The effect of aspirin and indomethacin on prostacyclin and thromboxane production by placental tissue incubated with immunoglobulin G fractions from patients with lupus anticoagulant.

OBJECTIVE: We investigated the hypothesis that nonsteroidal antiinflammatory agents can influence the abnormal prostanoid production associated with antiphospholipid antibodies. We specifically assessed whether aspirin or indomethacin could eliminate the increased placental thromboxane production previously observed with immunoglobulin G fractions from patients with lupus anticoagulant without adversely affecting prostacyclin production. STUDY DESIGN: Immunoglobulin G fractions were prepared from the plasma of eight nonpregnant patients with antiphospholipid antibody syndrome and demonstrable lupus anticoagulant. Samples from each patient were then placed in incubation wells containing explants from normal term pregnancies and 10(-4) mol/L aspirin, 10(-7) mol/L indomethacin, or no added drug. Aliquots were removed at intervals up to 48 hours of incubation and assessed for placental prostacyclin and thromboxane production by radioimmunoassay of the stable metabolites prostaglandin F1 alpha and thromboxane B2. RESULTS: The addition of aspirin to wells containing immunoglobulin G from patients with lupus anticoagulant was associated with a significant decrease in thromboxane production compared with wells without added drug, but prostacyclin production was unaffected. In contrast, the addition of indomethacin also decreased thromboxane production significantly, but prostacyclin production was also diminished, so the ratio of thromboxane to prostacyclin was unaffected. CONCLUSION: These results support a role for the use of aspirin for antiphospholipid antibody-related pregnancy loss through a mechanism similar to that postulated for preeclampsia, namely, selective inhibition of thromboxane production.

Fetal fibronectin levels are elevated in maternal plasma and amniotic fluid of patients with severe preeclampsia.

OBJECTIVE: Our purpose was to investigate levels of fetal fibronectin in maternal plasma, amniotic fluid, and umbilical cord plasma from patients with severe preeclampsia. STUDY DESIGN: The study group comprised 20 patients with severe preeclampsia (group A). An antepartum comparison group was composed of 20 healthy patients matched for gestational age (group B). An intrapartum control group consisted of 20 term normotensive patients (group C). Maternal plasma samples were collected before labor (groups A and B), then immediately after delivery, and again at 20 to 24 hours post partum (groups A and C). Amniotic fluid was also collected in early labor, and umbilical cord blood was collected at delivery (groups A and C). Samples were assayed for fetal fibronectin by a specific enzyme-linked immunoassay. RESULTS: Before labor maternal plasma levels of fetal fibronectin were significantly elevated in preeclamptic patients compared with patients in group B (p < 0.0001). Plasma levels of fetal fibronectin were also increased in preeclamptic patients compared with patients in group C at delivery (p < 0.0001) and post partum (p < 0.05). Additionally, amniotic fluid levels of fetal fibronectin in the preeclamptic patients were significantly increased (p < 0.05). In contrast, umbilical cord plasma fetal fibronectin concentrations from the preeclamptic and control patients were similar. CONCLUSIONS: Fetal fibronectin is elevated in the maternal plasma and amniotic fluid, but not umbilical cord plasma, of patients with severe preeclampsia. These findings suggest an increase in production of fetal fibronectin from chorionic trophoblast in patients with preeclampsia or an abnormal interaction between chorionic trophoblast and decidua with resultant increased leakage into the maternal circulation and amniotic fluid.

Immunoreactive tumor necrosis factor-alpha is elevated in maternal plasma but undetected in amniotic fluid in the second trimester.

OBJECTIVE: We investigated the participation of the cellular arm of the immune system in adaptation to pregnancy by assessing plasma and amniotic fluid levels of the cytokine tumor necrosis factor-alpha. STUDY DESIGN: Fifty-five healthy pregnant women who underwent second-trimester genetic amniocentesis at a mean gestational age of 17.0 +/- 1.4 weeks composed study group A. Blood was drawn from each patient before amniocentesis, and an aliquot of amniotic fluid was obtained for this study. Twenty-one healthy patients at a mean gestational age of 35.5 +/- 4.8 weeks composed study group B, and blood was obtained from each patient at an outpatient prenatal visit. Twenty-two healthy, nonpregnant women of reproductive age composed the control group (C). All specimens were stored at -70 degrees C and collectively assayed for tumor necrosis factor-alpha by a specific enzyme-linked immunoassay. RESULTS: All patients in group A had a normal karyotype and all patients in groups A and B had uneventful pregnancies. Tumor necrosis factor-alpha was detected in the plasma of 43 of 55 (78.2%) patients in group A compared with 7 of 21 (33.3%) patients in group B (p < 0.001); tumor necrosis factor-alpha was not detected in any of the 22 women in group C. The median plasma tumor necrosis factor-alpha level for group A was 135 pg/ml (range 0 to 625 pg/ml) compared with 0 pg/ml (range 0 to 110 pg/ml) in group B (p < 0.001). Tumor necrosis factor-alpha was not detected in any of the amniotic fluid specimens studied. CONCLUSIONS: Levels of tumor necrosis factor-alpha were elevated in the plasma but not detected in the amniotic fluid of normal pregnant patients in the second trimester. These findings suggest involvement of the cellular branch of the immune system and its products, the cytokines, in the normal adaptation of the mother to the fetal allograft, with a possible role in regulating trophoblast growth and invasion.

Tumor necrosis factor-alpha is elevated in plasma and amniotic fluid of patients with severe preeclampsia.

OBJECTIVE: Our purpose was to investigate whether markers for activation of the immune system are present in patients with preeclampsia by assessing maternal plasma and amniotic fluid for tumor necrosis factor-alpha and interleukin-1 beta. STUDY DESIGN: Twenty-one patients with severe preeclampsia composed the study group (group A). An antepartum comparison group was composed of healthy nulliparous patients not in labor and matched for gestational age (group B). Another control group consisted of term nulliparous patients in labor with uneventful pregnancies (group C). Maternal plasma samples were collected from all patients at recruitment and from patients in groups A and C immediately after delivery and again 20 to 24 hours post partum. Amniotic fluid was also collected from patients in groups A and C during labor. All samples were collectively assayed for tumor necrosis factor-alpha and interleukin-1 beta by specific enzyme-linked immunoassays. RESULTS: Before labor tumor necrosis factor-alpha was detected more frequently in the plasma of preeclamptic patients than in the plasma of patients in group B (12/16 vs 5/16, p < 0.05) and in higher concentrations (median 35 pg/ml vs median 0 pg/ml, p < 0.05). Although tumor necrosis factor-alpha was frequently detected in the plasma of patients in group C in early labor (16/20), concentrations were higher in the four preeclamptic patients first sampled in early labor (210 pg/ml vs 65 pg/ml, p < 0.05). Similarly, amniotic fluid levels of tumor necrosis factor-alpha were increased in preeclamptic patients compared with control patients. At delivery tumor necrosis factor-alpha was more likely to be identified in the plasma of preeclamptic patients and was found in higher concentrations, but by 20 to 24 hours post partum measurements in the preeclamptic and control patients were similar. There were no differences in the frequency with which interleukin-1 beta was detected or the concentration of interleukin-1 beta in any of the samples. CONCLUSIONS: Tumor necrosis factor-alpha is increased in the plasma and amniotic fluid of patients with severe preeclampsia. These data are suggestive of a role for abnormal immune activation in the pathophysiologic mechanisms of preeclampsia.

The effect of immunoglobulin G fractions from patients with lupus anticoagulant on placental prostacyclin and thromboxane production.

OBJECTIVE: We evaluated whether the production of prostacyclin and thromboxane by normal human placental tissue is consistently altered by incubation with immunoglobulin G fractions prepared from plasma of patients with lupus anticoagulant. STUDY DESIGN: The immunoglobulin G fractions were prepared from eight patients with lupus anticoagulant and eight control patients. Doses of these fractions (3 mg, 7.5 mg, and 12 mg) were incubated with placental explants obtained from normal pregnancies, and prostacyclin and thromboxane production was assessed over 48 hours. RESULTS: Prostacyclin production was similar for placental tissue incubated with immunoglobulin fractions from control and lupus anticoagulant patients at all of the doses tested. Placental production of thromboxane was significantly increased with immunoglobulin fractions from lupus anticoagulant patients for all three doses (p = 0.02). CONCLUSIONS: The immunoglobulin G fraction from patients with lupus anticoagulant consistently alters placental thromboxane production without affecting prostacyclin production. Increases in placental thromboxane production may contribute to antiphospholipid antibody-mediated pregnancy loss.

The immunoglobulin G fraction from plasma containing antiphospholipid antibodies causes increased placental thromboxane production.

OBJECTIVE: Our objective was to evaluate whether the immunoglobulin G fraction from plasma containing high levels of antiphospholipid antibodies alters the production of prostacyclin or thromboxane when incubated with normal human placental tissue. STUDY DESIGN: The immunoglobulin G fraction was prepared from the pooled plasma of five volunteers with normal obstetric histories and no antiphospholipid antibodies. The immunoglobulin G fraction was prepared similarly from a patient with the antiphospholipid antibody syndrome. Doses of these immunoglobulin G fractions ranging from 0.3 to 3.0 mg were incubated with placental explants obtained from eight normal pregnancies, and prostacyclin and thromboxane production was assessed over 48 hours. RESULTS: Placental prostacyclin production was unaltered by incubation with either immunoglobulin G fraction at any of the doses tested. Placental thromboxane production tripled by 32 hours with the addition of 0.6, 1.5, and 3.0 mg of the antiphospholipid antibody fraction (p < 0.05) compared with baseline production but was unaltered by the addition of the normal pooled plasma fraction at any dose. The increase in thromboxane production with antiphospholipid antibody immunoglobulin G appeared to be dose related. CONCLUSION: The immunoglobulin G fraction prepared from plasma containing antiphospholipid antibodies caused increased placental thromboxane production without altering prostacyclin production.

Dose-related prolongation of the bleeding time by intravenous nitroglycerin.

The effects of intravenous nitroglycerin (NTG) upon the bleeding time, platelet aggregation response, and plasma 6-keto-PGF1 alpha concentration were measured in 17 patients about to undergo coronary bypass grafting. NTG produced a dose-related prolongation of the bleeding time that correlated with the accompanying decrease in systolic blood pressure. Platelet aggregation was not affected and measurements of 6-keto-PGF1 alpha failed to reveal detectable levels (less than 10 pg/ml) either before or after NTG infusion. This suggests that the prolonged bleeding time associated with NTG infusion may be due to vasodilation and increased venous capacitance, rather than altered vascular-platelet interaction.