This case involved the differential diagnosis of macrocytosis and the investigations needed in order to secure the diagnosis of haemolytic anaemia.
Our gentleman presented with fatigue and dyspnoea. On examination he was pale and further blood tests revealed a macrocytic anaemia with an isolated raised bilirubin.
The team rightly named the most common causes of macrocytosis with help from pharmacists
- B12/folate deficiency
- Liver disease
- Alcohol excess
- Myelodysplastic syndromes
- Cold agglutinins
- Drugs – DMARDS, chemotherapy, folate antagonists e.g. methotrexate, sulfasalizine, hydrocycarbamide, azathioprine, HIV medicaton, metformin
- Post chemotherapy
- Aplastic anaemia
Pragmatically, checking a ferritin is also important as there could be a mixed deficiency; especially as the patient is on dual anti-platelet therapy. Early medical review was also felt to be important as we didn’t want to leave the patient anaemic for too long given the recent NSTEMI. However initial assessment in ambulatory care was felt to be appropriate as admission may not be required.
His B12 and folate were normal. Previous rheumatological drugs may be the cause of the macrocytosis, but wouldn’t explain the relatively new anaemia. Given the isolated raised bilirubin, haemolysis was on the cards and the splenomegaly fits with this. The team rightly identified the main investigations to screen for haemolysis:
- Blood film
- FBC with reticulocyte count
- Direct and indirect bilirubin
- Urine haemosiderin
- Direct antoglobulin test/Coombs
These showed evidence of reticlocytosis, raised LDH, spherocytosis and a low haptoglobin with positive DAT, in keeping with autoimmune haemolysis.
Classification of haemolysis
- Membrane disorders: hereditary spherocytosis, hereditary eliptocytosis, hereditary stomatocytosis, hereditary pyropoikilocytosis
- Metabolic: G6PD deficiency*, PK deficiency
- Haemoglobin disorder: Sickle cell, haemoglobin C disease, unstable haemoglobins*
- Warm antibody: idopathic, secondary to autoimmune disease, secondary to infection e.g. EBV, secondary to lymphoproliferative disorders or other malignancies, drugs e.g. methyldopa
- Cold antibody: cold haemoglutin disease, infections e.g. mycoplasma, EBV
- Paroxysmal cold haemoglobinuria
- Alloimmune – red cell antigens (haemolytic transfusion reactions*, haemolytic disease of the newborn, post stem cell transplant), drugs
- Red cell fragmentation syndromes*:
- Cardiac – valves, intra-aortic balloon pump, grafts, leaks
- Microangiopathic – TTP, HUS, DIC, malignancy, polyarteritis nodosa, malignant hypertension, pre-eclampsia, HELLP syndrome, ciclosporin, homograft rejection
- March haemoglobinuria*
- Infections – clostridium, malaria
- Paroxysmal nocturnal haemoglobinuria*
- Chemical and physical agents – drugs, industrial/chemical substances, burns
*those with asterix commonly result in intravascular haemolysis rather than extra vascular (NB autoimmune haemolysis can result in intravascular haemolysis if involve complement)
This gentleman may have haemolysis due to his underlying rheumatological disease, or could have developed a malignancy. Lymphoproliferative disorders should be top of the list, especially given history of DMARD use. Infections such as EBV/HIV/Hep C should be looked for. Further investigations include full autoimmune screen, immunoglobulins, full history and examination for malignancy (including testicles, rectal, lymph nodes). A CT chest abdomen and pelvis may be appropriate depending on where the history and examination points. The splenomegaly may be due to haemolysis, but may also be due to lymphoma or infection.
Autoimmune haemolyic anaemia (AIHA)
Due to antibody production by the body’s B cells against it’s own red cells. The red cells become coated with immunoglobulin and/or complement and are destroyed by the reticulo-endothelial system by macrophages mostly in the spleen. The bone marrow tries to compensate, by producing more red cells. Reticulocytes and nucleated red cells are commonly seen in the peripheral blood, representing marrow stress.
The DAT detects antibodies on the red cell surface. If a warm antibody (mostly polyclonal IgG) it reacts mores strongly at 37oC and cold antibodies react at 4oC (commonly IgM). 75% of AIHA is warm antibody-mediated. It affects men and women equally and often follows a relapsing/remitting course. It can be a benign phenomenon, but can also be catastrophic with haemoglobin falling rapidly. Treatment is predominantly with prednisolone. IvIg can also be used in the acute setting and rituximab has also been used. Removing and/or treating the cause is important. VTE is common in AIHA. Folate deficiency can ensue due to rapid marrow turnover; therefore folate replacement is important. Transfusions can be used in AIHA if they are clinically warranted.