凝固線溶系からみた妊娠中毒症の発症病態 (<シンポジウム>妊娠中毒症 : その病態論的アプローチ)

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It is well known that many pathophysiological findings in toxemia of pregnancy are explained by inbalance of coagulaton and fibrinolysis system. The purpose of this study is to elucidate a precise role of coagulation and fibrinolysis system in pathogenesis of toxemia of pregnancy. Subjects and Methods: 1) Classification of toxemia of pregnancy. Three houndred and thiry seven of toxemia of pregnancy are classified based on the onset period, and incidence of severity of disease and IUGR, rate of genetic factor of hypertension are compared in each group. 2) Platelet factor 4 (pf4) and β-thromboglobulin (β-TG), Fibrinopeptide A (FPA), thrombin-ATIII complex, ATIII fibrinopeptide B<β15-42>, D dimer FDP and plasmin-<α2> PI complex are assayed. The levels of PGI_2, tissue plasminogen activator (tPA) and thrombomodulin (TM) are measured after venous occlusion. Immunoreactivity and biological activity of TM in urine are analyzed. 3) Aminoacid sequence of TM from normal and toxemia of pregnancy are determined by analyzing cDNA for TM. Moreover, TM are synthesized from recombined DNA and enzymological properties of TM obtained from normal and toxemia of pregnancy are compared. 4) Release of PGI_2, tPA and TM by addition of thrombin are observed using monolayer culture of endotherial cells from cord. Enzymological properties of purified placental TM are analyzed. Results: 1) The incidence of severe type, IUGR and the rate of patients who possess genetic factors for hypertension are higher in early onset type, suggesting that hypertension is the predominant characteristics in early onset type and that genetic factors for hypertension are tightly involved. 2) All parameters such as platelets, coagulation and fibrinolysis system are elevated in toxemia of pregnancy compared to those in normal pregnancy. Coagulation index that consists of above parameters is well correlated with clinical index that consists of clinical findings (r=0.7006, p<0.0001). The net increase of PGI_2, tPA and TM by venous occlusion are decreased along with severity of toxemia of pregnancy. The potency of production of PGI_2 from endotherial cells in maternal omentum is impaired in the severe toxemia of pregnancy. Purified TM in urine from normal pregnancy and toxemia of pregnancy has 63K dalton of single band on SDS-PAGE. However, bioactivity/immunoreactivity ratio of TM in early onset type is lower than those in late onset type, and affinity of TM for thrombin and protein C is decreased in early onset type. 3) cDNA for TM contains 5 domains, one of which is structurally similar to EGF. The 455th amino residue in EGF domain of TM is valine, when DNA for TM in normal subject is analyzed. However, the 455th amino residue is alanine in one patient who had early onset type of toxemia and in another patient, the 455th amino residues is valine or alanine, suggesting that the point mutation might be responsible for impaired function of TM in toxemia of pregnancy. 4) The production and release of PGI_2 and tPA are stimulated by addition of thrombin in monolayer culture of endotherial cells in cord vessel from normal subjects, while response to thrombin is decreased in severe toxemia. The Km of PGI_2 synthetase in cord endotherial cells is higher in severe toxemia that results lower production of PGI2. Immunoreactive and bioactive TM in chorionic villi has a peak at 30 weeks and levels of immunoreactive TM and enzymological function of TM are low in the placenta from toxemia compared with those in normal placenta. In conclusion, the occurence of early onset type is tightly involved in hypertensive disposition and fetal development is severely impaired in early onset type. In the view of coagulation and fibrinolysis system, toxemia of pregnancy is in a state of chronic DIC. The severity of impairment of coagulation and fibrinolysis system is well correlated with clinical manifestations in toxemia. It is suggested that function of endotherial cells, especially
社団法人日本産科婦人科学会の論文
1988-08-01

凝固線溶系からみた妊娠中毒症の発症病態 (<シンポジウム>妊娠中毒症 : その病態論的アプローチ)

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