A unique phenotype of acquired Glanzmann thrombasthenia due to non‐function‐blocking anti‐αIIbβ3 autoantibodies

Abstract

Acquired Glanzmann thrombasthenia (aGT) is generally caused by function‐blocking antibodies (Abs). We demonstrated a unique aGT case due to marked reduction of αIIbβ3 with anti‐αIIbβ3 Abs. The anti‐αIIbβ3 Abs of the patient did not inhibit platelet function but reduced surface αIIbβ3. Internalization of αIIbβ3 induced by the Abs binding may be responsible for the phenotype. Summary BackgroundAcquired Glanzmann thrombasthenia (aGT) is a bleeding disorder generally caused by function‐blocking anti‐αIIbβ3 autoantibodies. AimWe characterize an unusual case of aGT caused by marked reduction of surface αIIbβ3 with non‐function‐blocking anti‐αIIbβ3 antibodies (Abs). MethodsA 72‐year‐old male suffering from immune thrombocytopenia since his 50s showed exacerbation of bleeding symptom despite mild thrombocytopenia. Platelet aggregation was absent with all agonists but ristocetin. Analysis of αIIbβ3 expression and genetic analysis were performed. We also analyzed effects of anti‐αIIbβ3 Abs of the patient on platelet function and αIIbβ3 expression. ResultsSurface αIIbβ3 expression was markedly reduced to around 5% of normal, whereas his platelets contained αIIbβ3 to the amount of 40–50% of normal. A substantial amount of fibrinogen was also detected in his platelets. There were no abnormalities in ITGA2B and ITGB3 cDNA. These results indicated that reduced surface αIIbβ3 expression caused a GT phenotype, and active internalization of αIIbβ3 was suggested. Anti‐αIIbβ3 IgG Abs were detected in platelet eluate and plasma. These Abs did not inhibit PAC‐1 binding, indicating that the Abs were non‐function‐blocking. Surface αIIbβ3 expression of a megakaryocytic cell line and cultured megakaryocytes tended to be impaired by incubation with the patient's Abs. After 2 years of aGT diagnosis, his bleeding symptom improved and surface αIIbβ3 expression was recovered to 20% of normal with reduction of anti‐αIIbβ3 Abs. ConclusionWe demonstrated a unique aGT phenotype due to marked reduction of surface αIIbβ3. Internalization induced by anti‐αIIbβ3 Abs may be responsible in part for the phenotype.

Acquired Glanzmann thrombasthenia associated with platelet desialylation

“…It was proposed that autoantibody binding to GPIbα resulted in platelet activation, NEU1 translocation to platelet surface, desialylation, and platelet removal via Ashwell‐Morell receptors on hepatocytes . Both α IIb β 3 activating and nonfunctioning antibody subtypes can be found in acquired GT. In contrast, our patient's anti‐α IIb β 3 antibody inhibited platelet function and induced desialylation, likely mediated via FcγRIIa.…”

Acquired Glanzmann's thrombasthenia with IgG and IgA against activated αIIbβ3

“…These symptoms are thought to be caused by antibodies (IgG) against α IIb β 3 causing either impaired function 6 or potential internalisation of this integrin. 2 Immune-mediated disorders are probably the most common paraneoplastic syndromes in lymphomas. 11 Although rare, acquired GT has been described with lymphoproliferative diseases and autoimmune conditions.…”

“…Acquired GT is often associated with the presence of another autoimmune disease or haematological malignant disorder, or is drug induced. 1 Only a few cases of acquired GT have been described, with this disorder being reported secondary to conditions such as immune thrombocytopaenia (ITP) particularly following splenectomy, [2][3][4] Hodgkin's or non-Hodgkin's lymphomas, [4][5][6] systemic lupus erythematosus or antiphospholipid syndrome. 7 Therapeutic strategies include plasma exchange, immunosuppressants, splenectomy, intravenous immunoglobulin, recombinant factor VII or rituximab, alongside the treatment of the underlying disease.…”

Heterogeneity of Integrin αIIbβ3 Function in Pediatric Immune Thrombocytopenia Revealed by Continuous Flow Cytometry Analysis

“…There is also an autoimmune condition closely related to ITP and GT, which is called the acquired GT (aGT) [30] when the GT-like phenotype without thrombocytopenia is induced by autoimmune antibodies formed against α IIb β 3 . These antibodies in aGT could block α IIb β 3 binding to fibrinogen [31], or cause mild thrombocytopenia [32], or both [33]. It could be speculated that aGT is a form of ITP with mild thrombocytopenia [30].…”