The effect of aprotinin on the response of the activated partial thromboplastin time (APTT) to heparin

Aprotinin, a broad spectrum serine proteinase inhibitor, is becoming increasingly used to control bleeding during surgery. Heparinized patients treated with aprotinin for cardiac surgery have a much longer activated clotting time (ACT) than expected for the dose of heparin used and a similar effect has been observed with the activated partial thromboplastin time (APTT). Since APTT reagents vary in their sensitivity to heparin we compared the effect of aprotinin on 25 commercially available products with respect to the APTT response to heparin. Aprotinin (Bayer) was added to normal, pooled, citrated plasma at concentrations of 0, 100, 200, 300 and 400 kallikrein inhibition units (KIU)/ml and mucosal heparin was then added to give concentrations of 0, 0.25, 0.5, 0.75 and 1.0 IU/ml. Duplicate APTTs were performed on each of these 25 plasma samples according to the manufacturers' instructions. As expected, different commercial reagents exhibited different sensitivities to heparin. There was also variation in the sensitivity to aprotinin but this did not correlate with the heparin sensitivity. The prolongation of the APTT by heparin was markedly increased by aprotinin. For example, APTT ratios at 0.5 IU/ml heparin increased up to eight-fold in the presence of ‘therapeutic’ levels of aprotinin (200 KIU/ml) and this effect was even more pronounced at higher heparin levels. The activator used did not significantly influence the effect of aprotinin on the APTT although there was a trend for kaolin-activated reagents to be less affected by the addition of aprotinin to heparinised plasma. These results suggest that therapeutic ranges for APTT ratios in heparin therapy should be re-evaluated for each APTT reagent used if high dose aprotinin is being given concomitantly.