RSS-Feed abonnieren
DOI: 10.1055/s-0038-1661560
A Low Molecular Weight Heparin Alters the Fetal Coagulation System in the Pregnant Sheep
Publikationsverlauf
Received 29. November 1985
Accepted 14. Februar 1986
Publikationsdatum:
18. Juli 2018 (online)
Summary
Standard heparin and a LMWH, CY222 do not cross the placenta nor alter fetal coagulation when injected into the pregnant ewe. We found that another LMWH, Pharmuka-10169 (PK-10169) alters fetal coagulation without crossing the placenta in the pregnant sheep. To characterize this anticoagulant we measured the in vitro and in vivo effects of 125I-PK-10169 in maternal and fetal plasmas following administration of PK-10169 to the mother or fetus. The fetal anticoagulant activity was not neutralizable by protamine sulphate and was attributable to the inhibition of thrombin but not factor Xa. In vitro, the fetal anticoagulant activity had properties similar to dermatan sulphate : both catalyzed the inhibition of thrombin but not factor Xa by sheep plasma; and neither was neutralizable by protamine sulphate. These effects were due to the enhanced neutralization of thrombin by heparin cofactor II. We conclude that PK-10169 does not cross the placenta, but does induce the release of an endogenous dermatan sulphate-like substance which alters fetal coagulation.
-
References
- 1 Arthur H. Maternal deaths form pulmonary embolism. J Obstet Gynaec Br Commonwealth 1968; 75: 1309-1312
- 2 Ullery JC. Thromboembolic disease complicating pregnancy and the puerperium. Am J Obstet Gynec 1954; 68: 1243-60
- 3 Villansanta U. Thromboembolic disease in pregnancy. Am J Obstet Gynec 1965; 93: 142-60
- 4 Wingfield JG. Anticoagulation for antenatal thromboembolic disease. J Obstet Gynaec Br Commonwealth 1969; 76: 518-522
- 5 Letsky EA, Swiet MD. Thromboembolism in pregnancy and its management. Br J Haemat 1984; 57: 543-552
- 6 Hall JG, Pauli RM, Wilson KM. 1980Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980; 68: 122-140
- 7 Hirsh J, Cade JF, Gallus AS. Fetal effects of coumadin administered during pregnancy. Blood 1980; 36: 623-627
- 8 Flessa HC, Kapstrom AB, Glueck HI, Will JJ. Placental transport of heparin. Am J Obstet Gynecol 1965; 93: 570-573
- 9 Howell R, Filder J, Letzky E, De Swiet M. The risks of antenatal subcutaneous heparin prophylaxis: a controlled trial. J Obstet Gynaecol 1983; 90: 1124-1128
- 10 Kelton JG, Hirsh J. Bleeding associated with antithrombotic therapy. Semin Hematol 1980; 17: 375-379
- 11 Barrowcliffe RW, Johnson EA, Eggleton CA, Thomas DP. Anticoagulant activities of lung and mucous heparins. Thromb Res 1978; 12: 27-36
- 12 Carter CJ, Kelton JG, Hirsh J, Cerskus A, Santos AV, Gent M. The relationship between the hemorrhagic and antithrombic properties of low molecular weight heparin in rabbits. Blood 1982; 59: 1239-1245
- 13 Lane DA, MacGregor IR, Michalski R, Kakkar VV. Anti-coagulant activities of four unfractioned and fractionated heparins. Thromb Res 1978; 12: 257-271
- 14 Fareed J, Walenga JM, Rock A, Davies P. Studies on the pharmacokinetics of heparin and its low molecular weight heparin fraction in primates. Predictive value in human dosimetry. Thromb Res 1983; 50: 72-80
- 15 Andrew M, Boneu B, Cade J, Cerskus AL, Hirsh J, Jefferies A, Towell ME, Buchanan MR. Placental transport of low molecular weight heparin in the pregnant sheep. Br J Haemat 1985; 59: 103-108
- 16 Yin ET, Wessler J. Bovine thrombin and activated factor X. J Biol Chem 1968; 243: 112-117
- 17 Proctor RR, Rappaport SI. The partial thromboplastin time with kaolin. Am J Clin Pathol 1961; 36: 212-218
- 18 Teien AN, Lie M, Abilgaard N. Assay of heparin in plasma using a chromogenic substrate for activated factor X. Thromb Res 1976; 8: 413-416
- 19 Quick AJ. The prothrombin in hemophilia and obstructive jaundice. J Biol Chem 1935; 109: 73-78
- 20 Biggs R. Human blood coagulation, haemostasis, and thrombosis. Blackwell; Oxford, UK: 1976
- 21 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237-246
- 22 Dawes J, Pepper DS. Catabolism of low dose heparin in man. Thromb Res 1979; 14: 845-860
- 23 Lundblad RL, Kingdon HS, Mann KG. In: Methods in Enzymology XLV, Part B. Thromb Lorand L. (ed) Academic Press; p 156 New York: 1976
- 24 Jesty J, Nemerson Y. In: The activation of bovine coagulation in factor X. Lorand L. (ed) Methods in Enzymology XLV, Part B. p Academic Press; 95 New York: 1976
- 25 Modi GJ, Blajchman MA, Ofosu FA. The isolation of prothrombin, factor IX and factor X from factor IX concentrates. Thromb Res 1984; 36: 537-547
- 26 Ofosu FA, Modi GJ, Smith LM, Cerskus AL, Hirsh J, Blajchman MA. Heparin sulphate and dermatan sulphate inhibit the generation of thrombin activity in plasma by complementary pathways. Blood 1984; 64: 742-747
- 27 Tollefsen DM, pestka CA, Monafo WJ. Activation of heparin cofactor II by dermatan sulphate. J Biol Chem 1983; 258: 6713
- 28 Towell ME, Salvadore HS. Intrauterine asphyxia and respiratory movement in the fetal goat. Am J of Obstet Gynecol 1974; 118: 1124-1131
- 29 Forestier F, Daffos F, Capella-Pavlovsky M. Low molecular weight heparin (PK 10169) does not cross the placenta during the second trimester of pregnancy study by direct fetal blood sampling under ultrasound. Thromb Res 1984; 34: 557-560
- 30 Marcum JA, McKenney JB, Rosenberg RD. Acceleration of thrombin-antithrombin complex formation in rat hindquarters via heparin-like molecules bound to the endothelium. J Clin Invest 1984; 74: 341-350
- 31 Marcum JA, Fritze L, Galli SJ, Karp G, Rosenberg RD. Microvascular heparin-like species with anticoagulant activity. Am J Physiol 1983; 245: H725-H733
- 32 Kjellen L, Oldberg A, Hook M. Cell surface heparan sulfate. Mechanisms of proteoglycan cell association. J Biol Chem 1980; 255: 10407-10413
- 33 Brennan MJ, Oldberg A, Perschbacher MD, Ruoslahti E. Chon-droitin/dermatan sulphate proteoglycan in human fetal membranes. Demonstration of an antigenically similar proteoglycan in fibroblasts. J Biol Chem 1984; 259: 13742-13750
- 34 Kraemer P. Heparin releases heparan sulfate from the cell surface. Biochem Biophys Res Commun 1977; 78: 1334-1340
- 35 Boneu B, Buchanan MR, Cerskus AL, Hirsh J. Heparin clearance: Evidence for a saturable and a reversible mechanism. Blood 1983; 62 (Suppl) (Suppl. 01) 297 a
- 36 Khoay MS, Nesheim ME, Bowie EJ, Mann KG. Circulating heparin sulfate proteoglycan anticoagulant from a patient with a plasma cell disorder. J Clin Invest 1980; 65: 666-674
- 37 Murphy TL, Walker FJ, Taylor III FB, Bellestodd B, Archer LT, Safer SS, Hinshaw LB. Endogenous anticoagulation during extracor-poreal perfusion: generation of a heparin-like inhibitor. Am J Physiol 1980; 239 (Heart Circ Physiol 8) H742-H750
- 38 Shiverly JE, Conrad HE. Formation of anhydrogens in the chemical depolymerization of heparin. Biochemistry 1976; 15: 3932-3942
- 39 Inoue Y, Nagasawa K. Depolymerization of heparin with diazomethane. Structure of N,0-methylated, even numbered oligosaccharides produced by B-eliminative cleavage of the 2-amino-2-deoxy-glyioidic linkage. Carbohydrate Res 1984; 131: 285-300
- 40 Dancis J. Fetomaternal Interaction. In: Neonatology, Pathophysiology and management of the newborn. 2nd ed Avery GB. (ed) p 91 Lippincott; Philadelphia: 1981