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102 Cards in this Set
- Front
- Back
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Mechanistic Classification of Anemias
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1. Blood Loss
2. RBC destruction (hemolytic Anemias) 3. Impaired RBC production (non-hemolytic anemias) |
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Blood loss
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Acute trauma
Chronic loss, GI/GU |
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RBC destruction (Hemolytic anemias)
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Intrinsic RBC abnormalities
Extrinsic abnormalities |
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Impaired RBC production (Non-hemolytic anemias)
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Erythroblast maturation defects
Stem cell production failure, e.g. aplastic anemia, renal failure, marrow failure |
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Erythroblast maturation defects
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Vitamin deficiencies
Hemoglobin synthesis defects – iron deficiency, thalassemia |
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Intrinsic RBC abnormalities
RBC destruction |
Membrane defects – Hereditary spherocytosis
Enzyme defects – G6PD deficiency Hemoglobin defects – thalassemias, hemoglobinopathies |
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Extrinsic RBC abnormalities
RBC destruction |
Immune mediated – transfusion reactions, drugs, autoimmune syndromes
RBC fragmentation syndromes – MAHA, cardiac, etc. |
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Microcytic Anemias
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1 Iron Deficiency
2 Anemia of chronic disease 3 Thalassemias 4 Sideroblastic anemia |
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Iron excess/sideroblastic states
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Hemosiderosis
Hemochromatosis Sideroblastic anemias Lead poisoning (Plumbism) |
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What is the most common microcytic anemia?
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iron deficiency
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Globin sysnthesis disorders
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Thalassemias
Hemoglobinopathies: HbC, HbE |
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microcytic anemia occur becuase of...
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deficiencies in hemoglobin synthesis (heme or globin)
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Decreased hemoglobin synthesis
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Normal cellular proliferation and DNA synthesis
Paler, smaller cells |
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Heme synthesis: iron metabolism disorders
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Iron Deficiency Anemia (IDA)
Anemia of Chronic Disease (ACD) Iron excess/sideroblastic states |
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Macrocytic Anemias
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1. Vitamin B12 Deficiency
2. Folate Deficiency 3. Inherited Megaloblastic Anemias 4. Drug-Induced (dilantin, sulfa, AZT, methotrexate) 5. Other (Alcoholism, Hypothyroidism, Liver Disease, MDS, Reticulocytosis) |
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Defective DNA synthesis
in Macrocytic Anemias |
Asynchrony between nuclear and cytoplasmic maturation
Gigantic cells with immature chromatin |
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megaloblasts
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Macrocytic-normochromic red cells (macro-ovalocytes)
Granulocytes are hypersegmented Megakaryocytes are abnormal resulting in thrombocytopenia |
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Normocytic Anemias
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1. Acute hemorrhage
2. RBC enzyme defects, e.g. G6PD deficiency 3. RBC membrane defects, e.g. Hereditary spherocytosis 4. Bone marrow disorders (aplastic anemia, leukemia) 5. Hemoglobinopathies: HbS 6. Autoimmune hemolytic anemia 7. Anemia of chronic disease |
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leptocyte
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RBC with very pale zone ½ - 2/3rds of cells
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MCV calculation
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Hematocrit (in L/L) X1000/ RBC count (in millions/uL)
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MCH (pg)
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Hemoglobin (in g/dL)/RBC count (in millions/uL)
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Reticulocytes
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Non-nucleated immature RBC with remnant RNA
>Polychromatophilic macrocytes on Romanowsky >Reticulum seen with Supravital stain Enumeration >Normal ranges -Adult: 0.5 – 1.5% -Infant: 2.0 – 6.0% |
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Reticulocytosis
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normally ↑ % in response to anemia
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Reticulocytopenia
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: abnormal ↓ % in response to anemia
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anisocytosis
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variation/range in cell volume
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RDW
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Standard deviation RBC volume x 10/mean MCV
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RDW
Normal range |
12 – 16%
>The MCV can be normal while individual RBCs vary in volume >Useful in early nutritional deficiency anemias, e.g. IDA >Increased/bimodal distributions: agglutination, fragmentation, transfusions, recently treated nutritional deficiency, reticulocytosis |
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MCHC [in g/dL]
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Hemoglobin [in g/dL]/Hematocrit [in L/L]
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Normochromic
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blood with normal MCHC
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Hyperchromic
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> 36 g/dL
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Hypochromic
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< 32 g/dL
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MCHC Normal Rnage
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32 - 36 g/dL
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What are the hematologic finding in Iron Deficiency Anemia
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1. Hb usually < 8 g/dL
-- Reduced indices (MCV, MCH, MCHC) -- RDW elevated 2. Reticulocytosis - mild 3. Thrombocytosis – may be twice normal (reactive) 4. BM – erythroid hyperplasia mild/moderate |
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Iron Deficiency Anemia
Diagnostic Labs (Fe Studies) |
1. Serum Ferritin decreased
2. TIBC increased 3. Saturation transferrin reduced <16% supply to marrow below minimal requirement for heme production 4. Serum transferrin receptors increased 5. BM Fe stores depleted |
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What is the gold standard of iron deficiency anemia
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Bone marrow Fe stores are depleted
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Folate is essential for:
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1. Purine/pyrimidine synthesis
2. Methionine synthesis 3. Methylation transfer reactions |
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FOlate Metabolism
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Polyglutamate deconjugated in GI/bile for absorption in jejunum
--Circulates unbound (5-methyl THF) --Requires Vitamin B12 for entry Green leafy vegetables, beans, legumes, whole grains, oranges (heat labile) |
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Normal levels of folate
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Serum levels >3.7 ng/mL
Liver stores 20 – 70 mg Sufficient for only 3 – 5 months |
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Mechanisms of Vitamin B12 Deficiency
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-Dietary lack (vegetarians)
-Increased requirement -Defective absorption -Rare causes: defective transport, disorders of metabolism |
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Defective absorption of B12
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-Gastrectomy
-Blind loop syndrome: intestinal bacterial overgrowth -Fish tapeworm (competes for B12) -Other: Crohn’s disease, Zollinger-Ellison, Tropical/celiac sprue, Imerslund Syndrome (familial selective B12 malabsorption), hemodialysis, HIV -Pernicious Anemia |
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Pernicious Anemia
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Most common syndrome
Gastric parietal cell atrophy: ↓ IF F>>M; disease of late adulthood Severe atrophic gastritis Neurologic problems |
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Clinical features of Megaloblastic Anemia
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- Insidious onset
- Moderate to severe fatigue, malaise - Lemon-yellow skin - Mucosal atrophy: tongue, vagina, GI with pain, malabsorption - Neurologic deficits/peripheral neuropathy (methionine loss) |
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Neurologic deficits/peripheral neuropathy (methionine loss) with Megaloblastic Anemia
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Posterior and lateral columns of spinal cord
>Paresthesias, numbness, tingling, ↓ vibration sense, ataxia, symmetric paralysis CNS deficits >Megaloblastic madness (paranoia, depression) |
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Ferritin
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- soluble protein-iron complex (apoferritin and Fe+3-phosphate core)
- Synthesis stimulated by the presence of iron |
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Hemosiderin
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- insoluble protein-iron complex
- Formed by lysosomal digestion of ferritin |
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Distribution of Iron
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65% in hemoglobin
30% in storage 3% myoglobin |
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Iron Absorption
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- 5-10% is absorbed in duodenum and jejunum
- Facilitated by acid and reducing agents (citrates, ascorbate) in Fe+2 form - Inhibited by tannins, phytates - Increased absorption with demand (pregnancy, growth) and excessive loss due to acute or chronic hemorrhage |
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Iron in your Diet
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- Present in food as ferric hydroxide and ferric-protein complexes
- Meat and liver is good source of dietary iron - Average western diet contains 10-15 mg - Daily requirement 1-2 mg per day |
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Transferrin
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- Synthesized in liver, serum half-life of 8-10 days
- Each molecule binds two iron atoms - Normally only about 30% saturated - Erythroblasts have transferrin receptors, CD71 |
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Iron Transport
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- iron binds to transferrin in the portal blood
- Transported to bone marrow for erythropoiesis - About 6g of Hb produced daily - Requires about 20mg of Fe from RES (Only small proportion comes from dietary Fe) -Total plasma iron turns over about seven times per day |
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Clinical Features in
Iron deficiency Anemia |
1. Insidious, slowly progressive
2. Fatigue, irritability, dizziness, headache, breathlessness 3. Pica – craving/ingestion of unusual substance 4. Impaired neuromuscular activity 5. Brittle, pitted nails 6. Atrophy of lingual papillae, burning/sore mouth 7. Dysphagia, gastritis |
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Etiology of Iron Deficiency Anemia
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Etiology is age-related:
- Infants/children – dietary insufficiency - Adults – chronic blood loss, malabsorption, menstruation, blood donation, emoglobinuria, etc. |
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What is the primary cause of defective heme synthesis?
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- Most common cause of anemia worldwide
- About 20% of women, 50% of pregnant women; and 3% of men |
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Mechanisms of Folate Deficiency
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- Dietary Insufficiency
- Increased requirement - Defective absorption (tropical/celiac sprue malabsorption) - Drugs |
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Folate Dietary insufficiency
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- Common in alcoholic, drug addicts
- Low SE status - Chronic liver/kidney disease |
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Increased requirement for Folate
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- Pregnancy - supplemented prior to and during pregnancy
- Cause neural tube defects in utero - Infancy - Hematologic diseases w/ rapid cellular proliferation, e.g. sickle cell anemia, leukemias |
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Drugs that effect Folate Deficiency
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- Methotrexate (chemotherapy drug that is a folate antagonist)
- Alcohol - Oral contraceptives - Others drug-induced folate deficiency (dilantin, sulfasalazine) |
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Vitamin B12 Metabolism
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- Cyanocobalamin synthesized by bacteria, found in meat, fish, dairy (heat stabile)
- B12 released by gastric acid - Binds to R-binder which is subsequently degraded by pancreatic enzymes - Binds to IF - B12-IF complex adheres to brush border of ileum (pH and Ca dependent) |
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TCI/III
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delivered to liver
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TCII
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delivers to liver, BM
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Diagnostic Approach to
Megaloblastic Anemia |
- Moderate to severe anemia
- Hypersegmentation of neutrophils - Bone Marrow Hypercellular with increased mitosis |
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Hematologic Findings in Folate Deficiency
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- 3 weeks: decrease Folate levels
- 5 – 7 weeks: hypersegmented neutrophils - 10 weeks: mild megaloblastosis - 17 – 18 weeks: macro-ovalocytes - 19 – 20 weeks: florid megaloblastosis |
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Hematologic Findings in B12 Deficiency
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Early: 1 – 2 years
- Early blood/marrow changes with hypersegmentation, macrocytosis - Early myelin damage to nerves Late: 2 – 3 years - Vitamin level markedly decreased - Florid megaloblastosis - Severe myelin damage |
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Can you distinguish between Folate and B12 deficiencies on a blood smear?
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NO
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Moderate to severe anemia
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- MCV range from 100 – 150 fL
- MCHC normal - Circulating macrocytes, minute RBC fragments, basophilic stippling, Howell-Jolly bodies - RDW usually markedly elevated - Reticulocytopenia |
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Hypersegmentation of neutrophils
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- Early sign
- ≥ 6 nuclear lobes (or significant % with > 5) |
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Bone Marrow
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- Hypercellular, with erythroid and myeloid hyperplasia
- Increased mitoses, apoptosis - Large cells, immature nuclei with mature cytoplasm, multinuclearity - Giant myelocytes, bizarrely nucleated metamyelocytes |
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What can you diagnose megaloblastic anemia?
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leukemia
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Intracorpuscular
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Intrinsic RBC defect
- Hereditary - RBC membrane defects - Enzyme defects - Hemoglobinopathies - Thalassemia syndromes - Acquired - Paroxysmal nocturnal hemoglobinuria (PNH) |
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Extracorpuscular
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(extrinsic RBC defect, i.e. premature RES removal)
- Immune hemolytic anemias - Infections - Allo/auto-antibodies - Non-Immune - Chemical agents, toxins, infections - Physical agents - Microangiopathic and macroangiopathic hemolytic anemias - Splenic sequestration (hypersplenism) |
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Hemolytic Anemias
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Anemias caused by hemolysis of red blood cells
- Reduction of normal RBC lifespan - Hemolytic state accompanied by compensatory hyperplastic bone marrow |
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Clinical Features
Hemolytic Anemias |
Depend on rate of hemolysis and bone marrow compensation
- Well-compensated anemias - symptoms minimal - Uncompensated - severe anemias - Pallor, fatigue - Fever, chills, headache - Jaundice - Long-standing hemolysis - gall stones - Mild to moderate splenomegaly (EMH possible) - Bone pain/deformities - in severe congenital hemolysis |
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Ask these questions when you get a CBC:
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1. Is anemia present?
2. Is there evidence of increased RBC breakdown? 3. Is there evidence of increased RBC production? |
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Polychromatophilia
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presence of mixed colors of RBCs in a blood smear
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Hemolytic Anemia
Hematologic Findings |
Anemia mild to severe (2 - 11 g/L)
- Usually normocytic, normochromic - Mildly elevated MCV up to 110 fL may be seen with reticulocytosis - RBC morphology - Polychromatophilia, increased macrocytes, nucleated RBCs - Spherocytes, schistocytes, targets depending on underlying hemolytic process - Reticulocytosis - Platelets, leukocytes usually unremarkable - may be reactive |
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Hemolytic Anemias
Bone Marrow Findings |
- Hypercellular, with associated erythroid hyperplasia
- Dyssynchronous/megaloblastic RBC precursors may be seen - Concomitant vitamin (folate) deficiency - Iron usually increased - Sideroblasts and RS may be present - Absent Fe associated with concomitant IDA or PNH (excessive urinary loss) - Thinned trabeculae in chronic cases |
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Hyperbilirubinemia
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increase RBC destruction, liver conjugation failure, excretory blockage
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Plasma Hemoglobin
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- Normal < 10mg/dL
- > 50 dg/dL threshold for visual detection - red tint - Indicates acute intravascular hemolysis |
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Indirect bilirubin
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- Increased in early hemolysis
- Misleading increase seen in Crigler-Najjar, Gilbert, breast milk jaundice |
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When is clinical jaudice seen?
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When serum bilirubin is > 3.0 mg/dL
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Serum haptoglobin
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- alpha2-globulin produced in liver binds free hemoglobin
- Normal 40-180 mg/dL - < 25 mg/dL or absent indicates - Hemolysis - Liver failure - Recent massive transfusion - Acute phase reactant, may be increased in inflammation masking hemolysis |
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Urine hemoglobin and hemosiderin
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- Cloudy, smoky, dark-red, cola-colored
- False positive with hematuria, myoglobinuria |
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Total Lactate Dehydrogenase (LDH)
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- Normal
- Increased with normal or pathologic cell destruction - RBC glycolytic pathway enzymes released into plasma, i.e. hemolysis |
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Hereditary Spherocytosis
Clinical features |
- Chronic hemolytic anemia with reticulocytosis
- Episodes of mild jaundice - Splenomegaly - Gall stones - Acute hemolytic crisis: fever, abdominal pain |
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Hereditary Spherocytosis
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- Autosomal dominant/recessive inherited disorder
- Intrinsic defect in RBC membrane renders erythrocytes spherical, less deformable and vulnerable to splenic destruction and spontaneous hemolysis - Prevalence - Northern European ancestry 1:5000 (most common form of hereditary hemolytic anemia) |
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What are the defects in Hereditary Spherocytosis?
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Ankyrin
Spectrin Band 3 Protein 4.2 genes |
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What is the effective cure for hereditary spherocytosis?
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splenectomy
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Hereditary Spherocytosis
Peripheral Blood |
- Normocytic anemia with (90+%) spherocytes
- Increased MCHC (hyperchromic anemia) - Reticulocytosis |
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Hereditary Spherocytosis
Increased osmotic fragility of RBCs |
- Osmotic Fragility Test - measures ability of RBCs to swell
- Normal RBCs can swell 1.8 times normal resting volume - Essential diagnostic feature of Hereditary Spherocytosis |
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Hereditary Spherocytosis
Blood Chemistry |
elevated LDH
elevated total bilirubin |
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Hereditary Spherocytosis
Viral Complication |
Transient Aplastic Crisis (TAC) caused by infections, including Parvovirus B19 - associated with about 90% of aplastic crises in HS
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Aplastic Anemia
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Stem cell failure!
- Destruction of ALL hematopoietic marrow elements by chemical agents or physical factors .: pancytopenia |
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Paroxysmal Nocturnal Hemoglobinuria
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cause and consequence of Aplastic Anemia
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Aplastic Anemia
Peripheral Blood |
PANCYTOPENIC
- Severe normocytic anemia (Hb < 7 g/dL) - Neutropenia (ANC < 500 /uL) - Thrombocytopenia (< 20) - Reticulocytopenia, usually marked (absolute AND corrected) |
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Aplastic Anemia
Bone Marrow |
marked panhypoplase for pt's age
R/o infiltrative process, viral changes, myelofibrosis |
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Transient erythroblastopenia of childhood (TEC)
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- causes Pure Red Cell Aplasia
- Virtual absence of RBC precursors in marrow, with spontaneous, permanent remissions - Immunologic basis for disease vs. post-viral infection - Gradual pallor in otherwise healthy child, Hb 5 – 7 g/dL - Manifests at >1 year |
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Parvovirus B19
Clinical Features in Immune-compromised |
Chronic B19 virus infection or transient aplastic crisis
- Chronic marrow stress, e.g. hemolytic anemias - Immunocompromised, e.g. chemotherapy/immunosuppressive drugs, congential/acquired immunodeficiency |
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Parvovirus B19
Clinical Features in Immune-competent |
Erythema infectiosum “Fifth Disease”
- Low-grade fever, malaise, or a "cold" - “Slapped-cheek" rash on the face and a lacy red rash on trunk/limbs - Polyarthropathy joint pain/swelling in adults - Resolves in 7 to 10 days |
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Parvovirus B19
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Infects only humans (ssDNA)
- Seropositivity 5-10% children (aged 2-5 y),↑ with age to 90% of adults > 60 years - Enters RBCs via P blood antigen receptor - Tropism for rapidly dividing RBC precursors, particularly pronormoblasts and normoblasts - Results in reticulocytopenia |
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Peripheral blood
Parvovirus B19 |
- Precipitous drop in Hb, Hct
- Reticulocytopenia |
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Bone Marrow
Parvovirus B19 |
- Erythroblastopenia, profound
- Rare giant pronormoblasts with viral inclusions - AIDS: erythroid lineage may be intact w/ numerous viral inclusions - Variable lymphocytosis |
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Laboratory Tests
Parvovirus B19 |
- Hb A stain may highlight the rare cells
- In situ hybridization parvovirus probes - Serologies: IgM, IgG parvovirus titers - Molecular PCR |
