Should JAK2 V617F Mutation Testing be Inducted into Routine Thrombophilia Screening?

To the Editor,

The classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are primarily driven by acquired mutations of JAK2, CALR and MPL genes that promote activation of downstream, intracellular JAK-STAT signalling pathways. The most recurrent mutation is the JAK2 V617F present in 95% of patients with polycythemia vera and in 50%–60% of patients with essential thrombocythemia and primary myelofibrosis. MPN have a significantly increased risk of both venous thromboembolism (VTE) and arterial thrombosis. Current thrombophilia testing guidelines limit the use of molecular screening for an underlying MPN to patients with thrombosis at an unusual site with full blood count anomalies suggestive of an MPN or to those patients with splanchnic vein thrombosis (SVT; including portal, mesenteric, splenic, renal vein thrombosis and Budd-Chiari syndrome) or cerebral venous sinus thrombosis (CVST) in the absence of clear provoking factors and with a normal blood count (NBC). ¹ However, a recent study highlights the potential benefit of JAK2 V617F testing in routine VTE thrombophilia screening.

Abbou and colleagues prospectively analysed 996 patients with VTE for the JAK2 V617F mutation by quantitative polymerase chain reaction (qPCR) in addition to other thrombophilia defects. ² Of 38 patients (3.8%) found to harbor the JAK2 V617F, ten were diagnosed with an MPN and 28 (2.8%) had an NBC. Furthermore, of the 28 NBC JAK2 V617F-positve patients, 24 (85.7%) had no other thrombophilic defect suggesting this mutation may be regarded as an independent risk factor for VTE. Of diagnostic importance, the mean variant allele frequency (VAF) of this group was reported as 0.13%. In the overall cohort, JAK2 V617F mutation was the third most common thrombophilia defect after factor V Leiden and G20210A prothrombin gene mutation but more common than antiphospholilpid antibodies, Protein C, Protein S and antithrombin deficiencies.

This study raises the question as to whether JAK2 V617F mutation testing should be incorporated into routine thrombophilia screening regardless of the site of thrombosis or whether or not full blood count abnormalities indicative of an MPN are present: the most common sites of thrombosis in this NBC JAK2 V617F-positive group were pulmonary embolism and deep vein thrombosis. It should be noted that this supposition is limited to one single-center study with further relevant studies required to enhance the robustness of this premise. This in turn would strengthen the proposal with regards to evidence hierarchy and benefit-risk ratio. JAK2 V617F mutations are present at a low frequency and a low VAF in the general population with increasing VAFs over many years proportional with MPN development. ³ It could therefore be argued that those NBC-VTE-JAK2 V617F patients detected by Abbou and colleagues represent an extremely early manifestation of a “pre-hematological” MPN that has acquired thrombotic potential. The economic-effectiveness of such an approach requires evaluation and would require considerable interaction between existing molecular thrombosis/hemostasis and hemato-oncology diagnostic services in order to optimise delivery. Screening for the JAK2 V617F is currently performed by a number of techniques with next-generation sequencing (NGS) panels widely adopted. Given that a JAK2 V617F VAF of 1%–2% is considered clinically relevant for MPN (and is the limit of detection of most NGS approaches) and the low levels of the mutation in those NBC-VTE patients identified by Abbou and colleagues, ² sensitive techniques of qPCR or droplet digital PCR would be necessary to allow detection of these low VAFs.