Can VEXAS syndrome cause macrocytosis?

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VEXAS Syndrome and Macrocytosis

Yes, VEXAS syndrome consistently causes macrocytic anemia and macrocytosis—this is one of its most prominent and characteristic hematologic features. 1, 2, 3

Hematologic Hallmarks of VEXAS Syndrome

Macrocytic anemia/macrocytosis occurs in 100% of VEXAS patients and serves as a key diagnostic clue. 1, 4, 5 This finding is so consistent that its presence in adult males with autoinflammatory symptoms should immediately prompt screening for UBA1 variants. 1

Core Hematologic Features

  • Macrocytic anemia is universal in VEXAS syndrome, affecting all patients and representing one of the defining laboratory abnormalities alongside the characteristic bone marrow vacuoles. 5

  • Bone marrow examination reveals pathognomonic cytoplasmic vacuoles in myeloid and erythroid precursors—this finding combined with macrocytosis in a patient with inflammatory symptoms is highly suggestive of VEXAS. 1, 2, 4

  • Lymphopenia occurs in 80% of patients, making the combination of macrocytic anemia plus lymphopenia particularly characteristic. 5

  • Thrombocytopenia and neutropenia develop more commonly in patients who progress to myelodysplastic syndrome (MDS), which occurs in approximately 38% (6 of 16) of VEXAS patients. 5

Pathophysiology

The macrocytosis results from somatic mutations in UBA1 (specifically at p.Met41) affecting hematopoietic stem and progenitor cells, leading to clonal expansion and myeloid-skewed differentiation. 1 The loss of UBA1b isoform impairs ubiquitination pathways, directly affecting erythroid maturation and producing the characteristic macrocytic changes. 1

Clinical Context and Diagnostic Approach

When to Suspect VEXAS

  • Adult males (typically >50 years) presenting with:
    • Recurrent fever, chondritis (especially ear/nose), neutrophilic dermatosis, pulmonary infiltrates, or vasculitis 2, 3
    • Macrocytic anemia with elevated inflammatory markers 2
    • Venous thromboembolism (occurs in 63% of patients) 5

Diagnostic Workup

  • Screen for UBA1 variant when macrocytosis is found in patients with autoinflammatory symptoms—this is the definitive diagnostic test. 1

  • Bone marrow examination shows:

    • Hypercellularity with myeloid hyperplasia 4, 5
    • Erythroid hypoplasia 5
    • Cytoplasmic vacuoles in myeloid and erythroid precursors (pathognomonic) 1, 2, 4
    • Varying degrees of dysplasia 4, 5

  • Exclude other causes of macrocytosis per standard guidelines: vitamin B12 and folate levels, thyroid function, medication review, and evaluation for MDS. 6, 7 However, the presence of inflammatory symptoms, vacuolated precursors, and male sex should elevate suspicion for VEXAS above typical causes.

Associated Hematologic Complications

VEXAS frequently coexists with other hematologic disorders:

  • Myelodysplastic syndrome develops in 38% of patients, though these are typically lower-risk MDS with low blast counts and favorable cytogenetics. 5

  • Plasma cell dyscrasias including multiple myeloma (13%) and monoclonal gammopathy of undetermined significance (13%) are common. 1, 5

  • Monoclonal B-cell lymphocytosis occurs in 13% of patients. 5

Critical Clinical Pitfall

Do not dismiss macrocytosis as "benign" or attribute it solely to inflammation in adult males with systemic inflammatory symptoms. The combination of macrocytic anemia, inflammatory manifestations, and bone marrow vacuoles should trigger immediate consideration of VEXAS syndrome, as early recognition impacts treatment decisions and prognosis. 1, 3

Prognostic Implications

Morbidity and mortality in VEXAS are primarily driven by progression to hematologic disease rather than inflammatory manifestations alone. 5 Surveillance for MDS and plasma cell disorders is essential, as these complications significantly impact outcomes. 5

Allogeneic hematopoietic stem cell transplantation remains the only curative therapy and should be considered for younger, fit patients with poor prognostic factors or refractory symptoms. 1, 2, 3

References

1
Research

VEXAS syndrome.

International journal of hematology, 2025

3
Research

VEXAS syndrome: An update.

Joint bone spine, 2024

6
Guideline

Management of Macrocytic Anemia

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

7
Guideline

Diagnosis and Management of Mild Macrocytic Anemia with Leukocytosis

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2025

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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