Autoimmune Haemolytic Anaemia (AIHA) (BSH 2016)

 

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.

65% Warm, 29% CHAD, 1% PCH, 5% Mixed

50% primary, 50% secondary

 

Secondary Causes of AIHA

 

Warm

  • Cancer (CLL, Lymphoma, Solid organ)

  • Infection (Hep C, HIV, CMV, VZV, Pneumococcal, TB, Leishmaniasis)

  • Immune dysregulation (SLE, 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, Reticuloytosis, , 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 IVIg, 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

typical antibodies.png

 

 

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, Cyclophosphamide, HSCT

 

Primary CHAD

Avoid cold exposure

First line: Rituximab

  • Use if symptomatic anaemia, transfusion dependence or severe symptoms

In cardiac surgery

  • Keep patient normothermic intra- and post-operatively

 

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

 

 ————————————————————————————

 

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

 

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