Unactivated Plasma Of Children With Cooley’s Anemia Has Serine Protease Activity

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Abstract
Twelve children with Cooley’s Anemia aged 2-17 had low biologic activity of factors XI, XII and prekaI Iikrein (PK), (mean ± S.E., XI:56%±6; XII:51%±7; PK:59%±6). This did not appear to reflect depressed hepatic function as other factors measured (fibrinogen, I I, V, VI I, VII I, IX and X) were in the normal range. To investigate the possibility that these factors were being activated in vivo and then removed, nonactivated plasma collected in Na Citrate and EACA was incubated with the chromogenic substrate for thrombin, S2238. The substrate was cleaved by every patient tested (34 samples from 12 patients); nm p-nitroanaline (pNA) released/ml/min was 33±5 compared to 3±4 in 20 samples from 10 healthy controls (p <.001). The substrates for plasma kallikrein (S2302) and Xa (S2222) were also cleaved. S2302 showed greatest sensitivity and S2222 the least (mean nm pNA/ml/min; 2302:I85±27; 2238:43±II; 2222:II±4; p <.001). This proteolytic activity was present in fresh plasma and remained stable at -70° for at least I month. It was inhibited by DFP indicating that it was a serine protease. Trasylol, which inhibits plasma kallikrein and plasmin, also inhibited it. It was unaffected by hirudin indicating that it was not thrombin. Children older than 10 years (N=6) had more protease activity than those (N=6) less than 10 (97±23 nm pNA/ml/min vs 24±6; p<.05). Thus patients with Cooley’s Anemia have a serine protease in unactivated plasma which increases with age and may be related to iron overload. We speculate that due to increased tissue iron a zymogen (?PK) is activated to a protease (?kaI Iikrein) which activates XII which in turn activates XI. The activated factors are then removed. This would explain the depletion of XI, XII and PK in these patients.

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