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Effects of an antiplatelet glycoprotein Ib antibody on hemostatic function
in the guinea pig
BH Becker and JL Miller
Department of Pathology, SUNY Health Science Center, Syracuse 13210.
Previous studies in the guinea pig model system have established a close
structural homology between human and guinea pig glycoproteins Ib (GPIb)
and IIb/IIIa (GPIIb/IIIa). Moreover, the murine monoclonal antibody (MoAb)
PG-1, which recognizes GPIb in guinea pig platelets and megakaryocytes,
exerted full inhibition on von Willebrand factor (vWF)- dependent platelet
agglutination without inhibiting aggregation induced by ADP, collagen, or
thrombin. The present research extends this animal model system to study of
the effects on hemostatic function following the in vivo injection of MoAb
PG-1 or its F(ab')2 fragments. A hind limb template bleeding time
methodology was developed for use in guinea pigs. Normal bleeding time was
determined to be 2.7 +/- 0.5 minutes (mean +/- SD), with an observed range
of two to four minutes. Platelet counts in these same animals were 501 +/-
82 x 10(3)/microL. After intraperitoneal (IP) injection of busulfan, guinea
pigs became increasingly thrombocytopenic. As long as the platelet count
remained above approximately 150 x 10(3)/microL, the bleeding time was not
more than five minutes; however, further decrease in the platelet count was
accompanied by more marked prolongations of the bleeding time. For 14 to 72
hours after IP injection of 1.3 mg/kg intact PG-1 MoAb, a hemorrhagic state
was produced with a bleeding time greater than 20 minutes. The platelet
count concurrently decreased to approximately 50% of its baseline value but
could not be further decreased either by raising the initial PG-1 dosage
tenfold or by administering a second, equal dose 24 hours after the initial
injection. This finding may reflect a heterogeneity of circulating
platelets with respect to GPIb, to Fc receptors, or to an interaction
between them. After IP injection of 0.63 to 2.5 mg/kg PG-1 F(ab')2
fragment, platelet counts did not decrease more than 21% below baseline
levels in a 72-hour period, and bleeding times never increased by more than
one minute over baseline values. Nevertheless, platelets obtained from
animals 24 hours after injection of 2.5 mg/kg PG-1 F(ab')2 showed full
inhibition of agglutination induced by ristocetin. The response of these
platelets to aggregation by asialo-vWF was also severely inhibited as
compared with control platelets. PG-1 F(ab')2 produced no effect on
aggregation induced by ADP. These studies show that virtually complete
functional block of the vWF receptor by F(ab')2 fragments of the anti-GPIb
MoAb PG- 1 is not sufficient to produce a hemorrhagic state in the guinea
pig animal model system.(ABSTRACT TRUNCATED AT 400 WORDS)
Volume 74,
Issue 2,
pp. 690-694,
08/01/1989
Copyright © 1989 by The American Society of Hematology
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