What are the implications and management of ovalocytes present in blood work?

Ovalocytes in Blood Work: Clinical Significance and Management

Primary Clinical Significance

Ovalocytes in peripheral blood are a morphological finding that can indicate either benign hereditary conditions (most commonly Southeast Asian ovalocytosis) or dysplastic changes associated with myelodysplastic syndromes (MDS), requiring differentiation based on clinical context and additional laboratory findings. 1

Differential Diagnosis Based on Ovalocyte Frequency

High Ovalocyte Frequency (≥25%)

• Southeast Asian ovalocytosis (SAO) is the primary consideration when ≥25% ovalocytes are present, particularly with accompanying stomatocytes and theta cells 2
• SAO is a benign hereditary condition caused by a 27-nucleotide deletion in the band 3 gene (amino acids 400-408), resulting in rigid red cells with reduced deformability 3, 4
• The condition is dominantly inherited and can occur in non-Asian populations, including White persons with ancestors from the Southwestern Indian Ocean region 3
• Red cells in SAO show markedly reduced lateral mobility, tight binding to ankyrin, and >50% reduction in sulfate transport 3, 4

Low Ovalocyte Frequency (<25%)

• Myelodysplastic syndromes should be considered when ovalocytes appear alongside other dysplastic features including anisocytosis, poikilocytosis, tear drop cells, fragmentocytes, basophilic stippling, or nucleated erythroid precursors 1
• MDS-associated ovalocytes typically occur with cytopenias (hemoglobin <11.0 g/dL, neutrophils <1500/mL, and/or platelets <100,000/mL) and bone marrow dysplasia >10% 1
• Other peripheral blood dysplastic features in MDS include pseudo-Pelger-Huët cells, hypogranulation of granulocytes, and giant platelets 1

Essential Diagnostic Workup

Initial Laboratory Assessment

• Complete blood count with red cell indices including MCV, MCH, and RDW to assess for microcytosis or macrocytosis 1
• Peripheral blood smear examination at x40 magnification (preferred over x100) to quantify ovalocyte percentage and identify accompanying morphological abnormalities 5
• Reticulocyte count to assess bone marrow response; elevated reticulocytes in SAO indicate compensated hemolysis 6, 2
• Lactate dehydrogenase and haptoglobin if hemolysis is suspected based on clinical presentation 6

Smear Quality Considerations

• Use modified thin malaria blood smear technique for optimal red cell morphology preservation 5
• Special hematology smears are unnecessary if proper technique is employed 5
• Quality control is essential as measurement error can be substantial without careful planning, threatening validity of ovalocytosis classification 5

Advanced Testing When Indicated

• Bone marrow aspiration and biopsy if cytopenias present, dysplasia suspected, or ovalocytes accompanied by other dysplastic features to evaluate for MDS 1
• Cytogenetic analysis to detect clonal abnormalities (present in >80% of MDS cases) including chromosome 7 abnormalities, trisomy 8, or complex karyotypes 1
• DNA analysis for SAO band 3 gene deletion via polymerase chain reaction if hereditary ovalocytosis suspected, particularly with family history or ethnic background suggestive of SAO 2
• Osmotic gradient ektacytometry demonstrates total lack of deformability in SAO when performed immediately after blood drawing 3

Clinical Implications by Condition

Southeast Asian Ovalocytosis

• Generally benign condition with normal red cell indices in most cases, though neonates may present with anemia and hyperbilirubinemia 2
• Newborns with SAO have significantly lower hemoglobin, packed cell volume, and RBC count compared to controls, with higher reticulocyte counts and RDW 2
• Approximately 50% of newborns with SAO develop hyperbilirubinemia, with 3% experiencing severe hyperbilirubinemia requiring intervention 2
• Protective effect against malaria: red cells show decreased invasion by Plasmodium falciparum due to increased rigidity 3, 4
• Some patients may develop compensated hemolysis with intermittent jaundice and pigment gallstones, requiring monitoring 6
• Variable results with blood grouping reagents may occur due to altered band 3 protein structure 6

Myelodysplastic Syndromes

• Requires comprehensive evaluation including bone marrow biopsy to assess cellularity, fibrosis, blast percentage, and megakaryocyte dysplasia 1
• Iron staining of bone marrow is mandatory to evaluate for ring sideroblasts 1
• Cytogenetic abnormalities provide prognostic information and are associated with disease severity 1
• Molecular testing for mutations (DNMT3A, ASXL1, TET2, JAK2, TP53) may be indicated if clonal cytopenias of uncertain significance (CCUS) or clonal hematopoiesis of indeterminate potential (CHIP) suspected 1

Management Approach

For Confirmed SAO

• No specific treatment required in asymptomatic individuals with normal hemoglobin and compensated hemolysis 6
• Monitor newborns closely for hyperbilirubinemia in the first week of life, with phototherapy or exchange transfusion if severe 2
• Counsel patients about the benign nature of the condition and dominant inheritance pattern 3, 4
• Consider genetic counseling for family planning, particularly given the protective effect against malaria in endemic regions 3
• Monitor for pigment gallstone formation in patients with compensated hemolysis 6

For Suspected MDS

• Refer to hematology for bone marrow evaluation and comprehensive diagnostic workup 1
• Exclude other causes of cytopenias and dysplasia including nutritional deficiencies (vitamin B12, folate), infectious diseases, and solid tumors 1
• Molecular assays to exclude BCR-ABL fusion gene and PDGFRA/PDGFRB rearrangements are mandatory 1
• Treatment depends on MDS subtype, blast percentage, cytogenetic risk, and presence of ring sideroblasts 1

Critical Pitfalls to Avoid

• Do not assume all ovalocytes indicate pathology: quantification is essential, as <25% may be within normal variation or related to smear preparation 5
• Avoid misdiagnosis of SAO as hemolytic anemia requiring intervention: SAO typically represents compensated hemolysis with normal or near-normal hemoglobin in adults 6
• Do not overlook MDS in elderly patients: ovalocytes with cytopenias and other dysplastic features warrant bone marrow evaluation regardless of ovalocyte percentage 1
• Ensure proper smear technique: poor quality smears can lead to substantial measurement error and invalid classification of ovalocytosis 5
• Consider ethnic background: SAO can occur in non-Asian populations with appropriate ancestral origins 3