You are looking after a 65 yer old female patient who was admitted to the ICU ten days ago for severe community acquired pneumonia on the background of immunosuppression (Rituximab) for rheumatoid arthritis.
This patient's haemoglobin trend is as follows:
What are the possible reasons for these findings?
This viva came with only the following stem document:
" Haematology.. Material presented demonstrated pancytopaenia secondary to bone marrow suppression. Subsequent questions included use of haematological tests to assess anaemia (including MCV and haemolysis screen). Twelve out of twenty-three candidates passed this section."
As this was not enough to work with, what follows is a completely made up unofficial viva.
The question really is, "why is this patient anaemic?"
Numerous possibilities arise:
- Dilution of RBC concentration
- dilutuonal anaemia with fluid replacement
- Artifactual anaemia due to sampling of a vessel with diluted content (i.e. the vein that has the fluids running through it).
- Increased loss of RBCs
- Extravascular loss
- Traumatic blood loss
- Upper or lower GI blood loss, eg. gastric erosion/ulceration
- Iatrogenic loss through samling and surgery
- Intravascular loss
- Intravascular haemolysis, eg. autoimmune hemolytic anaemia
- Mechanical haemolysis, eg. due to extravascular perfusion circuits, dialysis filters, or mechanical heart valves
- Appropriate reticuloendothelial sequestration of abnormal haemoglobin
- Sickle cell anaemia
- Decreased production of RBCs
- Decreased hematinics
- B12/folate deficiency
- Drugs which interfere with B12/folate metabolism
- Iron deficiency
- Decreased proliferation signals
- Decreased EPO in renal failure
- Anaemia of chronic inflammatory states
What investigations would help you narrow the list of differentials?
- History of fluid resusictation or trauma
- Resampling to confirm the diagnosis
- Imaging to look for obvious blood loss
- Faecal occult blood test and/or endoscopy to exclude GI blood loss
- Direct Coombs test, formal blood film, conjugated/unconjugated bilirubin, LDH, haptoglobin and reticulocyte count to investigate haemolysis
- RBC folate and B12 levels
- Iron studies
- Coagulation screen (looking for DIC and MAHA)
- Renal function tests and/or EPO levels
The patient's MCV and MCHC are low. How does this narrow the list of differentials?
- MCV and MCHC would be low in iron deficiency anaemia or anaemic of chronic disease.
- Where haematinic factors are absent (eg. B12, folate), the MCV would be high.
What is normally included in "iron studies"?
- Serum iron
- Transferrin saturation
This patient's serum iron is low. Does this mean she has an iron deficiency?
- In short, yes it could mean that.
- A patient's serum iron values may vary 10-40% within a single day
- There is a predictable diurnal variation
- This test measures all serum iron: both the small amount of soluble ionised ferric iron (Fe3+) and the transferrin-associated ferric ion.
- Serum iron is decreased in genuine iron deficiency, but it can also be low for other reasons.
This patient's ferritin is normal. What is ferritin, and what would a low ferritin mean?
- The gold standard for the assessment of iron stores.
- It consists of about 20% iron.
- It is found in all cells, but especially in hepatocytes and reticuloendothelial cells.
- A small amount of it is present in plasma, and this amount is proportional to the total amount. Ferritin is therefore a good marker of total body iron stores.
- A low ferritin suggests iron deficiency anaemia
The patient's transferrin is low. What could this mean?
- Transferrin is the binding protein which carries iron from the liver into the bone marrow.
- It is also a part of the innate immune system, and transferrin molecules are seen in mucosa, where they bind free elemental iron, reducing its availability to invading microorganisms.
- Transferrin decreases in inflammatory states.
- Its level can also diminish in liver disease, nephrotic syndrome, and due to malnutrition.
- In iron deficiency anaemia, transferrin should be HIGH.
This patient's TIBC is normal. What is meant by the TIBC?
- Unsaturated iron-binding capacity (UIBC) is the amount of "free" transferrin, unassociated with iron.
- TIBC is the sum of serum iron and UIBC
- The TIBC is therefore a surrogate for a transferrin level and these two laboratory tests can be used interchangeably (usually the lab will only report one or the other).
- UIBC represents the capacity to bind "extra" iron; a raised UIBC is associated with iron deficiency anaemia (and a low UIBC represents a state of iron overload, as all the transferrin molecules are saturated).
- A normal TIBC does not support the diagnosis of iron deficiency anaemia
So, the results are: low serum iron and transferrin, normal TIBC and ferritin. Does this patient need an iron infusion?
- No, they probably will not benefit
- This is anaemia of chronic inflammation, and it does not get very much benefit from iron supplementation
What is the mechanism of the anaemia associated with chronic inflammation?
- Decreased iron availability
- Cytokine release in inflammation stimulates the synthesis of hepcidin, a regulatory molecule which controls the release of iron into the circulation.
- A high hepcidin level decreases the availability of iron by promoting "iron trapping" within the bone marrow and macrophages. Thus, the iron stores in this form of anaemia are normal, which renders iron infusion pointless.
- In the absence of circulating iron, erythropoiesis is restricted.
- Increased erythrocyte phagocytosis
- Cytokine-activated macrophages destroy red cells at an increased rate
- This reduces the lifespan of erythrocytes.
- Decreased erythropoiesis signals
- Cytokines act directly on the bone marrow to reduce the rate of erythropoiesis, independent of the levels of circulating erythropoietin
- Occasionally the level of erythropoietin is also suppressed, which is thought to be a cytokine-related effect acting on its renal secretion.
What are the management options for this condition?
- Treatment of the underlying inflammatory condition is the mainstay of management.
- Conservative management: anaemia at this level is often well tolerated by the critically ill patients, and even transfusions are not essential
- Prevention of further losses, eg. rationalise blood sampling and minimise the volume of sampled blood (eg. use paediatric blood tubes)
- Supplementation of haematinic factors
- Erythropoietin, to help overcome the blunted EPO response
- Parenteral iron replacement may still be an option if EPO has failed, or if the ferritin level drops (suggesting a concomitant iron deficiency)