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      Coagulation Parameters in Adult Patients With Type-1 Gaucher Disease

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          Abstract

          Background

          Gaucher disease is a rare inborn error of lysosomal metabolism, characterized by lysosomal storage of the β-glucosylceramide. Bleedings observed in type-1 Gaucher disease (GD1) are commonly attributed to a low platelet count, but they can also occur when the platelet count is normal or slightly low. Abnormal platelet function has been described and deficiencies in coagulation factors too, such as factors II, V, VII, VIII, IX, X, XI, XII, and von Willebrand factor. However, studies are few in number, involving few patients and having varying conclusions. The aim of this study was to analyze clotting factor deficiencies in a larger cohort of French patients with GD1.

          Methods

          This is an observational national study. The coagulation parameters were collected during routine GD1 monitoring and described retrospectively.

          Results

          We highlighted low levels of various coagulation factors in 46% of the patients with GD1. The most frequent coagulation abnormalities encountered were factor V, X, XI, and XII deficiencies. Deficits were usually mild and coagulation abnormalities tended to be more frequent in non-splenectomized patients.

          Conclusions

          In conclusion, frequent and varied coagulation abnormalities were found in a high proportion of GD1 patients.

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          The role of saposin C in Gaucher disease.

          Rafael J. Tamargo, Arash Velayati, Ehud Goldin … (2012)
          Saposin C is one of four homologous proteins derived from sequential cleavage of the saposin precursor protein, prosaposin. It is an essential activator for glucocerebrosidase, the enzyme deficient in Gaucher disease. Gaucher disease is a rare autosomal recessive lysosomal storage disorder caused by mutations in the GBA gene that exhibits vast phenotypic heterogeneity, despite its designation as a "simple" Mendelian disorder. The observed phenotypic variability has led to a search for disease modifiers that can alter the Gaucher phenotype. The PSAP gene encoding saposin C is a prime candidate modifier for Gaucher disease. In humans, saposin C deficiency due to mutations in PSAP results in a Gaucher-like phenotype, despite normal in vitro glucocerebrosidase activity. Saposin C deficiency has also been shown to modify phenotype in one mouse model of Gaucher disease. The role of saposin C as an activator required for normal glucocerebrosidase function, and the consequences of saposin C deficiency are described, and are being explored as potential modifying factors in patients with Gaucher disease.
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            The French Gaucher’s disease registry: clinical characteristics, complications and treatment of 562 patients

            Jerome Stirnemann, Marie Vigan, Dalil Hamroun … (2012)
            Background Clinical features, complications and treatments of Gaucher’s disease (GD), a rare autosomal–recessive disorder due to a confirmed lysosomal enzyme (glucocerebrosidase) deficiency, are described. Methods All patients with known GD, living in France, with ≥1 consultations (1980–2010), were included in the French GD registry, yielding the following 4 groups: the entire cohort, with clinical description; and its subgroups: patients with ≥1 follow-up visits, to investigate complications; recently followed (2009–2010) patients; and patients treated during 2009–2010, to examine complications before and during treatment. Data are expressed as medians (range) for continuous variables and numbers (%) for categorical variables. Results Among the 562 registry patients, 265 (49.6%) were females; 454 (85.0%) had type 1, 22 (4.1%) type 2, 37 (6.9%) perinatal–lethal type and 21 (3.9%) type 3. Median ages at first GD symptoms and diagnosis, respectively, were 15 (0–77) and 22 (0–84) years for all types. The first symptom diagnosing GD was splenomegaly and/or thrombocytopenia (37.6% and 26.3%, respectively). Bone-marrow aspiration and/or biopsy yielded the diagnosis for 54.7% of the patients, with enzyme deficiency confirming GD for all patients. Birth incidence rate was estimated at 1/50,000 and prevalence at 1/136,000. For the 378 followed patients, median follow-up was 16.2 (0.1–67.6) years. Major clinical complications were bone events (BE; avascular necrosis, bone infarct or pathological fracture) for 109 patients, splenectomy for 104, and Parkinson’s disease for 14; 38 patients died (neurological complications for 15 type-2 and 3 type-3 patients, GD complications for 11 type-1 and another disease for 9 type-1 patients). Forty-six had monoclonal gammopathy. Among 283 recently followed patients, 36 were untreated and 247 had been treated during 2009–2010; 216 patients received treatment in December 2010 (126 with imiglucerase, 45 velaglucerase, 24 taliglucerase, 21 miglustat). BE occurred before (130 in 67 patients) and under treatment (60 in 41 patients) with respective estimated frequencies (95% CI) of first BE at 10 years of 20.3% (14.1%–26.5%) and 19.8% (13.5%–26.1%). Conclusion This registry enabled the epidemiological description of GD in France and showed that BE occur even during treatment.
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              Coagulation abnormalities in type 1 Gaucher disease are due to low-grade activation and can be partly restored by enzyme supplementation therapy.

              Johannes Aerts, C. E. M. Hollak, Marcel Levi … (1997)
              In type 1 Gaucher disease a bleeding tendency occurs which is partly caused by thrombocytopenia due to massive splenomegaly. In addition, low levels of factors IX and XI have been described. The mechanism responsible for these clotting factor abnormalities is unknown. We performed a detailed study of parameters of coagulation and fibrinolysis in 30 type 1 Gaucher disease patients (14 splenectomized) before and after treatment with enzyme supplementation therapy. Pre-treatment aPTT and PT were prolonged in 42% and 38% of patients, respectively. In 30-60% serious deficiencies (< 50%) of coagulation factors XI, XII, VII, X, V and II were observed. The low levels of factor V correlated with platelet count and were inversely associated with splenic volume. Levels of inhibitors were mildly decreased. Markers for activation of coagulation (thrombin-antithrombin (TAT) complex) and fibrinolysis (PAP complex, fibrin cleavage product D-dimer) were significantly elevated, especially in the splenectomized patients, indicating ongoing activation of these processes. After 12 months of enzyme supplementation therapy partial correction occurred. Thus, severe disorders of the coagulation system occur in Gaucher disease, contributing to the bleeding tendency. The deficiencies may be the result of consumption of coagulation factors caused by ongoing low-level coagulation activation. possibly due to mononuclear cell activation.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Hematol (Brossard)
                Journal ID (iso-abbrev): J Hematol (Brossard)
                Journal ID (publisher-id): Elmer Press
                Title: Journal of Hematology
                Publisher: Elmer Press
                ISSN (Print): 1927-1212
                ISSN (Electronic): 1927-1220
                Publication date (Print): September 2019
                Publication date (Electronic): 30 September 2019
                Volume: 8
                Issue: 3
                Pages: 121-124
                Affiliations
                [a ]Department of Internal Medicine of the Aged, University Hospital of Geneva, 1226 Thonex, Switzerland
                [b ]Department of Internal Medicine, Pitie-Salpetriere Hospital Group, 75013 Paris, France
                [c ]Internal Medicine Department, Groupe Hospitalier Diaconesses Croix Saint Simon, 75020 Paris, France
                [d ]Department of Internal Medicine, University Hospital of Strasbourg, 67091 Strasbourg, France
                [e ]Internal Medicine Department, University Hospital Hotel Dieu, 44093 Nantes, France
                [f ]Department of Internal Medicine and Clinical Immunology, University Hospital of Dijon, 21079, Dijon, France
                [g ]Department of Internal Medicine, CHRU Nancy, 54511 Vandoeuvre les Nancy, France
                [h ]Department of Internal Medicine, University Hospital of Rouen, INSERM U 905, 76031 Rouen, France
                [i ]Internal Medicine and Vascular Diseases Department, Angers University Hospital, 49933 Angers, France
                [j ]Internal Medicine Department, Tours University Hospital, University of Tours, UMR INSERM 1253, 37044 Tours, France
                Author notes
                [k ]Corresponding Author: Christine Serratrice, Department of Internal Medicine of the Aged, University Hospital of Geneva, Chemin du Pont Bochet 3, 1226 Thonex, Switzerland. Email: christine.serratrice@ 123456hcuge.ch
                Article
                DOI: 10.14740/jh543
                PMC ID: 7153659
                SO-VID: ab636207-97b1-4ff1-8f7e-c55eedb13999
                Copyright © Copyright 2019, Serratrice et al.
                License:

                This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 20 July 2019
                Date accepted : 16 August 2019
                Categories
                Subject: Short Communication

                Keywords: gaucher disease,coagulation,lysosomal storage disorder,clotting factors
                Data availability:
                Keywords: gaucher disease, coagulation, lysosomal storage disorder, clotting factors

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