Download PDF
Thromb Haemost 1996; 75(02): 346-351
DOI: 10.1055/s-0038-1650272
Original Article
Schattauer GmbH Stuttgart

Platelet Reactivity In Vitro in Relation to Thromboxane in Healthy Pregnancy

E H Horn
The Divisions of Therapeutics and Cardiovascular Medicine, University Hospital, Nottingham, UK
,
E Hardy
The Divisions of Therapeutics and Cardiovascular Medicine, University Hospital, Nottingham, UK
,
J Cooper
The Divisions of Therapeutics and Cardiovascular Medicine, University Hospital, Nottingham, UK
,
S Heptinstall
The Divisions of Therapeutics and Cardiovascular Medicine, University Hospital, Nottingham, UK
,
P C Rubin
The Divisions of Therapeutics and Cardiovascular Medicine, University Hospital, Nottingham, UK
› Author Affiliations
Further Information

Publication History

Received: 13 June 1995

Accepted after revision06 November 1995

Publication Date:
27 July 2018 (online)

Also available at
  PDF Download  Permissions and Reprints

Summary

There is substantial evidence of increased platelet reactivity in vivo and in vitro during pregnancy. Previous in vitro studies suggest that platelets from pregnant women show increased sensitivity to agonists, the response to which has a thromboxane dependent component. The aim of this study was to determine whether this is due to increased activity of the thromboxane biosynthetic pathway or to increased platelet sensitivity to the effects of thromboxane. During pregnancy, platelets were more sensitive to the pro-aggregatory effects in vitro of the thromboxane mimetic U46619, in whole blood and in platelet rich plasma, compared to those from non-pregnant controls. The difference in extent of U46619-induced platelet aggregation between groups was abolished in the presence of a high concentration of the specific thromboxane antagonist ICI 192605, but not by prior incubation of blood with aspirin. Platelets from pregnant women were significantly less sensitive to inhibition of arachidonic acid induced activation by the thromboxane synthetase inhibitor dazmegrel, but there was no change in platelet cyclic AMP accumulation under these conditions. Arachidonic acid induced platelet thromboxane B2 production was similar in pregnant and non-pregnant subjects. In conclusion, platelets are more sensitive to the activating effects of thromboxane during pregnancy, but there is no change in the intrinsic reactivity of the thromboxane biosynthetic pathway.

 

  • References

  • 1 Fay RA, Hughes AO, Hughes O, Farron NT. Platelets in pregnancy: Hyperdestruction in Pregnancy. Obstet Gynecol 1983; 61 (02) 238-240
    PubMedSearch in Google Scholar
  • 2 Douglas JT, Shah M, Lowe GDO, Belch JJF, Forbes CD, Prentice CRM. Plasma fibrinopeptide A and Beta-thromboglobulin in pre-eclampsia and pregnancy hypertension. Thromb Haemost 1982; 47 (01) 54-55
    PubMedSearch in Google Scholar
  • 3 Fitzgerald DJ, Mayo G, Catella F, Entman SS, Fitzgerald GA. Increased thromboxane biosynthesis in normal pregnancy is mainly derived from platelets. Am J Obstet Gynecol 1987; 157 (02) 325-330
    CrossrefPubMedSearch in Google Scholar
  • 4 Forbes CD, Greer IA. Physiology of haemostasis and the effect of pregnancy. In: Haemostasis and thrombosis in obstetrics and gynaecology Greer IA, Turpie AGG, Forbes CD. eds London: Chapman & Hall Medical; 1992: 1-25
  • 5 Redman CWG. Platelets and the beginnings of preeclampsia. Lancet 1990; 478-480
    PubMedSearch in Google Scholar
  • 6 Andrews NP, Broughton PipkinF, Heptinstall S. Blood platelet behaviour in mothers and neonates. Thromb Haemost 1985; 53: 428-432
    Thieme ConnectPubMedSearch in Google Scholar
  • 7 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: 607-611
    Thieme ConnectPubMedSearch in Google Scholar
  • 8 Yamazaki H, Motomiya T, Kikutani N, Sakakibara C, Watanabe S, Numa-ta M, Noguchi K. Platelet aggregation during menstrual cycle and pregnancy. Thromb Res 1979; 14 (02) 333-340
    CrossrefPubMedSearch in Google Scholar
  • 9 Louden KA, Broughton PipkinF, Heptinstall S, Fox SC, Mitchell JRA, Sy-monds EM. A longitudinal study of platelet behaviour and thromboxane production in whole blood in normal pregnancy and the puerperium. Br J Obstet Gynaecol 1990; 97: 1108-1114
    CrossrefPubMedSearch in Google Scholar
  • 10 Charo IF, Feinman RO, Detwiler TC. Interrelations of platelet aggregation and secretion. J Clin Invest 1977; 60: 866-873
    CrossrefPubMedSearch in Google Scholar
  • 11 Huang EM, Detwiler TC. Stimulus-response coupling mechanisms. In: Biochemistry of Platelets Phillips DR, Shuman MA. (eds) London: Academic Press Inc.; 1986: 1-68
  • 12 Moncada S, Vane JR. Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2and prostacyclin. Pharmacol Rev 1979; 30 (03) 293-331
    PubMedSearch in Google Scholar
  • 13 Louden KA, Broughton PipkinF, Symonds EM, Tuohy P, O’Callaghan C, Heptinstall S, Fox S, Mitchell JRA. A randomized placebo-controlled study of the effect of low dose aspirin on platelet reactivity and serum thromboxane B2 production in non pregnant women, in normal pregnancy, and in gestational hypertension. Br J Obst Gynaecol 1992; 99: 371-376
    CrossrefPubMedSearch in Google Scholar
  • 14 Ylikorkala O, Viinikka L. Thromboxane A2 in pregnancy and puerperium. Br Med J 1980; 281: 1601-1602
    CrossrefPubMedSearch in Google Scholar
  • 15 Pekonen F, Rasi V, Ammala M, Viinikka L, Ylikorkala O. Platelet function and coagulation in normal and pre-eclamptic pregnancy. Thromb Res 1986; 43: 553-560
    CrossrefPubMedSearch in Google Scholar
  • 16 Horn EH, Cooper J, Hardy E, Heptinstall S, Rubin PC. A cross sectional study of platelet cyclic AMP in healthy and hypertensive pregnancy. Clin Science 1991; 80: 549-558
    PubMedSearch in Google Scholar
  • 17 Sills T, Heptinstall S. Effects of a thromboxane synthetase inhibitor and cAMP phosphodiesterase inhibitor, singly and in combination on platelet behaviour. Thromb Haemost 1986; 55: 305-308
    Thieme ConnectPubMedSearch in Google Scholar
  • 18 Bertele V, Falanga A, Tomasiak M, Cerletti C, de Gaetano G. SQ22536, an adenylate cyclase inhibitor prevents the antiplatelet effect of dazoxiben, a thromboxane synthetase inhibitor. Thromb Haemost 1984; 51: 125-128
    Thieme ConnectPubMedSearch in Google Scholar
  • 19 Blockmans D, Gresele P, Deckmyn H, Vermylen J. Responder-nonrespon-der behaviour of human platelets towards thromboxane synthase inhibitors (TSI) is due to differences in adenylate cyclase sensitivity. Thromb Haemost 1985; 54: 114
    PubMedSearch in Google Scholar
  • 20 Bertele V, Falanga A, Tomasiak M, Chiabrando c, Cerletti C, de Gaetano G. Pharmacological inhibition of thromboxane synthetase and platelet aggregation: modulatory role of cyclo-oxygenase products. Blood 1984; 63: 1460-1466
    PubMedSearch in Google Scholar
  • 21 Fox SC, Burgess-Wilson M, Heptinstall S, Mitchell JRA. Platelet aggregation in whole blood determined using the ultra-flo 100 platelet counter. Thromb Haemost 1982; 48: 327-329
    Thieme ConnectPubMedSearch in Google Scholar
  • 22 Coleman RA, Humphrey PPA, Kennedy I, Levy GP, Lumley P. Comparisons of the actions of U46619, a stable prostaglandin H2 analogue, with those of prostaglandin H2 and thromboxane on some isolated smooth muscle preparations. Br J Pharmacol 1981; 73: 773-778
    CrossrefPubMedSearch in Google Scholar
  • 23 Coleman RA, Smith WL, Narumiya S. VIII International Union of Pharmacology Classification of Prostanoid Receptors: Properties, Distribution, and Structure of the Receptors and their Subtypes. Pharmacological Reviews 1994; 46: 205-229
    PubMedSearch in Google Scholar
  • 24 Brewster AG, Brown GR, Foubister AJ, Jessup R, Smithers MJ. The synthesis of a novel thromboxane receptor antagonist 4(Z)-6(2-o-chlorphenyl-4-0-hydroxyphenyl-l,3-doxan-cis-5-yl) hexenoic acid ICI 192605. Prostaglandins 1988; 36: 173-178
    CrossrefPubMedSearch in Google Scholar
  • 25 Jessup CL, Jessup R, Wayne M. ICI 192,605, a selective thromboxane A2 receptor antagonist, on platelets. Br J Pharmacol 1988; 95: 676P
    PubMedSearch in Google Scholar
  • 26 Bom GVR, Cross MJ. The aggregation of blood platelets. J Physiol 1963; 168: 178-95
    CrossrefPubMedSearch in Google Scholar
  • 27 Horn EH, Jalihal S, Bruce M, Dean A, Rubin PC. The Effect on Platelet Behaviour of Treatment with Atenolol and the Combination of Atenolol and Nifedipine in Healthy Volunteers. Platelets 1992; 3: 15-21
    CrossrefPubMedSearch in Google Scholar
  • 28 Orchard MA, Blair IA, Dollery CT, Lewis PJ. Blood can synthesise prostacyclin. The Lancet 1983 565. ii
    PubMedSearch in Google Scholar
  • 29 Horn EH, Cooper JA, Hardy E, Heptinstall S, Rubin PC. Longitudinal studies of platelet cyclic AMP in healthy pregnancy and pregnancies at risk of preeclampsia. Clinical Science 1995 (in press)
    PubMed
  • 30 Bills TK, Smith JB, Silver MJ. Selective release of arachidonic acid from the phospholipids of human platelets in response to thrombin. J Clin Invest 1977; 60: 1-6
    CrossrefPubMedSearch in Google Scholar
  • 31 Heptinstall S, Bienz N, Cockbill SR, Hanley SO, Peacock I. Different effects of thromboxane synthetase inhibitors on platelets from different individuals. The Lancet 1982; 1156
    PubMedSearch in Google Scholar
  • 32 Hamberg M, Svensson J, Wakabayashi T, Samuelsson B. Isolation and structure of two prostaglandin endoperoxides that cause platelet aggregation. Proc Natl Acad Sci USA 1974; 71: 345-349
    CrossrefPubMedSearch in Google Scholar
  • 33 Hanasaki K, Arita H. Recent aspects of TXA2 action on platelets and blood vessels. Platelets 1991; 2: 69-76
    CrossrefPubMedSearch in Google Scholar
  • 34 Arita H, Nakano T, Hanasaki K. Thromboxane A 2 its generation and role in platelet activation. Progress in Lipid Research 1989; 28: 273-301
    CrossrefPubMedSearch in Google Scholar
  • 35 Hanasaki K, Arita H. Characterization of a new compound, s-145 as a specific thromboxane receptor antagonist in platelets. Thromb Res 1988; 50: 365-376
    CrossrefPubMedSearch in Google Scholar
  • 36 Takahara K, Murray R, Fitzgerald GA, Fitzgerald DJ. The response to thromboxane A2 analogues in human platelets. J Biol Chem 1990; 265: 6836-6844
    PubMedSearch in Google Scholar
  • 37 Brass LF, Shaller CC, Belmonte EJ. Inositol 1,4,5-trisphosphate-induced granule secretion in platelets. J Clin Invest 1987; 79: 1269-1275
    CrossrefPubMedSearch in Google Scholar
  • 38 Liel N, Nathan I, Yermiyahu T, Zolotov Z, Lieberman JR, Dvilansky A, Halushka PV. Increased platelet thromboxane A2/prostaglandin H2 receptors in patients with pregnancy induced hypertension. Thromb Res 1993; 70: 205-210
    CrossrefPubMedSearch in Google Scholar
  • 39 Liel N, Mais DE, Halushka PV. Desensitisation of platelet thromboxane A2/prostaglandin H2 receptors by the mimetic U46619. J Pharmacol Exper Ther 1988; 247: 1133-1138
    PubMedSearch in Google Scholar
  • 40 Murray R, Fitzgerald GA. Regulation of thromboxane receptor activation in human platelets. Proc Natl Acad Sci USA 1989; 86: 124-128
    CrossrefPubMedSearch in Google Scholar