JAK2 unmutated erythrocytosis: current diagnostic approach and therapeutic views

Abstract

JAK2 unmutated or non-polycythemia vera (PV) erythrocytosis encompasses both hereditary and acquired conditions. A systematic diagnostic approach begins with documentation of historical hematocrit (Hct)/hemoglobin (Hgb) measurements and classification of the process as life-long/unknown duration or acquired. Further investigation in both categories is facilitated by determination of serum erythropoietin level (EPO). Workup for hereditary/congenital erythrocytosis requires documentation of family history and laboratory screening for high-oxygen affinity hemoglobin variants, 2, 3 biphosphoglycerate deficiency, and germline mutations that are known to alter cellular oxygen sensing (e.g., PHD2, HIF2A, VHL) or EPO signaling (e.g., EPOR mutations); the latter is uniquely associated with subnormal EPO. Acquired erythrocytosis is often elicited by central or peripheral hypoxia resulting from cardiopulmonary disease/high-altitude dwelling or renal artery stenosis, respectively; EPO in the former instance is often normal (compensated by negative feed-back). Other conditions associated with acquired erythrocytosis include EPO-producing tumors and the use of drugs that promote erythropoiesis (e.g., testosterone, erythropoiesis stimulating agents). “Idiopathic erythrocytosis” loosely refers to an otherwise not explained situation. Historically, management of non-PV erythrocytosis has been conflicted by unfounded concerns regarding thrombosis risk, stemming from limited phenotypic characterization, save for Chuvash polycythemia, well-known for its thrombotic tendency. In general, cytoreductive therapy should be avoided and phlebotomy is seldom warranted where frequency is determined by symptom control rather than Hct threshold. Although not supported by hard evidence, cardiovascular risk optimization and low-dose aspirin use are often advised. Application of modern genetic tests and development of controlled therapeutic intervention trials are needed to advance current clinical practice.

The Classification of Myeloproliferative Neoplasms: Rationale, Historical Background and Future Perspectives with Focus on Unclassifiable Cases

“…A definite diagnosis of PV should be rendered with great caution in the absence of identifiable JAK2 mutations, as these occur in >95% of cases [1,62]. A common instance related to this scenario is the occurrence of cases with low-burden driver gene mutations (i.e., VAF falling below the sensitivity of the available techniques) [41].…”

“…Less frequently, a clinical and morphologic picture fully consistent with PV may be sustained by a JAK2 wt clone. This imposes a challenging assessment of alternative congenital or acquired states of erythrocytosis [62]. Interestingly, sporadic JAK2 wt MPN cases featuring the clinical phenotype of PV have been associated with mutations of CALR, either canonical (type 1) [63] or noncanonical [64].…”

“…Rare JAK2 wt cases, some of which with PV features, may also carry mutations in LNK/SH2B3 [65]. This genetic event has been associated with an increased risk of blastic transformation in MPN [66], as well as with occasional cases of idiopatic erythrocytosis [62].…”

Potential limitations of diagnostic standard codes to distinguish polycythemia vera and secondary erythrocytosis

“…The term polycythemia denotes an increased total red cell volume, sometimes used interchangeably with erythrocytosis, the former recommended by some experts to be used only in the context of primary myeloproliferative diseases 1 . Erythrocytosis describes an increase above 2 standard deviations in hematocrit or hemoglobin.The measurement of these values is based on whole blood; therefore, it is based on plasma volume and subjects to its changes 2 . To avoid discrepancies, red blood cell mass must be measured for greater accuracy to demonstrate an increase of 125% in sex and body mass, however, this can be difficult to obtain 3 .…”

“…Therefore, described as an outcome of cardiopulmonary or hypoxia-related issues [smoking, chronic pulmonary disease (COPD), obstructive sleep apnea syndrome (OSA), right to left pulmonary shunts, high altitude habitat], or renal disorders such as arterial stenosis 10 . Acquired causes of this disorder also include hypoxia-independent SE, caused as a side effect of certain diuretic drugs, androgens, anabolic steroids, erythropoietin, post-renal transplantation, or as a result of autonomous EPO production in certain tumors 2 .…”