Prostaglandin E2 levels and platelet function are different in cord blood compared to adults

Axel Schlagenhauf; Harald Haidl; Bettina Leschnik; Hans-Joerg Leis; Akos Heinemann; Wolfgang Muntean

doi:10.1160/TH14-03-0218

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2015; 113(01): 97-106
DOI: 10.1160/TH14-03-0218

Cellular Haemostasis and Platelets

Schattauer GmbH

Prostaglandin E₂ levels and platelet function are different in cord blood compared to adults

Axel Schlagenhauf

¹Department of General Pediatrics and Adolescent Medicine, Medical University of Graz, Austria

,

Harald Haidl

¹Department of General Pediatrics and Adolescent Medicine, Medical University of Graz, Austria

,

Bettina Leschnik

¹Department of General Pediatrics and Adolescent Medicine, Medical University of Graz, Austria

,

Hans-Joerg Leis

²Research Unit of Osteology and Analytical Mass Spectrometry, Medical University of Graz, Austria

,

Akos Heinemann

³Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Austria

,

Wolfgang Muntean

¹Department of General Pediatrics and Adolescent Medicine, Medical University of Graz, Austria

› Author Affiliations

Abstract

Summary

Neonatal platelets support primary haemostasis and thrombin generation as well as adult platelets, despite observable hypoaggregability in vitro. High prostaglandin E₂ levels at accouchement could account for inhibited platelet function via the EP4 receptor. We set out to determine prostaglandin E₂ plasma levels in cord blood of healthy neonates and evaluate the impact of prostaglandin E₂ on platelet function in adult and cord blood samples. Prostaglandin E₂ plasma levels were measured in cord blood and venous adult blood using GC-MS. Impact of prostaglandin E₂ on platelet aggregation was measured by spiking cord blood and adult samples. Contributions of EP₃ and EP₄ receptors were evaluated using respective antagonists. Intracellular cAMP concentrations were measured using a commercial ELISA-kit. Prosta-glandin E₂ plasma levels were substantially higher in cord blood than in adult samples. Spiking with prostaglandin E₂ resulted in a slight but consistent reduction of platelet aggregation in adult blood, but response to PGE₂ was blunted in cord blood samples. Aggregation response of spiked adult samples was still higher than with non-spiked cord blood samples. Blockage of EP4 receptors resulted in improved platelet aggregation in adult platelets upon prostaglandin E₂ spiking, while aggregation in cord blood samples remained unaltered. Intracellular cAMP concentrations after preincubation with prostaglandin E₂ were only increased in adult samples. In conclusion, very high prosta -glandin E₂ concentrations in cord blood affect platelet function. This effect may partially explain neonatal platelet hypoaggregability. Peak levels of prostaglandin E₂ can potentially protect against birth stressinduced platelet activation.

Keywords

Cyclic AMP - neonate - prostaglandin E₂ - prostanoid receptor EP4 - platelet aggregation

Full Text

References

References
1 Michelson AD. Platelet function in the newborn. Semin Thromb Hemost 1998; 24: 507-512.
2 Israels SJ, Daniels M, McMillan EM. Deficient collagen-induced activation in the newborn platelet. Pediatr Res 1990; 27: 337-343.
3 Mull MM, Hathaway WE. Altered platelet function in newborns. Pediatr Res 1970; 04: 229-237.
4 Rajasekhar D, Kestin AS, Bednarek FJ. et al. Neonatal platelets are less reactive than adult platelets to physiological agonists in whole blood. Thromb Haemost 1994; 72: 957-963.
5 Patrick CH, Lazarchick J, Stubbs T. et al. Mean platelet volume and platelet distribution width in the neonate. Am J Pediatr Hematol Oncol 1987; 09: 130-132.
6 Kipper SL, Sieger L. Whole blood platelet volumes in newborn infants. J Pediatr 1982; 101: 763-766.
7 Simak J, Holada K, Janota J. et al. Surface expression of major membrane glyco-proteins on resting and TRAP-activated neonatal platelets. Pediatr Res 1999; 46: 445-449.
8 Wasiluk A. The expression of vWF receptor on newborn platelets. Med Sci Monit 2005; 11: R545-R548.
9 Hezard N, Potron G, Schlegel N. et al. Unexpected persistence of platelet hypo-reactivity beyond the neonatal period: a flow cytometric study in neonates, infants and older children. Thromb Haemost 2003; 90: 116-123.
10 Wasiluk A, Mantur M, Szczepański M. et al. The effect of gestational age on platelet surface expression of CD62P in preterm newborns. Platelets 2008; 19: 236-238.
11 Grosshaupt B, Muntean W, Sedlmayr P. Hyporeactivity of neonatal platelets is not caused by preactivation during birth. Eur J Pediatr 1997; 156: 944-948.
12 Nicolini U, Guarneri D, Gianotti GA. et al. Maternal and fetal platelet activation in normal pregnancy. Obstet Gynecol 1994; 83: 65-69.
13 Irken G, Mutafoglu Uysal K, Olgun N. et al. Platelet activation during the early neonatal period. Biol Neonate 1998; 73: 166-171.
14 Israels SJ, Cheang T, Roberston C. et al. Impaired signal tran SDuction in neonatal platelets. Pediatr Res 1999; 45: 687-691.
15 Gelman B, Setty BN, Chen D. et al. Impaired mobilisation of intracellular calcium in neonatal platelets. Pediatr Res 1996; 39: 692-696.
16 Corby DG, O’Barr TP. Decreased alpha-adrenergic receptors in newborn platelets: cause of abnormal response to epinephrine. Dev Pharmacol Ther 1981; 02: 215-225.
17 Weinstein MJ, Blanchard R, Moake JL. et al. Fetal and neonatal von Willebrand factor (vWF) is unusually large and similar to the vWF in patients with thrombotic thrombocytopenic purpura. Br J Haematol 1989; 72: 68-72.
18 Rehak T, Cvirn G, Gallistl S. et al. Increased shear stress- and ristocetin-induced binding of von Willebrand factor to platelets in cord compared with adult plasma. Thromb Haemost 2004; 92: 682-687.
19 Andrew M, Paes B, Bowker J. et al. Evaluation of an automated bleeding time device in the newborn. Am J Hematol 1990; 35: 275-277.
20 Boudewijns M, Raes M, Peeters V. et al. Evaluation of platelet function on cord blood in 80 healthy term neonates using the Platelet Function Analyser (PFA-100); shorter in vitro bleeding times in neonates than adults. Eur J Pediatr 2003; 162: 212-213.
21 Israels SJ, Cheang T, McMillan-Ward EM. et al. Evaluation of primary hemostasis in neonates with a new in vitro platelet function analyser. J Pediatr 2001; 138: 116-119.
22 Bernhard H, Rosenkranz A, Petritsch M. et al. Phospholipid content, expression and support of thrombin generation of neonatal platelets. Acta Paediatr 2009; 98: 251-255.
23 Schlagenhauf A, Schweintzger S, Birner-Gruenberger R. et al. Newborn platelets: lower levels of protease-activated receptors cause hypoaggregability to thrombin. Platelets 2010; 21: 641-647.
24 Echtler K, Stark K, Lorenz M. et al. Platelets contribute to postnatal occlusion of the ductus arteriosus. Nat Med 2010; 16: 75-82.
25 Coceani F, Baragatti B. Mechanisms for ductus arteriosus closure. Semin Perinatol 2012; 36: 92-97.
26 Smith GC. The pharmacology of the ductus arteriosus. Pharmacol Rev 1998; 50: 35-58.
27 Thorburn GD. The placenta, PGE2 and parturition. Early Hum Dev 1992; 29: 63-73.
28 Jones SA, Adamson SL, Bishai I. et al. Eicosanoids in third ventricular cerebrospinal fluid of fetal and newborn sheep. Am J Physiol 1993; 264: R135-R142.
29 Clyman RI. Mechanisms regulating the ductus arteriosus. Biol Neonate 2006; 89: 330-335.
30 Slomp J, van Munsteren JC, Poelmann RE. et al. Formation of intimal cushions in the ductus arteriosus as a model for vascular intimal thickening. An immunohistochemical study of changes in extracellular matrix components. Atherosclerosis 1992; 93: 25-39.
31 Clyman RI, Mauray F, Roman C. et al. Circulating prostaglandin E2 concentrations and patent ductus arteriosus in fetal and neonatal lambs. J Pediatr 1980; 97: 455-461.
32 Fabre JE, Nguyen M, Athirakul K. et al. Activation of the murine EP3 receptor for PGE2 inhibits cAMP production and promotes platelet aggregation. J Clin Invest 2001; 107: 603-610.
33 Philipose S, Konya V, Sreckovic I. et al. The prostaglandin E2 receptor EP4 is expressed by human platelets and potently inhibits platelet aggregation and thrombus formation. Arterioscler Thromb Vasc Biol 2010; 30: 2416-2423.
34 Smith JP, Haddad EV, Downey JD. et al. PGE2 decreases reactivity of human platelets by activating EP2 and EP4. Thromb Res 2010; 126: e23-e29.
35 Iyu D, Glenn JR, White AE. et al. The role of prostanoid receptors in mediating the effects of PGE(2) on human platelet function. Platelets 2010; 21: 329-342.
36 Leis HJ, Hohenester E, Gleispach H. et al. Measurement of prostaglandins, thromboxanes and hydroxy fatty acids by stable isotope dilution gas chromatography/mass spectrometry. Biomed Environ Mass Spectrom 1987; 14: 617-621.
37 Schlagenhauf A, Kozma N, Leschnik B. et al. Thrombin receptor levels in platelet concentrates during storage and their impact on platelet functionality. Transfusion 2012; 52: 1253-1259.
38 Jarvis GE. Platelet aggregation: turbidimetric measurements. Methods Mol Biol 2004; 272: 65-76.