Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists.
BACKGROUND
Both inherited predisposition and platelet hyperreactivity have been associated with ischemic coronary events, but mechanisms that support genetic differences among platelets from different subjects are generally lacking. Associations between the platelet Pl(A2) polymorphism of GP IIIa and coronary syndromes raise the question as to whether this inherited variation may contribute to platelet hyperreactivity.


RESULTS
In this study, we characterized functional parameters in platelets from healthy donors with the Pl(A) (HPA-1) polymorphism, a Leu (Pl(A1)) to Pro (Pl(A2)) substitution at position 33 of the GP IIIa subunit of the platelet GP IIb/IIIa receptor (integrin alpha(IIb)beta(3)). We studied 56 normal donors (20 Pl(A1,A1), 20 Pl(A1,A2), and 16 Pl(A2,A2)). Compared with Pl(A1,A1) platelets, Pl(A2)-positive platelets showed a gene dosage effect for significantly greater surface-expressed P-selectin, GP IIb/IIIa-bound fibrinogen, and activated GP IIb/IIIa in response to low-dose ADP. Surface expression of GP IIb/IIIa was similar in resting platelets of all 3 genotypes but was significantly greater on Pl(A2,A2) platelets after ADP stimulation (P=0.003 versus Pl(A1,A1); P=0.03 versus Pl(A1,A2)). Pl(A1,A2) platelets were more sensitive to inhibition of aggregation by pharmacologically relevant concentrations of aspirin and abciximab.


CONCLUSIONS
Pl(A2)-positive platelets displayed a lower threshold for activation, and platelets heterozygous for Pl(A) alleles showed increased sensitivity to 2 antiplatelet drugs. These in vitro platelet studies may have relevance for in vivo thrombotic conditions.
Michelson
A D
AD
Departments of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Furman
M I
MI
Goldschmidt-Clermont
P
P
Mascelli
M A
MA
Hendrix
C
C
Coleman
L
L
Hamlington
J
J
Barnard
M R
MR
Kickler
T
T
Christie
D J
DJ
Kundu
S
S
Bray
P F
PF
D000077284:Abciximab; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D018628:Gene Dosage; D005838:Genotype; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D008297:Male; D019007:P-Selectin / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics / Q000502:physiology*; D012016:Reference Values
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D000244:Adenosine Diphosphate; D005340:Fibrinogen; D001241:Aspirin; D000077284:Abciximab