What should be done for a patient with low Hemoglobin A1c (HbA1c) and leukocytosis?

Clinical Approach to Low HbA1c with Leukocytosis

When encountering a patient with unexpectedly low HbA1c and elevated white blood cell count, immediately investigate for conditions that shorten red blood cell lifespan, as these can falsely lower HbA1c and mask true glycemic status. 1

Primary Diagnostic Considerations

The combination of low HbA1c and leukocytosis should raise suspicion for:

Conditions Causing Falsely Low HbA1c

Any process that shortens erythrocyte lifespan will decrease HbA1c independent of actual glycemic control, because glycation increases with the age of red blood cells. 1 Key conditions include:

• Hemolytic anemia - The most critical consideration, as hemolysis dramatically shortens RBC lifespan and can result in HbA1c values that severely underestimate true glycemia 1, 2
• Acute or recent blood loss - Reduces the average age of circulating erythrocytes 1
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency - Causes increased red blood cell turnover and falsely lowers HbA1c 1
• Recent blood transfusion - Introduces younger red blood cells 1
• Erythropoietin therapy - Accelerates red blood cell production, lowering average cell age 1

Leukocytosis Etiologies to Evaluate

The elevated white blood cell count requires parallel investigation:

• Infection (most common) - Particularly bacterial infections that can cause acute stress response 3, 4
• Inflammatory conditions - Chronic inflammatory states can affect both WBC count and RBC turnover 3
• Medications - Corticosteroids, lithium, and beta agonists commonly cause leukocytosis 4
• Physical or emotional stress - Surgery, trauma, exercise, or emotional stress can double WBC count within hours 3, 4
• Hematologic malignancy - Must be excluded if other causes are not identified, particularly with WBC >100,000/mm³ 3, 4

Immediate Diagnostic Workup

Essential Laboratory Tests

1. Complete blood count with differential and peripheral smear - Assess RBC morphology, reticulocyte count, types and maturity of WBCs, and look for toxic granulations or abnormal cells 3, 4

2. Plasma glucose measurements - In conditions with altered RBC turnover, only plasma blood glucose criteria should be used to diagnose and monitor diabetes 1

   • Fasting plasma glucose
   • Random or postprandial glucose if symptomatic
   • Consider 2-hour oral glucose tolerance test if diabetes status unclear

3. Hemolysis markers - Lactate dehydrogenase (LDH), indirect bilirubin, haptoglobin, and reticulocyte count to detect hemolytic anemia 2

4. Iron studies - Paradoxically, iron deficiency anemia can falsely elevate HbA1c, so this helps differentiate the clinical picture 1, 5, 6

5. G6PD enzyme assay - Particularly important in African American patients (11% carry the G202A variant) or those with appropriate ethnic background 1

Alternative Glycemic Markers

When HbA1c is unreliable, consider:

• Fructosamine or glycated albumin - Reflect glycemic control over 2-3 weeks rather than months 1, 5
• Continuous glucose monitoring (CGM) - Provides real-time glycemic data independent of RBC lifespan 5
• Self-monitoring blood glucose (SMBG) - Multiple daily measurements to establish true glycemic patterns 1, 7

Clinical Decision Algorithm

Step 1: Assess Clinical Context

• Review medication list for drugs causing leukocytosis or affecting RBC turnover 4
• Identify recent illness, surgery, trauma, or transfusion 1, 3
• Screen for symptoms of infection, malignancy (fever, weight loss, bruising, fatigue), or hemolysis 3, 4

Step 2: Interpret Laboratory Discordance

Marked discrepancies between measured HbA1c and plasma glucose levels should prompt consideration that the HbA1c assay may not be reliable 1

• If plasma glucose is elevated but HbA1c is low → Suspect shortened RBC lifespan 1, 5
• If WBC >100,000/mm³ → Medical emergency requiring immediate hematology consultation 4
• If peripheral smear shows abnormal cells → Urgent hematology/oncology referral 3

Step 3: Management Based on Findings

For confirmed conditions affecting RBC turnover:

• Do not use HbA1c for diabetes diagnosis or monitoring 1
• Rely exclusively on plasma glucose measurements for glycemic assessment 1
• Use fructosamine or CGM for intermediate-term glycemic monitoring 1, 5
• Treat underlying condition (hemolysis, G6PD deficiency, etc.) 1

For leukocytosis management:

• If infection identified → Treat appropriately and recheck CBC after resolution 3
• If medication-induced → Consider alternatives if clinically appropriate 4
• If no clear benign cause → Refer to hematology/oncology for bone marrow evaluation 3, 4

Critical Pitfalls to Avoid

• Never rely solely on HbA1c when clinical presentation or glucose values are discordant - This can lead to missed diabetes diagnosis or inappropriate treatment decisions 1, 5
• Do not assume low HbA1c means excellent glycemic control - In the setting of hemolysis or increased RBC turnover, patients may have severe hyperglycemia despite reassuring HbA1c values 2
• Recognize that HbA1c may be a poor marker for both glycemia AND hemolysis in diabetic patients with hemolytic disease - It cannot reliably serve dual purposes 2
• Do not delay evaluation of significantly elevated WBC counts - Values >100,000/mm³ represent a medical emergency due to risk of brain infarction and hemorrhage 4

Special Populations

African American patients warrant particular attention:

• 11% carry the G6PD G202A variant, which can lower HbA1c by 0.7-0.8% 1
• Sickle cell trait (HbS heterozygosity) lowers HbA1c by approximately 0.3% 1
• Use NGSP-certified assays without hemoglobin variant interference when available 1

Patients with chronic kidney disease:

• Hemodialysis affects RBC turnover and invalidates HbA1c for diabetes monitoring 1
• Erythropoietin therapy further complicates HbA1c interpretation 1