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August 2014 - Test your knowledge in the quiz!

Which illness causes this woman’s poor condition? Aplastic anaemia
Beta-thalassaemia minor
Systemic lupus erythematosus under immunosuppressive therapy
Refractory anaemia

Online version of this month`s case:

THE CORRECT ANSWER TO AUGUST’S QUIZ IS:

Systemic lupus erythematosus (SLE) under immunosuppressive therapy

Scattergrams and microscopy

Patient history: a 39-year old woman with a known diagnosis visited her physician with a fever and in poor overall condition.

Analysis of the WDF channel showed normal leukocyte counts but an absolute reduction in the number of monocytes and lymphocytes.
Nucleated red blood cells (NRBC) were not visible in the WNR scattergram.
Blasts were not detected in the SSC-FSC scattergram of the WPC channel.
A reduced reticulocyte count and a low RET-He could be inferred from the RET scattergram.
Peripheral blood smear
Peripheral blood smear

Table

Interpretation and Differential Diagnosis

The answer can be inferred from…

  • Microcytic, hypochromic anaemia: low HGB, low MCV, low MCH
  • Anisocytosis: high RDW-SD and -CV
  • Monocytopenia: low MONO# and MONO%
  • Lymphopenia: low LYMPH# and LYMPH%

 

Case history

A 39-year old woman with a known diagnosis visited her physician with a fever and in poor overall condition. She suffered from fatigue and severe joint pain. A complete blood count with leukocyte differential was ordered to investigate her condition.

 

Case results

The differential diagnosis of this case is built on exclusion criteria because all four diagnoses – aplastic anaemia, systemic lupus erythematosus, β-thalassaemia minor and refractory anaemia – have some haematological characteristics in common. The most remarkable finding was a microcytic (high MicroR, low MCV), hypochromic (high HYPO-He, low MCH) anaemia. In addition, a low RBC count, anisocytosis (high RDW-CV) and a low RET-He value were found in combination with a negative Delta-He. The low RBC count, anisocytosis and negative Delta-He excluded a thalassaemia. The Urrechaga Index (MicroR - HYPO-He - RDW-CV) confirmed this: it showed a value of -26.8, while values above -5.1 would have led to a suspicion of thalassaemia. The Delta-He was negative but close to zero, indicating that the haemoglobinisation of mature RBC (RBC-He) was also low. Therefore, the microcytic, hypochromic anaemia observed here was most-likely caused by a chronic inflammatory process, which caused a functional iron deficiency. A decrease of the absolute monocyte and lymphocyte counts can also be observed in aplastic anaemia but not in combination with a normal to high neutrophil count and a normal platelet count. Furthermore, the relative lymphocyte concentration is often increased in aplastic anaemia so this diagnosis could also be excluded. Instead, the monocytopenia and lymphopenia were caused by the patient’s glucocorticoid therapy. A myelodysplastic syndrome type refractory anaemia was also unlikely because an isolated anaemia (without leukopenia or thrombocytopenia) is observed in only 5% of refractory anaemia cases. Furthermore, refractory anaemias are mostly normochromic and no dysplasia was observed in the presented patient (normal NEUT-SSC). In conclusion, this case shows a known systemic lupus erythematosus under immunosuppressive therapy. The overall poor condition of the patient was caused by an increase of anti-nuclear antibodies during an acute inflammatory relapse.

 

The following answers are incorrect for the described reasons

 

Aplastic anaemia

Aplastic anaemia can be hereditary, as in Fanconi anaemia, or acquired through exposure to chemicals, drugs or viruses such as the Epstein-Barr virus. It is probably caused by decreased numbers of pluripotent haematopoietic stem cells resulting in reduced haematopoiesis. The outcome of this is pancytopenia, which is the reduction of all types of blood cells: White blood cells, red blood cells and platelets. The neutrophil, platelet and reticulocyte counts were normal in this patient and therefore pancytopenia is not present. Aplastic anaemia is also often associated with a relative lymphocytosis so this observation makes an aplastic anaemia unlikely as well.

 

β-Thalassaemia minor

Thalassaemia is an autosomal heritable disease caused by defective globin chain synthesis. The severity of the clinical symptoms is used to classify thalassaemias into major, intermedia and minor. β-Thalassaemia minor (also called trait) can be either generally asymptomatic or exhibit anaemia-related symptoms such as tiredness, weakness, numbness in the extremities, a weak immune system and depression. Haematologically, it presents as a microcytic anaemia and should be differentiated from iron deficiency. Several different formulas, taking into account red blood cell parameters, have been proposed to differentiate thalassaemia from other microcytic anaemia conditions. Recently, it was demonstrated by Urrechaga et al. that an index using the Sysmex parameters MicroR, HYPO-He, RDW-CV shows a very good sensitivity and specificity (1):

 

Urrechaga Index (MicroR - HYPO-He - RDW-CV)

> -5.1 -> β-thalassaemia minor
< -5.1 -> iron deficiency

In this case, MicroR - HYPO-He - RDW-CV = -26.8, which strongly supports an iron deficiency condition and excludes thalassaemia. In addition, the low RBC count found in this patient is not typical for thalassaemia.

 

Refractory anaemia 

Refractory anaemia is part of the heterogeneous myelodysplastic syndromes (MDS) and may account for 30-40% of all MDS cases. It is a clonal disorder originating from a defective totipotent or pluripotent progenitor and characterized by ineffective haematopoiesis and dyserythropoiesis. Refractory anaemia is usually associated with hypercellular bone marrow and anaemia. There may be leukopenia and/or thrombocytopenia, but these features do not represent a diagnostic requirement. Ineffective erythropoiesis in refractory anaemia results in normocytic or macrocytic anaemia. This allows exclusion of refractory anaemia in this patient with microcytic red blood cells. In addition, MDS patients sometimes have dysplastic neutrophils, which were not observed in this case (NEUT-SSC was normal but increased in MDS patients (2)).

Underlying Disease

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease of unknown cause that can affect the skin, joints, kidneys, lungs, nervous system, serous membranes, and/or other organs of the body. Immunologic abnormalities, especially the production of a number of antinuclear antibodies, are another prominent feature of the disease (3).

The clinical course of SLE is variable and may be characterized by periods of remission and chronic or acute relapses. Women, especially in their 20s and 30s, are affected more frequently than men. Patients with SLE are subject to many symptoms and complaints, and inflammatory involvement can affect virtually every organ. The most common pattern of clinical symptoms in SLE patients is a combination of deep-rooted complications of the skin (skin lesions, rash, erythema over cheeks and nose, ulcers), musculoskeletal symptoms (arthritis), as well as mild haematological and serologic involvement. However, some patients have predominantly haematological, renal or central nervous system manifestations. The most common symptoms include fatigue, myalgia, weight changes and fever – especially in the active phase of the disease. Fifty percent of patients are predisposed to infections.
The major haematological manifestations of SLE are anaemia, leukopenia, thrombocytopenia, and the antiphospholipid syndrome. Many patients have a mild anaemia, which is most often due to anaemia of chronic disease. Haemolytic anaemia is rare but can be very severe. Leukopenia is common but, though diagnostically useful, it is not symptomatic unless severe (<2000/µL). Mild thrombocytopenia (platelet counts between 100,000 and 150,000/µL) is observed in 25-50% of patients, while counts of less than 50,000/µL occur in only 10%. Thrombocytosis is a less frequent finding in SLE patients.
The clinical heterogeneity of SLE and the lack of unique features and specific tests pose a diagnostic challenge for the clinician. Although antinuclear antibody tests are sensitive and 97% of SLE patients are positive for such tests, their specificity is low. To complicate matters, patients may have only a few clinical features of SLE, which can resemble other autoimmune, infectious, or haematological diseases. Given the multiple manifestations of SLE, the differential diagnosis is correspondingly broad. SLE should be differentiated from rheumatoid arthritis, systemic sclerosis, vasculitis, fibromyalgia, cytomegalovirus and Epstein-Barr virus infections, multiple sclerosis, malignancies (leukaemia, MDS and lymphoma) and thrombotic thrombocytopenic purpura.

Literature

  1. Urrechaga E et al. (2011): The role of automated measurement of RBC subpopulations in differential diagnosis of microcytic anemia and β-thalassemia screening.  Am J Clin Pathol. 135:374-379
  2. Le Roux G et al. (2010): Routine diagnostic procedures of myelodysplastic syndromes: value of a structural blood cell parameter (NEUT-X) determined by the Sysmex XE-2100™. Int J Lab Hematol. 2010 32(6-1):e237-243
  3. Lisnevskaia L et al. (2014): Systemic lupus erythematosus. Lancet: early online publication

Advanced clinical parameters

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