Laboratory Evaluation of Sickle Cell Disease in the ED

/

By Diana grib (Own work) [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons

By Diana grib (Own work) [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons

Sickle cell anemia (SCA) is one of the most common genetic disorders. As a result of a single point mutation in the beta-hemoglobin gene, the hemoglobin molecule of patients with sickle cell disease is less soluble under deoxygenated conditions. This leads to a chronic hemolytic anemia and vaso-occulsion that results in pain and tissue infarction with numerous secondary complications. (1) Given the morbidity of sickle cell disease, these patients frequently present to the emergency department, raising questions of: what laboratory testing is needed in these patients? And, how do we interpret commonly ordered labs in these patients? This article will discuss the basic principles of these commonly ordered studies in hopes of delineating when they are necessary and how they can help in the evaluation of the sickle cell patient presenting to the emergency department.

Bilirubin

Normal red blood cells (RBCs) have a typical life span of about 110 to 120 days and are subjected to a remarkable amount of mechanical stress as they move through capillaries millions of times over their lifetimes. They deform their membranes repeatedly and over time they lose this ability. About 1% of the body’s RBCs are destroyed daily by the reticuloendothelial system. In SCA, the RBC membranes become irreversibly misshapen after recurrent episodes of sickling and are removed from the circulation at a much younger age (about 20 days). Because of this, SCA is a disease of chronic extravascular hemolysis whereby macrophages of the reticuloendothelial system phagocytose the damaged RBCs. The macrophages metabolize hemoglobin to unconjugated bilirubin that is released into the plasma. Unconjugated bilirubin is often mildly elevated at baseline in sickle cell patients as a result. In an acute pain crisis, the unconjugated bilirubin may further rise due to an increase in hemolysis. (2,3)

Haptoglobin

In SCA, there is also a degree of intravascular hemolysis, and free hemoglobin is released into the serum rather than metabolized in the reticuloendothelial system. The free hemoglobin binds to haptoglobin, a scavenger of free hemoglobin. The haptoglobin-hemoglobin complex is transported to the liver and rapidly removed from circulation.  During hemolysis, the haptoglobin level falls. In SCA, the haptoglobin level might be low due to basal levels of hemolysis. It may further decrease during an acute crisis, but it may also be elevated because it is an acute phase reactant. (4)  Overall, haptoglobin may be indiscriminate in the emergent work-up of the SCA patient.

LDH

Another marker of hemolysis is LDH. This is a cytoplasmic enzyme found in almost all cells, including red blood cells. It catalyzes the reduction of pyruvate to lactate with concurrent oxidation of NADH to NAD+, which is an important step to provide further substrate for anaerobic metabolism. When there is cell death or tissue destruction, LDH is released and is a marker of tissue damage and hemolysis. LDH is elevated at baseline in SCA for these reasons. During acute vaso-occlusive crises (VOC), even uncomplicated cases, the LDH may further increase secondary to added hemolysis and tissue infarction. (5) When levels are elevated at 4x the upper of limit of normal in an acute exacerbation, there is some evidence that this is suggestive of impending severe disease. (6)  Therefore, LDH may serve as a prognostic marker in acute disease but only when significantly elevated. Overall, it may or may not further increase during acute VOC and it is non-specific.

Reticulocyte Count

Another lab test that is frequently ordered in the work-up of SCA patients is the reticulocyte count. Reticulocytes are immature but already anucleated erythroid cells with residual amounts of RNA. In healthy individuals, reticulocytes are in the bone marrow for about three days and then spend 1 day in the circulation before they lose their ribosomes and mature into an RBC. Under steady state conditions, RBC production equals RBC losses and about 1% of circulating RBCs are erythrocytes (normal range of 0.5-2.0%). With worsening anemia and increasing erythropoietin stimulation, the bone marrow releases reticulocytes at an earlier stage in their maturation and reticulocytes are in the peripheral circulation for a longer time. The reticulocyte count is therefore useful as a marker to estimate the degree of erythropoiesis and the appropriateness of the bone marrow response to anemia.  Absence of reticulocytosis in anemia usually signals a problem with the bone marrow like an aplastic anemia. Since SCA is a chronic anemia, the reticulocyte count will be elevated at baseline (4-15%) and it is important to measure when there is a drop in the hemoglobin to make sure the bone marrow is responding adequately. (7,8)

SCA is a disease that emergency medicine physicians encounter frequently given the acute exacerbations in the natural course of the disease and the numerous secondary complications that can occur.

  • In patients presenting with anything other than a simple pain crisis, a CBC and reticulocyte count should be ordered.
  • If the hemoglobin has fallen significantly from baseline ( >2 mg/dL), the reticulocyte count will be important in ascertaining the bone marrow response.
  • LDH is also often ordered but is a non-specific marker of hemolysis and tissue damage. It may signal severe disease if the level is significantly elevated.
  • Other markers of hemolysis, like haptoglobin and unconjugated bilirubin, are rarely helpful in the acute work up of the sickle cell patient as these studies are already deranged due to constant hemolysis.

Unfortunately, there is no laboratory test that can definitively determine if a patient is having a pain crisis. The best approach is a good history and physical exam, and trusting patient reported pain.

References

  1. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010; 376:2018.
  2. Red blood cell diseases: Red cell production, red cell indices, and the reticulocyte count. In: Hematology. A Pathophysiological Approach, Babior BM, Stossel TP (Eds), Churchill Livingstone, New York 1984. p.13.
  3. Berlin NI, Berk PD. Quantitative aspects of bilirubin metabolism for hematologists. Blood. 1981; 57:983.
  4. Marchand A, Galen RS, Van Lente F. The predictive value of serum haptoglobin in hemolytic disease. JAMA. 1980; 243:1909.
  5. Stojanovic KS, Lionnet F. Lactate dehydrogenase in sickle cell anemia. Clin Chimica Acta. 2016; 458:990102.
  6. Kato GJ, McGowan V, Machado RF, Little JA, Taylor J, Morris CR, Nichols JS, Wang X, Poljakovic M, Morris Jr. SM. Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. Blood. 2006;107:2279-2285.
  7. Bernard AW, Venkat A, Lyons MS. Best evidence topic report. Full blood count and reticulocyte count in painful sickle crisis. Emerg Med J. 2006; 23:302.
  8. Lopez, BL, Griswold, SK, Navek, A, and Urbanski, L. The complete blood count and reticulocyte count—Are they necessary in the evaluation of acute vasoocclusive sickle-cell crisis?. Acad Emeg Med. 1996; 3: 751–757. 

Authored by Eileen Hall, MD, PGY-1 University of Cincinnati Department of Emergency Medicine

Editing and Posting by Jeffery Hill, MD MEd, University of Cincinnati Department of Emergency Medicine