An international framework for anticoagulant control has been developed based on British Comparative Thomboplastin (B.C.T.) and the model provided by the British system for anticoagulant control. An alternative international system has been proposed, based on lymphilised thromboplastins prepared at the National Institute of Biological Standards and Control, London. Since 1969, stability studies on two of the N.I.B.S.& C. reagents, the primary material 67/40 and the secondary thromboplastin 69/223, have been in progress at the National (U.K.) Reference Laboratory for Anticoagulant Reagents and Control, Manchester. Both the proposed N.I.B.S.&C. reference preparations have deteriorated, while two lyophilised reagents prepared at the National (U.K.) Reference Laboratory have revealed no evidence of instability. In national and international standardisation reliance on B.C.T. should continue.

Anticoagulants↗

PubMed1977

Conjugated equine oestrogens and blood clotting: a follow-up report.

A follow-up study of blood clotting and platelet aggregation was performed on 21 women who had received long-term hormone replacement treatment with conjugated equine oestrogens. The prothrombin time and factor VII and X values were significantly accelerated after three months, but there was no further increase with continual administration for 18 months. After 12 to 18 months' treatment, however, thrombin-induced platelet aggregation (Chandler's tube) was also significantly accelerated, which suggested a widening spectrum of effect. No overall acceleration of "intrinsic" clotting (partial thromboplastin time and thromboelastography) was found during the study, but the relatively small numbers may have been responsible. Further efforts are therefore required to find formulations and doses of oestrogens which, while relieving menopausal symptoms, cause less acceleration of blood clotting and platelet aggregation.

Blood Coagulation↗

PubMed1977

Association of abnormal fibrin polymerisation with severe liver disease.

The frequent occurrence of abnormal fibrin polymerisation in patients with liver disease has recently been reported. To investigate this further, fibrin polymerisation was studied in 68 patients with cirrhosis or chronic active liver disease. Thirty-three of these patients demonstrated impairment of this phase of blood coagulation. When other tests of liver function were compared in patients demonstrating this abnormality and those in whom fibrin polymerisation was normal, it was found that the former group demonstrated significantly reduced albumin concentrations (p less than 0.0002), raised bilirubin and aspartate aminotransferase levels (p less than 0.0006 and less than 0.003 respectively), and greater prolongation of the one-stage prothrombin time (p less than 0.001) with more marked reduction in factor VII levels (p less than 0.002) compared with the latter patients. It is concluded that defective fibrin polymerisation occurring in patients with liver disease indicates the presence of severely impaired hepatocellular function. This might account for the grave prognosis reported in cirrhotic patients with abnormal fibrin polymerisation who also suffer bleeding from gastro-oesophageal varices.

Aspartate Aminotransferases↗

PubMed1976

Measuring partial thromboplastin-time. An international collaborative study.

A series of collaborative exercises on the partial thromboplastin-time (P.T.T.) test, involving over three hundred hospital centres in Britain and overseas, were performed in 1975. Lyophilised test plasmas were issued from the World Health Organisation Collaborating Centre for Anticoagulant Control Reagents to participants, together with a standardised reference P.T.T. reagent and a standard technique. Hospitals were asked to test the plasma samples with the standardised reagent and technique in parallel with their customary local P.T.T. reagent and method. The overall success-rate in detecting the intrinsic clotting abnormality in the eight abnormal test samples was higher with the standardised reagent and technique than with all other reagents. Furthermore, fewer hospitals obtained false positive results when the normal plasma sample was tested with the standardised method rather than with their usual routine reagents. An index was used to measure the success-rate of the P.T.T. reagents in correctly identifying the test plasmas as normal or abnormal. The eight test plasmas showed a varying degree of abnormality. A system of "weighting" was therefore introduced as the failure of a P.T.T. method to detect more severe defects was regarded as more serious. Although hospitals were unfamiliar with the standardised method, the results established its superiority over all other P.T.T. reagents included in the trials in sufficient numbers for analysis. Failures with commercial reagents may have been caused by insensitivity of the cephalin extracts or the unreliability of the manufacturers recommended techniques. Since the same laboratories obtained good results with the standardised method technical failure can be excluded.

Blood Coagulation Disorders↗

PubMed1976

Comparison of prothrombin complex concentrate and vitamin K1 in oral anticoagulant reversal.

A randomised clinical trial was undertaken to compare the value of a factor II, IX, and X concentrate (Prothromplex) with intravenous vitamin K1 (2-5 mg) in reversing an overdose of oral anticoagulants. Rapid partial correction of the prothrombin time, partial thromboplastin time, and the clotting factor assays were observed with the concentrate, but these changes were not always sustained. In contrast vitamin K1 did not show any great effect at two hours but at 24 hours there was always over-correction despite the conservative dosage, prothrombin times being shorter than the therapeutic range. The prothrombin complex concentrate provides a quicker, more controlled but less sustained method of reversing the coumarin defect than vitamin K1. But there remains a significant risk of hepatitis even with a preparation for which strenuous efforts have been made to minimise this risk by screening for hepatitis B virus. The risk should be carefully considered before such concentrates are infused in non-urgent conditions.

Anticoagulants↗

PubMed1976

Abnormal fibrin polymerization in liver disease.

Although there have been isolated reports of an acquired abnormal fibrinogen in patients with liver disease, its frequency and clinical significance is not known. In this study 121 consecutive patients with a wide spectrum of hepatic disorders were screened for abnormal fibrin polymerization. A simple colorimetric method using Reptilase was employed. Of 32 patients with proven cirrhosis, 16 (50%) showed abnormal fibrin polymerization. The incidence in decompensated alcoholic cirrhosis was particularly high. The abnormality was also detected in all patients with acute liver failure and seven of 15 with chronic active liver disease. Clinical improvement often correlated with its disappearance. Two patients with primary liver cell tumours demonstrated the abnormal polymerization. In patients with bleeding oesophageal varices the detection of abnormal fibrin polymerization was associated with a poor prognosis. None of the patients with surgical obstructive jaundice (26) or miscellaneous liver disorders (37) had abnormal fibrin polymerization. The occurrence of abnormal fibrin polymerization in liver disease is more frequent than previously suspected and usually signifies severe primary hepatocellular dysfunction. Evidence is presented to support the presence of a primary abnormality of fibrinogen as the cause of impaired fibrin monomer polymerization.

Batroxobin↗

PubMed1976

Factor VII as a marker of hepatocellular synthetic function in liver disease.

Factor VII levels have been measured in 100 patients with liver disease following parenteral vitamin K1 therapy. There was good agreement between specific factor VII measurements and the one-stage prothrombin time apart from six patients with compensated cirrhosis in whom the prothrombin time was prolonged despite the presence of normal factor VII levels. A mean activity of 58% was found in patients with cirrhosis. Cirrhotic patients with features of hepatic decompensation had a significantly lower mean level of activity (40%) than the "contrast" patients with surgical obstruction of the major bile ducts (93%). Patients with chronic active liver disease had moderate depression of factor VII levels and those with non-cirrhotic liver damage had mean activities similar to the contrast group. Factor VII levels could not be correlated with BSP retention but there was a correlation with serum albumin concentration. It is concluded that the prothrombin time using Quick test with a standardized thromboplastin showing good sensitivity to factor VII, eg, the Manchester reagent (BCT), provides a reliable index of coagulability in chronic liver disease, and specific factor VII assays are not indicated.

Cholestasis↗

PubMed1976

Natural oestrogen replacement therapy and blood clotting.

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Adult↗

PubMed1975

Oral anticoagulant therapy and its control: an international survey.

A survey for the International Study Group for Anticoagulant Control has been conducted in which a questionnaire was sent to members in 39 countries. Information based on 37 replies obtained indicated that the most widely used test in oral anticoagulant therapy is the Quick one stage prothrombin estimation. There is a great diversity in the method of reporting prothrombin time results. Percentage activity of normal on the basis of saline dilution curves is the most popular. Only six countries have national or regional systems for anticoagulant control. Recommendations for the therapeutic range of dosage vary widely. The upper limit in one country may be the lower limit in another. In many centres doses of anticoagulant drugs are advocated which elsewhere are considered either inadequate anticoagulation or dangerous overdosages. The variation of therapeutic range may still be considerable even when a standard thromboplastin is available. Data collected from the survey indicates the need for urgent measures to provide a uniform of laboratory control of clinical dosage of anticoagulant drugs. Until such measures are implemented it is meaningless to try to compare the efficacy of oral anticoagulant therapy from country to country or even to attempt multicentre trials within national boundaries.

Administration, Oral↗

PubMed1975

Effects of "natural oestrogen" replacement therapy on menopausal symptoms and blood clotting.

In a double-blind study on the value of equine ("natural") oestrogens 30 patients presenting with menopausal symptoms in a group practice were monitored for possible adverse effects on blood clotting, weight, and blood pressure. The women were randomly allocated to two groups and given either three months' hormone treatment followed by three months' placebo or vice versa. An appreciable amelioration of all symptoms on placebo made it difficult to asses the genuine value of oestrogen treatment during the period of study. Both groups made a dramatic clinical improvement during the first three months. Nevertheless, the symptoms of the 15 women who received oestrogen first returned after the cross-over to placebo without any suggestion of a placebo response. In contrast, the other group who took placebo first did not deteriorate after changing to oestrogen. The menopausal index and the karyopyknotic index were not reliable guides to the need for oestrogen treatment. Hot flushes, however, were proportionately reduced on oestrogen and they seemed to be more readily eliminated in individual cases by oestrogen. The results of blood clotting studies indicated that natural oestrogen administration raised the levels of the extrinsic clotting factors VII and X and accelerated the prothrombin time. The findings were similar to those observed after three months synthetic oestrogen administration with oral contraception. Long-term studies and epidemiological surveys of the clinical incidence of thrombotic and other sequelae are needed before large-scale oestrogen replacement treatment can be recommended.

Adult↗

PubMed1975

Use of factor-VII-rich prothrombin complex concentrate in liver disease.

A prothrombin complex concentrate rich in factor VII has been used in the management of the clotting defect in thirteen patients with liver disease. Adequate correction of coagulation was achieved immediately after infusion in all cases. Within 4 hours there was some deterioration and by 24 hours the results approximated to pre-fusion values. Liver biopsies were performed without haemorrhagic complication in the immediate post-infusion period. There was no evidence of induced intravascular coagulation. Since other prothrombin complex concentrates have proved disappointing, both in their failure to correct the clotting defect and in their production of disseminated intravascular coagulation, this factor-VII-rich concentrate may be the treatment of choice in patients with liver disease who require temporary correction of their coagulation defect.

Blood Coagulation Disorders↗

PubMed1975

The British system for anticoagulant control.

The British system for anticoagulant control based on the use of a national reagent with a national system of reporting supported by national quality control using lyophilized plasma preparations appears to offer a model which many countries abroad seem interested in adopting to solve their own national problems. Good progress has already been made in this direction in some Commonwealth countries and in South Africa. At a symposium at the 3rd Mediterranean Congress on Thromboembolism in 1973 invited participants from all over the world agreed to set up an International Study Group to provide an international organisation for anticoagulant control, and an encouraging start has been made.

Analysis of Variance↗

PubMed1975

Letter: Reliability of laboratory tests for the control of oral anticoagulation.

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Anticoagulants↗

PubMed1975

Coagulation studies as a prognostic index in acute liver failure.

A coagulation screen has been performed on 12 patients with acute liver failure. Six died and six recovered. All six fatal cases developed a haemorrhagic state with haemostatic failure. An attempt has been made to delineate the various mechanisms for the production of the coagulation defect. The significance of the different haematological parameters in assessing prognosis has been assessed. The study emphasizes the importance of the synthetic ability of the liver in determining survival prospects. A good correlation between the factor-VII level, which is a guide to liver synthesis, and recovery has been shown. The value of a specific factor-VII assay in acute liver failure appears considerable. Where this assay cannot be performed the clot opacity fibrinogen technique provides a reasonable guide to the prognosis. The presence or absence of DIC was not a determinant factor in survival in this series.

Adolescent↗