Clinical Manifestations of Hemogloinopathies and Thalassemias Flashcards
Hemoglobinopathies
Qualitative defects in primary and tertiary structure of hemoglobin
Sickle cells is an example
Rare except in malaria regions
Thalassemias
Quantitative defects in either alpha or beta globins which produce a shortage of one globin type and unbalanced excess of another
Hemoglobin A design
2 stable alpha-beta globin dimers loosely bound into a tetramer
Embryonic globin chain genes,
Fetal hemoglobin genes
Embryonic - zeta and epsilon…place taken by alpha and gamma…alpha globins present throughout life while gamma eventually replaced by beta
HbF genes
Beta globin gene turns on in 1st trimester…transition period usually completed during weeks of postnatal life
How to diagnose hemoglobin structural disorders
Hemoglobin electrophoresis or HPLC
Hemoglobin electrophoresis
Structural variants have different charge patterns…done at multiple pHs
HPLC
Liquid mobile phase of dissolved hemoglobin
HbS
HbS does not dissolve in blood plasma
Test 2 ways
1) Sodium dithionite added and plasma becomes cloudy
2) Sodium metabisulfite test where oxygen removed and RBCs will sickle
Sickle cell anemia
Hemoglobinopathy
Mutation at position 6 in beta globin primary chain
Replace glutamic acid with valine
Tower skull and leg ulcers
Sickle cell mutation
6th AA position (GAG) for glutamic acid replcaed with GTG for valine
Results in change from charged, polar hydrophilic to uncharged hydrophobic, nonpolar side chain
Deoxygenated sickle cell
Tense conformation has sticky valine that wants to bind to other valines on HbS molecules
THis is why dehydration and hypoxia cause aggregation
Oxygenated sickle cell
Adjacent HbS are not likely to aggregate
POlymerization of sickle cell
HbS line up like long, rod-like polymerized crystals
Can be undone with oxygen
HbS membrane effect
Leads to force on membrane that it eventually overcomes…overtime, the membrane retains a sickle shape even if sickle hemoglobin removed
Membrane performance changes
Malfunctioning ion transport channels permit Na and Ca influx with K, Cl and H2O efflux…leads to dehydration, RBC shrinkage, increased RBC hemoglobin concentration and more polymerization
Other membrane changes
Iron-mediated oxidative damage to membrane structural proteins makes membrane more rigid Denatured HbS (Heinz bodies) damage inner leaflet and promote extravascular hemolysis Distortion also exposes neoepitotpes that bind IgG
SIckle shell shape and other things
Misshaped, rigid, friable, subject to stress, hemolysis and phagocytosis
Adherent to vascular endothelium
More susceptible to phagocytosis
Sickle cell membrane pathology
Entagle one another
Adhere to endothelium
Interact with Igs and complement in od ways
Disturb NO biology
Stimulate - pro-coagulants, cytokines, pro-inflam molecules, free radicals
Vascular clumping
Clumping of sialic acid residues and glycophorin on membrane promoted by calcium loading and dehydration…endothelial Von Willebrand factors multimers as well as plasma fibrinogen, fibronectin, and thrombospondin may play roles
Vaso-occlusion
Entanglement and endothelial adhesion are likely at vessel bifurcations and areas of low flow or turbulence…produces ischemia and micro infarcts in many tissues
Bone involvement in sickle cells
Pain crisis, osteonecrosis of femoral head, scattered bone infarcts, predisposition to mosteomyelitis and septic arthritis
Acute chest syndrome
Sequestration of sickled cells into pulmonary vasculature
Also, embolization of infarcted bone marrow
May be confused with pneumonia and often accompanies it
Strokes
Increased flow velocity - increased risk
Median age 5
Strokes predispose to more strokes
Spleen pathology and sickle cell
Sequestration crisis due to rapid accumulation of sickled RBCs in enlarging spleen leading to acute anemia and schock
Also progressive microinfarction leading to gradual autospelenectomy
Prone to bacterial sepsis (encapsulated like S pneumo and H influ)
Bone marrow expansion and sickle cell
Chronic hemolytic anemia and increased hematopoietic drive lead to expansion of red marrow into bony spaces usually not occupied by these…leads to tower skull
Also, extramedullary hematopoiesis
Management of sickle cell
Antibiotic Hydration and rest Hydroxyurea (to express HbF) Exchange transfusion Iron overload monitoring (becasue of chronic transfusion)
Sickle trait
One mutant gene…typically HbA>50%…presence of HbA increases oxygenation and limits sickling
Sickling still possitble givne low oxygen partial pressure, unusual exertion or dehydration
Sickle cell malaria
Sickling cells bearing organized are cleared by spleen
Sickle syndromes can appear as
Compound heterozygotes
Compound heterozygote sickle cell dz
HbS/B-thalassemia - meditteranean
HbSS with alpha thalassemia - milder anemia but similar vaso occlusion
There are many others
HbSC dz
Different mutation in the same location…subs lysine for glutamic acid
HbC alone does NOT cause vaso-occlusion
Mild hemolytic anemia but don’t need tx
Significance is when found in compound heterozygous state with HbS…Milder but similar to sickle cell
Appearance of blood in thalassemias
Watery
Thalassemia naming and what happens
Named for deficient chain
Overall deficit of normal Hb tetramers
Excess unpaired chains lead to hemolysis or ineffective erythropoiesis
Thal classification and how different than sickle cell
Mahor, intermedia, and minor
Can begin in utero with severe anemia producing marrow expansion and bony deformoities
Normal genetics of HbA
4 alpha genes and 2 beta genes
Alpha thalassemias
One alpha missing - plenty left over and no anemia
2 alpha missing - mild anemia but only HbA present
3 alpha mising - small HbA made but excess of beta leads to B4 tetramer called HbH which is unstable but functional…this is called HBH dz
If all 4 genes missing, then only gamma4 tetramers (Barts) and Portland are present…lethal in utero
Alpha thal silent carrier
Only one gene is missing…all Hb is HbA and insignifcant amount of B left over
Cis alpha thal trait
2 genes missing on one chromosome…mildly def HbA and more unpaired B left over…form is inherited from a parent with a similar genotype and half of offspring affected
Trans alpha thal trait
Two genes missing but one on each chromosome…1/4 of offspring of two silent carriers would be affected and all susequent crosses with normals would be silent carriers
If one is cis and one trans
Could have 3 alpha genes missing
4 if both trans
HbH disease
3 alphas are missing…HbA moderately deficient and B4 tetramers are formed…recognize on Hb electrophoresis as a fast migrator
RBCs of HbH dz
Reduced RBC Hb content, producing target cells
Chronic anemia provokes erythropoeisis and polychromasia
HbH precipitates to form
Heinz bodies
Transfusion usually unnessecary because moderate anemia
Result of 4 alpha missing
Fetal dies from high output congestive heart failure secondary to profound anemia
B globin genes
Chromosome 11 each one copy
B0 and B+
B0 - defective or deleted
B+ - deficient and mediterranean type
Thalassemia major
Homozygous B-thalassemias
Absent or markedly decreased beta chains
Alpha chains wil form unstable precipitates that then form free radicals that contribute to hemolysis
Anemia due to decreased production and increased destruction and can be severe
Severity of thalssemia major depends on
Persistence of HbF
Cooley’s anemia
Homozygous B-thalassemiua
Severe anemia leading to bone marrow hyperplasia and skll and jaw malformations (crew cut)
Jaundice and splenomegaly
Growth stunted and puberty delayed
Liufelong transfusions needed and die young from iron overload
Heterozygous B-thalaseemia
B-thal trait
Anemia is mild and may be silent but sometimes presents as refractory anemia in pregnancy
Small increases in HbF and HbA2 present and may be clinically silent
Milder thalassemias mistaken often iwth
iron deficiency
Summary thalassemias
Less Hb produced in each RBC…fewer RBC produced…excess globin chains promote oxidative damage and precip of alpha chains promotes hemolysis…speen enlarges due to all RBCs that it is cleared and hemolysis causes jaundice…massive death of RBC precurosors in bone marrow…persistent anemia leads to high output congestive heart failure…chronic hypoxia leads to organ probsd and increased EPO production leads to marrow expansion and bone deformities…***Also lead to increased GI iron absorption which, coupled with defective utilization, leads to iron overload
Transfusion benefits and downfalls
Replaces O2 carrying capcity with normal donor RBCs and suppresses patients EPO drive
Each contains iron and there is no way to excrete the iron
