GI: RBC Disorders Flashcards
- 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
Microcytic Anemia Diseases?
Microcytic Anemia Diseases?
- Iron Deficiency (Late)
- Anemia of Chronic Disease
- Thalassemias
- Lead Poisoning
- Sideroblastic Anemia
Macrocytic Anemia Diseases?
Macrocytic Anemia Diseases?
- Megaloblastic
- Folate Deficiency
- B12 Deficiency
- Orotic Aciduria
- Non-Megaloblastic
- Liver Disease
- Alcoholism
- Reticulocytosis
Non-Hemolytic Normocytic Anemia Diseases?
Non-Hemolytic Normocytic Anemia Diseases?
- Iron Deficiency (Early)
- Anemia of Chronic Disease
- Aplastic Anemia
- Chronic Kidney Disease
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
- 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)
- 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
- 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
- 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
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
Plummer-Vinson Syndrome (Microcytic Anemia)
- Fe2+ deficiency anemia w/
- -> Microcytic Hypochromatic anemia
- Esophageal web –> Dysphagia
- Atrophic Glossitis –> Beefy-red tongue
- 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)
- 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)
- 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)
- 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)
- 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)
- 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+)
- 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)
- 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)
- 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)
- Most common cause of Vit. B12 deficiency
- Autoimmune destruction of Parietal cells (Body of Stomach) –> Leads to Intrinsic Factor (IF) deficiency
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
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
Non-Megaloblastic Macrocytic Anemias
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
- 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)
- 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 (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
- 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) (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
- 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