Flashcards in RBC Disorders Deck (60):
Anemia definition and symptoms
Reduction in Circulating RBC mass. Hb Below 13.5g/dL in Males and 12.5 g/dL in females
See symptoms of hypoxia = weakness, fatigue, dyspnea, pale conjunctiva and skin, headache/lightheaded, angina
Normal Lab values for Hemoglobin for Males and Females
Males = 13.5-17.5 g/dL
Females = 12.5-16 g/dL
Microcytic vs Normocytic vs Macrocystic
Microcytic = MCV < 80 μm3
normocytic = MCV 80-100μm3
Macrocytic = MCV > 100μm3
Mechanism of Microcytic Anemias
Hb = heme (made of fe and protoporphyrin) + globin
Hb therefore decreases if any of the components decrease
Fe decreases with decreases intake, excess loss, or chronic disease. Protoporphyrin decreases with defects in its synthesis. Globin decreases in thalssemias
Become microcytic because bone marrow does one "extra" division to try and maintain Hb concentration
Normal pathway of Fe
Iron is consumed in heme (meat) and non-heme (veggies)
1) absoprtion occurs in duodenum's enterocytes via DMT1 transporters (heme form is more readily absobred)
2) Enterocytes transport Fe across cell into blood via ferroportin
3) Transferrin picks up Fe in blood and carries it to liver and bone marrow macrophages for storage
4) Ferritin binds Fe intracellulary to store it and prevent it from forming free radicals
Laboratory measurements of Iron Status
1) Serum iron
2) Total Iron Binding Capacity
4) Serum Ferritin
1) Serum iron = meausre of Fe in blood
2) Total Iron Binding Capacity = measure of transferrin molecules in blood
3) %Saturation = percentage of transferrin binding a Fe (normally 33%)
4) Serum Ferritin = reflects Fe reserves in macrophages and liver
Causes of Iron deficiency
1) Infants - breast milk has low Fe
2) Children - poor diet
3) Adult males = peptic ulcer
4) Adult females = menorrhagia
5) Elederly = colon polyps / carcinoma
6) Hookwork infections = Ancyostoma duodenale and Nector Americanus
7)Malnutirition or malabsorption (celiac)
8) Gastrectomy = acid normally aids absorption of Fe by keeping it in 2+ state which is transported easier than 3+
Stages of Iron Deficiency and sumamry lab values
1) Storage of Fe is depleted - ↓ ferritin, ↑ TIBC
2) Serum Fe is depleted = ↓ serum iron, ↓%saturation
3) Normocytic Anemia = EARLY STAGE bone marrow makes fewer but normal sized RBCs
4) Microcytic, hypochromic Anemia = Bone marrow makes fewer and smaller RBCs.
Labs: microcytic, hypochromic RBS with ↑Red cell distribution Width (RDW = lots of different sized RBCs)
↓ ferritin, ↑ TIBC, ↓ serum iron, ↓%saturation
Treat with supplemental Fe (ferrous sulfate) and treat underlying condition
Plummer Vinson Syndrome
Iron deficiency Anemia with esophageal web and atrophic glossitis. Anemia, dysphagia, and beefy red tongue.
Anemia of Chronic Disease
Associated with chronic inflammation or cancer. Chronic disease get acute phase reactants from liver including hepcidin. Hepcidin sequesters Fe storage by (1) limiting iron transfer from macrophages to to erthyroid precursors (2) suppressing Erythropoietin; aim is to prevent bacteria access to Fe.
↓ available Fe, ↓ heme, ↓hemeglobin, normocytic, to microcytic
↑ferritin, ↓TIBC, ↓serum iron, ↑%saturation, ↑Free erythrocyte protoporphyrin
Acute phase reactant produced by liver. It sequesters Fe storage by (1) limiting iron transfer from macrophages to to erthyroid precursors (2) suppressing Erythropoietin; aim is to prevent bacteria access to Fe. Responisble for anemia seen in chronic disease
Microcytic Anemia due to defective protoporphoryin synthesis characterized by ringed sideroblasts on histology (iron trapped in mitchondira surround nucleus of erythroid precursors)
Fe enters erythroblasts's mitochondria, no protoporphyrin to attach to, Fe causes free radicals and damages cell, cell dies and releases Fe into serum, Some Fe is taken up by bone macrophages (↑ferritin)
See ↑ferritin, ↓TIBC, ↑serum iron, ↑%saturation = iron overloaded state.
Steps of Protoporphyrin Synthesis
1) Aminovulenic Acid synthetase (ALAS) converts Succinyl CoA to Aminolevulinic Acid (ALA) using B6 as a cofactor. Rate limiting step
2)Aminovulenic Acid Dehydratase (ALAD) converts ALA to porphobilinogen
3) Series of reactions converts porphobilinogen to protoporphyrin
4)Ferrocheletase INSIDE mitochondria attaches Fe to protoporphyrin to make Heme
A defect in any step will cause Fe to be trapped in the mitochondira and give rise to "ringed sideroblasts" and give sideroblastic anemia
Cells with Iron ladden mitochondria surrounding nucleus. Due to problems with protoporphyrin synthesis and sign of Sideroblastic Anemia
Congenital Defects of Sideroblastic Anemia
Deficiency in any of the enzymes needed to make protoporphyrin.
Most commonly seen is defect in ALAS that converts SCoA to ALA
Acquired Causes of Sideroblastic Anemia
Alcoholism - poisons mitochondria and impairs production of protoporphyrin
Lead Poisoning = inhibits ALAD and Ferrocheletase
Vitamin B6 deficiency = required cofactor for ALAS (most commonly seen in isoniazid treatment for TB)
Drug used in treatment of TB. Side effect is Vitamin B6 deficiency that leads to siderblastic anemia
Microcytic anemia due to decreased synthesis of globin chains
Inherited mutations. Carriers are protected against plasmodium falciprum
Normal types of Hemeglobin
Fetal = HbF = α2γ2
HbA = α2β2
HbA2 = α2δ2
-all variations and ethnicities
Normally 4 α genes, 2 each on chromosomes 16
(1)One deletion = asymptomatic
(2)Two Deleted = mild anemia with increased RBC count
Cis = ASIAN. deletions occur on same chromosomes and more liekly to produce severely anemic children
Trans = AFRICAN. Deletions on opposite chromosomes
(3) Three genes deleted = severe anemia. β chains form tetramers (HbH) that damages RBCs
(4) 4 genes deleted = hydrops fetals = lethal in utero. γ chains for tetramers (Hb Barts) that damage RBCs
Gene MUTATION seen in Africans and Mediterraneans
Two β genes on chromosome 11. Mutations result in absent β0 or diminished β+ production of β chain.
Get microcytic anemia with varying severity depending on mutations
β Thalassemia minor
β/β+ = mildest form of disease. Usually asymptomatic with slight increase in RBC count
Get microcytic, hypochromic RBCs, and traget cells on blood smear
Slightly decreased HbA and increased HbA2 and HbF
β Thalassemia Major
β0/β0. Most severe form of disease seen few months after birth since HbF is initially protective
α tetramers aggregate and damage RBC resulting in effective erythropoiesis and extravascualr hemolysis (removal of RBCs by spleen).
Get massive Erythroid hyperplasia ensues and see (1)hematopoiesis occuring not just in central axilia skeleton but also in skull (buzzcut appearance on xray) and facial bones (chipmunk facies) (2) extramedullary hematopoiesis (liver and spleen) (3) risk for aplastic crisis with parvovirus B19 infection of erythroid precursors.
Need chronic transfusions that can lead to sexondary hemochromatosis
Smear shows microcytic, hypochromic RBCs, target cells, nucleated RBCs.
Have HbA2 and HbF, and little to no HbA
Crewcut appearance on X-ray and Chipmunk Facies
β Thalassemia Major
Macroytic Anemia Definition and causes
Anemia with MCV >100microm3.
Commonly due to folate or vitamin B12 deficiency (megaloblastic anemia)
Alcholism, liver disease, and drugs (5-FU)
Vitamin B12 and Folate Deficiency and there role in Megaloblastic Anemia and signs
Folate and B12 are needed for synthesis of DNA precursors. If dont have precursors then cant replicate material enough for multiple divisions of RBC precursors.
See (1) imparied division and enlargement of RBC
(2) Impaired division of granulocytic precursors leads to hypersegmented neutrophils (greater than 5 lobes)
(3) Megaloblastic change in rapidly dividing cells (tongue and GI)
Megaloblastic, macrocytic anemia.
Get from greens and absorbed in jejunum. Not huge storage so develops within months.
Can arise due to poor diet (alcoholics and elderly), increased demand (pregnancy, cancer, hemolytic anemia), and folate antagonists (methotrexate inhibits dihydrofolate reductase)
Lab: macrocytic RBCs and hypersegmented neutrophils, ↓ serum folate, ↑ serum homocysteine (increased risk of thrombosis), NORMAL methylmalonic acid
Absorption of Vitamin B12
1)B12 released from food by amylase, R-binder (from salivary glands) binds B12 and escorts it through stomach,
2)pancreatic proteases in duodenum detach B12 from R-binder
3)Intrinsic factor made by parietal cells forms complex with B12 in small bowel
4) B12-intrinsic factor complex absorbed in ileum
5) large stores of B12
Causes of Vitamin B12 deficiency
Pernicious Anemia = auotimmune destruction of parital cells leads to no production of intrinsic factor so cant absorb B12. Most common cause
Vegans, pancreatic insufficiency, damage to terminal illeum (chrons disease or fish tapeworm = diphyllobothrium latum)
Vitamin B12 Deficiency
Labs - Macrocytic RBCs with hypersegmented neutrophils, ↑Serum homocysteine, ↑ MEATHYLMALONIC ACID, ↓ serum B12
Clinical - glossitis, Degneration of Spinal cord = poor proprioception, vibratory sensation, and spastic paresis. (all due to fat that B12 is cofactor for conversion of methylmalonic acid to SCoA. No B12 so get increased Mathylmalonic Acid that impairs myelinization of spinal cord)
Anemia with normal RBCs (MCV= 80-100) but have increased peripheral destruction or underproduction of RBC
Young RBCs that are released from the bone marrow that are slightly larger and stain blue due to presencr of RNA still in them. Normally account for 1-2% of RBCs as they rreplace the 1-2% of mature RBCs that are removed everyday (normal life is 120 days)
Recticulocyte Count (RC)
A properly functioning bone marrow should increase RC >3% to compensate for anemia. RC is falsely high in anemias so correct by multiplying it by (Hct/45).
RC >3% indicates good marrow response and peripheral destruction
RC<3% indicates poor marrow response and udnerprodcution
RBC destruction by the reticulendothelial system (macrophages of spllen, liver, and lymoh nodes).
See: Anemia with splenomegally, jaundice due to unconjugated bilirubin, and icnreased risk for bilirubin gallstones. See marrow hyperplasia with corrected RC >3%
Macrophage Consumption of RBC
1) Globin is broken down to AAs
2) Heme is broken down to Fe and protoporphyrin
3) Protoporphyrin is broken down to unconjugated bilirubin and carried by albumin to liver to be conjugated and excreted into bile
Destruction of RBCs within vessels
See: Hemoglobinemia, femoglobinuria, decreased serum haptoglobin (normally bins Hb and takes it to spleen to be recycled), and Hemosiderinuria (renal tubular cells take up hemeglobin and breaks it down into Fe which accumulates in the cell as hemosiderin. DAYS later when tubular cells are shed get hemosiderinuria)
Inherited defect of RBC cytoskeleton membrane tethering proteins (ankyrin, spectrin, or Band 3).
Membrane blebs are formed and lsot over time, loss of this membrane renders cells round (spherocytes) instead of disc shaped. Spherocytes cant maneuver through splenic sinusoids and are consumed by splenic macrophages resulting in anemia.
-labs and clinical findings
Spherocytes with loss of central pallor
Increase RDW and mean corpuscular hemoglobin concentration
Spleenomegally, jaundice, and increased risk for billirubin gallstones
Increased risk for aplastic crisis when infected with parovirus B19 infection of erythroid precursors
Diagnosis and treatment of Hereditary Spherocytosis
Osmotic fragility test (round so when put in hypotonic solution cant accomodate influx of water and burst easily)
Treat with splenectomy to resolve destruction of RBC and anemia. When remove spleen have nothing to remove fragments of nuclear material in RBCs so get "Howell-Jolly bodies
Howell Jolly Bodies
Fragments of nuclear material in RBC. Nuclear remnants are typically removed by spleen so when have splenectomy or damage to spleen these "bodies" persist in a blood smear
Sickle Cell Anemia
Autosomal recessive MUTATION in β chain of hemoglobin (hydrophilic glutamic acid replaced by hydrophobic valine)
See in 10% of African individuals
Sickle cell diseases arise when two abnormal β genes are present and get >90% HbS (alpha 2betaS2)
HbS POLYMERIZES REVERSIBLY when deoxygenated, and polymers aggregate into needle like sturctures giving "sickle" appearnace.
Increased risk of sickling occurs with hypoxemia, dehydration, and acidosis.
HbF is present for first 6 months of life and generally protects against sickling. (Treat with hydroxyurea to increase levels of HbF)
How Sickle cell progresses to anemia
cells continuously sickle and de-sickle while passing through microcirculation resulting in RBC membrane damage.
1) EXTRAVASCULAR hemolysis - reticuloendothelial system removes RBCs with damaged membranes, leading to anemai, jaundice, increase risk for bilirubin gallstones
2) intravascualr hemolysis - RBCs with damaged membranes dehydrate leading to hemolysis with decreased haptoglobin and target cells on blood smear
3) Erythroid hyperplasia ensues with expansion of hematopoiesis in skull and facial bones (buzz cut and chipmunk facies), extramedullary hematopoiesis and hepatomegaly
4) Risk of aplastic crisis with parovirus B19 infection of erythroid precursors
Vaso-occlusion in Sickle Cell anemia
Irreversible sickling leads to complications of vasocclusion
1) Dactylitis - swollen hands and feet due to vaso-occlusive infarcts in bone. Most common 1st sign in infants
2)Autosplenectomy - shrunken fibrotic spleen due to infarcts. Patients more susceptible to infection with encapsulated organisms (S pneumonia, Haemophilius Influenze), salmonella paratyphia osteomyelitis, and howell jolly bodies
3)Acute Chest Syndrome - vasocclusion in pulmonary microcirculation presents with chest pain, SOB, and lung infiltrates. Often precipitated by pneumonia and msot common cause of death
4) Pain crisis
5) Renal papillary necrosis - results in gross hematuria and proteinuria
swollen hands and feet due to vaso-occlusive infarcts in bone. Most common 1st sign in infants. Typically say "6month old, african american, baby with swollen hands and feet"
shrunken fibrotic spleen due to infarcts. Patients more susceptible to infection with encapsulated organisms (S pneumonia, Haemophilius Influenze), salmonella paratyphia osteomyelitis, and howell jolly bodies
Acute Chest Syndrome
vasocclusion in pulmonary microcirculation presents with chest pain, SOB, and lung infiltrates. Often precipitated by pneumonia and msot common cause of death
Sickle Cell Trait
Presence of one mutated one normal β chain. get less <50% HbS and therefore RBCs do not sickle unless they are in teh renal medulla. Get microinfections in renal medulla leading to micrscopic hematuria and eventually decreased ability to concentrate urine.
Can also sickle in EXTREME hypoxia andhypertonicity (as seen in medulla)
Lab findings for Sickle Cell Anemia and Trait
1)Sickle cells and target cells seen in anemia but not trait
2) Metabisulfite screen causes cells with ANY amount of HbS to sickle so is positive in both anemia and trait
3) Hb electrophoresis confirms the presence and amount of HbS
Autosomal Recessive mutation in β chain of hemoglobin where normal glutamic acid is replaced by lysine. Presents with mild anemia due to extravasucalr necrosis.
Characteristic HbC Crystals seen on blood smear
Paroxysmal Nocturnal Hemoglobinuria
Acquired Defect in myeloid stem cells resulting in absent glycoslyphosphatidylinositol (GPI) which normally anchors Decay Accelerating Factor (DAF) to blood cell membranes and prevents attack by complement by inhibiting C3 convertase. Intravascular hemolysis occurs episodically at night when shallow breathing leads to mild respiratory acidosis that activates complement.
Get hemoglobinemia, hemoglobinuria and days later hemosiderinuria.
Confirm with sucrose or acidififed serum test (activate complement or flow cytometry test
Complications of Paroxysmal Nocturnal Hemoglobinuria
Increased risk for thrombosis since lysed platelets release cytoplasmic contents that induce thrombosis. Thrombus to hepatic, portal, or cerebral veins get death.
Also get Fe deficiency anemia and AML in 10% of patients
Glucose-6Phosphate Dehydrogenase (G6PD) Deficiency
X linked recessive resulting in reduced half life of G6PD results in RBCs susceptible to oxidative stress.
↓G6PD -> ↓NADH - > ↓reduced glutathione -> ↑oxidative injury by H2O2 -> intravascular hemolysis
African (mild) and Mediterranean (severe) variant
Infections, drugs (primaquine, sulfa drugs, dapsone) and fava beans cause oxidative stess that precipitates Hb as Heinz bodies.
Removal on Heinz bodies by splenic macrophages gives rise to "bite cells"
Weeks later perform confirmatory enyzme study
IgG mediated Immune Hemolytic Anemia
Typically involves extravascualr hemolysis.
IgG binds RBCs in WARM temeperatures of CENTRAL body and tagged RBCs are consumed by splenic macrophages leading to spherocytes.
See with SLE, CLL, and drugs like penicilins or cephalosporins (drug may attach to RBC membrane and IgG attack drug-memb complex or drug may induce production of autoantibodies)
IgM mediated Immune Hemolytic Anemia
IgM binds RBCs and fixes complement in the COLD temps of EXTREMITIES.
Associated with Mycoplasma penumoniae and infectious mononucleosis
Direct vs Indirect Combs Test
Both used to diagnose Immune Hemolytic Anemia
Direct - confirms presence of antibody coated RBC by adding anti IgGto patients RBCs
Indirect - confirms presence of antibodies in patient serum
Microangiopathic Hemolytic anemia
Intravascualr hemolysis due to vascualr pathology. Get Fe deficient anemia with chronic hemolysis.
Occurs with microthrombi (TTP, HUS, DIC, HELLP, prosthetic heart valves, and aortic stenosis.
Microthrombi cause shistocytes on blood smear
Infection of RBCs with plasmodium. As plasmodium life cycle occurs part of it causes hemolysis and cyclical fever
Falciprum = daily fever while Vivax and Ovale cause fever every other day
Infects progenitor red cells and temporarily halts erythropoiesis. Get significant anemia in preexisting marrow stress
Damage to hematopoietic Stem Cells, resulting in pancocytopenia with low RC.
Can be caused by drugs, chemicals, iral infections, and autoimmune damage
See empty fatty marrow on biopsy.