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Summary Studies of the haemostatic mechanism were made on paired samples from the umbilical vein and artery and from a maternal peripheral vein immediately following delivery in 80 healthy patients with uncomplicated pregnancies. Neonatal blood showed a significant decrease in clotting ‘activity’ and platelet function, and a significant increase in fibrinolytic activity. The umbilical vein, in comparison to the umbilical artery, showed increased clotting ‘activity’, increased platelet function and decreased fibrinolytic activity. The possible adverse influence of the placenta on haemostasis in the fetus and newborn is discussed.

"the only category of caring staff essential when active treatment is no longer possible." However eirenic, the commissioners are not afraid to speak their minds. On fluoridation they are "certain that it is entirely wrong to deprive the most vulnerable section of the population of such an important public health measure for the sake of the views of a small minority of adults for whom its benefits come too late." They do not mince matters concerning the quality of, for example, recruitment into psychiatry, services for the mentally handicapped, and some urban primary care, where "the National Health Service is failing dismally." They recognise the less than altruistic pressure of pharmaceutical companies on GPs and make no bones about drawing up a limited list of drugs, eliminating "ineffective and unnecessarily expensive drugs." Depending on your point of view, you will accept or reject the report in part or in whole. Of course, it will be a disappoint ment to those whose favourite remedies have not been exhibited or who, unrealistically, expected the heavens to open and the NHS to be transformed by "some blinding revelation." The commission is well aware that "there are no magic wands to be waved." If accused of some complacency in their verdict that "we need not feel ashamed of our health service," which "is not suffering from a mortal disease," they could argue that their lofty view enables them to see the wood unimpeded by trees. Those of us working down among the roots may not be quite so sanguine. For me, however, the importance of the report lies in its perspective "overview," presumably free from sectional interest and given in good faith. Its overall attitudes seem healthy and should stimulate ideas and action. They are right that "our work can therefore be regarded only as a beginning." I hope, at a cost of ?918 000, that the exercise will prove to have been cost-effective.

Summary. The fibrin digestion products which appear in serum of patients having treatment with ancrod have been compared with derivatives of human fibrinogen produced by plasmin by means of immunoelectrophoresis, immunodiffusion and gel filtration techniques. In ancrod-treated patients the large molecular weight derivatives X and Y, as well as fragments D and E were seen 4 hr after the start of therapy. By 24 hr the main serum component was fragment D with low concentrations of large molecular weight derivatives still present, but fragment E had been cleared from the circulation. The identity of these fragments to the known products of fibrinogen proteolysis by plasmin has been confirmed. It is suggested that the initial degradation of fibrin micro-clots produced in the circulation during ancrod infusion is mediated by the fibrinolytic enzyme system.

The effects of orally ingested dihomo-gamma-linolenic acid (DHLA), the natural biosynthetic precursor of prostaglandin E1 (PGE1), were assessed in human volunteers. Single doses of DHLA (0.1--2g) increased the proportion of DHLA relative to arachidonic acid in plasma and platelets and also increased the ex-vivo capacity of platelets to produce PGE1 and PGE2. More pronounced effects were observed during sustained treatment (five days to four weeks) when DHLA also accumulated in red cell membranes. These biochemical changes were accompanied by potentially antithrombotic changes in haemostatic function. The most common effect, which was consistently detected after 0.1-g single doses of DHLA or its methyl ester, was a decrease in plasma heparin-neutralising activity. Inhibition of platelet aggregation induced by adenosine diphosphate was also detected, though this was generally less pronounced. Sustained treatment in one subject also produced definite inhibition of ristocetin-induced platelet aggregation. There was only one possible adverse effect--a transient cough in a subject with a history of asthma. DHLA therefore seems to have considerable potential as an agent for preventing and treating human thromboembolic disease.

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.

Summary A synthetic and a natural oestrogen were administered alternately for three months to nine women with primary amenorrhoea using a randomized cross-over schedule. Measurements of haemostatic function were performed before and at the end of each treatment period. No significant change in haemostatic function was observed after treatment with the‘natural’ oestrogen, oestriol succinate. In contrast, treatment with a synthetic oestrogen, ethinyloestradiol, caused shortening of the prothrombin time and an increase in plasma concentration of factor VII and plasminogen. These data support other observations in suggesting that natural oestrogens may have fewer potentially adverse effects on haemostatic function than synthetic oestrogen. We thank the Special Trustees of Leeds General Infirmary for financial support towards the technical costs of this project. Organon Laboratories Limited provided generous financial assistance and the oestriol succinate tablets used in the study. We are grateful to Mrs B. Griffin, Mrs A. Spencer, Mrs G. Levell and Mr J. Leek for technical help.

The action of the venom of the gaboon viper (Bitis gabonica) on blood coagulation, platelets, and the fibrinolytic enzyme system was studied. The results confirm that the venom of Bitis gabonica has a marked anticoagulant action in vitro. The venom appears to impair clot formation by a direct proteolytic action on fibrinogen, releasing soluble breakdown products.

RA233, a new pyrimido-pyrimidine compound, is a powerful inhibitor of platelet function tested in vitro; it inhibits calcium and adenosine diphosphate (A.D.P.)-induced platelet aggregation, inhibits the retention of platelets by glass beads, decreases the release of platelet factor 3 by kaolin, and inhibits clot retraction. In some in-vitro systems RA233 is significantly more potent that its analogue RA433 in inhibiting platelet function.

The venoms of three mambas (Dendroaspis angusticeps, Dendroaspis polylepis and Dendroaspis jamesoni) were shown to be anticoagulant, an effect due largely to interference with the blood thromboplastin mechanism. The venoms were also capable of inhibiting platelet aggregation and reactivity to ADP. All three venoms possessed proteolytic properties but paradoxically reduced euglobulin clot lysis activity. When studied in purified systems this effect was shown to be due to uncompetitive inhibition of plasmin.

Serum creatine kinase, lactate dehydrogenase, aspartate and alanine transaminases, and aldolase were determined in 41 hospital inpatients with haemophilia or Christmas disease and no significant differences from the normal ranges were found.(3) Levels of these enzymes in a further 10 such patients who had sustained muscle haematomata were determined: in all of these there was a consistent rise in the level of creatine kinase, the peak occurring between 36 and 96 hours. In bleeding disorders a rise in serum creatine kinase levels may be useful as a diagnostic test for intramuscular haemorrhage.

Summary. It is suggested that the immunological response in a severe haemophiliac to longstanding incompatible plasma infusions may have been responsible for the development of amyloidosis which culminated in the nephrotic syndrome. Serological studies showed that the patient had a circulating anti-Gm(1) antibody, and also that possibly he was on occasions reacting violently towards the infusion of immune complexes formed between the IgG1 (Fc region) antigens, Gm(1) and ISf(1) and their antibodies. Despite the fact that there was a marked reduction in the number and severity of transfusion reactions after treatment solely with selected Gm(-1) plasmas, there was a progressive deterioration in the patient's renal function.

In a patient with giant-cell carcinoma of the lung a secondary tumour deposit in the arm was incised and bled for three weeks. Investigations showed the tumour to be rich in plasminogen activator. Haemostasis in the tumour was achieved with aminocaproic acid therapy. For a period the plasminogen-activator properties were retained in cell culture of the tumour.

The main components of the fibrinolytic enzyme system are plasminogen, plasmin, activators, and inhibitors. Plasminogen, a naturally occurring plasma globulin, is converted by activators to plasmin, an enzyme which can digest many proteins, including fibrinogen and fibrin, prothrombin, factor V, and antihaemophilic globulin. Under physiological circumstances it is thought that natural inhibitors in the plasma restrict plasmin to digestion of fibrin, but in pathological fibrinolytic (hyperplasminaemic) states plasma proteins, including fibrinogen and antihaemophilic globulin, are digested. Activators of plasminogen include a plasma activator, trace quantities of which are probably responsible for physiological fibrinolytic activity, a urinary activator named urokinase, and activators of bacterial origin?for example, streptokinase. E.A.C.A., a potent competitive inhibitor of plasminogen activa tion (Alkjaersig et al., 1959), was first used in man by Sherry et al. (1959), who found it effective in inhibiting plasma fibrino lytic activity induced by a variety of plasminogen activators. The value of E.A.C.A. in the treatment of pathological fibrinolytic states has recently been reviewed by McNicol and Douglas (1964), who also discuss the pharmacology and toxicity of E.A.C.A. E.A.C.A., a synthetic amino-acid which closely resembles lysine in structure, is rapidly absorbed when taken by mouth. Peak plasma levels are found about two hours after a single oral dose. Urinary excretion is also rapid, the greater part of a single dose being recovered unchanged in the urine in 12 hours. The action of E.A.C.A. as an inhibitor of plasminogen activation is seen with plasma concentrations above 1 mg./100 ml. The first report of the use of E.A.C.A. in haemophilia was from McNicol et al. (1961a) who, during a study of the bene ficial effect on post-operative haemostasis of E.A.C.A. given to produce local inhibition of urokinase activity in the urinary tract, gave E.A.C.A. to a high-grade haemophiliac with haematuria. The haematuria ceased with E.A.C.A. administra tion, but at the same time the patient developed renal colic and was found subsequently to have permanent loss of function in one kidney, presumably because of ureteric blockage with unlysable clot. Steiger et al. (1962) and Barkhan (1964) have also reported successful control of haematuria in three patients and one patient respectively with haemophilia, without any adverse effects on renal function. Abe et al. (1962) and Reid et al. (1964) report favourably on the use of E.A.C.A. for other haemorrhagic complications in small numbers of haemophiliacs. On theoretical grounds there are reasons for considering that E.A.C.A. might have a beneficial systemic effect in the treatment of high-grade haemophilia, in addition to control of local

The coagulation and fibrinolytic mechanisms were investigated in a group of patients with severe pre-eclampsia and eclampsia and the findings were compared with those of healthy women in late pregnancy. In patients with pre-eclampsia the following significant differences were found: (1) greater depression of plasma fibrinolytic activity (euglobulin lysis time) than in normal pregnancy, (2) a higher level of inhibitor to urokinaseinduced lysis, (3) increased levels of serum fibrin degradation products, and (4) reduced platelet counts.In patients with eclampsia a progressive increase of the level of serum fibrin degradation products was found over the three days following eclamptic seizures. No such increase occurred after grand mal seizures in late pregnancy. The findings in this study support the view that intravascular clotting is taking place in pre-eclampsia and that this disturbance of the balance between coagulation and fibrinolysis may be localized to certain areas of the vascular compartment, particularly the placental and renal circulations. Fibrin deposition in the maternal vessels supplying the placenta would impair the placental blood flow, which may explain the placental insufficiency which occurs in pre-eclampsia. Likewise fibrin deposition in the renal vasculature will result in glomerular damage and proteinuria. Hypertension may be related to the renal ischaemic changes or a compensatory response to the presence of fibrin deposition in the vascular compartment. This evidence of intravascular fibrin deposition raises the question of the possible therapeutic value of antithrombotic agents to inhibit the clotting process. On a theoretical basis such treatment might be expected to improve blood flow to the placenta and thereby fetal growth.

Summary Thirty-four men with ischaemic heart disease were given 10 mg stanozolol per day, 10 mg stanozolol plus 100 mg phenformin per day, or a placebo for 12 mth, in a double blind randomized study. A panel of fibrinolytic and coagulation tests was performed at monthly intervals. Throughout the study the groups on active treatment showed significant enhancement of plasma fibrinolytic activity compared with their base-line values, and compared with the placebo group. No significant difference was found in the enhancement of fibrinolysis wliich was produced by either active treatment regimens, and it is concluded that 10 mg stanozolol daily-is as effective as 10 mg stanozolol plus 100 mg phenformin daily in increasing plasma fibrinolytic activity in men with ischaemic heart disease.

A haemophilic boy, aged 14 years, presented with rupture of the upper end of the ureter as a result of a crushing injury. Primary ureteral anastomosis was successfully carried out under cover of cryoglobulin precipitate therapy. Renal function tests carried out at 2 months were normal, although the isotope renogram showed slight diminution of function on the injured side and an intravenous pyelogram showed some narrowing of the site of the anastomosis.

A comparison was made between the effects of atheromatous and normal areas of the same aorta on coagulation, fibrinolytic, and platelet aggregating systems. In the thromboplastin generation test it was found that atheromatous aorta possessed significantly greater ability to generate intrinsic prothrombin activator than did normal aortic tissue. But, by the one-stage prothrombin time technique, the content of extrinsic thromboplastin in both types of aorta was similar. Aortic preparations, consisting of intimal and medial layers only, were not found to possess fibrinolytic ability and did not contain inhibitors of the fibrinolytic system. The adhesion of platelets to ulcerated atheromatous areas of aorta was significantly greater than to normal or non-ulcerated atheromatous areas. However, homogenates of atheromatous and normal aorta did not differ in their ability to accelerate platelet aggregation and fibrin clot formation when tested by a modified Chandler9s tube technique. The significance of the findings is discussed and the suggestion made that the mechanisms by which atheromatous aortic tissue might predispose towards intravascular thrombosis in vivo are the ability of such tissue to enhance intrinsic prothrombin activator formation and platelet aggregation.

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.

A range of clinical data was obtained from 124 patients about to undergo operation and several coagulation tests were performed. No patient received prophylaxis for deep vein thrombosis, and isotopic scanning after operation showed that 20 patients had developed thrombosis. a simiple prognostic index for predicting which patients would develop postoperative deep vein thrombosis was constructed using the clinical and coagulation data obtained before operation. The five variables with the best predictive power-euglobulin lysis time, age, presence of varicose veins, fibrin related antigen, and percentage overweight-produced an equation that identfied 95% of those who developed deep vein thrombosis and misallocated only 28% of those who did not develop thrombosis. In view of the complications that low-dose heparin and dextran can cause, giving prophylaxis to under a third of the patients who will not develop deep vein thrombosis is clearly better than giving it to all.

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.

The viscosity at low shear rate of whole blood, plasma and serum, the haematocrit, plasma fibrinogen, plasma proteins, and IgM were measured in maternal and cord blood immediately following delivery. The whole blood viscosity in maternal blood (mean 19.96 +/- 3.74 centipoise or c/p) was similar to cord blood viscosity (mean 19.44 +/- 4.28 c/p). The mean haematocrit in maternal blood (0.385 +/- 0.026) was significantly lower than the cord haematocrit (0.488 +/- 0.39). Mean plasma viscosity (1.86 +/- 0.47 c/p) and plasma fibrinogen (4.25 +/- 0.75 g/litre) in maternal blood were significantly higher than cord plasma viscosity (1.12 +/- 0.19 c/p) and cord plasma fibrinogen (1.81 +/- 0.61 g/l). Mean serum viscosity (1.22 +/- 0.28 c/p) and mean IgM levels (2.38 +/- 0.36 g/l) in maternal blood were significantly higher than cord serum viscosity (0.90 +/- 0.15 c/p) and cord IgM (0.48 +/- 0.06 g/l). The low low levels of IgM and fibrinogen may protect the fetus from the increased viscosity that could be expected in association with a high haematocrit.

Platelet counts, coagulation factors, and the fibrinolytic system were studied in seven regular dialysis patients during the course of haemodialysis by parallel flow (Gambro-Alwall) and coil (Travenol Ultra-Flo 100) dialysers. Significant falls in the patients' platelet counts and rises in their factor V levels were found with both dialysis systems. The changes were more pronounced over the course of a Gambro-Alwall dialysis, when significant falls in the partial thromboplastin clotting time and in the plasminogen levels were also noted. These haemostatic changes were associated with the retention of platelets on the dialysis membranes and, in the case of the Gambro-Alwall dialyser, with the formation of platelet-fibrin thrombus. This thrombus formation may take place in spite of efficient heparin anticoagulation and may cause excessive blood loss to the regular dialysis patient.

The effects of the venoms of Naja melanoleuca, Naja nigricollis , and Ophiophagus hannah on blood coagulation, platelet aggregation, and fibrinolysis were studied in vitro. All three venoms were shown to be anticoagulant. This action appeared to be due to an effect on both the extrinsic and blood thromboplastin mechanisms. Platelet aggregation in Chandler9s tubes and adenosine diphosphate reactivity were inhibited by the three venoms, although in the case of Ophiophagus hannah venom they were inhibited only with intermediate concentrations. The three venoms possessed proteolytic properties, but when incorporated into purified caseinolytic systems and euglobulin clot lysis systems inhibition of plasmin activity was observed.

The effect of pregnancy on the components of the fibrinolytic enzyme system was determined by serial observations on 10 healthy women during normal pregnancy, labour, and the puerperium. The plasminogen level was substantially increased in the third trimester; the increase occurred pari passu with a pronounced increase in fibrinogen concentration. After allowing for the expansion of plasma volume in pregnancy a twofold increase in the absolute amounts of circulating fibrinogen and plasminogen was found. In late pregnancy and during labour the level of plasminogen activator was greatly decreased, whereas a normal or increased level was present in the first week of the puerperium. No alteration in the levels of inhibitors of plasminogen activation by urokinase was found during normal pregnancy. The thrombin time and platelet count remained unchanged during pregnancy and labour but the platelet count rose significantly during the first week of the puerperium.The haemostatic mechanism in pregnancy appears to be altered towards an enhanced capacity to form fibrin and a diminished ability to lyse fibrin. These changes may be a physiological development to ensure the integrity of the foetal and maternal circulations and provide rapid and effective haemostasis in the uterus during and after placental separation. Nevertheless, the changes may also establish a vulnerable state for intravascular fibrin deposition.

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.