C0305: A2Macroglobulin does Not Compensate for Antithrombin Deficiency in Severe Liver Cirrhosis

Abstract

Background: In liver cirrhosis antithrombin (AT) decreases with the severity of the disease and may approach the level of heterozygous AT deficiency (50%). Alpha2Macroglobulin (a2M) may increase up to fourfold. We investigated in how far this makes up for the decrease of AT. Methods: In healthy controls (n = 32) and liver cirrhosis patients (n = 29) we measured AT and a2M with a chromogenic assay and fibrinogen according to Clauss. The overall inhibitory capacity of plasmas (AT plus a2M) was calculated from the descending leg of a thrombin generation (TG) curve after prothrombin conversion was over (after 3 min and at 50 pM tissue factor). Thrombin decay by a2M was calculated from the velocity of a2M-thrombin formation. A computer simulation of thrombin decay, based on ordinary differential equations, was validated by finding superposition of simulated and observed thrombin decay curves within the limits of experimental accuracy both in patients and controls. Results: Mean AT and a2M concentrations in healthy controls were 2.01uM (SD=0.36uM) and 3.34uM (SD=0.89uM), respectively. In liver cirrhosis patients, the average AT level was decreased (1.62uM; p=0.002) and the average a2M level was increased (5.05uM; p=0.001). In accordance, thrombin decay by a2M in patients is 180% of normal (p = 0.001), whereas AT-dependent thrombin decay is 88% of control (p = 0.009). Overall thrombin decay in cirrhosis patients was 95% of control (p = 0.345), so a2M increase compensates for AT decrease. However, in the subset of patients with AT lower than 75% of normal, the rate of thrombin decay is abnormally low (76% of normal, p = 0.001). Computer simulation of thrombin decay in this subset allowed to calculate that that the elevation in a2M levels increases the over-all thrombin decay rate significantly (10%, p = 0.016), but not enough to completely restore physiological thrombin decay rates (76%, p = 0.001). Conclusions: In liver cirrhosis thrombin inactivation by AT is substantially reduced but a simultaneous increase in a2M levels normalizes thrombin decay in patients with moderate AT loss (more than 75% of normal). In patients with severe AT deficiency (less than 75% of normal) complete compensation is no longer achieved.