Question 12.3

With respect to the peripheral blood film of an adult:

  • List four conditions in which plasma cells may appear.
  • List four conditions in which nucleated red blood cells may appear.
  • Explain the significance of rouleaux formation.

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College Answer


Multiple myeloma

B cell lymphoma



Varicella zoster infection


Hepatitis Active/chronic HBV

Serum sickness
Plasma cell leukaemia

Waldenstroms macroglobulinaemia


Compensatory erythropoeisis with anaemia

Marrow replacement/ invasion

Extramedullary haematopoeisis

Other – uraemia, sepsis, liver disease, renal transplant, thermal injury, chemotherapy.


Rouleaux are stacked/clumped groups of red cells caused by the presence of high levels of circulating acute-phase proteins which increase red cell 'stickiness'. They are often an indicator that a patient has a high ESR and are seen in infections, autoimmune conditions, chronic inflammation, paraproteinaemia and myeloma.


Plasma cells swarming in the blodstream can be a marker of numerous illnesses, and it is difficult to find just one article which might summarise the whole spectrum. In this Nature article, Table 2 lists several plasma cell disorders:

  • MGUS
  • Multiple myeloma
  • Waldenström's macroglobulinemia
  • Solitary plasmacytoma
  • Systemic AL amyloidosis
  • POEMS syndrome

A 1958 article reports on a few more causes:

  • Adenocarcinoma of the colon
  • Pulmonary tuberculosis
  • Cirrhosis of the liver
  • Aplastic anaemia
  • Syphilis

The college answer also includes the following causes, for which there is not much literature:

There are numerous others.

For instance, one article (recording the finding of peripheral plasmacytosis in a patient with Dengue fever) also mentions (and backs with references) the following causes:

  • Primary infection and reactivation of Epstein–Barr virus
  • Acute respiratory infections
  • Parvovirus B19 infection
  • Rubella
  • Hepatitis virus A infection

Nucleated red cells are an immature subtype, and their abundance in a blood sample reflects that either the bone marrow s struggling to keep up with the losses of red cells, or that there are insufficient resources to complete the normal maturation process.

Thus, any nutritional hematinic deficiency and any stimulus for erythropoisesis can cause their appearance.

A review article from Laboratory Medicine lists several causes of nucleated red cells in the peripheral blood:

  • Asplenia
  • Anaemia
  • Hypoxia
  • Bone marrow invasion by malignancy
  • Extramedulary haemopoiesis
  • Uremia
  • Sepsis
  • Liver disease
  • Diabetic ketoacidosis
  • Inflammatory bowel disease
  • Renal transplant
  • Thermal injury
  • Chemotherapy

If you notice those last few causes seem to be in a very familiar order, you are not crazy - the college has used this exact same article to write their answer. In fact, their list is a word-for-word facsimile of the table on page 225, "Mechanisms and Conditions Associated With Normoblastemia".

As for rouleaux formation, one can find numerous articles describing the phenomenon, but one really only needs a basic understanding of it. The answer to this CICM question does not require one to wax lyrical about macromolecule bridging. One merely needs to be familiar with this as a form of reversible RBC aggregation, and to be dimly aware of it as a cause of altered blood rheology. In 1926 Eric Ponder published on the subject, and his paper contains beautifully drawn diagrams of his experimental design. In short, anything which might increase your ESR will cause rouleaux formation, and thus the differentials include a broad range of conditions:

  • Infection of any sort
  • Inflammatory disease of any sort
  • Hyperviscosity syndromes
  • Multiple myeloma (or any sort of hyergammaglobulinaemia)
  • Malignancy of any sort
  • Dehydration
  • Diabetes
  • Chronic liver disease (albumin has a counter-aggregatory effect on RBCs)


Kyle, R. A., and S. V. Rajkumar. "Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma." Leukemia 23.1 (2009): 3-9.


Aherne, W. A. "The differentiation of myelomatosis from other causes of bone marrow plasmacytosis." Journal of clinical pathology 11.4 (1958): 326-329.

Constantino, Benie T., and Bessie Cogionis. "Nucleated RBCs—significance in the peripheral blood film." Lab Medicine 31.4 (2000): 223-229.

SCHMIDT, JOHN J., HAROLD J. ROBINSON, and CHARLES S. PENNYPACKER. "Peripheral plasmacytosis in serum sickness." Annals of internal medicine 59.4 (1963): 542-546.

Bäumler, H., et al. "Basic phenomena of red blood cell rouleaux formation."Biorheology 36.5 (1999): 439-442.

Wagner, Christian, Patrick Steffen, and Saša Svetina. "Aggregation of red blood cells: From rouleaux to clot formation." Comptes Rendus Physique 14.6 (2013): 459-469.

REPLOGLE, ROBERT L., HERBERT J. MEISELMAN, and EDWARD W. MERRILL. "SPECIAL ARTICLE Clinical Implications of Blood Rheology Studies." Circulation 36.1 (1967): 148-160.

Ponder, Eric. "On sedimentation and rouleaux formation-I." Experimental Physiology 15.3 (1925): 235-252.