These authors contributed equally to the manuscript.
Compromised ITAM-based platelet receptor function in a patient with immune thrombocytopenic purpura
Version of Record online: 28 JUN 2008
© 2008 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 6, Issue 7, pages 1175–1182, July 2008
How to Cite
GARDINER, E. E., AL-TAMIMI, M., MU, F.-T., KARUNAKARAN, D., THOM, J. Y., MOROI, M., ANDREWS, R. K., BERNDT, M. C. and BAKER, R. I. (2008), Compromised ITAM-based platelet receptor function in a patient with immune thrombocytopenic purpura. Journal of Thrombosis and Haemostasis, 6: 1175–1182. doi: 10.1111/j.1538-7836.2008.03016.x
- Issue online: 28 JUN 2008
- Version of Record online: 28 JUN 2008
- Received 26 February 2008, accepted 1 May 2008
- GPVI shedding;
- ITAM receptor;
Summary. Background: Receptors on platelets that contain immunoreceptor tyrosine-based activation motifs (ITAMs) include collagen receptor glycoprotein (GP) VI, and FcγRIIa, a low affinity receptor for immunoglobulin (Ig) G. Objectives: We examined the function of GPVI and FcγRIIa in a patient diagnosed with immune thrombocytopenic purpura (ITP) who had unexplained pathological bruising despite normalization of the platelet count with treatment. Methods and Results: Patient platelets aggregated normally in response to ADP, arachadonic acid and epinephrine, but not to GPVI agonists, collagen or collagen-related peptide, or to FcγRII-activating monoclonal antibody (mAb) 8.26, suggesting ITAM receptor dysfunction. Plasma contained an anti-GPVI antibody by MAIPA and aggregated normal platelets. Aggregating activity was partially (∼60%) blocked by FcγRIIa-blocking antibody, IV.3, and completely blocked by soluble GPVI ectodomain. Full-length GPVI on the patient platelet surface was reduced to ∼10% of normal levels, and a ∼10-kDa GPVI cytoplasmic tail remnant and cleaved FcγRIIa were detectable by western blot, indicating platelet receptor proteolysis. Plasma from the patient contained ∼150 ng mL−1 soluble GPVI by ELISA (normal plasma, ∼15 ng mL−1) and IgG purified from patient plasma caused FcγRIIa-mediated, EDTA-sensitive cleavage of both GPVI and FcγRIIa on normal platelets. Conclusions: In ITP patients, platelet autoantibodies can curtail platelet receptor function. Platelet ITAM receptor dysfunction may contribute to the increased bleeding phenotype observed in some patients with ITP.