Brains Review

8/8/2019 Brains Review

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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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(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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RBC-BLAST PROLIF / DIFF MEGALOBLASTIC ANEMIA (DNA SYNTHESIS)

VIT. B12 DEFICIENCY





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





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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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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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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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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RBC-BLAST PROLIF / DIFF MEGALOBLASTIC ANEMIA (DNA SYNTHESIS)

VIT. B12 DEFICIENCY


HYPOCHROMIC ANEMIA (HEMOGLOBINSYNTHESIS) HEME: IDA; SIDEROBLASTIC ANEMIA

GLOBIN: THALASSEMIAS


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



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(1) INTRINSIC HEREDITARY CELL MEMBRANE DEFECT

SPHEROCYTOSIS

ELLIPTOCYTOSIS

STOMATOCYTOSIS

PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

ENZYMOPATHIES GLUCOSE 6 PHOSPHATE DEHYDROGENASE 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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Mutation of Ankyrin Gene

(Most Common Defect)

Abnormal Ankyrin Protein

Deficiency of SpectrinAssembly



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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



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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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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



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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



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SPHEROCYTOSIS

ELLIPTOCYTOSIS

STOMATOCYTOSIS






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)


(1) INTRINSIC


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SPHEROCYTOSIS

ELLIPTOCYTOSIS

STOMATOCYTOSIS






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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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



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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



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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


(1) INTRINSIC


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SPHEROCYTOSIS

ELLIPTOCYTOSIS

STOMATOCYTOSIS






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


(1) INTRINSIC


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SPHEROCYTOSIS

ELLIPTOCYTOSIS

STOMATOCYTOSIS






PORPHYRIAS


(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



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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



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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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Documents

Brains Review