Master AIHA, warm vs. cold antibody types, DAT interpretation, and drug-induced hemolysis for ASCP BOC.

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Chapter 15 โ€” EXTRINSIC DEFECTS LEADING TO INCREASED ERYTHROCYTE DESTRUCTION: IMMUNE CAUSES

ASCP Board Exam ยท Lab-Focused Study Guide
IgG vs IgM Hemolysis ยท Classical Complement Pathway ยท DAT & IAT ยท Warm AIHA ยท Cold Agglutinin Disease ยท Paroxysmal Cold Hemoglobinuria (Donath-Landsteiner) ยท Mixed-Type AIHA ยท Drug-Induced Immune Hemolysis ยท Hemolytic Transfusion Reactions ยท HDFN (Rh vs ABO) ยท Practice Questions

1 ยท Priority Table & Quick Foundation

Topic Priority Why It’s Tested
IgG- vs IgM-mediated hemolysis: site, complement, spherocytes (Table 26-1) HIGH Mechanism questions โ€” Rodak review Q2โ€“Q3
Direct antiglobulin test (DAT) vs indirect antiglobulin test (IAT) HIGH Most important test in immune hemolysis (Rodak Q4โ€“Q5)
The 4 AIHA types โ€” class, temperature, DAT pattern, specificity (Table 26-2) HIGH Most-tested comparison table of the chapter
Warm AIHA: IgG, 37 ยฐC, panreactive, spherocytes, prednisone HIGH Most common AIHA; Rodak case study
Cold agglutinin disease: IgM anti-I, C3d only, agglutination artifacts on CBC HIGH Pre-analytical: warm the sample to 37 ยฐC
Paroxysmal cold hemoglobinuria: biphasic IgG anti-P, Donath-Landsteiner test HIGH Classic test procedure and child after viral infection
Drug-induced immune hemolysis: 3 mechanisms + drug-dependent vs drug-independent HIGH Penicillin vs quinine vs methyldopa/fludarabine (Rodak Q6, Q7, Q10)
Acute vs delayed hemolytic transfusion reaction HIGH ABO/intravascular vs anamnestic/extravascular (Rodak Q8)
HDFN: Rh vs ABO (Table 26-3), RhIG timing, anti-Kell HIGH Prevention and comparison (Rodak Q11)
Classical complement pathway: C1q needs 2 Fc; C3b vs C3d; MAC MEDIUM Why IgM fixes complement easily
Evans syndrome; secondary causes of WAIHA and CAD MEDIUM Associations (Rodak Q9)
Treatment: steroids, splenectomy, rituximab, warming, P-positive blood MEDIUM Why splenectomy fails in CAD
Nonimmune drug-induced protein adsorption (cephalosporins/clavulanate, cisplatin) LOW Positive DAT without hemolysis
๐ŸŽฏ KEY POINT โ€” Where to spend your time

Focus: Table 26-2 (WAIHA, CAD, PCH, mixed), IgG = spleen/spherocytes vs IgM = complement/liver, DAT interpretation (IgG, C3d or both), the Donath-Landsteiner procedure, drug mechanisms with example drugs, AHTR vs DHTR, and Rh vs ABO HDFN. Skim: incidence numbers, study statistics (Berentsen), steroid side-effect percentages.

Quick Foundation โ€” from zero

  • In immune hemolytic anemia, RBCs are normal but get tagged by antibodies (and often complement), which marks them for early destruction.
  • The antibody can be an autoantibody (against the patient’s own RBC antigen), an alloantibody (against someone else’s RBC antigen โ€” transfusion, pregnancy) or an antibody against a drug.
  • IgG (a small monomer) mostly tags cells for the spleen; macrophages nibble off membrane โ†’ spherocytes.
  • IgM (a large pentamer) is excellent at switching on complement; cells coated with C3b are removed mainly in the liver, and heavy coating can punch holes directly (intravascular lysis).
  • The direct antiglobulin test (DAT) detects antibody or complement already on the patient’s RBCs โ€” the key test proving the hemolysis is immune.
๐Ÿ’ก Analogy

Think of RBCs as parcels in a sorting center. IgG is a ‘return to sender’ sticker โ€” the spleen’s workers (macrophages) grab tagged parcels and tear off pieces of wrapping, leaving smaller, rounder parcels (spherocytes) that later jam in the conveyor. IgM is a fire alarm โ€” it calls in the complement crew. A small crew leaves a C3b stamp that the liver’s workers read; a big crew explodes the parcel on the spot (intravascular lysis). The DAT is the inspector checking each parcel for stickers or stamps.

๐Ÿฅ Why this matters clinically

The type of antibody decides treatment: WAIHA responds to steroids and splenectomy; CAD doesn’t respond to either and needs warming and rituximab; PCH is self-limited; drug-induced hemolysis stops when the drug stops. In the lab, a cold agglutinin can wreck the CBC (falsely โ†‘ MCV, โ†“ RBC) and ABO typing unless the sample is warmed. A mistyped unit can cause a fatal acute transfusion reaction.

Concept Plain-English Explanation
Autoantibody Antibody against the patient’s own RBC antigen
Alloantibody Antibody against an RBC antigen the patient lacks (from transfusion or pregnancy)
Sensitization Antibody and/or complement attached to the RBC surface
Polyspecific AHG Antihuman globulin reagent detecting both IgG and complement (C3b/C3d)
Monospecific AHG Reagent detecting only anti-IgG or only anti-C3b/C3d
Eluate Antibody removed (eluted) from the patient’s RBCs so its specificity can be tested
Panreactive Reacts with every RBC tested, including the patient’s own โ€” no clear specificity
Thermal amplitude Highest temperature at which an antibody still reacts; >30 ยฐC makes cold antibodies harmful

2 ยท Core Content Tables

2.1 Classification of Immune Hemolytic Anemias (Rodak Box 26-1)

Group Type Causes / Subtypes
Autoimmune hemolytic anemia Warm AIHA (WAIHA) Idiopathic ยท Secondary: lymphoproliferative disorders, nonlymphoid neoplasms, collagen-vascular disease, immunodeficiency, viral infections
Cold agglutinin disease (CAD) Idiopathic ยท Secondary acute: Mycoplasma pneumoniae, infectious mononucleosis, other viruses ยท Secondary chronic: lymphoproliferative disorders
Paroxysmal cold hemoglobinuria (PCH) Idiopathic ยท Secondary: viral infections, syphilis
Mixed-type AIHA โ€”
Drug-induced immune hemolytic anemia (DIIHA) Drug dependent ยท drug independent โ€”
Alloimmune hemolytic anemias Hemolytic transfusion reaction (HTR) ยท hemolytic disease of the fetus and newborn (HDFN) โ€”

2.2 IgG vs IgM Structure

Feature Details
IgG Monomer, Y-shaped: 2 identical heavy (ฮณ) and 2 identical light (ฮบ or ฮป) chains joined by disulfide bonds; 2 Fab (antigen-binding) domains; one Fc domain (stem)
IgG subclasses IgG1 and IgG3 bind C1q strongly; IgG2 and IgG4 bind complement minimally
IgM Pentamer of 5 units joined at the C-termini of their ฮผ heavy chains โ†’ 5 Fc domains
Complement activation C1q must bind two adjacent Fc domains. One IgM molecule is theoretically enough; at least two IgG molecules close together are needed โ†’ IgM is highly effective, IgG activates only at high density

2.3 Classical Complement Pathway on the RBC

Feature Details
Start C1q binds adjacent Fc domains (needs calcium and magnesium) โ†’ activates C1r โ†’ activates C1s
C3 convertase C1qC1rC1s cleaves C4 and C2 โ†’ C4bC2a on the membrane
C3b deposition C4bC2a cleaves C3 โ†’ many C3b molecules on the RBC
C3d C3b is cleaved (C3c released) โ†’ C3d remains on the cell โ†’ detected by AHG. Macrophages lack a C3d receptor โ†’ C3d-only cells are not prematurely removed
C5 convertase C4bC2aC3b converts C5 โ†’ C5b
Membrane attack complex C5b + C6, C7, C8 and multiple C9 โ†’ cylinder inserted into the bilayer โ†’ pore โ†’ water/ions enter โ†’ lysis
Regulators Negative regulators block uncontrolled activation; must be overwhelmed for full C1โ€“C9 activation

2.4 Major Mechanisms of Immune Hemolysis (Rodak Table 26-1)

Site IgM Mediated IgG Mediated
Extravascular Complement activated C1 โ†’ C3b only; C3b-sensitized RBCs cleared by macrophages mainly in the liver (Kupffer cells) Clearance by macrophages mainly in the spleen (Fc receptors for IgG1, IgG3) ยท partial phagocytosis โ†’ spherocytes โ†’ trapped in splenic cords ยท high-density IgG (IgG3, IgG1) activates C1 โ†’ C3b; IgG + C3b cells cleared in spleen and liver
Intravascular Full activation C1 โ†’ C9 and direct lysis; requires high-density IgM to overcome inhibitors Full C1 โ†’ C9 activation requires very high-density IgG; uncommon (except anti-P in PCH)

2.5 Laboratory Findings in Immune Hemolytic Anemia

Feature Details
General hemolysis โ†“ Hb ยท โ†‘ reticulocytes ยท โ†‘ indirect bilirubin ยท โ†‘ LDH ยท โ†“ haptoglobin
Intravascular or severe Haptoglobin moderately to severely โ†“ ยท โ†‘ plasma Hb ยท hemoglobinuria ยท hemosiderinuria (chronic)
CBC MCV may be โ†‘ (reticulocytes, agglutination); leukocytosis and thrombocytosis possible with marrow erythroid proliferation
Film Polychromasia ยท spherocytes (IgG) ยท agglutination (cold agglutinins) ยท occasionally nRBCs, schistocytes, erythrophagocytosis

2.6 Direct & Indirect Antiglobulin Tests

Feature Details
DAT โ€” purpose Detects in vivo sensitization of the patient’s RBCs by IgG, C3b or C3d โ€” shows the hemolysis is immune
DAT โ€” procedure Add polyspecific AHG (anti-IgG + anti-C3b/C3d) to saline-washed patient RBCs; no incubation. Agglutination = positive
If positive Repeat with monospecific anti-IgG and anti-C3b/C3d to identify what is attached
If IgG present Perform an elution; test the eluate against screening and panel cells (IAT) to find its specificity
IAT Patient serum (or reagent) + RBCs incubated at 37 ยฐC โ†’ wash โ†’ AHG. Detects antibodies in serum (in vitro sensitization); used for antibody screen/ID, crossmatch
Cautions DAT can be negative in immune hemolysis; other disorders can give a positive DAT โ†’ interpret with history, medications, transfusions, pregnancy and other tests

2.7 Characteristics of the Autoimmune Hemolytic Anemias (Rodak Table 26-2)

Feature Warm AIHA Cold Agglutinin Disease Paroxysmal Cold Hemoglobinuria Mixed-Type AIHA
Ig class IgG (rarely IgM, IgA) IgM IgG IgG + IgM
Optimum temperature 37 ยฐC 4 ยฐC; reacts to >30 ยฐC 4 ยฐC 4โ€“37 ยฐC
DAT detects IgG or IgG + C3d; C3d only uncommon C3d C3d IgG and C3d
Complement activation Variable Yes Yes Yes
Hemolysis Extravascular primarily Extravascular; rarely intravascular Intravascular Extravascular + intravascular
Specificity Panreactive or Rh complex; rarely specific Rh or other I (most), i (some), Pr (rare) P Panreactive; unclear

2.8 Autoimmune Hemolytic Anemia โ€” General

Feature Details
Definition Rare; premature RBC destruction by autoantibodies with or without complement
Incidence 1โ€“3 per 100,000 per year; children: more males; adults: more females
Causes of autoantibodies Immune dysregulation, loss of tolerance, exposure to an antigen similar to a self-antigen, B-cell neoplasm, genetic and environmental factors
Severity depends on Autoantibody titer, reactivity at 37 ยฐC, complement activation, specificity/affinity; antigen density and immunogenicity; patient age, marrow compensation, macrophage function, complement regulators, underlying disease

2.9 Warm Autoimmune Hemolytic Anemia (WAIHA)

Feature Details
Frequency Most common AIHA โ€” up to 70% of cases
Antibody Reacts optimally at 37 ยฐC; vast majority IgG. Rare IgA; rare fatal warm IgM
Secondary causes CLL, B-cell lymphomas, Waldenstrรถm macroglobulinemia ยท thymoma and cancers (colon, kidney, lung, ovary) ยท RA, scleroderma, polyarteritis nodosa, Sjรถgren, SLE ยท immunodeficiency ยท viral infections
Onset Usually insidious (fatigue, dizziness, dyspnea); can be acute with fever, jaundice, splenomegaly, hepatomegaly (children after viral infection). Massive splenomegaly, lymphadenopathy, petechiae in adults suggest a lymphoproliferative disorder
Hemolysis Predominantly extravascular; RBC life span may fall to โ‰ค5 days; fulminant intravascular hemolysis rare
Film Polychromasia and spherocytes
Evans syndrome WAIHA + immune thrombocytopenic purpura; mainly children
DAT Positive in ~95%: ~85% IgG alone or IgG + C3d; 10โ€“14% C3d only. 1โ€“4% DAT-negative (IgA or IgM autoantibody, IgG/C3d below detection limit, low-avidity IgG washed off, technical error) โ€” a negative DAT doesn’t rule out AIHA
Specificity Usually panreactive โ€” agglutinates all screening, panel, donor and the patient’s own cells. Sometimes Rh complex; rarely LW, Jk, K, Di, Ge, Lu, M, N, S, U, Enแตƒ, Wrแต‡. Autoantibody in serum in ~80%
Transfusion issue Panreactive autoantibody can mask alloantibodies โ†’ must rule out clinically significant alloantibodies; units may all be incompatible โ†’ give minimum volume and monitor closely

2.10 WAIHA โ€” Treatment

Feature Details
First line Glucocorticoid (prednisone) for symptomatic non-life-threatening WAIHA; 70โ€“80% improve; many adults need maintenance
Steroid side effects Osteoporosis, osteonecrosis, fractures (lumbar spine) in 30โ€“50%; give bisphosphonates, vitamin D, calcium
Second line Splenectomy for refractory/steroid-dependent chronic WAIHA โ€” favorable in 50โ€“70%
Other Immunosuppressants (cyclophosphamide, azathioprine); rituximab (anti-CD20) โ€” response 17โ€“100%; HSCT for severe cases (autologous, HLA-matched sibling, cord blood โ€” lethal risks)
Secondary WAIHA Treating the underlying condition often controls hemolysis
Transfusion For critically low Hb; minimum volume, careful monitoring

2.11 Cold Agglutinin Disease (CAD)

Feature Details
Nonpathologic cold agglutinins Common in healthy people: polyclonal IgM, low titer (<1:64 at 4 ยฐC), no reactivity above 30 ยฐC
Pathologic cold agglutinins Mostly monoclonal, high titer (>1:1000 at 4 ยฐC), react above 30 ยฐC (high thermal amplitude โ†’ more severe)
Nature Recently recognized as a clonal lymphoproliferative B-cell disorder; 15โ€“20% of AIHA
Mechanism IgM binds RBCs in cold peripheral circulation/skin (to ~30 ยฐC) โ†’ activates classical complement โ†’ IgM dissociates on warming but C3b stays โ†’ extravascular removal by hepatic macrophages. High thermal amplitude or regulator deficiency โ†’ full activation, intravascular hemolysis
Acute (secondary) Mycoplasma pneumoniae, infectious mononucleosis, other viruses; polyclonal IgM (normal ฮบ/ฮป); onset 2โ€“3 weeks after infection; resolves in days to weeks; titer usually <1:4000
Chronic Middle-aged/elderly (median onset 67 years); monoclonal IgM with ฮบ light chains; idiopathic or secondary to B-cell lymphoma, Waldenstrรถm, CLL
Clinical Hb 9โ€“12 g/dL usually; can fall <5 g/dL in cold; ~half need transfusion; fatigue, weakness, dyspnea, pallor, acrocyanosis (bluish fingers, toes, earlobes, nose โ€” capillary stasis from autoagglutination); hemoglobinuria after cold exposure

2.12 CAD โ€” Laboratory

Feature Details
DAT Positive with polyspecific AHG due to C3d (monospecific anti-C3d +, anti-IgG โˆ’)
Specificity Most often anti-I; can be anti-i; very rarely anti-Pr. Adult RBCs are I-positive โ†’ anti-I agglutinates all screening/panel/donor and own cells at room temperature; weaker with cord RBCs (I-negative, i-positive)
Titer Determined at 4 ยฐC; pathologic up to 1:10,000โ€“1:1,000,000
Specimen handling Keep the titer specimen at 37 ยฐC after collection (otherwise the antibody binds the patient’s own cells and the titer is falsely low) โ€” or warm an EDTA sample 15 min at 37 ยฐC to release bound antibody
Visible agglutination In the tube at room temperature and on the blood film
CBC interference Warm EDTA sample to 37 ยฐC for 15 min before analysis. Agglutination falsely โ†‘ MCV, falsely โ†“ RBC count, unpredictable other indices (e.g., MCHC โ†‘*). If it persists, recollect and keep at 37 ยฐC until tested; warm slide for film
ABO typing Cold agglutinins can interfere

*Falsely increased MCHC and decreased Hct are the classic pattern from general hematology references; Rodak says ‘unpredictable effects on other indices’.

2.13 CAD โ€” Treatment

Feature Details
Acute CAD Self-limiting; mild โ†’ no treatment; severe โ†’ transfusion, supportive care
Chronic mild Monitor; avoid cold
Chronic moderateโ€“severe Rituximab โ€” partial remission in about half, median <1 year; rituximab + fludarabine 76% response, 66-month remission, but hematologic toxicity in ~half. Rituximab is the best current second-line for CAD and primary AIHA
Plasmapheresis Severe cases; temporary benefit only
Not effective Corticosteroids, cyclophosphamide, chlorambucil and splenectomy โ€” C3b-coated cells are cleared mainly by the liver
Transfusion Only for life-threatening anemia or cardio/cerebrovascular symptoms; rule out alloantibodies; keep patient warm; small amounts; blood warmer

2.14 Paroxysmal Cold Hemoglobinuria (PCH)

Feature Details
Nature Acute cold-reactive AIHA; idiopathic or secondary. Historically with late-stage syphilis; now mostly young children after a viral respiratory infection; rare in adults
Frequency Up to 32โ€“40% of childhood AIHA; median age 5 years
Antibody Donath-Landsteiner antibody: complement-binding IgG hemolysin with anti-P specificity
Biphasic In the cold, binds P antigen and partially activates complement (C1โ€“C4); full activation (C3โ€“C9) and lysis occur only on warming to 37 ยฐC. Cold exposure isn’t actually required clinically (unexplained)
Thermal amplitude <20 ยฐC; titer usually <1:64
Clinical Acute fever, malaise, back/leg/abdominal pain 1โ€“2 weeks after URI; pallor, jaundice, dark urine (hemoglobinuria); Hb often <5 g/dL
Labs Reticulocytosis (may follow reticulocytopenia); polychromasia, spherocytes, also schistocytes, nRBCs, anisocytosis, poikilocytosis, erythrophagocytosis; early leukopenia then leukocytosis; intravascular hemolysis markers
DAT Usually positive for C3d only (anti-P dissociates at body temperature)
Prognosis / therapy Severe but self-limiting (days to weeks), excellent prognosis; transfusion often needed โ€” P-positive blood can be given (P-negative is very rare; antibody reacts only at low temperature)

2.15 Donath-Landsteiner Test

Feature Details
Tubes Two samples: patient test tube and patient control tube
Test tube 4 ยฐC for 30 min (anti-P binds, partial complement activation) โ†’ then 37 ยฐC for 30 min (full activation โ†’ lysis)
Control tube 37 ยฐC for both incubations (60 min total)
Read Centrifuge; examine supernatant for hemolysis
Positive Hemolysis in the test tube (4 ยฐC โ†’ 37 ยฐC), none in the 37 ยฐC control
False negative Low complement and/or anti-P in the sample from brisk in vivo hemolysis
Improved sensitivity Incubate patient serum with added complement and papain-treated group O RBCs (enzyme exposes P antigen)

2.16 Mixed-Type AIHA

Feature Details
Antibodies IgG autoantibody optimal at 37 ยฐC (WAIHA) + pathologic IgM optimal at 0โ€“10 ยฐC with thermal amplitude >30 ยฐC (CAD)
Not mixed-type WAIHA + a nonpathologic cold agglutinin (not reactive >20 ยฐC)
Hemolysis Extravascular + intravascular; chronic course with intermittent severe anemia
DAT IgG, C3d only, or IgG + C3d
Specificity Warm: panreactive, unclear ยท cold: usually anti-I
Treatment Same as WAIHA

2.17 Drug-Induced Immune Hemolytic Anemia (DIIHA)

Feature Details
Frequency Very rare โ€” ~1 per million per year; >125 drugs reported
Suspect when Sudden Hb drop after a drug + evidence of extravascular or intravascular hemolysis + positive DAT
Drug classes Antimicrobials, anti-inflammatories, antineoplastics
Most common (last 10 years) Cefotetan, ceftriaxone, trimethoprim, piperacillin; severe and fatal cases reported
Unifying theory Drug interacts with the membrane โ†’ multiple epitopes โ†’ antibody to drug alone, drugโ€“membrane protein combination, or membrane protein alone
Diagnosis Requires a positive antibody screen and an eluate containing antibody

2.18 DIIHA Mechanisms and Antibody Types

Mechanism Antibody Complement Hemolysis DAT IAT / Eluate Example Drugs
Drug adsorption (hapten) โ€” drug binds strongly to RBC; antibody reacts only with drug-treated cells IgG, drug-dependent Usually no Extravascular (spleen); gradual anemia; can be life-threatening if drug continued IgG +, C3 usually โˆ’ Serum and eluate react only with drug-treated RBCs Penicillin, cyclosporin
Drugโ€“RBC membrane protein immunogenic complex (immune complex) โ€” drug loosely bound IgM and/or IgG, drug-dependent Fully activated Acute intravascular; may cause renal failure; after short exposure or re-administration C3b/C3d +, occasionally IgG Serum reacts with untreated RBCs only in presence of the drug Phenacetin, trimethoprim, quinine, ciprofloxacin
RBC autoantibody induction IgG warm autoantibody, drug-independent โ€” Extravascular (spleen); gradual IgG + Serum and eluate react at 37 ยฐC with all screening/panel RBCs and own RBCs โ€” identical to WAIHA Fludarabine, methyldopa, procainamide
Nonimmunologic protein adsorption (membrane modification) None produced โ€” Hemolysis rare Positive (IgG, complement, other proteins adsorbed) IAT and eluate negative High-dose clavulanate, cisplatin

2.19 DIIHA โ€” Treatment

Feature Details
First step Discontinue the drug; most improve within days to weeks
Autoantibody type Positive DAT may persist for months after hematologic recovery
Severe RBC transfusion or plasma exchange
Prevention Avoid the drug in the future

2.20 Acute Hemolytic Transfusion Reaction (AHTR)

Feature Details
Timing Minutes to hours after starting the transfusion
Most common cause ABO-incompatible RBCs, usually from clerical error (โ‰ˆ1 in 38,000โ€“70,000 RBC transfusions). Example: group A cells into group O recipient
Mechanism Preformed, non-RBC-stimulated anti-A (IgM) fully activates complement to C9 โ†’ rapid intravascular hemolysis + coagulation activation
Severity Depends on rate and volume; mortality ~2%. Other blood groups rarely involved
Symptoms Chills, fever, urticaria, tachycardia, nausea/vomiting, chest and back pain, shock, anaphylaxis, pulmonary edema, heart failure, bleeding from DIC
Action Stop the transfusion immediately; treat shock, maintain renal circulation, control DIC
Lab investigation Clerical check ยท post-transfusion specimen examined for hemolysis ยท DAT (positive; may be negative if all donor cells lysed) ยท hemoglobinemia, hemoglobinuria ยท โ†“ Hb and haptoglobin ยท indirect bilirubin rises only after 2โ€“3 days ยท repeat ABO/Rh, antibody screen, crossmatch on recipient and donor ยท D-dimer, fibrinogen, factors V and VIII, platelets for DIC

2.21 Delayed Hemolytic Transfusion Reaction (DHTR)

Feature Details
Timing Days to weeks after transfusion
Mechanism Patient previously alloimmunized (pregnancy or transfusion) with titer below detection โ†’ re-exposure โ†’ anamnestic response โ†‘ titer
Antibody Usually IgG, reactive at 37 ยฐC; may partially or fully activate complement. Most often Duffy and Kidd antigens
Hemolysis Extravascular, with or without complement
Signs Inadequate post-transfusion Hb increase ยท positive DAT (IgG and/or C3d) ยท morphologic evidence of hemolysis ยท โ†‘ indirect bilirubin
Management Monitor kidney function, especially in acutely ill patients

2.22 Hemolytic Disease of the Fetus and Newborn (HDFN)

Feature Details
Mechanism Maternal IgG alloantibody crosses the placenta โ†’ binds antigen-positive fetal RBCs โ†’ removal by macrophages in the fetal spleen (extravascular) โ†’ gradual anemia
Fetal response Marrow erythroid hyperplasia; extramedullary erythropoiesis (spleen, liver, kidneys, adrenals); many nRBCs released
Severe Hydrops fetalis (generalized edema, ascites) โ€” fatal if untreated
Anti-Kell Also suppresses fetal erythropoiesis
Rh HDFN Most fetal fatalities. D-negative mother with preformed anti-D (IgG, 37 ยฐC) from prior D-positive pregnancy or transfusion; anti-D coats D-positive fetal cells โ†’ anemia, hyperbilirubinemia
Fetal assessment Amniocentesis (accurate, invasive, risk of fetal loss); percutaneous umbilical blood sampling for Hb; noninvasive ultrasound of fetal cerebral blood flow

2.23 HDFN โ€” Prenatal Testing & Prevention

Feature Details
Maternal testing ABO, Rh, antibody screen at 10โ€“16 weeks and again at 28 weeks
Positive screen RBC panel for specificity; retest monthly until 28 weeks, then every 2 weeks; titers reported
Titer role Does not predict severity; guides when to add monitoring (e.g., amniotic fluid bilirubin). After the first affected pregnancy, titer no longer useful
RhIG Unimmunized D-negative mother receives Rh immune globulin at 28 weeks and within 72 hours after delivery of a D-positive infant. One 200 ยตg antenatal dose halves the risk of anti-D. Also after spontaneous or induced abortion

2.24 HDFN โ€” Newborn Testing & Treatment

Feature Details
Cord blood Rh HDFN: โ†“ Hb, โ†‘ retics, โ†‘ indirect bilirubin; film: polychromasia, many nRBCs. ABO (forward typing only), Rh, DAT. Rh: DAT positive for IgG; anti-D in eluate
Intrauterine Intrauterine transfusion (into fetal abdomen via amniocentesis) or cordocentesis (umbilical vein); survival 85โ€“90%; death risk 1โ€“3%
After delivery Exchange transfusion and phototherapy to lower indirect bilirubin and prevent kernicterus
Prolonged anemia Slow decline of maternal antibody; rare after intrauterine transfusions

2.25 Rh vs ABO HDFN (Rodak Table 26-3 + text)

Feature Rh HDFN ABO HDFN
Mother / child Rh (D)-negative / Rh (D)-positive Group O / group A or B
Frequency Less common (RhIG prophylaxis) More common
First pregnancy Usually not (needs prior sensitization) Can occur (preformed IgG anti-A,B)
Severity Severe Mild / asymptomatic
Jaundice Severe Mild
Anemia Severe If present, mild
Spherocytes Rare Usually present
DAT Positive (IgG) Negative or weakly positive
Why ABO is milder โ€” A and B antigens poorly developed on fetal RBCs; other cells and tissues express A/B and absorb antibody
Other antibodies Anti-K, anti-c, anti-Fyแตƒ (other IgG antibodies) โ€” rare; first-trimester screening helps

3 ยท Visual Memory Hooks

๐Ÿง  IgG vs IgM site
โ€œG goes to the Spleen (Globes โ†’ spherocytes); M goes to the liver (coMplement)โ€.
๐Ÿง  Complement power
โ€œOne M, two Gsโ€ โ€” one IgM activates C1q; at least two adjacent IgG needed.
๐Ÿง  C3d
โ€œC3d = Dead endโ€ โ€” macrophages have no C3d receptor; the AHG detects it.
๐Ÿง  DAT vs IAT
โ€œDirect = on the cells (in vivo); Indirect = In serum (in vitro, 37 ยฐC)โ€.
๐Ÿง  Warm AIHA
โ€œWarm = G, 37, Spheres, Spleen, Steroids, Splenectomyโ€.
๐Ÿง  CAD
โ€œCold = M, I, Complement, Clumps, C3d, liver โ€” no Steroids, no Spleenโ€.
๐Ÿง  CAD specificity
โ€œAdults are I, Infants are iโ€ โ€” anti-I reacts weakly with cord cells.
๐Ÿง  CAD causes
โ€œMycoplasma โ†’ anti-I; Mono (EBV) โ†’ anti-i*โ€; chronic = B-cell clone, ฮบ.
๐Ÿง  PCH
โ€œDonath-Landsteiner: Double temperature, P antigen, Pediatric, Post-viralโ€.
๐Ÿง  D-L test
โ€œCold to Catch, Warm to Wreckโ€ โ€” 4 ยฐC binds, 37 ยฐC lyses.
๐Ÿง  DIIHA mechanisms
โ€œPenicillin Pastes (adsorption, IgG, extravascular); Quinine Quickly Kills (immune complex, complement, intravascular); Methyldopa Mimics (autoantibody = WAIHA)โ€.
๐Ÿง  Drug-dependent vs independent
โ€œDependent needs the Drug in the tube; Independent looks just like WAIHAโ€.
๐Ÿง  AHTR vs DHTR
โ€œAcute = ABO, IgM, Intravascular, Minutes; Delayed = Duffy/Kidd, IgG, extravascular, Days (anamnestic)โ€.
๐Ÿง  Kidd
โ€œKidd Kicks back laterโ€ โ€” classic DHTR antibody.
๐Ÿง  HDFN
โ€œRh = Rough (severe, DAT +, no spheres); ABO = All right (mild, spheres, DAT weak)โ€.
๐Ÿง  RhIG
โ€œ28 and 72โ€ โ€” 28 weeks antenatal, within 72 hours postpartum.
๐Ÿง  Anti-Kell
โ€œKell Kills productionโ€ โ€” suppresses fetal erythropoiesis.

*Infectious mononucleosis with anti-i is a general blood bank association; Rodak lists infectious mononucleosis as a cause of acute CAD without naming its specificity.

Pattern Triggers

If you seeโ€ฆ Thinkโ€ฆ Becauseโ€ฆ
Spherocytes, polychromasia, DAT + IgG, panreactive eluate Warm AIHA IgG extravascular splenic removal
Spherocytes, DAT negative, family history, โ†‘ MCHC Hereditary spherocytosis Not immune
Agglutination on film, MCV 130, RBC count falsely low, corrects at 37 ยฐC Cold agglutinin interference IgM clumps counted as single large cells
Acrocyanosis in cold, DAT + C3d only, anti-I, elderly, IgM ฮบ Chronic CAD Monoclonal B-cell clone
Hemolysis 2โ€“3 weeks after atypical pneumonia, anti-I Acute CAD (M. pneumoniae) Polyclonal IgM
Child, dark urine 1โ€“2 weeks after URI, DAT C3d only, Hb <5 PCH Biphasic IgG anti-P
WAIHA + low platelets in a child Evans syndrome Autoimmune to RBCs and platelets
WAIHA + massive splenomegaly + lymphadenopathy in adult Secondary WAIHA โ€” lymphoproliferative (CLL) B-cell dysregulation
Hemolysis on high-dose IV penicillin, DAT IgG, eluate reacts only with penicillin-coated cells Drug adsorption mechanism Drug-dependent IgG
Abrupt intravascular hemolysis, renal failure after quinine; DAT C3 Immune complex mechanism Complement fully activated
Gradual hemolysis on fludarabine/methyldopa, DAT IgG, eluate reacts with all cells Autoantibody induction Drug-independent, WAIHA-like
Positive DAT, no hemolysis, IAT and eluate negative, clavulanate/cisplatin Nonimmunologic protein adsorption No antibody produced
Fever, back pain, red urine minutes into transfusion Acute HTR (ABO) IgM anti-A/B, intravascular
Hb drops 7โ€“10 days after transfusion, DAT IgG, new anti-Jkแตƒ Delayed HTR Anamnestic response
Group O mother, A baby, mild jaundice, spherocytes, weak DAT ABO HDFN IgG anti-A,B
D-negative mother, D-positive baby, severe anemia, many nRBCs, DAT + IgG Rh HDFN Anti-D

Commonly Confused Pairs

Feature A B
DAT vs IAT Antibody on patient RBCs; no incubation Antibody in serum; 37 ยฐC incubation
Polyspecific vs monospecific AHG Anti-IgG + anti-C3b/C3d Anti-IgG or anti-C3b/C3d alone
WAIHA vs CAD IgG, 37 ยฐC, spleen, steroids work IgM, 4 ยฐC, liver, steroids/splenectomy don’t
CAD vs PCH IgM anti-I, extravascular, adults IgG anti-P biphasic, intravascular, children
Nonpathologic vs pathologic cold agglutinin Polyclonal, <1:64, not >30 ยฐC Monoclonal, >1:1000, reacts >30 ยฐC
Acute vs chronic CAD Polyclonal, post-infection, self-limited Monoclonal IgM ฮบ, elderly, lymphoproliferative
Anti-I vs anti-i Reacts weakly with cord cells Reacts strongly with cord cells*
Drug adsorption vs immune complex IgG, extravascular, penicillin, DAT IgG IgM/IgG, complement, intravascular, quinine, DAT C3
Drug-dependent vs drug-independent Needs drug in vitro Reacts without drug (WAIHA-like)
AHTR vs DHTR ABO, IgM, intravascular, minutesโ€“hours Duffy/Kidd, IgG, extravascular, daysโ€“weeks
Rh vs ABO HDFN Severe, DAT +, rare spherocytes Mild, DAT weak/โˆ’, spherocytes, first pregnancy
Mixed-type AIHA vs WAIHA + benign cold agglutinin Cold IgM reacts >30 ยฐC Cold agglutinin not reactive >20 ยฐC

*Anti-i reactivity with cord cells follows from Rodak’s statement that cord cells are i-positive.

Timeline Table

Event Onset Peak / Key Point Duration Best Exam Use
AHTR Minutes to hours Intravascular hemolysis, DIC โ€” Stop transfusion immediately
Indirect bilirubin after AHTR 2โ€“3 days โ€” โ€” Not an early marker
DHTR Days to weeks Anamnestic โ†‘ titer โ€” Duffy/Kidd antibodies
Acute CAD 2โ€“3 weeks after infection โ€” Resolves in days to weeks Mycoplasma/EBV
PCH 1โ€“2 weeks after URI Hb <5 g/dL Days to weeks, self-limited Child with hemoglobinuria
DIIHA recovery After stopping drug Improvement in daysโ€“weeks DAT + for months (autoantibody type) Positive DAT persistence
RhIG 28 weeks; โ‰ค72 h postpartum โ€” โ€” Prevention timing
Antenatal antibody screen 10โ€“16 weeks and 28 weeks Monthly to 28 wk, then every 2 wk if positive โ€” Monitoring schedule
Case study WAIHA Prednisone 1 mg/kg/d Hb 10 at 2 weeks Taper over 4 months; DAT โˆ’ at 3 weeks Response to steroids

4 ยท Diagnostic Flowcharts

Flowchart 1 โ€” Is the hemolysis immune? (DAT workup)

Hemolytic anemia confirmed โ†’ Polyspecific DAT on washed RBCs
Positive โ†’ Monospecific anti-IgG and anti-C3b/C3d
IgG ยฑ C3d โ†’ Warm AIHA, DHTR, HDFN, drug (adsorption or autoantibody) โ†’ elution + panel
C3d only โ†’ CAD, PCH, drug immune complex โ†’ cold agglutinin titer, D-L test, drug history
Negative but strong suspicion โ†’ DAT-negative AIHA (IgA, low-level IgG, low avidity) or nonimmune cause
โš ๏ธ Common mistake: concluding ‘not immune’ from a negative DAT โ€” 1โ€“4% of WAIHA are DAT-negative. Also, a positive DAT alone doesn’t prove immune hemolysis.

Flowchart 2 โ€” Classifying autoimmune hemolysis

DAT IgG (ยฑ C3d), panreactive eluate, spherocytes โ†’ Warm AIHA โ†’ look for secondary cause (CLL, SLE, drugs)
DAT C3d only, agglutination, high-titer anti-I at 4 ยฐC โ†’ Cold agglutinin disease
DAT C3d only, child after viral illness, hemoglobinuria โ†’ PCH โ†’ Donath-Landsteiner test
DAT IgG + C3d, warm IgG + cold IgM reactive >30 ยฐC โ†’ Mixed-type AIHA
Recent new drug โ†’ Consider DIIHA โ†’ drug-dependent vs drug-independent testing
โš ๏ธ Common mistake: labeling every DAT C3d-only case as CAD โ€” PCH and drug immune-complex reactions also give C3d only.

Flowchart 3 โ€” Handling a suspected cold agglutinin sample

Agglutinates in tube/film; โ†‘ MCV, โ†“ RBC, odd indices โ†’ Warm EDTA tube at 37 ยฐC for 15 min, rerun CBC
Corrects โ†’ Report warmed results
Still agglutinated โ†’ Recollect; keep at 37 ยฐC until testing; warm slide for film
Titer specimen โ†’ Keep clotted sample at 37 ยฐC (or warm EDTA 15 min) before separating serum
Blood bank โ†’ Watch for ABO typing interference
โš ๏ธ Common mistake: running the cold sample and reporting a falsely high MCV and falsely low RBC count.

Flowchart 4 โ€” Donath-Landsteiner test

Two tubes of patient blood โ†’ Test and control
Test tube โ†’ 4 ยฐC 30 min โ†’ 37 ยฐC 30 min
Control tube โ†’ 37 ยฐC for 60 min
Centrifuge and inspect โ†’ Hemolysis in test only โ†’ positive (anti-P)
Negative despite strong suspicion โ†’ Add complement + papain-treated group O RBCs
โš ๏ธ Common mistake: reading hemolysis in both tubes as positive โ€” the control must stay unhemolyzed.

Flowchart 5 โ€” Suspected drug-induced immune hemolysis

New drug + hemolysis + positive DAT โ†’ Antibody screen and eluate
DAT IgG; eluate reacts only with drug-coated RBCs โ†’ Drug adsorption (penicillin)
DAT C3; serum reacts only with drug present; intravascular โ†’ Immune complex (quinine, trimethoprim)
DAT IgG; eluate reacts with all cells without drug โ†’ Autoantibody induction (methyldopa, fludarabine)
DAT +; IAT and eluate negative; no hemolysis โ†’ Nonimmunologic protein adsorption (clavulanate, cisplatin)
โš ๏ธ Common mistake: missing autoantibody induction because it looks exactly like WAIHA โ€” always take a drug history.

Flowchart 6 โ€” Suspected transfusion reaction

Symptoms during transfusion โ†’ Stop the transfusion
Clerical check โ†’ Patient ID, labels, records
Post-transfusion sample โ†’ Visual hemolysis, DAT, repeat ABO/Rh, antibody screen, crossmatch
Minutesโ€“hours, hemoglobinemia, DAT + โ†’ AHTR (ABO) โ†’ monitor DIC (D-dimer, fibrinogen, factors V/VIII, platelets), renal
Daysโ€“weeks, poor Hb increment, DAT IgG, new alloantibody โ†’ DHTR (Duffy/Kidd)
โš ๏ธ Common mistake: trusting a negative DAT in AHTR โ€” all donor cells may already be lysed.

Flowchart 7 โ€” HDFN prevention and workup

First prenatal visit (10โ€“16 wk) โ†’ ABO, Rh, antibody screen
D-negative, screen negative โ†’ RhIG at 28 weeks + within 72 h of delivering a D-positive baby
Screen positive โ†’ Identify antibody; titers monthly โ†’ every 2 weeks after 28 weeks; ultrasound/amniocentesis
Severe fetal anemia โ†’ Intrauterine transfusion / cordocentesis
At birth โ†’ Cord ABO (forward), Rh, DAT, Hb, bilirubin โ†’ phototherapy/exchange
โš ๏ธ Common mistake: using the antibody titer to predict severity โ€” it only tells you when to start further monitoring.

5 ยท 25 High-Yield Facts

# Fact
1 Immune hemolytic anemia is caused by an allo- or autoantibody against an RBC antigen (or a drug).
2 IgM-mediated hemolysis always requires complement.
3 C1q must bind two adjacent Fc domains; one IgM or at least two adjacent IgG molecules are needed.
4 IgG1 and IgG3 bind complement well; IgG2 and IgG4 bind it poorly.
5 C3b-coated RBCs are removed mainly by liver macrophages; macrophages lack a C3d receptor.
6 IgG-sensitized RBCs are removed mainly in the spleen; partial phagocytosis creates spherocytes.
7 The DAT detects in vivo sensitization of RBCs by IgG, C3b or C3d.
8 The IAT detects antibody in serum after a 37 ยฐC incubation.
9 Warm AIHA is the most common AIHA (up to 70%); the autoantibody is IgG, optimal at 37 ยฐC.
10 In WAIHA the DAT is positive in about 95%; 1โ€“4% are DAT-negative.
11 WAIHA autoantibodies are usually panreactive and can mask alloantibodies.
12 Evans syndrome is WAIHA plus immune thrombocytopenic purpura, mainly in children.
13 Prednisone is first-line therapy for WAIHA; splenectomy helps 50โ€“70% of refractory cases.
14 Cold agglutinin disease is caused by IgM, usually anti-I, optimal at 4 ยฐC with thermal amplitude above 30 ยฐC.
15 The DAT in CAD and PCH is positive for C3d only.
16 Chronic CAD is a clonal B-cell disorder with monoclonal IgM ฮบ, mostly in the elderly.
17 Acute CAD follows Mycoplasma pneumoniae or infectious mononucleosis and is self-limited.
18 Cold agglutinin samples must be warmed to 37 ยฐC for 15 minutes before CBC analysis.
19 Steroids and splenectomy are not effective in CAD; rituximab is the best second-line option.
20 PCH is caused by the biphasic IgG anti-P Donath-Landsteiner antibody, usually in children after a viral infection.
21 Penicillin causes drug adsorption: IgG, extravascular hemolysis, DAT positive for IgG.
22 Quinine-type immune complex reactions cause acute intravascular hemolysis with a C3-positive DAT.
23 Methyldopa and fludarabine induce drug-independent autoantibodies that mimic WAIHA.
24 Acute HTR is usually ABO incompatibility from clerical error; delayed HTR is an anamnestic IgG response (Duffy, Kidd).
25 ABO HDFN is more common and milder than Rh HDFN; RhIG is given at 28 weeks and within 72 hours of delivery.
โญ EXAM TIP โ€” The single most testable pattern

DAT IgG + spherocytes + 37 ยฐC panreactive = WAIHA (steroids, spleen). DAT C3d only + agglutination + anti-I = CAD (warm the sample; no steroids or splenectomy). DAT C3d only + child + hemoglobinuria = PCH (Donath-Landsteiner, anti-P). For drugs: penicillin = adsorption/IgG, quinine = immune complex/C3/intravascular, methyldopa/fludarabine = autoantibody.

Quick Interpretation Table

Lab Finding Clinical Interpretation
Hb 7.1, MCV 105.4, retics 18.1%, spherocytes, nRBCs, DAT 3+ IgG, C3 negative, eluate panreactive Warm AIHA (Rodak case study) โ€” MCV โ†‘ from retics
DAT: polyspecific +, anti-IgG โˆ’, anti-C3d +; cold agglutinin titer 1:64,000 Cold agglutinin disease
D-L test: hemolysis in 4โ†’37 ยฐC tube, none in 37 ยฐC control PCH (anti-P)
63-year-old on fludarabine for CLL, DAT IgG only, eluate reacts with all panel cells and own cells Drug-induced autoantibody (RBC autoantibody induction) (Rodak Q10)
DAT +, antibody screen โˆ’, eluate โˆ’, patient on cisplatin, no hemolysis Nonimmunologic protein adsorption
Hb didn’t rise 7 days post-transfusion; DAT IgG; anti-Jkแตƒ found Delayed hemolytic transfusion reaction
Group O mother, group A baby, bilirubin mildly โ†‘, DAT weakly +, spherocytes ABO HDFN
MCV 132 fL, RBC 1.8 ร— 10ยนยฒ/L, MCHC 44 g/dL; normal after warming Cold agglutinin artifact

๐ŸŽด Flashcards โ€” Active Recall Practice

How it works: tap the card to flip it. Then mark it โœ“ Knew It or โœ— Review Again (buttons unlock after flipping). Use ๐Ÿ”€ Shuffle to randomize and ๐Ÿ Finish anytime โ€” your summary appears at the end, and you can drill only the cards you missed.

๐Ÿ“ Practice Quiz โ€” Test Your Knowledge

How it works: tap an answer for each case. You’ll get instant feedback with the full explanation and the examiner’s trap. Your final score appears once all 10 are answered.

๐Ÿชค Trap Questions โ€” Beat the Examiner

Harder on purpose. Each question targets a real misconception. After answering you’ll see the correct reasoning, the trap explained, why the examiner wrote it, and the wrong answer most students choose.

8 ยท Rapid Revision Sheet

๐Ÿ“– READ THIS 2 HOURS BEFORE YOUR EXAM

IgG vs IgM

  • IgG monomer ยท IgM pentamer
  • C1q needs 2 adjacent Fc: 1 IgM vs โ‰ฅ2 IgG
  • IgG1, IgG3 fix complement
  • IgG โ†’ spleen โ†’ spherocytes
  • IgM โ†’ C3b โ†’ liver; heavy โ†’ intravascular

Complement & DAT

  • C1qrs โ†’ C4bC2a โ†’ C3b โ†’ C3d
  • C5b-9 = MAC โ†’ lysis
  • No C3d receptor on macrophages
  • DAT: washed cells + polyspecific AHG, no incubation
  • IAT: serum + cells 37 ยฐC โ†’ AHG

Warm AIHA

  • Up to 70% ยท IgG ยท 37 ยฐC
  • DAT + 95% (IgG ยฑ C3d); 1โ€“4% negative
  • Panreactive; masks alloantibodies
  • Spherocytes ยท Evans syndrome (+ ITP)
  • Prednisone โ†’ splenectomy โ†’ rituximab

Cold Agglutinin Disease

  • IgM ยท 4 ยฐC ยท thermal amplitude >30 ยฐC
  • Anti-I (cord cells weak) ยท DAT C3d
  • Acute: Mycoplasma, EBV (polyclonal)
  • Chronic: IgM ฮบ clone, elderly, B-cell
  • Warm 37 ยฐC ร— 15 min ยท no steroids/spleen

PCH

  • IgG anti-P ยท biphasic D-L antibody
  • Children after viral URI (old: syphilis)
  • Intravascular ยท DAT C3d
  • D-L: 4 ยฐC โ†’ 37 ยฐC vs 37 ยฐC control
  • Self-limited ยท P+ blood OK

Mixed & DIIHA

  • Mixed: warm IgG + cold IgM >30 ยฐC
  • DIIHA ~1/million; cefotetan, ceftriaxone
  • Adsorption: penicillin, IgG, extravascular
  • Immune complex: quinine, C3, intravascular
  • Autoantibody: methyldopa, fludarabine

DIIHA Lab

  • Drug-dependent: needs drug in vitro
  • Drug-independent: like WAIHA
  • Nonimmune adsorption: clavulanate, cisplatin
  • Stop drug ยท DAT may stay + months
  • Diagnosis: screen + eluate positive

Transfusion Reactions

  • AHTR: ABO, IgM, minutes, intravascular, DIC
  • 1/38,000โ€“70,000 ยท mortality 2%
  • Stop ยท clerical check ยท DAT ยท repeat typing
  • DHTR: daysโ€“weeks, anamnestic, IgG
  • Duffy/Kidd ยท poor Hb increment

HDFN Basics

  • Maternal IgG crosses placenta
  • Fetal spleen removal ยท nRBCs ยท hydrops
  • Anti-Kell suppresses erythropoiesis
  • Screen 10โ€“16 wk + 28 wk
  • Titer doesn’t predict severity

Rh vs ABO HDFN

  • RhIG 28 wk + โ‰ค72 h postpartum
  • Rh: severe, DAT + IgG, rare spherocytes
  • ABO: O mom, A/B baby, 1st pregnancy
  • ABO: mild, spherocytes, DAT weak/โˆ’
  • Treat: IUT, exchange, phototherapy

9 ยท Final Memory Map

  • ๐Ÿ›ก๏ธ IMMUNE HEMOLYTIC ANEMIAS
    • Mechanisms
      • IgG: spleen, spherocytes, complement only at high density
      • IgM: complement always; C3b liver or C1โ€“C9 intravascular
      • DAT (in vivo) ยท IAT (in vitro) ยท elution
    • Warm AIHA
      • IgG, 37 ยฐC, panreactive
      • Idiopathic or secondary (CLL, SLE, tumors, viruses)
      • Steroids โ†’ splenectomy โ†’ rituximab
    • Cold Agglutinin Disease
      • IgM anti-I, 4 ยฐC, C3d
      • Acute (Mycoplasma, EBV) vs chronic (B-cell clone)
      • Warm specimens ยท rituximab ยท avoid cold
    • PCH
      • Biphasic IgG anti-P
      • Children post-viral ยท D-L test
    • Mixed-Type
      • Warm IgG + pathologic cold IgM
      • Treat like WAIHA
    • Drug-Induced
      • Adsorption (penicillin)
      • Immune complex (quinine)
      • Autoantibody (methyldopa, fludarabine)
      • Nonimmune adsorption (clavulanate, cisplatin)
    • Alloimmune
      • AHTR โ€” ABO, IgM, intravascular
      • DHTR โ€” anamnestic IgG, Duffy/Kidd
      • HDFN โ€” Rh (severe) vs ABO (mild); RhIG



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