What is the diagnosis and treatment for anisopoikilocytosis?

Anisopoikilocytosis: Diagnosis and Treatment

Anisopoikilocytosis is a descriptive finding on peripheral blood smear indicating variation in red blood cell size (anisocytosis) and shape (poikilocytosis), not a diagnosis itself—the critical task is identifying the underlying hematologic disorder through systematic evaluation of peripheral blood morphology, bone marrow examination, and targeted testing for myelodysplastic syndromes, hemolytic anemias, or inherited red cell disorders. 1

Understanding the Finding

Anisopoikilocytosis represents a morphologic abnormality that requires interpretation within the clinical context:

• Anisocytosis reflects heterogeneity in red blood cell volume, quantitatively measured by red blood cell distribution width (RDW), which serves as the gold standard for assessing size variability 2, 3
• Poikilocytosis describes abnormal red cell shapes including tear drops, elliptocytes, fragmentocytes, and other morphologic variants 1

Diagnostic Approach

Initial Peripheral Blood Smear Evaluation

Examine the blood smear systematically for specific morphologic features that guide diagnosis:

• Tear drop cells suggest myelofibrosis, MDS/myeloproliferative neoplasm overlap syndromes, or marrow infiltration 4
• Schistocytes indicate microangiopathic hemolytic anemia rather than primary marrow pathology 4
• Dysplastic features (pseudo-Pelger-Huët cells, hypogranulation, abnormal chromatin clumping) point toward myelodysplastic syndromes 1, 4
• Elliptocytes with fragments and microspherocytes suggest hereditary membrane disorders like hereditary pyropoikilocytosis 5
• Basophilic stippling with polychromasia may indicate congenital dyserythropoietic anemia or other inherited disorders 6

Laboratory Testing Algorithm

Obtain the following tests based on peripheral smear findings:

• Complete blood count with differential to assess for cytopenias (hemoglobin <11.0 g/dL, neutrophils <1500/μL, platelets <100,000/μL) suggesting MDS 1
• Reticulocyte count: elevated values suggest hemolytic process (autoimmune hemolytic anemia, microangiopathic hemolytic anemia), while inappropriately low counts suggest marrow dysfunction 1, 4
• Lactate dehydrogenase, haptoglobin, and bilirubin to evaluate for hemolysis 1
• Iron studies including ferritin to assess iron status and detect ring sideroblasts in lower-risk MDS 1

Bone Marrow Examination

Bone marrow aspiration and biopsy are mandatory when MDS, myelofibrosis, or marrow infiltration is suspected: 1

• Aspirate evaluation should include counting at least 500 cells with assessment of dysplasia in erythroid (≥100 cells), myeloid, and megakaryocytic (≥30 cells) lineages 1
• Dysplasia in ≥10% of cells in any lineage is significant for MDS diagnosis 1
• Prussian blue (Perls) stain must be performed to identify ring sideroblasts (≥15% of erythroid precursors defines refractory anemia with ring sideroblasts) 1
• Trephine biopsy with reticulin stain assesses cellularity, fibrosis, and megakaryocytic dysplasia 1, 4

Cytogenetic and Molecular Testing

Cytogenetic analysis is mandatory for suspected MDS, as clonal abnormalities occur in >80% of patients: 1, 4

• Conventional karyotyping detects recurrent abnormalities including del(5q), monosomy 7/del(7q), and complex karyotypes 1
• Molecular testing for MDS-related mutations (DNMT3A, ASXL1, TET2, JAK2, TP53) when cytogenetics are normal or uninformative 1
• Flow cytometry immunophenotyping detects abnormalities in erythroid, myeloid, and lymphoid compartments 1

Specific Diagnostic Entities

Myelodysplastic Syndromes

MDS presents with anisocytosis and poikilocytosis alongside specific dysplastic features: 1

• Peripheral blood shows dimorphic erythrocytes, megalocytes, basophilic stippling, tear drops, ovalocytes, and fragmentocytes 1
• Bone marrow demonstrates megaloblastoid changes, multinuclearity, nuclear budding, karyorrhexis, and ring sideroblasts 1
• Diagnosis requires persistent cytopenia for ≥4 months with dysplasia in ≥10% of cells or presence of specific cytogenetic abnormalities 1

Hereditary Red Cell Disorders

Consider inherited disorders when anisocytosis/poikilocytosis occurs without dysplasia or cytopenias:

• Pyruvate kinase deficiency shows unremarkable morphology with variable anisocytosis/poikilocytosis and 3-30% echinocytes, particularly post-splenectomy 1
• Hereditary pyropoikilocytosis demonstrates striking anisopoikilocytosis with elliptocytes, fragments, and microspherocytes, confirmed by thermal instability testing 5
• Congenital dyserythropoietic anemia presents with tear-drop forms, polychromasia, basophilic stippling, and characteristic bone marrow findings 6

Hemolytic Anemias

Hemolytic processes show anisocytosis/poikilocytosis with elevated reticulocyte count: 1, 4

• Microangiopathic hemolytic anemia demonstrates schistocytes with elevated LDH and low haptoglobin 4
• Autoimmune hemolytic anemia shows polychromasia and spherocytes with positive direct antiglobulin test 4

Treatment Approach

Treatment is directed at the underlying disorder, not the morphologic finding itself:

For Myelodysplastic Syndromes

• Higher-risk MDS (IPSS intermediate-2/high): Azacitidine is first-line therapy for patients ineligible for allogeneic stem cell transplantation 1
• Lower-risk MDS: Supportive care with transfusions, erythropoiesis-stimulating agents, and iron chelation as needed 1
• MDS with isolated del(5q): Lenalidomide is indicated 1

For Hereditary Disorders

• Pyruvate kinase deficiency: Supportive care with transfusions; splenectomy considered for severe cases; monitor for iron overload 1
• Hereditary pyropoikilocytosis: Transfusion support for severe hemolysis; splenectomy may reduce transfusion requirements 5
• Hypotransferrinemia: Plasma transfusion or apotransferrin infusion with iron status monitoring 1

For Hemolytic Anemias

• Microangiopathic hemolytic anemia: Treat underlying cause (thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, etc.) 4
• Autoimmune hemolytic anemia: Corticosteroids as first-line therapy 4

Critical Pitfalls to Avoid

• Do not diagnose MDS based solely on morphology—cytogenetic or molecular abnormalities are required when dysplasia is <10% or involves only one lineage without ring sideroblasts or excess blasts 1
• Repeat bone marrow examination after 6 months if initial evaluation shows only mild unilineage dysplasia without cytogenetic abnormalities or increased blasts 1
• Exclude nutritional deficiencies (B12, folate, copper) and drug effects before attributing dysplasia to MDS 1
• Consider paroxysmal nocturnal hemoglobinuria in patients with unexplained cytopenias and hemolysis 1