We recently described a new case of alpha 1-antithrombin (alpha 1-AT) Pittsburgh, a mutation that transforms alpha 1-AT into a potent inhibitor of
thrombin. In contrast to the originally described patient, who had a severe
hemorrhagic diathesis, our proband had only a mild
bleeding tendency. The current article explores possible mechanisms for the relative
hemostatic competence of our patient. The levels of both normal and mutant alpha 1-AT were similar to those of the previously reported case, as was the rise in plasma
antithrombin level during an
acute phase reaction. The level of
protein C, however, was found on several occasions to be approximately 20% of normal. Family studies and examination of the patient's
protein C gene on a denaturing gel failed to identify an abnormality. Moreover, the patient's
protein C showed no abnormalities suggestive of faulty intracellular processing. However, the
protein C in his plasma was for the most part in the activated form and bound to the mutant alpha 1-AT. Thus it is likely that the strong affinity of mutant alpha 1-AT for
protein C leads to an increased turnover and thus to a low circulating level. A seeming flaw in that scenario is that the mutant alpha 1-AT also has a very high affinity for
thrombin and might be expected therefore to block the activation of
protein C. When
thrombin was complexed with
thrombomodulin (as it is when
protein C is physiologically activated at the endothelial surface), mutant alpha 1-AT was far less able to inhibit
thrombin than was the case for the free
enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)