Autoimmune Haemolytic Anaemia (AIHA) (BSH 2016, ICM 2019)
Notes mainly based on BSH. ICM guideline much longer but contains some interesting small print facts that I have omitted so as not to crowd out the basics (e.g. did you know that hereditary ahaptoglobinaemia exists?)
Intro
Definition
Decompensated acquired haemolysis caused by the host’s immune system acting against its own red cell antigens.
Incidence
1 per 100,000 per year. Rises with age.
May occur in up to 10% of SLE pts / 5-10% of CLL pts / 5% of stem cell allograft / 5% of ITP (Evans Syn)
Breakdown of cases
65% Warm, 29% CHAD, 1% PCH, 5% Mixed
50% primary, 50% secondary
Secondary Causes of AIHA
Warm
Cancer (CLL, Lymphoma, Solid organ)
Infection (Hep B & C, HIV, EBV, CMV, VZV, Pneumococcal, TB, Leishmaniasis)
Immune dysregulation (SLE, APS, RA, UC, PBC, Sarcoidosis, Post-Transplant, Immunodef Syn, Connective Tissue disorder)
Cold Haemaglutinin Disease (CHAD)
Cancer
Infection (Mycoplasma, Viral infection inc IM)
Autoimmune disease
Post-Allograft
Paroxsymal Cold Haemoglobinuria (PCH)
Infection (Adenovirus, Flu, Syphilis, CMV, IM, VZV, Measles, Mumps, Mycoplasma, Haemophilus, E. coli)
Mixed
Infection, SLE, Lymphoma
Differential Diagnosis for Haemolysis
Hereditary
Membrane disorders – HS, HE
Enzyme disorders – G6PD, PK Def
Haemoglobinopathies – Sickle, Unstable Hbpathy
Acquired Immune
Allogeneic – HDFN, Blood Transfusion, Post-Transplant
Autologous – i.e AIHA
Drug-induced
Acquired Non-Immune
Infection – Malaria, Clostridium perfringens
Mechanical – Heart Valves, Extra-corporeal circuits
Oxidative – Dapsone, Arsine Gas
Pregnancy - HELLP, Eclampsia, Acute fatty liver of pregnancy
PNH, TMA, Hypersplenism, DIC, Severe burns, Renal failure
Presenting Features
Symptomatic Anaemia – weakness, dizziness, breathlessness
Haemolysis – jaundice, dark urine
Symptoms of underlying disorders (see above)
Examination – Hepatosplenomegaly, heart failure, or normal
Cold Haemaglutinin Disease (CHAD)
Primary – chronic clonal disorder in middle-late years. 40-90% have cold-induced acrocyanosis
Secondary – Often self-limiting following a childhood infection
Paroxsymal Cold Haemoglobinuria (PCH)
Donath-Landsteiner Antibody (IgG Anti-P) – see bottom of page for testing
Transient, occurs 1-2 weeks after URTI
Severe intravascular haemolysis, but self-limiting to a few weeks
Acute fever, back pain, abdo pain, limb pain, haemoglobinuria
Diagnostic Approach
1. Is there haemolysis?
Unconjugated hyperbilrubinaemia, Reticulocytosis, , Raised LDH, Low haptoglobins
Film – spherocytes, agglutination, polychromasia, NRBC
Urinary haemosiderin – detectable one week after intravascular haemolysis
N.B. All tests have confounding factors, esp in medical inpatients!
2. Is the haemolysis immune?
DAT positivity indicates presence of IgG, IgM, IgA or C3d bound to the red cell membrane
Most labs use monospecific IgG & C3d DAT first line
Non-specific test, may be positive due to passive deposition of antibody, e.g. liver disease, chronic inf, cancer, SLE, post IVIg, post ATG.
3. DAT + haemolysis present, now ask:
?Blood transfusion in last 3 months --> ?Delayed Haemolytic Transfusion Reaction
?HSCT --> ABO mismatch, passenger lymphocytes
?HDFN in infants
?Any relevant drugs that could cause AIHA
?Any other known causes of non-immune haemolysis present
N.B. If DAT negative but strong suspicion of AIHA consider column agglutination DAT that includes IgG, IgA, C3d. If still negative, consider red cell eluate.
4. It is AIHA, so what type is present?
Warm – IgG (usually) autoantibodies binding in vivo at 37 degrees. 35% IgG only, 58% IgG + C3d, 9% C3d only.
CHAD – IgM autoantibodies binding in vitro at 4 degrees. 70-80% C3d only (but only 10-30% of C3d only AIHA is due to CHAD because warm AIHA much more common). CHAD must be distinguished from insignificant cold agglutinins my measuring antibody titre. CHAD typically has a titre >1:500, as compared <1:250 for insignificant cold agglutinins.
PCH – Biphasic IgG binding at low temp but causing complement lysis as temperature rises. Usually C3d only. Donath-Landsteiner test is diagnostic but difficult. D-L test recommended if <18 yo, CHAD excluded, and presence of haemoglobinuria plus cold-associated symptoms.
Mixed – Combination of warm IgG and cold IgM. Often low titre <1:64
Investigations
1st line – Immunoglobulin profile, Protein electrophoresis, HIV, Hep B/C, ANA, Anti-dsDNA
Selected patients – BM Biopsy, U&E, LFT, Coag, Urine dip, Preg test, Infection screening, Staging CT
If reticulocytopenia – B12, Folate, Parvovirus B19, BM Biopsy
Typical Antibody Profiles
Management
Emergencies
Emergency/Rescue management of severe, immediately life-threatening warm AIHA
Transfuse ABO, Rh, & K matched cells
IVIg – dosing regimens vary – e.g. 1g/kg x2, 0.5g/kg daily for 5 days
Plasma Exchange to buy time
Methylprednisolone
Emergency splenectomy / Splenic embolization
For cold haemolysis
Steroids, plasma exchange and use a blood warmer when transfusing
Normal Management
Supportive Care
Thromboprophylaxis for all inpatients, consider for outpatients with active haemolysis
Folic Acid 5mg daily
Gastroprotection if >60, prev ulcer, NSAIDS or thrombocytopenia (In practice, all patients)
Osteoporosis prevention – Calcium+Vit D for all patients on steroids +/- Bisphosphonate for men >50 / post-menopausal women (Or see this section)
Primary Warm AIHA
First line: Prednisolone
1mg/kg/day for maximum 3 weeks then taper if responding
80% respond, 66% get a CR, 20% remain in CR, 40% maintain an acceptable Hb on long term pred
If no response after 3 weeks, move to second line treatment
Second line: Rituximab
375mg/m2 weekly for four weeks
80% respond, 40% get a CR, 50% relapse at 30 months
Third line: Immunosuppressant
Azathioprine, Ciclosporin, Danazol, MMF depending on local practice
Third line alternative: Splenectomy
70% respond, 40% get a CR, 33% relapse
Vaccinate 2 weeks prior or 2 weeks post (Men B, Hib/Men C, Men ACWY, Pneumococcal, Flu)
Beyond third line: Alemtuzumab, Bortezomib, Cyclophosphamide, HSCT
Primary CHAD
Avoid cold exposure
First line: Rituximab
Use if symptomatic anaemia, transfusion dependence or severe symptoms
50% respond, median rise in Hb of 40g/l. Complete response is uncommon.
In cardiac surgery
Keep patient normothermic intra- and post-operatively
Refractory/Relapsed scenarios
Trial/experimental options - eculizumab, ibrutinib, bendamustine, bortezomib
Childhood Primary Warm AIHA
77% self-limiting
RBC transfusion often unnecessary unless CVS compromise
Check for congenital disorders (e.g. Diamond Blackfan), transient erythroblastosis, parvovirus B19, giant cell hepatitis & immunodeficiency prior to starting treatment
Treatment: Steroids or Rituximab
AIHA in Pregnancy
1 in 140,000 pregnancies
Maternal outcomes are good
Dx and Ix the same except avoid CT scan and consider pregnancy causes of haemolysis
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Note: Donath-Landsteiner Antibody Testing
IgG unlike other high titre cold antibodies
More lytic to red cells in relation to its titre than IgM Anti-I or –i.
Indirect D-L test preferred
Principle: Biphasic IgG binding at low temp but causing complement lysis as temperature rises.
Patient serum sample left to clot at 37 degrees
Pt serum : 50% suspension of washed O P+ red cells in a ratio of 9:1
Chill at 0 degrees for one hour. Then 37 degrees for 30 minutes
Centrifuge and examine for lysis – presence of lysis positive for D-L antibodies
Use positive and negative controls
Drug-Induced and Other Secondary AIHA (BSH 2017)
Intro
50% of AIHA is secondary, of that:
50% haematological malignancy, 33% infection, 15% collagen disorders, 10% drugs
All general management principles from primary AIHA should be followed
Drug-Induced AIHA (DIIHA)
>130 implicated drugs
Cephalopsorins, Diclofenac, Rifampicin, Oxaliplatin & Fludarabine most common
Two case series (total 188 patients), reported the following drugs:
Top offenders: Ceftriaxone (20), Other Cephalosporins (37), Tazocin (17), Diclofenac (15), Fludarabine (6)
Anti-infectives – Ciprofloxacin, Doxycycline, Amoxicillin, Co-trimoxazole, ‘Flu vaccine
Cytotoxics – Oxaliplatin, Chlorambucil
Musculoskeletal – Ibuprofen, paracetamol
Cardiovascular – Amlodipine, Ramipril, Enalapril
Clinical Features
Can present within hours of exposure or after several months
Can be drug-dependent or drug-independent when test serologically
May be mistaken for acute haemolytic transfusion reaction (HTR)
Investigations
Serological testing may require the medication + patient’s blood/urine for drug metabolites
Drug-Dependent Antibodies
E.g. Ceftriaxone, Tazocin
IgG or IgM Antibodies that do require drug to be present to detect in vitro
Drug binds non-covalently to red cell membrane protein. Drug+Antibody combo creates an immunogen --> complement activation and intravascular haemolysis
Drug-Independent Antibodies
E.g. Fludarabine, Penicillins, Methyldopa
IgG antibodies that do not require drug to be present to detect in vitro
Drug binds covalently to red cell membrane --> antibody-coated RBC taken up by macrophages
Management
Stop drug
Liaise with RCI reference laboratory
Steroid benefit unclear
Haematological Malignancies
Difficult diagnosis
Multifactorial anaemia, reticulocytopenia due to BM suppression, increased LDH due to disease
Need to exclude CMV and Parvovirus B19
BM Biopsy may help
Considerations
IVIg may be an effective rescue option for uncontrolled haemolysis
CLL – steroids, IVIg or rituximab for the haemolysis if the CLL does not otherwise require treating
NHL – treat the disease, or as per primary AIHA if complete remission confirmed
Hodgkin – AIHA may indicate relapse, look hard for this before treating
Allogeneic Stem Cell Transplant (HSCT)
2-4% of patients within first year post-transplant
Difficult diagnosis
May coincide with CMV, GVHD, Disease relapse
Separate from alloimmune haemolysis (ie ABO mismatch transplant with a mixed chimerism)
Separate from thrombotic microangiopathies (TMAs)
Separate from drug-induced AIHA with calcineurin inhibitors
Management
Switch immunosuppressant, treat infection / GVHD
Steroids / IVIg / Rituximab
Solid Organ Malignancies
Ovarian teratomas – require surgical resection. Steroids not effective.
Thymomas – surgical resection or pred 1mg/kg if urgent treatment required
AIHA also reported in renal cell and colonic carcinomas.
Solid Organ Transplant
5-10% of childhood transplants
Underlying causes – CMV, EBV-PTLD, Parvovirus B19
Infections
Mycoplasma & Viral Pneumonia
Secondary CHAD is a rare complication of mycoplasma, but 33% of CHAD is due to mycoplasma
Occurs 2-3 weeks after original infection
Usually self-limiting after 2-3 weeks of supportive care
Infectious Mononucleosis (IM)
AIHA in 3% of IM patients, usually 1-2 weeks after onset
Anti-i antibody
Self-limiting for 4-8 weeks
Hepatitis C
Stop interferon as may be drug-induced
Treat the hepatitis
Steroids effective but risk aggravating the hepatitis
Immune Disorders
Systemic Lupus Erythematosus (SLE)
10% of SLE patients have AIHA, but 60% have a positive DAT
75-90% respond to steroids
2nd line options: Azathioprine, Danazol, MMF, Rituximab
Avoid splenectomy - increases pre-existing infectious and thrombotic susceptibility
Common Variable Immunodeficiency (CVID)
Steroids --> Rituximab --> Immunosuppression / Splenectomy
Patients need maintenance IVIg +/- long-term antibiotics
Ulcerative Colitis (UC)
If AIHA occurs, usually at same time as active colitis
--> 1st line treatment is to control colitis
Evans Syndrome
Original referred to Acquired AIHA + Primary ITP, but also now includes 2o AIHA + 2o ITP.
>50% cases also neutropenic
Rule out Autoimmune Lymphoproliferative Syndrome (ALPS) by flow cytometry
Steroids / IVIg --> Aza/ciclo/danazol/MMF/Ritux/Splenectomy --> Cyclophos/Campath/HSCT
New: Romiplostim?
Giant Cell Hepatitis
Age 2 months to 2 years with jaundice, hepatomegaly, transaminitis, conjugated hyperbilirubinaemia
Diagnosis by liver biopsy
If AIHA occurs, usually severe and relapsing
Treatment: Immunosuppression or liver transplant