Coagulation abnormalities in a prospective cohort of 50 patients with PMM2-congenital disorder of glycosylation

• Published in: Molecular genetics and metabolism 2023-06, Vol.139 (2), p.107606-107606, Article 107606
• Main Authors: De Graef, Diederik, Ligezka, Anna N., Rezents, Joseph, Mazza, Gina L., Preston, Graeme, Schwartz, Kaitlin, Krzysciak, Wirginia, Lam, Christina, Edmondson, Andrew C., Johnsen, Christin, Kozicz, Tamas, Morava, Eva
• Format: Article
• Language: English
• Subjects: Abnormal coagulation; Antithrombin; Antithrombins - therapeutic use; Bleeding; CDG; Congenital Disorders of Glycosylation - complications; Congenital Disorders of Glycosylation - diagnosis; Congenital Disorders of Glycosylation - genetics; Factor XI; Glycosylation; Humans; Male; Phosphotransferases (Phosphomutases) - genetics; Prospective Studies; Thrombosis; Thrombosis - epidemiology; Thrombosis - genetics
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2023.107606

Given the lack of reliable data on the prevalence of bleeding abnormalities and thrombotic episodes in PMM2-CDG patients, and whether coagulation abnormalities change over time, we prospectively collected and reviewed natural history data. Patients with PMM2-CDG often have abnormal coagulation studies due to glycosylation abnormalities but the frequency of complications resulting from these has not been prospectively studied. We studied fifty individuals enrolled in the Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC) natural history study with molecularly confirmed diagnosis of PMM2-CDG. We collected data on prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), platelets, factor IX activity (FIX), factor XI activity (FXI), protein C activity (PC), protein S activity (PS) and antithrombin activity (AT). Prothrombotic and antithrombotic factor activities were frequently abnormal in PMM2-CDG patients, including AT, PC, PT, INR, and FXI. AT deficiency was the most common abnormality in 83.3% of patients. AT activity was below 50% in 62.5% of all patients (normal range 80–130%). Interestingly, 16% of the cohort experienced symptoms of spontaneous bleeding and 10% had thrombosis. Stroke-like episodes (SLE) were reported in 18% of patients in our cohort. Based on the linear growth models, on average, patients did not show significant change in AT (n = 48; t(23.8) = 1.75, p = 0.09), FIX (n = 36; t(61) = 1.60, p = 0.12), FXI (n = 39; t(22.8) = 1.88, p = 0.07), PS (n = 25; t(28.8) = 1.08, p = 0.29), PC (n = 38; t(68) = 1.61, p = 0.11), INR (n = 44; t(184) = −1.06, p = 0.29), or PT (n = 43; t(192) = −0.69, p = 0.49) over time. AT activity positively correlated with FIX activity. PS activity was significantly lower in males. Based on our natural history data and previous literature, we conclude that caution should be exercised when the AT levels are lower than 65%, as most thrombotic events occur in patients with AT below this level. All five, male PMM2-CDG patients in our cohort who developed thrombosis had abnormal AT levels, ranging between 19% and 63%. Thrombosis was associated with infection in all cases. We did not find significant change in AT levels over time. Several PMM2-CDG patients had an increased bleeding tendency. More long-term follow-up is necessary on coagulation abnormalities and the associated clinical symptoms to provide guidelines for therapy, patient management, and appro