Lec 5 Hemoglobin Disorders Flashcards
On what chromosome are alpha globin genes located?
chr 16
On what chromosome are beta globin genes located?
chr 11
What 2 chains make up hemoglobin F?
2 alpha and 2 gamma
What 2 chains make up hemoglobin A?
2 alpha and 2 beta
What 2 chains make up hemoglobin A2?
2 alpha and 2 delta
When do first RBCs in embryo appear?
3rd wk of gestation in the yolk sac
Does hemoglobin F have high or low affinity for oxygen?
relatively high!
When does hemoglobin A replace hemoglobin F?
by about 6 months of age
What percent of hemoglobin is normally A2?
1% of adult hemoglobin
How many heme molecules in one hemoglobin?
4 heme molecules = 1 heme for each globin
What is the structure of heme?
four pyrrole groups with an Fe molec in the center
Where does heme synthesis occur?
in the mitrochondria
What diseases associated with deficiency of some of the enzymes in heme biosynthesis?
porphyrias
sideroblastic anemia
What are porphyrias?
group of metbaolic disorders in which defects in enzymes of heme synthesis –> accumulation and excretion of porphyrins = toxic compounds
What is defect in acute intermittent porphyria? WHat 2 things accumulate
deficiency of porphobilinogen [PBG] deaminase –> leads to accumulation of ALA and PBG
What are clinical signs of acute intermittent porphyria?
nervous system abnormalities –> psychosis, convulsions, ANS dysfunction, peripheral neuropathy, parlaysis
What is the defect in porphyria cutanea tarda?
deficiency of urogen decarboxylase
What is the function of hemoglobin?
reversible bind O2 for delivery
- pick O2 up in lungs and deliver to tissues postnatally
- pick O2 from placenta and deliver to the fetus in utero
Does T or R state of hemoglobin have more affinity for oxygen?
T state = taut = low affinity
R state = relaxed = higher affinity
What does increased O2 affinity do to P50?
lower P50
Is ferrous [Fe2+] or ferric [Fe3+] better state for O2 unloading?
ferrous
if stuck in ferric = high affinity for O2 but don’t unload it
What part of hemoglobin binds the 2-3 DPG?
the beta chain N terminus region
What is the P50?
oxygen pressure at which 50% of hemoglobin is saturated with oxygen
What is the Bohr effect on hemoglobin O2 affinity?
decrease in Ph –> decrease in hemoglobin affinity for O2 –> more unloading of O22 at tissue
What is effect of 2,3-DPG on hemoglobin affinity for O2?
shifts the curve to the right = less affinity for O2
What happens when you have high affinity hemoglobin? Treatment?
O2 bound tightly to Hgb –> lower o2 tension than normal –> increase EPO –> erythrocytosis or polycythemia
treatment = phlebotomy
What happens when you have low affinity hemoglobin [familial cyanosis]? treatment?
hemoglobin binds O2 poorly so mostly in deoxyhemoglobin state = bluesh hue known as cyanosis
will have cyanosis even though they are not hypoxic
no treatment required
What is methemoglobinemia?
abnormal accumulation of methemoglobin in RBC = hemoglobin in which Fe oxidized to ferric [Fe3+] state and is unable to let go
What are some causes of methemoglobinemia?
hemoglobin M = inherited disroder where abnormal Hgb has Fe in oxidized state
exposure to oxidizing agents [nitrites]
What signs of methemoglobinemia?
cyanosis and chocolate-colored blood
What is treatment for methemoglobinemia?
methylene blue
What happens in CO poisoning?
hemoglobin binds CO to form carboxyhemoglobin = high affinity hemoglobin
reddish color = cherry red skin
What defect specifically causes sickle cell disease?
single point mutation causing substitution glutamate –> valine in position 6 of the beta globin chain
What chains in hemoglobin S?
2 alpha and 2 beta-S
Why does sickle cell promote inflammation?
- polymerization of HbS disrupts RBC cytoskeleton and leads to flipping of phosphatidylserine lipids in the membrane –> negative charged glycolipids on outside + activate coagulation cascade and promote inflammation
What are some factors that promote sickling of HbS?
- low O2
- infection
- dehydration
- acidosis
- low levels of HbF
What are 3 consequences of sickling HbS?
- microvascular occlusions b/c sickled cells trapped in small blood vessels –> infarction and necrosis of tissue
- chronic extravascular hemolysis b/c poorly deformable sickled cells trapped and phagocytized by macrophages in the reticuloendothelial system
- NO depletion by free hemoglobin from intravascular RBC breakdown
How does life span of RBCs that are sickled compare to normal?
shortens life span by 2-3 weeks
What is effect of sickle cell on the spleen?
extravascular hemolysis within the spleen –> recurrent infarction of spleen b/c HbS stuck –> atrophy and autosplenectomy
What are 3 complications of microvascular occlusion?
- pain
- splenic infarction
- end organ damage to lungs, CNS, etc
What are 3 complications of chronic extravascular hemolysis in sickle cell?
- anemia
- expansion of erythropoiesis in bone marrow
- gallstones
What are 4 consequences of NO depletion in sickle cell?
- pulm HTN
- stroke
- priapism
- leg ulcers
What is sickle cell disease?
pts who are homozygous for sickle mutation
When do clinical manifestations of sickle begin?
around 6 months of age; earlier than that protected by HbF
What type of infections are people with sickle cell more at risk for?
encapsulated organisms like strep pneumo
What is a tip off that pt with sickle might be undergoing aplastic crisis?
inappropriately low reticulocyte count
What is splenic sequestration syndrome?
only occurs in children w/ functional spleens
see massive sudden intersplenic sickling –> acute severe LUQ pain, rapid increase in spleen size; abrupt fall in hematocrit + shock
What cardiovascular complications in sickle?
high output CHF secondary to chronic anemia
thrombosis
stroke
What are signs of acute chest syndrome in sickle?
chest pain, fever, cough, pulm infiltrate of abrupt onset due to sickling in microvasculature of lung and causing pulmonary infarction
How do you distinguish acute chest syndrome from infection?
clinically indistinguishable
What kind of gallstones do you see in sickle?
bilirubin gallstones from hemolysis
What renal complications of sickle?
low O2 in kidney medulla –> prone to infarction from vaso-occlusion –> medullary infarcts –> impaired ability to concentrate urine; hematuria
have renal papillary necrosis and microhematuria
What do you see on peripheral smear in sickle?
- sickle shaped RBCs
- polychromasia [reticulocytes]
- nucleated RBCs [b/c chronic active hemolysis –> increase bone marrow activity]
- howell jolly bodies [normally would be cleared by spleen but these pts have functional asplenia]
- target cells
How do you diagnose sickle?
hemoglobin electrophoresis + CBC
What is treatment for sickle?
hydroxyurea to increase HbF and bone marrow transplant
WHat do you see in bone marrow of pt with sickle?
hypercellular; erythroid hyperplasia
What do you see on CBC in pt with sickle?
- low Hbg
- WBC may be falsely elevated if not corrected for presence of nucleated RBCs
- high retic count
What happens to LDH in sickle?
increased
Why give folic acid to pt with sickle?
at risk of folate deficiency b/c they are trying to make so much more blood
What is sickle cell trait?
people who are heterozygous
will have 60:40 HbA to HbS
can be clinically normal; not anemia; may be at risk for renal complications
What is hemoglobin C disease defect?
mutation at residue 6 on B-globin from glutaminc acid –> lysine
What are symptoms of hemoglobin C defect?
have mild hemolytic anemia w/ splenomegaly if homozygous
What happens in patient with double heterozygote SC disease?
resembles mild form of sickle cell disease PLUS have splenomegaly
How can you distinguish between patient with sickle disease and patient with SC disease?
SC patient will have splenomegaly; SS will not
What is clinical course of patient with sickle-beta thalassemia?
depends on how much normal beta globin is produced
How can you distinguish sickle-beta thalassemia from homozygous sickle cell disease?
sickle beta have splenomegaly and target cells
homozygous sickle will not
What is the defect in beta thalaseemia?
beta globin synthesis decreased or absent due to point mutations in splice site and promotor sequences
Who primarily gets thalassemias?
mediterranean, middle eastern, african, indian, southeast asian
What is beta thalassemia minor?
heterozygote of decreased beta chain synthesis [B+]
What is beta thalassemia major?
homozygote of loss of activity of B chain gene
[Bo/Bo or Bo/B+]
What are the two major consequences of decreased beta globin synthesis?
- overall decreased production of hemoglobin A –> hypochromic microcytic anemia
- unbalanced synthesis of a and b chains –> accumulation free excess alpha chain in RBCs –> combine to form alpha tetramers that are insoluble and precipitate in RBCs = heinz bodies
What happens to levels of HbA, HbA2, and HbF in beta thelassemia?
HbA decreases
HbA2 and HbF increase = compensatory mech both in and outside bone marrow
Why do you get hepatosplenomegaly in beta thalassemia?
extramedullary hematopoiesis
What are the heinz bodies of B-thalassemia made of?
made of hemoglobin alpha chain tetramers [a4]
What happens to RBCs with heinz bodies in beta thalassemia?
- most are prematurely destroyed in marrow = intramedullary hemolysis
- the rest get hemolyzed in spleen = extravascular hemolysis
What are signs of B-thalassemia major?
severe anemia requiring blood transfusion
increase in erythryopoiesis –> marrow expansion and extramedullary hematopoiesis
What happens to reticulocyte count in B-thalassemia major?
reticulocyte count increases
What do you see on physical exam in B thalassemia major?
chipmunk facies
crew cut on skull xray
hepatosplenomegally
What do you see on smear in B thalassemia major?
microcytic hypochromic RBCs poikilocytosis target cells basophilic stippling polychromasia 2ndary to increased retics
What is treatment for B thalassemia major?
transfusions + iron chelation therapy
splenectomy
BM transplant
What is the defect in alpha thalassemia?
deletion of one or more of the 4 alpha globin genes –> leading to decreased alpha globin synthesis and deposition of gamma-globin tetramers
What are the consequences of decreased alpha globin chain synthesis?
- reduction in conc of all hemoglobins since all contain alpha chain
- excess free beta and gamma –> HbH [beta4] and Hb Barts [gamma4]
What is hydrops fetalis?
if all 4 alpha genes are deleted –> no alpha globin + excess HbBarts [gamma x4] which cannot release O2 to tissue
incompatible with life
What is HbH disease?
if 3 of 4 alpha genes are deleted –> very little alpha globin + excess B globin that forms HbH [beta x4]
HbH can precipitate in membrane of RBC –> causes extravascular hemolysis in spleen
have mild to moderate hypchromic microcytic anemia and splenomegaly
What is alpha thalassemia minor?
2 alpha globin genes defective –> mild hypochromic microcytic anemia with splenomegaly
not clinically significant
What is alpha thalassemia trait?
silent carrier = 1 alpha globin gene defective
asymptomatic and no anemia
What is major cause of anemia in b-thalassemia?
ineffective erythropoiesis
What is major cause of anemia in HbH disease?
hemolysis
