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Platelet prothrombinase activity and intracellular calcium responses in
patients with storage pool deficiency, glycoprotein IIb-IIIa deficiency, or
impaired platelet coagulant activity--a comparison with Scott syndrome
HJ Weiss and B Lages
Department of Medicine, St Luke's-Roosevelt Hospital Center, New York, NY
10019, USA.
The procoagulant activity of platelets induced by collagen, thrombin, and
collagen plus thrombin, measured as their capacity to promote the
conversion of prothrombin to thrombin in the presence of factors Va and Xa,
was studied in patients with alpha, alpha delta, and delta storage pool
deficiency (SPD), thrombasthenia, and in two new patients with isolated
defects in platelet coagulant activity, and compared with that in Scott
syndrome. The most significant abnormality in the new patients, whose
defect may differ from that in Scott syndrome, is an impairment in collagen
plus thrombin-induced prothrombinase activity in the absence of added
factor Va. In one of these patients this may be caused by an abnormality in
platelet alpha-granule factor V distinct from that described for factor V
Quebec, alpha delta-SPD, or alpha-SPD (gray platelet syndrome).
Prothrombinase activity in response to all agonists was impaired in
delta-SPD and was associated with an inability of these platelets to
maintain elevated intracellular calcium levels. Both the rapid decline in
agonist-induced [Ca2+]i levels and the impaired prothrombinase activation
in delta-SPD platelets were corrected by the addition of adenosine
diphosphate (ADP) after stimulation. These findings suggest that secreted
ADP may play an important role in the generation of prothrombinase activity
by contributing to the maintenance of a critical [Ca2+]i level necessary to
maintain aminophospholipids on the outer surface of the platelet membrane,
and provide evidence that dense granules may be a major source of ADP which
can contribute to calcium influx in stimulated platelets. Parallel
alterations, including both increases and decreases, in the [Ca2+]i and
prothrombinase responses were also observed in thrombasthenia, depending on
the agonist and stirring conditions. Both responses were increased in
collagen-stimulated, unstirred platelets, whereas an inability to maintain
increased [Ca2+]i levels, associated with decreased prothrombinase activity
in all but one atypical patient, was seen in stirred collagen plus
thrombin- activated platelets. Although the parallel alterations in these
responses in thrombasthenia, as in SPD, further show the close association
between the generation of prothrombinase activity and the maintenance of
increased intracellular Ca2+ levels, the specific role that GPIIb-IIIa may
play in both these events remains unresolved. Our findings of both
enhancement and inhibition of these activation-related events in
thrombasthenic platelets may be related to previous conflicting reports on
the promotion or inhibition of fibrin formation by GPIIb-IIIa, and could be
relevant to the use of specific inhibitors of GPIIb-IIIa as antithrombotic
agents. In addition, the study provides further support for the concept
that the development of agents that could induce a Scott syndrome defect in
normal platelets may provide a new approach to antithrombotic therapy.
Volume 89,
Issue 5,
pp. 1599-1611,
03/01/1997
Copyright © 1997 by The American Society of Hematology
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