This weeks case was a case of primary warm AIHA in a 36 ear old lady.
Haemolysis can seem complex to investigate and treat and there is excellent new BSH guidance ( see references) on the subject of Haemolysis which is worth a read.
A few points to assist in the diagnosis and management are listed here.
- Recent changes to medication and medication history (Drug induced Haemolysis)
- Family history (Inherited causes of haemolysis (SCD/HS/HE/PK def/G6PD) /Autoimmune conditions)
- Recent transfusion, transplantation or pregnancy (Allo Antibodies).
- Cardiac problems (Valve haemolysis)
- Recent exertion (March haemolysis)
- Travel history (Malaria, Bartonella, Babeosis)
- Alcohol History (Liver Dx)
- Recreational drug use (Amyl Nitrate)
- Bloody Diarrhoea (HUS)
- Dark urine and acute episodes of illness (PNH, PCH)
- Nt sweats, LN, weight loss (underlying malignancy)
- Splenomegly (Haemolysis or underlying LPD or Malaria/Viral infection)
- Lymphadenopathy (LPD)
- Cardiac surgery scars/murmurs (Valve haemolysis)
- Confusion (TTP)
Initial Investigations for Haemolysis should include:
- FBC (may show Reticulocytosis, mild macrocytosis)
- Blood Film :
- Fragments (MAHA or Mechanical heamolysis)
- Irregularly contracted cells or bite cells (Oxidative Haemolysis)
- Parasites (Malaria)
- Spherocytes (AIHA or Hereditary spherocytosis)
- Target cells (Liver disease).
- Haptoglobin (usually low)
- LDH (usually elevated)
- Bilirubin (usually unconjugated bilirubin elevated)
- DAT (positive if immune but see below for details)
- Reticulocytes (usually elevated if low consider checking B12/folate and ferritin)
- Renal function, coagulation and liver function are also important tests and may assist in diagnosis particularly for conditions such as MAHA or DIC.
It is worth remembering although our patient had all the classical features of haemolysis not all patients will. This is where the history and examination are helpful in narrowing the wide differential.
The Direct Antiglobulin test (DAT) shows red cells that are coated in antibody through the use of monospecific Anti Ig G or C3 Ab. The DAT is not hugely specific with a high rate of false positives in hospital inpatients due to immunoglobulin absorption onto red cells. The sensitivity of a conventional DAT is also not high, hence additional testing can be performed using an eluate and Indirect Antiglobulin Testing (3% of AIHA patients are negative by DAT but positive on eluate techniques).
If the DAT is positive it is important to contemplate if there is an allo or auto antibody present. A history of recent blood transfusion, pregnancy or transplant would be guides to this potential issue. It would also be important to review drug history as mentioned above.
In our case we has a lady with a positive DAT for Ig G and C3d and it was therefore important to perform a direct agglutination test ( saline suspended red cells with patients serum to establish if visible agglutination). If positive this test suggests there may be a cold component to the haemolysis and a titre of the antibody should be performed to confirm if an incidental cold agglutinin or a real cold agglutinin disease. Thermal amplitude studies can be performed if there is diagnostic uncertanty.
At this point hopefully you will have a clear idea if the patient you are investigating has evidence of imune or non-immune haemolysis.
General priniciples in Management of Haemolysis:
- Folic acid replacement in all patients
- Consider thrombotic risk
- If using steroids dont forget Bone and Gastric protection and to consider history of diabetes.
Transfusions may be required in management of haemolysis and ABO, Rh and K matched units should be provided in an urgent setting. It should be stressed no patient should be put at risk through lack of compatible units. If necessary the consequences of an incompatible unit can be dealt with later if there is severe haemolysis.
Warm AIHA is the commonest type of immune haemolysis accounting for 70% of cases. It can be primary or secondary. The secondary causes include: Infection, Malignancy and Autoimmune conditions. In our case the patient had a history of a sister with lupus so it would be important to perform autoantibodies to exclude an underlying connective tissue disorder.
Management of any active haemolysis should include consideration of the thrombotic risk. It has been estimated in a retrospective study that 22.9% of patients with warm haemolysis had a VTE (Audia et al 2016). The risks were greatest in the first week of haemolysis. It has therefore been suggested that LMWH should be considered for prophylaxis in these groups. Clearly individual factors need to be considered with these recommendations, however our patient had a normal platelet count and no bleeding risk factors so was given LMWH prophylaxis.
Our patient was also given folic acid and placed on calcium and vitamin D tablets as bone protection. A PPI was not given as she was not on antiplatelet agents, nor did she have a history of peptic ulceration. A Bisphosphonate should be considered if over 50 years according to the latest BSH guidance.
In an emergency IVIG, plasma exchange, methylprednisolone and even emergency splenectomy are possible options.
Management traditionally commences with a trial of prednisolone 1mg/kg/day with around an 80% response rate. Our patient showed good response to this and commenced on a reducing dose following the BSH guidance reducing by 20-30mg over 4- 6 weeks then by 5mg a month. She did well initially with her reticulocyte count falling and Hb normalising but at 15mg dose she relapsed.
Our patient was given a Rituximab infusion and responded well to this. Other options for treatment would include MMF, Azathioprine (If TPMT ok), Ciclosporin, Splenectomy. The choices for the third line options are all down to patient factors and preference.
Many thanks for your help this week. Any questions or comments are welcome.
Hill et al. Diagnosis and management of primary autoimmune Haemolytic anaemia. BSH Guideline 2016.
Hill etal. Guidelines on the management of drug-induced immune and secondary autoimmune, haemolytic anaemia. BSH Guideline 2016.
Audia et al. High Incidence of Venous Thromboembolism Events during Warm Autoimmune Haemolytic anaemia. Blood 2016 128:2448.