Kevin Lee MD

Morning Report 7/1/02

AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA)

(auto)antibodies that react with red blood cells

Subtypes: Warm, Cold (agglutinin/PCH), Mixed, & Drug-induced

WARM AIHA
most common type (40-70% of aiha)
usually secondary to warm agglutinins IgG1 and IgG3 (both fix complement) which react
w/ protein antigens on rbc surface at body temp (>37 C); exact mechanism unknown
incidence: 1:50,000-80,000 (overall incidence of aiha 1-2/100,000)
female: male 2:1 predominance
etiology:
idiopathic (30-50%); often predate lymphoproliferative d/o (18% incid.@ two yr)
viral (usually childhood); HIV
autoimmune dz (SLE, RA, scleroderma, UC)
malignancies (CLL, Hodgkins/NHL, rarely multiple myeloma/waldenstroms)
misc: post-chemo w/ purine analogs; pregnancy; thymoma; teratoma;
drug-induced (discussed separately)

symptoms: DOE/dyspnea (9%), fatigue (88%), bounding pulses/palpitations,

dizziness (50%), HA, unexplained fever (37%), abd pain/anorexia (5%), angina (2%)

at rest, able to compensate w/ preserved O2 delivery until Hgb drops to 8-9 g/dl;
w/ exercise and concomitant increased HR/SV, able to compensate until Hgb 5 g/dl
impending circulatory collapse: severe lethargy/confusion, dyspnea w/incr HR
(high-output CHF/MI/fatal arrhythmia)

signs/lab findings:
mean HCT 24 at presentation (though 30% present w/ HCT<20)
increased MCV/MCHC/reticulocytosis 4-5% but may be as high as 9%
increased LDH/decreased haptoglobin (90% sensitive for dx aiha)
direct coombs/DAT positive (in 95% of cases); indirect coombs of little value
moderate splenomegaly (82%) // spherocytosis
hepatomegaly (45%) / lymphadenopathy (25% of idiopathic cases)
jaundice: indirect hyperbilirubinemia (usually TB < 5)
severe cases may have evidence of intravasc. hemolysis (hemoglobinemia/uria)
petechiae/purpura/thrombocytopenia + aiha = Evans syndrome

rx/therapy:

goal is to decrease amount of antibody being produced or to decrease its efficiency in

destroying rbcs
(1)
(2)
(3)
(4)
(5)

folate supplementation
treat underlying d/o (i.e. SLE, CLL, etc)
stop offending drug (if suspect drug-induced)
immunosuppression (*steroids/IVIG/cyclophosphamide vs. azathioprine)
splenectomy

COLD AIHA
16-30% of aiha; cold agglutinins & paroxysmal cold hemoglobinuria
antibody binds most strongly at 0-4 C; therefore rx is to avoid cold
IgM antibody against polysaccharide antigen on rbc surface
90% anti-C3 alone
can occur via paraneoplastic/neoplastic growth of single immunocyte clone
also may be precipitated by infection (mycoplasma and EBV most frequent)
others: CMV, listeria, VZV, E.coli, and syphilis

sx/signs: similar to warm aiha with the following exceptions

rbc agglutination on peripheral smear after exposure to ambient room temp;

may also see this in severe warm aiha
acrocyanosis: dark, purplish discoloration to fingertips/toes/nose/ears;
disappears w/ warming; no reactive hyperemia (unlike raynauds phenomenon);
may progress to digital ulceration
can have pain w/ swallowing cold food/liquid
cold agglutinins: maintain specimen at 37-40 C until clot formed and retracted;
nl titer = < 1:40; rarely see hemolysis w/ titer <1:1000

MIXED AIHA: warm aiha w/ additional cold agglutinin

chronic course punctuated by severe exacerbation (hgb < 5 g/dl)
idiopathic or secondary to lymphoproliferative d/o or SLE
no acrocyanosis; episodes not triggered by cold
direct coombs+ for IgG and C3
responds to rx in similar fashion to warm aiha
DRUG-INDUCED 1ST reported in 1949
behaves like warm aiha (+direct coombs)

(n.b. 3-12% of pts give PCN/cephalosporins will develop +direct coombs w/o hemolysis)

mechanisms of action (may have combo of any of the three)

(1) drug adsorption (i.e. PCN) Ab reacts w/drug tightly bound to rbc
membrane; usually gradual onset over 7 days; life-threatening if drug not d/c
(2) neoantigen or immune complex (i.e. cephalosporins) drug combines
w/ rbc membrane and Ab reacts w/ new Ag site created by drug-membrane
combo; only small dose of drug required to set in motion; sudden/severe
presentation; may see associated renal failure
(3) autoimmune (i.e. methyldopa) Ab bind to rbc membr(similar to warm
aiha)

THERAPEUTIC AGENTS (most useful for warm and drug-induced

aiha)
Steroids: first-line therapy; minimal dose to induce remission is unknown

Prednisone 1 mg/kg/day (or if severe, IV methylprednisolone 100-200 mg/day)

response usually seen w/n 5 days; 60-70% have remission by 3 weeks; 20% no response
mechanism of action thought to be a decrease in rbc removal by monocyte/macrophages
goal: hgb 10 g/dlthen may begin slow taper

2/3 of patients will relapse

if remission not maintained w/taper or no response to steroids at 3 weeks > splenectomy
Splenectomy: second-line therapy; 60-70% improve w/n 2 weeks post-op;
removes primary site of rbc destruction; rbcs coated w/ IgG removed by spleen
*neither steroids nor splenectomy are indicated for cold aiha b/c IgM-mediated
problem

Others: steroid-sparing for pts w/ DM, PUD, osteoporosis/myopathy or

nonresponders
cyclophosphamide =3rd-line agent; 50% of pts who failed steroids/splenectomy
will respond; dose 100 mg po QD or 500-700 mg IV q month
azathioprine fewer side effects/less efficacious; dose 100-150 mg/day
cyclosporine 4-5 mg/kg/day
vincristine/vincristine-loaded platelets (?selective macrophage injury); can
induce transient, rapid remission while waiting for cyclophosphamide rx effect
rituximab (monoclonal anti CD20 antibody) : reported + results; limited use
danazol androgen which ?inhibits binding of Ab to rbc; dose 600-800 mg/day;
given in conjunction w/ steroids & can delay/obviate need for splenectomy
heparin temporizing agent if aiha is clearly complement-mediated
erythropoietin 4000 U 1-2x/wk; increase rbc production

IVIG: if very severe/life-threatening hemolysis, may be given with initial steroid course
500 mg/kg/day x 5 days (1000-2000 mg/kg/day high dose can be used)
only 40% response rate; effect is transient and f/u doses given q month
side effects: acute renal failure, hyperviscosity (PE, MI, TIA/CVA)

Transfusion: if rbc can survive 2-3 days, then BM production may allow for steady

state
If hemolysis greater than 20% rbcs/day >> hypovolemic shock
Transfuse w/o delay if severe dyspnea/CHF sx/angina; use slow rate
May need washed rbcs; call blood bank early

Lancet 1992 340:1515

53 pts received blood transfusion b/c of decompensated aiha
no patients had transfusion-related alloimmunization
no patients had definite increase in rate of hemolysis even when transfused rbcs
were serologically incompatible b/c of free serum autoantibodies

Plasmapheresis: very cumbersome/time-consuming b/c antibodies confined to

intravascular space large vol. of distribution; transient b/c half-life of protein 5 days
Indications:
severe hemolysis (if due to infection)
severe acrocyanosis (cold aiha) / polyneuropathy
pre-operative (CABG/transplant) in pts w/ known cold agglutinins

REFERENCES
Gehrs and Friedberg. AIHA. American Journal of Hematology 69, 4/02
Lee. Wintrobes Clinical Hematology. 10th Edition
Rosse. AIHA. UpToDate 10.1, 2002
Saito. Conns Current Therapy. 54th Edition, 2002