MARÍA EUGENIA DE LA MORENA BARRIO, IRENE MARTINEZ MARTINEZ, CARMEN DE COS, EWA WYPASEK, VANESSA ROLDAN SCHILLING, ANETTA UNDAS, MONIQUE VAN SCHERPENZEEL, DIRK LEFEBER, MARA TODERICI, TERESA SEVIVAS, FRANCISCO ESPAÑA, JAAK JAEKEN, JAVIER CORRAL DE LA CALLE, VICENTE VICENTE GARCÍA,

• [GI/IMIB/C001/2011] HEMATOLOGÍA Y ONCOLOGÍA MÉDICA CLÍNICO-EXPERIMENTAL

Since the discovery of antithrombin deficiency, 50 years ago, few new thrombophilic defects have been identified, all with weaker risk of thrombosis than antithrombin deficiency. The fatal morbi-mortality associated with thromboembolic diseases together with the high incidence in the world today, firmly encourage the search of new causes of thrombosis. Thus, the aim of the present study was to identify new thrombophilic mechanisms.

We studied 30 patients with antithrombin deficiency but with no genetic defects in the gene encoding this key anticoagulant (SERPINC1) selected from 139 cases. AT, antitrypsin and transferrin glycoforms were evaluated by electrophoresis, HPLC and Q-TOF. Genetic analysis included sequencing of candidate genes and whole exome analysis.

A high proportion of these patients (8/30: 27%) had increased hypoglycosylated forms of antithrombin. All N-glycoproteins tested in these patients (a1-antitrypsin, FXI and transferrin) had electrophoretic, HPLC and Q-TOF patterns indistinguishable from those of the congenital disorders of glycosylation (rare recessive multisystem disorders). However, all except for one had no mental disability. Moreover, intermittent antithrombin deficiency and hypoglycosylation was recorded in five out of these eight patients, all associated with moderate alcohol intake. Genetic analysis, including whole exome sequencing, revealed mutations in different genes involved in the N-glycosylation pathway.

Our study provides substantial and novel mechanistic insights into two disease processes, with potential implications for diagnosis and clinical care. An aberrant N-glycosylation causing a recessive or transient antithrombin deficiency is a new form of thrombophilia. Our data suggest that congenital disorders of glycosylation are probably underestimated, especially in cases with thrombosis as the main or only clinical manifestation.