Subscribe to RSS
Download PDF
DOI: 10.1055/a-2633-7948
JAK2 V617F Mutation Screening for Peripheral Arterial Thrombosis
Arterial thrombosis is a rare and potentially serious condition associated with significant morbidity and mortality. Its occurrence requires investigation for common causes, including atherosclerosis and embolism, as well as uncommon causes, including medications and substances, vascular and anatomical abnormalities, systemic disorders, and thrombophilias. However, there remain cases where arterial thrombosis remains unexplained despite thorough investigation. The role of systematic or targeted investigation of the JAK2 V617F mutation has not been established.[1]
Since the discovery of the JAK2 V617F mutation in 2005,[2] its prothrombotic role has been studied in patients with and without myeloproliferative neoplasms (MPN). Arterial thrombosis rates in MPN patients are reported to be approximately 0.75 per patient per year.[3] It is known that the presence of the JAK2 V617F mutation, with or without MPN, is associated with an increased risk of venous thrombosis.[4] [5] [6] However, the role of the JAK2 V617F mutation in arterial thrombosis in the presence or absence of MPN is controversial.[3] [7] Current studies suggest a very low prevalence (0.7–1%) of JAK2 V617F in individuals with arterial thrombosis. However, these studies mainly focused on patients with stroke and myocardial infarction.[8] [9] Therefore, the estimated prevalence in cases of nonstroke/nonmyocardial infarction arterial thrombosis is not known. From both a medical and economic point of view, it is crucial to identify individuals at risk of carrying the JAK2 V617F mutation in the case of peripheral arterial thrombosis in order to assess screening utility and define a target population. This study specifically aimed to determine the significance of the JAK2 V617F mutation screening in peripheral arterial thrombosis cases.
We conducted a single-center retrospective study between 2016 and 2022. A total of 147 patients with arterial thrombosis (excluding strokes and myocardial infarctions) were systematically screened for the JAK2 V617F mutation using a TaqMan allelic discrimination assay on genomic DNA (sensitivity threshold 1%). The JAK2 V617F testing was performed in real time on fresh peripheral blood samples, as part of routine clinical care, and no samples were stored. Clinical data were collected retrospectively. We recorded their past medical history, clinical characteristics, treatments, and biological parameters 7 days before (D − 7), at the time (D0), and 7 days after (D7) the thrombosis. MPNs were diagnosed based on the 2016 World Health Organization recommendations.[10] JAK2 V617F is a well-recognized mutation associated with clonal hematopoiesis of indeterminate potential (CHIP), which can occur independently of MPN. However, our study was not designed to distinguish between CHIP and MPN, as bone marrow biopsies were not systematically performed. The statistical analysis was done by the R software (R version 4.2.3, Vienna, Austria). Data are expressed as mean [ ± standard deviation]. Patient characteristics were compared using chi-2 or Fisher's exact test as required. Biological parameters were compared using Wilcoxon's rank-sum test. Significance is set for p-value < 0.05. Multiple receiver operating characteristics (ROC) curves were used to propose a sensitive and specific platelet threshold regarding JAK2 V617F mutation screening. This study was conducted in accordance with the AP-HP (Assistance publique–hôpitaux de Paris) institutional patient protection charter and followed the MR-004 methodology for retrospective studies, allowing the use of routine care data with the possibility for patients to object to the collection and analysis of their personal data.
The clinical and biological characteristics of the 147 patients are shown in [Table 1]. Briefly, the mean age at diagnosis was 56 (±9) years and 97 (66%) were male. A history of arterial and venous thrombosis was reported in 13 and 9.5% of cases, respectively. At the time of diagnosis of arterial thrombosis, 39% were treated with antiplatelet agent or anti-P2Y12 and 14% with anticoagulation. There were 107 cases (73%) of lower limb thrombosis, 23 (16%) of upper limb thrombosis, and 17 (12%) of gastrointestinal arterial vessel thrombosis. The JAK2 V617F mutation was found in 12 (8%) of these cases.
|
Characteristics |
All patients, N = 147[ 1 ] |
JAK2, N = 12[ 1 ] |
None, N = 135[ 1 ] |
p-Value 2 |
|---|---|---|---|---|
|
Age |
56 (47, 65) |
62 (53, 75) |
56 (46, 65) |
0.12 |
|
Female |
50 (34%) |
5 (42%) |
45 (33%) |
0.5 |
|
Male |
97 (66%) |
7 (58%) |
90 (67%) |
0.5 |
|
Past medical history |
||||
|
Arterial thrombosis |
19 (13%) |
2 (17%) |
17 (13%) |
0.7 |
|
Hypertension |
55 (37%) |
6 (50%) |
49 (36%) |
0.4 |
|
Tobacco smoking |
101 (69%) |
7 (58%) |
94 (70%) |
0.5 |
|
Diabetes mellitus |
20 (14%) |
2 (17%) |
18 (13%) |
0.7 |
|
Dyslipidemia |
41 (28%) |
2 (17%) |
39 (29%) |
0.5 |
|
Myocardial infarction |
21 (14%) |
1 (8.3%) |
20 (15%) |
>0.9 |
|
Peripheral arterial disease |
49 (33%) |
0 (0%) |
49 (36%) |
0.009 |
|
Stroke |
5 (3.4%) |
1 (8.3%) |
4 (3.0%) |
0.4 |
|
Venous thrombosis |
14 (9.5%) |
0 (0%) |
14 (10%) |
0.6 |
|
Active neoplasm |
6 (4.1%) |
0 (0%) |
6 (4.4%) |
>0.9 |
|
Cardiovascular risk factors[a] |
132 (90%) |
11 (92%) |
121 (90%) |
>0.9 |
|
ARTS modified score[b] |
0.060 |
|||
|
0 |
14 (9.5%) |
1 (8.3%) |
13 (9.6%) |
|
|
1 |
80 (54%) |
5 (42%) |
75 (56%) |
|
|
2 |
45 (31%) |
3 (25%) |
42 (31%) |
|
|
3 |
8 (5.4%) |
3 (25%) |
5 (3.7%) |
|
|
Family history |
||||
|
None |
46 (31%) |
5 (42%) |
41 (30%) |
0.5 |
|
Cardiovascular events |
22 (15%) |
4 (33%) |
18 (13%) |
0.083 |
|
Arterial thrombosis |
2 (1.4%) |
0 (0%) |
2 (1.5%) |
>0.9 |
|
Venous thrombosis |
7 (4.8%) |
0 (0%) |
7 (5.2%) |
>0.9 |
|
Treatment at the time of diagnosis |
||||
|
Aspirin |
40 (27%) |
2 (17%) |
38 (28%) |
0.5 |
|
Anticoagulation |
21 (14%) |
0 (0%) |
21 (16%) |
0.2 |
|
AntiPY12 |
17 (12%) |
1 (8.3%) |
16 (12%) |
>0.9 |
|
Thrombus location |
||||
|
Lower limb |
107 (73%) |
10 (83%) |
97 (72%) |
0.5 |
|
Upper limb |
23 (16%) |
2 (17%) |
21 (16%) |
>0.9 |
|
Digestive organs |
17 (12%) |
0 (0%) |
17 (13%) |
0.4 |
|
Biological parameters |
||||
|
D − 7 |
||||
|
Platelets D − 7 (G/L) |
268 (212, 348) |
475 (364, 676) |
260 (210, 331) |
0.022 |
|
Hemoglobin D − 7 (g/dL) |
13.25 (11.90, 14.60) |
13.35 (12.08, 14.18) |
13.25 (11.90, 14.60) |
>0.9 |
|
Hematocrit D − 7 (%) |
38.6 (36.1, 42.1) |
39.4 (36.5, 42.0) |
38.6 (36.0, 42.2) |
>0.9 |
|
WBC D − 7 (G/L) |
9.2 (7.4, 12.2) |
12.1 (11.2, 17.3) |
9.0 (7.3, 12.0) |
0.017 |
|
D0 |
||||
|
Platelets D0 (G/L) |
278 (205, 363) |
452 (389, 542) |
267 (202, 338) |
<0.001 |
|
Hemoglobin D0 (g/dL) |
12.80 (10.70, 14.20) |
13.30 (10.53, 13.63) |
12.70 (10.70, 14.30) |
0.9 |
|
Hematocrit D0 (%) |
37 (31, 41) |
38 (29, 41) |
37 (31, 42) |
0.8 |
|
WBC D0 (G/L) |
8.8 (6.9, 11.3) |
8.9 (7.4, 13.1) |
8.8 (6.8, 11.2) |
0.6 |
|
CRP D0 (mg/L) |
16 (2, 48) |
14 (5, 45) |
16 (2, 47) |
>0.9 |
|
D7 |
||||
|
Platelets D7 (G/L) |
321 (241, 432) |
416 (341, 914) |
308 (235, 420) |
0.017 |
|
Hemoglobin D7 (g/dL) |
11.70 (9.90, 13.80) |
11.10 (9.90, 12.45) |
11.70 (9.90, 13.90) |
0.5 |
|
Hematocrit D7 (%) |
36 (29, 40) |
33 (29, 37) |
36 (29, 40) |
0.5 |
|
WBC D7 (G/L) |
8.7 (7.0, 11.0) |
8.2 (7.7, 10.1) |
8.7 (7.0, 11.0) |
0.9 |
|
Mean |
||||
|
Platelets mean (G/L) |
287 (236, 366) |
464 (390, 649) |
283 (229, 352) |
<0.001 |
|
Hemoglobin mean (g/dL) |
12.85 (10.98, 14.20) |
13.30 (10.79, 13.68) |
12.75 (11.02, 14.20) |
0.9 |
|
White blood count mean (G/L) |
9.0 (7.2, 11.3) |
9.5 (7.4, 13.5) |
8.8 (7.2, 11.3) |
0.5 |
|
Hematocrit mean (%) |
37.2 (32.4, 41.3) |
38.9 (31.2, 40.6) |
37.0 (32.5, 41.5) |
0.8 |
Abbreviations: ARTS, Atraumatic Restorative Treatment; CRP, C-reactive protein; IQR, interquartile range; WBC, white blood cell.
1 Median (IQR); n (%) 2 Wilcoxon rank-sum test; Fisher's exact test; Pearson's chi-squared test.
a Cardiovascular risk factors include at least one of the following factors: smoking, arterial hypertension, diabetes, or hypercholesterolemia.
b Arterial Thrombosis Score based on Pasquer et al based on: prior arterial thrombosis, age > 60 years, cardiovascular risk factors.
Compared with patients without the mutation, patients with the JAK2 V617F mutation did not show a statistically significant difference in terms of age, sex, antiplatelet or anticoagulant treatment at diagnosis, or site of thrombosis. However, patients with the JAK2 V617F mutation had a higher platelet count than nonmutated patients at D − 7 (475 [interquartile range, IQR: 364–676] vs. 260 [IQR: 210–331] G/L; p = 0.022), D0 (452 [IQR: 389–542] vs. 267 [IQR: 202–338] G/L; p < 0.001), D7 (416 [IQR: 341–914] vs. 308 [IQR: 235–420] G/L; p = 0.017), and the average of the 3 counts (464 [IQR: 390–649] vs. 283 [IQR: 229–352] G/L; p < 0.001). Other blood test results (hematocrit, white blood cell [WBC] count, hemoglobin, C-reactive protein) did not show a statistically significant difference, except for a higher WBC count at D − 7 in JAK2 V617F mutant patients (12.1 [IQR: 11.2–17.3] G/L vs. 9 [IQR: 7.3–12.0]; p = 0.017).
None of the 12 patients carrying the JAK2 V617F mutation were known to harbor the mutation prior to the thrombotic event. Among them, six underwent a bone marrow biopsy. The main reasons for not performing a biopsy were loss to follow-up or patient refusal. Based on available data, seven patients met diagnostic criteria for a myeloproliferative neoplasm (MPN): four were classified as essential thrombocythemia (ET), one as primary myelofibrosis, one had a JAK2-positive atypical chronic MPN with concurrent mutations in U2AF1 and ETNK1, and one presented with JAK2-positive clonal hematopoiesis suggestive of ET ([Table 2]).
Abbreviations: Hct, hematocrit; Hgb, hemoglobin; MPN, myeloproliferative neoplasms; PLT, platelet; RBC, red blood cell; WBC, white blood cell.
When comparing patients with a confirmed MPN diagnosis (n = 7) to those without (n = 5), the latter were older (mean age 73 ± 17 years vs. 58 ± 19 years) and exhibited lower platelet counts at the time of thrombosis (mean platelet at D0: 397 ± 133 G/L vs. 512 ± 199 G/L). These observations suggest that some patients without a confirmed diagnosis may harbor clonal hematopoiesis of clinical significance rather than overt MPN. Moreover, WBC counts were generally higher in MPN-confirmed patients, further supporting a proliferative profile. Overall, these findings reinforce the relevance of integrating mutational screening with hematological workup, particularly in patients with unexplained thrombosis and elevated platelet counts.
When analyzing multiple ROC curves for platelet counts obtained at three different time points (D–7, D0, and D + 7), the platelet count at D0 provided the best discriminatory performance for identifying patients with the JAK2 V617F mutation ([Fig. 1]). A threshold of 365 G/L yielded a sensitivity of 0.83 and a specificity of 0.81, correctly identifying 10 out of 12 JAK2-positive patients, with a negative predictive value (NPV) of 98%. A lower threshold of 300 G/L achieved an NPV of 99% and identified 11 out of 12 mutated patients. Full performance metrics for each threshold are presented in [Table 3].
Given that none of the JAK2 V617F-positive patients in our cohort had a prior history of peripheral arterial disease (PAD), we explored whether restricting the analysis to patients without PAD could improve predictive performance. In this subgroup, the area under the ROC curve (AUC) for platelet count at D0 showed a modest improvement (AUC = 0.844) compared with the full cohort (AUC = 0.837), with similar slight increases observed at D–7 and D + 7. These findings suggest that absence of PAD history may slightly enhance the predictive accuracy of platelet count-based screening. However, due to the limited number of JAK2-positive cases, these results should be interpreted with caution.
This study provides new insights into the association between the JAK2 V617F mutation and peripheral arterial thrombosis. The complication rate of peripheral arterial thrombosis in JAK2 V617F polycythemia vera is estimated to be 2.2%.[11] However, the prevalence of JAK2 V617F in peripheral arterial thrombosis remains insufficiently characterized. Raimbeau et al evaluated the etiology of digital ischemia in 323 patients, 5 (1.5%) patients had MPN, but the JAK2 V617F mutation status was not described and screening for JAK2 V617F mutation was not systematic.[12] In contrast, a study by Muendlein et al investigated the prevalence of JAK2 V617F in 287 patients with PAD, identifying a 3.1% prevalence, which was significantly higher than in a matched control population. However, these patients did not necessarily present with an acute thrombotic event.[13] Our study shows an 8% prevalence of the JAK2 V617F mutation in cases of peripheral arterial thrombosis. This rate prompts a comparative analysis with existing rates in similar thrombotic conditions, highlighting potential selection bias or underestimation in other studies.
Almost half of the patients were not diagnosed with a definite MPN. Although they didn't have a bone marrow biopsy, their platelet count was lower than those with a definite MPN, raising the concept of clonal hematopoiesis of clinical significance.
This study has several limitations. First, its retrospective, single-center design may limit generalizability, and selection bias cannot be excluded. Second, while we systematically screened for JAK2 V617F, bone marrow biopsies were not systematically performed in mutation-positive patients, making it difficult to distinguish between MPN and CHIP. Third, we did not routinely screen for antiphospholipid antibodies, which could be a confounding factor in cases of unexplained arterial thrombosis. Fourth, the sample size of JAK2 V617F-positive patients was relatively small, limiting the power of subgroup analyses. Finally, our study did not include a control group of nonthrombotic individuals, which would have strengthened the interpretation of JAK2 V617F prevalence in arterial thrombosis. Future multicenter, prospective studies are needed to further investigate these findings and refine JAK2 V617F screening strategies in arterial thrombosis cases.
Recommending platelet thresholds as indicators for JAK2 V617F mutation screening in cases of arterial thrombosis paves the way for more systematic and personalized screening approaches. We have identified specific platelet thresholds that can guide JAK2 V617F mutation testing, with levels of 300 G/L and 350 G/L offering NPVs of 99 and 98%, respectively. Elevated platelet counts associated with JAK2 V617F mutation prompt consideration of different treatment modalities. The discussion extends to the relevance of aspirin, anticoagulants, and cytoreductive therapies.[10] [14]
In conclusion, in our study, JAK2 V617F mutation prevalence in case of peripheral arterial thrombosis was 8%. Using a platelet threshold of 365 G/L, this mutation would be detected with a sensitivity of 0.83 and a specificity of 0.80. Further prospective studies are needed to determine the exact prevalence of the JAK2 V617F mutation in arterial thrombosis.
Author Contributions
A.V., C.B., A.L.J.: study design, data collection, statistical analysis, and drafting of the manuscript. N.G., A.M., T.C., L.C., S.C., F.D., P.C., D.S.: data collection, editing, and revising the manuscript.
Publication History
Received: 18 February 2025
Accepted: 11 June 2025
Article published online:
24 June 2025
© 2025. Thieme. All rights reserved.
Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA
-
References
- 1 Sène D, Elalamy I, Ancri A, Cacoub P. JAK2V617F mutation is not associated with unexplained recurrent arterial and venous thrombosis. Thromb Res 2008; 122 (03) 427-428
- 2 Baxter EJ, Scott LM, Campbell PJ. et al; Cancer Genome Project. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 365 (9464): 1054-1061
- 3 Pasquer H, Daltro de Oliveira R, Vasseur L. et al. Distinct clinico-molecular arterial and venous thrombosis scores for myeloproliferative neoplasms risk stratification. Leukemia 2024; 38 (02) 326-339
- 4 Lussana F, Caberlon S, Pagani C, Kamphuisen PW, Büller HR, Cattaneo M. Association of V617F Jak2 mutation with the risk of thrombosis among patients with essential thrombocythaemia or idiopathic myelofibrosis: a systematic review. Thromb Res 2009; 124 (04) 409-417
- 5 Finazzi G, Rambaldi A, Guerini V, Carobbo A, Barbui T. Risk of thrombosis in patients with essential thrombocythemia and polycythemia vera according to JAK2 V617F mutation status. Haematologica 2007; 92 (01) 135-136
- 6 Xavier SG, Gadelha T, Pimenta G. et al. JAK2V617F mutation in patients with splanchnic vein thrombosis. Dig Dis Sci 2010; 55 (06) 1770-1777
- 7 Abel GA, DeAngelo DJ, Connors JM, Sholl LM, McCaffrey RP, Longtine JA. Clinical JAK2V617F mutation testing: limited utility for general hospital patients with venous and arterial thromboses in common locations. Am J Hematol 2008; 83 (06) 519-520
- 8 Dentali F, Squizzato A, Appio L, Brivio L, Ageno W. JAK2V617F mutation in patients with arterial thrombosis in the absence of overt myeloproliferative disease. J Thromb Haemost 2009; 7 (04) 722-725
- 9 Smalberg JH, De Maat MPM, Leebeek FWG. Absence of the JAK2 V617F mutation in patients with arterial thrombosis without overt myeloproliferative disease. J Thromb Haemost 2008; 6 (09) 1606-1607
- 10 Barbui T, Thiele J, Gisslinger H. et al. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J 2018; 8 (02) 15
- 11 Wang D, Yu X, Sun Y. et al. Incidence of thrombosis at different sites during the follow-up period in essential thrombocythemia: a systematic review and meta-analysis. Clin Appl Thromb Hemost 2023; 29: 10 760296231181117
- 12 Raimbeau A, Pistorius M-A, Goueffic Y. et al. Digital ischaemia aetiologies and mid-term follow-up: a cohort study of 323 patients. Medicine (Baltimore) 2021; 100 (20) e25659
- 13 Muendlein A, Kinz E, Gasser K. et al. Occurrence of the JAK2 V617F mutation in patients with peripheral arterial disease. Am J Hematol 2015; 90 (01) E17-E21
- 14 Shapira Cohen T, Chodick G, Steinberg DM, Grossman E, Shohat M, Salomon O. JAK2V617F is a risk factor for TIA/stroke in young patients. Thromb Haemost 2022; 122 (08) 1333-1340