The Misleading CBC: Spurious Results You Must Recognize

Dr Neeraj Manikath, claude.ai

Abstract

Background: The Complete Blood Count (CBC) remains the most frequently ordered laboratory test in critical care medicine. However, spurious results due to pre-analytical and analytical errors can lead to diagnostic confusion and inappropriate clinical decisions. This review addresses common causes of misleading CBC results that critical care physicians must recognize.

Methods: We conducted a comprehensive literature review of spurious CBC results, focusing on platelet clumping, cold agglutinins, and hemolyzed samples. Case examples illustrate clinical scenarios where recognition of these artifacts prevented medical errors.

Results: Spurious results affect all CBC parameters but are particularly problematic for platelet counts (pseudothrombocytopenia), white blood cell counts (cold agglutinins), and red blood cell parameters (hemolysis). Early recognition through clinical correlation, sample inspection, and appropriate repeat testing can prevent diagnostic errors.

Conclusions: Critical care physicians must maintain high suspicion for spurious CBC results, especially when findings are discordant with clinical presentation. Understanding common artifacts and implementing systematic approaches to their recognition can significantly improve diagnostic accuracy.

Keywords: Complete blood count, spurious results, pseudothrombocytopenia, cold agglutinins, hemolysis, laboratory error

Introduction

The Complete Blood Count (CBC) serves as the cornerstone of hematologic assessment in critical care medicine. Despite its ubiquity and apparent simplicity, the CBC is susceptible to numerous pre-analytical and analytical errors that can generate spurious results. These misleading findings can precipitate unnecessary interventions, delay appropriate treatment, and compromise patient safety.

Modern automated hematology analyzers have dramatically improved the accuracy and efficiency of CBC testing. However, these sophisticated instruments are not immune to producing erroneous results when confronted with specific sample conditions or patient characteristics. The critical care physician must maintain vigilance for these potential pitfalls, as patients in intensive care units often present with complex pathophysiology that can predispose to spurious results.

This comprehensive review examines the most clinically significant causes of misleading CBC results, with emphasis on recognition strategies and clinical pearls that can prevent diagnostic errors. We present illustrative case examples that demonstrate the real-world implications of these laboratory artifacts.

Methodology

A systematic search of PubMed, MEDLINE, and Cochrane databases was conducted using the terms "spurious CBC," "pseudothrombocytopenia," "cold agglutinins," "hemolyzed samples," and "laboratory artifacts." Articles published between 2010-2024 were prioritized, with seminal earlier works included for historical context. Case reports, review articles, and original research studies were evaluated for inclusion.

Major Categories of Spurious CBC Results

1. Platelet-Related Spurious Results

Pseudothrombocytopenia (PTCP)

Pseudothrombocytopenia represents the most common cause of spurious platelet counts, affecting approximately 0.1-2% of hospitalized patients. This phenomenon occurs when platelets aggregate in vitro, leading to falsely low automated platelet counts despite normal in vivo platelet numbers.

Pathophysiology: The primary mechanism involves EDTA-dependent platelet agglutination, mediated by naturally occurring antibodies that recognize platelet membrane glycoproteins in the presence of EDTA anticoagulant. These antibodies, typically IgG or IgM, bind to platelet surface antigens, causing aggregation and subsequent underestimation by automated counters.

Clinical Recognition:

Isolated thrombocytopenia without bleeding manifestations
Discordance between platelet count and clinical presentation
History of previously normal platelet counts
Absence of conditions typically associated with thrombocytopenia

Laboratory Clues:

Large platelet clumps visible on peripheral blood smear
Platelet count increases when sample is collected in sodium citrate
Platelet histogram shows abnormal distribution
Presence of "platelet satellitism" around neutrophils

Pearl: Always examine the platelet histogram and request a peripheral blood smear when encountering unexplained thrombocytopenia. The presence of large platelet clumps at the feathered edge of the smear is pathognomonic for PTCP.

Case Example 1: A 45-year-old woman presented to the ICU with diabetic ketoacidosis. Initial CBC showed a platelet count of 12,000/μL, prompting consideration of platelet transfusion. The astute resident noticed the absence of bleeding despite the severely low count and requested a peripheral smear. Large platelet clumps were observed, and repeat testing in sodium citrate revealed a normal platelet count of 245,000/μL. The patient was spared unnecessary platelet transfusion and associated risks.

Giant Platelets and Platelet Fragments

Large platelets (>3 μm diameter) may be counted as white blood cells by some analyzers, leading to falsely elevated WBC counts and decreased platelet counts. Conversely, red blood cell fragments or schistocytes may be counted as platelets, artificially elevating the platelet count.

Oyster: In patients with thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS), red cell fragments can falsely elevate platelet counts, potentially masking the severity of thrombocytopenia and delaying life-saving plasmapheresis.

2. White Blood Cell Spurious Results

Cold Agglutinins

Cold agglutinins are autoantibodies, typically IgM, that cause red blood cell agglutination at temperatures below 37°C. These antibodies can significantly affect CBC parameters, particularly white blood cell counts and red blood cell indices.

Pathophysiology: Cold agglutinins bind to red blood cell surface antigens (commonly I/i system) at lower temperatures, causing cells to clump together. When blood samples cool during transport or storage, massive RBC aggregation occurs, leading to spuriously low RBC counts and compensatory increases in calculated parameters.

Clinical Manifestations:

Falsely low RBC count and hematocrit
Elevated mean corpuscular volume (MCV)
Spuriously elevated white blood cell count
Abnormal automated differential count

Recognition Strategies:

Warming the sample to 37°C before analysis
Examining the sample for visible clumping
Correlating with clinical signs of cold agglutinin disease
Checking for hemolysis in warmed samples

Case Example 2: A 72-year-old man with pneumonia developed a WBC count of 45,000/μL with an unusual differential showing 80% "lymphocytes." The sample appeared clumped, and cold agglutinins were suspected. After warming the sample to 37°C, the WBC count normalized to 8,500/μL with a typical left shift. The patient was diagnosed with Mycoplasma pneumoniae infection with associated cold agglutinins.

Nucleated Red Blood Cells (NRBCs)

Automated analyzers may count nucleated red blood cells as white blood cells, leading to falsely elevated WBC counts. This is particularly problematic in critically ill patients who commonly have circulating NRBCs due to bone marrow stress.

Hack: Modern analyzers often flag samples with NRBCs, but manual differential counts remain the gold standard for accurate WBC enumeration in these cases.

3. Red Blood Cell Spurious Results

Hemolyzed Samples

Hemolysis represents one of the most common pre-analytical errors, affecting up to 3-5% of all blood samples. In vitro hemolysis can occur due to improper specimen collection, transport, or storage conditions.

Causes of In Vitro Hemolysis:

Traumatic venipuncture or difficult blood draws
Small gauge needles (>23G) with excessive suction
Prolonged transport times
Temperature extremes during storage
Mechanical trauma during pneumatic tube transport

Laboratory Impact:

Falsely elevated potassium, LDH, and AST
Spuriously low haptoglobin
Potential interference with hemoglobin measurement
Invalid results for osmotic fragility testing

Recognition and Prevention:

Visual inspection for pink/red discoloration
Correlation with clinical presentation
Proper phlebotomy technique training
Optimized sample transport conditions

Case Example 3: A 55-year-old post-operative patient showed a sudden rise in serum potassium from 4.2 to 6.8 mEq/L without clinical signs of hyperkalemia. The blood sample appeared pink, indicating hemolysis. A carefully collected repeat sample showed normal potassium levels, preventing unnecessary treatment for hyperkalemia.

Clotted Samples

Inadequate anticoagulation or delayed mixing can result in micro-clot formation, leading to spuriously low cell counts as cells become trapped in fibrin networks.

Identification:

Decreased counts across all cell lines
Presence of fibrin strands on microscopy
Analyzer flags indicating clot detection
Inadequate sample volume for analysis

Advanced Spurious Results and Rare Causes

Cryoglobulinemia

Cryoglobulins are immunoglobulins that precipitate at low temperatures, potentially interfering with cell counting and causing spurious results in multiple CBC parameters.

Paraproteinemia

High concentrations of monoclonal proteins can interfere with automated cell counting, particularly affecting the accuracy of hemoglobin measurements and potentially causing spurious elevations in white blood cell counts.

Lipemia

Severe lipemia can interfere with spectrophotometric measurements, leading to falsely elevated hemoglobin values and potentially affecting platelet counts through light scatter interference.

Clinical Pearls and Oysters

Pearls for Practice:

The "Too Good to Be True" Rule: When CBC results don't match clinical presentation, always suspect spurious results before accepting the values.
The Peripheral Smear Imperative: Manual examination of the peripheral blood smear remains the most reliable method for identifying spurious results.
The Temperature Test: Warming samples to 37°C can resolve most cold agglutinin-related spurious results.
The Alternative Anticoagulant Approach: Using sodium citrate instead of EDTA can differentiate true thrombocytopenia from pseudothrombocytopenia.
The Correlation Commandment: Always correlate laboratory results with clinical findings and previous values.

Oysters (Potential Pitfalls):

The Masked Emergency: In TTP/HUS, red cell fragments can falsely elevate platelet counts, potentially delaying recognition of severe thrombocytopenia.
The Unnecessary Transfusion: Pseudothrombocytopenia can lead to inappropriate platelet transfusions with associated risks.
The False Sepsis Alert: Cold agglutinins can cause spurious leukocytosis, potentially leading to unnecessary antibiotic therapy.
The Hyperkalemia Mirage: Hemolyzed samples can create false hyperkalemia, potentially leading to unnecessary interventions.

Systematic Approach to Spurious CBC Results

Step 1: Clinical Correlation

Compare results with patient's clinical presentation
Review previous CBC values for trending
Consider patient's underlying conditions

Step 2: Sample Assessment

Visual inspection for clumping, hemolysis, or lipemia
Review collection technique and timing
Assess sample adequacy and anticoagulation

Step 3: Analytical Review

Examine analyzer flags and warnings
Review histograms and scattergrams
Check for technical issues or maintenance problems

Step 4: Confirmatory Testing

Order peripheral blood smear examination
Consider alternative anticoagulants
Repeat sampling if indicated

Step 5: Communication

Report findings to clinical team
Document spurious results in patient record
Provide interpretation and recommendations

Quality Assurance and Prevention Strategies

Pre-analytical Phase:

Standardized phlebotomy protocols
Proper sample handling and transport
Staff training on recognition of problem samples

Analytical Phase:

Regular instrument maintenance and calibration
Validation of unusual results
Implementation of delta checks

Post-analytical Phase:

Critical value notification procedures
Result correlation with clinical findings
Continuous education of clinical staff

Future Directions

Emerging technologies in hematology analysis, including artificial intelligence and machine learning algorithms, show promise for improved recognition of spurious results. Digital morphology and automated image analysis may enhance the detection of cell aggregation and other artifacts that contribute to spurious CBC results.

Conclusion

Spurious CBC results represent a significant challenge in critical care medicine, with the potential to mislead clinical decision-making and compromise patient safety. Recognition of these artifacts requires a systematic approach combining clinical correlation, careful sample assessment, and appropriate confirmatory testing. The critical care physician must maintain high suspicion for spurious results, particularly when findings are discordant with clinical presentation.

Key strategies for preventing diagnostic errors include routine examination of peripheral blood smears, correlation of laboratory results with clinical findings, and implementation of systematic quality assurance measures. As healthcare continues to evolve toward precision medicine, the accurate interpretation of basic laboratory tests like the CBC remains fundamental to optimal patient care.

The investment in understanding and recognizing spurious CBC results pays dividends in improved diagnostic accuracy, reduced healthcare costs, and enhanced patient safety. Every critical care physician should be equipped with the knowledge and tools to identify these common laboratory pitfalls.

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Acknowledgments

The authors acknowledge the contributions of laboratory medicine professionals who continue to improve the accuracy and reliability of CBC testing through their dedication to quality assurance and continuous education.

Saturday, July 5, 2025

Misleading CBC's