Selective testing for calreticulin gene mutations in patients with splanchnic vein thrombosis: A prospective cohort study

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, JAK2^V617F 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 JAK2^V617F, 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 JAK2^V617F. 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 JAK2^V617F. This strategy avoids 96% of unnecessary CALR mutations testing.

Keywords: Budd-Chiari syndrome; CALR mutations; DNA mutational analysis; Genetic testing; JAK2(V617F); MPL mutation; Myeloproliferative neoplasms; Platelets count; Portal vein thrombosis; Splenomegaly.