Jean M. Thomson

Clotting Factors during Oral Contraception: Further Report

Coagulation studies were performed on 97 women taking a variety of oral contraceptives (OCs) 100 normal control women and 76 pregnant women (13 in the first trimester 26 in the second and 37 in the third). Prothrombin activity cephaline time and factor 7 8 and 10 assays were performed before the start and after 1 2 and 3 months then between 3-6 months 7-12 months and between 1-2 years. Prothrombin activity showed only slight variation throughout. There was little difference in cephalin time between the OC and the normal group. In contrast the pregnant patients showed progressively shorter cephalin times which became shortened during the second trimester the most marked acceleration occurring postpartum. There was little change in factor 7 during the first trimester of pregnancy but from the second trimester on a rise was recorded. A rise in factor 7 and 10 levels was seen from the third month on with the maximum in those patients who had been on OCs for more than 2 years. A broader spectrum of clotting tests appeared to be accelerated during normal pregnancy than during OC therapy and both factor 7 and 10 were higher when comparing trimesters of pregnancy with a similar period on OCs. After a 2 year course the rise in factor 7 levels was of the same order. It was concluded that it is important to determine whether factor 7 goes on increasing with more prolonged courses of oral contraception.

Progesterone oral contraception and blood coagulation.

The effects on blood coagulation of oral contraception with continuous progestorone (0.5 mg chlormadinone acetate daily for 3 months) were studied in 76 women 37 (group 1) who had not previously taken any oral contraceptive and 23 (group 2) who had already been taking some combined or sequential preparations. Group 1 women had no significant increase in coagulability and platelet aggregation though an increase in fibrinolytic activity was suggested. Those tested by thromboelastography in this group showed no change in their thromboelastographic pattern. Before chlormadinone therapy group 2 women showed significant shortening of the prothrombin time and raised levels of factors VII and X. By the second month of chlormadinone administration the prothrombin time was normal. After the third month the factor VII level was no longer significantly increased but factor X although falling was still significantly high. Test results are encouraging for use of progesterone alone. Long-term work must be done to substantiate whether the thrombogenic element in the conventional oral contraceptive may have been eliminated by the use of progesterone alone.

Platelet aggregation during oral contraception

Platelet aggregation has been found to be significantly accelerated with the coagulation-induced Chandlers tube technique in women taking combined oestrogen-progestin oral contraceptives, though this was less than in the third trimester of pregnancy. Women taking the pure progestogen, chlormadinone acetate, have not shown this change up to the sixth month of study. In contrast the accelerated platelet aggregation resulting from conventional oral contraception became normal one month after changing to the progestogen. There was no change in the platelet aggregation response to adenosine diphosphate (A.D.P.) during oral contraception.

Oestrogen-progestogen oral contraception and blood clotting: a long-term follow-up.

In a long-term study of women taking the combined oestrogen/progestogen oral contraceptives Ortho-Novin and Norinyl-1 the follow-up has been continued for three years and four years respectively. Acceleration of both “intrinsic” and “extrinsic” clotting tests and of specific factor VII and X assays, reported previously at the nine-month stage, persisted throughout the period of study. Acceleration of Chandlers tube platelet aggregation and hypercoagulable thrombelastographic patterns were recorded. There was, however, no evidence of a cumulative effect after the first nine months.

Blood Clotting and Platelet Aggregation during Oral Progestogen Contraception: A Follow-up Study

A two-year follow-up study of progestogen-only contraception with chlormadinone acetate indicates no increase of the level of factors VII and X, as found after three cycles with all oestrogen-progestogen oral contraceptives. Clotting factors which were raised with combined preparations became normal after the sixth monthly cycle of progestogen and remained normal during the two-year period of study. From 12 months onwards significant changes in the thromboelastograph pattern were recorded, but not to the same extent as with combined preparations. At two years platelet aggregation was significantly accelerated with chlormadinone acetate but was not as rapid as with combined preparations.

Effects of Low-dose Oral Contraceptives on Blood Coagulation

A study has been performed on the effect of Norinyl-1 and Ortho-Novin, two low-dose oral contraceptives, on blood-clotting factors. Ortho-Novin contains twice the amount of hormone as Norinyl-1. It was therefore possible to observe whether any changes detected were related to the dose of oestrogen-progestin combination. The women were tested in parallel with matched normal female controls and a group in the third trimester of pregnancy. Significant rises in factor VII and X levels were found with both low-dose preparations from the third month onwards. There was no difference between patients on Norinyl-1 and Ortho-Novin, and hence the clotting changes do not appear to be dose-dependent. The long-term effects on clotting factors of these low-dose oral contraceptive preparations remain to be investigated.

ORAL CONTRACEPTIVE HORMONES AND BLOOD COAGULABILITY.

A study was made on the effects of oral contraception on blood coagulability in women being treated with a variety of commercial preparations. The results were compared with those in a group of normal female controls and they were also contrasted with the effects of exercise on coagulability in normal women using the same techniques and with the results in patients with deep-vein thrombosis who presented during the period of the trial. It was found that oral contraceptives caused a rise in factor 7 levels significant from Month 3 onwards. No significant changes in cephalin times or antihemophili antihemophilic globulin (AHG) levels were recorded in the oral contraceptive group unlike the physiological changes found after physical exercise in normal women. Increases in factor 7 levels were detected also in a concurrent study of patients with deep-vein thrombosis but these were also associated with shortened heparin clotting-times not found in the women on oral contraceptives. It is considered that this increase in factor 7 levels which is also found in normal pregnancy and the postpartum state as well as in venous thrombosis is an undesirable side-effect of oral contraception. No woman in the study had been on treatment for more than 2 1/2 years and further study is necessary to determine whether different changes occur at a later date. In future investigations it should be determined whether all the preparations available are equally liable to produce raised factor 7 levels.

Platelet aggregation and strenuous exercise

1. Platelet aggregation in the Chandlers tube has been found to be increased in a group of normal male and female volunteers who undertook strenuous physical exercise. This coincided with acceleration of the ‘intrinsic’ blood clotting system and a rise in fibrinogen. The rise in fibrinogen occurred despite increased fibrinolysis.

A DOUBLE‐BLIND CROSS‐OVER STUDY OF PIPERAZINE OESTRONE SULPHATE AND PLACEBO WITH COAGULATION STUDIES

A double‐blind trial of piperazine oestrone sulphate was performed over a period of 14 months on 55 menopausal women complaining of depression and hot flushes. Depression was not affected but the hot flushes were significantly lessened by the oestrogen treatment. After three months of piperazine oestrone sulphate there were no significant accelerations of prothrombin time or increases in factors VII or X but, after six months, there was an acceleration in the prothrombin time. After 14 months those who received piperazine oestrone sulphate for the first six months showed a significant increase in α1‐antitrypsin and factor VIIR:AG. Oestrone piperazine sulphate appears to produce less marked changes in coagulation than oestrogen‐containing oral contraceptives or conjugated equine oestrogens.

Coumarin therapy and platelet aggregation.

Platelet aggregation has been related to blood coagulation studies in patients on nicoumalone, a coumarin anticoagulant. Aggregation studies were performed by means of Chandlers tube and the adenosine diphosphate (A.D.P.)-induced optical density method. Platelet aggregation in Chandlers tube has been shown to be quite different from A.D.P. aggregation and to be dependent on the “intrinsic” (blood) clotting system. When the intrinsic system was depressed by coumarin anticoagulant, aggregation was delayed in Chandlers tube, but patients with a predominantly “extrinsic” (tissue) system defect gave normal results even when their prothrombin time was excessively prolonged. In contrast there was an increased response to A.D.P. in the anticoagulated patients. The study emphasizes the different mechanisms of platelet aggregation, which we have referred to as coagulation-induced and A.D.P.-induced aggregation. It also shows the limitations of routine control of oral anticoagulants by prothrombin time alone, as the coagulation-induced platelet aggregation appears to be quantitatively related to the overall level of clotting factors in the intrinsic system and independent of the extrinsic system.