Why does hemolysis of a blood sample cause a falsely high potassium result?

Why Hemolysis Causes Falsely Elevated Potassium Results

Blood sample hemolysis causes falsely high potassium results because red blood cell rupture releases massive amounts of intracellular potassium into the serum—since 98% of total body potassium resides inside cells, even minor hemolysis can dramatically elevate measured values. 1

The Fundamental Mechanism

Red blood cells contain potassium concentrations approximately 23 times higher than plasma (roughly 140 mEq/L intracellular vs. 3.5-5.0 mEq/L extracellular). 1 When hemolysis occurs during or after blood collection, this intracellular potassium leaks into the serum sample, creating pseudohyperkalemia—a laboratory artifact rather than a true clinical abnormality. 2, 3

What Defines Pseudohyperkalemia

Pseudohyperkalemia is formally defined as a serum-to-plasma potassium difference exceeding 0.4 mEq/L, with serum values artificially elevated when both samples are obtained simultaneously and processed under identical conditions. 2, 4

Common Causes of In Vitro Hemolysis

During Blood Collection

• Traumatic venipuncture with excessive vacuum or small-gauge needles 5
• Repeated fist clenching during phlebotomy, which mechanically damages red cells 3, 5
• Prolonged tourniquet application causing local tissue hypoxia and cell fragility 5

After Blood Collection

• Delayed sample processing at room temperature, where reduced Na⁺/K⁺-ATPase pump activity allows passive potassium leakage 3
• Mechanical agitation during transport 1
• Improper storage conditions 2

High-Risk Clinical Scenarios

Hematologic Conditions

Patients with thrombocytosis (platelet counts >450,000/μL) or leukocytosis (WBC >100,000/μL) are particularly susceptible because platelets and white blood cells also release potassium during clot formation in serum tubes. 2, 4 In one case series, a patient with chronic lymphocytic leukemia and 86% blast cells demonstrated massive serum-plasma potassium discrepancies despite normal whole blood potassium. 4

Familial Pseudohyperkalemia

This rare autosomal dominant condition causes increased red cell membrane permeability to potassium at room temperature. 3 While compensated in vivo by enhanced Na⁺/K⁺-ATPase activity, cooling after venipuncture unmasks the defect, producing extreme pseudohyperkalemia (sometimes >7.0 mEq/L) despite normal clinical status. 3

Clinical Implications and Recognition

When to Suspect Pseudohyperkalemia

• Elevated potassium with normal ECG in patients with preserved renal function (eGFR ≥60 mL/min) 5, 6
• Hemolysis index flagged by the laboratory analyzer 1, 5, 6
• Discordance between clinical presentation and laboratory value—no cardiac symptoms, muscle weakness, or other hyperkalemia manifestations 2, 4
• Thrombocytosis or leukocytosis on complete blood count 2, 4

Evidence-Based Approach to Repeat Testing

In a prospective emergency department study of 45 patients with hemolyzed samples showing potassium ≥5.5 mEq/L, the negative predictive value for true hyperkalemia was 100% (95% CI 93.1-100%) when patients had normal renal function (GFR ≥60 mL/min) AND a normal ECG. 5 This suggests repeat testing may be unnecessary in this specific population.

Similarly, a pediatric study found that 97.9% of children with hemolyzed hyperkalemia had normal potassium on repeat sampling, with the 2.1% who had true hyperkalemia all having underlying conditions (renal disease, tumor lysis syndrome) that appropriately raised clinical suspicion. 6

Practical Laboratory Considerations

Why Plasma Samples Are Superior

Plasma potassium concentrations are 0.1-0.4 mEq/L lower than serum because serum collection requires clotting, during which platelets release their intracellular potassium. 7 For patients with thrombocytosis or suspected pseudohyperkalemia, plasma samples (collected in heparin or EDTA tubes) should be routinely measured to avoid false elevation. 2

Critical Timing Factors

Samples must be processed within 1 hour of collection when kept at room temperature to minimize in vitro potassium release. 4 The laboratory's hemolysis index (measured spectrophotometrically at 405 nm) quantifies hemoglobin in the supernatant, providing objective evidence of red cell rupture. 1

Common Pitfalls to Avoid

• Treating pseudohyperkalemia aggressively can cause dangerous iatrogenic hypokalemia, particularly in dialysis patients where overzealous potassium removal has led to cardiac arrest 2
• Failing to check concurrent platelet and WBC counts in patients with unexplained hyperkalemia 2, 4
• Not obtaining plasma potassium when serum values seem discordant with clinical picture 7, 2
• Ignoring the hemolysis flag from automated analyzers, which reliably detects even minor hemolysis 1, 5

Algorithm for Clinical Decision-Making

For patients with hemolyzed hyperkalemia:

1. Assess renal function immediately (creatinine, eGFR) 5, 6
2. Obtain 12-lead ECG to evaluate for true hyperkalemia manifestations (peaked T waves, widened QRS) 5, 6
3. If GFR ≥60 mL/min AND ECG normal: Pseudohyperkalemia is highly likely; repeat testing may be unnecessary 5
4. If GFR <60 mL/min OR abnormal ECG OR clinical suspicion: Obtain plasma potassium immediately 2, 5
5. Check CBC for thrombocytosis (>450,000/μL) or leukocytosis (>100,000/μL) 2, 4

This evidence-based approach prevents both unnecessary repeat testing in low-risk patients and dangerous delays in treating true hyperkalemia in high-risk populations.