What are the likely causes and recommended evaluation and management for macrocytic anemia with thrombocytosis and lymphopenia in a 69‑year‑old man with prior cerebrovascular accident (stroke), hypertension, hyperlipidemia, chronic kidney disease (CKD), vascular dementia, and a known myeloproliferative disorder?

Macrocytic Anemia with Thrombocytosis and Lymphopenia in a Patient with Myeloproliferative Disorder and CKD

This patient requires immediate comprehensive hematologic evaluation focusing on his known myeloproliferative disorder as the primary cause, with concurrent assessment for nutritional deficiencies (B12, folate) and iron status given his CKD and macrocytosis.

Likely Causes

Primary Consideration: Myeloproliferative Disorder

• The known myeloproliferative disorder is the most likely unifying diagnosis explaining the constellation of macrocytic anemia (MCV 105.2), thrombocytosis (platelets 461), and lymphopenia (absolute lymphocytes 735) 1, 2.
• Myeloproliferative neoplasms commonly present with cytopenias in one lineage while showing proliferation in others, particularly as they evolve or transform 1.
• The macrocytosis may reflect dysplastic erythropoiesis characteristic of myelodysplastic/myeloproliferative overlap syndromes 1.

Secondary Considerations

Nutritional Deficiencies (B12/Folate):

• Macrocytic anemia with MCV >100 fL warrants evaluation for vitamin B12 and folate deficiency, which are common in elderly patients with chronic disease 1, 3.
• CKD patients frequently develop nutritional deficiencies that contribute to macrocytosis 4.

CKD-Related Anemia:

• Hemoglobin 12.3 g/dL in a male with CKD represents anemia (normal >13 g/dL) 4.
• CKD typically causes normocytic anemia from erythropoietin deficiency, but concurrent nutritional deficiencies can produce macrocytosis 1, 4.

Medication Effects:

• Review all medications for agents causing macrocytosis (hydroxyurea if used for myeloproliferative disorder, certain anticonvulsants, immunosuppressants) 3.

Recommended Evaluation

Immediate Laboratory Testing

Complete hematologic workup per KDIGO guidelines 1:

• Peripheral blood smear to assess for hypersegmented neutrophils (megaloblastic anemia), dysplastic features, or blast cells 1, 3.
• Reticulocyte count (absolute) to assess bone marrow response 1.
• Serum vitamin B12 and red blood cell folate levels 1, 3.
• Iron studies: serum ferritin, transferrin saturation (TSAT), serum iron 1.
• Thyroid function tests (TSH) to exclude hypothyroidism as a cause of macrocytosis 3.
• Liver function tests to exclude hepatic causes of macrocytosis 3.

Myeloproliferative Disorder Assessment 1:

• Bone marrow biopsy with cytogenetics if not recently performed, to assess for disease progression or transformation.
• JAK2V617F mutation testing if not previously done 2.
• Evaluate for PDGFRA/PDGFRB rearrangements given the clinical picture 1.
• Assess blast percentage in peripheral blood and bone marrow to exclude transformation to acute leukemia 1.

Risk Stratification

Cerebrovascular Risk Assessment:

• This patient's prior CVA, vascular dementia, and myeloproliferative disorder create extremely high thrombotic risk 1, 5.
• CKD increases stroke risk by 40% and is strongly associated with poor functional outcomes after stroke 1, 6.
• Myeloproliferative disorders cause hyperviscosity and qualitative platelet dysfunction, substantially increasing arterial and venous thrombosis risk 2, 5.

Management Approach

Immediate Management

Address the Myeloproliferative Disorder:

• If polycythemia vera is confirmed, maintain hematocrit strictly below 45% through phlebotomy to reduce thrombotic risk 2, 5.
• Low-dose aspirin (81-100 mg daily) is recommended for all myeloproliferative disorder patients without contraindications to reduce cardiovascular events 2.
• Consider cytoreductive therapy (hydroxyurea for patients >60 years) given his age and prior stroke history, which classifies him as high-risk 2.

Nutritional Repletion:

• If B12 deficiency confirmed (level typically <200 pg/mL), initiate B12 supplementation: 1000 mcg intramuscularly daily for 1 week, then weekly for 4 weeks, then monthly 1.
• If folate deficiency confirmed, initiate folic acid 1-5 mg daily 1, 3.
• Critical caveat: Never give folate alone without checking B12, as folate can mask B12 deficiency while allowing neurological damage to progress 3.

Iron Management in CKD:

• If TSAT ≤30% and ferritin ≤500 ng/mL, consider trial of intravenous iron (preferred in CKD) or 1-3 month trial of oral iron 1.
• Balance benefits of correcting iron deficiency against risks, as iron deficiency in myeloproliferative disorders can paradoxically increase thrombotic risk through microcytosis 1, 2.

Anemia Target in CKD Context

• Do not aggressively correct hemoglobin to normal levels in this patient with CKD, prior stroke, and diabetes-equivalent risk 1.
• Target hemoglobin should be individualized but generally avoid exceeding 11-12 g/dL, as the TREAT trial showed increased stroke risk with normalization of hemoglobin using erythropoiesis-stimulating agents in CKD patients 1.
• Erythropoiesis-stimulating agents should only be considered if hemoglobin falls below 9 g/dL and after correcting nutritional deficiencies 1.

Thrombocytosis Management

• Platelet count of 461 is mildly elevated and requires monitoring 1.
• If platelets exceed 600,000 or patient develops thrombotic symptoms, cytoreductive therapy becomes more urgent 1, 2.
• Critical pitfall: Avoid routine anticoagulation solely for thrombocytosis, as myeloproliferative disorders cause both thrombotic and bleeding diathesis 1.

Lymphopenia Considerations

• Absolute lymphocyte count of 735 represents mild lymphopenia (normal >1000) 1.
• This may reflect chronic disease, immunosuppression from the myeloproliferative disorder, or medication effects 1.
• Monitor for infectious complications and ensure appropriate vaccinations (annual influenza, pneumococcal) 1.

Monitoring Strategy

Short-term (every 2-4 weeks initially):

• Complete blood count with differential to assess response to nutritional repletion and monitor cytopenias 1.
• Reticulocyte count to confirm bone marrow response 1.
• If on cytoreductive therapy, monitor for myelosuppression 1, 2.

Long-term (every 3-6 months):

• Reassess iron studies, B12, and folate levels 1.
• Monitor for myeloproliferative disorder progression or transformation to myelofibrosis/acute leukemia 1, 2.
• Assess for hyperviscosity symptoms (headache, visual disturbances, dizziness) 2.
• Continue aggressive management of cardiovascular risk factors (hypertension, hyperlipidemia) given extremely high stroke risk 1, 2.

Critical Pitfalls to Avoid

• Do not assume macrocytosis is solely from B12/folate deficiency without peripheral smear review – dysplastic features suggest primary bone marrow pathology 1, 3.
• Do not overlook iron deficiency in the setting of normal/high ferritin – ferritin is an acute phase reactant and can be falsely elevated in chronic disease; TSAT <20% indicates functional iron deficiency 1.
• Do not aggressively correct anemia with erythropoiesis-stimulating agents in this high-risk patient with prior stroke and CKD, as this increases thrombotic risk 1.
• Do not perform inappropriate phlebotomy if the myeloproliferative disorder is not polycythemia vera, as this can worsen anemia 2.
• Do not delay hematology consultation – this complex case requires subspecialty expertise for optimal management of the myeloproliferative disorder 1, 2.