Flashcards in Red Blood Cell Disorders Deck (216):
Reduction in circulating red blood cell mass
What symptom does anemia present like?
Is anemia of pregnancy actually anemia?
No, just increased plasma volume
Symptoms of hypoxia/anemia include? (4)
2. Pale conjunctiva and skin
3. Headache and lightheadedness
What measurements are used to determine RBC mass?
1. RBC count
How is anemia defined in terms of Hb?
Males: Less than 13.5
Females: Less than 12.5
How is anemia defined in terms of MCV?
Microcytic: Less than 80
Anemias due to red cell production decrease are due to what? (2)
1. Hematopoietic cell damage
2. Deficiency of factors for heme synthesis of DNA synthesis
Anemias due to increased red cell loss are due to what? (2)
1. External blood loss
2. Red cell destruction
What is acute posthemorrhagic anemia?
What are clinical symptoms similar to
Following acute blood loss, there may be no decrease in any RBC mass markers but an increase in platelet count.
What are the four microcytic anemias?
1. Iron deficiency
2. Anemia of chronic disease
3. Sideroblastic anemia
Microcytic anemia has what MCV?
Less than 80
Microcytic anemias are simply the result of what?
Decreased production of hemoglobin
Why does the microcytosis occur in microcytic anemias?
Extra cellular divisions to make smaller cells with same hemoglobin concentration as normal RBC's.
Hemoglobin is made of what?
Heme and globin
Heme is made of what?
Iron and protoporphyrin
A decrease in what substances will result in a microcytic anemia? (3)
What is the most common type of anemia?
Most common nutritional deficiency in the world.
Absorption of iron occurs where?
What are the two forms iron is absorbed in?
Which is absorbed more readily?
What are the transporters for each
1. Heme form (from meat): Absorbed quicker
2. Non heme form (from vegetables)
1. Heme: Heme transporter
2. Non-heme: DMT-1
What is the key regulatory step of iron absorption?
Will iron be transferred from enterocyte into the blood via ferroportin
What is the function of transferrin?
Transports iron in the blood and delivers it to the liver and bone macrophages for storage.
Stored intracellular iron is bound by what?
Purpose of this?
Prevent free radical formation
What is serum iron?
Measurement of iron in the blood
What is TIBC?
Total-iron binding capacity which is a measure of transferrin in blood
What is % saturation?
What is normal
Percentage of transferrin molecules that are bound by iron
What is serum ferritin?
Measure of iron stored in macrophages and liver
Iron deficiency is usually caused by what two paths?
1. Dietary lack of iron
2. Blood loss
Most common causes of blood loss leading lack of iron? 3
2. Peptic ulcer disease in males
3. Bleeding GI lesions
What two types of GI lesions are seen causing iron deficiency?
What population demographic specifically?
1. Colon polyps/carcinoma in the Western world
2. Hookworms in developing world
What populations see menorrhagia and peptic ulcer disease?
1. Menorrhagia: Females between 20 and 50
2. Peptic ulcer: Males between 20 and 50
Dietary deficiency is seen in what 3 manifestations?
1. Infants: Human milk has very low iron
2. Children: Poor diet or grow quickly
3. Pregnant mothers: Need more iron for baby and herself
What effect does gastrectomy have on iron absorption?
Stomach acid normally maintains iron in Fe2+ state which absorbs fast. Without stomach acid, iron is in Fe3+ state in GI tract.
What are the four stages of iron deficiency?
1. Storage iron depleted: Low ferritin and high TIBC
2. Serum iron depleted: Low serum iron & percent saturated
3. Normocytic anemia: Make fewer normal RBC's
4. Microcytic anemia: Make smaller and fewer RBC's
What are the clinical features of iron deficiency? 6
6. Dyspnea on exertion
What is Plummer Vinson syndrome? 3
How does it present?
1. Severe iron deficiency anemia
2. Atrophic glossitis
3. Esophageal web
3. Beefy-red tongue
Lab findings of Iron-deficiency anemia?
1. Appearance of RBC's
5. Serum Iron
6. Percent saturated
7. Free erythrocyte protoporphyrin (FEP)
10. RBC count
1. Small hypochromic RBC's
2. Increased (some normo and some micro)
What is most sensitive diagnostic of iron-deficient anemia?
What is one negative?
Serum ferritin elevates in pro-inflammatory states
Where is iron in terms of chronology of heme synthesis?
How to differ between Iron-deficiency and anemia of chronic disease?
Anemia of chronic disease has a low TIBC compared to ID-A.
How to differ between Beta-thalassemia minor and ID-A?
Increased Hb A2 in Beta-thalaseemia minor
Treatment of ID-A?
Supplemental iron (Ferrous sulfate)
Anemia of chronic disease is secondary to what types of diseases? 2
1. Chronic inflammation (arthritis, infection)
Anemia of chronic disease is most common in what population of patients?
Chronic inflammation results in production of what?
Production of acute-phase reactants
What is the function of hepcidin?
Hepcidin sequesters iron in storage sites by limiting iron transfer from macrophages to erythroid precursors AND suppressing EPO production.
How does A-CD appear at first?
Then what does it become?
1. Normochromic and normocytic
2. Hypochromic and microcytic
What are the lab findings in A-CD?
3. Serum iron
4. % saturation
3. Decreased serum iron
Treatment of A-CD? (2)
1. EPO for cancer patients
2. Auto-immune disease treatment for chronic inflammed patients
Sideroblastic anemia is due to what?
Defective protoporphyrin synthesis
What is the first reaction in heme synthesis?
What is the co-factor?
Aminolevulinic acid synthetase (ALAS) converts succinyl CoA to aminolevulinic acid (ALA)
What is the second reaction of heme synthesis?
Aminolevulinic acid dehydratase (ALAD) converts ALA to porphobilinogen
What is the final reaction of heme synthesis?
Where is this located?
Ferrochelatase attaches protoporphyrin to iron to make heme
What is the rate limiting step of heme synthesis?
First reaction to make ALA
If proto-porphyrin is deficient what happens to iron?
How does this appear?
Remains trapped in mitochondria
These iron-laden mitochondria form a ring around nucleus in erythroid precursors that are called ringed sideroblasts
What is the congenital cause of sideroblastic anemia?
X-linked defect in ALAS enzyme
What are the three acquired causes of sideroblastic anemia?
1. Alcoholism: Mitochondrial poison
2. Lead poisoning (Inhibits ALAD and ferrochelatase)
3. B6 deficiency: Required cofactor for ALAS and is decreased when treated with isoniazid
Lab findings in sideroblastic anemia?
3. Serum iron
4. % saturated
5. Cell appearance
1. Increased ferritin
2. Decreased TIBC
3. Increased serum iron
4. Increased % saturated
5. Ringed sideroblasts
Treatment for sideroblastic anemia?
Thalassemia is an anemia due to what?
Decreased synthesis of globin chains of hemoglobin
Why is there a decrease in globin chain synthesis in thalassemia?
Mutations in the genes for certain globin chains
Mutated carriers of thalassemia have protection against what?
Plasmodium falciparum malaria
Alpha thalassemia is due to what mutation?
Deletion in alpha-globin gene
How many alpha thalassemia genes are normally present?
4, 2 on each chromosome
One gene deletion of alpha-globin results in what?
Two genes deleted of alpha-globin results in what?
Mild anemia with elevated RBC count.
A cis-deletion of alpha-globin genes has an increased risk of what?
Severe thalassemia in offspring
Cis deletion of alpha globin is seen in what population?
Trans deletion of alpha globin gene is seen in what population?
Three alpha globin genes deleted results in what?
What type of hemoglobin dominates in 3 alpha gene deletions?
Tetramers of Beta chains (Hemoglobin H)
Hemoglobin H has what effect?
Damages RBC membranes
Four genes deleted usually results in what?
Death of fetus (hydrops fetalis)
What hemoglobin dominates in 4 alpha gene deletions?
Tetramers of gamma chains (Hemoglobin Barts)
Beta thalassemia is due to what mutation?
Point mutation in promoter or splicing sites.
What population usually has Beta thalassemia? 2
2. Mediterranean descent
What are the locations of alpha and beta globin genes?
1. Alpha = Chromosome 16
2. Beta = Chromosome 11
What is Beta thalassemia minor?
1 normal Beta gene
1 mutated Beta gene
How does beta-thalassemia minor present? 6
2. Increased RBC count
3. Hypochromic microcytic anemia
4. Increased in hemoglobin A2 and HbF
5. Decrease in hemoglobin A
6. Target cells
What is beta thalassemia major?
Homozygous mutated Beta globin genes
When do symptoms of beta-thalassemia present?
Several months after birth when HbF begins to decrease.
What forms in Beta thalassemia major?
What does this result in? (2)
Extravascular hemolysis (spleen removes RBC's)
How does the bone marrow respond to beta thalassemia major?
What does this result in? (3)
Massive erythroid hyperplasia
1. Hematopoiesis into skull (crewcut x-ray) and facial bones (chipmunk facies)
3. Risk of aplastic crisis with parvovirus B19
Chronic transfusions in Beta-thalassemia majorsometimes lead to what?
Secondary hemochromatosis (Extra iron in blood)
How does a smear in beta-thalassemia major appear?
Microcytic hypochromic RBC's with target cells and nucleated red blood cells
How do hemoglobin concentrations change in beta-thalassemia major?
Elevated HbA2 and HbF
little or no HbA
What is sickle cell thalassemia the result of?
Coinheritance of hemoglobin S genea dn thalassemic variant of the Beta-globin gene.
How does sickle cell's thalassemia compare to the other Beta-thalassemias?
Less severe than sickle cell
How does lead poisoning present? (LEAD)
1. Lead lines on gingiva (Burton's lines) and on metaphyses of long bones
2. Encephalopathy and Erythrocyte basophilic stippling
3. Abdominal colic and sideroblastic Anemia
4. Drops of wrist and foot (Dimercaprol and eDta to treat)
In terms of macrocytic anemia, what is the MCV?
Greater than 100
Three main causes of macrocytic anemia?
1. Folate deficiency
2. B12 deficiency
3. Orotic aciduria
Folate and B12 are necessary for synthesis of what?
Folate circulates in serum as what form?
Methyltetrahydrofolate (methyl THF)
Removal of methyl group from methyl-THF allows for what?
What takes the methyl group?
Allows folate to participate in DNA synthesis
Vitamin B12 transfers methyl group to what?
To create what?
Lack of DNA precursors has what effect on RBC's?
Lack of nucleotide precursors --> RBC's can't divide enough --> Large RBC's.
Lack of DNA precursors has what effect on granulocytes?
Overall, 3 areas that see a change due to folate or B12 deficiency?
1. RBC's --> Megaloblastic anemia
2. Granulocytes --> Hypersegmented neutrophils
3. Megaloblastic epithelial cells
3 other causes of macrocytic anemia without megaloblastic change? (3)
2. Liver disease
Dietary folate is obtained from what?
Green vegetables and fruit
Dietary folate is absorbed where?
Folate deficiency develops over what period of time?
Causes of folate deficiency? (3)
1. Poor diet: Alcoholics and elderly
2. Increased demand: Pregnant, cancer, hemolytic anemia
3. Folate antagonists: Methotrexate, Dilantin
Clinical and lab findings of folate deficiency?
1. Appearance of RBC's and neutrophils
3. Serum folate levels
4. Serum homocysteine
5. Methylmalonic acid levels
1. 1. Macrocytic RBC's and hypersegmented neutrophils
3. Decreased serum folate
4. Increased serum homocysteine
5. Normal methylmalonic acid
Dietary B12 enters the body how?
1. Salivary gland amylase liberates B12
2. B12 binds to R-binder (also from saliva)
3. In the duodenum, pancreatic proteases detach vitamin B12 from R-binder.
4. Vitamin B12 then binds intrinsic factor (from gastric parietal cells)
5. VitaminB12-Intrinsic factor is absorbed in ileum
Which is more common, folate or B12 deficiency?
How long does B12 deficiency take to develop?
Huge hepatic stores of B12
What is most common cause of vitamin B12 deficiency?
What is pernicious anemia due to?
Autoimmune destruction of parietal cells of stomach --> No intrinsic factor --> No absorbed B12
Other causes of Vitamin B12 deficiency? 5
1. Pancreatic insufficiency
2. Damage to terminal ileum (Crohn's, tapeworm)
3. Dietary deficiency in vegans
4. Auto-immune gastritis
5. Diphyllobothrium latum infections
Lab findings in B12 deficiency?
1. Smear appearance
2. Methylmalonic acid
3. Serum B12
4. Serum homocysteine
1. Macrocytic RBC's with hypersegmented neutrophils
2. High methylmalonic acid
3. low B12
4. High serum homocysteine
Clinical findings in B12 deficiency? 2
2. Subacute combined degeneration of spinal cord
Autoimmune gastritis is associated with what other effects? (3)
1. Achlorhydria (No HCl)
2. Anti-intrinsic factor and antiparietal cell Ab's
3. Increased incidence of gastric carcinoma
What test will determine if intrinsic factor alone will solve B12 deficiency?
Orotic aciduria is due to what?
Genetic mutation in enzyme that synthesizes uridine from orotic acid
How does orotic aciduria present?
Megaloblastic anemia that cannot be cured by folate or B12
Findings in orotic aciduria? (3)
1. Hypersegmented neutrophils
3. Orotic acid in urine
Normocytic anemia is characterized how?
MCV of 80 to 100
What is normocytic anemia due to? (2)
increased peripheral destruction or underproduction of RBC's
What distinguishes whether a normocytic anemia is due to increased peripheral destruction or underproduction of RBC's?
Reticulocytes are what?
How are they identified?
Young RBC's from the bone marrow
Larger cells with bluish cytoplasm
Normal reticulocyte count is what?
RBC lifespan is how long?
What percentage of RBC's are removed per day?
How can you determine if a healthy marrow is responding correctly to anemia?
Reticulocyte count greater than 3%
Reticulocyte count is corrected for by doing what?
Multiplying reticulocyte count by Hct/45
Corrected count >3% indicates what?
Good marrow resonse --> peripheral destruction
Corrected count <3% indicates what?
Poor marrow response --> Underproduction
Peripheral RBC destruction is divided into what two types?
Extravascular and Intravascular
Extravascular hemolysis involves RBC destruction by what?
Reticuloendothelial system (macrophages of the spleen, liver, and lymph nodes)
In extravascular hemolysis, macrophages consume RBC's, what do the parts of the RBC become?
Globin --> Amino acids
Heme --> Iron and protoporphyrin
Iron --> Recycled
Protoporphyrin --> Unconjugated bilirubin --> Binds to albumin --> delivered to liver--> Conjugated --> Excreted in bile
Clinical and laboratory findings of extravascular hemolysis? (6)
3. Jaundice due to unconjugated bilirubin
4. Bilirubin gallstones
5. Marrow hyperplasia with RC of >3%
6. increased LDH
Intravascular hemolysis involves destruction of RBC's where?
Clinical and laboratory findings of intravascular hemolysis? (5)
4. Decreased serum haptoglobin
5. Increased LDH
What are the 3 main extravascular hemolysis normocytic anemias?
1. Hereditary spherocytosis
2. Sickle Cell anemia
3. Hemoglobin C
Hereditary spherocytosis is a inherited defect of what?
RBC cytoskeleton-membrane tethering proteins
3. Band 3.1
What happens to the RBC's in hereditary spherocytosis
Membrane blebs are formed and lost over time --> Cells become round --> Can't maneuver in spleen --> Splenic macrophages consume --> Anemia
Lab findings of hereditary spherocytosis? (3)
1. Spherocytes with loss of central pallor
2. Increased RDW: Older cells smaller than newer
3. Increased MCHC: Loss of space --> Increased Hb concentration
Clinical findings of hereditary spherocytosis:
2. Jaundice with unconjugated bilirubin
3. Increased risk for bilirubin gallstones
4. Increased risk of parvovirus B19 infection
What test diagnoses hereditary spherocytosis:
Osmotic fragility test: Spherocytes in hypotonic solution will burst
Treatment for hereditary spherocytosis?
What does this result in?
Anemia resolves --> Spherocytes still exist --> Howell-Jolly bodies emerge on blood smear
Sickle cell anemia is due to what?
Autosomal recessive mutation in Beta chain of hemoglobin (glutamic acid [hydrophilic] to valine [hydrophobic]
Sickle cell gene is carried by 10% of what descent?
Protective against falciparum malaria
Homozygous sickle cell gene results in what % of HbS?
What does HbS do when deoxygenated?
Polymerizes --> Aggregates into needle like structures --> Sickle cells form
Increased risk of sickling is in what conditions? (3)
What hemoglobin form protects against sickling?
What treatment will increase HbF levels in sickle cell patient?
Reversible sickling results in what? (3)
1. Extravascular hemolysis: Damaged RBC membranes are removed --> 3 symptoms
2. Intravascular hemolysis: Damaged RBC's dehydrate --> hemolysis
3. Massive erthroid hyperplasia
Result of amssive erythroid hyperplasia in sickle cell patients? (4)
1. Hematopoiesis in skull --> Crewcut on x-ray
2. Hematopoiesis in facial bones --> Chipmunk facies
3. Extramedullary hematopoiesis with hepatomegaly
4. Risk of aplastic crisis with parvovirus B19
Irreversible sickling leads to complications of what?
Complications of vasoocclusion include? 5
3. Acute chest syndrome
4. Pain crisis
5. Renal papillary necrosis
What is dactylitis?
Swollen hands and feet due to infarcts in bones
What are consequences of autosplenectomy in sickle cell patients?
1. Increased risk of infection with encapsulated organisms
2. Increased risk of salmonella paratyphi osteomyelitis
3. Howell-Jolly bodies on blood smear
What is most common cause of death in sickle cell kids?
H. influenzae infection due to autosplenectomy
What is most common cause of death in adult sickle cell patients?
Acute chest syndrome
Sickle cell trait is the presence of what alleles?
One mutated and one normal Beta chain
Sickle cell trait has what % of HbS?
Less than 50
Where do people with HbS less than 50% experience sickling?
Renal medulla due to extreme hypoxia nad hypertonicity
Laboratory findings in sickle cell?
1. Sickle cells and target cells (Disease only)
2. Metabisulfite screen: Causes HbS RBC's to sickle (Both)
3. Hb electrophoresis to confirm presence of HbS
Full disease Sickle cell has what array of Hb's?
No HbA (No Beta globin chains)
Trait sickle cell has what array of Hb's?
What is hemoglobin C the result of?
Autosomal recessive mutation in Beta chain of hemoglobin
Gluatmic acid to lysine
How does hemoglobin C present?
Mild anemia with extravascular hemolysis
What is the dead giveaway in HbC lab?
HbC crystals in RBC's on a smear
What are the 5 normocytic anemias with predominant intravascular hemolysis?
1. Paroxysmal nocturnal hemoglobinuria
2. Glucose-6-Phosphate dehydrogenase
3. Immune hemolytic anemia
4. MIcroangiopathic hemolytic anemia
What is paroxysmal nocturnal hemoglobinuria due to?
Acquired defect in myeloid stem cells --> Absent glycosylphosphatidylinositol (GPI) --> Cells can be destroyed by complement
What normally protects blood cells from complement mediated damage? 2
DAF and MIRL
Inhibits C3 convertase
DAF and MIRL are secured to RBC membrane by what?
In PNH, when does intravascular hemolysis occur?
Usually at night during sleep
Mild respiratory acidosis during shallow breathing of sleep --> Activates complement --> RBC's, WBC's, and plateltes are lysed
What are lab tests for PNH? 5
4. Sucrose test
5. Acidified serum test/flow cytometry for lack of CD55/DAF on blood cells
Main cause of death in PNH patients?
Thrombosis of hepatic, portal, or cerebral veins
Why does thrombosis occur in PNH?
Destroyed platelets release their contents into circulation --> Induce thrombosis
Complication of PNH? (2)
1. Iron deficiency anemia
2. Acute myeloid leukemia
Glucose-6-phosphate dehydrogenase deficiency is due to what?
X-linked recessive disorder resulting in reduced half life of G6PD --> Cells susceptible to oxidative stress
How do RBC's deal with oxidative stressors like H2O2? 3
1. Glutathione neutralizes H2O2 --> Glutathione becomes oxidized
2. G6PD generates NADPH
3. NADPH reduces glutathione to regenerate reduced glutathione
What are the two major variants of G6PD?
1. African variant: Mildly reduced G6PD --> Mild intravascular hemolysis
2. Mediterranean variant: Markedly reduced G6PD --> Marked intravascular hemolysis
Carriers of G6PD are protective against what?
Oxidative stress has what effect on Hb?
Precipitates them into Heinz bodies
Causes of oxidative stress? (3)
2. Drugs (primaquine, sulfa, dapsone)
3. Fava beans
Heinz bodie are removed from RBC's by what?
Splenic macrophages which causes lysis
What does G6PD deficiency present as after exposure to oxidative stress? (2)
2. Back pain
What is used to screen for G6PD?
Immune hemolytic anemia (IHA) is mediated by what? 92)
IgG or IgM destruction of RBC's
IgG IHA usually involves what type of hemolysis?
IgG in IHA does what?
IgG binds RBC's in warm temp of central body (warm agglutinin) --> Membrane of antibody coated RBC consumed by splenic macrophages --> Spherocytes form
What is IHA IgG associated with? (3)
Which one is most common?
SLE (most common)
Drugs: Penicillin and cephalosporins
How do drugs cause IgG IHA? (2)
1. Drug attaches to RBC membrane --> Antibody binds to drug membrane complex
2. Drug induces production of autoantibodies that bind self antigens
Treatment of IgG IHA (5)
1. Quit the problem drug
Purpose of giving IVIG to IgG IHA patient?
Splenic macrophages like to consume this most
IgM mediated IHA involves what type of hemolysis?
How does IgM cause IHA?
IgM binds RBC's --> Fixes complement in cold temp of extremities (Cold agglutinin)
IgM mediated IHA is associated with what two infections?
1. Mycoplasma pneumoniae
2. Infectious mononucleosis
What is used to diagnose IHA?
Direct Coombs test confirms what?
How does it do so?
Presence of antibody coated RBC's
Anti-IgG added to patient's RBC's --> Agglutination if RBC's are already coated with Ab's
Indirect Coombs test confirms what?
How does it do so
Presence of antibodies in patient serum
Anti-IgG and test RBC's are mixed with patient serum --> Agglutination occurs if serum antibodies are present
Microangiopathic hemolytic anemia is what?
Intravascular hemolysis that occurs to RBC's as they pass through ciruclation
What are the results of microangiopathic hemolytic anemia? (2)
1. Iron deficiency anemia
2. Chronic hemolysis
What types of patients get microangiopathic hemolytic anemia?
1. Microthbomi patients (TTP-HUS, DIC, HELLP)
2. Prosthetic heart valves
3. Aortic stenosis
What do patients with MHA have as special cells?
Malaria is what?
Infection of RBC's and liver with plasmodium
What transmits malaria?
Female anopheles mosquito
What happens to RBC's in malaria?
What does this result in?
They rupture as part of plasmodium life cycle
1. intravascular hemolysis
2. cyclical fever
P. falciparum fever frequency?
P. vivax and p. ovale fever frequency?
Every other day
What happens to spleen in malaria?
Consumes infected RBC's --> Mild extravascular hemolysis --> Splenomegaly
Anemia due to underproduction is characterized how?
Low reticulocyte count
Etiologies of underproduction anemia? 3
1. Causes of micro and macrocytic anemias
2. Renal failure (decreased EPO)
3. Damage to bone marrow precursor cells
Anemias due to underproduction include? 3
1. Parvovirus b19
2. aplastic anemia
3. Myelophthisic process
Parvovirus B19 infects what cells?
What effect does this have?
Progenitor red cells
Halts erythropoiesis --> Significant anemia in setting of preexisting marrow stress
What is treatment for parvovirus B19?
Aplastic anemia is what?
What does that result in? (2)
Damage to Hematopoietic stem cells
Low reticulocyte count
Etiologies of aplastic anemia? (4)
4. Autoimmune damage
Biopsy of aplastic anemia will show what?
Empty fatty marrow
Treatment of aplastic anemia? (2)
1. Cessation of any causative drugs
2. Supportive care of transfusions and marrow-stimulating factors
last resort of aplastic anemia treatment?
Bone marrow transplant