Johanne Poisson1, Aurélie Plessier2, Jean-Jacques Kiladjian3, Fanny Turon4, Bruno Cassinat3, Annalisa Andreoli3, Emmanuelle De Raucourt5, Odile Goria6, Kamal Zekrini3, Christophe Bureau7, Florence Lorre8, Francisco Cervantes9, Dolors Colomer10, François Durand11, Juan-Carlos Garcia-Pagan12, Nicole Casadevall8, Dominique-Charles Valla11, Pierre-Emmanuel Rautou13, Christophe Marzac8. 1. Inserm, U970, Paris Cardiovascular Research Center - PARCC, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 2. DHU Unity, Pôle des Maladies de l'Appareil Digestif, Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, Hôpital Beaujon, AP-HP, Clichy, France. 3. Centre d'Investigations Cliniques, Hôpital St Louis, AP-HP, Clichy, France. 4. Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, IDIBAPS, Barcelona, Spain. 5. Service d'Hématologie Biologique, Hôpital Beaujon, AP-HP, Clichy, France. 6. Service d'Hépato-gastroentérologie, CHU Rouen, Rouen, France. 7. Liver-Gastroenterology Department, University Hospital and Paul Sabatier University, Toulouse, France. 8. UPMC, Univ Paris 06, GRC n°7, Groupe de Recherche Clinique sur les Myéloproliférations Aiguës et Chroniques MYPAC, Paris, France; Laboratoire d'Immunologie et Hématologie Biologique, Hôpital Saint-Antoine, AP-HP, Paris, France. 9. Hematology Department, Hospital Clínic, IDIBAPS, University of Barcelona, Spain. 10. Hematopathology Unit, Hospital Clínic, IDIBAPS, CIBERONC, Spain. 11. DHU Unity, Pôle des Maladies de l'Appareil Digestif, Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, Hôpital Beaujon, AP-HP, Clichy, France; Inserm U1149, Centre de Recherche sur l'Inflammation (CRI), Paris, Université Paris 7-Denis-Diderot, Clichy, UFR de Médecine, Paris, France; Université Paris Diderot, Sorbonne Paris cité, Paris, France. 12. Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, IDIBAPS, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain. 13. Inserm, U970, Paris Cardiovascular Research Center - PARCC, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; DHU Unity, Pôle des Maladies de l'Appareil Digestif, Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, Hôpital Beaujon, AP-HP, Clichy, France; Université Paris Diderot, Sorbonne Paris cité, Paris, France. Electronic address: pierre-emmanuel.rautou@inserm.fr.
Abstract
BACKGROUND AND AIMS: Myeloproliferative neoplasms (MPN) are the leading cause of splanchnic vein thrombosis (SVT). Janus kinase 2 gene (JAK2)V617F mutations are found in 80 to 90% of patients with SVT and MPN. Mutations of the calreticulin (CALR) gene have also been reported. However, as their prevalence ranges from 0 to 2%, the utility of routine testing is questionable. This study aimed to identify a group of patients with SVT at high risk of harboring CALR mutations and thus requiring this genetic testing. METHODS: CALR, JAK2V617F and thrombopoietin receptor gene (MPL) mutations were analysed in a test cohort that included 312 patients with SVT. Criteria to identify patients at high risk of CALR mutations in this test cohort was used and evaluated in a validation cohort that included 209 patients with SVT. RESULTS: In the test cohort, 59 patients had JAK2V617F, five had CALR and none had MPL mutations. Patients with CALR mutations had higher spleen height and platelet count than patients without these mutations. All patients with CALR mutations had a spleen height ⩾16cm and platelet count >200×109/L. These criteria had a positive predictive value of 56% (5/9) and a negative predictive value of 100% (0/233) for the identification of CALR mutations. In the validation cohort, these criteria had a positive predictive value of 33% (2/6) and a negative predictive value of 99% (1/96). CONCLUSION: CALR mutations should be tested in patients with SVT, a spleen height ⩾16cm, platelet count >200×109/L, and no JAK2V617F. This strategy avoids 96% of unnecessary CALR mutations testing. Lay summary: Mutations of the CALR gene are detected in 0 to 2% of patients with SVT, thus the utility of systematic CALR mutation testing to diagnose MPN is questionable. This study demonstrates that CALR mutations testing can be restricted to patients with SVT, a spleen height ⩾16cm, a platelet count >200×109/L, and no JAK2V617F. This strategy avoids 96% of unnecessary CALR mutations testing.
BACKGROUND AND AIMS: Myeloproliferative neoplasms (MPN) are the leading cause of splanchnic vein thrombosis (SVT). Janus kinase 2 gene (JAK2)V617F mutations are found in 80 to 90% of patients with SVT and MPN. Mutations of the calreticulin (CALR) gene have also been reported. However, as their prevalence ranges from 0 to 2%, the utility of routine testing is questionable. This study aimed to identify a group of patients with SVT at high risk of harboring CALR mutations and thus requiring this genetic testing. METHODS:CALR, JAK2V617F and thrombopoietin receptor gene (MPL) mutations were analysed in a test cohort that included 312 patients with SVT. Criteria to identify patients at high risk of CALR mutations in this test cohort was used and evaluated in a validation cohort that included 209 patients with SVT. RESULTS: In the test cohort, 59 patients had JAK2V617F, five had CALR and none had MPL mutations. Patients with CALR mutations had higher spleen height and platelet count than patients without these mutations. All patients with CALR mutations had a spleen height ⩾16cm and platelet count >200×109/L. These criteria had a positive predictive value of 56% (5/9) and a negative predictive value of 100% (0/233) for the identification of CALR mutations. In the validation cohort, these criteria had a positive predictive value of 33% (2/6) and a negative predictive value of 99% (1/96). CONCLUSION:CALR mutations should be tested in patients with SVT, a spleen height ⩾16cm, platelet count >200×109/L, and no JAK2V617F. This strategy avoids 96% of unnecessary CALR mutations testing. Lay summary: Mutations of the CALR gene are detected in 0 to 2% of patients with SVT, thus the utility of systematic CALR mutation testing to diagnose MPN is questionable. This study demonstrates that CALR mutations testing can be restricted to patients with SVT, a spleen height ⩾16cm, a platelet count >200×109/L, and no JAK2V617F. This strategy avoids 96% of unnecessary CALR mutations testing.