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Calcium-dependent cysteine protease activity in the sera of patients with
thrombotic thrombocytopenic purpura
WG Murphy, JC Moore and JG Kelton
Department of Pathology, McMaster University, Hamilton, Ontario, Canada.
Plasma and serum from patients with thrombotic thrombocytopenic purpura
(TTP) can cause activation and aggregation of normal human platelets in
vitro. It is possible that this platelet-activating factor contributes to
the disease. In this report we describe studies designed to identify the
platelet-activating factor in TTP. Platelet activation by sera from 15
patients with TTP was inhibited by leupeptin, iodoacetamide, and antipain
but not by phenylmethylsulphonylfluoride, epsilon-aminocaproic acid,
soybean trypsin inhibitor, aprotinin, and D-phenylanyl-1-prolyl-1- arginine
chloromethyl ketone. These studies suggested that the platelet- activating
factor in TTP serum was a cysteine protease. We confirmed that a
calcium-dependent cysteine protease (CDP) was present in the sera of each
of the 15 patients when we used an assay based on the ability of CDP to
proteolyse platelet membrane glycoprotein 1b (GP1b) and hence to abolish
the ability of CDP-treated normal platelets to agglutinate in the presence
of ristocetin and von Willebrand factor. This proteolytic activity was
inhibited by EDTA, leupeptin, antipain, iodoacetamide, and by
N-ethyl-maleamide (NEM) but not by the serine protease inhibitors. Activity
was detected in 15 of 15 patients with TTP tested before therapy was begun.
In contrast, no activity was detected in the serum of any of five of the
TTP patients tested in remission or in any of the sera from 36 patients
with thrombocytopenia and 423 nonthrombocytopenic controls. To look for in
vivo CDP activity in patients with TTP, we studied platelets from two
patients with acute TTP (drawn into acid-citrate-dextrose, NEM, and
leupeptin). These platelets showed a loss of GP1b from the platelet
surface. Both patients were also studied in remission: GP1b on the platelet
surface had returned to normal. These studies provide evidence that CDP is
present in the sera of patients with TTP, that it is specific to this
disease, and that is is active in vivo as well as in vitro. We postulate
that a disorder of CDP homeostasis plays a major role in the
pathophysiology of TTP.
Volume 70,
Issue 5,
pp. 1683-1687,
11/01/1987
Copyright © 1987 by The American Society of Hematology
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