Compromised ITAM-based platelet receptor function in a patient with immune thrombocytopenic purpura

Receptors on platelets that contain immunoreceptor tyrosine-based activation motifs (ITAMs) include collagen receptor glycoprotein (GP) VI, and FcgammaRIIa, a low affinity receptor for immunoglobulin (Ig) G.

We examined the function of GPVI and FcgammaRIIa in a patient diagnosed with immune thrombocytopenic purpura (ITP) who had unexplained pathological bruising despite normalization of the platelet count with treatment.

Patient platelets aggregated normally in response to ADP, arachadonic acid and epinephrine, but not to GPVI agonists, collagen or collagen-related peptide, or to FcgammaRII-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 (approximately 60%) blocked by FcgammaRIIa-blocking antibody, IV.3, and completely blocked by soluble GPVI ectodomain. Full-length GPVI on the patient platelet surface was reduced to approximately 10% of normal levels, and a approximately 10-kDa GPVI cytoplasmic tail remnant and cleaved FcgammaRIIa were detectable by western blot, indicating platelet receptor proteolysis. Plasma from the patient contained approximately 150 ng mL(-1) soluble GPVI by ELISA (normal plasma, approximately 15 ng mL(-1)) and IgG purified from patient plasma caused FcgammaRIIa-mediated, EDTA-sensitive cleavage of both GPVI and FcgammaRIIa on normal platelets.

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.