PDF herunterladen
Thromb Haemost 2000; 84(04): 583-590
DOI: 10.1055/s-0037-1614071
Review Article
Schattauer GmbH

Antithrombin Therapy for Severe Preeclampsia

Results of a Double-blind, Randomized, Placebo-controlled Trial
Masahiro Maki
1   From the Department of Obstetrics & Gynecology, Akita University School of Medicine, Akita, Japan
,
Takao Kobayashi
2   Department of Obstetrics & Gynecology, Hamamatsu University School of Medicine, Shizuoka, Japan
,
Toshihiko Terao
2   Department of Obstetrics & Gynecology, Hamamatsu University School of Medicine, Shizuoka, Japan
,
Tsuyomu Ikenoue
3   Department of Obstetrics & Gynecology, Miyazaki Medical College, Miyazaki, Japan
,
Kazuo Satoh
4   Department of Obstetrics & Gynecology, Nihon University School of Medicine, Tokyo, Japan
,
Masao Nakabayashi
5   Department of Obstetrics & Gynecology, Tokyo Women’s Medical University, Tokyo, Japan
,
Yusuke Sagara
6   Department of Obstetrics & Gynecology, Kochi Medical School, Kochi
,
Yayoi Kajiwara
7   Drug Innovation & Approval, Aventis Pharma, Ltd., Tokyo, Japan
,
Masao Urata
7   Drug Innovation & Approval, Aventis Pharma, Ltd., Tokyo, Japan
,
for BI51.017 Study Group › Institutsangaben
Weitere Informationen

Publikationsverlauf

Received 17. Dezember 1999

Accepted after resubmission 18. April 2000

Publikationsdatum:
11. Dezember 2017 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Summary

A double-blind, randomized, placebo-controlled trial was conducted to evaluate whether treatment with Antithrombin (AT) concentrates improved the clinical and perinatal outcome in patients with severe preeclampsia. Severe preeclamptic patients (24 to 35 weeks of gestation, Gestosis Index (GI) > 6 points) were randomized into two groups: 66 received AT and 67 received placebo. There were no statistical differences in the clinical profiles of the two groups. Study drugs were given intravenously once daily for 7 consecutive days. Maternal symptoms were evaluated from the difference of GI between before and after treatment, and fetal findings were evaluated from the changes of the biophysical profile score and the estimated fetal weight gain. Improvement was significantly greater in the AT group for both the GI (p = 0.020) and the estimated fetal weight gain (p = 0.029). The improvement of coagulation parameters was also evaluated. The D-dimer levels increased significantly in the placebo group (p = 0.026), but did not change in the AT group. Gestation was significantly prolonged (p = 0.007), and the number of low-birth weight infants was significantly smaller (p = 0.011) in the AT group. No adverse events related to AT were observed. It is revealed that AT concentrate therapy for preeclampsia is effective and safe, leading to an improved perinatal outcome.

Key words

Preeclampsia - hypercoagulable state - vasoconstriction - antithrombin (AT) concentrate - low-birth weight infant

* The members of BI51.017 study group are listed in the Appendix, on pp. 588–9.


 

  • References

  • 1 Mushambi MC, Halligan AW, Williamson K. Recent developments in the pathophysiology and management of preeclampsia. Brit J Anaesth 1996; 76: 133-48.
    CrossrefPubMedGoogle Scholar
  • 2 Vu T-KH, Thien-Khai H, Hung DT, Weaton VI, Coughlin SR. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 1991; 64: 1057-68.
    CrossrefPubMedGoogle Scholar
  • 3 Chen J, Ishii M, Wang L, Ishii K, Coughlin SR. Thrombin receptor activation. J Biol Chem 1994; 269: 16041-5.
    PubMedGoogle Scholar
  • 4 Rabiet MJ, Plantier JL, Dejana E. Thrombin-induced endothelial cell dysfunction. Brit Med Bull 1992; 50: 936-65.
    PubMedGoogle Scholar
  • 5 Perry KG, Martin JN. Abnormal hemostasis and coagulopathy in preeclampsia and eclampsia. Clin Obstet Gynecol 1992; 35: 338-50.
    CrossrefPubMedGoogle Scholar
  • 6 Weiner CP, Brandt J. Plasma antithrombin III activity: an aid in the diagnosis of preeclampsia-eclampsia. Am J Obstet Gynecol 1982; 142: 275-81.
    CrossrefPubMedGoogle Scholar
  • 7 Weenink GH, Treffers PE, Vijin P, Smorenberg-Schoorl ME, ten Cate JW. Antithrombin III levels in preeclampsia correlate with maternal and fetal morbidity. Am J Obstet Gynecol 1984; 148: 1092-7.
    CrossrefPubMedGoogle Scholar
  • 8 He S, Bremme K, Blombäck M. Acquired deficiency of antithrombin in association with a hypercoagulable state and impaired function of liver and/or kidney in preeclampsia. Blood Coag and Fibrin 1997; 08: 232-8.
    PubMedGoogle Scholar
  • 9 Kobayashi T, Terao T. Preeclampsia as chronic disseminated intravascular coagulation; study of two parameters: thrombin-antithrombin III complex and D-dimers. Gynecol Obstet Invest 1987; 24: 70-8.
    PubMedGoogle Scholar
  • 10 Harpel PC. Alpha2-plasmin inhibitor and alpha2-macrogloblin-plasmin complexes in plasma. J Clin Invest 1981; 68: 46-55.
    CrossrefPubMedGoogle Scholar
  • 11 Kobayashi T, Sugimura M, Kanayama N, Nishiguchi T, Tokunaga N, Terao T. Coagulation/fibrinolysis disorders in patient with severe preeclampsia. Semin Thromb Hemost 1999; 25: 451-4.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 12 Ballegeer VC, Spitz B, DeBaene LA, Van Assche AF, Hidajat M, Criel AM. Platelet activation and vascular damage in gestational hypertension. Am J Obstet Gynecol 1992; 166: 629-33.
    CrossrefPubMedGoogle Scholar
  • 13 Terao T, Maki M, Ikenoue T, Gotoh K, Iwasaki H, Shibata J, Nakabayashi M, Muraoka M, Takeda Y, Sakamoto S, Kobayashi T, Imai N, Oda H, Samejima H. The relationship between clinical signs and hypercoagulable state in toxemia of pregnancy. Gynecol Obstet Invest 1991; 31: 74-85.
    CrossrefPubMedGoogle Scholar
  • 14 Terao T, Kobayashi T, Imai N, Oda H, Karasawa T. Pathological state of the coagulatory and fibrinolytic system in preeclampsia and the possibility of its treatment with AT-III concentrate. Asia-Oceania J Obstet Gynecol 1989; 15: 25-32.
    PubMedGoogle Scholar
  • 15 The Japan Society of Obstetrics and Gynecology. The definition of preeclampsia in Japan. Acta Obst Gynaec Jpn. 1992 44. (07): 5-6 (in Japanese).
    PubMedGoogle Scholar
  • 16 Von Goecke C, Schwabe G. Vorschlag einer Stadien-Einteilung der Gestose. Zbl Gynäk 1965; 87: 1439-43.
    PubMedGoogle Scholar
  • 17 Jürgens H, Dichmann R. Gestosis index and perinatal mortality. Zbl Gynäk 1975; 97: 1201-11.
    PubMedGoogle Scholar
  • 18 Kaminski K, Rechberger T. Concentration of digoxin-like immunoreactive substance in patients with preeclampsia and its relation to severity of pregnancy-induced hypertension. Am J Obstet Gynecol 1991; 165: 733-6.
    CrossrefPubMedGoogle Scholar
  • 19 Manning FA, Lange IR, Morrison I, Harman CR. Fetal biophysical profile score and the nonstress test: a comparative trial. Obstet Gynecol 1984; 64: 326-31.
    PubMedGoogle Scholar
  • 20 Shinozuka N, Okai T, Kohzuma S, Mukubo M, Shih CT, Maeda T, Kuwabara Y, Mizuno M. Formulas for fetal weight estimation by ultrasound measurements. Based on neonatal specific gravities and volumes. Am J Obstet Gynecol 1987; 157: 1140-5.
    CrossrefPubMedGoogle Scholar
  • 21 Nishida H, Sakamoto S, Sakanoue M. New fetal growth curves for Japanese. Acta Paediatr Scand Suppl 1985; 319: 62-7.
    PubMedGoogle Scholar
  • 22 Harpel PC. Blood proteolytic enzyme inhibitors: their role in modulating blood coagulation and fibrinolytic enzyme pathways. In: Hemostasis and Thrombosis. Colman RW, Hirsh J, Marder VJ, Salzman EW. Philadelphia: J.B. Lippincott; 1982: 738-41.
    Google Scholar
  • 23 Rosenberg RD, Damus PS. The purification and mechanism of action of human antithrombin-heparin cofactor. J Biol Chem 1973; 248: 6490-5.
    PubMedGoogle Scholar
  • 24 Shinyama H, Akira T, Uchida T, Hirahara K, Watanabe M, Kagitani Y. Antithrombin III prevents renal dysfunction and hypertension induced by enhanced intravascular coagulation in pregnant rats: Pharmacological confirmation of the benefits of treatment with antithrombin III in preeclampsia. J Cardiovasc Pharm 1996; 27: 702-11.
    CrossrefPubMedGoogle Scholar
  • 25 Maki M, Terao T, Ikenoue T, Takemura T, Sekiba K, Shirakawa K, Soma H. Clinical evaluation of antithrombin III concentrate (BI6.013) for disseminated intravascular coagulation in obstetrics. Gynecol Obstet Invest 1987; 23: 230-40.
    CrossrefPubMedGoogle Scholar
  • 26 Fujiwara K, Okita K, Akamatsu K, Abe H, Tameda Y, Sakai T, Inoue N, Kanai K, Aoki N, Oka H. Antithrombin III concentrate in the treatment of fulminant hepatic failure. Gastroenterol Jpn 1988; 23: 423-7.
    CrossrefPubMedGoogle Scholar
  • 27 Weenink GH, ten Cate JW, Treffers PE. Hypertensive disorders. Clin Obstet Gynecol 1985; 28: 37-45.
    CrossrefPubMedGoogle Scholar
  • 28 Rippman ET. Gestosis of late pregnancy. Nomenclature and scoring. Gynaecologia (Basel) 1968; 165: 12-20.
    PubMedGoogle Scholar
  • 29 Davey DA, MacGillivray I. The classification and definition of the hypertensive disorders of pregnancy. Am J Obstet Gynecol 1988; 158: 892-8.
    CrossrefPubMedGoogle Scholar
  • 30 Campbell DM, Campbell AJ. Evans Blue disappearance rate in normal and pre-eclamptic pregnancy. Clin Exp Hypertens 1983; B2: 163-9.
    PubMedGoogle Scholar
  • 31 Malik AB, Fenton II JW. Thrombin-mediated increase in vascular endothelial permeability. Semin Thromb Hemost 1992; 18: 193-9.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 32 DeMichele MAA, Minnear FL. Modulation of vascular endothelial permeability by thrombin. Semin Thromb Hemost 1992; 18: 287-95.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 33 Kwawukume EY, Ghosh TS. Oral nifedipine therapy in the management of severe preeclampsia. Int J Gynecol Obstet 1995; 49: 265-9.
    CrossrefPubMedGoogle Scholar
  • 34 Sibai BM. Treatment of hypertension in pregnant women. New Engl J Med 1996; 335: 257-65.
    CrossrefPubMedGoogle Scholar
  • 35 Montan S. Medical prevention of pre-eclampsia. Acta Obstet Gynecol Scand (Supplement) 1997; 164: 111-5.
    PubMedGoogle Scholar
  • 36 Wacker J, Werner P, Walter-Sank I, Bastert G. Treatment of hypertension in patients with preeclampsia: a prospective parallel-group study comparing dihydralazine with urapidil. Nephrol Dial Transpl 1998; 13: 318-25.
    CrossrefPubMedGoogle Scholar
  • 37 Sibai BM. Prevention of preeclampsia: a big disappointment. Am J Obstet Gynecol 1998; 179: 1275-8.
    CrossrefPubMedGoogle Scholar
  • 38 Marcus AJ. Platelet aggregation. In: Hemostasis and Thrombosis. Colman RW, Hirsh J, Marder VJ, Salzman EW. Philadelphia: J. B. Lippincott; 1982: 380-9.
    Google Scholar
  • 39 White RP, Chapleau CE, Dngdale M, Robertson JT. Cerebral arterial contractions induced by human and bovine thrombin. Stroke 1980; 11: 363-8.
    CrossrefPubMedGoogle Scholar
  • 40 Fenton JW. Thrombin specificity. Ann NY Acad Sci 1981; 370: 468-95.
    CrossrefPubMedGoogle Scholar
  • 41 Minnear FL, Martin D, Hill L, Taylor AE, Malik AB. Lung morphological and permeability changes induced by intravascular coagulation dogs. Am J Physiol 1987; 253: H634-44.
    PubMedGoogle Scholar
  • 42 Zimmerman GA, Mclntyre TM, Prescott SM. Thrombin stimulates the adherence of neutrophils to human endothelial cells in vitro. J Clin Invest 1985; 76: 2235-46.
    CrossrefPubMedGoogle Scholar
  • 43 Yamauchi T, Umeda F, Inoguchi T, Nawata H. Antithrombin III stimulates prostacyclin production by cultured aortic endothelial cells. Biochem Bioph Res Co 1989; 163: 1404-11.
    CrossrefPubMedGoogle Scholar
  • 44 Weiner CP, Herrig JE, Pelzer GD, Heilskov J. Elimination of antithrombin III concentrate in healthy pregnant and preeclamptic woman with an acquired antithrombin III deficiency. Thromb Res 1990; 58: 395-401.
    CrossrefPubMedGoogle Scholar
  • 45 Kario K, Matsuo T, Kodama K, Matsuo M. Prophylactic antithrombin III administration during pregnancy immediately reduces the thrombin hyperactivity of congenital antithrombin III deficiency by forming thrombin-antithrombin III complexes. Thromb Res 1992; 66: 509-15.
    CrossrefPubMedGoogle Scholar
  • 46 Maki M. Pathogenesis and management of preeclampsia from the view point of endothelial cell functions. Jpn J Obstet Gyencol Neonatal Hematol 1994; 04: 118-35.
    PubMedGoogle Scholar
  • 47 Friedman KD, Borok Z, Owen J. Heparin cofactor activity and antithrombin III antigen levels in preeclampsia. Thromb Res 1986; 43: 409-16.
    CrossrefPubMedGoogle Scholar
  • 48 Mannucci PM, Boyer C, Wolf M, Tripodi A, Larrieu MJ. Treatment of congenital antithrombin III deficiency with concentrates. Brit J Haematol 1982; 50: 531-5.
    CrossrefPubMedGoogle Scholar
  • 49 Mutoh S, Komatsu Y, Kobayashi M, Maki M, Itoh N, Ohno Y, Sasa H, Kuroda K. Plasma coagulation-fibrinolysis system in the uteroplacental circulation in severe preeclampsia: especially on tPA/PAI-1/C and active PAI-1. Jap J Thromb Hemost 1994; 05: 54-65.
    PubMedGoogle Scholar
  • 50 Fairley KF, Adey FD, Ross IC, Kincaid-Smith P. Heparin treatment in severe preeclampsia and glomerulonephritis in pregnancy. Perspect Nephrol Hypertens 1976; 05: 103-12.
    PubMedGoogle Scholar
  • 51 Howie PW, Prentice CR, Forbes CD. Failure of heparin therapy to affect the clinical course of severe preeclampsia. Brit J Obstet Gynaecol 1975; 82: 711-7.
    CrossrefPubMedGoogle Scholar
  • 52 Riyazi N, Leeda M, de Vries JI, Huijgens PC, van Geijn HP, Dekker GA. Low-molecular-weight heparin combined with aspirin in pregnant women with thrombophilia and a history of preeclampsia or fetal growth restriction: a preliminary study. Eur J Obstet Gynecol Reprod Biol 1998; 80: 49-54.
    CrossrefPubMedGoogle Scholar
  • 53 Nakabayashi M, Asami M, Nakatani A. Efficacy of antithrombin replacement therapy in severe early-onset preeclampsia. Semin Thromb Hemost 1999; 25: 463-6.
    Artikel in Thieme ConnectPubMedGoogle Scholar