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Brains Review
Hematology: Anemia
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General Principles
A sign, not a disease
Acquired or hereditary abnormality (RBCs/
precursors); or non- hematologic A dynamic process
Elderly are more prone to anemia, but is
not a cause of anemia Diagnosis of iron deficiency anemia
mandates further work-up
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Definition
Decrease circulating RBC mass
(decrease in any: Hct, Hgb, RBC)
+
Decrease O2- carrying capacity of theblood
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Main consequence:Main consequence:Tissue HypoxiaTissue Hypoxia
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Mild Severe chronic
Asymptomatic
Exertional dyspnea
Fatigue
Lightheadedness/fainting
Palpitation
Pica
Syncope (postexercise)
Bounding pulseanemia
Dizziness
Headache
Syncope
Tinnitus or vertigo
Irritability
Difficulty sleeping or
concentrating
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Common signs:
Pallor
Tachycardia
Ejection systolic (flow) murmur Mild peripheral edema
Venous hums & wide pulse pressure
Angina pectoris (elderly) Abnormal menstruation
Decrease in libido & impotence
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Cardiovascular Adaptations
Rapid:
Sudden marked
contraction of IV vol
Postural hypotension Fall in cardiac output
Shunting of blood- skin to
central organs
Sweating Restlessness
Thirst and air hunger
Slow:
Adaptations for O2
mantainance
Increase of plasmavolume
Right shift- O2-hgb
dissociation curve
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History:
Age
Duration & time of onset
Previous anemia / intake of hematinics
Other subjacent illness (gallbladder, liver, renal, endocrine dse/surgery)
Associated symptoms related w/ one specific etiology (change inbowel habits, rheumatic)
Family / Social history
Occupation
Hemotransfusion
Blood loss Drug / Toxin exposure
Diet
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Physical findings:
Skin: Jaundice; Petechiae; Leg ulcers
Urine: dark urine
Spleen: enlargement
Neurologic symptoms: loss of vibrationsensibility, paresthesia, ataxia
HEENT: Tongue atrophy
Lymphadenopathy
Evidence of blood in feces or vomit Signs of primary dse leading to secondary
anemia
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Basic Laboratory Exams
CBC (Retic, Platelet, Diff ct)
RBC Indices (MCH, MCV, MCHC)
PBS (Color/Inclusions/Aniso- Poikilo-cytosis)
Serum ferritin
Serum iron TIBC
BMA
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Others:
Stool Guaiac, Creatinine,
B1 (increase)
Haptoglobin (decrease) Urine hemosiderin (present)
Hemoglobin-emia/uria (present)
Serum LDH (increase) Stool/urine urobilinogen (increase)
Methgb (increase)
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PATHOPHYSIOLOGIC
CLASSIFICATION OF ANEMIA
1. Impaired production
2. Increased destruction (Hemolytic)3. Blood loss
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IMPAIRED PRODUCTION
(1) STEM CELL PROLIFERATION/
DIFFERENTIATION APLASTIC ANEMIA
PURE RED CELL APLASIA
ENDOCRINE DEF (PITUITARY,THYROID, ADRENAL, TESTIS)
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IMPAIRED PRODUCTION
(2) RBC-BLAST PROLIF / DIFF MEGALOBLASTIC ANEMIA (DNA SYNTHESIS) VIT. B12 DEFICIENCY
FOLIC ACID DEFICIENCY
HYPOCHROMIC ANEMIA (HEMOGLOBIN
SYNTHESIS) HEME: IDA; SIDEROBLASTIC ANEMIA GLOBIN: THALASSEMIAS
MULTIPLE MECHANISMS ACD (INFLAMMATORY, INFECTIOUS, NEOPLASTIC)
RDA
MYELOPHTHISIC ANEMIA (BM INFILTRATION)
REFRACTORY ANEMIA W/ CELLULAR BM
PROTEINMALNUTRITION
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INCREASED DESTRUCTION
(1) INTRINSIC HEREDITARY CELL MEMBRANE DEFECT SPHEROCYTOSIS
ELLIPTOCYTOSIS
STOMATOCYTOSIS
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA ENZYMOPATHIES
GLUCOSE 6 PHOSPHATE DEHYDROGENASE DEFICIENCY
PYRUVATE KINASE DEFICIENCY
HEMOGLOBINOPATHIES
SICKLE CELL ANEMIA HEMOGLOBIN C DISEASE
HEMOGLOBIN E
PORPHYRIAS
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INCREASED DESTRUCTION
(2) EXTRINSIC ANTIBODY:ANTIBODY: AIHA (IgG)
COLD REACTING (IgM)
DRUG INDUCED
MECHANICAL:MECHANICAL:
PROSTHETIC HEART
VALVE
MAHA BURNS
INFECTION:INFECTION:
BACTEREMIA
PARASITEMIA
MALARIA
BARTONELLOSIS
OTHERS:OTHERS:
HYPERSPLEENISM
OXIDIZING AGENTS
VENOM (SNAKE,
INSECT)
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BLOOD LOSS
ACUTE CHRONIC
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Classification of anemia
Reduced production
Def of hematinics
IDA
Folate & B12 def
Dyserythropoiesis
ACD
MDS
Sideroblastic a
Marrow infiltration
Failure of production
Aplastic anemia
Pure red cell aplasia
Increased destruction Hemolytic anemia
Intrinsic causes
Membrane defects
Enzymopathies
Hemoglobinopathy
Extrinsic causes
Immune reactions
Microangiopathic
Parasitic
Hypersplenism
Bleeding
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MORPHOLOGIC
CLASSIFICATION
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MICROCYTIC HYPOCHROMIC
(MCV < 80)
IDA
ACD (25%)
THALASSEMIA SIDEROBLASTIC A
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MACROCYTIC (MCV > 100)
MEGALOBLASTICMEGALOBLASTIC
BMBM
FOLIC ACID DEF
VIT B12 DEF
THIAMINE DEF
NORMOBLASTIC BMNORMOBLASTIC BM
RETICULOCYTOSIS
LIVER DSE/ OBSTRUCTIVE
JAUNDICE POSTSPLEENECTOMY
HYPOTHYROIDISM
APLASTIC A
MYELOPROLIFERATIVE DSE
ALCOHOL ABUSE DRUGS
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NORMOCYTIC
RPI > 3 INTRINSICRPI > 3 INTRINSIC
HEMOLYSISHEMOLYSIS:
ENZYMOPATHIES
HEMOGLOBINOPATHY MEMBRANE DEFECTS
RPI > 3 EXTRINSICRPI > 3 EXTRINSIC
HEMOLYSISHEMOLYSIS:
AIHA
MAHA
BLOOD LOSS > 1 WEEK
RPI < 3RPI < 3
BLOOD LOSS < 5- 7 DAYS
CHRONIC DSE A (75%)
MILD IDA
SIDEROBLASTIC A
REFRACTORY A
RDA
MYELOPHTHISIC A
ENDOCRINE DYSFXN A HYPO- / A- PLASTIC A
HEPATIC DISEASE A
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MICROCYTIC & NORMOCYTIC
IDAIDA
ACD (25%)ACD (25%)
THALASSEMIA
SIDEROBLASTICASIDEROBLASTICA
RPI < 3
BLOOD LOSS < 5- 7DAYS
ACD (75%)ACD (75%)
MILD IDAMILD IDA SIDEROBLASTICASIDEROBLASTICA
REFRACTORY A
RDA
MYELOPHTHISIC A
ENDOCRINE DYSFXN A
HYPO- / A- PLASTIC A
HEPATIC DSE A
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Erythrocytes
Structurally the
simplest cell in the
body
Basic function: Create& maintain an
environment for
physical integrity &
functionality of Hgb
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Erythropoiesis
(Kinetics)
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Substances necessary for RBC
production:
Metals (iron, cobalt,
manganese)
Vitamins (B12, B6, C,
E, folate, riboflavin,pantothenic, thiamine)
Amino acids
Regulatory
substances:
Erythropoietin
Thyroid hormones
Androgens
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IMPAIRED PRODUCTION (1)
STEM CELL PROLIFERATION/
DIFFERENTIATION APLASTIC ANEMIA
PURE RED CELL APLASIA
ENDOCRINE DEF (PITUITARY,THYROID, ADRENAL, TESTIS)
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Aplastic Anemia
BM Aplasia (Lack of
Cells)
Failure ofMultipotent
Stem Cell T cell MediatedSuppression or
Genetic Damage
BM: Markedly
Hypocellular PBS: Pancytopenia;
Normochromic
Normocytic RBCs
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Aplastic Anemia
Largely empty
marrow spaces
Fat cells, fibrous
stroma, scattered orclustered foci of
lymphocytes / plasma
cells
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Aplastic A: Causes
Idiopathic (70 % or >) w/ Poor Prognosis esp if < 40 y/o
Inherited:
Fanconi anemia (rare, AR; defects in DNA repair;multiple congenital anomalies)
Familial aplastic anemia
Dyskeratosis congenita
Shwachman Diamond Syndrome
Dubowitz syndrome
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Causes Of Aplastic Anemia
Acquired:
Drugs 6 mecaptopurine
Methotrexate
Cyclophosphamide
Chloremphenicol
Chemicals: insecticides
Toxin (benzene, CCl4)
Whole body Irradiation Infection: *Viral hepatitis; HIV; IM; CMV
MDS
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CAUSES
DEPRESSION OR CESSATION OF ACTIVITY OF
ALL BLOOD PRODUCING ELEMENT
DAMAGE TO STEM CELL
LEUKOPENIA
THROMBOCYTOPENIA
DECREASE IN FORMATION OF RBC
PANCYTOPENIA
REPEATEDINFECTION;
FREQUENTSICK DAY
BLEEDINGTENDENCY AEB
ECCHYMOSIS,PURPURA,PETICHIAE,
LEEDING FROM NOSE,MOUTH,
VAGINA, RECTUMPALLOR OF SKIN & MUCOUSMEMBRANE, CYANOSIS
APLASTIC ANEMIA
PATHOGENESIS
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Aplastic A: Clinical Features
Anemia: pallor, easy fatigability, weakness, loss ofappetite
Thrombocytopenia: petechiae, easy bruising, severenosebleeds, bleeding into GIT & renal tract
Leukopenia: increased susceptibility to infections & oralulcer
Hepatosplenomegaly & LAD do not occur; their presencesuggest underlying leukemia
Hyperplastic gingivitis Special features
Skin: Hyperpigmentation, caf au-lait spots, erythematous rash
Head:Microcephaly, micro-ophthalmia
Mouth: cleft lip, leukoplakia
General: small stature
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Treatment: Aplastic Anemia
Treatment of identifiable cause
Supportive care Blood component therapy
Treatment of infections Severe acquired AA:
Stem cell transplantation
Immunosuppression
ALG or ATG + cyclosporine Moderate
Androgens
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ANTITHYMOCYTE GLOBULIN
Immunosuppressant for post BMT or
undergo treatment forAplastic Anemia
Reduces activity ofT lymphocytesattacking BMstem cells.
Prevents GVH Rxn via eliminating reactive
WBCs
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Precautions
Allergic reaction to horses or rabbits
Inc chance of getting other infections
Fever, chills, shakes w/in few hours afterthe 1st dose
Side Effect: H20 retention
Report: heart working harder, bloating orswelling
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Cyclophosphamide
Anti - cancer & immunosuppressant
Drug of choice for BMT
Side Effects: nausea, vomiting, hair loss; affects heart, lungs liver
Severe bladder damage through acrolein production (colorless liquidirritant used in chemical warfare as a tear gas)
Another drug may be given before and after each dose ofcyclophosphamide to reduce its toxicity
InformMD of dysuria
May lead to abnormal bleeding, inc risk of infection due topancytopenia & reduced fertility in men
Drink lots of water while taking this drug to prevent bladder irritation
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Side Effects of Cyclosporine
Confusion
Nervousness
Unusual weakness/ tiredness
DOB
Shortness of breath Tender, enlarged, or bleeding
gums
Nausea or vomiting
Stomach pain (severe)
Irregular heartbeat Convulsions
Numbness
When taking cyclosporine :
Avoid eating excessiveamounts of foods high inpotassium
Avoid grapefruit juice, mayblock breakdown ofcyclosporine by liver
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IMPAIRED PRODUCTION (2)
RBC-BLAST PROLIF / DIFF MEGALOBLASTIC ANEMIA (DNA SYNTHESIS)
VIT. B12 DEFICIENCY
FOLIC ACID DEFICIENCY
HYPOCHROMIC ANEMIA (HEMOGLOBIN
SYNTHESIS) HEME: IDA; SIDEROBLASTIC ANEMIA GLOBIN: THALASSEMIAS
MULTIPLE MECHANISMS ACD (INFLAMMATORY, INFECTIOUS, NEOPLASTIC)
RDA
MYELOPHTHISIC ANEMIA (BM INFILTRATION)
REFRACTORY ANEMIA W/ CELLULAR BM
PROTEINMALNUTRITION
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Myelophthisic Anemia
BM Replacement
BM failure:
Mets Ca (MC)
Destruction by non-
neoplastic process
(Fibrosis, Infection)
PBS: Pancytopenia,immature circulating
cells
Breast CancerBreast Cancer
Replacing BMReplacing BM
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IMPAIRED PRODUCTION
(2) RBC-BLAST PROLIF / DIFF MEGALOBLASTIC ANEMIA (DNA SYNTHESIS)
VIT. B12 DEFICIENCY
FOLIC ACID DEFICIENCY
HYPOCHROMIC ANEMIA (HEMOGLOBIN
SYNTHESIS) HEME: IDA; SIDEROBLASTIC ANEMIA GLOBIN: THALASSEMIAS
MULTIPLE MECHANISMS ACD (INFLAMMATORY, INFECTIOUS, NEOPLASTIC)
RDA
MYELOPHTHISIC ANEMIA (BM INFILTRATION) REFRACTORY ANEMIA W/ CELLULAR BM
PROTEINMALNUTRITION
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Megaloblastic anemia
disorder caused by impaired DNA
synthesis
Cells primarily affected: blood cells,G
Iepithelial cells
slowed nuclear cell division with normal
progression of cytoplasmic maturation
megaloblastosis in bone marrow
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Causes ofMegaloblastic
anemia Cobalamin deficiency Inadequate intake (vegans)
Malabsorption
Gastric achlorydia, partial gastrectomy, drugs that
block acid secretion
Pernicious anemia, total gastrectomy
Terminal ileal disease: sprue, enteritis, resection,
tumors
Competition of cobalamin: fish tapeworm, blind
loop syndrome
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Causes of megaloblastic anemia
Folic acid deficiency Inadequate intake: unbalanced diet (alcoholics,
teenagers, some infants)
Increased requirements Pregnancy
Infancy
Malignancy
Increased hematopoiesis (chronic hemolytic anemias)
Chronic exfoliative skin disorders
Hemodialysis
Malabsorption
Impaired metabolism
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Other causes of megaloblastic
anemia Drugs that impair DNA metabolism
Purine antagonists: 6 mercaptopurine, azthioprine
Pyrimidine antagonists: 5FU, cytosine arabinoside,others
Others: procarbazine, hydroxyurea, zidovudine Metabolic disorders (rare)
Hereditary orotic aciduria
Lesch Nyhan syndrome
Megaloblastic anemia of unknown etiiology Refractory megaloblastic anemia DiGuglielmos syndrome
Congenital dyserythropoietic anemia
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Megaloblastic A
LAB DX:
NEUTRO/ THROMBO- CYTOPENIA
INC. SERUM Fe; DEC. TIBC
INC. OF SERUM BILIRUBIN PBS: MACROOVALOCYTES; B. STIPPLINGS; HJ
BODIES;MACROPOLYCYTES (HYPERSEG. PMN)
BM: DYSERYTHROPOIESIS- MEGALOBLASTS;
GIANT METAMYELOCYTES INEFFECTIVEERYTHROPOIESIS
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VIT. B12 DEF. vs FOLIC A. DEF.
PERNICIOUS A
+ -
IF DEF (CHRONIC GASTRITIS)
ANTI PARIETAL CELL Ab & ANTI IF Ab
S/ S: SPASTIC ATAXIA
+ -
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VIT. B12 DEF. vs FOLIC A. DEF.
LAB DX:
LDH INCREASE INCREASE
PBS/B.M.
MACRO- OVALOCYTES/ HYPERSEGMENTED PMN(MACROPOLYCYTE)/ GIANT METAMYELOCYTE;LEUCO- /THROMBO- CYTOPENIA
URINARY MMA
INCREASE NORMAL
FIGLU NORMAL INCREASE
GASTRIC ANALYSIS HISTAMINE FAST NONE
ACHLORYDRIA
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Macrocytic: RPI < 2
Megaloblastic Anemia. PBS Macro-ovalocytic
Polychromasia
Hypersegmentedneutrophil
Other Labs: Homocysteine Folate
def.
Methylmalonic acid B12def.
IF Ab test: specific for PAbut only 50% sensitive
Parietal cell Ab test:sensitive (90%) but notspecific
Schilling test
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VIT. B12 DEF. vs FOLIC A. DEF.
SCHILLING TEST
+ -
Non radioactive B12 1st given to bind to all
available transcobalamin in the PB: Prevents any reabsorbed radioactive B12 from
binding to transcobalamin
Forces it to be excreted into the urine
Radioactive B12 given by mouth followed by 24hurine to test for % radioactive B12 reabsorbed:
no radioactive B12 in 24h urine confirms BI2 def
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VIT. B12 DEF. vs FOLIC A. DEF.
SCHILLING TEST
+ -
If corrected w/ addition of IF to oralradioactive B12: patient has Pernicious a
If corrected after antibiotic therapy: patient
has bacterial overgrowth
If corrected w/ addition of pancreatic
extract followed by intake oral radioactive
B12: patient has chronic pancreatitis
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Clinical Manifestations:
Anemia with slight icteresia
GI manifestations glossitis, smooth,
beefy red tongue, malabsorption
Neurologic manifestations (Cobalamin) -
subacute combined degeneration of CNS
peripheral neuropathy numbness,
weakness, ataxia, paresthesia,disturbances of mentation
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Management:
Treatment of underlying problem
Replacement therapy: oral folic acid;
parenteral B12
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Treatment ofMegaloblastic anemia
Treat the cause
Cobalamin deficiency
IM
cyanocobalamin: 1000 mcg per week for 8weeks then monthly
Oral cobalamin: 2 mg crystalline B12 per day
Folic acid: 1 mg/day po
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IMPAIRED PRODUCTION (2)
RBC-BLAST PROLIF / DIFF MEGALOBLASTIC ANEMIA (DNA SYNTHESIS)
VIT. B12 DEFICIENCY
FOLIC ACID DEFICIENCY
HYPOCHROMIC ANEMIA (HEMOGLOBINSYNTHESIS) HEME: IDA; SIDEROBLASTIC ANEMIA
GLOBIN: THALASSEMIAS
MULTIPLE MECHANISMS ACD (INFLAMMATORY, INFECTIOUS, NEOPLASTIC)
RDA
MYELOPHTHISIC ANEMIA (BM INFILTRATION) REFRACTORY ANEMIA W/ CELLULAR BM
PROTEINMALNUTRITION
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Hemoglobin
Heme = Fe++ Plus Porphyrin
+Globin
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Hemoglobin
Conjugated protein for transport of O2 &
CO2
&
Buffer (O2 Dissociation Curve)
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Basic Structure of All Human
Hemoglobin
Each Hgb molecule:
4 iron-containing,
tetrapyrrole heme
rings 4 polypeptide globin
chains
2 alpha chains
2 non-alpha chains
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Normal Hgb:
Hgb A1 95 - 98% (adult)
15 - 40% at birth predominates at 6 12 mons
Hgb A2 2 - 3% (adult)
0 - 1.8%- cord blood 5 - 6 mons- adult levels
Hgb F < 2% (adult)
1 - 0.8% (3 y/o)
90 - 95% - fetal life
Hgb Gower 1 & 2; Portland Hgb - Embryonic
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Hgb derivatives (CHON (N) but Fe
& nature of organic grp changed) Oxyhgb
O2 + reduced hgb (purple red) bright red
Maintained by methemoglobin- cytochrom C reductase
575 nm
Carboxyhgb CO + Hgb cherry pink
Collect in citrate
200 X affinity vs O2
Heavy smokers
Test: ammonia + blood (25% COHgb); 540 nm
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Hgb derivatives (CHON (N) but Fe
& nature of organic grp changed) Methgb (0.5% normal in blood)
Fe++ Fe+++ brown
No O2 binding cyanotic
Induced by oxidizing agents
525 nm Sulfhgb (0- 2.2% normal in blood)
Sulfa drugs or trinitrotoluene + hgb
Irreversible binding RES
Myoglobins
Porphyrins
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Dietary sources of iron
Sources of ironHeme iron: Meat,
fish, liver
Fe+2
Non-heme iron:Vegetables
Fe+3
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Absorption of Iron
Vit C, amino acids promote absorption
Gastric acid helps in solubility
Tea, veg. fiber decrease absorption
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Major Iron Compartments
Metabolic:
Hgb 1800 - 2500 mg
Myoglobin 300 - 500 mg
Storage:
Iron storage 0 - 1000 mg
Transit:
Serum iron 3 mg
Total 3000 - 4000 mg
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A i d t d fi i f
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Anemia due to deficiency of
hematinics- Iron deficiency
MCC of anemia & is due to chronic blood
loss, deficient intake, increased demand
(pregnancy & lactation)
Chronic blood loss - MCC of IDA in adults
(peptic ulcers, ca of the stomach & colon,
menorrhagia, UT lesions)
A i d t d fi i f
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Anemia due to deficiency of
hematinics- Iron deficiency
Microcytic hypochromic anemia with a low
serum total iron, increased iron binding
capacity, and decreased serum ferritin
indicating reduced iron stores
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Microcytic Anemia (IDA)
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IDA
Low retic ct
DEC SERUM Fe
INC TIBC (high
specificity- near 100%but poor sensitivity 100 ng/ml r/o IDAExcept in acute hepatitisor liver necrosis but notchronic liver dse(elevated- release of Festores)
Falsely elevated in
disseminated TB &Hodgkin's dse
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Iron Deficiency Anemia:
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Iron Deficiency Anemia:
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Status
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iron
transferrin
Prussian Blue Stain
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Prussian Blue Stain
of Bone Marrow
Iron Present No Iron Present
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Low MCV and Low Retics
Differential diagnosis
Iron deficiency Sideroblastic anemia
Thalassemia trait
Lead poisoning Anemia of chronic disease
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Treatment
Severity and cause determine approach to
treament
Elderly+/- cardiovasular instability: RBC
transfusions
Younger individuals with compensated
anemia: iron replacement
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Oral Iron Therapy
Optimal response occurs when about 200
mg of elemental iron given per day
Absorption more complete on empty
stomach
With or after a meal, absorption decreases
by 40 to 50%
However gastric irritation is common,
hence, advise to take tablet immediately
after a meal may increase compliance
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Oral Iron Therapy
Absorption enhanced by orange juice,meat, poultry, fish
Absorption inhibited by cereals, tea, milk
Side Effects of Oral Iron: GIT: heartburn,nausea, abdominal cramps, diarrhea
Dose related
Continue iron treatment 3 to 6 monthsafter anemia resolves
Allows repletion of iron stores
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Preparation Size Iron
Content
Usual Adult daily
dose
Ferrous sulfate
tablets (hydrated) 300 mg 60 mg 3 tablets
tablets (exsiccated) 200 mg 60 mg 3 tablets
syrup & elixirs 40 mg/ml 8 mg/ ml 25 ml
Ferrous gluconate 300 mg 37 mg 5 tablets
Ferrous fumarate 200 mg
300 mg
67 mg
100 mg
3 tablets
2 tablets
Oral Iron PreparationsOral Iron Preparations
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Indications for Parenteral Iron
Unable to tolerate iron compounds orally
Poor compliance
Persistent loss of blood or iron at a rate too rapid
for oral intake to compensate for the loss Disorder ofGI tract e.g. ulcerative colitis
Malabsorption of iron
Inability of maintain iron balance during
treatment with hemodialysis Donating large amounts of blood for
autotransfusion
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Computing for the dose of parenteral
iron
= Body weight (kg) x 2.3 x (15 patients
Hgb g/dL) + 500 or 1000 mg (for stores)
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IDANormal
ACD
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SIDEROBLASTIC ANEMIA
ETIOLOGY /MECHANISM:
HEREDITARY (X LINKED/ AR) HEPATOSPLENOMEGALY; THROMBOEMBOLISM
ACQUIRED
IDIOPATHIC NEUTROPENIA W/ PELGER HUET CELLS PRONE TO Fe OVERLOAD; TE
10% DEVELOP AML
DRUG INDUCED ALCOHOL- FOLATE DEF. +MALNUtrition
INH- VIT. B12 METABOLISM CHLORAMPHENICOL-MITOCHONDRIAL INHIBITION
LEAD- HEME PATHWAY
DISEASE ASSO (THYROID; CA; LYMPHOMA; MM; RA)
S O S C
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SIDEROBLASTIC ANEMIA
MECHANISM:
REFRACTORY A. (RESISTANT TO TX)
INEFFECTIVE ERYTHROPOIESIS
(ANEMIA W/ HYPERPLASTIC BM)
Sid bl i A L b D
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Sideroblastic A Lab Dx:
PBS: Papenheimer
Bodies; Basophilic
stippling in Pb
poisoning; Dimorphic(macrocytic +
intensely microcytic
RBCs) in patient w/
acquired sideroblastica; anisopoikilocytosis;
Target cells
Sid bl ti A L b D
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Sideroblastic A Lab Dx:
Serum Fe: Inc
Stigmata ofMDS
BM: Ringed
sideroblasts on BMFe stain; inc
hemosiderin
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Ferritin
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Iron deficiency
Reduced
HBelectrophoresis Anemia of Chronic Disease
Normal
Bone marrow
Ringed sideroblasts
Increased
Furthe
r invest
igat
ionstofind
thecauseare necessary
If HB electrophoresis is normal then doalpha gene mapping
H
ypochromi
a
Microcytic
Note: Anisocyosis: RDW
poikilocytes
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Hemosiderosis
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Hemosiderosis
H h t i
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Hemochromatosis
Genetic dse
Excess amounts of
iron
Arthritis, cirrhosis,DM, heart failure,
HCC
INCREASED DESTRUCTION
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(1) INTRINSIC HEREDITARY CELL MEMBRANE DEFECT
SPHEROCYTOSIS
ELLIPTOCYTOSIS
STOMATOCYTOSIS
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
ENZYMOPATHIES GLUCOSE 6 PHOSPHATE DEHYDROGENASE DEFICIENCY
PYRUVATE KINASE DEFICIENCY
HEMOGLOBINOPATHIES SICKLE CELL ANEMIA
HEMOGLOBIN C DISEASE HEMOGLOBIN E
PORPHYRIAS
Erythrocytes: Normal mature
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y y
RBC Biconcave disc
Approximatly 8 um in
dia
2.5 um thick at theperiphery
1.0 um thick at center
Contains 27- 34 pg
(10-12 g) of hgb
(about 95% of dry wt
of RBC)
B kd f th RBC
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Breakdown of the RBC
Toward the end of 120 day life span, 1%
of RBCs per day
Membrane becomes less flexible
Concentration of cellular hemoglobinincreases
Enzyme activity (esp glycolysis) diminishes
Erthroc te Destr ction
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Erthrocyte Destruction
Extravascular Hemolysis (major- 90% via RES)
Intravascular Hemolysis (minor- 5-10%)
Extravascular Hemolysis
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Extravascular Hemolysis
Intravascular Hemolysis
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Intravascular Hemolysis
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Areas of RBC metabolism crucial
for RBC survival & function
RBC membrane
RBC metabolic pathways
Hemoglobin structure & function
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RBC MEMBRANE: Hereditary
Membrane Dse.Hereditary Spherocytosis
Hereditary Ovalocytosis /
Elliptocytosis
Hereditary Stomatocytosis
RBC MEMBRANE:
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3 Major Structural Proteins
Semi-permeable bilayer
of lipids (including
cholesterol) & proteins
Deformable to pass
through microvessels &
permeable to allow H2O
& electrolytes to
exchange (inc surfacearea)
Major protein is spectrin
Cytoskeletal Proteins: Maintain
RBC Shape, Strength, Flexibility
Case
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Case
HS
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HS
AD- MC
AR- More Severe
MC in Northern
European ancestry A spectrin def w/
principal defect in
abnormality of
ankyrin
Vertical stabilization
defect of phospholipidbilayer spectrin -
phospholipid bilayer
separates
Portions PL bilayer
forms vesicles (lost)
decreased surface
area
spherocytosis
Hereditary Spherocytosis
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Hereditary Spherocytosis
Mutation of Ankyrin Gene
(Most Common Defect)
Abnormal Ankyrin Protein
Deficiency of SpectrinAssembly
Hereditary Spherocytosis
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Hereditary Spherocytosis
Defects may be in:
Actin - spectrin - band
3 complex
Spectrin - 4.1 -glycophorin complex
Connection between
bilayer & spectrin
HS: S/S:
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HS: S/S:
Waxing / waning anemia, jaundice
(hemolysis accelerated by infection)
Splenomegaly (hyperplasia secondary to
increased workload), pigmented gallstones(hx cholecystectomy), ankle ulcers
Family hx: (AD 1: 5000 people of
European descent)
HS Lab Dx:
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HS Lab Dx:
PBS: Moderate Anemia;Spherocytes;Reticulocytes(polychromatophilia)
Inc retic ct, inc LDH, inc
B1, inc EOFT Normal MCH w/ an incMCHC
BM - ErythroidHyperplasia
Coombs Test - Negative Inc Autohemolysis Test
corrected by glucose
Hereditary Spherocytosis
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Hereditary Spherocytosis
Tx: folate replacement, splenectomy in
some circumstances
Pearl: Parvovirus B19 infection in patients
w/ hemolytic anemias in general aplasticcrisis
Management:
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Management:
Splenectormy for moderate to severe
hemolysis
Folic Acid supplementation
Case
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Case
14 mon old African-
American child
presents w/ mild
anemia
What are they
Hereditary elliptocytosis &
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Hereditary pyropoikilocytosis
Defects in horizontaljunctions:
Between a- & b-spectrin dimers or
Between spectrin,actin & band 4.1
RBC cytoskeletonloose structuralstrength & lateralintegrity
Hereditary elliptocytosis
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Hereditary elliptocytosis
Autosomal dominant
Structural abnormality of spectrin or def ofRBC membrane protein 4.1
W/o anemia & usually w/o splenomegaly &only mild hemolysis; Most patientsasymptomatic
EV hemolysis, thus splenectomy correctshemolysis, but not the RBC membranedefect
Hereditary elliptocytosis
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Hereditary elliptocytosis
PBS: large #s of
elliptocytes &/or
ovalocytes
# of elliptocytes does not
correlate w/ severity ofhemolysis
EOFT is usually normal
Reticulocytes mild inc
(
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Hereditary pyropoikilocytosis
Rare AR
Severe hemolysis, bizarre
poikilocytosis & RBC
fragmentation (hallmarks)
Structural abnormality ofspectrin, RBCs fragment
when heated (45C)
Normal RBCs fragment at
49C
Case
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Case
Biochemical changes that can
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cause shape change in RBC Accumulation of cholesterol causes
increased membrane
Target cell
Acanthocyte
Decreased spectrin causes decreased
membrane
Spherocyte Bite cell
INCREASED DESTRUCTION
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(1) INTRINSIC HEREDITARY CELL MEMBRANE DEFECT
SPHEROCYTOSIS
ELLIPTOCYTOSIS
STOMATOCYTOSIS
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
ENZYMOPATHIES GLUCOSE 6 PHOSPHATE DEHYDROGENASE DEFICIENCY
PYRUVATE KINASE DEFICIENCY
HEMOGLOBINOPATHIES SICKLE CELL ANEMIA
HEMOGLOBIN C DISEASE HEMOGLOBIN E
PORPHYRIAS
Paroxysmal Nocturnal
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Hemoglobinuria
Rare, acquired,chronic
S/s: Recurrent abdominal
pain, vomiting,headaches, eye pain,thrombophlebitis
Breathlessness atnight
Episodic Hgb in urine,Hemosiderinuria
Complications:
Aplastic anemia
Leukemia Venous thrombosis
PNH
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PNH
Mutation of Stem Cells - No Anchor
Protein (Chronic Hemolysis) + SERUM C
vs RBC, WBC, PLATELETS; INC C3
FIXATION; INC MAC; INC CPENETRATION OF LIPID MEMBRANe
Complement-Induced Lysis
(Intravascular
- Hgb in Urine)C
CC
PNH: Pathophysiology
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PNH: Pathophysiology
Acquired Somatic mutation in PIG-A gene
Dec GPI proteins esp DAF (DAF usually binds to
GPIs on RBC surface to breakdown C
components from lysing cell (specifically C3convertase) inc C activity
Clonal cell disorder (affects all cell lines), w/
ongoing IV & EV hemolysis, classically at night
(due slight acidosis during sleep; C componentsmore active in pH (likewise exercise)
PNH: Lab Dx
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PNH: Lab Dx
PANCYTOPENIA
DEC. NAP
SUCROSE HEMOLYSIS T (SCREEN)
> 10%= PNH5-10%= MEGA. A; AIHA
ACIDIFIED SERUM TEST/ HAMS
(CONFIRM
) 10- 15% HEM
OLYSIS Flow cytometry: CD 59 negative (a productof the PIG-A gene)
INCREASED DESTRUCTION
(1) INTRINSIC
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(1) INTRINSIC HEREDITARY CELL MEMBRANE DEFECT
SPHEROCYTOSIS
ELLIPTOCYTOSIS
STOMATOCYTOSIS
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
ENZYMOPATHIES GLUCOSE 6 PHOSPHATE DEHYDROGENASE DEFICIENCY
PYRUVATE KINASE DEFICIENCY
HEMOGLOBINOPATHIES SICKLE CELL ANEMIA
HEMOGLOBIN C DISEASE HEMOGLOBIN E
PORPHYRIAS
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RBC Metabolic Pathways
Essential for O2 transport &
maintaining physical
characteristics of RBC
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Red cell metabolic pathways
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Red cell metabolic pathways
Generates 90% of energy
Glucose 2 ATP(energy)
90-95% of intracellular
glucose thru free-energy
diffusion
RBCs have no glycogen
Glucose (Na-K ATPase
pump & Ca-Mg ATPase
pump affected in PK Def
Red cell metabolic pathways
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Red cell metabolic pathways
Metabolizes 5-10% ofglucose
Protects RBC fromoxidative injury
G6PD also producesNADPH (keepsglutathione reduced)
Glutathione protects
via break down ofH2O2 H2O + O
Case
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Case
5 y/o African-
American boy
recently presented w/
fever. Prescribed
Bactrim for presumed
otitis media. Brought
back in by mom due
to increased fatigue &
PBS showed
G6PD Pathophysiology
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G6 a op ys o ogy
Defect in HMP
G6PD def dec GSH
oxidant stresses
oxidized hgb (Heinzbodies) RES
phagocytose inclusion
body bite cells
hemolysis
Quali > Quanti defect
decrease half-life later
stages of RBCs life (> 20days), functional levels of
enzyme decline
G6PD Pathophysiology
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p y gy
African AmericanAfrican American:
Asso w/ intermittent
hemolysis since older
RBCs have dec levelsofG6PD & usually
occurs in response to
oxidative states
(infections)
MediterraneanMediterranean:
Asso w/ fava bean
ingestion
More severehemolysis because all
RBCs have dec
G6PD activity due to
dec synthesis &stability
X-linked common in African Americans & Mediteraneans
G-6-PD def
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> 400 Variants
> 200 M people (Mediterranean, West
African,Mid-East & SEA) w/ chronic
hemolysis
Blacks often have an episodic variant in
w/c oxidant cmpds (antimalarials,
sulfonamides, or infections) Women heterozygotes (half the normal
amount of RBC) show increased
resistance to P falciparum
G6PD Deficiency
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y
Jaundice in 1st 24 hrs of
life (pathologic jaundice)
Acute self-limited IV
Episodic hemolytic a
triggered by oxidantstress (drugs, infection)
More severe, chronic
form seen in men of
Mediterranean descent
(fava beans)
G6PD Deficiency
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y
PBS: Bite cells &blister cells
Dx: PBS, G6PD level,Heinz body prep
G6PD levels may benormal in acutesetting due toselective removal of
older RBCs w/ lowerbaseline G6PD levels
G6PD Deficiency
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y
Tx: Get rid of offending oxidant stress
G-6-PD def:
Stressors of G6PD System
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Stressors ofG6PD System
Antimalarials Sulfonamides
Nitrofurans
Phenacetin
Dapsone Synthetic Vit K
Naphthalene (moth balls)
Fava beans
Infection Diabetic ketoacidosis
Red cell metabolic pathways
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p y
Methemoglobin
reductase Pathway:
Maintains iron in the
ferrous (Fe2) state In the absence of the
enzyme (methgb
reductase), methgb
accumulates & itcannot carry O2
INCREASED DESTRUCTION
(1) INTRINSIC
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(1) INTRINSIC HEREDITARY CELL MEMBRANE DEFECT
SPHEROCYTOSIS
ELLIPTOCYTOSIS
STOMATOCYTOSIS
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
ENZYMOPATHIES GLUCOSE 6 PHOSPHATE DEHYDROGENASE DEFICIENCY
PYRUVATE KINASE DEFICIENCY
HEMOGLOBINOPATHIES SICKLE CELL ANEMIA
HEMOGLOBIN C DISEASE HEMOGLOBIN E
PORPHYRIAS
Porphyria cutanea tarda
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p y
Etiology:Uroporphyrin
ogen decarboxylase
def
S/S: Cutaneousphotosensitivity
Lab tests:
Inc urine uroporphyrin
Inc aminotransferase
Features:
Portal inflam w/
cirrhosis
HCC (Anti HC Ab +)
Inc hepatic Fe
Inc urinary
uroporphyrin
Acute intermittent porphyria
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p p y
AD w/ incomplete penetrance (other family
members w/ the condition maybe asymptomatic)
Attacks precipitated by drugs & alcohol (P450
enzyme inducers) Acute attack: urine turns dark on standing due to
high ALA & PBG levels. Levels remain
moderately raised between attacks
Other Porphyria
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p y
Variegate porphyria:
AD
Features:
Cutaneous fragility &
photosensitivity
Acute neurological
attacks common
Hereditarycoproporphyria:
AR
Uroporphyrinogen
synthetase defectexpressed in RBCs w/ inc
porphyrin levels in stool
Acute neurological
attacks + cutaneousmanifestations
INCREASED DESTRUCTION
(1) INTRINSIC
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(1) INTRINSIC HEREDITARY CELL MEMBRANE DEFECT
SPHEROCYTOSIS
ELLIPTOCYTOSIS
STOMATOCYTOSIS
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
ENZYMOPATHIES GLUCOSE 6 PHOSPHATE DEHYDROGENASE DEFICIENCY
PYRUVATE KINASE DEFICIENCY
HEMOGLOBINOPATHIES SICKLE CELL ANEMIA
HEMOGLOBIN C DISEASE HEMOGLOBIN E
PORPHYRIAS
INCREASED DESTRUCTION
(2) EXTRINSIC
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(2) EXTRINSIC ANTIBODY:ANTIBODY:
AIHA (IgG)
COLD REACTING (IgM)
DRUG INDUCED
MECHANICAL:MECHANICAL:
PROSTHETIC HEART
VALVE
MAHA
BURNS
INFECTION:INFECTION:
BACTEREMIA
PARASITEMIA MALARIA
BARTONELLOSIS
OTHERS:OTHERS:
HYPERSPLEENISM
OXIDIZING AGENTS VENOM (SNAKE,
INSECT)
HA: Others
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Antibody Mediated(Spherocytes)
VS Mechanical Trauma
(Schistocytes)
Heart Valves,
Microthrombin FibrinStrands in Vessels
(DIC, TTP, HUS)
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Coombs (+) w/ Spherocytes
Immune & Autoimmune HA
Immune Hemolytic Anemias
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Ab Mediated:
RBC Destruction Caused By Ab to RBC
Surface Ag
Phagocytosis in Spleen
More Common w/ Aging
2 Types - Warm & Cold Autoimmune HA
Immune Hemolytic Anemias
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Warm Ab Type (IgG, 37o C):
IgG + RBC Surface Ags
Primary: Idiopathic (60%)
Secondary: Leukemia, Lymphoma, SLE,
Drugs
Spherocytes - Spleen Removes
Membrane Protein from Ab Coated RBCs
Positive Direct Coombs Test
Immune Hemolytic Anemias
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Cold Ab Type (IgM,
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Autoimmune hemolytic a Warm AIHA: Abrupt onset
IgG
Anti-Rh, e, C, c, LW,U
Jaundice
Splenomegaly
SLE, CLL, Lymphoma Drugs: methyl-dopa,
mefenamic acid,cimetidine, cefazolin
Cold AIHA:
Insidious onset
IgM, complement
Anti-I, I, P (PCH) Cold agglutinin titer
Absent jaundice
M
ycoplasma Virus
Coombs (+) w/ Spherocytes
Other immune hemolytic a
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Other immune hemolytic a Alloantibody hemolytic anemia:
Transfusion reaction
Feto-maternal incompatibility (Kleihauer-Betke
test)
Drug related Hemolytic anemia:
Toxic immune complex (drug+Ab+C3)
Quinine, Quinidine, Rifampin, INH, Sulfonamides,
Tetracyclin
Hapten formation (anti-IgG)
PCN, methicillin, ampicillin
Management:
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Steroids
Splenectomy
Immunosuppresants
HA: Others
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Antibody Mediated(Spherocytes)
VS Mechanical Trauma
(Schistocytes)
Heart Valves,
Microthrombin FibrinStrands in Vessels
(DIC, TTP, HUS)
TTP- HUS
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TTP - HUS:
Thrombocytopenia
MAHA
Neurologic symptoms& signs
Renal failure
Fever
Idiopathic:37%
Drug asso:13%
Autoimmune dse:13%
Sepsis: 9% Pregnancy:7%
Bloody diarrhea: 6%
Hematopoietic celltransplantation: 4%
DIC
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DIC: Depletion of clotting factor (TTP: normal)
Thrombocytopenia
Bleeding (64%)
Renal dysfunction (25%) Hepatic dysfunction (19%)
Respiratory dysfunction (16%)
Shock (14%)
Thromboemboli (7%) CNS involvement (2%)
Sepsis, trauma, malignancy
TTP-HUS / DIC
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Acanthocytosis:
Intrinsic vs Extrinsic
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Intrinsic vs Extrinsic
AR
MECHANISM:
ABETALIPOPROTEIN
EMIA
MALABSORPTION;
RETINAL & CNS C
LAB DX:
DEC LCAT/ INCSPHI:LECI
DEC SERUM CHOLE.
ACQUIRED
MECHANISM:
TERMINAL
CIRRHOSIS
LAB DX:
INC RBC MEMBRANE
CHOLE.
DEC LCAT
Malaria
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Infections Malaria - Organisms
Destroy RBCs
Most Common Acquired
HA Worldwide
Tropical Distribution w/
Variety of Species
Parasites Destroy RBCs
Cyclical HemolysisProduces Fever & Chills
Splenomegaly - o
Mononuclear Cells
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