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Glucosamine (UDP-N-Acetyl)-2-Epimerase and N-Acetylmannosamine Kinase (GNE) is the rate-limiting enzyme in the synthesis of sialic acid. Mutations in the GNE gene are associated with adult-onset myopathy. Recently, four GNE variants were identified in patients with congenital macrothrombocytopenia. The relationship between GNE mutations and macrothrombocytopenia is incompletely understood, as most myopathy patients have normal platelet counts. Here, we investigated the molecular mechanism underlying GNE-related thrombocytopenia. We identified 2 female siblings with a severe congenital macrothrombocytopenia, a severe bleeding pattern and a homozygous p.R420Q mutation in the GNE gene. Functional characterization of the 420Q-GNE variant confirmed loss of function. Patient platelets showed hyposialylation, but plasma markers for glycosylation were normal. 111 Indium-labeled autologous platelet scanning in one patient indicated hepatic platelet sequestration and a decreased platelet half-life. Consistent with these findings, uptake of patient platelets by THP-1 macrophages and HepG2 liver cells was strongly increased. One patient was treated with romiplostim, which increased the platelet count and ameliorated the bleeding tendency. In conclusion, this study shows that the 420Q-GNE variant results in hyposialylation of glycans on platelets, which leads to rapid clearance by the liver and causes thrombocytopenia. Bleeding symptoms can be treated with romiplostim.

Background Thrombosis is a frequent and severe complication in patients with coronavirus disease 2019 (COVID‐19) admitted to the intensive care unit (ICU). Lupus anticoagulant (LA) is a strong acquired risk factor for thrombosis in various diseases and is frequently observed in patients with COVID‐19. Whether LA is associated with thrombosis in patients with severe COVID‐19 is currently unclear. Objective To investigate if LA is associated with thrombosis in critically ill patients with COVID‐19. Patients/Methods The presence of LA and other antiphospholipid antibodies was assessed in patients with COVID‐19 admitted to the ICU. LA was determined with dilute Russell's viper venom time (dRVVT) and LA‐sensitive activated partial thromboplastin time (aPTT) reagents. Results Of 169 patients with COVID‐19, 116 (69%) tested positive for at least one antiphospholipid antibody upon admission to the ICU. Forty (24%) patients tested positive for LA; of whom 29 (17%) tested positive with a dRVVT, 19 (11%) tested positive with an LA‐sensitive aPTT, and 8 (5%) tested positive on both tests. Fifty‐eight (34%) patients developed thrombosis after ICU admission. The odds ratio (OR) for thrombosis in patients with LA based on a dRVVT was 2.5 (95% confidence interval [CI], 1.1–5.7), which increased to 4.5 (95% CI, 1.4–14.3) in patients at or below the median age in this study (64 years). LA positivity based on a dRVVT or LA‐sensitive aPTT was only associated with thrombosis in patients aged less than 65 years (OR, 3.8; 95% CI, 1.3–11.4) and disappeared after adjustment for C‐reactive protein. Conclusion Lupus anticoagulant on admission is strongly associated with thrombosis in critically ill patients with COVID‐19, especially in patients aged less than 65 years.