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R. Vollenberg et al.
functional effects of anti-GP V with subsequent changes in platelet reactivity. Since this was a laboratory-based study with one-stage clinical and laboratory data only, and no follow up, no definite conclusions can be drawn.
The low level of phagocytosis induced by these autoan- tibodies may hint at a unique mechanism of thrombocy- topenia, or could indicate that a co-factor found in vivo but not in vitro (complement components, C-reactive protein, or serum amyloid A) is required.30 Alternatively, it is pos- sible that the highest affinity antibodies remain bound to platelets and those in the sera have lower affinity and, therefore, trigger lower levels of phagocytosis.
Antibodies against GP V could exert different functional effects on platelets: GP V is cleaved by thrombin or, fol- lowing platelet activation with collagen, by ADAM17/TACE.31,32 GP V is thought to function as a neg- ative modulator of thrombin-induced platelet activation.33 In vivo studies in mice have demonstrated that the absence of GP V increases both platelet adhesion and aggregation; but also decreases thrombus stabilization.34 Whether any of these physiological processes are affected by anti-GP V autoantibodies is currently not known. Since we have now established GP V as an important immune target in ITP, it will be important to study whether the presence (or absence) of anti-GP V antibodies also affects treatment efficacy, as previously reported for the two other autoan- tibody specificities.35,36
This study has some limitations. Only ITP patients in
whom a complete direct MAIPA test could be performed qualified. This cohort may not be representative for all ITP patients. In addition, antibodies of the IgA or IgM type, which are rarely detected in ITP,27,28,37 were not studied. We were also unable to characterize IgG subclasses in our cohort. Whereas others have shown that the majority of anti-GPIIb/IIIa autoantibodies are of the IgG1 subclass, some IgG2, 3 and 4 have been reported.38 The IgG subclass distribution of anti-GP V may differ from anti-GPIIb/IIIa. Finally, any blood sample taken from an ITP patient may not reflect the in vivo situation, since platelets sensitized with high-avidity antibodies may have been cleared (together with these antibodies) from the circulation before the sample was taken.
Despite these restrictions, we have confirmed GP V as a frequent immune target in ITP and demonstrated that anti-GP V autoantibodies are of clinical relevance since they can remove platelets from the circulation. We have also, for the first time, demonstrated that low platelet autoantibody avidity might be the main reason why cur- rent serology does not detect platelet autoantibodies more often. We would suggest that studies including GP V as an immune target are required before ITP treatment can be tailored according to platelet autoantibody specificities.
Acknowledgments
The authors would like to thank Astrid Giptner, Heike Berghöfer and Renate Marschall for excellent technical support.
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