Autoimmune hemolytic anemia (AIHA) - .Autoimmune hemolytic anemia (AIHA) AIHA is characterized by

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Text of Autoimmune hemolytic anemia (AIHA) - .Autoimmune hemolytic anemia (AIHA) AIHA is characterized by

Autoimmune hemolytic anemia (AIHA)

Sacha Zeerleder, MD PhD

Internist hematologist

Department of Hematology Academic Medical Center Amsterdam

Department of Immunopathology, Sanquin Research, Amsterdam

Autoimmune hemolytic anemia (AIHA)

AIHA is characterized by an increased breakdown of red blood cells (RBC) due to autoantibodies (auto-Abs) with/without complement activation.

Pathogenesis AIHA

AIHA is characterized by an increased breakdown of red blood cells (RBC) due to autoantibodies (auto-Abs) with/without complement activation.

RBC antigens Rh-related polypeptides Molecular mimicry Oxidative changes in RBC antigen structure?

Complement system Altered expression of CR1 Decreased experssion membran- boud complement regulators (CD59)

Ineffective antigen presentation Immature DCs Decreased co-stimulatory help by T- cells

Functional B/T cell abnormalities Polyclonal lymphocyte activation Alteration of cytokine profile Dysregulation of T-Regs


Laboratory analyses:

Hemolysis (LDH , haptoglobine , hyperbilirubinemia)

Positive Coombs


Diagnosis AIHA

Specificity of autoantibodies:

Rhesus antigen (50% in AHIA with warm autoantibodies)

I/i antigen (AHIA cold antibodies)

P-antigen (paroxsysomal cold hemoglobinuria)

But: biological activity of the autoantibody determines the clinical activity rather then than the specificity of the autoantibody

AIHA is characterized by an increased breakdown of red blood cells (RBC) due to autoantibodies (auto-Abs) with/without complement activation.

Isotype autoantibody:

determines complement activation and Fc gamma receptor binding

Complement activation:

IgM: most efficient

IgG1, IgG3: efficient

IgG2, IgA: weak

IgG4: no complement activation

Fc-gamma receptors

IgG1, IgG3 FcgRI (CD64)

IgG (low affinity) FcgRIIa

AIHA: biological activity of autoantibodies

C1r C1s

C1r C1s

AIHA: complement activation

C1r C1s

C2a C4b



AIHA: complement activation


C3b C3b C3d





AIHA: complement activation


C6 C7

C8 C5b


AIHA: complement activation

Complement activation


Fc-gamma receptor

CR receptor depositie

AIHA destruction of autologous RBCs

C3d C3c


IgG C3c C3d

positive positive



AIHA: direct Coombs (antiglobuline test)

C3d C3c


AIHA: direct Coombs (antiglobuline test)

IgG (IgA) IgM C3c C3d


Cold antibodies

mostly IgM

binding at

Warm autoantibodies:

Idiopathic (primary)

Secondary: CLL, lymphoma, SLE

Cold autoantibodies

Idiopathic (primary)

Secondary: mycoplasma infection, viral infections (EBV), lymphoproliferative diseases

Paroxysmal cold hemoglobinuria

Idiopathic (primary)

Secondary: viral infections, syphilis

Mixed warm and cold autoantibodies


Incidence 1:80000

>40 years, peak >70

Very rare

>50 years

Very rare


AIHA: classification

18% will develop overt

lymphoma in the


AHIA with warm autoantibodies

2008: Chronic lymphatic leukemia (Rai III), del17p (poor prognosis)

Treatment with chlorambucil, achievement of very good partial remission

IH: direct Coombs negative

05/2009: Non-STEMI infarction

Lab: Hb 6.9 g/dl, Lc 4.5x109/l (slightly increased lymph), Tc 230x109/l;

LDH 667 U/L, bilirubin 27 umol/l, haptoglobin


Decrease the production of autoantibodies


plus immunosuppressive therapy

Monoclonal antibodies (antiCD20)


inhibit the breakdown/removal of RBCs

intravenous gammaglobulines


Treatment of the underlying disease






AIHA with warm autoantibodies - treatment

Transfusion AHIA

Analyst calls: everything is positive.

Type: RBC coated with autoantibodies

Screen: patient serum reacts with test RBCs

Hence: T&S not possible (needs time!)

Is there really a need for transfusion (vital indication)?

are there clinical signs of hypoxia??

Is there time for extensive IH analyses?

Important: prevention of alloantibody formation

Patients with alloantibodies have an increased risk to develop additional alloantibodies

Transfusion can exacerbate hemolysis!

AIHA transfusion: recommendation

Compatible for alloantibodies (and complement-binding antibodies)

Negative for the respective antigen

Prevention of alloantibody formation

Blood product as far as possible compatible with the recipient antigens

Compatible for specific autoantibodies (in case of fulminant hemolysis)

Transfusion: slow! Check vital signs as well as hemolysis parameters

laboratory procedures may take

hours..(absorption techniques etc)

Selection blood product

Select compatible for Rh (phenotype) and K

If possible: Kidd > Duffy > S > s

AIHA with WA auto-Abs steroids + cytotoxic agents


2 important effects: decrease

RBC removal (breakdown) in the spleen (decrease of the density of Fcg-receptors on MP)

production of autoantibodies

in approx. 60-70% of the patients achieve a remission (10-15% CR), frequently a

maintaining dose of steroids is needed Gehrs et al. 2002, Pirofsky et al. 1975, Murphy et al. 1976, Zupanska et al. 1981

In case there is - no response on steroids

- prednisolon maintenance dose >15-20 mg/d

- side effects steroids

combination with cytotyoxic drugs

Cyclophosphamide (100 mg/d vs pulse regime 50mg/kg bw over 4 days) Murphy et al. 1976, Zupanska et al.1981, Panceri et al. 1992, Silva et al. 1994, Moyo et al 2002

Azathioprine (100-150 mg/dag) Pirofsky 1975, Worlledge et al. 1968

Treatment AIHA with WA-Abs splenectomy


Reduce removal of RBCs in the spleen (+ reduction of autoantibody formation) Allgood et al. 1967, Habibi et al 1974

Difficult to predict which patients will benefit from splenectomy

50% shows improvement of anemia (in 2 weeks)

20% show long-time remissions

in 50% of the patients in remission: reduction of the prednisolon dosage Coon 1985, Chertkow et al. 1956, Allgood e al. 1967, King et al. 2005, Pirofsky 1974

Elective splenectomy laparoscopy

CAVE: Vaccination!! (H. influenzae, Str. meningitidis, Str. pneumoniae)

But: mortality after splenectomy ~1.3% (children 1.7%) Bisharat et al. 2001, Collins et al. 1992, Katkhouda et al. 1998

Treatment AIHA with WA-Abs gammaglobulins


decrease de removal of RBCs in de spleen


Treatment of refractory AIHA with WA

additional to the basic therapy in severe AIHA (improvement of the recovery of RBC transfusions)


1g/kg bw during 2 days or 0.4g/kg during 5 days

40% temporary improvement of anemia (however: no longstanding CR) Flores et al. 1993, Macintyre et al. 1985, Bussel et al. 1986, Majer et al. 1988, Bjorkholm et al. 1993

Treatment AIHA with WA-Abs anti-CD20

Retrospective studies: CR 20-75% Shanafelt et al 2003, Narat et al. 2005, DArena et al. 2006, DArena et al. 2006, Pealver 2010

Prospective studies:

2 studies with CR>85%, 3 studies with CR>60%, 1 study CR 40% Zja et al. 2003, Zecca et al. 2003, Gupta et al. 2002, Quartier et al 2001, Trape et al. 2003, Barcellini 2012

Dose: 375 mg/m2, 1x/week, 4 gifts (low dose: 100 mg/m2, 1x/week, 4 times)

Anti-CD20 (Rituximab):

Chimeric (mouse/human) antibody recognizing CD20

CD20 is expressed on all B-cells (pre-pre-B cells) except on plasma cells

Mechanism: decrease the production of autoantibodies by specifically eliminating B-cells

Efficacy: not clear; convincing concept, little data from RCT, publication bias

Treatment AIHA with WA Abs


Steroids + immunopressivs/

cytotoxic medication

Anti-CD20 Rituximab



Transfusion Treatment underlying



Female patient (77 yrs) diagnosed with cholangio carcinoma (Klatskintumor) admission for staging laparoscopy

Preoperative screening:

A positief, CcDee

directe Coombs 4+, anti-IgG negative, anti-IgA negative, anti-IgM weak positive, anti-C3c negative, anti-C3d positive

Patient with AIHA with cold auto-Abs

What is your advice???

Cold Abs: agglutination vs hemolysis

C1r C1s


C6 C7

C8 C5b