Why is a hematology referral being made for a patient with hypoglycemia, elevated Immunoglobulin A (IgA), and a polyclonal increase in immunoglobulins, who also has a hemolyzed specimen that prevented a complete blood count (CBC) with differential/platelet test?

Hematology Referral for Unexplained Cytopenias and Immunologic Abnormalities

A hematology referral is being made because the combination of hypoglycemia, elevated IgA, polyclonal immunoglobulin increase, and inability to obtain a complete blood count due to specimen hemolysis raises concern for underlying hematologic disorders including autoimmune cytopenias, plasma cell dyscrasias, or lymphoproliferative disorders that require specialized evaluation and bone marrow assessment. 1, 2

Primary Concerns Driving the Referral

Unexplained Cytopenias Requiring Specialist Evaluation

• Patients with unexplained persistent cytopenias should be referred to hematology for evaluation, particularly when there are progressive cytopenias with other cell line abnormalities or suspected autoimmune cytopenia requiring bone marrow evaluation. 2

• The hemolyzed specimen preventing CBC analysis is itself concerning, as hemolysis can indicate either pre-analytical issues or true hemolytic anemia requiring urgent investigation. 3, 4

• Grade 3-4 hematologic toxicities warrant hematology consultation, and unexplained cytopenias fall into this category requiring specialist input for diagnostic work-up including bone marrow biopsy and aspirate analysis. 1

Polyclonal Immunoglobulin Elevation as a Red Flag

• The polyclonal increase in immunoglobulins with elevated IgA suggests chronic inflammation, chronic infection, autoimmune disease, or potentially an underlying lymphoproliferative disorder. 5

• You must differentiate polyclonal increases from monoclonal gammopathies, as approximately 10% of cases initially appearing polyclonal may harbor monoclonal proteins requiring hematologic evaluation. 5

• In patients with immune complex-mediated patterns showing polyclonal immunoglobulin increases, evaluation for plasma cell dyscrasias should occur even in the absence of obvious monoclonal peaks, particularly in adults ≥50 years. 1, 5

Hypoglycemia in Context of Immunologic Abnormalities

• Hypoglycemia combined with immunologic derangements raises concern for autoimmune processes, including autoimmune hypoglycemia which can be associated with plasma cell disorders or lymphoproliferative diseases. 1

• The constellation of metabolic and immunologic abnormalities requires comprehensive hematologic work-up to exclude underlying malignancy or severe autoimmune disease. 1

Essential Diagnostic Work-Up Required by Hematology

Immediate Laboratory Priorities

• CBC with differential and reticulocyte count must be obtained with a non-hemolyzed specimen to evaluate for neutropenia, lymphopenia, thrombocytopenia, or anemia. 1

• Peripheral blood smear examination is essential to identify abnormal cell morphologies including schistocytes (suggesting microangiopathic hemolysis), spherocytes, or circulating plasma cells. 1, 4

• Quantitative immunoglobulin levels (IgG, IgA, IgM) are necessary to determine which specific immunoglobulins are elevated and to what degree. 6

Hemolysis Evaluation

• Laboratory confirmation of hemolysis requires: reticulocyte count, lactate dehydrogenase (LDH), unconjugated bilirubin, haptoglobin, and direct antiglobulin test (DAT). 1, 3, 4

• If hemolytic anemia is confirmed, the direct antiglobulin test differentiates immune-mediated from non-immune causes, guiding further management. 4

• Autoimmune hemolytic anemia can occur as part of Evans syndrome (concurrent immune thrombocytopenia and hemolytic anemia), requiring specific hematologic management. 1

Plasma Cell Dyscrasia and Lymphoproliferative Disorder Screening

• Serum and urine protein electrophoresis with immunofixation and serum free light chain analysis are essential to exclude monoclonal gammopathy of renal significance (MGRS) or other plasma cell disorders. 1

• B-cell enumeration by flow cytometry is necessary to evaluate for lymphoproliferative disorders and to distinguish between various B-cell abnormalities. 6

• Bone marrow biopsy and aspirate analysis may be required if peripheral blood evaluation shows abnormalities or if plasma cell dyscrasia is suspected. 1

Infection and Autoimmune Screening

• Viral studies including CMV, EBV, parvovirus, HIV, hepatitis B and C are recommended as these infections can cause both cytopenias and polyclonal immunoglobulin increases. 1, 5

• Autoimmune serologies including ANA and specific autoantibodies should be obtained based on clinical presentation, as autoimmune diseases commonly cause polyclonal hypergammaglobulinemia. 5

Critical Clinical Scenarios Requiring Urgent Hematology Input

Autoimmune Cytopenias

• Grade 3-4 immune-mediated cytopenias require holding immunotherapy (if applicable), hematology consultation, and initiation of corticosteroids (prednisone 1-2 mg/kg/day). 1

• If immune thrombocytopenia is confirmed, patients should undergo testing for HIV, hepatitis C, hepatitis B, and Helicobacter pylori. 1

Thrombotic Microangiopathy Considerations

• The combination of hemolysis and potential thrombocytopenia raises concern for thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS), which are medical emergencies. 1

• ADAMTS13 activity level and inhibitor titer should be obtained urgently if TTP is suspected, as delay in identification is associated with increased mortality. 1

Plasma Cell Disorders

• Involvement of a hematologist is often useful for diagnosis of clonal processes and treatment of monoclonal gammopathy of renal significance, even when a B-cell clone may not ultimately be found. 1

• Approximately 30% of cases with proliferative glomerulonephritis with monoclonal immune deposits have an identifiable clonal process requiring hematologic management. 1

Common Pitfalls to Avoid

• Do not dismiss polyclonal immunoglobulin increases as purely reactive without excluding underlying lymphoproliferative disorders or plasma cell dyscrasias, particularly in patients over 50 years. 1, 5

• Do not delay hematology referral while waiting for repeat CBC if clinical suspicion for serious hematologic disorder is high based on other laboratory abnormalities. 2

• Do not assume hemolyzed specimens are solely due to pre-analytical error without clinical correlation, as true hemolytic anemia may be present. 3, 4

• Do not overlook the possibility of Evans syndrome when evaluating for autoimmune hemolytic anemia, as concurrent immune thrombocytopenia requires specific management. 1