The Clinical Profile of JAK2 Negative,Normal Erythropoeitin,Normal Arterial Oxygen Saturation Erythrocytosis in an Indian Tertiary Centre

Introduction:

Polycythemia Vera (PV) is a myeloproliferative syndrome characterized by JAK2 mutation with evidence of panmyelosis in the bone marrow [WHO 2016]. PV has risk of thrombosis and transformation to myelofibrosis /leukemia.

Etiologies enlisted for JAK2 negative erythrocytosis include high-oxygen affinity hemoglobin variants, 2,3 biphosphoglycerate deficiency, and germline (e.g., PHD2, HIF2A, VHL) or EPO signaling (e.g., EPOR) mutations. Investigating for such causes is not feasible in rural India.

JAK2 negative erythrocytosis is the category comprising these mutations and idiopathic causes. The treatment recommendations for JAK2 negative erythrocytosis is limited. The risk of thrombosis in this group is unknown. We present the clinical profile of subgroup of JAK2 Negative erythrocytosis with normal Erythropoietin [EPO] and normal arterial oxygen saturation [PaO2] from a tertiary care center in India.

Method of study:

Retrospective analysis of all the patients presented to the hematology outpatient clinic with high Hb /Hematocrit >16.5/49 for males and >16/48 for females from August 2019 to November 2021 were evaluated. Secondary causes evaluated. They underwent clinical examination, Complete blood count, ABG analysis for arterial oxygen saturation, Serum EPO estimation by chemiluminescence immunoassay [Normal: 2.6 - 18.5 mIU/mL], blood JAK2 V617F and JAK2 exon 12 mutation analysis by NGS at Medgenome Labs Pvt Limited, Bengaluru, Unilateral bone marrow aspiration and biopsy if willing.

Inclusion criteria:

1.Hb /HCT >16.5gram%/ 49 for men and >16gram% /48 for women.

Exclusion Criteria:

1.History of smoking, cyanosis or obstructive sleep apnea, COPD or cyanotic heart disease or high altitude, anabolic steroids.

2.Family history.

3.PaO2 below normal.

4.WBC > 11000/microliter, Platelets > 450000/microliter.

5.Palpable splenomegaly.

6.Erythropoietin levels <2.6mIU/ml or>8.5mIU/ml.

7.Jak2 V617F or Exon 12 mutation in NGS.

8.Panmyelosis in bone marrow [WHO 2016 criteria]

Results:

Total 256 patients were with elevated Hemoglobin.122 patients were excluded in view of meeting one of the exclusion criteria. Additional 58 patients were excluded because of lack of JAK2 mutational analysis. 76 patients who met the inclusion criteria of JAK2 negative erythrocytosis with normal EPO and normal PaO2.75 patients were males, mean age was 40 years [Range:15 -75]. Mean Hemoglobin at presentation was 18gram% [Range:16.8 to 22]. Mean erythropoietin was 6.69mIU/ml [Range 3-16.3]. The median follow up was for 8 months [Range:1 month to 24 months]. 37 patients were asymptomatic at presentation, for whom high Hb was detected while screening for blood donation or as a part of routine checkup. 16 patients developed thrombosis at the presentation. Median age of the patient's developing thrombosis was 42 [range 24 to 68 years].8 patients developed stroke,3 patients developed coronary artery disease,4 patients developed venous thrombosis.15 patients had hypertension at presentation. Other presenting symptoms were headache, redness of eyes, giddiness. Only 13 patients underwent bone marrow examination, in which 9 had normal bone marrow, 4 had isolated erythrocytosis. 47 patients took aspirin regularly. 32 patients underwent phlebotomy once a month if Hb/HCT >15gram/45. 13 of the 16 patients with thrombosis at presentation were continuing aspirin and were adhering to phlebotomy during follow up.3 patients received hydroxyurea as they were not tolerating phlebotomy. No patients developed new thrombotic events during the follow up. There was no correlation with level of Hb or EPO with thrombosis.

Discussion:

Our retrospective of JAK2 negative erythrocytosis data showed that the majority of patients were male,48 % patients were asymptomatic and had no thrombotic complications during the follow up. 21% developed thrombotic events at presentation. The duration of follow up is short in our study. Ideal treatment for thrombosis in this group needs further clinical trials. Treatment protocol for asymptomatic patients also need further clinical trials.

No relevant conflicts of interest to declare.