College of American Pathologists
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  Q & A





June 2010

Fredrick L. Kiechle, MD, PhD

Question Q. I worked in a commercial lab whose hematology supervisor said not to report smudge cells, that they are due to inversion of A/G ratio. Another lab says to report them. Which one is right?

A. Smudge cells (or basket cells) are the remnant of a fragile cell that has been damaged in the process of making a blood smear. Most commonly, these cells are lymphoid in nature. Precise lineage assignment cannot be done because the cell is not intact. The “smudge” is condensed nuclear material without identifiable cytoplasm. This artifact can be avoided by adding a drop of serum albumin to four or five drops of blood before making the blood smear. Smudge cells are most commonly seen in disorders characterized by lymphocyte fragility, such as chronic lymphocytic leukemia and infectious mononucleosis.

Controversy persists about whether to report smudge cells in the white blood cell differential. In some laboratories the smudge cells are reported with a comment as “other” cells on the manual differential. In other laboratories the automated differential is reported with a qualitative comment that smudge cells are present, and in most laboratories an albumin smear is prepared and a manual differential is reported. The current Clinical and Laboratory Standards Institute document on reference leukocyte differential count (H20-A2) says that smudge/basket cells can be diminished by special preparations, such as the addition of 22 percent albumin to the blood.1

A study performed at Mayo Clinic and published last year found that the percentage of smudge cells on peripheral blood smear predicts survival in chronic lymphocytic leukemia.2 The results have not yet been confirmed by other studies.


1. Reference leukocyte (WBC) differential count (proportional) and evaluation of instrumental methods; approved standard—second edition, H20–A2. Wayne, Pa.: Clinical and Laboratory Standards Institute. 2007.

2. Nowakowski GS, Hoyer JD, Shanafelt TD, et al. Percentage of smudge cells on routine blood smear predicts survival in chronic lymphocytic leukemia. J Clin Oncol. 2009;27:1844–1849.

Deborah A. Perry, MD
Department of Pathology
Children’s Hospital and Medical Center
Omaha, Neb.

Former member, CAP Hematology/Clinical Microscopy Resource Committee

Question Q. Our lab recently switched from BNP to NT-proBNP testing. The emergency department physicians, some of the clinicians, and a few of the cardiologists rejected the NT-proBNP test as not ready for prime time. The ED physicians who are used to the simple numbers and cut-off value for BNP say they do not have use for the NT-proBNP test because they are not sure how to interpret the sometimes higher values that many of the ED patients present with in the ER (most patients are elderly). We even had a PhD scientist from the analyzer company come in to explain the usefulness of the test and the benefits it has over BNP (stability, standardization, prognostic value, to name a few). Are there any articles you can point me to as a reference to convince our physicians that NT-proBNP is useful?

A. Interpreting natriuretic peptide results is far from straightforward and nowhere near as easy as the “single cut-point for all patients” approach that we’d all like to use. Furthermore, the physiologies that trigger natriuretic peptide apply equally for BNP and NT-proBNP, which arise from the same trigger and a common precursor peptide—so wherever there is BNP, there is NT-proBNP and vice versa.

Unfortunately, as years have passed, we have come to recognize that the complex physiologies that drive the release of both peptides necessitate the willingness of the clinician to understand the differential diagnosis for an elevated BNP or NT-proBNP, particularly in the patient in whom no clinical heart failure is present.

Moreover, we also now realize that the optimal cut-points for use of these peptides differ based on the venue in which they are used—so that in acutely dyspneic patients much higher cut-points are applied, versus the patient in the office with more subtle symp-toms.

As noted, the physiologies of the two natriuretic peptide assays are largely the same, so it should come as no surprise that head-to-head comparisons of these tests in acute dyspnea have largely yielded superimposable accuracy for heart failure diagnosis.

If we were to restrict ourselves to a “one cut-point approach” for BNP and NT-proBNP, the cut-points that yield comparable performance are 100 pg/mL (BNP) and 900 pg/mL (NT-proBNP). However, as the physiology of the natriuretic peptide system is complex, it’s necessary to examine where the weakness of such an approach is.

First, the negative predictive value of both cut-points is <90 percent, so a patient with a BNP of 90 pg/mL cannot be confidently “ruled out” for heart failure—indeed, the optimal cut-point to exclude heart failure with >95 percent negative predictive value using BNP and NT-proBNP is probably 20 pg/mL (BNP) and 300 pg/mL (NT-proBNP), which are considerably lower values.

Second, while both peptides at their “optimal” single cut-points (100 and 900 pg/mL) perform comparably, the positive predictive value for these cut-points is at best 85 percent to 88 percent, suggesting that up to 15 percent or more of patients have an elevated value for either peptide in the absence of heart failure.

To clarify the most common reason for such a situation, we can turn to the BNP literature, which shows that age is one of the most powerful predictors of a “false-positive” BNP (with a 30 percent per decade increase in the likelihood for a BNP of more than 100 pg/mL without heart failure1).

To better address this issue, we developed an age-adjusted NT-proBNP strategy in the ICON study.2 Using cut-points of 450 pg/mL, 900 pg/mL, and 1,800 pg/mL for ages <50, 50 to 75, and >75 years, we improved the positive predictive value considerably.

This does not mean that NT-pro-BNP is any more affected by age than is BNP; it’s just that this approach is published only for NT-proBNP.


1. Knudsen CW, Clopton P, Westheim A, et al. Predictors of elevated B-type natriuretic peptide concentrations in dyspneic patients without heart failure: an analysis from the breathing not properly multinational study. Ann Emerg Med. 2005; 45: 573–580.

2. Januzzi JL, van Kimmenade R, Lainch-bury J, et al. NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients: the International Collaborative of NT-proBNP Study. Eur Heart J. 2006;27:330–337.

James L. Januzzi, MD
Associate Professor of Medicine
Harvard Medical School