Recurrent Aortic Thromboembolism Associated With TET2 Mutation in Chronic Myelomonocytic Leukemia

Abstract

Ten-eleven translocation 2 (TET2) plays a pivotal role in epigenetic regulation, cell differentiation, and the inflammatory response. It also mediates the transcriptional regulation for inflammatory cytokines, particularly interleukin-6. While loss-of-function mutation in TET2 has been associated with hematological malignancies, it has been increasingly recognized to cause atherosclerotic disease. The increased atherogenicity is thought to be the result of increased production of pro-inflammatory interleukin-1β cytokines following activation of NLRP3 inflammasomes. We present a unique case of recurrent atherothrombosis in an elderly man who was diagnosed with chronic myelomonocytic leukemia in the setting of TET2 mutation.

Introduction

The process of aging is associated with a frequent occurrence of somatic mutations in the hematopoietic stem cells. ¹ Some of these mutations, particularly involving the ten-eleven translocation 2 (TET2) gene, induce clonal expansion of the mutant blood cells. ² TET2 encodes a protein, an epigenetic regulatory enzyme, that promotes hematopoietic stem or progenitor cell (HSPC) self-renewal. ² Studies have demonstrated that TET2 mutations not only heighten risk of hematological malignancies but also have a causal link with accelerated atherosclerosis. ³ We present a case of a patient with recurrent thrombosis in the context of TET2-driven clonal hematopoiesis. Patient consent was formally obtained for this case report.

Case Presentation

A 74-year-old man with history of hyperlipidemia, hypertension, and seizure disorder presented to the emergency department with a chief complaint of left-lower-quadrant abdominal pain for 1 day. Contrast-enhanced computed tomography (CT) scan of the abdomen noted a wedge-shaped defect in the left kidney suggestive of infarct and severe atherosclerosis of the descending aorta (Figures 1 and 2). The patient was afebrile, white blood cell count was within normal limits of 6.2 th/µL, and urinalysis did not reveal pyuria. He was evaluated by cardiovascular service and underwent transesophageal echocardiogram that did not show intracardiac thrombus. Given the concern for an embolic phenomenon, he was started on rivaroxaban 20 mg daily along with aspirin 81 mg daily. A 30-day event recorder was placed, which was negative for arrhythmia. Hypercoagulable workup, including lupus anticoagulant, anti-cardiolipin antibody, beta-2 glycoprotein antibody, serum protein electrophoresis, methylene tetrahydrofolate mutation, Janus Kinase-2 mutation, and paroxysmal nocturnal hemoglobinuria flow cytometry was unremarkable.

Figure 1.

Left-sided renal infarct found on initial presentation.

Figure 2.

Severe atherosclerosis of distal thoracic and abdominal aorta.

Three months later, he again presented to the emergency department with left-upper-quadrant pain. Computed tomography angiogram of the abdomen demonstrated acute splenic infarct. Thrombus in the distal thoracic aorta was also noted. His rivaroxaban was stopped, and the patient was started on unfractionated heparin infusion and switched from aspirin to clopidogrel. Interestingly, routine laboratory workup was notable for thrombocytosis with a platelet count of 555 k/uL along with new anemia, hemoglobin of 9.7 g/dL, and monocytosis at 33%. These abnormal results were also noted on his prior hematological studies, but it was never addressed earlier. A peripheral smear suggested chronic myelomonocytic leukemia (CMML). He underwent bone marrow biopsy revealing hypercellular marrow with granulocytic dysplasia, increased megakaryocytes, and accompanying absolute monocytosis. CD43 immunoperoxidase stain revealed scattered blasts 3% to 4% overall favoring CMML with the presence of NRAS G12V activating mutation and TET2 mutation. At the time of discharge, he was started on enoxaparin and bridged to warfarin with a target international normalized ratio (INR) 2-3 and was scheduled to follow up with hematology as outpatient.

The patient subsequently had third hospitalization within a span of 8 months for similar complaint. He was found to have another acute splenic infarct, as well as multiple renal infarcts despite being adequately anticoagulated with warfarin with INR on 2.5. He was started on unfractionated heparin infusion. Repeat echocardiogram was negative for intracardiac thrombus. He underwent clopidogrel reactivity test and was found to be resistant to clopidogrel. He was ultimately discharged on enoxaparin 1.5 mg/kg daily for anticoagulation and switched from clopidogrel to ticagrelor. He unfortunately presented again after 2 months with recurrent splenic infarcts and was noted to have progressively worsening clot burden in the descending aorta. The dose of enoxaparin was increased to 1 mg/kg twice daily, and ticagrelor was continued.

During this time, his hypertension was consistently well-controlled to a goal of <130/80 mm Hg, and his lipid profile was unremarkable with total cholesterol of 160 mg/dL, low-density lipoprotein of 75 mg/dL, and high-density lipoprotein of 41 mg/dL while being on atorvastatin 40 mg daily. He did not report any family history of arterial thrombosis. He was eventually evaluated by hematology and deemed that his recurrent atherothrombosis was potentially explained by his somatic mutation profile that was significant for TET2 mutations. Subsequently, different treatment options, including stem cell transplant, were discussed with the patient. The patient opted for medical management, and cytoreductive therapy was initiated. In the coming months, the patient did not have any recurrence of thrombotic events.

Discussion

Somatic deoxyribonucliec acid (DNA) mutations can result in selective expansion of hematopoietic stem cells, resulting in increased risk of hematological neoplasms and cardiovascular disease. ⁴ TET2, alongside DNMT3A and ASXL1, is one of the most frequently involved genes associated with myeloid neoplasms. It is located on chromosome 4q24 and modulates DNA methylation by catalyzing conversion of 5-methylcytosine to 5-hydroxymethylcytosine. TET2 mutations are found in approximately 60% patients with CMML, and our case is one such example.^5,6

Inflammation plays a pivotal role in atherothrombosis, involving cytokine-mediated plaque initiation, progression, and sudden fibrous cap rupture that triggers local thrombosis. ⁷ Elevated C-reactive protein has been correlated with the risk of atherosclerotic cardiovascular disease, and roles of interleukin (IL)-1 and IL-6 have been well established in causation and progression of atherothrombosis. ⁸ Preclinical data have demonstrated heightened inflammatory response with TET2 mutation, mediated by IL-1β and IL-6 signaling. ³ Fuster et al ³ demonstrated in mice studies that TET2 deficiency enhances NLRP3 priming that drives IL-1β production in macrophages, ultimately resulting in plaque buildup in the aorta. The proatherogenic tendency of IL-1 signaling is mediated primarily by its effects on vascular cells through modulation of endothelial cell adhesion expression. ⁹

Jaiswal et al ¹⁰ demonstrated that age-related clonal hematopoiesis is associated with increased risk of hematologic cancer and cardiovascular-related all-cause mortality. In this study, mutations were predominantly seen in DNMT3A, TET2, and ASXL1 genes, and the presence of a somatic mutation was associated with an increase in the risk of hematologic cancer alongside increased all-cause mortality, incident coronary heart, and ischemic stroke. ¹⁰ In our case, the patient’s cardiovascular risk factors including hypertension and hyperlipidemia were optimally controlled, and he did not have a family history of thrombosis or any notable coagulopathy that could explain recurrent thrombosis. Therefore, his thrombogenicity was deemed to be associated with TET2 mutation.

Conclusions

Clonal hematopoiesis driven by TET2 mutation can not only increase risk of hematological malignancies but also result in atherosclerotic cardiovascular disease. In our patient, TET2 mutation, while resulting in CMML, was also associated with recurrent atherothrombotic events involving thrombus in the descending aorta as well as renal and spleen infarcts, despite anticoagulation with rivaroxaban and warfarin. The increased atherogenicity associated with TET2 mutation is thought to be related to increased production of IL-1β cytokines following activation of NLRP3 inflammasomes.