6-oxo-prostaglandin F1 alpha and thromboxane B2 in uterine vein blood--a possible role in menstrual bleeding.

The role of the haemostatic system in relation to menstrual bleeding is poorly understood. Platelet retention to glass beads and plasma concentrations of 6-oxo-PGF1 alpha and thromboxane B2 were measured in uterine and peripheral venous blood obtained from 18 women undergoing abdominal hysterectomy. Concentrations of 6-oxo-PGF1 alpha were significantly (p less than 0.01) higher in uterine (1.4 +/- 0.3 ng/ml, mean +/- SEM) than in peripheral vein blood (0.2 +/- 0.1 ng/ml) as was the level of thromboxane B2 (0.5 +/- 0.1 and 0.2 +/- 0.1 ng/ml, respectively). Platelet retention in uterine vein blood (11 +/- 4%) was significantly lower than in peripheral blood (42 +/- 4%; p less than 0.01) and the degree of platelet retention correlated inversely with the plasma concentration of 6-oxo-PGF1 alpha (r -0.43; p less than 0.01). There was a significant rank correlation between time since menstruation and concentrations of 6-oxo-PGF1 alpha in uterine (tau + 0.69; p less than 0.001) and peripheral (tau + 0.56; p less than 0.05) vein blood. The results indicate that an increased local production of prostacyclin (PGI2) relative to thromboxane A2 at the time of menstruation could contribute to the mechanism of uterine bleeding.

Aspirin, dipyridamole and platelet survival in patients with diabetes mellitus.

1. Platelet survival in 27 insulin-dependent diabetic patients with severe retinopathy was studied in a double-blind cross-over trial using placebo, aspirin (990 mg/day) and a combination of dipyridamole (225 mg/day) with aspirin at two dosage levels (330 mg and 990 mg/day). 2. Twenty patients (group I) had 51Cr-labelled-platelet survival after treatment with placebo and the high-dose-aspirin/dipyridamole combination. The remaining seven patients (group II) had platelet-regeneration times measured after each of the four treatment periods. 3. Treatment of group I patients with the high-dose-aspirin/dipyridamole combination resulted in significant (P less than 0.001) prolongation of platelet survival from 7.3 +/- 0.2 (mean +/- SEM days to 8.4 +/- 0.1 days. 4. In group II patients, when compared with the mean placebo result of 7.2 +/- 0.2 days, the mean aspirin-labelled-platelet-regeneration time was significantly (P less than 0.01) longer only after high-dose-aspirin/dipyridamole (9.8 +/- 0.5 days) but not after low-dose-aspirin/dipyridamole (8.3 +/- 0.5 days) or aspirin alone (7.3 +/- 0.3 days). 5. These results suggest that it may be premature to consider reducing the dose of aspirin in aspirin/dipyridamole combinations below 1 g/day when used as antithrombotic therapy.

Effects of diet and gliclazide on the haemostatic system of non-insulin-dependent diabetics.

The effect of the sulphonylurea gliclazide on tests of haemostatic function was studied in 14 newly diagnosed non-insulin-dependent diabetics. After two months' treatment with diet alone 11 of the 14 were given gliclazide; the three others remained on dietary treatment. Compared with pretreatment values, significant reductions in platelets retention, factor VIII-related antigen, factor VIII coagulant activity, and plasma heparin neutralising activity accompanied a fall in the plasma glucose concentration due to either diet alone or diet and gliclazide. The beneficial effects of gliclazide on platelet abnormalities seem likely to be due to its hypoglycaemic action rather than to any direct effect on haemostatic function.

The influence of a combined oral contraceptive pill and menstrual cycle phase on digital microvascular haemodynamics.

1. Nailfold capillary pressure, digital blood flow and skin temperature have been measured on days 7, 14, 21 and 28 of the menstrual cycle in 10 women on a combined oral contraceptive pill and 10 control subjects with normal menstrual cycles. 2. Capillary pressure and digital blood flow were statistically significantly higher in the group taking an oral contraceptive pill compared with control subjects. 3. Capillary pressure values for women failed to show the same positive correlation with skin temperature previously described in normal men. 4. The results are interpreted as evidence for a powerful modulating influence of sex steroids on digital microvascular haemodynamics.

Thrombotic disorders associated with pregnancy and the pill.

PIP: A wide range of procoagulant changes has been observed with oral contraceptive (OC) therapy during pregnancy. The thrombotic disorders which are clinically important during pregnancy and the puerperium are venous thromboembolism, thrombosis as a component of preeclamptic toxemia, myocardial infarction, and cerebral infarction and thrombosis. Changes observed in blood coagulability/rheology/flow, platelet function, glucose/lipid metabolism, and blood pressure partially explain the relative tendency towards arterial events. On the other hand, cyclical changes in hemorrheological/hemodynamic factors observed in nonpill users prevent in some way the development of arterial diseases; however, it is possible that cessation of these cyclical changes over a long period may remove the protection from arterial events normally enjoyed by women. The 1977 Royal College of General Practitioner study found that duration of pill use affected risk of circulatory disease: women who had been on the pill continuously for more than 5 years had twice the age-adjusted death rate from circulatory diseases than women who had taken it for a shorter period. Although epidemiological evidence supports the association between pregnancy, OC, and thrombotic disorders, and many procoagulant changes have been demonstrated in both pregnancy and combined pill use, many questions need to be resolved regarding pathogenesis, such as the protective mechanism of menstrual cycle against vascular thrombotic disease and the importance of cyclical variation in hormonal concentration. Because retrospective prevalence studies can not distinguish cause and consequence and cannot provide data on sudden death (perhaps the 1st manifestation of a thrombotic disorder), further prospective studies on OCs with varying chemical formulations should be done.^ieng

Changes in thrombin-stimulated platelet malondialdehyde production during the menstrual cycle.

Forty normal women had thrombin-stimulated platelet malondialdehyde (MDA) production measured during their menstrual cycle. Twenty women in this group were taking the combined oral contraceptive pill (OCP). Platelet MDA production was found to fall by 30% during normal menstruation and the week when the subjects were not taking a combined OCP, but it remained constant throughout the remainder of the cycle. No significant change in initial platelet aggregation response to stimulation by thrombin, change in plasma thrombin clotting time, plasma heparin neutralising activity (HNA), or plasma antithrombin III (AT-III) activity was seen when the platelet MDA production was reduced. The bleeding time results showed some variation throughout the menstrual cycle but these did not appear to be related to the variation in platelet MDA production.

Postoperative deep vein thrombosis: identifying high-risk patients.

A prospective study was carried out to confirm the validity of a predictive index for patients at risk of developing deep vein thrombosis. The index, which correctly identified nine out of 10 patients and incorrectly identified seven out of 52 patients as being at risk, is based on five variable--namely, the euglobulin lysis time, serum concentration of fibrin-related antigen, age, percentage overweight for height, and presence of varicose veins. Thus a population of patients at particularly high risk of developing postoperative deep vein thrombosis may be identified preoperatively by means of this index, so that prophylaxis may be used more rationally.

Prophylaxis of postoperative deep vein thrombosis: selective use of low-dose heparin in high-risk patients.

Administration of prophylactic low-dose subcutaneous heparin to prevent postoperative deep vein thrombosis is expensive, entails treating many patients unnecessarily, and causes some side effects. By using a predictive index a population of patients who are at particularly high risk of developing postoperative deep vein thrombosis may be identified preoperatively. Prophylaxis was given only to these patients, resulting in an incidence of deep vein thrombosis of 3.8% compared with 16.1% in previous studies in which no specific prophylaxis was given. By limiting prophylaxis to the group of patients identified by the predictive index as being at high risk of developing postoperative deep vein thrombosis results may be obtained that are as good as those expected from treating the whole population. Thus many patients are saved from exposure to low-dose subcutaneous heparin.

Coagulation studies in rheumatic heart disease.

The clotting characteristics of pulmonary and systemic blood were studied in 10 patients with chronic rheumatic mitral valve disease complicated by atrial fibrillation and in seven patients with aortic valve disease in sinus rhythm. A haemostatic basis for the association of rheumatic mitral valve disease with thrombotic emboli was sought. Both groups of patients showed differences in platelet function between pulmonary and systemic arterial blood. In patients with mitral valve disease aggregation of platelets was significantly greater in pulmonary than in systemic arterial blood at rest; the converse was true during exercise. In aortic valve disease platelet aggregation was greater in systemic than in pulmonary arterial blood at all times. Only the patients with mitral valve disease showed changes in blood coagulation during passage through the lungs and left heart; there was a small but statistically significant shortening in partial thromboplastin time in systemic as compared with pulmonary arterial blood both at rest and during exercise. Similarly, the effects of exercise on the various haemostatic factors measured were largely confined to the patients with mitral valve disease; in these patients exercise stimulated an increase in factor VIII in pulmonary arterial blood and an increase in platelet adhesiveness and aggregability in left heart blood. These changes provide a basis for the suggestion that in patients with rheumatic mitral valve disease, unlike those with aortic valve disease, there is an increased thrombotic tendency in blood in the left heart which is particularly pronounced during exercise.

The haemostatic mechanism and menstruation: the role of intra-uterine contraceptive devices.

PIP: A multidisciplinary study was conducted to examine the hemostatic mechanism in the uterus during menstruation with and without an IUD in situ. The subjects were 40 female patients undergoing menstruation -- 20 with IUDs and 20 without (control group). The patients' coagulation profiles, fibrinolytic system and platelet functions were examined before and after hysterectomy. No significant differences were found in the coagulation, fibrinolytic and platelet function tests in the 2 groups, but in each group the expected changes after operation occurred. Platelet survival time, consumption and radioactivity in the tampons revealed no significant differences between the IUD and control groups. 6 patients in the IUD group had low platelet survival times. Resected uteri revealed a lack of concentration of platelets. This may have been due in part to blood loss at operation and handling of the uterus. Platelet survival time in response to the severe hemostatic challenge of menstruation was normal, but 6 patients in the IUD group showed shortening of platelet survival.^ieng

Platelet function in hairy-cell leukaemia.

A quantitative study of various aspects of platelet function was carried out in eight patients with typical hairy-cell leukaemia (HCL). In at least two patients platelet aggregation was convincingly reduced to more than one aggregating agent (ADP, adrenaline, collagen, thrombin, and ristocetin). Granular storage capacity for {(14)C} 5-HT was reduced in five of the six patients tested. The two patients with definitely abnormal aggregation had the greatest reduction in granular storage pool and the longest bleeding times of those tested but, like the other patients, they did not have a clinical haemostatic defect. It was concluded that a granular storage pool defect (SPD) was at least partly responsible for aggregation abnormalities in HCL since the platelet release reaction in response to thrombin appeared to be normal. All our patients ran a chronic course uncomplicated by any of the factors known to predispose to a platelet SPD acquired in the circulation. Although in the one patient tested before and after splenectomy there was some improvement in platelet aggregation after operation, there was no clear general relationship between defective platelet function and either previous splenectomy or platelet count. Since a direct involvement of the megakaryocytic series in the underlying cell proliferation of HCL seems unlikely, it is concluded that the platelet defect can most reasonably be attributed to the production of abnormal platelets as a result of marrow fibrosis and/or infiltration by hairy cells.

Effect of intrauterine contraceptive device on uterine haemostasis: a morphological study.

The effect of the intrauterine contraceptive device (IUCD) on uterine haemostasis was studied at various stages of the menstrual cycle in a series of 46 patients by light- and electron-microscopy and by following the distribution of an infusion of 51Cr-labelled autologous platelets. The endometrium in contact with the IUCD in the majority of cases showed grooving with atrophy and mild chronic inflammation in the surrounding tissues. The adjacent stroma also showed increased vascularity and occasional foci of haemorrhage but the increased blood loss associated with the presence of the IUCD could not be attributed to mechanical erosion or stromal blood vessels by the device. During menstruation the presence of an IUCD does not appear to inhibit the formation of fibrin/platelet thrombi although both in control and IUCD patients there was a striking paucity of platelet/fibrin thrombi in circumstances where their formation should be enhanced. In contrast to other workers we have not observed that gaps or breaks in the endothelial lining of endometrial blood vessels occur with any greater frequency in patients fitted with an IUCD. The principal mechanism by which uterine haemostasis is achieved remains to be established.

The metabolism of dihomo-gamma-linolenic acid in man.

Orally administered dihomo-gamma-linolenic acid (DHLA) is well absorbed in man; it appears in blood after ca. 4 hr first as triglyceride ester and later as phospholipid. After sustained-dosing, DHLA penetrated membrane pools and all phospholipid components but, depending on the dosage, reached a metabolic equilibrium in 4-16 days. Intact platelets do not accumulate arachidonate following DHLA administration, and species differences occur in the capacity of animals to metabolize DHLA to arachidonic acid (AA). The rat appears to be unusual in having a very active hepatic delta5-desaturase enzyme system. Potentially antithrombotic changes in platelet function which followed the administration of DHLA to man were accompanied by a significant increase in the capacity of platelets to synthesize PGE1. Concomitant increases in PGE2 synthesis do not apparently result from an increased production of AA and suggest that DHLA, or a DHLA metabolite, interferes with the metabolism of AA. Effects on thromboxane and prostacyclin synthesis are being studied.