Anaemia

Anaemia refers to a state in which the level of haemoglobin (Hb) in the blood is below the
reference range appropriate for age and sex. Other factors, including pregnancy and
altitude, also affect Hb levels.
•Anemia is present in adults if the hematocrit is below 41%
(hemoglobin less than 13.6 g/dL (135 g/L]) in males or
below 36% (hemoglobin less than 12 g/dL [120 g/L]) in
female
Clinical manifestations • Symptoms: 1 Oz delivery -» fatigue, exertional dyspnea, angina
(if CAD)
• Signs: pallor (mucous membranes, palmar creases), tachycardia, orthostatic hypotension
• Other findings: jaundice (hemolysis), splenomegaly (thalassemia, neoplasm, chronic
hemolysis), petechia/purpura (bleeding disorder), glossitis (iron, folate, vitamin B12
defic.), koilonychia (iron defic.), neurologic abnormalities (Bi2 defic.)
 Types of anemia The first step in diagnosis is to look at the mean cell volume
(McV). Normal Mcv is 76-96 femtolitres (1015 fL = 1L).
Low Mcv (microcytic andemia):
1 Iron-deficiency anemia (IDA), the most common cause: see p326.
2 Thalassaemia (suspect if the McV is 'too low' for the Hb level and the red cell
count is raised, though definitive diagnosis needs DNA analysis): see p342.
3 Sideroblastic anemia (very rare): p326.
NB: there is iron accumulation in the last two conditions, and so tests will show in-creased
serum iron and ferritin with a low total iron-binding capacity (TIBC).
Normal cv (normocytic andemia):1 Acute blood loss.2 Anemia of chronic disease (or
IMCV).3 Bone marrow failure.4 Renal failure.5 Hypothyroidism (or tMCV).6 Haemolysis
(or 1MCV).
7 Pregnancy.
 High cv (macrocytic anaemia):
1.B12 or folate deficiency 2.alcohol axcess or liver dis 3.reticulocytosis
4.cytotoxics eg hydroxycarbmide 5.myelodysplastic syndrome 6.marrow infiltration
7.hypothyrodism 8. Antifolate drugs ( phenytoin)
Haemolytic anemias: These do not fit into the above-mentioned classification
as the anemia may be normocytic or, if there are many young (hence larger)RBCsand
reticulocytes, macrocytic (p332). Suspect if there is a reticulocytosis (>2%ofRBs; or
reticulocyte count >100x10%/L), mild macrocytosis,thaptoglobin,tbilirubin,
1LDH, or turobilinogen. These patients will often be mildly jaundiced (but note that
haemolysis causes pre-hepatic jaundice so there will be no bilirubin in their urine
 APPROACH TO THE PATIENT
1)Historu
The evaluation of the patient with anemia requires a careful history and physical
examination•Nutritional history related to drugs or alco- hol intake and family history of
anemia should always be assessed. Certain geographic backgrounds and ethnic origins are
associated with an increased likelihood of an inherited disorder of the hemo- globin
molecule or intermediary metabolism. Glucose-6-phosphate
dehydrogenase (G6PD) deficiency and certain hemoglobinopathies
Other information that may be useful includes exposure to certain toxic agents or drugs and
symptoms related to other dis- orders commonly associated with anemia. These include
symptoms and signs such as bleeding, fatigue, malaise, fever, weight loss, night sweats, and
other systemic symptoms.
 2)physical examination may demonstrate a forceful heartbeat, strong peripheral
pulses, and a systolic “flow” murmur. The skin and mucous membranes may be
pale if the hemoglobin is <80–100 g/L (8–10 g/dL). This part of the physical
examination should focus on areas where vessels are close to the sur- face such as
the mucous membranes, nail beds, and palmar creases. If the palmar creases are
lighter in color than the surrounding skin when the hand is hyperextended, the
hemoglobin level is usually <80 g/L (8 g/dL).
3)LABORATORY
EVALUATION
MICROCYTIC ANEMIAS
Iron deficiency anemia
Decrease marrow iron & depleted body iron stores -› decrease heme
synthesis -› microcytosis -› anemia

Special clinical manifestations: angular cheilosis, atrophic glossitis, pica (consumption of

nonnutritive substances such as ice, clay), koilonychia (nail spooning)
Plummer-Vinson syndrome (iron deficiency anemia, esophageal web & atrophic glossitis)

: chronic bleeding (GI-incl. cancer, menstrual, parasites, NSAIDs, etc.),

Decrease supply (malnutrition; & absorp. due to celiac sprue, Crohn's, increase gastric
pH, subtotal
gastrectomy), increase demand (preg., Epo). Iron-refractory iron-defic. anemia (IRIDA;
rare
Fe refractory genetic disorder due to hepcidin dysregulation;
 Diagnosis (eval ideally before Rx): I Fe, 1 TIBC, I ferritin (esp. <15), 4 transferrin sat
(Fe/TIBC; esp. <15%), 1 soluble transferrin receptor; 1 plt
Unless hx c/w other etiology, initiate workup for GIB, incl. H. pylori serology
? Celiac sprue labs (anti-TTG, antigliadin, antiendomysial Ab)
Cytogenetic & molecular testing as indicated
Treatment
Oral Fe tid (-6 wk to correct anemia; -6 mo to replete Fe stores; nb, oral Fe
does not give ® Hemoccult). In excessive/persistent Gl losses or dialysis, cancer: CHF.
or prior to Epo Rx, /V iron (Fe-sucrose, -gluconate, -dextran) should be considered.
 seen w/ Southeast Asian, Mediterranean,
Thalassemias African, Middle East ancestry
3 a -› o-thal-2 trait = silent carrier: 2 a -› o-thal-1 trait or a-thal minor = mild anemia
1 a -› HbH (BA) disease = severe anemia, hemolysis and splenomegaly
0 a genes -› Hb Barts (14) = intrauterine hypoxia and hydrops fetalis
-thalassemia: mutations in ß-globin gene -› absent or 4 gene product
seen w/ Mediterranean (espec. Greek or Italian), African, or Asian ancestry
1 mutated ß gene -› thal minor (or trait) = mild anemia (no transfusions)
2 mutated ß genes -› thal intermedia (occasional transfusions) or thal major (= Cooley's
anemia; transfusion dependent) depending on severity of mutations
Severe clinical manifestations: chipmunk faces, pathologic fractures, hepatosplenomegaly
(due to extramedullary hematopoiesis), high-output CHF, bilirubin gallstones, Fe overload
 Diagnosis: MCV <70, normal Fe, MCV/RBC count <13
T retics, basophilic stippling; Hb electrophoresis: 1 HbA2 (0282)
in -thal; normal pattern in o-thal trait, .. PC or supravital stain for dx
• Treatment: folate; transfusions + Fe chelator [either deferoxamine (V) or deferasirox (PO)];
? splenectomy if ≥50% 1 in transfusions; consider allo-HSCT in children w/ severe ß-thal
 Anemia of chronic inflammation
Sideroblastic anemia
• Defective heme biosynthesis within BC precursors
• Etiologies: hereditary/X-linked (ALAS2 mutations), idiopathic, MDS-RARS,
reversible (alcohol, lead, isoniazid, chloramphenicol, copper deficiency, hypothermia)
Special clinical manifestations: hepatosplenomegaly, iron overload syndromes
Dx: social, work & TB hx; can be micro-, normo- or macrocytic; variable populations of
hypochromic RBCs; 1 Fe, nl TIBC, † ferritin, basophilic stippling. RBC Pappenheimer
bodies (Fe-containing inclusions), ring sideroblasts (w/ iron-laden mitochondria) in BM
Treatment: treat reversible causes; trial of pyridoxine, supportive transfusions for
severe anemia with chelation therapy; high-dose pyridoxine for some hereditary cases
Pancytopenia NORMOCYTIC ANEMIAS

Anemia of chronic inflammation

1 RBC production due to impaired iron utilization and functional iron deficiency
from 1 hepcidin; cytokines (IL-6,TNF-0) cause & Epo responsiveness/production
Etiologies: autoimmune disorders, chronic infection, inflammation,
Dx: 1 Fe, | TIBC (usually normal or low transferrin sat), ‡ 1 fer
normochromic, normocytic (-70% of cases) but can be microcyti
Coexisting iron deficiency common. Dx clues include I serum ferrit
of iron staining on BM bx, ® response to a trial of oral iron and
transferrin receptor/ferritin index
Treatment: treat underlying disease + iron and/or erythropoiesis-st
(ESA; eg, Epo). Iron if ferritin <100 or Fe/TIBC <20%. Consider E
Avoid ESA in cancer if treatment goal is cure (Lancet 2009;373:153
should treat highly sx Pts w/ goal Hb 10-12 g/dL; weigh risk of
 Anemias of other chronic disorders
Anemia of chronic kidney disease: I Epo; treat w/ Epo (see "Chronic Kidney Disease")
• Endocrine deficiencies: hypometabolism and I O demand with thyroid, pituitary, adrenal,
or parathyroid disease -› / Epo; can be normocytic or macrocytic

Sideroblastic anemia
Pure red cell aplasia
• Destructive antibodies or lymphocytes -› ineffective erythropoiesis
Associated with thymoma, CLL and parvovirus infection, autoimmunity, drugs
• Diagnostic studies: lack of erythroid precursors on BM bx, other lines normal
Treatment: thymectomy if thymus enlarged; /lg if parvovirus infection; immuno-
suppression/chemoRx if CLL or idiopathic; supportive care w/ PRBC transfusions;
? erythropoietin receptor agonist if due to antierythropoietin Ab (NEIM 2009:361:1848)
consider hematopoietic cell transplantation.
 MACROCYTIC ANEMIAS
includes megaloblastic and nonmegaloblastic causes
Megaloblastic anemia
• Impaired DNA synthesis - cytoplasm matures faster than nucleus -› ineffective
erythropoiesis and macrocytosis; due to folate or Biz deficiency; also in MDS
/ folate and vitamin B12: 1 LDH & indirect bilirubin (due to ineffective erythropoiesis)
Smear: neutrophil hypersegmentation, macro-ovalocytes, anisocytosis, poikilocytosis
 Folate deficiency
• Folate present in leafy green vegetables and fruit; total body stores sufficient for 2-3 mo
• Etiologies: malnutrition (alcoholics, anorectics, elderly), + absorption (sprue),
impaired metabolism (methotrexate, pyrimethamine, trimethoprim; NEJM 2015;373:1649),
† requirement (chronic hemolytic anemia, pregnancy, malignancy, dialysis)
Diagnosis: 1 folate; I RBC folate, 1 homocyst. but ni methylmalonic acid (unlike Biz defic.)
• Treatment: folate 1-5 mg PO qd for 1-4 mo or until complete hematologic recovery;
critical to rio Biz deficiency first
 Vitamin Bi deficiency (NEJM 2013:368:149)
• Biz present only in foods of animal origin; total body stores sufficient for 2-3 y
Binds to intrinsic factor (IF) secreted by gastric parietal cells; absorbed in terminal ileum
• Etiologies: malnutrition (alcoholics, vegans), pernicious anemia (PA, autoimmune dis-
ease against gastric parietal cells, a/w polyglandular endocrine insufficiency and 1
risk of gastric carcinoma), other causes of I absorption (gastrectomy, sprue, Crohn's
disease), † competition (intestinal bacterial overgrowth, fish tapeworm)
• Clinical manifestations: neurologic changes (subacute combined degeneration)
affecting peripheral nerves, posterior and lateral columns of the spinal cord and cortex
-› numbness, paresthesias, I vibratory and positional sense, ataxia, dementia
• Dx: 1 Biz: 1 homocysteine and methylmalonic acid; anti-IF Ab; Schilling test; † gastrin in P
• Treatment: 1 mg Bi2 IM qd x 7 d -› q wk × 4 8 wk - q month for life
neurologic abnormalities are reversible if treated w/in 6 mo
folate can reverse hematologic abnormalities of Biz deficiency but not neurologic
changes (and can lead to "steal" of Bi stores -› worsening of neuro complications)
oral supplementation (2 mg qd) appears feasible as well
 Nonmegaloblastic macrocytic anemias
• Liver disease: often macrocytic, may see target cells, or spur cell anemia w/ hemolysis
Alcoholism: BM suppression & macrocytosis independent of folate/B12 defic. or cirrhosis
Reticulocytosis
Other causes: hypothyroidism; MDS; meds that impair DNA synthesis (zidovudine,
5-FU, hydroxyurea, Ara-C); hereditary orotic aciduria; Lesch-Nyhan syndrome
 PANCYTOPENIA
Etiologies
• Hypocellular bone marrow (n cellularity -100 - age): aplastic anemia, hypoplastic MDS
Cellular bone marrow: MDS, aleukemic leukemia, PNH, severe megaloblastic anemia
Marrow replacement (myelophthisis): myelofibrosis, metastatic solid tumors, granulomas
• Systemic diseases: hypersplenism, sepsis, alcohol, toxins
Clinical manifestations
• Anemia -› fatigue
Neutropenia -› recurrent infections
Thrombocytopenia -› mucosal bleeding & easy bruisability
 Aplastic anemia = stem cell failure (NEIM 2015:373:35)
Epidemiology: 2-5 cases/10°/y; biphasic (major peak in adolescents, 2nd peak in elderly)
Diagnosis: pancytopenia w/ 1 retics, BM bx w/ cytogenetics showing hypocellularity
Etiologies: idiopathic (½ - ⅔ of cases)

stem cell destruction: radiation, chemotherapy, chemicals (eg, benzene)

idiosyncratic med rxn (eg, chloramphenicol, NSAIDs, sulfa drugs, gold,
carbamazepine, antithyroid)
viruses (HHV-6, HIV, EBV, parvovirus B19); post-viral hepatic failure (not Hep A/B/C)
immune disorders (SLE, GVHD post-HSCT, thymoma)
PNH (see below); Fanconi's anemia (congenital disorder w/ pancytopenia, macrocytic
anemia, 1 risk of MDS, AML, & SCC of head & neck, and multiple physical
anomalies
shortened telomeres: seen w/ telomerase (TERT, TERC) mut. (10% of aplastic
anemia),
dyskeratosis congenita/DKC1 mut; a/w IPF, cirrhosis (NE)M 2009:361:2353)
somatic mutations: NH clones in ~50% of aplastic anemia
 Treatment and prognosis
allogeneic HSCT: for young Pts - -80% long-term survival and significantly & risk
of malignant evolution, but has risk of transplant-related morbidity & mortality; if
possible avoid transfusions (and alloimmunization) pretransplant
mmunosuppression (CsA/tacrolimus, ATG): 70-80% respond, with 80-90% 5-y survival
in responders (96% vs. 76% w/ horse vs. rabbit ATG; NE/M 2011:365:430);
15-20% 10-y incidence of clonal disorders (mostly MDS, AML, PNH)
TPO mimetics (eg, eltrombopag) an option in refractory disease (Blood 2014; 123:1818)
upportive care: transfusions, antibiotics, possible utility of G-CSF and Epo (if Epo <500)
 Myelodysplastic syndromes (MDS) (qv)
Paroxysmal nocturnal hemoglobinuria (PH) (Blood 2009;113:6522)
• Acquired clonal stem cell disorder = inactivating somatic mutation of PIG-A gene -
deficiency of GPl-anchor for CD55 & CD59 (inhib of complement) -
complement-mediated BC lysis, pIt aggreg., & hypercoagulability
• Clinical: intravascular hemolytic anemia, hypercoagulability (venous >
arterial; esp. intraabdominal, cerebral), smooth muscle dystonias, deficient
hematopoiesis (cytopenias); a/w aplastic anemia, MDS and evolution to AML
Dx: flow cytometry (1 CD55 & CD59) on RBCs and granulocytes; urine hemosiderosis
Treatment: supportive care (iron, folate, transfusions); consider anticoagulation
allogeneic HSCT for hypoplasia or severe thrombosis
eculizumab (Ab inactivates terminal complement C5s): | hemolysis, improves Qol
& stabilizes Hb levels (NE|M 2004:350:552 & 2006:355:1233: Lancet 2009:373:759);
effective in pregnancy (NEIM 2015:373:1032); must have meningococcal vaccination
 Myelophthisic anemia (see also "Primary Myelofibrosis")

Infiltration of bone marrow by cancer, leukemia, infection, fibrosis (primary myelofi.

brosis), granulomas, lysosomal storage disorders
HEMOLYTIC ANEMIAS
 Diagnostic evaluation
reticulocyte count (RI >2%), 1 LDH, 4 haptoglobin (83% Se, 96% Sp), 1 indirect bill
• Autoimmune hemolysis: Coombs' test = direct antiglobulin test (DAT) - © if
agglutination occurs when antisera against lg or C3 are applied to patient BCs
ravascular: 11 LDH, I haptoglobin; hemoglobinemia, hemoglobinuria, hemosiderinuria
• Extravascular: splenomegaly
• Family h/o anemia; personal or family h/o cholelithiasis
 Glucose-6-phosphate dehydrogenase (G6PD) deficiency (Lancet 2008:371:64)
linked defect of metabolism (G6PD mutations) w/ 1 susceptibility to oxidative damage
Most common in 8 of African or Mediterranean descent (malaria-endemic areas)
Hemolysis precipitated by drugs (sulfonamides, dapsone, nitrofurantoin, rasburicase,
primaquine, doxorubicin, methylene blue), infection, DKA or foods (fava beans)
Diagnosis: smear may show BC Heinz bodies (oxidized Hb) that result in bite cells
nce removed by spleen; | G6PD levels (may be normal after acute hemolysis as older
RBCs have already lysed and young RBCs may still have near normal levels)
 Sickle cell anemia (Lancet 2016:387:2545. 2554 & 2565)
• Recessive ß-globin mutation -› structurally abl hemoglobin (HbS). -8% African Americans
heterozygotes ("sickle trait", usually w/o sx); ~1/400 homozygotes (sickle cell disease).
• 1 02 -› HbS polymerizes -› RBC sickles, & BC deformability -› hemolysis &
microvascular occlusion due to endothelial activ. & MN adhesion (Blood 2013;122:3892)
• Anemia: chronic hemolysis ‡ acute aplastic (parvo. B19) or splenic sequestration crises
 sequestration, hand-foot syndrome, renal papillary necrosis, aseptic necrosis, priapism
Infection: splenic infarction -› overwhelming infection by encapsulated organisms;
infarcted bone -y osteomyelitis (Salmonella, Staph. aureus)
• Diagnosis: sickle-shaped RBCs and Howell-Jolly bodies on smear; Hb electrophoresis
• Treatment: hydroxyurea causes 1 HbF -> I painful crises, acute chest episodes and
may 4 mortality (NE/M 2008:358:1362); allogeneic HSCT may have a role in young Pts
w/ severe disease (Blood 2000.95:1918) and adults (NEIM 2009:361:2309: Blood 2012:120-
4285)
• Supportive care: folic acid qd; pneumococcal, meningococcal, H. flu & HBV vaccination;
pain crises Rx'd w/ hydration, O2 & analgesia; simple or exchange transfusion for TIA or
stroke, severe acute chest syndrome, or preop (goal Hb 10 g/dL; Lancet 2013:381.930)
 Hereditary spherocytosis (HS) (Br) Hemato! 2004:126:455)
• Defect in a cytoskeletal protein of BC membrane -› membrane loss
mutations in ankyrin, a- and B-spectrin, band 3, and pallidin have been identified
• Most common in N. European populations (1/5000 births); © FHx (75% of Pts)
• Anemia, jaundice (mostly neonates), splenomegaly, pigmented gallstones
• Diagnosis: spherocytes on smear; © osmotic fragility test (-80% Se), I eosin-5-maleimide
(EMA) binding (93% Se;: 99% Sp: Haemat 201297516), acidified glycerol lysis test (Se-
95%)
• Treatment: folate, transfusions, splenectomy for moderate and severe HS (balance w/
risk of future thrombosis and infection;
 Paroxysmal nocturnal hemoglobinuria (see above)
Autoimmune hemolytic anemia (AIHA)
• Acquired, antibody-mediated BC destruction
Warm AHA: IgG Abs opsonize RBCs at body temp › removal by spleen
Etiologies: idiopathic, lymphoproliferative (CLL, NHL), autoimmune (SLE), drugs, HIV
• Cold AHA: IgM Ab binds to RBCs at temp <37°C -› complement fixation
-› intravascular hemolysis and acrocyanosis on exposure to cold
Etiologies: idiopathic, lymphoprolif. disorders (eg, Waldenström's; monoclonal),
Mycoplasma pneumonia infxn and infectious mononucleosis (polyclonal)
Diagnosis: spherocytes on smear; © Coombs'; / cold agglutinin titer, splenomegaly
• Treatment: treat underlying disease
warm AHA: corticosteroids ‡ splenectomy, IVlg, cytotoxic agents, rituximab
cold AHA: avoid cold; steroids ineffective; rituximab (Blood 2004:103:2925)
 Drug-induced hemolytic anemia
Acquired, antibody-mediated, BC destruction precipitated by a medication:
ax: cephalosporins, sulfa drugs, rifampin, ribavirin
CV: methyldopa, procainamide, quinidine, thiazides
phenothiazines, NSAIDs, sulfonylureas, MTX, 5-FU, rasburicase (G6PD defic.)
Diagnosis: Coombs' usually negative, 1 LDH
Treatment: discontinue offending agent
 Microangiopathic hemolytic anemia (MAHA; NEIM 2014:371:654)
• Intra-arteriolar fibrin damages RBCs -› acquired intravascular hemolysis
• Etiologies: hemolytic-uremic syndrome (HUS), thrombotic thrombocytopenic
purpura (TTP), disseminated intravascular coagulation (DIC), malignancy,
malignant HTN, eclampsia/HELP, mech. cardiac valves, infected vascular prostheses
• Diagnosis: schistocytes + thrombocytopenia ‡ abnormalities a/w specific disorders
(eg, 1 PT in DIC, 1 Cr in HUS, 1 LFTs in HELLP)
• Rx underlying dx; urgent plasma exchange w/ TTP (replace low ADAMTS13)
 Hypersplenism
• Stasis/trapping in spleen -› Mo attack & remodeling of BC -› spherocytosis -,
hemolysis
Physiological regulation of red cell
production
 RED BLOOD CELL COUNT

1) HEMOGLOBIN : NORMAL VALUES

• 2) HAEMATOCRIT : NORMAL VALUES
 RETIC COUNT
Reticulocyte is the immediate precursor of RBC.
It is the most effective measure of erythropoitic activity
Stained by : SUPRAVITAL STAIN (Brilliant cresyl blue)
NORMAL VAUE : 0.5-1.5%
CORRECTED RETIC COUNT
• (Retic % X patient hematocrit) /normal hematocrit for
age
• This provides an estimate of the count corrected for
anemia.
RETICULOCYTE PRODUCTION INDEX
Corrected retic count / 2
Inference: <2 = hypoproliferative,>2=
hyperproliferative