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Blood, Vol. 95 No. 12 (June 15), 2000:
pp. 3796-3803
Effect of recombinant von Willebrand factor reproducing type
2B or type 2M mutations on shear-induced platelet aggregation
Nadine Ajzenberg,
Anne-Sophie Ribba,
Ghassem Rastegar-Lari,
Dominique Meyer, and
Dominique Baruch
From the INSERM U143, Paris, France.
The aim was to better understand the function of von Willebrand
factor (vWF) A1 domain in shear-induced platelet aggregation (SIPA), at
low (200) and high shear rate (4000 seconds-1) generated by
a Couette viscometer. We report on 9 fully multimerized recombinant
vWFs (rvWFs) expressing type 2M or type 2B von Willebrand disease (vWD)
mutations, characterized respectively by a decreased or increased
binding of vWF to GPIb in the presence of ristocetin. We expressed 4 type 2M (-G561A, -E596K, -R611H, and -I662F) and 5 type 2B
(rvWF-M540MM, -V551F, -V553M, -R578Q, and -L697V). SIPA was strongly
impaired in all type 2M rvWFs at 200 and 4000 seconds-1.
Decreased aggregation was correlated with ristocetin binding to
platelets. In contrast, a distinct effect of botrocetin was observed,
since type 2M rvWFs (-G561A, -E596K, and -I662F) were able to bind to
platelets to the same extent as wild type rvWF (rvWF-WT).
Interestingly, SIPA at 200 and 4000 seconds-1 confirmed the
gain-of-function phenotype of the 5 type 2B rvWFs. Our data indicated a
consistent increase of SIPA at both low and high shear rates, reaching
95% of total platelets, whereas SIPA did not exceed 40% in the
presence of rvWF-WT. Aggregation was completely inhibited by monoclonal
antibody 6D1 directed to GPIb, underlining the importance of vWF-GPIb
interaction in type 2B rvWF. Impaired SIPA of type 2M rvWF could
account for the hemorrhagic syndrome observed in type 2M vWD. Increased
SIPA of type 2B rvWF could be responsible for unstable aggregates and
explain the fluctuant thrombocytopenia of type 2B vWD.
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