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Flashcards in GI: RBC Disorders Deck (46):
1

  • Due to decreased production of Hemoglobin
  • RBC progenitor cells in the Bone marrow divide multiple times to achieve the correct MCV: 80 -100
  • Microcytosis is due to an “Extra division” --> Too small
  • Macrocytic  anemia is due to “One less” division --> Too big
  • Hemoglobin = Heme + Globin

Microcytic Anemia

2

Microcytic Anemia Diseases?

Microcytic Anemia Diseases?

  • Iron Deficiency (Late)
  • Anemia of Chronic Disease
  • Thalassemias
  • Lead Poisoning
  • Sideroblastic Anemia

3

Macrocytic Anemia Diseases?

Macrocytic Anemia Diseases?

  • Megaloblastic
    • Folate Deficiency
    • B12 Deficiency
    • Orotic Aciduria
       
  • Non-Megaloblastic
    • Liver Disease
    • Alcoholism
    • Reticulocytosis

4

Non-Hemolytic Normocytic Anemia Diseases?

Non-Hemolytic Normocytic Anemia Diseases?

  • Iron Deficiency (Early)
  • Anemia of Chronic Disease
  • Aplastic Anemia
  • Chronic Kidney Disease

5

Hemolytic Normocytic Anemia Diseases?

Hemolytic Normocytic Anemia Diseases?

  • Intrinsic
    • RBC membrane defect: Hereditary Spherocytosis
    • RBC Enzyme Deficiency
      • G6PD
      • Pyruvate Kinase
    • HbC defect
    • Paroxysmal Nocturnal Hemoglobinuria
    • Sickle Cell Enemia
       
  • Extrinsic
    • Autoimmune
    • Microangiopathic
    • Macroangiopathic
    • Infections

6

  • Decreased Levels of Fe2+
    --> decreased Heme --> decreased Hemoglobin ---> Microcytic anemia
  • Most common type of Anemia
  • Nutritional deficiency (1/3 world)
  • Meat and non-meat consumption
  • Absorption occurs in the Duodenum
  • Enterocytes have Heme and non-Heme (DMT1) transporters
  • Transport Fe2+ across the Cell membrane via Ferroportin
  • Transferrin transports Fe2+ to Liver and Bone marrow Macrophages
  • Intracellular Fe2+ is bound to Ferritin

Iron Deficiency Anemia (Microcytic Anemia)

7

  • Serum Iron = measure of Iron in the Blood
  • Total Iron-binding Capacity = measurement of Transferrin molecules in the Blood
  • % Saturation = % Transferrin- Fe2+ complexes
  • Serum Ferritin = Fe2+ stores in Macrophages and Liver

Laboratory Measurements of Iron Status

8

  • Infants – Breast feeding (Human milk is low in Fe2+)
  • Children – Poor diet
  • Adults (20 – 50) – Peptic ulcer disease in Males / Menorrhagia or Pregnancy in Females
  • Elderly – Colon polyps / Carcinoma in Western world; Hookworm (Ancylostoma duodenale and Necator americanus) in the Developing world
  • Other – Malnutrition, Malabsorption, Gastrectomy (acid state)

Iron Deficiency Typical

9

  • Storage of Iron is depleted --> Decreased Ferritin; Increased TIBC
  • Serum Iron is depleted --> Decreased Iron, Decreased % Saturation
  • Normocytic anemia – BM makes fewer but normal sized
  • Microcytic Hypochromatic anemia – BM makes smaller, and Fewer

Stages of Iron Deficiency

10

Clinical Features of Iron Deficiency

  • Anemia w/ Conjunctival pallor
  • Microcytic Hypochromatic
  • Increased RDW
  • Decreased Ferritin, Serum Fe2+, % Saturation
  • Increased TIBC, Increased Free Erythrocytic Protoporphyrin (FEP)
  • Pica
  • Koilonychia – spoon nails

11

Plummer-Vinson Syndrome (Microcytic Anemia)

  • Fe2+ deficiency anemia w/
    --> Microcytic Hypochromatic anemia
  • Esophageal web --> Dysphagia
  • Atrophic Glossitis --> Beefy-red tongue

12

  • A/w Chronic Inflammation or Cancer
  • Most common in Hospitilized pts.
  • Production of Acute phase reactants from the Liver; Including Hepcidin
  • Inflammation --> Hepcidin (Liver) – sequesters Fe2+ in Storage sites, binds Ferroportin to Intestinal mucosal cells and Macrophages, inhibit transport
    • Limiting Fe2+ transfer from Macrophages or Erythroid precursors
    • Suppressing EPO production --> Prevents Bacterial growth
  • Increased Ferritin, Free Erythrocyte Protoporphyrin (FEP)
  • Decreased TIBC, Serum Fe2+, % Saturation

Anemia of Chronic Disease

(Microcytic / Normocytic Anemia)

13

  • Defective Protoporphyrin (Heme) synthesis
  • Protoporphyrin is synthesized via a series of RXNs
  • Ferrochelatase attaches Protoporphyrin to Fe2+ to make Heme
  • Final RXN occurs in the Mitochondria
  • Fe2+ is transferred to Erythroid Precursors and Enters the Mitochondria to form Heme --> If Protoporphyrin is def. --> Fe2+ trapped in Mitochondria
  • Fe2+ laden Mitochondria --> Ring around the Nucleus of Erythroid precursors --> ‘Ringed Sideroblasts’ Mito. In Bone marrow
  • Congenital: Aminolevulinic acid synthesis def. (ALA Synthase def.)
  • Acquired: Alcoholism – Mito. Poison, Lead Poisoning inhibits ALAD and Ferrochelatase, Vit. B6 def. – cofactor for ALAS – TB treatment (Isoniazid Tx)
  • Increased Ferritin, Serum Iron, % Saturation
  • Decreased TIBC
  • Tx: Pyridoxine (B6) cofactor for ALA synthase

Sideroblastic Anemia

(Microcytic Anemia)

14

  • Decreased Synthesis of the Globin Chains of Hemoglobin
  • Inherited mutation
  • Protected against Plasmodium falciparum malaria
  • Alpha and Beta variant chains
  • Normal Hemoglobin are HbF(alpha2, gamma2), HbA(alpha2,beta2), HbA2(alpha2,delta2)

Thalassemia

(Microcytic Anemia)

15

  • 4 Alpha genes are normally present
  • One gene – Asymptomatic
  • Two genes – Mild anemia w/ Increased RBC count
    • Cis deletion – Asians (worse)
    • Trans deletion – African Americans
  • Three genes – Severe anemia --> Beta chains form Tetramers (HbH) that damage RBCs --> HbH seen on Electrophoresis
  • Four genes – Not compatible w/ Life --> Hydrops Fetalis --> Gamma cahins form Tetamers --> Hb Barts syndrome seen on Electrophoresis

Alpha-Thalassemia

(Microcytic Anemia)

16

  • Point mutations in Promoter or Splicing sites
  • Mediterranean and African
  • Two genes – present on Chrom 11 --> Absent Beta0 or Diminsed Beta+

Beta-Thalassemia

(Microcytic Anemia)

17

  • Mildest form of disease and is Asymptomatic w/ increased RBC count
  • Beta chain underproduced (Heterozygote)
  • Microcytic Hypochromatic RBCs and Target cells on Blood smear
  • Hemoglobin Electrophoresis shows:
  • Slightly Decreased HbA w/ Increased HbA2 (5%, normal 2.5%) and HbF (2%, normal 1%)

Beta-Thalassemia minor

(Beta/Beta+)

18

  • Most severe form of the disease and Severe anemia
  • Few months after birth - Homozygote
  • High HbF (alpha2gamma2) at birth --> Temporarily protective
  • Unpaired alpha chains precipitate --> Dmg RBC membrane --> Ineffective erythropoiesis and Extravascular hemolysis (Removal of circulating RBCs by Spleen)
  • Massive Erythroid Hyperplasia --> Expansion of Hematopoiesis into the Skull --> ‘Crewcut’ and ‘Chipmunk face’
  • Extramedullary Hematopoiesis w/ Hepatosplenomegaly
  • Risk of Aplastic crisis w/ Parvovirus B19 inf. Of Erythroid precursors
  • Tx: Chronic transfusions --> Hemochromatosis (Tx: Deforaxamine)
  • Microcytic Hypochromic RBCs w/ Target cells and Nucleated RBCs
  • Electrophoresis shows HbA2 and HbF w/ little/none HbA

Beta-Thalassemia major

(Beta0/Beta0)

19

  • Macrocytic RBCs and Hypersegmented neutrohils (>5 lobes)
  • Glossitis
  • Decreased Serum Folate
  • Increased Serum Homocysteine (Risk for Thrombosis
  • Normal Methylmalonic acid
  • Obtained from Green vegatables and Fruits
  • Absorbed in the Jejnum - Malabsorption
  • Develops w/in Months
  • Poor diet (Alcoholics and Elderly)
  • Drugs  - Methotrexate (Folate antagonist – Inhibits Dihydrofolate reductase)
    • (Methotrexate, Trimethoprim, Phenytoin)
  • Pregnancy, Cancer, and Hemolytic anemia (Increased Demand)

Folate Deficiency

(Macrocytic Anemia - Megaloblastic)

20

  • Macrocytic anemia w/ Hypersegmented neutrophils
  • Glossitis
  • Subacute combined degeneration fo the Spinal cord due to Increased Methylmalonic aicd --> Degeneration --> Loss Proprioception and Vibratory sensation w/ Spastic paresis (LCS tract) (Not seen in Folate Def.) --> Dementia!
  • Increased Homocysteine (same as Folate Def.) --> Thrombosis
  • Salivary gland enzymes (amylase) liberate B12 --> R-binder --> through the Stomach
  • Pancreatic Proteases detach from R-binder
  • B12 + IF --> Absorbed in Ileum
  • Less common than Folate def. and takes Years to develop
  • Pernicious Anemia
  • Pancreatic insufficiency
  • Damage to the Terminal Ileum (Crohn disease or Diphyllobothrum latum [fish tapeworm])
  • Vegans, Strict dietary deficiency very rare

Vitamin B12 (cobalamin) Deficiency

(Macrocytic Anemia - Megaloblastic)

21

  • Most common cause of Vit. B12 deficiency
  • Autoimmune destruction of Parietal cells (Body of Stomach) --> Leads to Intrinsic Factor (IF) deficiency

Pernicious Anemia

22

  • Children w/ Megaloblastic anemia – that cannot be cured w/ Folate or B12
  • Failure to thrive
  • Hypersegmented neutrophils, Glossitis
  • Orotic acid in urine
  • No Hyperammononemia
  • Defect UMP synthase --> Inability to convert Orotic acid to UMP (de novo Pyrimidine synthesis pathway)
  • Autosomal recessive
  • Tx: Uridine Monophosphate to bypass mutated Enzyme

Orotic Aciduria

(Macrocytic Anemia – Megaloblastic)

23

  • Macrocytic anemia in which DNA synthesis is Unimpaired
  • Macrocytosis and Bone marrow suppression can occur in the Absence of Folate / B12 deficiency
  • Liver Disease
  • Alcoholism
  • Reticulocytosis
  • Increased MCV w/ Drugs
    • 5-Fluorouracil (cancer)
    • Zidovudine (HIV)
    • Hydroxyurea

Non-Megaloblastic Macrocytic Anemias

24

Corrected Reticulocyte Count

  • Normal reticulocyte count (RC) = 1 – 2%
  • RC lifespan 120 days
  • 1 – 2% are removed and replaced per day
  • Properly functioning marrow replaces > 3%
  • Falsely elevated in Anemia
  • RC corrected = RC x Hct / 45
    • > 3% --> Good marrow response --> Peripheral destruction
    • < 3% --> Poor marrow response --> Underproduction

25

  • Defect of RBC cytoskeleton-membrane tethering protiens and Plasma membrane
  • Ankyrin, Spectrin, Protein 4.2, and Band 3
  • Osmotic fragility test --> spherocyte fragility in Hypotonic solution
  • Eosin-5-maleimide binding test for Screening
  • Membrane blebs are removed --> Spherocytes --> Less maneuverable --> Consumed by Splenic macrophages --> Anemia
  • Spherocytes w/ loss of Central palor --> uniformly reddish
  • Increased  RDW and MCHC (only this disease)
  • Splenomegaly --> premature removal by Spleen
  • Jaundice w/ Unconjugated Bilirubin and Bili-Gallstones
  • Aplastic crisis w/ Parvovirus B19 of Erythroid precursors
  • Tx: Splenectomy --> Spherocytes persist w/ Howell-Jolly bodies

Hereditary Spherocytosis
(Normocytic – Hemolytic – Intrinsic)

26

  • Beta chain hemoglobin --> replaced Glutamic acid w/ Valine (hydrophobic) at Position 6
  • Autosomal recessive
  • Protective Falciparum malaria
  • Disease --> two abnormal Beta genes --> >90% HbS RBCs
  • HbS polymerizes when Deoxygenated --> Needle like
  • Hypoxemia, Dehydration, and Acidosis
  • HbF protects against sickling for first few months
  • Extravascular / Intravascular Hemolysis
  • Erythroid hyperplasia --> ‘Crewcut and Chipmunk face’
  • Hematopoiesis w/ Hepatomegaly
  • Aplastic Crisis w/ Parvovirus B19
  • Renal papillary necrosis

Sickle Cell Anemia

(Normocytic – Hemolytic – Intrinsic)

27

What diseases give ‘Crewcut and Chipmunk face’?

What diseases give ‘Crewcut and Chipmunk face’?

  • Beta-Thalasemia
  • Sickle cell Anemia

28

  • Painful Swollen Hands and Feet due to Vaso-occlusion --> Infarction
  • Common presenting sign in Infants
  • Complication of Sickle cell Anemia
  • (Normocytic – Hemolytis – Intrinsic)

Dactylitis w/ Sickle cell Anemia

29

  • Shrunken, Fibrotic, Spleen
  • Increased risk of infection w/ encapsulated organism
    • Streptococcus pneumoniae and Haemophilus influenza (death in Children) – vaccinated by 5 y.o.
    • Increased Risk of Salmonella paratyphi Osteomyelitis
  • Howell-Jolly bodies on Blood smear
  • Complication of Sickle cell Anemia
  • (Normocytic – Hemolytis – Intrinsic)

Autosplenectomy w/ Sickle cell Anemia

30

  • Vaso-occlusion in Pulmonary microcirculation
  • Chest-pain, Shortness of Breath, Lung infiltrates
  • Precipitated by Pneumonia
  • Stroke
  • Most common cause of Death in Adults
  • Pain Crisis (vaso-occlusive)!
  • Complication of Sickle cell Anemia
  • (Normocytic – Hemolytis – Intrinsic)

Acute Chest Syndrome w/ Sickle cell Anemia

31

  • One normal and One mutated Beta chain
  • 50% HbS in RBCs
  • Generally asymptomatic w/ no anemia
  • RBCs w/ <50% HbS do not Sickle in vivo except in the Renal medulla
  • Extensive Hypoxia and Hypertonicity of Medulla cause Sickling --> Microinfarctions --> Microscopic Hematuria --> Decreased ability to concentrate urine
  • Metabisulfite screen to cause Sickling
  • Hb electrophoresis w/ Bone marrow Transplantation

Sickle Cell Trait

32

  • Autosomal recessive mutations in Beta chain of Hemoglobin
  • Normal Glutamic acid is replaced by Lysine at Residue 6 in Beta-globin
  • Mild anemia due to extravascular Hemolysis
  • HbC crystals seen in RBCs on Blood smear
    • Rectangular w/ points on both sides

Hemoglobin C

(HbC - Normocytic – Hemolytic – Intrinsic)

33

  • Defective Myeloid Stem cells --> Absent Glycosylphosphatidylinositol (GPI)
  • Susceptible to Complement destruction
  • Blood cells coexist w/ Complement
  • Decay Accelerating Factor (DAF) protective --> Inhibit C3 convertase
  • Absencne of GPI (anchoring protein) --> No DAF --> Complement dmg
  • Hemolysis episodic and Often at Night during Sleeping --> Acidosis --> Compliment activation --> Absent GPI --> dmg
  • Sucrose Test to screen for disease --> Sucrose activates Complement
  • Flow cytometry test for CD 55 (DAF) and CD 59 (GPI)
  • Hepatic, Portal, Cerebral Thrombosis --> Death from release of Cytoplasmic contents --> Coag cascade
  • Complications: Fe2+ def. anemia, Acute myeloid Leukemia (AML -10%)
  • Triad: Coombs Negative Hemolytic anemia (non-Ab), Pancytopenia, and Venous Thrombosis
  • Tx: Eculizumab

Paroxysmal Nocturnal Hemoglobinuria

(PNH – Normocytic – Hemolytic – Intrinsic)

34

  • X-linked Recessive Enzyme Disorder (most common)
  • Heinz-bodies and Bite cells
  • RBCs susceptible to Oxidative Stress
  • Back pain, Hemoglobinuria a few days after Oxidant Stress
  • Glutathione (antioxidant) neutralizes H2O2
  • NADPH byproduct of G6PD required to regenerate Glutathione
  • Reduced Glutathione --> Oxidative injury --> Intravascular Hemolysis
  • Precipitates Hb as Heinz bodies --> Splenic macrophages --> Hemolysis
  • Infections, Drugs (Primaquine, Sulfa drugs, Dapsone), and Fava beans
  • (2) Major Varients – Both protect against Falciparum
    • African – Mildly reduced half-life of G6PD leading to mild Intravascular Hemolysis w/ oxidative stress
    • Mediterranean – Markedly reduced half-life of G6PD leading to marked intravascular Hemolysis w/ Ox. Stress

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency (Normocytic – Hemolytic – Intrinsic)

35

  • Ab Destruction of RBCs
  • IgM or IgG
  • Coombs Test Positive +
    • Direct Coombs Test – anti-Ig Ab (Coombs reagent), added to Pts. blood, RBCs agglutinate if RBCs are coated w/ Ig
    • Indirect Coombs Test – normal RBCs added to Pts. serum, if serum has anti-RBC surface Ig, RBCs agglutinate when anti-Ig Ab (Coombs reagent) added

Immune Hemolytis Anemia

(IHA – Normocytic – Hemolytic – Extrinsic)

36

  • Extravascular Hemolysis
  • IgG binds to RBCs in the Warm temperature of the Central body (Warm agglutinin); Membrane of Ab – Coated RBS is consumbed by Splenic Macrophages --> Spherocytes --> Slowly pick of Membrane Ab
  • A/w SLE (most common cause)
  • CLL and Drugs (Penicillin, Alpha-Methyldopa and Cephalosporins ‘Cef-‘)
    • Drug-RBC membrane complex binding site for Ab
    • Alpha-Methyldopa (Drug) may produce Ab that bind to Self-RBCs
  • Tx: Cessation of offending Drug, Steroids, IVIG, and Splenectomy (Last)

IgG-mediated Disease (IHA)

37

  • Extravascular Hemolysis
  • IgM binds to RBCs and fixes complement in Cold temperature of Extremeties (Cold agglutinin)
  • RBCs inactivate complement, but residual C3b serves as an Opsonin for Splenic Macrophages resulting in Spherocytes
  • CLL
  • Extreme activation --> Intravascular Hemolysis
  • A/w Mycoplasma pneumoniae and Infectious Mononucleousis

IgM-mediated Disease (IHA)

38

  • Small blood vessel pathology --> Intravascular Hemolysis --> RBCs are destroyed as they pass through the Circulation
  • Fe2+ deficiency anemia occurs w/ Chronic Hemolysis --> Hematuria
  • Occurs w/ Microthrombi (TTP, HUS, DIC, HELLP Schistocytes on Blood smear and SLE

Microangiopathic Hemolytic Anemia

(Normocytic – Hemolytic – Extrinsic)

39

  • Prosthetic heart valves and Aortic Stenosis may cause Hemolytic anemia Secondary to Mechanical Destruction
  • Schistocytes on Peripheral Blood smear

Macroangiopathic Hemolyitic Anemia

(Normocytic – Hemolytic – Extrensic)

40

  • Infection of RBCs and Liver w/ Plasmodium
  • Anopheles mosquito
  • RBCs rupture as part of the Plasmodium life cycle --> Intravascular hemolysis and Cyclical Fever
    • P falciparum – daily fever (24 hrs)
    • P vivax and P ovale – fever every other day (48 hrs)
  • Splenic Macrophages consume infected RBCs --> Mild extravascular hemolysis w/ Splenomegaly

Malaria

(Normocytic – Hemolyitic – Extrinsic)

41

  • Infects Progenitor Red cells and Temporarily halts Erythropoiesis
  • Leads to significant Anemia in the setting of Pre-existing Marrow Stress (e.g. Sickle cell anemia)
  • Tx: Supportive (Infection is self-limited)

Parovirus B19

(Normocytic – Hemolytic – Extrinsic)

42

  • Damage to Hematopoietic Stem Cells --> Pancytopenia (Anemia, Thrombocytopenia, Leukopenia) w/ Low Reticulocyte count
  • Drugs or Chemicals
  • Viral infections
  • Autoimmune damage
  • Biopsy --> Empty Fatty marrow
  • Tx: Cessation of Drugs, Supportive care w/ Transfusions and Marrow stimulating Factors (EPO, GM-CSF, and G-CSF) --> Produce Granulocytes
    • Immunosuprresion may be helpful in cases of Abnormal T-cell activation w/ release of Cytokines
    • Bone marrow Transplantation (Last)

Aplastic Anemia

(Normocytic – Non-Hemolytic)

43

  • Increased RBC Protoporphyrin
  • Inhibits rRNA degradation --> RBCs retain aggregates of rRNA --> Microcytic anmeia w/ ‘Basophilic stippling’
  • Old Houses and Chipped paint
  • Adults: Encephalopathy, Memory loss, Delerium, Mental deterioration, Demylination, Colicky Abdomanal pain, Renal Failure
  • ‘Ringed Sideroblasts’ in Bone marrow
  • Inhibits ALA Dehydratase (2nd Step of Heme syn.) – Delta-ALA UP
  • Inhibits Ferrochelatase and (Final Step of Heme syn.) – Protoprphyrin UP

Lead Poisoning (Microcytic Anemia)

  • L-L-L-E-E-A-A-D-D-D -S
  • Lead Lines on Gingivae (Burton lines) and on Metaphysis of Long bones
  • Encephalopathy and Erythrocyte ‘Basophilic stippling’
  • Adominal colic and Sideroblastic Anemia
  • Drops – Wrist and Foot drop, Dimecaprol and EDTA are 1st Line of Treatment
  • Succimer used for Chelation for Kids

44

  • Autosomal recessive
  • Defect in Pyruvate kinase --> Decreased ATP --> Rigid RBCs
  • Hemolytic anemia in Newborn
  • Extravascular

Pyruvate Kinase Deficiency

(Normocytic – Hemolytic – Intrinsic)

45

  • Deficiency of Uroporphyrinogen-1-Synthase (Porphobilinogen deaminase) (3rd Step in Heme syn.)
    --> Increase Porphobilinogen, Delta-ALA, Coporphobilinogen (urine)
  • 5 P’s
    • Painful Abdomen (neuro-toxic)
    • Port wine-colored Urine
    • Polyneuropathy
    • Psychological disturbances
    • Precipated by Drugs (Barbituates, Seizure drugs), Alcohol, and Starvation
  • Tx: Glucose and Heme --> Inhibit ALA synthase

Acute Intermittent Porphyria

46

  • Deficiency in Uroporphyrinogen Decarboxylase (5th Step in Heme Syn.)
  • Increase Uroporphyrin (‘Tea Colored Urine’ – Uroporphyrinogen III)
  • Blistering cutaneous Photosensitivity (face and hands)
  • Hypertrichosis (hair growth)
  • HCV
  • Alcoholism (AST + ALT)

Porphyria Cutanea Tarda