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,

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)

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

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 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

rx/therapy:

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) 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

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

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