APPROACH TO ANEMIA-

IRON DEFICIENCY, MEGALOBLASTIC AND HEMOLYTIC

ANEMIA
CHINCHU MARIAM SANTY
JUNIOR RESIDENT
ANEMIA- DEFINITION

According Hb <13 g/dl in adult males

to WHO
Hb < 12 g/dl in adult females
Hb < 11 g/dl in adult pregnant females
 BFU (e)  CFU (e ) – EPO dependent , iron independent
 CFU (e)  proerythroblast – EPO and iron dependent
 EPO is produced from the cortical and outer medullary peritubular interstitial fibroblast
APPROACH TO ANEMIA

 Single lineage or multiple lineage affected

 If only anemia – hypoproliferative / hyperproliferative
RETICULOCYTES

 Reticulocytes are the prematurely released RBCs from the bone marrow
 Their greyish blue colour is due to residual ribosomal RNA
 They can appear in circulation due to EPO stimulation or bone marrow architectural damage(fibrosis, infiltration
by malignant cells).
 Their residual r-RNA is metabolized over the first 24-36 hours of its lifespan
 Normal reticulocyte count is 1-2% reflects the daily replacement of 0.8-1% of circulating RBCs.
 RETIC COUNT : No of Reticulocytes per 100 RBC
 RC% = (No: of Reticulocytes/ No of RBC ) x 100
 Normal RC% = 0.5 – 2%
 Normally , if Hb drops < 10 , RBC production increases to 2-3 times normal within 10 days of onset of anemia .
 Premature release of reticulocytes is due to increased EPO stimulation.
CORRECTIONS IN RETICULOCYTE COUNT

 First correction adjusts the reticulocyte count based on the reduced number of circulating RBC.(In anemia % of
reticulocytes is increased but their absolute number is unchanged).

 After the first correction, the reticulocyte count is called the corrected reticulocyte count.

 CRC = Hb (patient) / 15 (normal Hb) x RC

 CRC = Hct (patient) / 45 (normal Hct) x RC
 Second correction is to convert the corrected reticulocyte count to an index of marrow production. The second
correction is needed if some of the reticulocytes are prematurely released- Polychromatophilic macrocyte – these
cells are known as shift cells- they can survive as reticulocyte for more than 1 day -> falsely high estimate of
daily red cell production.
SHIFT CORRECTION FACTOR
 Second correction is done by dividing the corrected reticulocyte count by 2 (correction factor can be 1-3).
 If smear doesnt show polychromasia, correction is not done.
 Shift correction is always done in high reticulocyte count anemia.
 The double corrected reticulocyte count is known as Reticulocyte Production Index(RPI).
IRON DEFICIENCY ANEMIA
BASIC TERMS

 Iron deficiency- Reduced stores

 Iron deficiency anemia- Reduced stores + anemia
 Functional iron deficiency- increased demand + iron –poor erythropoiesis due to insufficient mobilization of iron
from stores.
 Iron restricted erythropoiesis- Iron delivery to tissues impaired irrespective of stores.
EPIDEMIOLOGY

 Iron deficiency is one of the most prevalent forms of malnutrition.

 Globally , 50 % of anemia is attributable to iron deficiency.
 Nearly 1 million deaths annually worldwide.
BODY IRON DISTRIBUTION
IRON ABSORPTION
 For 1000 calories in diet, we get 6 mg of elemental iron
 During iron deficiency, iron absorption can be increased to 20% of Fe in meat diet or 10% in vegetarian diet.
 Amount of iron absorbed depends on source of iron , acidic environment in stomach and other dietary factors
( phytates, phosphates, tannates)
Avg dietary intake Amount absorbed
Males 15 mg/day 6% absorption = 1mg /day
Females 11 mg/day 12% absorption= 1.5
mg/day
IRON CYCLING
CAUSES OF IRON DEFICIENCY

PHYSIOLOGICAL ENVIRONMENTAL
 Pregnancy  Insufficient intake
 Infancy  Malnutrition
 Rapid growth  Poor diet
 Menstrual blood loss
 Blood donation
CAUSES OF IRON DEFICIENCY
DECREASED ABSORPTION
 Gastrectomy
 Duodenal bypass
 Bariatric surgery
 Helicobacter pylori infection
 Celiac sprue
 Atrophic gastritis
 Inflammatory bowel disease
CHRONIC BLOOD LOSS
 GI tract- Angiodysplasia
 Genitourinary- heavy menses
 Intravascular hemolysis- PNH, March
hemoglobinuria
 Systemic bleeding
CAUSES OF IRON DEFICIENCY

DRUGS GENETIC
 Glucocorticoids  Iron refractory iron deficiency anemia- due to
 Salicylates TMPRSS-6 or matriptase -2 mutation

 NSAIDS
 Proton pump inhibitors
STAGES OF IRON DEFICIENCY

 Negative iron balance- demands or losses (in excess of 10-20 ml per day ) exceeds iron absorption

mobilization from iron stores

 Iron deficient erythropoiesis- serum iron falls, Tsat falls, Hb synthesis impaired
 Iron deficiency anemia – Hb falls, microcytic hypochromic RBC, poikilocytes
CLINICAL PRESENTATION

 Symptoms- Fatigue, irritability, decreased exercise tolerance

 Appearance of iron deficiency in an adult male or postmenopausal female means GI blood loss until proven
otherwise
Signs of advanced tissue iron deficiency
 Angular stomatitis
 Cheilosis- fissures at corners of mouth
 Koilonychyia- spooning of fingernails
 If palmar creases are lighter in colour than surrounding skin- Hb <8 g/dl
 Plummer Vinson syndrome- Dysphagia (esophageal webs) + iron deficiency + atrophic glossitis
 Pagophagia – craving ice
 Pica
 Restless leg syndrome
 Precipitation of heart failure
DD OF MICROCYTIC ANEMIA

Tests Iron def Inflammation Thalassemia Sideroblastic

Smear Micro/hypo Normal or Micro/hypo Variable
micro/hypo
Serum iron <30 <50 Normal to high Normal to high
TIBC >360 <300 Normal Normal
% saturation <10 <10-20 30-80 30-80
Ferritin <15 30-200 50-300 50-300
Hb pattern on normal normal Abnormal Normal
electrophoresis
TREATMENT

 PRBC transfusion
 Oral iron
 Iv iron
PRBC TRANSFUSION

 Indication – severe anemia with hemodynamic instability

excessive blood loss and need an immediate intervention

 Advantages- correct anemia acutely

transfused RBC provide a source of iron for reutilisation

ORAL IRON

 Ferrous calcium citrate, ascorbate, ammonium citrate, fumarate, bisglycinate, pyrophosphate, sulphate
 Dosage- 100-200 mg of elemental iron per day ( 50 mg / day absorption)
 With normal bone marrow and normal EPO stimulus , this results in RBC production of 2-3 x normal
 As Hb increases , EPO decreases, hence iron absorption decreases over time
 Goal of treatment- correct anemia + 0.5- 1 g for stores
 Hence treatment duration is 6-12 months
 Alternate day single doses oral iron optimizes iron absorption
RESPONSE TO ORAL IRON

 Reticulocyte response begins in 4-7 days

 Reticulocyte response peaks in 1-1.5 weeks
 Increase in Hb 14-21 days
 Normal iron stores 4-5 months
 Absence of response – rule out compliance , absorption issues
 Iron tolerance test- 2 iron tablet given to patient on empty stomach , serum iron measured serially over subsequent
2-3 hrs
 n/l absorption- increase in serum iron by atleast 100
 S/E - slower rise in Hb, metallic taste, heart burn, abdominal discomfort, constipation, nausea , vomiting
 Sucrosomial iron – ferric pyrophosphate protected by a phospholipid bilayer plus sucrester matrix,

excellent tolerability
IRON REFRACTORY IDA

 AR
 Absence of hematologic response (Hb increase of 1 g/dl after 4-6 weeks of treatment with oral Fe)
 TMPRSS 6 or matriptase 2 inhibit hepcidin
 Suspect when : normal ferritin +microcytes+ low Tsat
 Other causes – Hpylori , gastrectomy, celiac sprue, autoimmune gastritus
PARENTRAL IRON

Indications
 Inadequate response to oral iron
 Intolerance to oral iron
 Need for rapid response( later part of pregnancy)
 Postpartum anemia
 Persistent bleeding
 GI causes- bariatric sx, IBD ,celiac sprue
 Organ dysfunction- CKD ,CRS

Iv iron avoided in first trimester of pregnancy

GENERATIONS
 First- iron dextran
 Second – iron sucrose , ferric gluconate
 Third – ferumoxytol, ferric carboxy maltose, iron isomaltoside
 Dosage (Ganzoni formula)
 Body weight (kg) x 2.3 x (15 – patients Hb )+ 500-1000 mg (for stores)
 Or 100mg of elemental Fe weekly for 10 weeks to augment response to recombinant EPO
MEGALOBLASTIC ANEMIA
 Megaloblastic anemias are group of disorders characterized by the presence of distinctive morphological
appearances of the developing red cells in the bone marrow.
 Marrow is usually hypercellular and the anemia is based on ineffective erythropoiesis.
COBALAMIN

3 FORMS :
 In nature its mainly in 2 deoxy adenosyl form ( Ado ) – located in mitochondria and cofactor for the enzyme L-
methylmalonyl Coenzyme A mutase (methyl malonyl CoA succinyl CoA – kreb cycle, precursor for heme
synthesis)
 Methylcobalamin – form in human plasma and cell cytoplasm. Cofactor for methionine synthase
( homocysteinemethionine  S – adenosyl methionine – methyl donor for lipids for myelination, dopamine)
 Methyl and ado cobalamin are converted to hydroxocobalamin rapidly by exposure to light.
Dietary sources:
 Only source for humans : animal products such as meat, fish and diary products
 Adult daily requirement : 1 to 3 mcg per day
 Body stores – 2-3 mg ( sufficient for 3-4 years ,even if no dietary supply)
 ABSORPTION

Intestine- After 6
Stomach- Binds Haptocorrin is
Ileum –IF –B12 Enterohepatic
complex attaches to it hours ,B12
with salivary digested by circulation
receptor (cubulin) on appears in portal
glycoprotein- pancreatic trypsin , enterocytes, clathrin (major part),
blood attached to
haptocorrin B12 binds to IF. mediated endocytosis plasma release
TC II
Transport
 2 main transport proteins-
 Transcobalamin 1 : encoded by gene TCNL, derived from specific granules in neutrophils

Binds with cobalamin and plays a role in the transport of cobalamin analogues in the liver for excretion in bile.

 Transcobalamin 2: transport of cobalamin to the marrow , placenta and other tissues via receptor mediated
endocytosis involving the transcobalamin receptor and megalin.
FOLATE

DIETARY FOLATE
 Highest conc. In liver, yeast, spinach and nuts.
 Daily adult requirement 1000 ug/day
 Stores sufficient for 3-4 months
 70-90% of natural folate are polyglutamates. It has to be reduced to monoglutamate/DHF/THF.
ABSORPTION
 Dietary folate converted to 5 methyl THF in enterocytes.
 Monoglutamates are actively transported across the enterocyte by a proton coupled folate transporter(PCFT).
 60 to 90 ug enters the bile
TRANSPORT
 One third is loosely bound to albumin and two thirds unbound.

3 types of transporters
 Reduced folate transporter- delivery of plasma folate to tissues.
 Folate receptors FR2 and FR3 transport folate into cell
 PCFT transports folate from vesicle to the cell cytoplasm.
ROLE OF FOLATES IN DNA SYNTHESIS
B12/ FOLIC ACID DEFICIENCY LEADS TO

 No methyl group donor

 No methylation of lipids
 No myelination
 Lesser neurotransmitters
 Lesser DNA synthesis
 No formation and conversion of methionine
 Homocysteine accumulates  thrombosis
 THF  polyglutamate; retention of folate within the cells
BIOCHEMICAL BASIS OF MEGALOBLASTIC ANEMIA

 Disparity in the rate of synthesis or availability of the immediate precursors of DNA.

 In deficiencies of either folate or cobalamin, there is failure to convert deoxyuridine
monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) .
 Nuclear cytoplasmic asynchrony
 DNA replication from multiple origins is slower.
 Failure of joining of incomplete replicons.
In megaloblastic anemia ,when only FA is corrected,
 Anemia is corrected due to tetrahydrofolate formation from FA .
 Neurological manifestations worsen as methionine is not formed ( methyl B12 absent)
HEMATOLOGIC FINDINGS

PERIPHERAL BLOOD
 Oval macrocytes with considerable anisocytosis and poikilocytosis
 MCV usually> 100 fL
 Hypersegmented neutrophils
 There may be leukopenia due to reduction in granulocytes and lymphocytes
 Platelet count may be moderately reduced
 In a non anemic patient, the presence of a few macrocytes and hypersegmented neutrophils
may be the only indication of the underlying disorder.
BONE MARROW
 Hypercellular marrow
 Erythroblast nucleus appears primitive despite maturation and hemoglobinization of the cytoplasm.
 Giant and abnormally shaped metamyelocytes and enlarged hyperploid megakaryocytes are characteristic.
CHROMOSOMES
 Bone marrow cells, transformed lymphocytes and other proliferating cells in the body show random breaks
reduced contraction, spreading of the centromere, and exaggeration of secondary chromosomal constrictions and
overprominent satellites.
 Similar abnormalities may be caused by antimetabolite drugs (e.g: cytosine arabinoside, hydroxyurea, and
methotrexate)
INEFFECTIVE HEMATOPOIESIS
 Accumulation of unconjugated bilirubin, raised urine urobilinogen, reduced haptoglobins and positive urine
hemosiderin
 Raised s. LDH
 A weakly positive direct antiglobulin test due to complement can lead to false diagnosis of autoimmune hemolytic
anemia.
NEUROLOGICAL MANIFESTATIONS

 Demyelination neuropathy – posterior column + pyramidal  ataxic gait +spasticity

optic atrophy, anosmia

 No methylation of biogenic amines  cognitive impairment ,dementia
CLINICAL FEATURES

EPITHELIAL SURFACES:
 Epithelial cell surfaces of the mouth (glossitis), stomach and small intestine and the respiratory, urinary and
female genital tracts.
 Cells show macrocytosis, with increased numbers of epithelial and dying cells.
 Deficiencies may cause cervical smear abnormalities.
 Gonads- infertility is common in both men and women.
 Maternal folate and cobalamin deficiency- prematurity, recurrent fetal loss and neural tube defects.
 Reversible hyperpigmentation knuckles
 Impairs bactericidal function of phagocytes
 Osteoporosis
 NEURAL TUBE DEFECTS:

FA supplements has reduced the incidence of neural tube defects

(anencephaly, meningomyelocele, encephalocele and spina bifida)
Incidence of cleft lip and palate can also be reduced.

Polymorphism in the MTHFR gene leading to reduced activity of 5, 10 methylene THF Reductase.
 Cardiovascular disease-

Patients with deficiency of one of the three enzymes, methionine synthase, MTHFR, or cystathionine synthase with
homocystinuria have increased incidence of vascular disease like IHD, cerebrovascular disease or pulmonary
embolus.

Venous thrombosis is found to be more common in folate or b12 deficient subjects.

 MALIGNANCY-

Prophylactic folic acid has been found to have reduced the incidence of ALL and leukemias with mixed lineage
leukemias.

Other tumors associated with folate polymorphisms include follicular lymphoma, breast cancer and gastric cancer.

Because FA may “feed” tumors, it probably should be avoided in those with established tumors unless there is severe
megaloblastic anemia due to folate deficiency.
CAUSES OF COBALAMIN DEFICIENCY

Inadequate dietary intake- vegans

 Deficiency usually does not progress to megaloblastic anemia as the vegan diet is not completely lacking in
cobalamin and the enterohepatic circulation is intact.
 Infants born to severely cobalamin-deficient mothers have shown growth retardation, impaired psychomotor
development, and other neurological sequelae. MRI shows delayed myelination and atrophy.
GASTRIC CAUSES OF COBALAMIN DEFICIENCY

 Pernicious anemia
 Juvenile pernicious anemia- one half have associated endocrinopathy
 Congenital IF deficiency or functional abnormality- antibodies are absent. Child usually presents with
megaloblastic anemia in the first to third yr. autosomal recessive.
 Gastrectomy
 Food cobalamin malabsorption- failure of release of cobalamin from binding proteins.
PERNICIOUS ANEMIA

 severe lack of IF due to gastric atrophy;

 Occurs more commonly in persons with other autoimmune diseases
 Gastric output of pepsin, hydrochloric acid and IF is severely reduced.
 Gastric biopsy- atrophy of all layers of the body and the fundus, with loss of glandular elements, absence of
parietal and chief cells replaced by mucus cells, a mixed inflammatory cell infiltrate and intestinal metaplasia.
 H. pylori infection occurs infrequently in PA.
IF immunoglobulin antibodies:
 “blocking” or type 1 antibody- prevents combination of IF and cobalamin
 Type II antibody – prevents attachment of IF to ileal mucosa.
INTESTINAL CAUSES OF COBALAMIN MALABSORPTION

 Intestinal stagnant loop syndrome

 Ileal resection
 Selective malabsorption of cobalamin with proteinuria (Imerslund Grasbeck syndrome; congenital cobalamin
malabsorption; autosomal recessive megaloblastic anemia)
 Tropical sprue
 Fish tapeworm infestation
 Gluten induced enteropathy
 severe pancreatitis,
 HIV infection
 Radiotherapy
 Zollinger Ellison syndrome
 Drugs -colchicine, para aminosalicylic acid, neomycin, slow release potassium chloride, anticonvulsant drugs,
metformin, cytotoxic drugs
 Graft versus host disease.
 Alcohol
ABNORMALITIES OF COBALAMIN METABOLISM

 Congenital transcobalamin II deficiency or abnormality

 Congenital methyl melonic acidemia or aciduria
 Acquired abnormality of cobalamin metabolism: nitrous oxide inhalation.
CAUSES OF FOLATE DEFICIENCY

 NUTRITIONAL: Nutritional folate deficiency occurs in infants with repeated infections, solely fed by goats
milk, kwashiorkor, scurvy

 MALABSORPTION:

tropical sprue, gluten induced enteropathy

jejunal resection, partial gastrectomy
sulfasalazine, cholestyramine and triamterene.
 EXCESS UTILIZATION OR LOSS

pregnancy
prematurity
Hematologic disorders- chronic hemolytic anemia
Chronic inflammatory disease
Homocystinuria
Long term dialysis
Congestive heart failure, liver disease- release of folate from damaged liver cells
 ANTIFOLATE DRUGS

PHENYTOIN OR PRIMIDONE
Alcohol
Methotrexate, pyrimethamine and trimethoprim

 CONGENITAL ABNORMALITIES OF FOLATE METABOLISM

THIAMINE RESPONSIVE MEGALOBLASTIC ANEMIA

 Rogers syndrome
 Affects Krebs cycle (energy generation), ribose pentose pathway (nucleic acid formation)
 Defect in SLC19A2 gene
 Thiamine def succinyl CoA not utilized.
 Triad – MA with ringed sideroblast +DM+SNHL
DIAGNOSIS OF COBALAMIN AND FOLATE
DEFICIENCIES
COBALAMIN DEFICIENCY

Serum cobalamin: (ELISA)

 Normal levels range from 148 to 738 pmol/L

Serum methyl malonate and homocysteine:

 Serum MMA levels can be used for the early diagnosis of cobalamin deficiency, even in the absence of
hematological abnormalities.
 S. homocysteine is raised both in early cobalamin and folate deficiency
TESTS FOR THE CAUSE OF COBALAMIN DEFICIENCY
 Studies of cobalamin absorption- obsolete
 Tests to diagnose PA- raised s.gastrin, reduced s. pepsinogen 1, gastric endoscopy, IF and parietal cell antibodies.
FOLATE DEFICIENCY
 S. folate- 11 to 82 nmol/L
 S folate rises in severe cobalamin deficiency.
 Red cell folate- 880 to 3520 umol/L
 S. folate rises in B12 def (block in conversion of MTHF to THF), intestinal stagnant loop syndrome
TESTS FOR THE CAUSE OF FOLATE DEFICIENCY
 Diet history
 Transglutaminase antibodies.
TREATMENT
 Indications- established megaloblastic anemia or neuropathy
 Prophylaxis – gastrectomy, ileal resection, long term therapy with PPI
 Unusual issues – hypokalemia , thrombocytosis
COBALAMIN DEFICIENCY

 Indications for starting cobalamin – well documented megaloblastic anemia or other hematologic abnormalities
and neuropathy due to deficiency
 Replenishment of body stores- six 1000ug im inj of hydroxocobalamin given at 3 to 7 day intervals
 Maintanence :once every 3 months
 More frequent doses in neuropathy
FOLATE DEFICIENCY

 Oral doses of 5 to 15mg folic acid daily for about 4 months till all folate deficient red cells have been eliminated
and replaced.
 Long term folic acid therapy is required when underlying cause cannot be corrected or is likely to recur
 FOLINIC ACID – given orally or parenterally to overcome the toxic effects of methotrexate or other DHF
reductase inhibitors. Gets converted to methylene tetrahydrofolate.
PROPHYLACTIC FOLIC ACID

Pregnancy –
 400mcg daily before and through out pregnancy to prevent megaloblastic anemia and neural tube defects
 Folic acid reduces risk of birth defect in babies born to diabetic mothers
 In women who have had a previous fetus with NTD 5mg daily folic acid is recommended
Infancy & childhood –
 Folic acid should be given routinely to premature babies and who develop feeding difficulties, infections or
vomiting and diarrhoea
 Routine dose is 1mg daily
APPROACH TO HEMOLYTIC ANEMIA
 In hemolytic anemia, there is premature destruction of RBC (<120 days ), which in turn to compensate there is
increase in production capacity of RBCs by bone marrow.
 When the rate of destruction exceeds the BM capacity of producing more RBC, the hemolytic disorder will
manifest as hemolytic anemia.
HEMOLYTIC ANEMIA – CLASSIFICATION :

 Inherited / Acquired
 Acute / Chronic
 Intravascular / Extravascular
 Intracorpuscular / Extracorpuscular
Extravascular destruction except
PNH Intravascular destruction except AIHA
Attributable to Bone marrow response:
 Increased reticulocytes
 Increased MCV, MCH
 Peripheral smear – macrocytes polychromasia, nucleated RBC
 BM aspirate - erythroid hyperplasia
 Essential pathophysiologic process in all hemolytic anemia: Increased Red cell turnover
 Chronic intravascular hemolysis

Persistent hemoglobinuria
Signficant iron loss
 Chronic extravascular hemolysis

Iron overload
Secondary hemochromatosis
 Intravascular hemolysis Extravascular hemolysis

Site of hemolysis Within the circulation Mononuclear phagocytes of

reticuloendothelial system – spleen
and liver
Free hemoglobin Released in blood Engulfed by macrophages

Fate of free hemoglobin Binds to haptoglobin Converted to bilirubin

Serum haptoglobin Decreased Normal or slightly decreased

When haptoglobin is depleted Free heme binds to hemopexin or

hemoglobin is oxidised to
methemoglobin
Serum hemopexin Decreased Normal

In blood Hemoglobinemia Moderate unconjugated

Methemoglobinemia hyperbilirubinemia
Mild unconjugated
hyperbilirubinemia
Increased LDH
 Intravascular hemolysis Extravascular hemolysis

Consequences of hemoglobinemia Renal failure No hemoglobinemia

(nitric oxide scavenging capacity of Hypertension
hemoglobin) Smooth muscle spasm
Prothrombotic state
Urine Hemoglobinuria(brown ) Increased urobilinogen, urobilin
Hemosiderinuria (yellow)
Spleen and liver Normal Enlarged
Kidneys Iron and hemosiderin deposition Normal
leading to AKI
Peripheral blood smear Schistocytes/burr cells/helmet cells in Spherocytes – spherocytosis,
microangiopathic hemolytic anemia AIHA,G6PD
Spherocytosis not corrected by
addition of glucose ;high MCHC –
hereditary spherocytosis
Bite cells, Heinz body – G6PD def
Target cells , Howel jolly body- sickle
cell anemia , beta thalassemia
Sickle cell ,polychromatophilia in
sickle cell disease
Basophilic stippling- beta thalassemia

Coombs test
Osmotic fragility test
Sickling test
NESTROFT test (0.35 % NS added
to control and patients blood
sample)
CD 55/59 flow cytometry, Hams
acidified serum test , sucrose lysis
test
Intravascular hemolysis Extravascular hemolysis
IgM in cold AIHA IgG in warm AIHA
Positive in hereditary spherocytosis
Sickling in sickle cell anemia
Screening test for beta thalassemia
(black line in white paper behind
patients tube is not visible )
Positive in PNH
ACUTE VS CHRONIC HEMOLYSIS

 ACUTE HEMOLYSIS
 Rapid onset and is isolated, episodic or paroxysmal
 Normal between episodes
 Eg: intravascular hemolysis in PNH, paroxysmal cold hemoglobinuria, ABO incompatible transfusion.
 Fever ,chills, acute chest and back pain, acute renal failure
 COMPENSATED CHRONIC HEMOLYSIS
 RBC life span is chronically shortened but BM compensation prevents anemia
 Dramatic acute hemolytic event occurs when the cells are challenged with oxidizing agents
 No features of c/c hemolysis like gall stones and splenomegaly
 Eg: G6PD deficiency
 UNCOMPENSATED CHRONIC HEMOLYSIS
 Chronic onset with extramedullay hematopoiesis inadequate to compensate severe anemia
 Pigment gall stones , splenomegaly
 Eg: extravascular hemolysis in RBC membrane defects, thalassemia.
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