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Analysis of platelet aggregation disorders based on flow cytometric
analysis of membrane glycoprotein IIb-IIIa with conformation-specific
monoclonal antibodies
MH Ginsberg, AL Frelinger, SC Lam, J Forsyth, R McMillan, EF Plow and SJ Shattil
Department of Molecular and Experimental Medicine, Research Institute of
Scripps Clinic, La Jolla, CA 92037.
Normal primary platelet aggregation requires agonist-mediated activation of
membrane GPIIb-IIIa, binding of fibrinogen to GPIIb-IIIa, and cellular
events after ligand binding. PAC1 monoclonal antibody distinguishes between
resting and activated states of GPIIb-IIIa, and other antibodies
preferentially recognize GPIIb (PMI-1) or IIIa (anti- LIBS1) after the
binding of fibrinogen or fibrinogen-mimetic peptides, such as GRGDSP. Using
these antibodies and platelet flow cytometry, we studied two distinct
persistent platelet aggregation abnormalities. Platelets from a
thrombasthenic variant, which contained near-normal amounts of GPIIb-IIIa,
failed to aggregate or bind PAC1 in response to agonists. In addition,
GRGDSP, which binds to normal GPIIb-IIIa without prior cell activation,
failed to increase the binding of PMI-1 or anti- LIBS1 to the
thrombasthenic platelets, suggesting a primary defect in ligand binding.
Chromatography of detergent-solubilized platelets on a KYGRGDS affinity
column confirmed that the patient's GPIIb-IIIa lacked the fibrinogen
binding site. In another patient with myelofibrosis and defective
aggregation, PAC1 failed to bind to adenosine diphosphate- stimulated
platelets, but did bind when protein kinase C was directly activated with
phorbol myristate acetate. Furthermore, the binding of PMI-1 and anti-LIBS1
increased in response to GRGDSP, confirming a defect in agonist-mediated
fibrinogen receptor activation rather than in fibrinogen binding or events
distal to binding. These studies indicate that this immunochemical approach
is useful in classification of clinical abnormalities of platelet
aggregation as defects in either (a) fibrinogen receptor activation, (b)
fibrinogen binding, or (c) postoccupancy events.
Volume 76,
Issue 10,
pp. 2017-2023,
11/15/1990
Copyright © 1990 by The American Society of Hematology
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