnancy controls (p < 0.0001). Similar results were obtained for cases demonstrating an increasing in utero growth trajectory. When IUGR preceded preeclampsia or gestational hypertension, platelet function was significantly reduced compared with normotensive IUGR.

Conclusion Using this comprehensive platelet assay, we have demonstrated a functional impairment of platelets in IUGR. This may reflect platelet-derived placental growth factor release. Further evaluation of platelet function may aid in the development of future platelet-targeted therapies for uteroplacental disease.

Keywords

platelet function - platelet reactivity - light transmission aggregometry - agonist - intrauterine growth restriction

• References

• 1 Redman CW, Sargent IL. Pre-eclampsia, the placenta and the maternal systemic inflammatory response—a review. Placenta 2003; 24 (Suppl A): S21-S27
• 2 Bujold E, Roberge S, Lacasse Y , et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol 2010; 116 (2 Pt 1) 402-414
• 3 Sato Y, Higuchi T, Yoshioka S, Tatsumi K, Fujiwara H, Fujii S. Trophoblasts acquire a chemokine receptor, CCR1, as they differentiate towards invasive phenotype. Development 2003; 130 (22) 5519-5532
• 4 Sato Y, Fujiwara H, Zeng BX, Higuchi T, Yoshioka S, Fujii S. Platelet-derived soluble factors induce human extravillous trophoblast migration and differentiation: platelets are a possible regulator of trophoblast infiltration into maternal spiral arteries. Blood 2005; 106 (2) 428-435
• 5 Barker DJ. Adult consequences of fetal growth restriction. Clin Obstet Gynecol 2006; 49 (2) 270-283
• 6 Manten GT, Sikkema MJ, Voorbij HA, Visser GH, Bruinse HW, Franx A. Risk factors for cardiovascular disease in women with a history of pregnancy complicated by preeclampsia or intrauterine growth restriction. Hypertens Pregnancy 2007; 26 (1) 39-50
• 7 Mylotte D, Foley D, Kenny D. Platelet function testing: methods of assessment and clinical utility. Cardiovasc Hematol Agents Med Chem 2011; 9 (1) 14-24
• 8 Trip MD, Cats VM, van Capelle FJ, Vreeken J. Platelet hyperreactivity and prognosis in survivors of myocardial infarction. N Engl J Med 1990; 322 (22) 1549-1554
• 9 Can MM, Kaymaz C, Can E , et al. Whole blood platelet aggregation failed to detect differences between preeclampsia and normal pregnancy. Platelets 2010; 21 (6) 496-497
• 10 Janes SL, Goodall AH. Flow cytometric detection of circulating activated platelets and platelet hyper-responsiveness in pre-eclampsia and pregnancy. Clin Sci (Lond) 1994; 86 (6) 731-739
• 11 Morrison R, Crawford J, MacPherson M, Heptinstall S. Platelet behaviour in normal pregnancy, pregnancy complicated by essential hypertension and pregnancy-induced hypertension. Thromb Haemost 1985; 54 (3) 607-611
• 12 Louden KA, Broughton Pipkin F, Heptinstall S, Fox SC, Mitchell JR, Symonds EM. Platelet reactivity and serum thromboxane B2 production in whole blood in gestational hypertension and pre-eclampsia. Br J Obstet Gynaecol 1991; 98 (12) 1239-1244
• 13 Norris LA, Gleeson N, Sheppard BL, Bonnar J. Whole blood platelet aggregation in moderate and severe pre-eclampsia. Br J Obstet Gynaecol 1993; 100 (7) 684-688
• 14 Greer IA, Calder AA, Walker JJ, Lunan CB, Tulloch I. Increased platelet reactivity in pregnancy-induced hypertension and uncomplicated diabetic pregnancy: an indication for antiplatelet therapy?. Br J Obstet Gynaecol 1988; 95 (11) 1204-1206
• 15 Nicolini U, Guarneri D, Gianotti GA, Campagnoli C, Crosignani PG, Gatti L. Maternal and fetal platelet activation in normal pregnancy. Obstet Gynecol 1994; 83 (1) 65-69
• 16 Gatti L, Tenconi PM, Guarneri D , et al. Hemostatic parameters and platelet activation by flow-cytometry in normal pregnancy: a longitudinal study. Int J Clin Lab Res 1994; 24 (4) 217-219
• 17 Harlow FH, Brown MA, Brighton TA , et al. Platelet activation in the hypertensive disorders of pregnancy. Am J Obstet Gynecol 2002; 187 (3) 688-695
• 18 Sheu JR, Hsiao G, Lin WY , et al. Mechanisms involved in agonist-induced hyperaggregability of platelets from normal pregnancy. J Biomed Sci 2002; 9 (1) 17-25
• 19 Norris LA, Sheppard BL, Burke G, Bonnar J. Platelet activation in normotensive and hypertensive pregnancies complicated by intrauterine growth retardation. Br J Obstet Gynaecol 1994; 101 (3) 209-214
• 20 Ahmed Y, Sullivan MH, Pearce JM, Elder MG. Changes in platelet function in pregnancies complicated by fetal growth retardation. Eur J Obstet Gynecol Reprod Biol 1991; 42 (3) 171-175
• 21 Missfelder-Lobos H, Teran E, Lees C, Albaiges G, Nicolaides KH. Platelet changes and subsequent development of pre-eclampsia and fetal growth restriction in women with abnormal uterine artery Doppler screening. Ultrasound Obstet Gynecol 2002; 19 (5) 443-448
• 22 Lees CC, Brown AS, Harrington KF, Beacon HJ, Martin JF, Campbell S. A cross-sectional study of platelet volume in healthy normotensive women with bilateral uterine artery notches. Ultrasound Obstet Gynecol 1997; 10 (4) 277-281
• 23 Piazze J, Gioia S, Cerekja A , et al. Doppler velocimetry alterations related to platelet changes in third trimester pregnancies. Platelets 2007; 18 (1) 11-15
• 24 Bednar B, Condra C, Gould RJ, Connolly TM. Platelet aggregation monitored in a 96 well microplate reader is useful for evaluation of platelet agonists and antagonists. Thromb Res 1995; 77 (5) 453-463
• 25 Burke N, Flood K, Murray A , et al. Platelet reactivity changes significantly throughout all trimesters of pregnancy compared with the nonpregnant state: a prospective study. Br J Obstet Gynaecol 2013; 120 (13) 1599-1604
• 26 Flood K, Peace A, Kent E , et al. Platelet reactivity and pregnancy loss. Am J Obstet Gynecol 2010; 203 (3) 281.e1-281.e5
• 27 Peace AJ, Egan K, Kavanagh GF , et al. Reducing intra-individual variation in platelet aggregation: implications for platelet function testing. J Thromb Haemost 2009; 7 (11) 1941-1943
• 28 Konijnenberg A, van der Post JA, Mol BW , et al. Can flow cytometric detection of platelet activation early in pregnancy predict the occurrence of preeclampsia? A prospective study. Am J Obstet Gynecol 1997; 177 (2) 434-442
• 29 Kim JH, Bae HY, Kim SY. Clinical marker of platelet hyperreactivity in diabetes mellitus. Diabetes Metab J 2013; 37 (6) 423-428
• 30 Rey E, Rivard GE. Is testing for aspirin response worthwhile in high-risk pregnancy?. Eur J Obstet Gynecol Reprod Biol 2011; 157 (1) 38-42
• 31 Stubbs TM, Lazarchick J, Van Dorsten JP, Cox J, Loadholt CB. Evidence of accelerated platelet production and consumption in nonthrombocytopenic preeclampsia. Am J Obstet Gynecol 1986; 155 (2) 263-265
• 32 Shanley DK, Kiely PA, Golla K , et al. Pregnancy-specific glycoproteins bind integrin αIIbβ3 and inhibit the platelet-fibrinogen interaction. PLoS ONE 2013; 8 (2) e57491
• 33 Italiano Jr JE, Richardson JL, Patel-Hett S , et al. Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood 2008; 111 (3) 1227-1233
• 34 Battinelli EM, Markens BA, Italiano Jr JE. Release of angiogenesis regulatory proteins from platelet alpha granules: modulation of physiologic and pathologic angiogenesis. Blood 2011; 118 (5) 1359-1369
• 35 Gourvas V, Dalpa E, Konstantinidou A, Vrachnis N, Spandidos DA, Sifakis S. Angiogenic factors in placentas from pregnancies complicated by fetal growth restriction (review). Mol Med Rep 2012; 6 (1) 23-27
• 36 Verheul HM, Hoekman K, Luykx-de Bakker S , et al. Platelet: transporter of vascular endothelial growth factor. Clin Cancer Res 1997; 3 (12 Pt 1) 2187-2190
• 37 Ma L, Perini R, McKnight W , et al. Proteinase-activated receptors 1 and 4 counter-regulate endostatin and VEGF release from human platelets. Proc Natl Acad Sci U S A 2005; 102 (1) 216-220
• 38 Carr DJ, Wallace JM, Aitken RP , et al. Uteroplacental adenovirus vascular endothelial growth factor gene therapy increases fetal growth velocity in growth-restricted sheep pregnancies. Hum Gene Ther 2014; 25 (4) 375-384
• 39 Cody F, Unterscheider J, Dicker P , et al. Intrauterine growth restriction–are you a grower or a shower?. Am J Obstet Gynecol 2014; 210 (1) S63
• 40 Kenny LC, Black MA, Poston L , et al. Early pregnancy prediction of preeclampsia in nulliparous women, combining clinical risk and biomarkers: the Screening for Pregnancy Endpoints (SCOPE) international cohort study. Hypertension 2014; 64 (3) 644-652
• 41 Jackson SP. The growing complexity of platelet aggregation. Blood 2007; 109 (12) 5087-5095