Benign Hematology

BIOLOGY OF HEMATOPOIESIS

Anita Kumar

Definition of Hematopoiesis: The formation of blood cells

Sites of Hematopoiesis

Bone marrow (BM) is the principal site of hematopoiesis in adults, predominantly in pelvis, vertebrae, ribs, sternum, & skull
During fetal development, sites include yolk sac → liver → spleen → BM

Stem Cell Niche

In the BM, hematopoietic stem cells (HSCs) develop in a complex microenvironment of stromal cells (fibroblasts, smooth muscle cells, endothelial cells, adipocytes, osteoblasts, osteoclast, & MΦ) & extracellular matrix
Unique sites w/in the marrow, termed niches, favor HSC self-renewal vs. differentiation

Bone Marrow Morphology

BM comprises hematopoietic tissue islands & adipose cells surrounded by vascular sinuses
In nl adults, the ratio of fat cells to hematopoietic elements is 1:1
Thin-walled sinusoids are lined by endothelial cells, & differentiated blood cells enter the circulation by transcellular migration through endothelial cells

Hierarchical Map of Hematopoietic Development

HSCs: 2 cardinal features (1) pluripotency (can give rise to all mature blood cell types) & (2) self-renewal capacity
HSCs give rise to all formed elements of blood – RBCs, granulocytes, monocytes, plt, & lymphocytes
HSCs give rise to two kinds of multipotent cells, the common lymphocyte progenitors (CLPs) & common myeloid progenitors (CMPs)
CMPs give rise to committed progenitors called colony forming units (CFUs) that develop into specific mature cells

Figure 28-1 Cantor, A. B. et al. ASH-SAP 2010;2010:331-372.
CLP = common lymphoid progenitor, CFU = colony forming unit, CMP = common myeloid progenitor, GMP = granulocyte-MΦ progenitor, LT-HSC = long-term repopulating hematopoietic stem cell, MEP = megakaryocyte-erythroid progenitor, MPP = multipotential progenitor cell, NK = natural killer, ST-HSC = short-term repopulating hematopoietic stem cell

Regulation of Blood Cell Differentiation and Production

Various factors modulate BM response to physiologic needs & production of mature blood cells
Cytokines (IL-1, IL-2, IL-3, IL-5, IL-6, & IL-7) & chemokines
Hematopoietic growth factors: Epo, GM-CSF, G-CSF, & Tpo act on myeloid progenitors

Bone Marrow Examination:

Sites: Preferred site is the posterior iliac spine. Alternate sites include anterior iliac crest or sternum.
BM aspiration: Advance needle through cortex into medullary space. Aspirate marrow using syringe & spread on glass slides. Additional cell suspensions used for cytogenetics (karyotype & FISH), flow cytometry, & molecular studies (eg, FLT-3 or JAK-2 Mt). Use aspirate to assess morphology of hematopoietic cells.
BM bx: Use longer needle (such as Jamshidi needle) to cut a cylinder of bone from the medullary space. W/bx, assess BM architecture, cellularity, iron stores, cell lineage.
Risks: Hemorrhage, infxn

Interpretation of Aspirate and Biopsy:

Cellularity: 100 – pt age = nl % cellularity.
Myeloid: Erythroid ratio: Nl range 1.2:1-5:1 → assess on bx or aspirate. >5:1 ratio – physiologic stress (infxn), <1.2:1 ratio – erythroid response to anemia (hemolysis).
Megakaryocytes: Assess number & appearance. Nl cells are large, multilobulated, irregularly lobed nuclei.
Myeloid maturation (see below), erythroid maturation (see below). Excess blasts or differentiation arrest suggestive of leukemia
Dysplasia: Nuclear & cytoplasmic blebs & dysmorphic nuclei.
- Erythroid dysplasia: Multinucleated erythroid precursors, nuclear-cytoplasmic dyssynchrony, RS
- Myeloid dysplasia: Hypersegmented neutrophils, hyposegmented neutrophils (Pseudo-Pelger-Huet), hypogranular neutrophils, Auer rods, dimorphic granules (basophilic & eosinophilic granules in eosinophils)
- Megakaryocyte dysplasia: Hyper-/hypolobulated megakaryocytes, micromega-karyocytes (smaller in size)
Lymphocytes & plasma cells: Benign lymphoid population, more T cells than B cells. Abnl, such as a monotonous B-cell lymphocyte population, is suggestive of lymphoma. Plasma cells <2% of BM cells in nl adult, ↑ % in plasma cell dyscrasia
Iron stores: Can be ↑ (hemochromatosis) or ↓ (IDA)
Other cells: Marrow infiltration by tumor or fibrosis (“myelophthisis”)

Hematology Maturation

Erythroid maturation: The nucleus becomes progressively smaller and nuclear chromatin more condensed. The cytoplasm gradually loses the bluish color from RNA, w/c is replaced by the pink-staining Hb.
- Stages of maturation:
- Proerythroblast, basophilic erythroblast, polychromatophilic erythroblast, orthochromatic erythroblast (normoblast), polychromatic erythrocyte (reticulocyte), erythrocyte
Myeloid maturation: Granulocytes are the precursors & mature forms of leukocytes w/neutrophilic, eosinophilic, or basophilic granules in their cytoplasm in mature forms
- Stages of maturation:
- Myeloblast, promyelocyte, myelocyte, metamyelocyte, band cell, mature cell (basophil, neutrophil, eosinophil)

ANEMIAS OF UNDERPRODUCTION

Patrick W. Burke

Definition (ASH-SAP 2010;1:109)

↓ RBC mass. Hb < 13 g/dL (men), < 12 g/dL (nonpregnant women), < 11 g/dL (pregnant women) w/RI < 2 or absolute retic inapprop for anemia degree.

Microcytic (MCV < 80 fL); Normocytic (MCV 80-100 fL); Macrocytic (MCV > 100 fL).

Mechanism	Egs
Nutritional Deficiency	↓ Fe, ↓ Folate, ↓ Cu, ↓ Vit B12, ↓ A, ↓ B₆ & ↓ E; ↑ Zn (↓ Cu)
Functional Nutritional Deficiency	Anemia of chronic inflammation; Drugs (Megaloblastoid Δs/Macrocytosis)
Sideroblastic Anemia	Congenital; Acquired (MDS, Pb Toxicity, Drugs, ↓ Cu)
Hemoglobinopathy (Ineffective Erythropoiesis)	α Thalassemia; β Thalassemia (see Hemoglobinopathy Chapter)
Endocrinopathy	↓ Thyroid, ↓ Androgens, & ↓ Cortisol; ↑ PTH
EPO Deficiency/Resistance	CKD, ESRD, EPO AutoAbs, EPO/ESA Resistance & ↓↓↓ Protein
Infxn → ± Pure red cell aplasia/Aplastic anemia	Parvovirus, HIV, CMV, EBV, HHV-6, HBV, HCV, & Sepsis
Drugs → ± Pure red cell aplasia/Aplastic anemia	Chloramphenicol, Phenytoin/Antiepileptics, Gold Salts, INH, Rifampin, EPO (AutoAb), Lindane, SMX-TMP, Cytotoxic Chemotherapy, & Sulfasalazine
IgG AutoAb Against Erythroblasts → Pure red cell aplasia	Transient Erythroblastopenia
BM Infiltration/Myelophthisic Anemia	Met Solid Tumor, Myeloid/Lymphoid Neoplasm, MF, Hemophagocytic Lymphohistiocytosis, Osteopetrosis & Gaucher Disease
Immune-mediated Pure red cell aplasia/Aplastic anemia	Idiopathic, Thymoma, LPD, Rheumatologic/Autoimmune Disease, ABO-mismatched Allo-HSCT
1° BM Failure/Disorder	PNH, Diamond-Blackfan Anemia, Dyskeratosis Congenita, Fanconi Anemia, Shwachman-Diamond Syndrome & Amegakaryocytic Thrombocytopenia
Toxins	EtOH; Benzene
Enzymopathy	Hereditary Orotic Aciduria; Lesch-Nyhan Syndrome

Fe Deficiency Anemia (ASH-SAP 2010;1:109)

Commonest anemia worldwide. ↑ Developing world. 7% U.S. women aged 12-49 y.

Developed world: Premenopausal women: Menstrual blood loss. Adult Men: GIB.

Infancy: Dietary def (↑↑ cow milk intake/breast milk intake w/o Fe supplementation). Children: Diet def. Developing World: GIB (parasitic infxn).

Blood Loss. ↑ Phlebotomy. HD. Intravascular hemolysis w/hemoglobinuria.

Rapid infancy growth. Pregnancy/lactation (↑Fe demand). Nutritional def. Malabsorption: Celiac disease, gastric bypass, H. pylori, achlorhydria (↑ w/age), gastric/duodenal infiltration or resection. AbNl transferrin function.

S/s: General anemia sxs. Pica (uncommon), stomatitis, glossitis, koilonychia, esophageal webs: Plummer-Vinson Syndrome (rarer).
Peripheral Blood Smear: Normocytic RBC (early) or microcytic RBC (later).
- Hypochromia, anisopoikilocytosis, ↑ RDW. Cigar/pencil-shaped RBC. ± reactive thrombocytosis (↑EPO cross-reacts w/TPO receptor).
Lab W/u: ↓↓ Ferritin (< 15 µg/L diagnostic; >100 µg/L unlikely).High nl to ↑ TIBC. ↓↓ Fe sat (<10%). Nl MCV (early) → ↓ to ↓↓ MCV (adv). ↑ RDW. Experimental: ↓ Hepcidin. ↑ Soluble transferrin receptor. Anemia/Fe parameters improve w/Fe administ.
Tx: Uncomplicated/Mild Fe Deficiency: PO Fe. Ferrous salts ↑ solubility & absorption but ↑ GI tox. Ascorbic acid → ↑ absorption. ↓ Absorption w/antacids, full meals, whole grains, tannins & Ca supplements. Fe sulfate = 66 mg elemental Fe per 325-mg tab.
- Complicated Fe Deficiency: Parenteral Fe in true ↓ absorption, gastric or duodenal resection, ↑ Fe deficit, PO Fe intolerance & chronic bleeding.
- Fe Dextran: ↓↓cost. Can replete Fe in one infusion. ↑ Risk anaphylaxis (11.3/1000000) → small test dose. Fe Sucrose & Fe Gluconate: ↓↓↓ Rate anaphylaxis → no test dose. A/w arthralgias/myalgias. ↑↑ cost.
- Response: ↑ Retics after 4-7 d & ↑ Hb starts 1-2 wks post-tx. Anemia responds over wks (cont tx to replete Fe store). Ferritin ˜ Fe store.

Anemia of Chronic Inflammation (AOCI) (N Engl J Med 2005;352:1011)

Hypoproliferative anemia (functional Fe def) a/w chronic inflammation: CTD, other autoimmune disorders, chronic infxn, & malignancy.
Also in post-trauma/-surgery & critical illness. Commonest anemia in hospital.
Mild/mod. (Hb rarely <7 g/dL) anemia. Sometimes ↑ ESR/CRP.
Pathogenesis: ↑ Cytokines (TNFα, IL-1, IL-6, IFNs) →↓ response to EPO in RBC precursor, ↓ EPO c/w anemia degree, & mod. ↓ RBC survival.
- Altered Fe metabolism (Blood 2003;102:783): ↑ IL-6 →↑ hepcidin →↓ intestinal Fe absorption/↓ Fe release from enterocytes →↓ plasma Fe/Fe def.
Dx: Nl chromic. Nl/↓ MCV. Nl to ↑ RDW. ↓ to nl Fe. ↓ to low nl TIBC. ↓ Fe sat. Nl to ↑↑ ferritin. Experimental: Nl sol transferrin receptor/↑ Hepcidin.
Tx: Tx Fe def if present (Low nl ferritin). Most mild cases resolve w/Tx 1° condition. EPO administration in sev. disease

Megaloblastic Anemia (ASH-SAP 2010;1:109) (N Engl J Med 2013;368;149)

Impaired DNA synthesis → RBC lineage usu affected before other cells

Blood Smear: ↑ MCV earliest sign. Hypersegmented PMNs (≥5% w/5 lobes & some w/≥6 lobes). Macroovalocytes. Cabot Rings. Howell-Jolly Bodies. Promegaloblasts. ↑↑ MCV but may be ↓/nl w/concurrent microcytic process.

BM: ↓ M:E ratio. ±↑ RS. Other Labs: ↑ LDH, ↑ indirect bili. & ↑ UA.

Folate Deficiency: Duodenum/proximal jejunum absorption. No A/w neuro sxs.
- Etiologies: ↓ Intake, ↓ absorption, ↑ use (chronic hemolysis), drug interaction. ↑Risk in alcoholics, elderly, TPN w/o supplemental folate, duodenal or jejunal resection/infiltration, celiac disease, chronic hemolysis.
- Dx: ↓ Serum folate ± RBC folate (may better reflect folate def but also ↓ in B₁₂ Def), ↑ homocysteine, nl methylmalonic acid (MMA). Also a/w falsely ↓ B₁₂ in some cases.
- Tx: R/O ↓ B₁₂. ↓ Folate: ↑ doses PO folate (1-5 mg/d). Ppx prenatal/pregnancy.
B₁₂ Deficiency: Multiple steps for dietary B₁₂ absorption in terminal ileum.
- ↓Intake (no animal products/vegans). Hypochlorydia (age, PPIs, atrophic gastritis). ↓ Pancreatic Proteases. ↓ Binding B₁₂ & IF (bacterial overgrowth, Diphyllobothrium, pernicious anemia, & gastric resection). ↓ Absorption w/Meds (cholestyramine, colchicine, & metformin). Ileal Resection/Dysfunction (Celiac, NHL, Crohn’s, etc.).
- A/w neuropsych sxs: ↓ vibriosensation, spastic paralysis, psychosis/dementia.
- Full B₁₂ stores take longer to deplete than folate stores: ˜ few y.
- Dx: Subclinical B₁₂ Def (↑ in elderly): Low nl B₁₂, ↑ homocysteine, ↑ MMA.
- Clinical B₁₂ Def: ↓ B₁₂, ↑↑ homocysteine, ↑↑ MMA.
- Tx: Beware folate supp only correcting anemia & not neuro sxs. IM B₁₂ 1 mg/d × 14 d → 1 mg/wk until anemia resolves → 1 mg/mo.
- Some respond to PO B₁₂. Quick Δ to parenteral B₁₂ if PO not working.
Other Megaloblastic Anemias: Pyrimidine Analog
- (5-FU), Purine Analog (AZA), DNA Synthesis Inhibitor (cytarabine), Antifolate (MTX), RNA Reductase Inhibitor (hydroxyurea), PPI, NO, Antiepileptic, zidovudine.
Macrocytic Anemias w/Similar Morphologic Δ’s: Myelodysplasia, erythroleukemia, Lesch-Nyhan Syndrome, Hereditary Orotic Aciduria.

Other Nutrional Deficiency (see table)

↑ Starvation/Anorexia Nervosa: Normochromic/normocytic anemia → BM necrosis.

↓ Cu: Malnourished infants/adults ± TPN. Postbarriatric surgery/gastrectomy. ↑ Zn intake →↓ Cu absorbed → reversible myelodysplasia/sideroblastic anemia.

Endocrinopathy

Gen: Usu mild anemia. Often asymptomatic.

Hypothyroidism: A/w pernicious anemia (check for ↓ B₁₂). Nl to ↑ MCV. ↓ T₃, ↓ T₄, ↓ rT₃ → ↓ EPO-stimulated erythroid colony formation.
↓ Androgens: A/w 1-2 g/dL ↓ Hb. Androgens → ↑ EPO production/response.
↓ Cortisol: ↓ RBC mass often masked by ↓ plasma volume.
↑ PTH: Potential PTH myelotoxicity & a/w bone remodeling/myelosclerosis.

EPO Deficiency

CRI/ESRD → ↓ renal cortex peritubular capillary lining cells & ↑↑ uremia → ↓ EPO.
CKD Anemia a/w nl MCV/normochromic unless concurrent other process.
Echinocytes in ↑↑ CKD. BM normocellular (hypocellular in long-standing 2° ↑ PTH → osteitis fibrosa). Tx: Follow Fe Sat/ferritin & replete Fe stores. ESA Tx: Goal Hb recs Δ’d in recent y. Balance ↑ QoL vs. ↑ mort, CV, thrombotic outcomes? → esp w/solid tumor. TREAT (N Engl J Med 2009;361:2019). CHOIR (N Engl J Med 2006;355:2085). EPO-CAN-20 (J Clin Oncol 2007;25:1027).
EPO Resistance: ˜25% HD pts w/some EPO resistance. A/w ↑ inflamm (↑ IL-6).

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Clonal HSC disorder w/Coombs neg intravascular hemolysis & ↑ thrombosis risk → pancytopenia → AA. Blood cells sensitive to activated C′. Dx: ↓ CD55 (DAF) & ↓ CD59 (MIRL) on flow cytometry. Somatic Mt pig-A. Tx w/eculizumab (anti-C5 mAb) → inhibit terminal C′.

HEMOLYTIC ANEMIAS

Patrick W. Burke

Gerald A. Soff

General Overview (ASH-SAP 2010;1:133)

Definition: RBC-accelerated destruction → ↓ RBC lifespan (Nl ˜ 120 d).
- RBC intrinsic vs. extrinsic disorder. Intravascular vs. extravascular (most hemolysis in-between on spectrum & manifest s/s of both.
- Extravascular destruction 2° to mφ of RE system in spleen >> liver.
- Inherited vs. acquired. Compensated vs. decompensated.
Sxs: General anemia Sxs: ↓ CaO₂ → ↓ DO₂ → fatigue, DOE, CP, & CNS Sxs.
Signs: Gen- pale, jaundice, ↓ Hb (decompensated), ↑ indirect bili., ↑ LDH, ↑ retic (RI > 2 & ↑ absolute number if nl BM response), ↓ haptoglobin. ↑ urobilinogen.
- Extravascular- splenomegaly, pigmented cholelithiasis.
- Intravascular- ↑↑ LDH. ↓↓ haptoglobin. ↑↑ indirect bili. ↑ plasma Hb → ↓ NO (scavenged by free Hb) → esophageal spasm & vasoconstriction → nonhealing ulcers (esp lower ext). ↑ hemoglobinuria. ↑ hemosiderinuria.

Hemolytic Anemia	Site	Etiology	Development
Thalassemias (α, β)	Intrinsic	Quantitative Hbopathy	Inherited
Sickle Cell Disease (Hb SS, SB°, SB⁺, SC)	Intrinsic	Qualitative Hbopathy (Hb S) ± Quantitative Hbopathy (β Thal)	Inherited
Hb E, C, D	Intrinsic	Qualitative Hbopathy	Inherited
Hb H	Intrinsic	Quantitative Hbopathy	Inherited/Acquired
Unstable Hb	Intrinsic	Qualitative Hbopathy	Inherited
Methemoglobinemia	Intrinsic	Qualitative Hbopathy	Inherited/Acquired
HS, HE, HPP, Rh Deficiency (Null)	Intrinsic	Membrane Abnormality	Inherited
Acanthocytosis, Stomatocytosis	Intrinsic	Membrane Abnormality	Inherited/Acquired
↓ PK/Other Glycolytic Enzyme	Intrinsic	Glycolytic Enzymopathy	Inherited/Acquired
↓ G6PD/Other HMP Shunt Enzyme	Intrinsic	HMP Shunt Enzymopathy	Inherited
AIHA, Drug-induced	Extrinsic	Immune-mediated	Acquired
Paroxysmal nocturnal hemoglobinuria	Intrinsic	Membrane Abnormality	Acquired
Microangiopathic hemolytic anemia	Extrinsic	Trauma-microvascular	Inherited/Acquired
Macrovascular/Prosthesis	Extrinsic	Trauma-macrovascular	Acquired
Toxins: Pb, Cu, Drugs, Spider/Snake Venom	Extrinsic	Direct Toxic Effect	Acquired
Malaria, Babesia	Extrinsic	Intracellular Infxn	Acquired
Clostridium, Gram negative rods, Gram positive cocci	Extrinsic	Direct Toxic Effect	Acquired
Mycoplasma, EBV, CMV, HSV	Extrinsic	Immune-mediated; Cold AIHA	Acquired
Hypersplenism	Extrinsic	Entrapment/RE System	Acquired

Germline Hemoglobinopathies (Hbopathy): See “Hemoglobinopathies” Chapter.

Acquired α thal a/w MDS: Clonal del α gene cluster/inactivating somatic Mt: ATRX (Blood 2005;105:443) → B₄ (Hb H) ˜5-40% Hb H. Phenotypic variance.

G6PD Deficiency (ASH-SAP 2010;1:133; Lancet 2008;371:64)

G6PD: X-linked gene. > 300 variants → ↓ G6PD in males. Lyonization pattern determines female phenotypic variance.

Commonest human enzyme defect. HMP Shunt 1^st enzyme: ↓ G6PD → ↓ NADPH → ↓ renewal reduced glutathione →↑ RBC/Hb oxidant stress susceptibility → extravascular + ↑↑ intravascular hemolysis w/↑↑ oxidant + ↓↓G6PD. DAT-. Smear: Eccentrocytes, bite cells, Heinz bodies.

Oxidant challenges: DKA, hepatic injury, drugs, infxn, naphthalene, & “favism.”

Polymorphisms (Class I-V). Variants’ G6PD levels: Near nl →↓↓↓↓. G6PD B = nl.

G6PD A: 10-15% African-American males. Unstable enzyme → ↓ activity in aged RBCs, not retics. Vital oxidants may be continued b/c ↑↑ retics.
G6PD Mediterranean: B variant. Both retics/mature RBCs affected → ↑↑↑ sev. course. Must stop oxidant agent/process.
Other Variants: ↓ G6PD activity + marked instability/↓ production → mature RBC & retics affected. ↑↑ severity. Seen in Asia/Mediterranean area.
- False negative/false – G6PD enzyme level during acute hemolysis b/c ↑↑ retics compensation. Screen before starting oxidant drug or mos postacute hemolytic episode.
- Variants determined w/restriction enzyme analysis/electrophoresis pattern.

Other RBC Enzymopathies (ASH-SAP 2010;1:133)

Other HMP Shunt: Rare-phosphogluconate dehydrogenase; glutathione reductase.

Glycolysis: ↓ PK > 80% hemolytic anemias a/w glycolysis. ↑ N. & E. Europeans. Nl osmotic fragility/MCV. Dx w/quant. RBC enzyme analysis.

Tx depends on severity. Consider folate supplementation & splenectomy.

Wilson disease → ↑ Cu inhibits hexokinase → acquired hexokinase deficiency.

Nucleotide Metabolism AbNl: ↓ Pyrimidine-5′-NT (Pb tox) & ↓ ADA.

RBC Membrane Abnormalities (Br J Haematol 1999;104:2)

Wide clinical spectrum a/w AbNl membrane protein: ↓ or dysfunction → RBC AbNl shape/deformability → extravascular hemolysis. Splenomegaly/cholelithiasis.

Hereditary spherocytosis (HS) ↑ in N. Europeans: ˜1/2000. Variable penetrance. 75% autosomal dominant. Etiologies: 30-45% ↓ ankyrin & spectrin, 30% ↓ spectrin, 20% band 3 Mt. ↓ Protein 4.2 as well.
- AbNl protein → unstable membrane → ↓ bilayer/↓surface area → spherocyte.
- Range: Asymptomatic → Symptomatic sev. A/w aplastic/megaloblastoid/hyperhemolytic crises.
- Dx: Spherocytes, DAT-, ↑ MCHC, + osmotic fragility test, EMA-binding test.
- Tx: Consider folic acid in ↑ hemolysis. Definitive Tx: Splenectomy if ↑↑ severity.
Hereditary elliptocytosis (HE) and Hereditary pyropoikilocytosis (HPP):
- Defect spectrin dimerization/spectrin-protein 4.1 interaction → weakened cytoskeleton → deformation under shear stress → ↓ membrane fidelity.
Acanthocytosis: Liver disease → nonesterified cholesterol in RBC membrane → AbNl shape → splenic remodeling. A/w Zieve syndrome.
- Abetalipoproteinemia: AbNl RBC membrane lipid structure.
- McLeod Phenotype: No K_x protein (X-linked) → ↓ RBC Kell Ag.
Stomatocytosis: Inherited: AbNl RBC cation permeability. Acquired: CA, Alcoholism, & hepatobiliary disease. ↑ Thrombosis postsplenectomy.
Rh Deficiency/Null: No or ↓↓↓ Rh (RhCE, RhD, & Rh50). Autosomal recessive → Δ cation xport/RBC dehydration → spherocytes/stomatocytes.

Autoimmune Hemolytic Anemia (AIHA) (Blood 2010;116:1831; ASH-SAP 2010;1:133)

AutoAbs characterized by temperature of optimal RBC binding. 1° (idiopathic) vs. 2°.

Warm AIHA: 80-90% adult AIHA cases. IgG bind RBCs optimally at 37°C. ± C′ fixation. No agglutination. IgG-coated RBCs → removed by splenic mφ w/F_c receptors. 2° Warm AIHA a/w: HL, NHL, CTD (SLE), solid tumor (ovary), chronic inflammation, (UC) & drugs (α-methyldopa).
Tx: 1°: 1st-line steroids. 2nd-line splenectomy/rituximab. 3rd-line cyclophosphamide, AZA, MMF, CsA, danazol, alemtuzumab. ↓↓ Efficacy w/IVIg. 2°: SLE: 1st-line steroids. 2nd-line rituximab. ↓↓ Efficacy w/splenectomy. CLL: Steroids, R-CVP, R-CD, chlorambucil, rituximab, CsA, splenectomy, alemtuzumab. NHL: Tx malignancy. splenectomy in splenic MZL. Drugs: Stop agent; steroids.
Cold AutoAb: Mostly IgM optimally binding RBCs <37°C. A/w agglutination.
- RBC destruction mediated by C′ C3b fixation → removal by splenic mφ/hepatic Kupffer cells. + Intravascular lysis w/terminal C′.
- Cold Agglutinin: A/w B-cell LPD (monoclonal IgM against Carbohydrate I or i Ags). Cold agglutinin w/2° Cold AIHA (IgM): Mycoplasma & EBV.
- Cold (Hemolysin) AIHA: 1°: Paroxysmal cold hemoglobinuria (IgG). 2°: Donath-Landsteiner Hemolytic Anemia (1/3 pediatric AIHA; a/w viral infxn; anti-P system IgG). Congenital/3° syphilis cold AIHA (IgG).
- Tx: General-avoid cold; rituximab. No efficacy w/steroids/IVIg. Plasmapheresis acute ↓ IgM. Tx LPD. Donath-Landsteiner: Nl self-limited. ?Eculizumab; ?bortezomib.
Mixed AIHA: IgM + IgG (↑severity) or IgA + IgG. 1° or 2° a/w CTD (esp SLE).
- Dx: Usu DAT+. Coombs level ≠ hemolysis level necessarily. ELISA ↑ Sn.
- DAT: IgG: Warm AIHA, hapten-mediated/drug adsorption or true autoAb. C3d: Warm AIHA w/↓IgG bound, cold agglutinin, paroxysmal cold hemoglobinuria or ternary/immune complex. IgG + C3d: Warm AIHA or true autoAb.
- Xfusion is complex → autoAbs mask alloAbs (potentially sev.) → work w/blood bank to find compatible units. Obtain Hx of prior pregnancy/abortion/xfusion.

Drug-induced Hemolytic Anemia (ASH-SAP 2010;1:133)

True autoAb formation: Several drugs (α-methyldopa) → IgG autoAb formation → hemolysis w/o requiring drug presence. Hapten-mediated/Drug Adsorption: Drug binds RBC membrane proteins (PCNs) → IgG against drug epitope while drug coats RBC → hemolysis. Ternary/Immune Complex: IgG/IgM Ab against complex of drug/metabolite + RBC membrane protein → hemolysis.

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