Tests of haemolysis - reticulocyte count

What it measures

Reticulocytes = immature anucleate red cells retaining residual ribosomal RNA, released from the marrow, maturing in the circulation over ~1-2 days
*The single most useful test for classifying anaemia* - it separates a marrow that is responding from one that is not
Normal 0.5-2.5% (absolute 25-100 x10^9/L)
- *Always use the ABSOLUTE count, not the percentage* - the percentage rises simply because the red cell denominator has fallen
Detected by RNA-binding supravital stain (new methylene blue, brilliant cresyl blue) or automated fluorescent flow cytometry
Immature reticulocyte fraction (IRF) - the youngest, most RNA-rich reticulocytes. Rises before the total count and before the haemoglobin - the earliest marker of marrow recovery

Reticulocytes are ~1% of circulating red cells in health; red cell lifespan ~120 days, so ~1% is replaced daily
Physiologically high in neonates (2-6%, falling by ~1 week) and at altitude
Modest rise in pregnancy

Anaemia -> renal EPO -> marrow erythroid hyperplasia -> increased output
- Marrow can increase red cell production 6-8 fold if iron, B12, folate and marrow architecture are all intact
Reticulocytes released early under EPO drive spend longer in the circulation - the "shift" phenomenon
- -> inflates the raw count -> corrected by the reticulocyte production index

HIGH reticulocytes	LOW / inappropriately normal reticulocytes
Haemolysis (any cause)	Iron, B12 or folate deficiency
Acute blood loss (peaks day 3-7)	Anaemia of chronic disease/inflammation
Response to iron, B12 or folate replacement (peaks day 5-10)	CKD (EPO deficiency)
Recovery from marrow suppression	Marrow failure - aplastic anaemia, MDS, PRCA
Response to EPO	Marrow infiltration - leukaemia, lymphoma, myeloma, metastases, fibrosis
Hypersplenism (compensating)	Hypothyroidism; drugs, alcohol, chemotherapy

Reticulocytosis with high LDH, high unconjugated bilirubin, low haptoglobin = the haemolysis quartet
*Reticulocytosis is expected - its ABSENCE in a haemolytic anaemia demands explanation*
- Parvovirus B19 aplastic crisis - the classic; catastrophic in a patient with a short red cell lifespan (sickle cell, hereditary spherocytosis, thalassaemia)
- Concurrent iron, B12 or folate deficiency (folate is consumed by chronic haemolysis)
- Autoantibody or infiltration also targeting erythroid precursors
- Early in the illness - it takes 3-5 days for reticulocytosis to develop

Confirming a response to haematinic replacement - check at 1 week; the reticulocyte peak precedes the haemoglobin rise
Monitoring engraftment after stem cell transplant (IRF rises first)
Distinguishing pure red cell aplasia - profound reticulocytopenia with normal white cells and platelets
Reticulocyte haemoglobin content (CHr/RET-He) - reflects iron availability to the marrow over the last 2-3 days; useful where ferritin is confounded by inflammation, and in dialysis patients

High reticulocytes -> *look for haemolysis or bleeding*
- Send LDH, haptoglobin, bilirubin, DAT, blood film
- Examine for bleeding; check the ferritin and iron studies
Low reticulocytes with anaemia -> *the marrow is the problem*
- Iron studies, B12, folate, TFT, UEC, EPG/free light chains, CRP
- Marrow aspirate and trephine if unexplained, or if other lineages are affected
Reticulocytopenia in a known haemolytic disorder -> *urgent: think parvovirus B19*, send parvovirus IgM and PCR, and be prepared to transfuse

*A "normal" reticulocyte percentage in a patient with severe anaemia is an inadequate response* - convert to absolute count or RPI
Reticulocytes rise for days after a transfusion-free recovery - interpret in context of any recent transfusion, which suppresses EPO and the count
Automated counts are affected by Howell-Jolly bodies, malaria parasites, nucleated red cells and giant platelets

Haemolytic anaemias - AIHA, hereditary spherocytosis, G6PD deficiency, sickle cell disease, thalassaemia, PNH, TMA, mechanical valve haemolysis
Acute haemorrhage
Response to iron, B12, folate or erythropoietin therapy
Parvovirus B19 aplastic crisis (reticulocytopenia in a haemolytic patient)
Pure red cell aplasia - thymoma, parvovirus, drugs, anti-EPO antibodies, large granular lymphocytic leukaemia
Diamond-Blackfan anaemia (congenital PRCA)
Marrow failure and infiltration syndromes
Post-stem-cell transplant engraftment monitoring

Expected time courses - the numbers she needs

Event	Reticulocyte response
Acute blood loss	Rises from day 2-3, peaks day 3-7
Iron replacement	Rises within 3-5 days, peaks day 7-10; Hb rises ~10 g/L per week
B12 or folate replacement	Peaks day 5-8 - brisk and dramatic. Watch for hypokalaemia as the marrow consumes potassium
Parvovirus aplastic crisis	Reticulocytes near zero for ~7-10 days, then abrupt recovery
Marrow engraftment post-transplant	IRF rises before neutrophils

*Failure of the expected reticulocyte response to haematinic replacement means the diagnosis is wrong, the treatment is not being taken, or there is a second deficiency*

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