Phosphomannomutase 2 (PMM2-CDG) is the most common congenital disorder of N-glycosylation and is caused by a deficient PMM2 activity. The clinical presentation and the onset of PMM2-CDG vary among affected individuals ranging from a severe antenatal presentation with multisystem involvement to mild adulthood presentation limited to minor neurological involvement. Management of affected patients requires a multidisciplinary approach. In this article, a systematic review of the literature on PMM2-CDG was conducted by a group of international experts in different aspects of CDG. Our managment guidelines were initiated based on the available evidence-based data and experts' opinions. This guideline mainly addresses the clinical evaluation of each system/organ involved in PMM2-CDG, and the recommended management approach. It is the first systematic review of current practices in PMM2-CDG and the first guidelines aiming at establishing a practical approach to the recognition, diagnosis and management of PMM2-CDG patients.
To cite this article: de la Morena-Barrio ME, Mart ınez-Mart ınez I, de Cos C, Wypasek E, Rold an V, Undas A, van Scherpenzeel M, Lefeber DJ, Toderici M, Sevivas T, España F, Jaeken J, Corral J, Vicente V. Hypoglycosylation is a common finding in antithrombin deficiency in the absence of a SERPINC1 gene defect. J Thromb Haemost 2016;14: 1549-60. Essentials• We investigated the molecular base of antithrombin deficiency in cases without SERPINC1 defects.• 27% of cases presented hypoglycosylation, transient in 62% and not restricted to antithrombin.• Variations in genes involved in N-glycosylation underline this phenotype.• These results support a new form of thrombophilia.
SARS-CoV-2 infection increases the risk of thrombosis by different mechanisms not fully characterized. Although still debated, an increase in D-dimer has been proposed as a first-line hemostasis test associated with thromboembolic risk and unfavorable prognosis. We aim to systematically and comprehensively evaluate the association between thrombin generation parameters and the inflammatory and hypercoagulable state, as well as their prognostic value in COVID-19 patients. A total of 127 hospitalized patients with confirmed COVID-19, 24 hospitalized patients with SARS-CoV-2-negative pneumonia and 12 healthy subjects were included. Clinical characteristics, thrombin generation triggered by tissue factor with and without soluble thrombomodulin, and also by silica, as well as other biochemical parameters were assessed. Despite the frequent use of heparin, COVID-19 patients had similar thrombin generation to healthy controls. In COVID-19 patients, the thrombin generation lag-time positively correlated with markers of cell lysis (LDH), inflammation (CRP, IL-6) and coagulation (D-dimer), while the endogenous thrombin potential (ETP) inversely correlated with D-dimer and LDH, and positively correlated with fibrinogen levels. Patients with more prolonged lag-time and decreased ETP had higher peak ISTH-DIC scores, and had more severe disease (vascular events and death). The ROC curve and Kaplan Meier estimate indicated that the D-dimer/ETP ratio was associated with in-hospital mortality (HR 2.5; p = 0.006), and with the occurrence of major adverse events (composite end-point of vascular events and death) (HR 2.38; p = 0.004). The thrombin generation ETP and lag-time variables correlate with thromboinflammatory markers, and the D-dimer/ETP ratio can predict major adverse events in COVID-19.
The balance between actions of procoagulant and anticoagulant factors protects organisms from bleeding and thrombosis. Thus, antithrombin deficiency increases the risk of thrombosis, and complete quantitative deficiency results in intrauterine lethality. However, patients homozygous for L99F or R47C antithrombin mutations are viable. These mutations do not modify the folding or secretion of the protein, but abolish the glycosaminoglycan-induced activation of antithrombin by affecting the heparinbinding domain. We speculated that the natural -glycoform of antithrombin might compensate for the effect of heparinbinding mutations. We purified ␣-and -antithrombin glycoforms from plasma of 2 homozygous L99F patients. Heparin affinity chromatography and intrinsic fluorescence kinetic analyses demonstrated that the reduced heparin affinity of the ␣-L99F glycoform (K D , 107.9 ؎ 3nM) was restored in the -L99F glycoform (K D , 53.9 ؎ 5nM) to values close to the activity of ␣-wild type (K D , 43.9 ؎ 0.4nM). Accordingly, the -L99F glycoform was fully activated by heparin. Similar results were observed for recombinant R47C and P41L, other heparin-binding antithrombin mutants. In conclusion, we identified a new type of mosaicism associated with mutations causing heparin-binding defects in antithrombin. The presence of a fully functional -glycoform together with the activity retained by these variants helps to explain the viability of homozygous and the milder thrombotic risk of heterozygous patients with these specific antithrombin mutations. (Blood. 2012;120(4): 900-904) IntroductionSince 1965, when E. Egeberg described the first family with an association between antithrombin deficiency and venous thrombosis, 1 many data have sustained the key hemostatic role of this anticoagulant. Actually, heterozygous deficiency significantly increases the risk of thrombosis, making its diagnosis essential for possible prophylactic or therapeutic treatment of carriers. 2 Two types of antithrombin deficiencies have been distinguished on the basis of functional and immunologic assays. Type I antithrombin deficiency is classically detected by a low level of functional and immunologic antithrombin assays, whereas type II antithrombin deficiency occurs when a dysfunctional variant is present in the circulation. Within type II deficiencies, 3 subtypes have been established depending on the location in the antithrombin molecule: reactive site, heparin-binding site, or pleiotropic. 3 However, although this classification seeks to distinguish better between the type II deficiencies, it sometimes ignores the inherent complexity of the disease.The key hemostatic role of antithrombin is also recognized by the embryonic lethality of homozygotes. 4 Two relevant exceptions have been identified: antithrombin Toyama (R47C) and, especially, antithrombin Budapest-III (L99F), which are associated with a moderate risk of thrombosis in heterozygosis and embryonic viability in homozygous state. [5][6][7] Neither of the mutations impair the folding or secr...
Background Congenital disorders of glycosylation are rare inherited diseases affecting many different proteins. The lack of glycosylation notably affects the hemostatic system and leads to deficiencies of both procoagulant and anticoagulant factors. Objective To assess the hemostatic balance in patients with multiple coagulation disorders by using a thrombin generation assay. Method We performed conventional coagulation assays and a thrombin generation assay on samples from patients with congenital disorder of glycosylation. The thrombin generation assay was performed before and after activation of the protein C system by the addition of soluble thrombomodulin. Results A total of 35 patients were included: 71% and 57% had low antithrombin and factor XI levels, respectively. Protein C and protein S levels were abnormally low in 29% and 26% of the patients, respectively, whereas only 11% displayed low factor IX levels. Under baseline conditions, the thrombin generation assay revealed a significantly higher endogenous thrombin potential and thrombin peak in patients, relative to controls. After spiking with thrombomodulin, we observed impaired involvement of the protein C system. Hence, 54% of patients displayed a hypercoagulant phenotype in vitro. All the patients with a history of stroke‐like episodes or thrombosis displayed this hypercoagulant phenotype. Conclusion A thrombin generation assay revealed a hypercoagulant in vitro phenotype under baseline condition; this was accentuated by impaired involvement of the protein C system. This procoagulant phenotype may thus reflect the risk of severe vascular complications. Further research will have to determine whether the thrombin generation assay is predictive of vascular events.
MPI-CDG with transient hypoglycosylation and antithrombin deficiencyAntithrombin deficiency is a strong risk factor for venous thromboembolism (VTE) whose testing has demonstrated usefulness. [1][2][3][4][5] Most cases of antithrombin deficiency are explained by mutations in SERPINC1, the gene encoding this anticoagulant, with detection rate ranging from 70-80%. 6,7 In about 20-30% of cases without SERPINC1 gene defect, the underlying mechanism was hypoglycosylation. 8 An aberrant N-glycosylation causing a recessive or transient antithrombin deficiency is a new form of thrombophilia which is still underestimated. 8 Congenital disorders of glycosylation (CDG), a rare disease, are actually usually associated with antithrombin deficiency. 9 The relevance of glycosylation in multiple haematologica 2019; 104:e81 CASE REPORTS
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