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2023-12-06T12:11:03.000Z

Cumulative thrombotic risk between CALR1, CALR2 and JAK2V617F mutations in ET

Dec 6, 2023
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Learning objective: After reading this, learners will be able to cite differences in thrombotic risk according to comparisons in mutation profiles for patients with ET.

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Thrombosis is one of the main complications experienced by patients diagnosed with essential thrombocythemia (ET) and confers significant morbidity and mortality.1 While it is well known that the presence of the Janus kinase 2 (JAK2)V617F mutation is an important risk factor for thrombosis, there is increasing evidence to suggest that other mutations, especially those involving calreticulin (CALR), may also increase thrombotic risk.1

As JAK2V617F and CALR mutations represent two distinct subtypes of ET, Neupane et al.1 performed a systematic review and meta-analysis in American Journal of Hematology, comparing the cumulative thrombotic risk between CALR1-, CALR2-, and JAK2V617F-mutated ET. Here, we summarize the key results.

For more information on the risk of thromboembolic complications in myeloproliferative neoplasms (MPN), check out this article and discussion from the MPN Hub Steering Committee published on the MPN Hub.

Study design

  • Relevant peer-reviewed studies were searched across PubMed, Google Scholar, MEDLINE OVID, Cochrane Library, and Cumulative Index to Nursing and Allied Health Literature database
    • Study publish date was set as from database inception to January 2023
  • A total of 15 studies were selected for meta-analysis
    • Most were retrospective in design
    • 10 of the 15 studies were deemed to have a low bias risk, the rest had a moderate risk of bias

Results

  • A total of 4,894 patients were analyzed:
    • 795 patients had a CALR1 mutation;
    • 561 patients had a CALR2 mutation; and
    • 3,538 patients had a JAK2 mutation.
  • The pooled odds ratios for thrombotic risk across the 15 studies are shown in Figure 1

Figure 1. Pooled odds ratios for thrombotic risk across all selected studies* 

*Adapted from Neupane, et al.1

 

After sensitivity analysis and the removal of studies with medium and high bias risk, the pooled odds ratios of thrombotic risk across the remaining eight studies are shown in Figure 2.

Figure 2. Pooled odds ratios of thrombotic risk across eight studies post sensitivity analysis*  

*Adapted from Neupane, et al.1

 Subgroup analysis of the site of thrombosis did not reveal any statistically significant results; however, there was lower venous thrombotic risk in patients with a CALR2 mutation vs a JAK2 mutation.

Conclusion

Results from this meta-analysis show that patients with either a CALR1 or CALR2 mutation have a lower thrombotic risk compared with patients with a JAK2 mutation and patients with a CALR1 mutation have a higher risk of thrombosis vs patients with a CALR2 mutation. The pathophysiology underlying this difference remains unknown; however, it has been suggested that CALR2 reduces activation of the thrombopoietin receptor and adenosine diphosphate-induced platelet activation due to its lower net positive charge.

Limitations of this analysis include variations in population sizes, study designs, and follow-up periods. While further investigation is needed, the analysis highlights the potential and need for individual management strategies based on specific mutational profiles.

  1. Neupane N, Low SK, Kharel H, et al. Comparative thrombotic risk associated with CALR1, CALR2, and JAK2 V617F mutations in essential thrombocythemia. Am Jr of Hemat Online ahead of print. DOI: 10.1002/ajh.27148

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