EDITORIAL

EDITORIAL

Thrombophilia Screening:
Little Role for the JAK2V617F Mutation

I n the past 2 years, a relatively large number of studies

have investigated the prevalence of the somatic
JAK2V617F mutation in retrospective cohorts of patients
the mutation is an index of higher thrombotic risk in pa-
tients with chronic myeloproliferative disorders, because
JAK2V617F-positive patients have more activated granu-
with unexplained venous and arterial thromboembolism,1-3 locytes and heightened platelet-leukocyte in-
including a report by Pardanani et al4 published in this issue teractions, which may lead to a thrombo- See also
of Mayo Clinic Proceedings. At a glance, the reason for philia phenotype.10,11 However, the evidence page 457
doing these studies is not obvious, because JAK2V617F is that patients with chronic myeloproliferative
a gain-of-function genetic variant that, unlike the gain-of- disorders who harbor JAK2V617F have a higher incidence
function variants of coagulation factor genes (factor V of thrombotic complications than noncarriers12,13 is not
G1691A and prothrombin G20120A), is not associated per strong, because not all clinical studies are concordant in
se with hypercoagulability. The mutation causes the consti- finding that the presence of the mutation is associated with
tutive activation of JAK2, which in turn results in cytokine- an enhanced risk of thrombosis.8,14-16
independent myeloproliferation, mobilization of blood cell It could be argued that identification of the JAK2V617F
progenitors, and the spontaneous formation of endogenous mutation in patients with unexplained arterial and venous
erythroid colonies.5 thrombosis might help to diagnose atypical or occult
The clinical importance of the somatic mutation is re- chronic myeloproliferative disorders, which in turn could
lated to its well-established association with BCR/ABL1- be the causes of venous and arterial thrombosis. However,
negative chronic myeloproliferative disorders; it is present the diagnosis of chronic myeloproliferative disorders is
in most patients with polycythemia vera and approximately usually not difficult on the basis of the revised criteria of
half of those with essential thrombocythemia and chronic the World Health Organization (WHO)8 and does not
idiopathic myelofibrosis.5 Much more rarely, JAK2V617F is require a marker such as JAK2 positivity. Indeed, absent
found in patients with chronic myelomonocytic leukemia, in approximately half of the patients diagnosed as having
myelodysplastic syndromes, systemic mastocytosis, chron- essential thrombocythemia and idiopathic myelofibrosis,
ic neutrophilic leukemia, and acute myeloid leukemia.6 JAK2 positivity has a suboptimal negative predictive
Surprisingly, in a Chinese study, the mutation was detected value.
in blood samples of nearly 1% of 3935 study participants Conditions in which the WHO criteria may be mislead-
who were healthy or had miscellaneous diseases apparently ing, based as they are on high cell counts, are thromboses
unrelated to chronic myeloproliferative disorders.7 of the hepatic veins (Budd-Chiari syndrome) and the por-
Why then is JAK2V617F screening being performed in tal and mesenteric veins. In these patients, the ensuing
patients with unexplained venous and arterial thromboem- portal hypertension and hypersplenism could well mask
bolism? Long before the discovery of the mutation, chronic the increase in blood cell counts, even in the presence
myeloproliferative disorders were well known to be associ- of ongoing myeloproliferation. Hence, search for the
ated with an increased incidence of large-vessel arterial and JAK2 mutation can lead to a diagnosis of occult chronic
venous thrombosis. The incidence of thrombosis is higher myeloproliferative disorders17,18 that would not be pos-
in patients with polycythemia vera than in those with es- sible using solely the WHO diagnostic criteria; such a
sential thrombocythemia. It is also higher in patients who diagnosis would establish that cytoreductive therapy is
smoke, are elderly, have a history of thrombotic episodes, indicated.
or have other thrombotic risk factors (diabetes, hyperten- Screening for the JAK2V617F mutation has been car-
sion, and gain-of-function coagulation factor mutations). ried out in several retrospective cohorts of patients with
Recently, an increased leukocyte count was found to be a venous or arterial thrombosis in whom there was no ap-
prominent predictor of thrombotic risk, both in poly- parent reason to postulate that myeloproliferation would
cythemia vera and essential thrombocythemia.8,9 This find- be hidden as after splanchnic venous thromboses.1-4 Not
ing gave some biological plausibility to the hypothesis that surprisingly, these studies found that the mutation either
was absent or was present at a very low prevalence (≤1%),
Address correspondence to Pier Mannuccio Mannucci, MD, Via Pace 9,
not higher than that found in healthy people.1-3 For in-
20122 Milan, Italy ([email protected]). stance, Pardanani et al,4 who screened as many as 664
© 2008 Mayo Foundation for Medical Education and Research patients who had developed venous thromboembolism,

398 Mayo Clin Proc. • April 2008;83(4):398-399 • www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
 EDITORIAL

stroke, or myocardial infarction, found the mutation in only 1. Remacha AF, Estivill C, Sarda MP, et al. The V617F mutation of JAK2
is very uncommon in patients with thrombosis [letter]. Haematologica.
6 patients (<1%). 2007;92(2):285-286.
Why some people not diagnosed as having chronic my- 2. Colaizzo D, Amitrano L, Iannaccone L, et al. Gain-of-function gene
mutations and venous thromboembolism: distinct roles in different clinical
eloproliferative disorders are JAK2V617F positive remains settings. J Med Genet. 2007 Jun;44(6):412-416. Epub 2007 Feb 16.
unclear. One obvious possibility is that the mutation is an 3. Ugo V, Le Gal G, Lecucq L, Mottier D, Oger E, EDITH Collaborative
Study Group. Prevalence of the JAK2 V617F mutation is low among unselected
early beacon of a myeloproliferative neoplasm that has not patients with a first episode of unprovoked venous thromboembolism [letter]. J
yet become clinically manifest. Only follow-up of those Thromb Haemost. 2008 Jan;6(1):203-205. Epub 2007 Oct 22.
4. Pardanani A, Lasho TL, Hussein K, et al. JAK2V617F mutation
apparently healthy people who carry the mutation can con- screening as part of the hypercoagulable work-up in the absence of splanchnic
firm or rule out this hypothesis. Pardanani et al,4 who venous thrombosis or overt myeloproliferative neoplasm: assessment of value
in a series of 664 consecutive patients. Mayo Clin Proc. 2008;83(4):457-459.
followed up their 6 JAK2V617F-positive patients for a 5. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation
median period of 40 months, found that none developed an of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352(17):1779-
1790.
overt myeloproliferative disorder or recurrent thrombosis. 6. Jones AV, Kreil S, Zoi K, et al. Widespread occurrence of the JAK2
It is also unlikely that all apparently healthy carriers of the V617F mutation in chronic myeloproliferative disorders. Blood. 2005 Sep
15;106(6):2162-2168. Epub 2005 May 26.
mutation will ultimately develop a chronic myeloprolifera- 7. Xu X, Zhang Q, Luo J, et al. JAK2(V617F): prevalence in a large
tive disorder given that the JAK2V617F prevalence of Chinese hospital population. Blood. 2007 Jan 1;109(1):339-342. Epub 2006
Aug 31.
nearly 1% found in the largest normal population investi- 8. Carobbio A, Finazzi G, Guerini V, et al. Leukocytosis is a risk factor for
gated so far7 is much higher than that of polycythemia vera, thrombosis in essential thrombocythemia: interaction with treatment, standard
risk factors, and JAK2 mutation status. Blood. 2007 Mar 15;109(6):2310-2313.
the most frequent chronic myeloproliferative disorder, Epub 2006 Nov 16.
which has an annual incidence in the United States of only 9. Landolfi R, Di Gennaro L, Barbui T, et al. Leukocytosis as a major
thrombotic risk factor in patients with polycythemia vera. Blood. 2007 Mar
0.002%.19 15;109(6):2446-2452. Epub 2006 Nov 14.
For a number of reasons, screening for the JAK2V617F 10. Falanga A, Marchetti M, Vignoli A, Balducci D, Barbui T. Leukocyte-
platelet interaction in patients with essential thrombocythemia and
mutation is not recommended as part of the battery of polycythemia vera. Exp Hematol. 2005;33(5):523-530.
investigations that are performed to understand the 11. Passamonti F, Rumi E, Pietra D, et al. Relation between JAK2 (V617F)
mutation status, granulocyte activation, and constitutive mobilization of
mechanism of unexplained arterial and venous thrombo- CD34+ cells into peripheral blood in myeloproliferative disorders. Blood. 2006
sis. First, the yield in terms of positivity is likely to be May 1;107(9):3676-3682. Epub 2005 Dec 22.
12. Campbell PJ, Scott LM, Buck G, et al, United Kingdom Myelo-
very low and will definitely not be cost effective. Second, proliferative Disorders Study Group, Medical Research Council Adult
the finding of positivity would only raise anxiety in pa- Leukaemia Working Party, Australasian Leukaemia and Lymphoma Group.
Definition of subtypes of essential thrombocythaemia and relation to
tients and their caregivers without allowing for a more polycythaemia vera based on JAK2 V617F mutation status: a prospective
accurate diagnosis or meaningful therapeutic interven- study. Lancet. 2005;366(9501):1945-1953.
13. Vannucchi AM, Antonioli E, Guglielmelli P, et al. Clinical profile of
tion. Exceptions to this negative recommendation are homozygous JAK2 617V>F mutation in patients with polycythemia vera or
splanchnic venous thromboses; in these patients, a finding essential thrombocythemia. Blood. 2007 Aug 1;110(3):840-846. Epub 2007
Mar 22.
of JAK2V617F positivity could help diagnose a hidden 14. Wolanskyj AP, Lasho TL, Schwager SM, et al. JAK2 mutation in
chronic myeloproliferative disease and might indicate the essential thrombocythaemia: clinical associations and long-term prognostic
relevance. Br J Haematol. 2005;131(2):208-213.
need for the addition of cytoreductive therapy to antico- 15. Tefferi A, Strand JJ, Lasho TL, et al. Bone marrow JAK2V617F allele
agulant therapy. burden and clinical correlates in polycythemia vera [letter]. Leukemia. 2007
Sep;21(9):2074-2075. Epub 2007 May 3.
16. Arellano-Rodrigo E, Alvarez-Larran A, Reverter JC, Villamor N,
Pier Mannuccio Mannucci, MD Colomer D, Cervantes F. Increased platelet and leukocyte activation as
contributing mechanisms for thrombosis in essential thrombocythemia and
Flora Peyvandi, MD, PhD correlation with the JAK2 mutational status. Haematologica. 2006;91(2):169-
Angelo Bianchi Bonomi Hemophilia and 175.
17. Patel RK, Lea NC, Heneghan MA, et al. Prevalence of the activating
Thrombosis Center JAK2 tyrosine kinase mutation V617F in the Budd-Chiari syndrome. Gastro-
Department of Medicine and Medical Specialties enterology. 2006;130(7):2031-2038.
18. Primignani M, Barosi G, Bergamaschi G, et al. Role of the JAK2
University of Milan mutation in the diagnosis of chronic myeloproliferative disorders in splanchnic
IRCCS Ospedale Maggiore Foundation vein thrombosis. Hepatology. 2006;44(6):1528-1534.
19. Spivak JL. Polycythemia vera: myths, mechanisms, and management.
Milan, Italy Blood. 2002 Dec 15;100(13):4272-4290. Epub 2002 Aug 8.

Mayo Clin Proc. • April 2008;83(4):398-399 • www.mayoclinicproceedings.com 399

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.