Enhanced Coagulation Activation in Preeclampsia: the Role of APC Resistance, Microparticles and Other Plasma Constituents

 

 Buy Article Permissions and Reprints

Summary

Coagulation activation in pregnancy is further enhanced in preeclampsia. We investigated whether this results from increased thrombin generation by the plasma itself or its cell-derived microparticles. Plasma samples were obtained from preeclamptic, normal pregnant and nonpregnant women (each n = 10). Prothrombin fragment 1+2 (F₁₊₂) and thrombin-antithrombin complex (TAT) concentrations were increased in pregnancy and further increased in preeclampsia. In pregnancy and preeclampsia, increased activated protein C resistance occurred (APC sensitivity ratio: 3.3 ± 0.8 and 2.5 ± 0.8, both P < 0.001 vs. nonpregnant). In normal pregnant microparticle-free plasma the thrombin generation correlated with TAT (r = 0.84, P = 0.005) and APC resistance correlated with F₁₊₂ (r = 0.68, P = 0.04). In preeclampsia thrombin generation by plasma was increased (P = 0.005), independent of APC resistance. Thrombin generation by microparticles was similar in all groups, although different coagulation activation pathways were utilized, indicating that circulating microparticles are not directly involved in coagulation activation in pregnancy and preeclampsia. In contrast, APC resistance can explain coagulation activation in pregnancy, while enhanced coagulation activation in preeclampsia results, in part, from an increased thrombin generating capacity of plasma independent of APC resistance.

• References

• 1 Greer IA. Haemostasis and thrombosis in pregnancy. In: Bloom AL, Forbes CD, Thomas DP, Tuddenham EGD. Haemostasis and thrombosis. Edinburgh: Churchill Livingstone; 1994: 987-1015.
  Google Scholar
• 2 Roberts JM, Redman CW. Pre-eclampsia: more than pregnancy-induced hypertension. Lancet 1993; 341: 1447-51.
  CrossrefPubMedGoogle Scholar
• 3 Paternoster D, Stella A, Simioni P, Trovo S, Plebani P, Girolami A. Clotting inhibitors and fibronectin as potential markers in preeclampsia. Int J Gynaecol Obstet 1994; 47: 215-21.
  CrossrefPubMedGoogle Scholar
• 4 Perry KGJ, Martin JNJ. Abnormal hemostasis and coagulopathy in preeclampsia and eclampsia. Clin Obstet Gynecol 1992; 35: 338-50.
  CrossrefPubMedGoogle Scholar
• 5 Cumming AM, Tait RC, Fildes S, Yoong A, Keeney S, Hay CR. Development of resistance to activated protein C during pregnancy. Br J Haematol 1995; 90: 725-7.
  CrossrefPubMedGoogle Scholar
• 6 Mimuro S, Lahoud R, Beutler L, Trudinger B. Changes of resistance to activated protein C in the course of pregnancy and prevalence of factor V mutation. Aust N Z J Obstet Gynaecol 1998; 38: 200-4.
  CrossrefPubMedGoogle Scholar
• 7 Lindoff C, Ingemarsson I, Martinsson G, Segelmark M, Thysell H, Astedt B. Preeclampsia is associated with a reduced response to activated protein C. Am J Obstet Gynecol 1997; 176: 457-60.
  CrossrefPubMedGoogle Scholar
• 8 Kobayashi T, Tokunaga N, Sugimura M, Kanayama N, Terao T. Predictive values of coagulation/fibrinolysis parameters for the termination of pregnancy complicated by severe preeclampsia. Semin Thromb Hemost 2001; 27: 137-41.
  Article in Thieme ConnectPubMedGoogle Scholar
• 9 Kupferminc MJ, Fait G, Many A, Gordon D, Eldor A, Lessing JB. Severe preeclampsia and high frequency of genetic thrombophilic mutations. Obstet Gynecol 2000; 96: 45-9.
  PubMedGoogle Scholar
• 10 van Pampus MG, Dekker GA, Wolf H, Huijgens PC, Koopman MM, von Blomberg BM, Buller HR. High prevalence of hemostatic abnormalities in women with a history of severe preeclampsia. Am J Obstet Gynecol 1999; 180: 1146-50.
  CrossrefPubMedGoogle Scholar
• 11 Kobashi G, Yamada H, Asano T, Nagano S, Hata A, Kishi R, Kondo K, Fujimoto S. The factor V Leiden mutation is not a common cause of pregnancy-induced hypertension in Japan. Sem Thromb Hemost 1999; 25: 487-9.
  Article in Thieme ConnectPubMedGoogle Scholar
• 12 Lee YJ, Jy W, Horstman LL, Janania J, Reyes Y, Kelley RE, Ahn YS. Elevated platelet microparticles in transient ischemic attacks, lacunar infarcts, and multi-infarct dementias. Thromb Res 1993; 72: 295-304.
  CrossrefPubMedGoogle Scholar
• 13 Mallat Z, Benamer H, Hugel B, Benessiano J, Steg PG, Freyssinet JM, Tedgui A. Elevated levels of shed membrane microparticles with procoagulant potential in the peripheral circulating blood of patients with acute coronary syndromes. Circulation 1999; 101: 841-3.
  PubMedGoogle Scholar
• 14 Berckmans RJ, Nieuwland R, Boïng AN, Romijn FP, Hack CE, Sturk A. Cell-derived microparticles circulate in healthy humans and support low grade thrombin generation. Thromb Haemost 2001; 85: 639-46.
  Article in Thieme ConnectPubMedGoogle Scholar
• 15 Combes V, Simon AC, Grau GE, Arnoux D, Camoin L, Sabatier F, Mutin M, Sanmarco M, Sampol J, Dignat-George F. In vitro generation of endothelial microparticles and possible prothrombotic activity in patients with lupus anticoagulant. J Clin Invest 1999; 104: 93-102.
  CrossrefPubMedGoogle Scholar
• 16 Horstman LL, Ahn YS. Platelet microparticles: a wide-angle perspective. Crit Rev Oncol Hematol 1999; 30: 111-42.
  CrossrefPubMedGoogle Scholar
• 17 Nieuwland R, Berckmans RJ, McGregor S, Boïng AN, Romijn FP, Westendorp RG, Hack CE, Sturk A. Cellular origin and procoagulant properties of microparticles in meningococcal sepsis. Blood 2000; 95: 930-5.
  PubMedGoogle Scholar
• 18 Minagar A, Jy W, Jimenez JJ, Sheremata WA, Mauro LM, Mao WW, Horstman LL, Ahn YS. Elevated plasma endothelial microparticles in multiple sclerosis. Neurology 2001; 56: 1319-24.
  CrossrefPubMedGoogle Scholar
• 19 Nomura S, Imamura A, Okuno M, Kamiyama Y, Fujimura Y, Ikeda Y, Fukuhara S. Platelet-derived microparticles in patients with arteriosclerosis obliterans. Enhancement of high shear-induced microparticle generation by cytokines. Thromb Res 2000; 98: 257-68.
  CrossrefPubMedGoogle Scholar
• 20 Joop K, Berckmans RJ, Nieuwland R, Berkhout J, Romijn FP, Hack CE, Sturk A. Microparticles from patients with multiple organ dysfunction syndrome and sepsis support coagulation through multiple mechanisms. Thromb Haemost 2001; 85: 810-20.
  Article in Thieme ConnectPubMedGoogle Scholar
• 21 Nieuwland R, Berckmans RJ, Rotteveel-Eijkman RC, Maquelin KN, Roozendaal KJ, Jansen PG, ten Have K, Eijsman L, Hack CE, Sturk A. Cell-derived microparticles generated in patients during cardiopulmonary bypass are highly procoagulant. Circulation 1997; 96: 3534-41.
  CrossrefPubMedGoogle Scholar
• 22 Nomura S, Yanabu M, Kido H, Fukuroi T, Yamaguchi K, Soga T, Nagata H, Kokawa T, Yasunaga K. Antiplatelet autoantibody-related microparticles in patients with idiopathic (autoimmune) thrombocytopenic purpura. Ann Hematol 1991; 62: 103-7.
  CrossrefPubMedGoogle Scholar
• 23 Tate DA, Bode AP, Nichols TC, Dehmer GJ. Platelet activation detected by platelet-derived microparticles in coronary sinus blood from patients with unstable coronary syndromes. Circulation 1992; 86: 3193A.
  PubMedGoogle Scholar
• 24 Jy W, Horstman LL, Arce M, Ahn YS. Clinical significance of platelet microparticles in autoimmune thrombocytopenias. J Lab Clin Med 1992; 119: 334-45.
  PubMedGoogle Scholar
• 25 Boulanger CM, Scoazec A, Ebrahimian T, Henry P, Mathieu E, Tedgui A, Mallat Z. Circulating microparticles from patients with myocardial infarction cause endothelial dysfunction. Circulation 2001; 104: 2649-52.
  CrossrefPubMedGoogle Scholar
• 26 VanWijk MJ, Nieuwland R, Boer K, van der Post JA, VanBavel E, Sturk A. Microparticle subpopulations are increased in preeclampsia: possible involvement in vascular dysfunction?. Am J Obstet Gynecol. in press.
  PubMedGoogle Scholar
• 27 Davey DA, MacGillivray I. The classification and definition of the hypertensive disorders of pregnancy. Am J Obstet Gynecol 1988; 158: 892-8.
  CrossrefPubMedGoogle Scholar
• 28 Rosing J, Tans G, Nicolaes GA, Thomassen MC, Van Oerle R, van der Ploeg PM, Heijnen P, Hamulyak K, Hemker HC. Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second- and third-generation oral contraceptives. Br J Haematol 1997; 97: 233-8.
  CrossrefPubMedGoogle Scholar
• 29 Sibai BM. The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): much ado about nothing?. Am J Obstet Gynecol 1990; 162: 311-6.
  CrossrefPubMedGoogle Scholar
• 30 Kobayashi T, Tokunaga N, Sugimura M, Suzuki K, Kanayama N, Nishiguchi T, Terao T. Coagulation/fibrinolysis disorder in patients with severe preeclampsia. Sem Thromb Hemost 1999; 25: 451-4.
  Article in Thieme ConnectPubMedGoogle Scholar
• 31 Maki M, Kobayashi T, Terao T, Ikenoue T, Satoh K, Nakabayashi M, Sagara Y, Kajiwara Y, Urata M. Antithrombin therapy for severe preeclampsia: results of a double-blind, randomized, placebo-controlled trial. BI51.017 Study Group. Thromb Haemost 2000; 84: 583-90.
  Article in Thieme ConnectPubMedGoogle Scholar
• 32 Tans G, Rosing J, Thomassen MC, Heeb MJ, Zwaal RF, Griffin JH. Comparison of anticoagulant and procoagulant activities of stimulated platelets and platelet-derived microparticles. Blood 1991; 77: 2641-8.
  PubMedGoogle Scholar
• 33 Berckmans RJ, Nieuwland R, Tak PP, Boïng AN, Romijn FP, Kraan M, Breedveld FC, Hack CE, Sturk A. Cell-derived microparticles from synovial fluid of inflamed arthritic joints support coagulation exclusively via a factor VII-dependent mechanism. Arthritis Rheum. Accepted for publication.
  PubMedGoogle Scholar
• 34 Roberts JM. Endothelial dysfunction in preeclampsia. Semin Reprod Endocrinol 1998; 16: 5-15.
  Article in Thieme ConnectPubMedGoogle Scholar
• 35 Grisaru D, Zwang E, Peyser MR, Lessing JB, Eldor A. The procoagulant activity of red blood cells from patients with severe preeclampsia. Am J Obstet Gynecol 1997; 177: 1513-6.
  CrossrefPubMedGoogle Scholar
• 36 Bevers EM, Comfurius P, Zwaal RF. The nature of the binding for prothrombinase at the platelet surface as revealed by lipolytic enzymes. Eur J Biochem 1982; 122: 81-5.
  CrossrefPubMedGoogle Scholar