GI: RBC Disorders Flashcards by James Wren

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

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Microcytic Anemia Diseases?

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

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Macrocytic Anemia Diseases?

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

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Non-Hemolytic Normocytic Anemia Diseases?

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

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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

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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)

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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

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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

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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

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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

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Plummer-Vinson Syndrome (Microcytic Anemia)

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

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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)

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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)

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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)

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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)

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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)

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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+)

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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)

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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)

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Folate Deficiency

(Macrocytic Anemia - Megaloblastic)

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

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Vitamin B12 (cobalamin) Deficiency

(Macrocytic Anemia - Megaloblastic)

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

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Pernicious Anemia

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

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Orotic Aciduria

(Macrocytic Anemia – Megaloblastic)

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

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Non-Megaloblastic Macrocytic Anemias

Corrected Reticulocyte Count

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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

* 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 * ****_Sphero_**cytes 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)

* 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)

What diseases give ‘Crewcut and Chipmunk face’?

What diseases give ‘Crewcut and Chipmunk face’? * Beta-Thalasemia * Sickle cell Anemia

* 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

* 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

* 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

* 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

* 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)

* 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)

* 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)

* **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)

* 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)

* 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)

* 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)

* **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)

* 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)

* 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)

* 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)

* *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** (2^nd 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** * **L**ead **L**ines on _Gingivae (Burton lines)_ and on Metaphysis of **L**ong bones * **E**ncephalopathy and **E**rythrocyte ‘Basophilic stippling’ * **A**dominal colic and _Sideroblastic_ **A**nemia * **D**rops – Wrist and Foot drop, **D**imecaprol and E**D**TA are 1^st Line of Treatment * **S**uccimer used for Chelation for Kids

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

Pyruvate Kinase Deficiency | (Normocytic – Hemolytic – Intrinsic)

* Deficiency of **Uroporphyrinogen-1-Synthase (Porphobilinogen deaminase)** (3^rd 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

* Deficiency in Uroporphyrinogen Decarboxylase (5^th 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

GI: RBC Disorders Flashcards

(46 cards)