L2 Anemia I Flashcards
Requirements for Erythropoiesis?
oIron - necesary for formation of hemoglobin
oFolic acid
oVitamin B12
oErythropoietin (EPO) – colony stimulating factor, growth factor that induces the synthesis of RBCs
How long does the production of new red blood cell take?
~ 7 days
Where is Erythropoietin (EPO) Made?
Kidneys produce in response to low O2- disease can disrupt
Stages of Erythropoiesis and requirements of each?
Pro-Erythroblast (EPO) → Erythroblast (Iron, Folate, B12)→ Reticulocyte (NO NUCLEUS)
Ribosome synthesis → Hemoglobin Accumulation → Ejection of Nucleus
What does an increase in number of Reticulocytes indicate?
Indicate increased RBC synthesis/turnover → Implying increased peripheral RBC destruction
Reticulocyte Characteristics?
Reticulocytes constitute ~ 1 % of normal RBC count
Recently released from marrow, ‘young/immature’ larger RBCs
NO nucleus
Blue tinge to cytoplasm (normally pink) as contain ribosomal RNA
Reticulocyte maturation to a mature erythrocyte: ~ 1 day
Erythrocyte Characteristics
Biconcave discs with NO nucleus
No protein synthesis
Cytoplasm contains haemoglobin (Hb)
Primary function: to deliver oxygen
Metabolically active (Glycolysis → ATP; Pentose phosphate pathway → counteract oxidative stress)
What leads to a shift toward HIGHER Hemoglobin O2 Affinity?
Direction of dissociation curve shift?
LEFT shift
Lower CO2
Lower Temp
Higher pH
What leads to a shift toward LOWER Hemoglobin O2 Affinity?
Direction of dissociation curve shift?
RIGHT shift
Higher CO2
Higher Temperatures
Lower pH
Higher Altitude
Proteins in RBC membrane that contribute to shape/felxibility?
What do mutations with these lead to?
Ankyrin, Spectrin, Band 3
Mutations → Hemolytic Anemia
Lifespan/Removal of RBC?
Live for 120 Days in circulation
Removed by macrophages in the spleen
Process of RBC Breakdown?
Side Effect of Excess?
Macrophages Breaks blood into Heme and Globin
Globin further broken into AA
Heme
=> iron extracted
=> stored as ferritin in liver
=> Iron transferred to Bone marrow for new RBC
=> Biliverdin
=> Bilirubin
=> Excessive buildup of Bilirubin => Jaundice
The threshold for diagnosis of Anemia?
Measured as FALL IN HAEMOGLOBIN LEVEL
- Hb<13 g/dL in men
- Hb<11.5 g/dL in women
Symptoms of Anemia?
Symptoms:
- Weakness, fatigue, dyspnoea
- Pale conjunctiva and skin
- Headache, dizziness, angina
Clinical Manifestation of Acute Anemia?
Volume depletion
o Shortness of breath
o Tachycardia
o Decreased blood pressure
o Loss of consciousness
o Organ failure
o Shock
LIFE THREATENING
Casued by Traumatic injury, massive GI hemorrhage, ruptured ectopic pregnancy, ruptured aneurysm
Clinical Manfiestation of Chronic Anemia
- Pallor
- Fatigue, lassitude
- With haemolysis:
- Jaundice
- Gallstones
- With ineffective erythropoiesis
- Iron overload
- Heart failure (myocardial iron overload)
- Endocrine failure
- If severe and congenital:
- Growth retardation
- Bone deformities
- If severe and congenital:
Most useful Classification for diagnosing Anemia?
Morphological Classification of Anaemia
Morphological Classification of Anemia?
Microcytic Hypochromic (MCV <80 fL)
Normocytic normochromic (MCV: 80 - 100 fL)
Macrocytic (MCV > 100 fL)
Classification of Anemia by Cause
Causes of Microcytic Hypochromia? (MCV <80)
▪ Iron deficiency (due to chronic blood loss)
▪ Anaemia of chronic disease (~20%)
▪ Thalassaemia
Causes of Normocytic Normochromatic Anemia? (MCV 80-100)
▪ Hyperproliferative Anemia:
Acute blood loss
Haemolytic anaemia
▪ Anaemia of chronic disease (~80%)
▪ Renal disease
▪ Leukaemia
Causes of Macrocytic Anemia (MCV >100)
-
Megaloblastic Anemia:
- B12 Deficiency
- Folate Deficiency
- Chemotherapy
-
Non-Megoblastic Anemia:
- LIver Disease
- Chronic Alcholoism
- Increased Reticulocytes
Most Common Types of Anemia?
Iron deficiency anemia (microcytic hypochromic)
Anemia of chronic disease (normocytic OR microcytic)
Absorption of Iron from Diet
- Heme and ferrous Fe2+ absorbed in small intestine
- Iron transported in the plasma bound to TRANSFERRIN
- Stored as Ferrtin
Causes of Iron Deficiency Anemia?
Deficient iron stores:
Poor dietary intake
Impaired iron absorption (Celiac disease, Small intestine removal
Chronic blood loss (Gastrointestinal/ Gynaecologic problems)
Increased Demand:
Pregnancy
Growth
The most common cause of blood loss and iron deficiency anemia in males and post-menopausal females?
GI BLEEDING is the most common cause of blood loss and iron deficiency anaemia in males and post-menopausal females!!!
GI workup is mandatory if the source of bleeding has not been identified!!!
Failure to evaluate the GI tract →failing to diagnose potentially resectable colon cancers before they metastasize and become incurable!!!
Clinical Presentations Characteristic of Iron Deficiency Anemia?
➢Angular cheilitis
➢Koilonychia–“spoon nail”
-Cytic versus -chromic with regard to anemia Morphilocal Classification?
TERMS:
-cytic→refers to cell size (MCV –Mean Corpuscular Volume)
-chromic→refers to hemoglobin content (MCHC –Mean Corpuscular Haemoglobin Conc.)
Treatment for Iron Deficiency Anemia
Iron replacement:
- Oral iron is preferable to parenteral iron
- Ferrous (Fe2+) sulphate therapy
- For several months to restore iron stores
- Significant increase in Hb within 3 weeks of therapy
Inappropriate iron therapy can lead to haemosiderosis
Transfusions: only to avoid life-threatening complications of anaemia
Pathogenesis of Anemia of Chronic Disease
Pathogenesis:
o Abnormality in iron utilization: Inflammatory cytokines (IL-6)
→ increased hepcidin levels
→ iron sequestered in macrophages
→ Decreased utilization of endogenous iron stores
o Relative deficiency of EPO (decrease in EPO production and marrow responsiveness to EPO)
→ Inhibition of erythropoiesis
o Reduced proliferation of erythroid precursors in response to EPO and decreased lifespan of erythrocytes
Chronic Diseases that can lead to Anemia?
o Chronic infections (tuberculosis)
o Chronic inflammatory conditions (Crohn’s Disease)
o Rheumatologic disorders
o Malignancy
o Chronic kidney disease
Investigations/Management for Anemia of Chronic Disease?
Investigations:
o Low serum iron
o Low serum iron binding capacity
o Normal or increased serum ferritin
Management: Treatment of underlying cause. DON’t GIVE IRON!!
_____________ regulates iron levels in criculation
Hepcidin: regulates iron level in circulation
Inflammation
→ HIGH hepcidin level
→ serum iron level falls (due to iron trapping in macrophages)
→ anemia
Hemochromatosis
→ hepcidin is low
→ Iron Overload
Etiology of Aplastic Anemia?
Bone marrow failure → Marrow hypoplasia and peripheral pancytopenia
Anaemia is often NORMOCYTIC, mild macrocytosis can also be observed in association with stress erythropoiesis
Aetiology:
- -Alkylating agents, insecticides*
- -Radiation*
- -Viruses (parvovirus, EBV, CMV)*
- -Idiosyncratic reactions to drugs*
- -Inherited defects in telomerase and DNA repair (e.g., Fanconi anaemia)*
- -Immune-mediated or acquired stem cell defects*
Types of Macrolytic Anemia?
Megaloblastic anemia (Defective DNA synthesis)
Non-megaloblastic anemia (NO impairment of DNA synthesis)
- Liver disease (RBCs become stuffed with cholesterol and are larger)
- Alcoholism
- Hypothyroidism
- Myelodysplastic syndromes (MDS)
Common Causes of Megaloblastic Anemia?
Vitamin B12 Defciency
Folate Deficiency
Drugs interfering with DNA synthesis (e.g., methotrexate given for chemotherapy/rheumatology. Folate given to avoid deficiency)
Megaloblastic Anemia Pathogenesis?
Presentation?
- Defective DNA synthesis leading to unbalanced growth and delayed cell division without impairment of RNA synthesis
→ Nuclear-cytoplasmic asynchrony (affects all rapidly growing cells)
→ Unusally large erythroid precursor cells: ‘megaloblasts’
→ Mature into unusually large RBCs: ‘macro-ovalocytes
- Macro-ovalocytes are removed prematurely in the circulation
- Autohaemolysis of affected megaloblasts in bone marrow (ineffective erythropoiesis)
→ Low reticulocyte count
→ increased bilirubin and increased LDH
→ pancytopaenia
Testing for Megaloblastic Anemia
BLOOD FILM
Raised MCV →macro-ovalocytes (MCHC normal)
Anisocytosis (variation in size), poikilocytosis (variation in shape)
Neutrophils are larger than normal, platelets are not increased in size
Hypersegmentation of neutrophils (> 5 lobes)
BONE MARROW: Hypercellular with large forms of precursor cells
Dietary Origin of B12/ Cobalalim
Fish, animal muscle, milk products, egg yolks
B12 Deficiency Etiology
DECREASED ABSORPTION OF B12
-
Loss of gastric parietal cells that produce Intrinsic Factor and hydrochloric acid
- Gastrectomy
- Atrophy
- Lye injury to gastric mucosa
- PERNICIOUS ANAEMIA -Autoimmune: anti-parietal cell, anti-IF antibodies (B12 used to create Intrinsic factor)
- Ileal Disorders
- Defects in B12 Transpoert
- Metabolic Disorders
DIETARY DEFICIENCY: RARE only in strict vegetarians (Stored in liver takes years to develop deficiency)
What causes PERNICIOUS ANAEMIA?
PERNICIOUS ANAEMIA -Autoimmune Disorder: anti-parietal cell, anti-IF antibodies created => loss of gastric parietal cells that produce Intrinsic Factor and Hydrochloric Acid
Clinical Consequences/Treatment of B12 Deficiency?
Macrocytic Anemia with hypersegmented neutrophils (>5 Lobes)
Glossitis- Smooth tongue, beefy red appearance
Neurological symptoms
Polyneuropathy →Paraesthesia (abnormal burning senstation)
Subacute combined degeneration of the spinal cord → progressive weakness, ataxia
TREATMENT: Vitamin B12 replacement (intramuscular hydroxocobalamin injections)
Clinical Consequences/Treatment of Folate Deficiency
Folate Normally absorbed via passive diffusion in small intestine
Deficiency Etiology:
oDecreased intake (alcoholics, older adults)
oIncreased requirements (pregnancy, infancy)
oMalabsorption
oDrugs (methotrexate)
NO neurologic symptoms (As opposed to B12 Deficiency)
Treatment: folate replacement
