Summary
Thrombin, while reacting in the presence of heparin, impairs the inhibitory capacity
of antithrombin III so that subsequent inhibition of thrombin or factor Xa is decreased
or abolished. This adverse effect of heparin has been observed directly with at least
1.5 Iowa units of thrombin per each unit of purified human antithrombin III participating
in the reaction. The inhibitory capacity was then totally destroyed and some residual
thrombin remained in the active form. With a lower enzyme/inhibitor ratio inactivation
of thrombin in the presence of heparin was fast and complete, however, a significant
decrease of inhibitory capacity below that found in reaction without heparin, has
been established by measuring the residual antithrombin III activity. In defibrinated
human plasma at least 2 units of thrombin per each antithrombin III unit were required
to demonstrate directly the adverse effect of heparin, but a fast depletion of inhibitory
capacity has been also observed after repeated additions of small thrombin portions
into plasma heparinized in vitro or in vivo. Portions of enzyme initially added disappeared
with great velocity; subsequent portions, however, accumulated building up a high
thrombin level not seen in the absence of heparin. The accumulation of residual enzyme
was more extensive in plasma containing about 1 heparin unit per ml than anticoagulant
at lower concentrations and was particularly noticeable in antithrombin III deficient
plasma. These results may have some bearings on the approach to heparin therapy in
the event when thrombin continuously generates or when a marked deficiency of antithrombin
III exists.
