JAK2 exon 12 mutation-positive myeloproliferative neoplasm associated with recurrent thromboembolism

Vahid Tavakoli; Sundee Naing

doi:10.5045/br.2017.52.1.67

TO THE EDITOR: Detailed analysis of Philadelphia (Ph) chromosome-negative myeloproliferative neoplasms, essential thrombocythemia (ET), and polycythemia vera (PV) paved the way for the recognition of Janus kinase 2 (JAK2) as a potential genetic factor [1]. While most cases of these diseases are related to JAK2 V617F, some are associated with JAK2 exon 12 mutation. JAK2 exon 12 mutation is a rare phenomenon that is not yet well studied. Although, the presence of JAK2 exon 12 mutation is linked to PV and ET, its phenotypic features are not clear, especially in cases without ET and PV. The JAK2 exon 12 G571S variant has also not been studied well, and its phenotypic features are unknown. We present a case of recurrent deep vein thrombosis (DVT) and pulmonary embolism that had a negative coagulation workup, but was positive for JAK2 exon 12 (G571S) mutation. The presented case suggests a possible relationship between JAK2 exon 12 mutation and recurrent thrombosis. While JAK2 V617F is inherently related to thrombotic events, irrespective of the platelet level, JAK2 exon 12 might have similar procoagulant effects. It is hypothesized that further molecular studies can reveal the underlying factors that cause this co-occurrence.

CASE

A 38-year-old Hispanic woman with a past medical history of pulmonary embolism, DVT, and asthma was seen for an evaluation of her recurrent episodes of thrombosis. She had experienced three episodes of DVT and one episode of pulmonary embolism. The first episode of DVT occurred 5 years ago, and the second episode happened 3 years ago. The pulmonary embolism occurred 1 year ago, following her third episode of DVT. Each DVT episode presented with lower leg edema and pain, and was confirmed by lower extremity ultrasound. The pulmonary embolism episodes presented as shortness of breath and low oxygen saturation.

She was given the following medications to take at home: Ipratropium-Albuterol (Duoneb Neb), 3 mL by inhalation every 4 hours as needed, and warfarin sodium (Coumadin), 12 mg orally once daily. However, she was non-adherent to the use of warfarin. The notable aspects of her family history were that her mother had diabetes mellitus and hypertension, while her father had colon cancer at age of 42. She was a current smoker and had been smoking 2 packs of cigarettes daily for 20 years. She denied alcohol and drug use. A review of systems was non-contributory.

A recent complete blood cell count revealed the following: white blood count 11.1×10⁹/L, hemoglobin level 14.9 g/dL, hematocrit 45.4%, mean corpuscular volume (MCV) 81.6 fL, mean corpuscular hemoglobin (MCH) level 30.7 pg, mean corpuscular hemoglobin concentration (MCHC) 32.8 g/dL, platelet count 555×10⁹/L, neutrophil 46%, lymphocyte 41%, monocyte 4.6%, eosinophil 3.9%, and basophil 0.1%. A basic metabolic profile (BMP) showed the following levels: sodium 139 mmol/L, potassium 4.1 mmol/L, chloride 109 mmol/L, carbon dioxide 29 mmol/L, blood urea nitrogen (BUN) 6 mg/dL, creatinine 0.6 mg/dL, glucose 86 mg/dL, calcium 9.1 mg/dL, phosphorus 3.8 mg/dL, magnesium 2.2 mg/dL, total protein 7.8 g/dL, albumin 3.7 g/dL, aspartate amino-transferase (AST) 16 U/L, alanine amino-transferase (AST) 20 U/L, and alkaline phosphatase 119 U/L.

Her latest chest computed tomography showed a small incomplete filling defect in the right upper lobe, suggesting a chronic non-occluding pulmonary embolism. A coagulation workup, including lupus anticoagulant, protein C and S level/activity, antithrombin III level/activity, factor V level/activity, anti-cardiolipin IgG antibody, anti-cardiolipin IgM antibody, beta 2-GPI antibody (IgG,IgA, and IgM), Von Willebrand factor (VWF), factor VIII, methylenetetrahydrofolate reductase (MTHFR) gene mutation, homocysteine level, and prothrombin mutation analysis showed normal findings. For evaluation of high-normal platelet level, JAK2 mutation was analyzed; no other cause of thrombocytosis had been identified in the patient's history or laboratory findings. The result showed G571S mutation in JAK2 exon 12, and negative for CALR mutation. Total nucleic acid from plasma was used to sequence exons 12 and 13 using the polymerase chain reaction technique. The patient refused to undergo a bone marrow study.

DISCUSSION

The patient's platelet count has been in the higher range, from 350×10⁹/L to 800×10⁹/L, during the last 5 years. Some articles have mentioned that, in order to diagnose ET, it is necessary to have two platelet counts above 600×10⁹/L that were measured 1 month apart. On the other hand, the recent World Health Organization definition reduces this threshold to 400×10⁹/L, if that value is sustained. However, the laboratory findings for our patient did not satisfy either of the definitions of ET. The co-occurrence of the high platelet level and recurrent thrombosis, in the absence of other procoagulant abnormalities, highlights the possibility of a myeloproliferative disorder.

There is a proven correlation between PV and ET, and JAK2 mutation [1]. Although most of the relevant cases are JAK2 V617F, some are associated with JAK2 exon 12 mutation. To date, there are more than 30 known JAK2 exon 12 mutations. Nonetheless, JAK2 exon 12 mutations are rare and have not been widely studied. In general, JAK2 exon 12 mutations appear in younger individuals. Most of the reported cases of JAK2 exon 12 mutation have been linked to PV or ET. Bone marrow analysis of JAK2 exon 12 mutation cases show moderately hypercellular marrow with predominant erythroid hyperplasia. Patients with JAK2 exon 12 mutation lack the prominent megakaryocyte clusters that can be seen in patients with JAK2 V617F-positive PV. However, some patients with JAK2 exon 12 mutation have elevated numbers of megakaryocytes [2].

JAK2 V617F has been associated with thrombotic events, such as Budd-Chiari syndrome. Interestingly, in JAK2 V617F-positive patients, thrombotic events can occur even in the absence of increased red blood cells or platelets [3]. It has been shown that, in comparison with platelet quantity, platelet dysfunction is more important in thrombosis formation. To date, no association has been observed between JAK2 exon 12-positive status (without erythrocytosis or essential thrombosis) and recurrent thrombus events. Limited number of studies regarding JAK2 exon 12 have shown that mutations are more predominantly related to PV, with fewer cases of thrombosis [2].

ET is mainly caused by mutations in exon 9 of CALR, exon 10 of MPL, or JAK2 V617F in more than 90% of cases. The remaining cases are known as “triple negative.” In a recent study, Milosevic Feenstra et al. [4] performed whole-exome sequencing (WES) on samples from eight triple-negative patients. The authors were able to identify somatic mutations in three of the eight patients. For the three patients with clonal hematopoiesis, the analysis showed S204P and V285E mutations in MPL, and G571S mutation in JAK2 exon12. However, Milosevic Feenstra et al. [4] did not describe any thrombotic event in the triple-negative patients (including the G571S mutation). Additionally, our case does not satisfy the criteria for ET, despite having high-normal platelet levels.

To date, the phenotypic features of the individual mutations of JAK2 exon 12 are understudied and unknown. One study has described five cases of the abovementioned G571S variant [5]. Here, we have reported a case of recurrent DVT and pulmonary embolism in which the patient had a negative coagulation workup, but was positive for JAK2 exon 12 (G571S) mutation. The presented case did not satisfy the criteria for PV and ET, even though our patient had a higher than normal platelet count over several years.