Acquired Glanzmann thrombasthenia associated with platelet desialylation

Abstract

Background The notable discrepancy between platelet count and bleeding manifestations in immune thrombocytopenia (ITP) patients with acquired Glanzmann thrombasthenia (GT) has been described. Objectives We aimed to examine the mechanisms responsible for thrombocytopenia and the bleeding phenotype in a patient with acquired GT. Patient, methods, and results A patient with primary ITP underwent splenectomy due to steroid intolerance. Despite platelet count normalization, bleeding continued. Platelet aggregometry was abnormal with all agonists except for ristocetin. Flow cytometry demonstrated the presence of antiplatelet antibody, which caused dose‐dependent inhibition of fibrinogen and PAC‐1 binding, induction of neuraminidase‐1 expression as well as platelet desialylation in donor platelets. Indirect monoclonal antibody immobilization of platelet specific antigen assay (MAIPA) confirmed specificity to αIIbβ3 only, corroborated by binding on Chinese hamster ovary (CHO) cells expressing human glycoprotein αIIbβ3 but not GP Ib/IX. Both desialylation and neuraminidase expression were observed with plasma adsorbed on Ib/IX CHO cells and with the immunoglobulin G (IgG) fraction. Desialylation was inhibited in the presence of anti‐Fc‐gamma receptor IIa (FcγRIIa) antibody. A nonobese diabetic/severe combined immunodeficient ITP murine model was established, which showed rapid hepatic donor platelet clearance in the presence of patient IgG. Treatment of mice with the neuraminidase inhibitor oseltamivir significantly reduced antibody‐induced platelet destruction. Conclusions We report the first case of a patient with acquired GT due to ITP with FcγRIIa mediated platelet desialylation, independent of platelet activation. Treatment with neuraminidase inhibitor may prevent platelet clearance by anti‐αIIbβ3 antibodies.

Glanzmann Thrombasthenia: A Case Report of a Rare Inherited Coagulation Disorder Presenting with Traumatic Head Injury

“…Haemorrhagic symptoms occurred only in patients who were homozygous for GT-causing mutations; heterozygous diseases are often asymptomatic, although they have only a semi-normal platelet α IIb β 3 concentration. 13 Zheng et al 14 explored the mechanisms underlying thrombocytopenia and the bleeding phenotype in a patient with acquired GT, concluding that platelet desialylation was mediated by anti-Fc-γ receptor IIa, independent of platelet activation, in a patient with acquired GT.…”

Measuring beta‐galactose exposure on platelets: Standardization and healthy reference values

“…21 Furthermore, a case report described a patient with acquired Glanzmann thrombasthenia due to ITP with Fc-γ receptor IIa (FcγRIIa) mediated platelet desialylation who was inhibited in the presence of anti-FcγRIIa antibody. 22 The sialidase inhibitor oseltamivir phosphate (used as an anti-influenza drug) reportedly increased the platelet count in a pediatric ITP patient who experienced platelet desialylation during an influenza virus A infection 19 and in an adult with chronic, anti-GPIb/IXpositive ITP. 15 Furthermore, the combination of a sialidase inhibitor with drugs that boost platelet production induced a sustained platelet response in a proportion of patients with anti-GPIbα-positive ITP and who had failed to respond to previous treatments.…”

“…Indeed, those containing anti‐GPIIb/IIIa antibodies also showed the ability to induce cleavage of sialic acid and expose β‐galactose 21 . Furthermore, a case report described a patient with acquired Glanzmann thrombasthenia due to ITP with Fc‐γ receptor IIa (FcγRIIa) mediated platelet desialylation who was inhibited in the presence of anti‐FcγRIIa antibody 22 …”

Inhibition of NADPH oxidase blocks NETosis and reduces thrombosis in heparin-induced thrombocytopenia

“…For select studies, L012 (25 mg/kg) was administered intraperitoneally 5 minutes prior to euthanasia. Extracted lungs were imaged immediately using the IVIS Spectrum running Living Image 4.5.5 software (Perkin Elmer, MA) 9,[17][18][19] . Platelet counts were analysed by flow cytometry and calculated relative to time 0, prior to IgG and heparin injection.…”