Question 7.1

The following blood results are from a 51 -year-old female who presented with arthralgia, jaundice and dark urine.

Parameter	Patient Value	Normal Adult Ran e
Haemoglobin	68 g/L	115 - 160
White Cell Count	33.1 x 10⁹/L	4.0 — 11.0
Platelets	307 x 10⁹/L	150 - 400
Red Cell Count	2.22 x 10¹²/L *	3.80 - 4.80
Haematocrit	0.19*	0.37 - 0.47
Mean Cell Volume	88 fL	80 - 100
Mean Cell Haemoglobin	30.7	27.0 - 32.0
Mean Cell Haemoglobin Concentration	350 g/L	320 - 360
Reticulocyes	2.5%*	0.2 - 2.0
Reticulocytes Absolute	56 x 10⁹/L	20 - 130
Comment: The red cells show moderate numbers of spherocytes

Serum Haptoglobins	< 0.10 g/L	0.30 - 2.00

Serum Lactate Dehydrogenase	948 U/L*	140 - 280

Total Protein	69 g/L	60 - 80
Albumin	33 g/L	35 - 50

Globulins	36 g/L	25 - 42
Total Bilirubin	119 mol/L*	< 20
Alanine Aminotransferase	276 U/L*	< 35
Alkaline Phosphatase	120 U/L*	30 - 1 10
Gamma-GlutamyI Transferase	114 U/L*	< 40

Direct Antiglobulin Test:
IgG	Positive
C3d	Positive

a) What is the diagnosis? (20% marks)

b) List three treatment options. (15% marks)

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College Answer

Warm autoimmune haemolytic anaemia.

Corticosteroids
IV immunoglobulin
Rituximab
Splenectomy
Danazol
Other cytotoxics / immunosuppressants (e.g. cyclophosphamide, azathioprine, cyclosporine)
Red cell transfusion

Discussion

a) The only possible answer is autoimmune haemolytic anaemia. Overall, the differential diagnosis of autoimmune haemolytic anaemias looks like this:

Differential Causes of Autoimmune Haemolytic Anaemia
Warm haemolytic anaemia	Cold haemolytic anaemia
Idiopathic primary haemolytic anaemia Viral infections, including HIV Drugs, eg. penicillin, methyldopa, 5-FU, diclofenac, etc... Lymhoproliferative disorders: CLL Lymphoma Multiple myeloma Hodgkins lymphoma Waldenstrom's macroglobulinaemia Autoimmune disorders, particularly SLE and rheumatoid arthritis	Post-infectious colad agglutinin disease Syphilis Post-viral Mycoplasma pneumoniae EBV, VZV, CMV, HIV Adenovirus Influenza viruses Paroxysmal cold haemoglobinuria Idiopathic Virus-associated (EBV, CMV, etc)

In this scenario, the patient probably has one of the warm haemolytic anaemias, because both the IgG and C3d were found coating the red cells (IgM and C3d are found in cold haemolysis). The WCC is raised suggestive of a lymphoproliferative disorder as the cause. Arthralia may be due to some sort of autoimmune disease (SLE or RA), or it may be a subtle hint that the patient has been taking diclofenac to soothe her aching joints (which is a drug known to cause warm autoimmune haemolysis).

Generic management of warm autoimmune haemolytic anaemia could have included any three of the following options:

Corticosteroids appear to be effective as the first-line treatment. Among other thngs, the steroids reduce the synthesis of autoantibodies by B-cells.
Splenectomy is the second-line treatment. The spleen's macrophages are responsible for removing IgG-coated RBCs; also the spleen is a site of antibody production.
Cyclophosphamide / azathioprine are reserved for those who fail steroids and splenctomy (or cannot have a splenectomy).
IV immunoglobulin is not strongly indicated: some reports show benefit, others don't.
Plasmapheresis is only indicated in fulminant acute haemolysis. Only a temporary improvement is to be expected, as this treatment does nothing to treat the underlying autoantibody production.
Rituximab, a CD20 monoclonal antibody, has been effective in cases of cold haemolytic anaemia where a B-cell dominant lymphoproliferative disorder is at fault. It seems to be more effective in warm haemolysis.
Eculizumab, a terminal complement inhibitor (monoclonal C5 antibody) has been found effective in various case reports (eg. Kim et al, 2016), even though it is indicated only for atypical HUS and paroxysmal nocturnal haemolobinuria.
Danazol, a synthetic steroid derivative of ethisterone, is very old school (Pignon et al, 1993) - it is usually used for endometriosis.

References

Zeerleder, S. "Autoimmune haemolytic anaemia-a practical guide to cope with a diagnostic and therapeutic challenge." Neth J Med 69.4 (2011): 177-84.

Gehrs, Bradley C., and Richard C. Friedberg. "Autoimmune hemolytic anemia."American journal of hematology 69.4 (2002): 258-271.

Birgens, Henrik, et al. "A phase III randomized trial comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in patients with autoimmune haemolytic anaemia." British journal of haematology 163.3 (2013): 393-399.

Lechner, Klaus, and Ulrich Jäger. "How I treat autoimmune hemolytic anemias in adults." Blood 116.11 (2010): 1831-1838.

Salama, A., and B. Mayer. "Diagnostic pitfalls of drug-induced immune hemolytic anemia." Immunohematology 30.2 (2014): 80-4.

Zantek, Nicole D., et al. "The direct antiglobulin test: a critical step in the evaluation of hemolysis." American journal of hematology 87.7 (2012): 707-709.

Ma, Kim, and Stephen Caplan. "Refractory IgG Warm Autoimmune Hemolytic Anemia Treated with Eculizumab: A Novel Application of Anticomplement Therapy." Case reports in hematology 2016 (2016).

Pignon, Jean‐Michel, Emmanuelle Poirson, and Henri Rochant. "Danazol in autoimmune haemolytic anaemia." British journal of haematology 83.2 (1993): 343-345.

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