Q: Should I always order a whole blood when there is concern for hemolysis?
The Bottom Line: No. During analysis of whole blood, instruments do not have the functionality for spectrophotometric hemolysis measurement.. Serum potassium measurements are recommended for most clinical situations. Whole blood potassium should be ordered in the following scenarios:
- for immediate management, such as during codes or surgeries
- when significant thrombocytosis, leukocytosis, hyperproteinemia, or hyperlipidemia are present
Context: Medical decision making is contingent upon reliability of lab testing. Like all lab tests biological, pre-analytical, and analytical variation can affect the final result. For potassium, the largest concern is rupture of erythrocytes leading to release of potassium.
Serum testing in the centralized laboratory uses a spectrophotometric measurement of serum hemoglobin to estimate hemolysis and thus ensure the reliability of reported results. For potassium, which is released from erythrocytes upon cell rupture, even low levels of hemolysis can significantly increase serum potassium measurements. When hemolysis is measured above the laboratory’s established threshold, the corresponding serum result is not reported.
Instruments that measure whole blood potassium do not have the functionality for spectrophotometric hemolysis measurement. Therefore, whole blood potassium measurements may be at risk of false elevations due to unrecognized in vitro hemolysis. Due to the inability to measure hemolysis in whole blood testing, serum potassium measurements are recommended in most situations.
The Data: In vitro hemolysis is prevalent throughout both inpatient and outpatient settings. Certain collection techniques increase hemolysis, such as collection through an IV line, use of small gauge needles, and collection using a syringe. The American Society of Clinical Pathology suggests a hemolysis goal of 2%, however, variable collection practices often lead to much higher hemolysis rates (1,2).
When significant leukocytosis, thrombocytosis, hyperproteinemia, or hyperlipidemia are present, whole blood potassium is recommended over serum potassium.
In samples from patients with leukocytosis, the force experienced during centrifugation can cause the excess white blood cells to lyse, releasing potassium and falsely elevating serum potassium results. High risk for leukocytosis-related pseudohyperkalemia has been identified in samples with a white blood cell (WBC) count of 50-100 K/cu mm or greater (3,4). Patients with chronic lymphoid leukemia (CLL), T-cell acute lymphoblastic leukemia (T-ALL), and mantle cell lymphoma are most at risk for pseudohyperkalemia in serum samples due to the fragility of abnormal white cells (3,5).
In samples from patients with thrombocytosis, the increased clotting causes increased release of potassium from platelets, falsely elevating serum potassium results. High risk for thrombocytosis-related pseudohyperkalemia has been identified for samples with platelet counts above 400-500 K/cu mm (3,5,6). Patients with essential thrombocythemia, polycythemia vera, and myelofibrosis were most at risk for pseudohyperkalemia (7). Additionally, post-splenectomy reactive thrombocytosis has been reported to cause pseudohyperkalemia in numerous case studies (8–11).
Importantly, rupture of leukocytes and increased clotting cannot be detected by spectrophotometric measurements of hemolysis.
In serum samples from patients with significant hyperproteinemia, the electrolyte exclusion effect can cause the measurement of electrolytes, including potassium, to be falsely decreased. The electrolyte exclusion effect is most noticeable through the identification of falsely decreased sodium measurement, termed pseudohyponatremia, however it affects potassium and chloride measurements as well. Case studies have identified patients with multiple myeloma or hypergammaglobulinemia (either pathological or iatrogenic) as being at high risk for hyperproteinemia-related pseudohyponatremia (12–14). No total protein threshold has been proposed, however case studies suggest that total protein levels of 9-10 g/dL are sufficient to cause noticeable depressions in electrolyte results (12,13).
In serum samples from patients with severe hyperlipidemia, the electrolyte exclusion effect can cause the measurement of electrolytes, including potassium, to be falsely decreased. Severe hypertriglyceridemia (>1000 mg/dL) with depressed electrolyte results has been described in patients with acute pancreatitis and severe hyperlipidemia in the setting of poorly-controlled diabetes (15–18). Reports of severe hypercholesterolemia (>900 mg/dL) with significantly depressed electrolyte results have been reported in patients with cholestasis, primary biliary cirrhosis, pancreatic cancer, and graft-versus-host disease (19,20).
Conclusion: Serum potassium measurements are recommended for most clinical situations, due to the capacity to detect in vitro hemolysis. However, when significant leukocytosis, thrombocytosis, hyperproteinemia, or hyperlipidemia are present, whole blood potassium measurements should be utilized. Additionally, in emergent scenarios where potassium levels are critically needed for subsequent decision-making, whole blood testing should be utilized.
- Lowe G, Stike R, Pollack M, Bosley J, O’Brien P, Hake A, et al. Nursing Blood Specimen Collection Techniques and Hemolysis Rates in an Emergency Department: Analysis of Venipuncture Versus Intravenous Catheter Collection Techniques. J Emerg Nurs. 2008;34:26–32.
- Howanitz PJ, Lehman CM, Jones BA, Meier FA, Horowitz GL. Practices for identifying and rejecting hemolyzed specimens are highly variable in clinical laboratories. Arch Pathol Lab Med. 2015;139:1014–9.
- Ranjitkar P, Greene DN, Baird GS, Hoofnagle AN, Mathias PC. Establishing evidence-based thresholds and laboratory practices to reduce inappropriate treatment of pseudohyperkalemia. Clin Biochem. 2017;50:663–9.
- Katkish L, Rector T, Ishani A, Gupta P. Incidence and severity of pseudohyperkalemia in chronic lymphocytic leukemia: a longitudinal analysis. Leuk Lymphoma. 2016;57:1952–5.
- Lábadi Á, Nagy Á, Szomor Á, Miseta A, Kovács GL. Factitious hyperkalemia in hematologic disorders. Scand J Clin Lab Invest. 2017;77:66–72.
- Roccaforte V, Daves M, Alfreijat A, Riva M, Leitner M, Filippi S, et al. Spurious elevation of serum potassium concentration measured in samples with thrombocytosis. Diagnosis. 2016;3:71–4.
- Ong YL, Deore R, Rl-Agnaf M. Pseudohyperkalaemia is a common finding in myeloproliferative disorders that may lead to inappropriate management of patients. Int J Lab Hematol. 2010;32:151–7.
- Nakhoul F, Ramadan R, Maron M, Abassi Z. Post-splenectomy pseudohyperkalemia in a patient with chronic idiopathic myelofibrosis and thrombocytosis. Clin Nephrol. 2005;64:243–6.
- Grech M. A case of undiagnosed pseudohyperkalaemia following a splenectomy. Age Ageing. 2018;47:758–9.
- Alizadeh K, Hadjinicolaou A V., Hadjittofi C, Shankar A. Postsplenectomy thrombocytosis with pseudohyperkalaemia. BMJ Case Rep. 2015;2015:1–5.
- Ahmed R, Isaac AM. Postsplenectomy thrombocytosis and pseudohyperkalemia in trauma: A case report and review of literature. J Trauma - Inj Infect Crit Care. 2009;67:1979–81.
- Yu Z, Parker KM, Blick KE. Markedly Decreased Serum Sodium Concentration in a Patient With Multiple Myeloma. Lab Med. 2008;36:224–6.
- Steinberger BA, Ford SM, Coleman TA. Intravenous immunoglobulin therapy results in post-infusional hyperproteinemia, increased serum viscosity, and pseudohyponatremia. Am J Hematol. 2003;73:97–100.
- Garibaldi BT, Cameron SJ, Choi M. Pseudohyponatremia in a patient with HIV and hepatitis C coinfection. J Gen Intern Med. 2008;23:202–5.
- Hinson A, Newbern D, Linardic CM. Asparaginase-Induced Hypertriglyceridemia Presenting as Pseudohyponatremia during Leukemia Treatment. Case Rep Pediatr. 2014;2014:1–5.
- Wang Y, Attar BM, Abu Omar Y, Agrawal R, Demetria M V. Pseudohyponatremia in Hypertriglyceridemia-Induced Acute Pancreatitis. Pancreas. 2019;48:126–30.
- Frier BM, Steer CR, Baird JD, Bloomfield S. Misleading plasma electrolytes in diabetic children with severe hyperlipidaemia. Arch Dis Child. 1980;55:771–5.
- Howard JM, Reed J. Pseudohyponatremia in Acute Hyperlipemic Pancreatitis. Arch Surg. 1985;120:1053.
- Hussain I, Ahmad Z, Garg A. Extreme hypercholesterolemia presenting with pseudohyponatremia - A case report and review of the literature. J Clin Lipidol. 2015;9:260–4.
- Adashek ML, Clark BW, Sperati CJ, Massey CJ. The Hyperlipidemia Effect: Pseudohyponatremia in Pancreatic Cancer. Am J Med. 2017;130:1372–5.
-Written by Claire Knezevic, PhD, DABCC, NRCC, Director, Critical Care Laboratories and Pre-Analytical Testing, for the Department of Medicine High Value Care Committee