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SUMMARY Liver diseases are associated with complex haemostasis defects, in which platelets, coagulation, and fibrinolysis may all be affected. The low plasma concentrations of clottinlg factors often found can be the result of many changes such as impaired synthesis, increased catabolism due to intravascular coagulation, or alternate distribution.In this study, we investigated the metabolism of purified human antithrombin III(AT III) labelled with 125I in 25 patients with histologically established liver disease and in nine control subjects. The results showed that, in general, low plasma concentrations of AT III in liver cirrhosis are not due to consumption in the central compartment but rather to altered transcapillary flux ratio. Such altered transcapillary flux ratios may already exist even with normal plasma AT III concentrations. Altered ratios are not only found for coagulation proteins but also for albumin and thus may be a general phenomenon of liver disease. In micronodular cirrhosis the a phase, the transcapillary efflux (ks, 2) and influx (k2, 1) were significantly increased compared with the normal subjects.Liver disease is associated with a complex haemostasis defect, in which platelets, coagulation, and fibrinolysis may all be affected.' In this study we describe the metabolism of human antithrombin III (AT III) in patients with chronic liver disease.Antithrombin III neutralises thrombin and several other activated serine proteases of the coagulation system.23 Congenital or acquired AT III deficiencies are associated with recurrent thromboembolism.46 Plasma concentrations of this physiological inhibitor of the coagulation system are low in severe chronic liver disease'-" and Tytgat et al have evidence for low grade diffuse intravascular coagulation." I They found a shorter ,3 half life of radiolabelled fibrinogen in patients with liver disease, which could be prolonged by heparinisation.Other studies have shown that selective correction of AT III activity with human AT III concentrate reverses the increased turnover of radiolabelled fibrinogen in these patients.'2 These observations indicate that decreased AT III activity contributes to a major part of the increased radiolabelled fibrinogen turnover.

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We describe a mechanized chromogenic assay for factor X, the results of which correlate well with those for the one-stage clotting assays for factor X in which it is activated either via the extrinsic pathway by thromboplastin or directly by Russell's viper venom. We purified human factor X and raised monospecific antibodies to it in rabbits. We used our chromogenic assay for factor X to develop a factor-X-inhibitor neutralization assay for determination of factor-X antigen. Patients receiving oral anticoagulant treatment had significantly different factor-X activities after activation via thromboplastin or with Russell's viper venom. The concentration of factor-X antigen, although decreased, significantly exceeded factor-X clotting activity or chromogenic activity in this group of patients. Results of the chromogenic assay for factor X correlated well with results of "Thrombotest," a clotting test introduced by Owren (Lancet ii: 754, 1959) to control anticoagulant therapy. For patients taking oral anticoagulant drugs, the therapeutic range by our assay is 180 to 300 units/L.

Antithrombin III (AT-III) heparin cofactor activity and its antigen levels have been determined in 106 plasma samples from 42 term and preterm neonates. In contrast to healthy adult controls, a reduced activity/antigen (act/ag) ratio (ranging from 0.26 to 0.86) was observed in 90% of the samples and was independent of the state of health of the infant. By modifying the routine assay techniques, laboratory artefacts were excluded as the cause of the observed discrepancy. The relative increase in antigenic AT-III could not be accounted for by circulating AT-III-thrombin complexes, or by increased heparin cofactor II plasma levels in neonates.