Wk 1 Hemoglobinopathies Flashcards
When is an urgent blood transfusion required for patients w/ iron deficiency anemia?
- pregnant female w/ Hb <7mg/dL to prevent fetal M&M
- patients w/ severe anemia, Hb <7mg/dL or 8-10 mg/dL for those w/ acute coronary syndrome
How does iron deficiency anemia classically present?
- decreased Hb
- microcytic, hypochromatic RBCs
- decreased iron stores
What groups are at a higher physiologic risk for iron deficiency?
- breastfed infants w/o iron supplementation
- toddlers & young children w/ high intake of cow’s milk
- female adolescents in growth spurt
- pregnant females
What are 3 other common causes of iron deficiency?
- dietary insufficiency
- malabsorption
- acute or chronic blood loss
What signs might be seen in iron deficiency w/o anemia?
neurocognitive symptoms
How is iron deficiency anemia defined by labs?
- Hb level lower than 2 SD below mean
- MCV <80fL (a late finding)
- elevated RBC distribution width
- decreased reticulocyte count
- decreased ferritin (lower than 15 ng/mL is single, most highly suggestive result)
- decreased serum iron
- increased TIBC
- decreased transferrin
Signs and symptoms of any anemia and specifically iron deficiency
- reflect hypoxic functioning: fatigue, dyspnea, headache
- infants & toddlers - irritability, lethargy, feeding difficulties
- iron - pagophagia
- may be asymptomatic
What is a typical iron supplement?
ferrous sulfate: 60-120 mg/day, kids 3-6 mg/kg/day
What other diseases might cause iron malabsorption?
- celiac disease
- H. pylori colonization
- IBD
What is a commonality of Sickle Cell Disease and Thalassemias?
Both have increased RBC destruction (hemolysis)
What is the major defect in Sickle Cell Disease?
Structurally abnormal globins
What is the major defect in Thalassemias?
Deficient globin synthesis
What is Sickle Cell Disease caused by?
Hereditary hemoglobinopathy caused by a point mutation in beta-globin -> polymerization of deoxygenated hemoglobin
What happens in Sickle Cell Disease?
Red cell distortion, hemolytic anemia, microvascular obstruction, and ischemic tissue damage
What hemoglobins are in adult, fetal, and sickle cell disease?
Adult: HbA
Fetal: HbF
Sickle Cell Disease: HbS
What characterizes HbS?
Missense mutation in the beta-globin gene. Charged glutamate residue replaced w/ hydrophobic valine (G->V)
What is the term for heterozygous HbS?
Sickle cell trait, mostly asymptomatic
How many individuals in the US are homozygous for the sickle mutation?
70-100k
- almost all Hb in the red cell is HbS (alpha2, beta^2)
How did HbS arise?
It has risen independently in at least 6 areas in Africa where malaria is endemic. Parasite densities are lower in infected, heterozygous HbAS children and they are much less likely to have severe disease or to die
What 2 ideas could explain the benefit of HbS for malaria?
- Intracellular parasites consume O2, which decreases pH. Both promote sickling of AS red cells, which may be cleared faster by splenic and hepatic phagocytes faster, decreased parasite load.
- Sickling impairs formation of membrane knobs containing a PRO made by the parasite called PfEMP-1 that may -> adhesion of infected red cells to endothelium and may have role in cerebral malaria
What other diseases might protect against malaria?
G6PD deficiency and thalassemia
How might G6PD deficiency and thalassemia protect against malaria?
By increasing clearance and decreasing adherence of infected red cells
What causes the major pathologic manifestations of SCD?
HbS molecules stack into polymers when deoxygenated -> cytosol becomes viscous gel -> sickle shape
What variables affect the rate and degree of sickling?
- interaction of HbS w/ other types of Hb (HbC, HbSC, HbF)
- Mean Cell Hemoglobin Concentration (MCHC): increases w/ dehydration of cells -> sickling. Decreased MCHC condition decrease disease severity
- Intracellular pH: decrease pH -> reduced O2 affinity of Hb -> increased fraction of deoxygenated HbS -> greater sickling
- Red cell transit time through microvascular beds: sluggish blood flow and inflammation -> sickling and occlusion
- Exposure to hypoxia
What is the Hb in those with heterozygote sickle cell trait?
About 40% is HbS and the rest is HbA, which interferes w/ HbS polymerization (HbF interferes more)
What is the term when HbF expression stays relatively high?
Hereditary persistence of fetal hemoglobin
What is HbSC disease?
Heterozygotes w/ HbSC red cells have a higher percentage of HbS (50% vs 40% than HbAS cells). They tend to become dehydrated, increasing the [HbS] and thus polymerization. Disease is somewhat milder than SCD.
What happens if a patient is homozygous for HbS and has alpha-thalassemia?
Hb synthesis is decreased and there is milder disease
How does sickling cause damage?
- HbS polymers grow & herniate through the membrane, ensheathed only by the lipid bilayer
- Membrane changes -> influx of Ca2+, inducing efflux of K+ and H2O.
- Red cells become dehydrated, dense and rigid that becomes irreversible
- extravascular and intravascular hemolysis
Extravascular vs intravascular hemolysis
extravascular: red cell destruction occurs by macrophages in liver and spleen
intravascular: destruction w/in blood vessels due to mechanical injury, complement fixation, intracellular parasites or exogenous toxic factors
What might be the pathogenesis of microvascular occlusions?
Not related to # of irreversibly sickled cells
May be related to increased adhesion molecules that arrest movement, cause inflammation -> stagnation and vascular obstruction
-depletion of NO may have role, which may increase vascular tone
What are Howell-Jolly bodies?
small nuclear remnants due to asplenia
What are signs of SCD?
- irreversibly sickled cells
- reticulocytosis
- target cells
- Howell-Jolly bodies
- hyperplastic BM due to erythroid hyperplasia
- marrow expansion -> bone formation, changes in skull
- extramedullary hematopoiesis
- increased Hb breakdown -> hyperbilirubinemia, pigment gallstones
- splenomegaly in childhood
- autosplenectomy in adulthood
- leg ulcers
- vaso-occlusive crises - hypoxic injury and infarction -> severe pain (most commonly in bones, lungs, liver, brain, spleen, and penis)
- increased susceptibility to infection (partially due to altered splenic fxn)
Dx of SCD
Clinical findings, presence of sickled cells, confirmed by tests for HbS
Prenatal dx by fetal DNA analysis by amniocentesis or chorionic biopsy
Newborn screening for HbS w/ heel stick at birth
Primary tx for SCD
- hydroxyurea, an inhibitor of DNA synthesis -> increase in HbF and anti-inflammatory effect by inhibiting leukocyte production
- L-glutamine as an addition decreases pain crises maybe by decreasing oxidant stress
- HSC transplantation
- gene editing w/ CRISPR to reverse Hb switching
What is thalassemia?
Genetically heterogenous disorder caused by germline mutations that decrease the synthesis of either alpha-globin or beta-globin -> anemia, tissue hypoxia, red cell hemolysis b/c of imbalance in globin chain synthesis
On what chromosomes are the globin genes?
- identical pair of alpha-globin genes on chromosome 16
- 2 beta chains encoded by single beta-globin gene on chromosome 11
What defines alpha vs beta thalassemias?
beta-thalassemia caused by deficient synthesis of beta chains, alpha-thalassemia caused by deficient synthesis of alpha chains
-name for the deficiency
Through what mechanisms do thalassemias cause anemia?
- decreased red cell production
- decreased red cell lifespan
What are the 2 categories of beta-thalassemias?
- β 0 mutations, associated with absent β-globin synthesis
- β + mutations, characterized by reduced (but detectable) β-globin synthesis
What are the causative mutations in beta-thalassemias?
Mostly point mutations:
1. splicing mutations - most common cause of β + -thalassemia
What variant in SCD causes HbS to ploymerize?
beta chain Glu6->Val (E6V) creates a hydrophobic patch that causes Hb to polymerize only when it’s in the T (deoxy) state)
What are the 3 ways you can get anemia?
- blood loss
- make too little blood
- destroy too much blood
What are 2 reasons for decreased production -> anemia?
- lack of necessary building block (i.e. iron or B12)
- lack of enough room in BM (ie full of malignant cells)
What are 3 causes of anemia due to increased destruction?
- problem w/ RBC (abnorm membrane, abnorm Hb form, lack of enzyme)
- Abs mark the cell for destruction
- fibrin strands in vessel lumen can tear RBCs as they pass
List of anemias classified by cause
Classifications of anemia based on morphology
- microcytic
- normocytic
- macrocytic
List of anemias classified by morphology
Mnemonic for microcytic anemias
TAILS
thalassemia
anemia of chronic disease
iron deficiency anemia
lead poisoning
sideroblastic anemia
