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Detecting CALR mutations in splanchnic vein thrombosis: Who and how?

  • Stephen E. Langabeer EMAIL logo
Published/Copyright: June 26, 2018
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Journal of Translational Internal Medicine
From the journal Journal of Translational Internal Medicine Volume 6 Issue 2

The mainstay of therapy for the myeloproliferative neoplasms (MPN) has been phlebotomy, antiplatelet drugs and cytoreductive agents to control constitutional symptoms and to prevent leukemic transformation and thrombotic events. There exists an increased incidence of both arterial and venous thrombosis in MPN patients, of which the latter may manifest in the microcirculation or as deep vein thrombosis, pulmonary embolism, cerebral venous thrombosis or splanchnic vein thrombosis (SVT).[1] SVT can be the first presenting feature of either a hematologically evident or latent MPN with the molecular identification of the JAK2 V617F MPN driver mutation an essential component of the molecular diagnostic work up in such cases in order to assign appropriate clinical management.[2, 3] Subsequently identified low frequency MPN-driving mutations in JAK2 exon 12 and MPL exon 10 are generally considered to be absent in SVT,[4, 5] although rare case reports exist.[6, 7] The landmark discovery in 2013 of insertion and/or deletion (indel) mutations of CALR (the gene that encodes the endoplasmic reticulum-associated, calcium binding protein Calreticulin) in up to 80% of JAK2 V617F-negative essential thrombocythemia and primary myelofibrosis patients[8, 9] prompted several groups to investigate whether these mutations were also prevalent in patients presenting with SVT, enabling a prompt diagnosis of MPN.

To date, multiple studies have reported the incidence of CALR mutations in patient cohorts presenting with SVT and are summarized in Table 1.[10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23] Of more than 1500 SVT patients now analyzed, CALR mutations were present in only 1.3% of patients, roughly equating to one patient in seventy-five. Screening all SVT patients for CALR mutations would therefore appear to be an inappropriate use of resources; however, this issue has been recently addressed. Incorporating a spleen size of greater than 16 cm and a platelet count of more than 200 × 109/L into the diagnostic algorithm allows for the positive identification of the majority of CALR mutation-positive cases, sparing the remainder of patients from an invasive bone marrow biopsy required to assess morphological appearances.[20] As marked geographical differences exist in the etiology of SVT and Budd-Chiari syndrome, [24, 25] the above algorithm requires verification in regional-specific cohorts.

Table 1

Studies reporting the incidence of CALR mutations in patients with splanchnic vein thrombosis.

Reference No.SVT patients (n)CALR+SVT siteMPN diagnosis
[10]2094 (1.9%)BCS (n = 2), PVT (n = 2)ET (n = 3), PMF (n = 1)
[11]1440 (0%)--
[12]290 (0%)--
[13]661 (1.5%)Not specifiedNot specified
[14]400 (0%)--
[15]1411 (0.7%)PVTPMF
[16]1320 (0%)--
[17]832 (2.4%)PVT (n = 2)ET (n = 1), MPN-U (n = 1)
[18]1000 (0%)--
[19]412 (4.9%)BCS (n = 2)ET (n = 1), PMF (n = 1)
[20]312[∗]5 (1.6%)BCS (n = 1), PVT (n = 4)ET (n = 1), PMF (n = 4)
[21]2102 (1.0%)BCS (n = 2)Not specified
[22]11 (100%)PVTET
[23]242 (8.3%)BCS (n = 2)Not specified
Total153220 (1.3%)

  1. SVT: splanchnic vein thrombosis; MPN: myeloproliferative neoplasm; BCS: Budd Chiari syndrome; PVT: portal vein thrombosis; ET: essential thrombocythemia; PMF: primary myelofibrosis; MPN-U: myeloproliferative neoplasm-unclassified.

From a laboratory perspective, a further two issues require consideration. Some recent evidence suggests that MPN patients with SVT have a significantly lower JAK2 V617F allele burden (< 10%) than those MPN patients without SVT.[26] Whether this phenomenon is also observed in patients with CALR+ SVT remains to be answered. Given the number of methodological approaches available for the detection of CALR mutations,[27, 28] careful validation and selection of a sensitive technique is required so as not to underdiagnose the potential underlying MPN. Secondly, all the pathologically annotated, MPN-associated CALR indel mutations result in a +1 alteration of the reading frame leading to a loss of the terminal calreticulin localization domain. CALR mutations in two SVT patients have been reported as being in-frame[19, 21]: caution in interpretation is required as these mutations may be of germ-line origin and of uncertain pathogenicity.[29] Sequencing of CALR in patient constitutional material is consequently needed for clarification.

Screening for CALR mutations in SVT patients remains a worthwhile endeavor as diagnosis of the underlying MPN is critical for fitting patient treatment. Future work on CALR mutation type and allele burden may reveal insights into the pathogenetic mechanisms at play in patients with SVT.

Dr. Stephen E. Langabeer, Cancer Molecular Diagnostics, Central Pathology Laboratory, St. James’s Hospital, Dublin, D08 E9P6, Ireland

  1. Conflicts of Interest: The author has no conflicts of interest to declare.

References

1 Barbui T, Finazzi G, Falanga A. Myeloproliferative neoplasms and thrombosis. Blood 2013; 122: 2176-84.10.1182/blood-2013-03-460154Search in Google Scholar PubMed

2 Smalberg JH, Arends LR, Valla DC, Kiladjian JJ, Janssen HL, Leebeek FW. Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis. Blood 2012; 120:4921-8.10.1182/blood-2011-09-376517Search in Google Scholar PubMed

3 De Stefano V, Qi X, Betti S, Rossi E. Splanchnic vein thrombosis and myeloproliferative neoplasms: molecular-driven diagnosis and long-term treatment. Thromb Haemost 2016; 115:240-9.10.1160/th15-04-0326Search in Google Scholar

4 Kiladjian JJ, Cervantes F, Leebeek F, Marzac C, Cassinat B, Chevret S, et al. The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases. Blood 2008; 111: 4922-9.10.1182/blood-2007-11-125328Search in Google Scholar PubMed

5 Fiorini A, Chiusolo P, Rossi E, Za T, De Ritis DG, Ciminello A, et al. Absence of the JAK2 exon 12 mutations in patients with splanchnic vein thrombosis and without overt myeloproliferative neoplasms. Am J Hematol 2009; 84: 126-7.10.1002/ajh.21335Search in Google Scholar PubMed

6 Colaizzo D, Amitrano L, Tiscia GL, Grandone E, Guardascione MA, Margaglione M. A new JAK2 gene mutation in patients with polycythemia vera and splanchnic vein thrombosis. Blood 2007; 110:2768-9.10.1182/blood-2007-05-092502Search in Google Scholar PubMed

7 Bergamaschi GM, Primignani M, Barosi G, Fabris FM, Villani L, Reati R, et al. MPL and JAK2 exon 12 mutations in patients with the Budd-Chiari syndrome or extrahepatic portal vein obstruction. Blood 2008; 111:4418.10.1182/blood-2008-02-137687Search in Google Scholar PubMed

8 Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013; 369:2379-90.10.1056/NEJMoa1311347Search in Google Scholar PubMed

9 Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 2013; 369:2391-405.10.1056/NEJMoa1312542Search in Google Scholar PubMed PubMed Central

10 Turon F, Cervantes F, Colomer D, Baiges A, Hernández-Gea V, Garcia-Pagán JC. Role of calreticulin mutations in the aetiological diagnosis of splanchnic vein thrombosis. J Hepatol 2015; 62:72-4.10.1016/j.jhep.2014.08.032Search in Google Scholar PubMed

11 Haslam K, Langabeer SE. Incidence of CALR mutations in patients with splanchnic vein thrombosis. Br J Haematol 2015; 168:459-60.10.1111/bjh.13121Search in Google Scholar PubMed

12 Iurlo A, Cattaneo D, Gianelli U, Fermo E, Augello C, Cortelazzi A. Molecular analyses in the diagnosis of myeloproliferative neoplasm-related splanchnic vein thrombosis. Ann Hematol 2015; 94:881-2.10.1007/s00277-014-2249-zSearch in Google Scholar PubMed

13 Rocques M, Park JH, Minello A, Bastie JN, Girodon F. Detection of the CALR mutation in the diagnosis of splanchnic vein thrombosis. Br J Haematol 2015; 169:601-3.10.1111/bjh.13235Search in Google Scholar PubMed

14 Castro N, Rapado I, Ayala R, Martinez-Lopez J. CALR mutations screening should not be studied in splanchnic vein thrombosis. Br J Haematol 2015; 170:588-9.10.1111/bjh.13314Search in Google Scholar PubMed

15 Plompen EP, Valk PJ, Chu I, Darwish-Murad SD, Plessier A, Turon F, et al. Somatic calreticulin mutations in patients with Budd-Chiari syndrome and portal vein thrombosis. Haematologica 2015; 100:e226-8.10.3324/haematol.2014.120857Search in Google Scholar PubMed PubMed Central

16 Colaizzo D, Amitrano L, Guardascione MA, Favuzzi G, Tiscia GL, D’Andrea G, et al. Clinical utility of screening for CALR gene exon 9 mutations in patients with splanchnic vein thrombosis. Thromb Haemost 2015; 113:1381-2.10.1160/TH14-12-1055Search in Google Scholar PubMed

17 Sekhar M, Patch D, Austen B, Howard J, Hart S. Calreticulin mutations and their importance in splanchnic vein thrombosis. Br J Haematol 2016; 174:158-60.10.1111/bjh.13756Search in Google Scholar PubMed

18 Zhang P, Ma H, Min Q, Zu M, Lu Z. CALR mutations in Chinese Budd-Chiari patients. Eur J Gastroenterol Hepatol 2016; 28:361-2.10.1097/MEG.0000000000000526Search in Google Scholar PubMed

19 Ho WK, Hong FS. CALR exon 9 mutations in idiopathic splanchnic vein thrombosis in an Australian cohort. Thromb Res 2017; 150:51-2.10.1016/j.thromres.2016.12.010Search in Google Scholar PubMed

20 Poisson J, Plessier A, Kiladjian JJ, Turon F, Cassinat B, Andreoli A, et al. Selective testing for calreticulin gene mutations in patients with splanchnic vein thrombosis: a prospective cohort study. J Hepatol 2017; 67:501-7.10.1016/j.jhep.2017.04.021Search in Google Scholar PubMed

21 Jain A, Tibdewal P, Shukla A. Calreticulin mutations and their importance in Budd-Chiari syndrome. J Hepatol 2017; 67:1111-2.10.1016/j.jhep.2017.06.017Search in Google Scholar PubMed

22 Karam D, Iyer V, Agrawal B. Occult myeloproliferative neoplasms: not so occult any more. BMJ Case Rep 2017; 2017. pii: bcr-2017-21938810.1136/bcr-2017-219388Search in Google Scholar PubMed PubMed Central

23 Mo A, Testro A, French J, Robertson M, Angus P, Grigg A. Early radiological intervention and haematology screening is associated with excellent outcomes in Budd-Chiari syndrome. Intern Med J 2017; 47:1361-7.10.1111/imj.13544Search in Google Scholar PubMed

24 Qi X, Han G, Guo X, et al. Review article: the aetiology of primary Budd-Chiari syndrome – differences between the West and China. Aliment Pharmacol Ther 2016; 44:1152-67.10.1111/apt.13815Search in Google Scholar PubMed

25 Rai P, Kumar P, Mishra S, Aggarwal R. Low frequency of V617F mutation in JAK2 gene in Indian patients with hepatic venous outflow obstruction and extrahepatic portal venous obstruction. Indian J Gastroenterol 2016; 35:366-71.10.1007/s12664-016-0691-7Search in Google Scholar PubMed

26 How J, Trinkaus KM, Oh ST. Distinct clinical, laboratory and molecular features of myeloproliferative neoplasm patients with splanchnic vein thrombosis. Br J Haematol 2017; Oct 19 [Epub ahead of print]. 10.1111/bjh.14958.Search in Google Scholar PubMed

27 Jones AV, Ward D, Lyon M, Leung W, Callaway A, Chase A, et al. Evaluation of methods to detect CALR mutations in myeloproliferative neoplasms. Leuk Res 2015; 39: 82-7.10.1016/j.leukres.2014.11.019Search in Google Scholar PubMed

28 Haslam K, Langabeer SE. Monitoring minimal residual disease in the myeloproliferative neoplasms: current applications and emerging approaches. Biomed Res Int 2016; 2016:7241591.10.1155/2016/7241591Search in Google Scholar PubMed PubMed Central

29 Szuber N, Lamontagne B, Busque L. Novel germline mutations in the calreticulin gene: implications for the diagnosis of myeloproliferative neoplasms. J Clin Pathol 2016 Jul 27; pii: clinpath-2016-203940.10.1136/jclinpath-2016-203940Search in Google Scholar PubMed

Published Online: 2018-06-26

© 2018 Stephen E. Langabeer, published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

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  2. Detecting CALR mutations in splanchnic vein thrombosis: Who and how?
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https://doi.org/10.2478/jtim-2018-0015
Creative Commons
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Articles in the same Issue

  1. Editorials
  2. Detecting CALR mutations in splanchnic vein thrombosis: Who and how?
  3. Shear stress regulation of endothelium: A double-edged sword
  4. Highlight
  5. What a clinician should know about a renal replacement membrane?
  6. Perspective
  7. Hypoxia-inducible factor may induce the development of liver fibrosis in Budd–Chiari syndrome by regulating CD248/endosialin expression: A hypothesis
  8. Review Articles
  9. Adenosquamous carcinoma of the esophagus: A literature review
  10. Acute respiratory distress syndrome: An update and review
  11. Original Articles
  12. Dyspepsia amongst end stage renal disease undergoing hemodialysis: Views from a large tertiary care center
  13. Hepatitis C screening in commercially insured U.S. birth-cohort patients: Factors associated with testing and effect of an EMR-based screening alert
  14. Letter to the Editor
  15. Does hepatic impairment influence renal function parameters in liver cirrhosis?
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