Issues in women's health: John Bonnar. Interview by Jonathan Spencer Jones and Daniel J. Ncayiyana.
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Abortion, Induced↗
Biomedical subjects
J Bonnar
Publications and source records attributed to J Bonnar.
The in vitro effect of aspirin on increased whole blood platelet aggregation in oral contraceptive users.
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Adolescent↗
Platelet activation in normotensive and hypertensive pregnancies complicated by intrauterine growth retardation.
OBJECTIVE: To study platelet function in normotensive and hypertensive intrauterine growth retardation (IUGR). DESIGN: ADP and collagen induced whole blood platelet aggregation, beta-thromboglobulin release and platelet count were measured in the IUGR groups at a mean gestational age of 36 weeks (28-40), and at 1, 24, 48 h and six weeks post delivery. The normal pregnancy group were studied serially at 12, 20, 28, 32 and 36 weeks of gestation and at 1, 24, 48 h and six weeks post delivery. SETTING: Trinity College Medical School, St. James's Hospital, Dublin. SUBJECTS: Twenty-nine women with a fetus with diagnosed IUGR were recruited for the study. Of these, 15 were normotensive throughout their pregnancy and the remaining 14 pregnancies were complicated by both hypertension and proteinuria. Twenty healthy primigravida acted as controls. RESULTS: In the hypertensive IUGR group, levels of collagen and ADP induced aggregation were almost 50% lower before delivery than in normal pregnancy. Platelet count in the hypertensive group was decreased by 30% compared with normal pregnancy. Levels of beta-thromboglobulin were 40 to 50% higher in both the normotensive and hypertensive IUGR groups compared with normal pregnancy. Unlike the hypertensive IUGR group, the normotensive IUGR group showed similar levels of platelet count and ADP and collagen induced aggregation to those found at 36 weeks of normal pregnancy. In the early puerperium of hypertensive pregnancies, the platelet parameters measured returned gradually to normal. The normotensive IUGR group had increased levels of ADP induced aggregation in the first 24 to 48 h post delivery. The platelet count in the normotensive but not the hypertensive group correlated with birthweight. CONCLUSIONS: Normotensive and hypertensive IUGR are accompanied by platelet activation. In normotensive IUGR, this activation appears to be confined to the uteroplacental circulation. In hypertensive IUGR, the results suggest that platelet activation also extends into the peripheral circulation resulting in a reduced platelet responsiveness and a lower platelet count. Release of vasoactive amines from activated platelets in the peripheral circulation may be responsible for the clinical syndrome of hypertension and proteinuria present in pregnancies complicated by pre-eclampsia and IUGR but absent in normotensive IUGR.
Analysis of Variance↗
Haemostatic, fibrinolytic and endothelial variables in normal pregnancies and pre-eclampsia.
OBJECTIVE: To determine the behaviour of the coagulation variables antithrombin III (ATIII), protein C, thrombin/antithrombin III (TATIII); fibrinolytic activity, tissue plasminogen activator antigen (t-PA), plasminogen activator inhibitors (PAI) 1 and 2, and endothelial involvement by fibronectin assay in normal and pre-eclamptic pregnancies. DESIGN: Longitudinal and cross-sectional observational study. SETTING: Antenatal clinic and maternity hospital. SUBJECTS: Thirty-six primigravid normotensive caucasian patients, four of whom subsequently developed pre-eclampsia, and 12 patients with established pre-eclampsia. MAIN OUTCOME MEASURES: Plasma levels of PAI-1, PAI-2 and t-PA antigen were determined using an ELISA technique as were TATIII complex levels of fibronectin. ATIII and protein C plasma levels were assayed using chromogenic substrate techniques. RESULTS: PAI-1 and PAI-2 antigen levels rose progressively throughout normal pregnancy. Among the established pre-eclamptic group compared with matched normal pregnancies, the PAI-2 antigen level was significantly lower (48.5 +/- 22.8 versus 183.5 +/- 37.4; P < 0.001), the PAI-1 antigen level was significantly higher (122 +/- 34.4 versus 79.2 +/- 19.7; P < 0.001), ATIII activity was significantly lower (87.8 +/- 27.1 versus 110.9 +/- 19.3; P < 0.001) and TATIII complex levels were significantly higher (16.9 +/- 6.4 versus 10.2 +/- 5.9; P < 0.001). Among the four initially normotensive patients who subsequently developed pre-eclampsia, fibronectin levels were significantly elevated from as early as nine weeks of gestation. CONCLUSION: Significantly elevated levels of PAI-1 and fibronectin occurring early in pregnancies that subsequently develop pre-eclampsia suggest that these variables may have predictive values. PAI-2 would seem to be a marker of placental function in pre-eclampsia while increased t-PA and TATIII complex levels reflect the severity of the condition.
Adolescent↗
The effect of tranexamic acid on measured menstrual loss and endometrial fibrinolytic enzymes in dysfunctional uterine bleeding.
Fibrinolytic activity of the menstrual fluid is increased in dysfunctional uterine bleeding (DUB). We measured the effect of tranexamic acid on the menstrual blood loss and endometrial fibrinolytic enzymes in women with DUB (> 80 ml menstrual loss/cycle). Endometrial biopsies were taken between 24 and 36 hours after the onset of menstruation. Enzyme activity was assayed by measuring the rate of conversion of Glu-plasminogen to plasmin, using a chromogenic plasmin substrate. Antigen levels were measured using an enzyme linked immunoassay (ELISA) technique. Tranexamic acid reduced menstrual blood loss by 58% (p < 0.05). Endometrial tissue plasminogen activator activity and antigen and plasminogen activator inhibitor--type 1 antigen levels were significantly decreased by tranexamic acid. The effect of tranexamic acid on the fibrinolytic enzymes at local endometrial level may be responsible for its success in the treatment of menorrhagia.
Adolescent↗
Effect of oestrogen dose on whole blood platelet activation in women taking new low dose oral contraceptives.
Oral contraceptive use is known to cause changes in the haemostatic system. These changes are thought to be related to oestrogen dose and to provide a possible link between the increased risk of thromboembolic disease known to occur in women taking oestrogen containing oral contraceptives. This study measured whole blood platelet activation, serially, in women taking oral contraceptives containing 20 micrograms and 30 micrograms ethinyloestradiol combined with desogestrel. Increased levels of ADP and arachidonic acid induced aggregation were observed in women taking the 30 micrograms ethinyloestradiol combination. Platelet release of beta-thromboglobulin (beta TG) was also significantly increased. Increased collagen induced aggregation was observed but this failed to reach statistical significance for the individual treatment groups. In women taking the 20 micrograms ethinyloestradiol combination, a significant increase was only observed when platelets were stimulated with arachidonic acid. Platelet factor 4 (PF4) levels were unchanged in both groups. Significantly higher levels of beta TG were observed in women taking the 30 micrograms ethinyloestradiol combination compared with women taking the 20 micrograms ethinyloestradiol combination. These results show that oral contraceptive use is associated with platelet activation. Women taking the 20 micrograms ethinyloestradiol combination show less changes in platelet activation than women taking the 30 micrograms ethinyloestradiol combination. This lower dose pill may therefore be particularly suitable for high risk women wishing to use oral contraception.
Adolescent↗
Plasminogen activator inhibitors in endometrial adenocarcinoma.
BACKGROUND: Plasminogen activators (PA) play an important role in the mediation of pathologic processes, including cancer invasion. Levels of urokinase are increased in malignant endometrium compared with normal endometrium. The role of PA inhibitors (PAI) in the malignant process is not known. METHODS: PAI-1 (endothelial type inhibitor) and PAI-2 (placental type inhibitor) in extracts of malignant (n = 14) and normal (n = 7) postmenopausal endometrium were measured. The results were correlated with the standard prognostic variables in endometrial carcinoma, namely, stage, histologic grade, depth of myometrial invasion, and estrogen receptor status of the tumor. RESULTS: PAI-1 was not detectable in normal endometrium and was present in small quantitities (0.11-1.54 ng PAI-1/mg protein) in 4 of 14 specimens of malignant endometrium. PAI-2 was present in 4 of 7 normal and all (14 of 14) malignant endometrial cytosols. PAI-2 levels were higher in Stage II and III compared with Stage I cancers (P < 0.05) and in malignant endometrium that invaded the myometrium to more than half its depth compared with those with less than 50% invasion (P < 0.05). No significant correlation was found between PAI-2 and estrogen receptor levels (r = -0.32). CONCLUSIONS: Endometrial adenocarcinoma has higher levels of PAI-2 than does normal postmenopausal endometrium. Highest levels of PAI-2 were found in the poorer prognostic categories of endometrial cancer.
Adenocarcinoma↗
Cyclical variation in endometrial oestrogen and progesterone receptors in women with normal menstruation and dysfunctional uterine bleeding.
The majority of women with dysfunctional uterine bleeding ovulate and have normal cyclical changes in gonadotrophins, oestrogen and progesterone. To investigate whether the hormonal milieu at tissue level is different in these women, we measured the endometrial concentration of oestrogen and progesterone receptors at various stages of the menstrual cycle in women with normal menstrual loss (< or = 80 ml/cycle, n = 40) and dysfunctional uterine bleeding (> 80 ml/cycle, n = 44). Menstrual blood loss was measured using the alkaline haematin method. Receptor levels were measured in nuclear and cytosol extracts of endometrium using solid phase immunoassays, based on monoclonal antibodies against receptor protein, which measure the bound and unbound fractions of the receptors. We found endometrial oestrogen (P < 0.01) and progesterone (P < 0.05) receptor levels were higher in the late secretory phase in women with dysfunctional uterine bleeding compared with women with normal menstrual loss. The receptor levels were the same in both groups at all other stages of the menstrual cycle. There was a strong positive correlation between the level of late secretory endometrial oestrogen receptor and measured menstrual blood loss (r = 0.81, P < 0.01). Increased local oestrogen effect is present in the premenstrual endometrium in dysfunctional uterine bleeding.
Adult↗
Whole blood platelet aggregation in moderate and severe pre-eclampsia.
OBJECTIVE: To compare whole blood platelet aggregation in moderate and severe pre-eclampsia with normal pregnancy. DESIGN: Whole blood platelet aggregation in response to collagen, ADP, PAF, adrenalin and arachidonic acid was measured in the pre-eclampsia group at 36 weeks gestation and at 1, 24 and 48 h and at five days and six weeks post delivery. The normal pregnancy group were studied serially at 12, 20, 28, 32, and 36 weeks gestation and at 1, 24, 48 h and six weeks post delivery. SETTING: Trinity College Medical School, St James's Hospital, Dublin. SUBJECTS: Thirty women with diagnosed pre-eclampsia were recruited for the study. Fifteen of these women had severe pre-eclampsia and the remaining 15 had moderate disease. The pre-eclampsia group were compared with 20 healthy primigravid women with uncomplicated pregnancies and deliveries. RESULTS: In women with severe pre-eclampsia, platelet aggregation in response to collagen, ADP, adrenalin and arachidonic acid was significantly lower at 36 weeks gestation compared with normal pregnancy. Lower levels of collagen induced aggregation were also found at 1 h post delivery when compared with normal pregnancy. Women with moderate pre-eclampsia showed a decreased response to aggregating agents at 36 weeks gestation but this was not significant. ADP, collagen and PAF induced aggregation was higher in women with moderate pre-eclampsia at 36 weeks gestation and during the early puerperium compared with severe pre-eclampsia. CONCLUSIONS: The clinical signs of pre-eclampsia are accompanied by a reduction in platelet responsiveness, the extent of which is related to the severity of the disease. This suggests that an abnormal platelet activation occurs early in pregnancies destined to be complicated by pre-eclampsia. This activation may be involved in the pathogenesis of pre-eclampsia since its inhibition using low dose aspirin has been shown to modify the disease in high risk pregnancies.
Adenosine Diphosphate↗
Endometrial fibrinolytic enzymes in women with normal menstruation and dysfunctional uterine bleeding.
OBJECTIVE: To study fibrinolysis in the endometrium in women with normal menstruation and dysfunctional uterine bleeding (DUB). DESIGN: Tissue plasminogen activator activity (t-PA) and antigen (t-PAAg) and plasminogen activator inhibitor Type 1 antigen (PAI-1) were measured in homogenates of endometrium sampled between 24 and 36 h after the onset of menstruation. SUBJECTS: Women complaining of menorrhagia who had negative findings at clinical examination and curettage had their menstrual blood loss (MBL) measured from the third cycle after D&C. Those with MBL greater than 80 ml per cycle formed the DUB group. MEASUREMENTS: Fibrinolytic enzyme antigen levels were measured with ELISAs. Tissue plasminogen activator activity was assayed by measuring the rate of conversion of Glu-plasminogen to plasmin, using a chromogenic plasmin substrate. CONCLUSIONS: There is a strong positive correlation between endometrial t-PA activity on the second day of menstruation and measured menstrual loss (P < 0.05). Concentrations of endometrial t-PAAg and PAI-1 antigen are higher in women with DUB compared with normal women during menstruation.
Endometrium↗
An unusual case of traumatic primary amenorrhoea.
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Accidents, Traffic↗
Menstrual blood loss measurement with gynaeseal.
The diagnosis of menorrhagia is usually based on the subjective complaint of heavy menstrual bleeding, although up to 50% of women describing menorrhagia have measured menstrual loss within normal limits. Treatment is usually started without first establishing an objective diagnosis, because menstrual blood loss measurement is not widely available to clinicians. Current laboratory methods of measuring menstrual loss involve extraction of menses from sanitary wear. Many women find collection of sanitary wear unacceptable and laboratory staff find the menstrual extraction procedure unpleasant and time-consuming. We investigated the use of Gynaeseal, a vaginally placed latex menstrual seal, in women with normal menstrual loss (n = 10) and menorrhagia (n = 12) with regard to its suitability for the measurement of menstrual loss and efficacy as alternative sanitary protection. Twenty-one of the 22 women found the device easy to insert, but 16 found it messy to remove. All of the 6 couples having coitus found the device caused no discomfort. All women with menorrhagia and 4 of 12 women with normal menstrual losses were dissatisfied with the menstrual seal provided by gynaeseal. Gynaeseal does not contain menstrual blood efficiently in women with menorrhagia and is therefore unsuitable for the measurement of menstrual blood loss.
Evaluation Studies as Topic↗
Acquired bleeding disorders: bleeding in obstetrics and surgery.
Hemorrhage continues to be the leading cause of maternal mortality and morbidity throughout the world. In England and Wales from 1970-87 hemorrhage, including ectopic pregnancy, was a major factor in over 40 maternal deaths. In the majority of deaths the care was substandard. In 70% of obstetric deaths from hemorrhage defective hemostasis contributes to the bleeding. Inappropriate correction of hypovolemia, failure to recognise and treat coagulation failure, and failure to control traumatic bleeding are the main causes of preventable death. In developing countries, cross matched blood and blood products may not be readily available. Surgical intervention should be preceded or accompanied by correction of the hemostatic defect with fresh frozen plasma and if necessary platelet concentrates. Teamwork with experienced staff is the essence of successful management of severe hemorrhage in obstetrics and surgery. A protocol should be agreed between medical nursing and laboratory staff for dealing with massive blood loss.
Blood Coagulation Disorders↗
Uterine fibrinolytic enzymes in endometrial cancer.
Urokinase (u-PA) induced proteolysis of the extracellular matrix appears to be involved in stromal invasion by tumor cells and metastasis. Many malignant cells are known to secrete u-PA. Plasminogen activator inhibitor-type 2 (PAI-2) is an inhibitor of u-PA and is present in several neoplastic cell lines and malignant ascites. We measured u-PA and PAI-2 antigen in tissue homogenates of normal and malignant endometrium from 21 postmenopausal patients. Enzyme linked immunoassays which measure the bound and unbound, single and two chain form of the activators and bound and unbound form of the inhibitor were used. Urokinase was present in four of seven normal (range 0.15-0.5, median 0.15 ng/mg protein) and in all malignant endometrial homogenates (range 0.41-9.2, median 3.4 ng/mg protein), p < 0.001. PAI-2 was detectable in four of seven normal endometrial homogenates at low concentrations (range 1.1-3.1, median 1.1 ng/mg protein) and in all malignant tissue homogenates at higher levels (range 1.6-27.3, median 4.9 ng/mg protein), p < 0.01. Levels of PAI-2 were higher in Stage II/III compared to Stage I malignancy (p < 0.01) and in cancers that had invaded 50% or more of the uterine wall compared to less invasive cancers, p < 0.01. PAI-2 may be useful as a prognostic marker in endometrial cancer.
Adenocarcinoma↗
The plasminogen activator urokinase and its inhibitor PAI-2 in endometrial cancer.
Invasion and metastasis of malignant cells require the disruption of the extracellular matrix, degradation of basement membranes, and intrusion into connective tissue and vascular and lymphatic spaces. Several studies have indicated a role for urokinase (u-PA) in proteolysis of the extracellular matrix and hence in stromal invasion and metastasis. Many malignant cells are known to secrete u-PA. Plasminogen activator inhibitor-type 2 (PAI-2) is an inhibitor of u-PA and is present in several neoplastic cell lines and malignant ascites. We measured u-PA and PAI-2 antigen in tissue homogenates of normal and malignant endometrium from 21 postmenopausal patients. Enzyme-linked immunoassays which measure the bound and unbound, single-and two-chain form of the activator and bound and unbound form of the inhibitor were used. Urokinase was present in four of seven normal (range, 0.15-0.5; median, 0.15 ng/mg protein) and in significantly higher concentrations in all malignant endometrial homogenates (range, 0.41-9.2; median, 3.4 ng/mg protein), P < 0.001. PAI-2 was detectable in four of seven normal endometrial homogenates at low concentrations (range, 1.1-3.1; median, 1.1 ng/mg protein) and in all malignant tissue homogenates at significantly higher levels (range, 1.6-27.3; median, 4.9 ng/mg protein), P < 0.01. Levels of endometrial PAI-2 were higher in stages IC or greater compared to those in stages IA and 1B cancers (P < 0.05). PAI-2 may be useful as a prognostic marker in endometrial cancer.
Aged↗
Increased whole blood platelet aggregation in normal pregnancy can be prevented in vitro by aspirin and dazmegrel (UK38485).
OBJECTIVE: To determine the effect of normal pregnancy and the early puerperium on whole blood platelet aggregation and to assess the role of thromboxane A2 (TXA2) in platelet aggregation in pregnancy. DESIGN: A prospective descriptive study. SETTING: TCD Medical School, St James's Hospital, Dublin. SUBJECTS: Twenty healthy primigravidae who remained normotensive during pregnancy and the puerperium. INTERVENTIONS: 20 ml blood samples were obtained serially at 12, 20, 28, 32 and 36 weeks gestation, during established labour and at 1 h, 24 h, 48 h and 6 weeks after delivery. MAIN OUTCOME MEASURES: Whole blood platelet aggregation in response to aggregating agents ADP, PAF (platelet aggregating factor) collagen, adrenaline and arachidonic acid (AA) at each stage of pregnancy and peuerperium was measured using a particle counting technique. The in vitro effect of aspirin and dazmegrel (thromboxane synthetase inhibitor UK38485) on platelet aggregation in pregnancy was also investigated. RESULTS: Platelet aggregation in response to collagen, adrenaline, ADP and AA were increased in the last trimester, during labour and at 1 h after delivery but decreased 24-48 h after delivery. Platelet aggregation in response to AA, collagen and adrenalin was reduced by both aspirin and dazmegrel. CONCLUSIONS: The earliest and most marked increases in platelet aggregation during normal pregnancy were found in response to AA and collagen. These platelet changes were prevented when whole blood was pre-incubated with either aspirin or dazmegrel. This suggests that enhanced production of TXA2 is responsible for increased platelet reactivity in normal pregnancy.
Adenosine Diphosphate↗
The mast cell and histamine concentration of the human post-menopausal uterus.
Mast cells and histamine concentrations have been studied in uteri removed by hysterectomy from women in their post-menopausal years. Mast cell numbers were expressed as mean numbers/mm2 following fixation in 10% formalin and staining with Azure B. The majority of mast cells, in both the endometrium and myometrium, were very densely stained. Mast cells in the myometrium showed a significant negative correlation with years post-menopausal (rs = -0.52, P less than 0.05). Extracted histamine from uterine tissue was condensed with o-phthaldialdehyde to form a fluorophore and its fluorescence was measured at 450 microns using a spectrofluorometer. No significant correlation was found between histamine concentrations in the uterine wall and years post-menopausal.
Aged↗
Mast cells in the normal uterus and in dysfunctional uterine bleeding.
Mast cells in the human uterus were examined following fixation in 10% formalin and staining with Azure B. Mast cells were present in all parts of the corpus uteri. Cyclical changes were observed by light microscopy for mast cell numbers/mm2 in the functional endometrium, basal endometrium and the endometrial/myometrial border throughout the menstrual cycle. No significant differences were found for mast cell numbers in the menstrual, proliferative or secretory phases of the menstrual cycle in dysfunctional uterine bleeding (DUB). No correlation was found between mast cell numbers in the uterine wall in the secretory phase of the menstrual cycle and average menstrual blood loss for patients with DUB.
Cell Count↗