Lecture 29: RBCs IV
B-thallasemia intermedia
- variable genotype - severe but does not require regular blood transfusion
Burr cells
- RBC with HbC: susceptible dehydration (xerocytosis) - MCHC may increase it and cause Burr cells C and B= burr cells
Hb barts: hydrops fetalis
- (-/-, -/-): all 4 chains deleted a. developing fetus: hydrops fetalis -- very high affinity for O2: poor O2 delivery to peripheral tissues - lethal in utero without transfusion
HbH disease
- (-/-, -/a) - severe: resembles B-thalassemia intermedia - excess of B chains (due to lack of alpha) --> HbH - very high affinity for O2: poor O2 delivery to peripheral tissues - as RBCs age HbH precipitate: RBC inclusions a. extravascular hemolysis
a-thalassemia trait: cis vs trans
- (-/-, a/a) - asymptomatic: like B-thalassemia minor -cis -asians Trans: (-/a, -/a) -black
silent carrier alpha thalassemia
- (-a/a, a/a) - asymptomatic: no red cell abnormality
pathogenesis of HbC vs HbA and HbS
- HbC: less soluble than HbA in RBCS: hexagonal crystal formation - may increase blood viscosity: vaso-occlusion not common like HbS - may increase cellular rigidity: extravascular hemolysis - does not cause intracellular polymerization at low O2 (crystals may disappear in low O2) like HbS
G6PD deficiency
- X linked: many variants (boys are fly like a G6 so X linked) a. most important G6PD- and G6PD Mediterranean - mutated G6PD prone to proteolytic degradation --> makes a RBC decrease in G6PD over time - RBCs become increasingly susceptible to oxidative stress and lysis. as they age (reduced half life due to oxidative stress that normally Glu will protect against but won't cause it decreases with age cause of the mutation) - protective effect against malaria
B-thalassemia
- anemia due to deficient B chain: deficient HbA synthesis - reduced O2 carrying ability of blood - unpaired alpha chain: Hb precipitates in circulating RBCs (extravascular hemolysis) also in RBC precursors (ineffective erythropoiesis)
B-thalassemia peripheral blood smear
- anisopoiliocytosis - microcytic, hypochromic - target cells - reticulocytosis - signs of stressed BM: normoblasts, basophilic stippling
warm antibody type
- autoimmune hemolytic anemia - IgG active at 37 degrees C
cold agglutinin type
- autoimmune hemolytic anemia - IgM active at < 37 degrees C
free radicals/oxidants
- damage membrane proteins - denature globin chains - Fe2+ --> Fe3+: methemaglobin: decreased O2 affinity a. cyanosis
alpha thalassemia
- deficiency in alpha globin chains: leads to unpaired beta, gamma, or epsilon chains
compensatory mechanisms for beta thalassemia
- erythroid hyperplasia 1. expansion of bone marrow: skeletal abnormalities (crew cut image on skull xray) 2. extramedullary hematopoiesis: liver, spleen (hepatosplenomegaly), LNs
clinical manifestations of HbC
- from asymptomatic to mild anemia - may be problematic in compound heterozygosity (inherited with HbS, beta thalassemia)
sickle cell peripheral blood smear
- generally: normocytic, normochromic - anisocytosis, poikilocytosis, sickle cells, pencil cells, target cells, reticulocytosis can be observed a. especially in patients with decreased splenic function - increased RDW
renal manifestations of sickle cell disease
- hematuria - glomerular dysfunction - proteinuria and nephrotic syndrome - renal papillary necrosis - UTIs - HTN - renal excretion defects: acidosis, hyperkalemia - acute/chronic renal failure - renal medullary carcinoma sickle cells can clump in kidneys and cause necrosis
B-thalassemia minor
- heterozygous B-thalassemia a. B0/B b. B+B - asymptomatic with mild or absent anemia - RBC abnormalities seen -has one normal gene
therapy for sickle cell disease
- hydroxyurea: shown to increase HbF, MCV, and NO (prevent clotting) - BM stem cell transplant
Ineffective erythropoiesis in Beta-T
- ineffective erythropoiesis: reduced hepcidin levels a. increased iron absorption (overload): hemochromatosis
thalassemia
- inherited disorder leading to decreases in globin (alpha or beta) synthesis of adult HbA (a2b2) - one of the most common inherited disorders in humans - protection from malaria in heterozygotes 1. B thalassemia: deficient synthesis of B chain 2. a thalassemia: deficient synthesis of alpha chain
sickle cell disease
- inherited mutation a. heterozygous: sickle trait (asymptomatic mostly) b. homozygous: sickle cell disease (symptomatic) - missense mutation: glutamic acid to valine substitution at position of 6 globin gene creating HbS
clinical presentation of immunohemolytic anemia
- insidious onset (months) - or severe anemia (within days) a. fever b. pallor c. jaundice d. hepatospleomegaly e. renal failure - +/- signs and symptoms of underlying disease
G6PD function
- pentose phosphate pathway - RBCs need G6PD to form NADPH: used to generate anti-oxidant glutathione -Glu protects RBC against oxidative stress
extravascular hemolysis sickle cell disease
- phagocytes eliminate deformed RBCs
autoimmune hemolytic anemia: causes
- primary: idiopathic - secondary: a. CLL (proliferative lymph disorders) b. lymphoma (proliferative lymph disorders) c. SLE (autoimmune disease) d. mononucleosis (infections) e. mycoplasma PNA (infections) f. chicken pox (infections) h. drugs (penicillin, methydopa) - auto-Ab bind to RBC surface Lymphoproliferative disorders, autoimmune, drugs, infections
facial abnormalities b-thalassemia
- prominence of malar bones - depressed bridge of nose -exposed upper incisors - chipmunk facies
clinical manifestations in sickle cell disease
- related to 1. chronic hemolysis: anemia (SOB, fatigue, jaundice) 2. microvascular occlusions: visual defects, infarcts, stroke 3. hypoxic injury: vaso-occlusive crisis
intravascular hemolysis sickle cell disease
- secondary to damaged RBC membrane - releases Hb that inactivates NO a. vasodilator and inhibitor of platelet aggregation - compounds vascular occlusion
erythroid hyperplasia
- seen in BM of sickle cell patients - increased erythroid precursors in BM - leads to more marrow between trabeculae: widening of diploic space a. crewcut appearance on skull xray
Heinz bodies
- seen in G6PD deficiency - precipitation and aggregation on RBC membrane of Hb H for H: Heinz are hemoglobin precipitates
bite cells
- seen in G6PD deficiency: extravascular hemolysis - deposition of IgG and complement: opsonization for macrophages - splenic phagocytes pluck at Heinz bodies and lead bite cells can lead to splenomegaly
Hemoglobin C
- substitution of glutamic acid (negative) with lysine (positive) at position 6 of B hemoglobin chain - HbC becomes more positively charged
what increases in beta-thalassemia
-HgbA2 ( 2 alpha chains and 2 delta chains (instead of normal alpha and beta chains)) - increased HbF: increased affinity for O2 a. may affect O2 delivery to tissues
splenic infarcts
-increased susceptibility to infections: especially with splenic defects a. Pneumococcus, Haemophilus, meningitis b. parvovirus B19 (aplastic crisis) sickle cell: Pnemah, hidayah, men
two types of immune hemolytic anemias
-these are anemias cause by Ab that destroy the RBC -associated with drugs or autoimmunity
features of G6PD deficiency
1. Heinz bodies 2. intravascular hemolysis: hemoglobinemia, hemoglobinuria 3. extravascular hemolysis: bite cells
mechanism of sickle cell disease: hemolysis
1. deoxygenated RBC 2. K+ and H20 leave cell, Ca2+ enters cell and sickles it (lineraization) -increased MCHC facilitates the sickling 3. Repeated HbS polymerization leads to extensive RBC membrane damage 4. That leads to hemolysis
triggers of oxidative stress
1. infections 2. drugs: a. antimalarials b sulfonamides c. nitrofuratoin d. isoniazid e. rasburicase 3. certain foods: fava beans a. can generate free radicals
how does sickle cell lead to infarcts
3. prolonged transit time: spleen, bone marrow, inflamed tissue 4. Leads to sickle cell clumping and leading to microvascular occlusion 5. leads to infarcts Decreased NO will also lead to activation of platelets and infarcts
when do beta thal symptoms occur
6-9 weeks after brith becuase that is when HbF is replaced by HbA
HbSC disease
compound heterozygosity: vascular events are more common here than just in HbS (vascular retinopathy/avascular necrosis)
renal papillary necorsis
looks like a lobster claw
immunohemolytic anemia: drug associated: IC formation
Drug is seen as immunogenic and Ab bind to it (antigen binds AB = IC) Complement (C3b) will bind the IC and all 3 will bind RBC MAC will be activated --> intravascular hemolysis
what gives HbS the sickle shape
Hb will clump in low O2, low Ph, or hypertonicity --> sickle cell (lineralization)
4 microcytic anemias
Fe2+ def, sideroblastic, anemia of chronic disease, thalassemia
what happens when HbH precipitates
Heinz bodies --> RBC inclusions --> macrophages get it in the spleen --> extravascular hemolysis --> splenomegaly
what can cause cell to sickle
Na-metabisulfite it will decrease O2 tension in RBC --> cause HbS to sickle (regardless of genotype)
when will there be increased target cells
Post splenectomy (hereditary spherocytosis) or autosplenectomy (hemoglobin S) no longer cleared because no spleen
what makes a cell microcytic
RBC will try to adapt to the reduced Hb and shrink their cells by reducing volume of RBC and cell divisions --> this is all to maintain the right [Hb]
when does acrocyanosis occurs
agglutination that occurs in the cold clumps in distal parts of limbs immunohemolytic anemia (autoimmune): cold --> infections
what is HbH
beta 4
verterbral deformities of sickle cell: Fish mouth
biconcave appearance: fish mouth deformity of vertebrae due to bone softening because of bone marrow expansion in patient with sickle cell disease
Senicaproc
blocks Gardos channel activity so K+ and H2O can't leave sickle cell and it is less prone to dehydration
is sickle cell extravascular or intravascular hemolytic anemia?
both
patho of thalassemai
decreased globin means decreased hb which means microcytic anemia
another name for microcytic anemias:
deficiency anemias that actually decrease erythropoiesis and that is why we have anemia
verterbral deformities of sickle cell: H shaped vertebrae
due to ischemia and infarction of central growth plate
what can distinguish HbA from HbS
electrophoresis
what is in excess if all 4 alpha genes get deleted
excess gamma chains --> Hb barts which is gamma 4 in developing fetus
how to cold agglutinin types work?
fix complement on RBC, leading to MAC and intravascular hemolysis mononucleosis, M, pneumonia, LPD infections fs (think mycoplasma)
importance of charge change: sickle cell
glutamic acid is negative and valine is no charge HbS will not travel as far to the positive side as HBA heterozygous HbA and HbS will have two lines
mutation of HbC
glutamic acid to lysine at position 6 of the beta hemolgobin chain negative to positive vs HbS (glu to val (neutral))
B thalassemia major (Cooley's anemia)
homozygous B-thalassemia: a. (B0/B0) b. (B+/B+) c. (B0/B+) - severe: requires blood transfusions - B0: absent globin synthesis - B+: reduced globin synthesis
importance of cis and trans mutation
if two parents are both cis, there is a 25% chance of death if two parents are both trans: all kids will be fine if one parent is cis and the other is trans, there is a 50% chance of a silent carrier
what type of anemia is G6PD
intravascular normocytic anemia and extravascular!
how does MCV treat sickling
it can increase the volume of RC to dilute HbS and decrease sickling
G6PD as RBC progress
it decreases, so old RBC are more susceptible to oxidative stress and they are the ones lysing
for all the normocytic anemias, what is BM doing
it is increasing its activity to compensate for the loss of RBC --> reticulocyte will increase! this may deplete iron stores --> make a microcytic anemia
immunohemolytic anemia: autoimmune
just a normal Ab will recognize our RBC's as foreign :( and bind to AG on RBC Complement/Ab will bind and signal macrophages for opsonization ---> extravascular hemolysis Ab can also signal MAC and lead to intravascular hemolysis
classification of sickle cell
normocytic and normochromic it only sickles when we have decreased O2
what cell is at risk for intravascular hemolysis in G6PD def
older cells --> hemoglobinemia, hemoglobinuria
what does infarction and bone necrosis increase risk for
osteomyelitis
where are glomeruli occluded by sickle cells
peritubular capillaries
what is a vaso-occlusive crissi
severe pain: hand foot syndrome --> dactylitis of digits of hand and feet acute chest syndrome: chest pain, cough, hypoxia because of pulmonary vaso-occlusion of vessels splenic infarction --> LUQ pain (hard to get rid of sickle cells now) think about clotting going to digits, pulmonary, and spleen
how does sickle cell protect us against malaria
sickled cell RBC do not have the adhesion molecules that malarial parasites need parasites will consume O2 --> sickle the RBC --> macrophages will eliminate RBC with the parasite --> decreased parasite load so decreased adhesions and increased clearance
what causes acrocynaosis and levido reticularis
sludging of microcirculation secondary to agglutination of RBCs by cold agglutinins --> disappears on warming
beta thalassemia
symptoms depend on number of beta globin genes involved and how well the other Hgb can compensate
what disease has target cells
thalassemias, Hemoglobin S disease, Iron def, obstructive liver diseases (lecithin-cholesterol acyltransferase) -increases cholesterol to phospholipid ratio
what kind of cells are in sickle cell patients that have a decreased splenic function
the decrease in macrophages means we have increased in RDW aka diff size cells so we have anisocytosis, poikilocytosis, sickle (falciform) cells, pencil cells, target cells, reticulocytosis with decreased splenic function, even heterozygous patients have have symptoms
immunohemolytic anemia: drug associated: hapten model
the drug is not immunogenic on its own but it binds to a RBC and becomes immunogenic an IgG Ab is going to recognize that immunogenic-hapten-drug complex and activate complement it will lead to MAC --> intravascular hemolysis or IgG will act as opsonin and macrophages will recognize it in the spleen and lead to extravascular hemolysis
what prevents hetero sickle cell patients from developing symptoms
the spleen! it will eat the sickle cell
what are target cells
there is more cell membrane compared to cell content: abnormal increase in ratio of surface membrane are to volume membrane collapses on itself at center and protrudes
fava beans
they have vicine, alkaloid glycoside that can make free radicals
how do warm Ab's work?
they opsonize RBC's and call macrophages to eat them and cause extravascular hemolysis LPD, Autoimmune, drugs (everything else)
how to associate heinz bodies with G6PD
think of lil fava beans as heinz bodies
G6PD assay in G6PD def
we have constant reticulocytes being made and they are all new (meaning they have normal levels of G6PD), so it is possible the assay will not show a deficiency since we have so much always being made (in acute crisis)
what can cause microcytic anemias
well Hb is globin + heme (iron and protoporphyrin) if any of the components above decrease, we have decreased Hb