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Blood, 15 July 2001, Vol. 98, No. 2, pp. 257-265
PLENARY PAPER
Platelets from patients with the Quebec platelet disorder contain
and secrete abnormal amounts of urokinase-type plasminogen activator
Walter H. A. Kahr,
Shilun Zheng,
Prameet M. Sheth,
Menaka Pai,
Alison Cowie,
Madeleine Bouchard,
Thomas J. Podor,
Georges E. Rivard, and
Catherine P. M. Hayward
From the Departments of Pathology and Molecular
Medicine, and Medicine, McMaster University, Hamilton; the Hamilton
Regional Laboratory Medicine Program, Ontario; and the Department of
Hematology/Oncology, Hôpital St Justine, Montreal, Quebec,
Canada.
The Quebec platelet disorder (QPD) is an autosomal dominant
platelet disorder associated with delayed bleeding and  -granule protein degradation. The degradation of -granule, but not plasma, fibrinogen in patients with the QPD led to the investigation of their
platelets for a protease defect. Unlike normal platelets, QPD platelets
contained large amounts of fibrinolytic serine proteases that had
properties of plasminogen activators. Western blot analysis, zymography, and immunodepletion experiments indicated this was because
QPD platelets contained large amounts of urokinase-type plasminogen
activator (u-PA) within a secretory compartment. u-PA antigen was not
increased in all QPD plasmas, whereas it was increased more than
100-fold in QPD platelets (P < .00009), which
contained increased u-PA messenger RNA. Although QPD platelets
contained 2-fold more plasminogen activator inhibitor 1 (PAI-1)
(P < .0008) and 100-fold greater u-PA-PAI-1
complexes (P < .0002) than normal platelets, they
contained excess u-PA activity, predominantly in the form of two chain
(tcu-PA), which required additional PAI-1 for full inhibition. There
was associated proteolysis of plasminogen in QPD platelets, to forms
that comigrated with plasmin. When similar amounts of tcu-PA were
incubated with normal platelet secretory proteins, many -granule
proteins were proteolyzed to forms that resembled degraded QPD platelet
proteins. These data implicate u-PA in the pathogenesis of -granule
protein degradation in the QPD. Although patients with the QPD have
normal to increased u-PA levels in their plasma, without evidence of
systemic fibrinogenolysis, their increased platelet u-PA could
contribute to bleeding by accelerating fibrinolysis within the
hemostatic plug. QPD is the only inherited bleeding disorder in humans
known to be associated with increased u-PA.
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