Mechanism of protein C deficiency in a patient with arginine 358 alpha 1-antitrypsin (Pittsburgh mutation): role in the maintenance of hemostatic balance.
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)
Emmerich
J
J
Laboratoire d'Hémostase, Hôpital Broussais, Paris, France.
Alhenc-Gelas
M
M
Gandrille
S
S
Guichet
C
C
Fiessinger
J N
JN
Aiach
M
M
D000293:Adolescent; D006487:Hemostasis; D006801:Humans; D008297:Male; D011486:Protein C / Q000235:genetics; D020151:Protein C Deficiency; D013917:Thrombin / Q000037:antagonists & inhibitors; D018180:Thrombomodulin / Q000502:physiology; D000515:alpha 1-Antitrypsin / Q000032:analysis*
D011486:Protein C; D018180:Thrombomodulin; D000515:alpha 1-Antitrypsin; C038915:alpha 1-antitrypsin Pittsburgh; D013917:Thrombin