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56 Cards in this Set
- Front
- Back
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Q: Describe the pathophysiology of sickle cell disease.
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-intrinsic defect in hemoglobin structure, with valine replacing glutamic acid in 6th position of beta chain
-autosomal recessive-carrier has few problems -extravascular hemolysis (abnormal RBCs removed by fixed macrophages after coating with IgG and C’, increased indirect bilirubin and jaundice) -hypoxia, acidosis, > 60% Hgb S or other abnormal Hgb causes sticking and sickling -Hb F at birth (first 3-4 months) inhibits sickling |
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Q: What are the clinical manifestations of sickle cell disease?
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-vaso-occlusive crises cause most problems
-homozygous individuals have first crises at 3-4 months with occlusion of vessels in fingers and toes -infections: Osteomyelitis-Salmonella, especially S. typhimurium. |
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Q: What are the hematologic findings associated with sickle cell disease?
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-normocytic anemia, leukocytosis with neutrophilia
-RBC morphology-sickle cells (anisocytosis, polychromasia, and target cells), nucleated RBCs, INC RDW, retic index of >3%, bone marrow -> erythroid hyperplasia |
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Q: Describe the serum chemistry associated with sickle cell disease.
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-hyperbilirubinemia, elevated LDH, decreased haptoglobin, increased transaminases
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Q: What is the test for sickle cell disease?
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-sickle cell screen (sickledex is fast, cheap and reliable)
-the gold standard is Hb electrophoresis -+ screen always confirmed by Hgb electrophoresis or other confirmatory test |
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Q: When performing Hgb electrophoresis, what are the normal and abnormal Hb findings and components?
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-normal: Hgb A = 2 alpha 2 beta
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Q: What are the treatment options for sickle cell disease?
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-vigorous hydration and symptomatic treatment of pain.
-increase Hgb F by use of hydroxyurea |
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Q: Describe HgbC.
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-Hgb C – Rarely seen with Hb S, if heterozygous (no disease), homozygous (mild disease)
-lysine replaces glutamic acid in beta-chain at the 6th position |
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Q: Describe Hgb E.
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-most common hemoglobinopathy in Southeastern Asians
-heterozygous (no disease), homozygous (mild disease, similar to thalassemia, mild microcytic anemia) -lysine replaces glutamic acid in β-chain at 26th position |
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Q: What is the pathophysiology for alpha thalassemia minor?
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-1-2 alpha gene deletions, has normal Hgb electrophoresis
-Hgb ELECTROPHORESIS CANNOT DIAGNOSE ALPHA THALASSEMIA OF THIS TYPE , alpha thal minor is a diagnosis of exclusion for microcytosis |
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Q: What is the pathophysiology for severe alpha thalassemia?
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-rare, has 3 or 4 alpha gene deletions
-3 gene deletion leads to Hgb H disease (excess beta-chains form B4 tetramers) -4 gene deletion leads to excess gamma chains form gamma4-tetramers called Hgb Bart’s, which is incompatible with life -Hgb electrophoresis is useful for diagnosis |
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Q: What is the pathophysiology of beta-thalassemia minor?
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-deficient beta chains so increased Hgb A2 and F
-usually detected on electrophoresis with increased Hgb A2 and Hgb F, quantitate A2 -usually asymptomatic with microcytes and target cells |
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Q: What is the pathophysilogy of beta thalassemia major (Cooley’s anemia)?
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-severe with little (beta+) or no (betao) beta chains, manifest at 2-3 months of age
-excess alpha chains form RBC inclusions (alpha-tetramers) producing extravascular hemolysis by macrophages in marrow -hyperplastic marrow causes widening of diploic spaces – chipmunk facies, frontal bossing and “hair on end x-ray.” -massive hepatosplenomegaly leading to extramedullary hematopoiesis -transfusions eventually cause iron overload |
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Q: What are the lab findings associated with mild alpha (2 gene deletions) and beta thalassemia minor?
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-microcytic, hypochromic anemia
-no changes in WBC -RBC morphology-normal RDW, >5 x 10^6 RBCs/uL, target cells present, basophilic stippling, Hgb electrophoresis |
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Q: What are the lab findings for beta-thalassemia major?
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-microcytic, hypochromic anemia, hemolytic
-no changes in WBC -RBC morphology-increased RDW, nucleated RBCs, target cells, basophilic stippling |
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Q: What are some abnormal laboratory tests for beta-thalassemia major?
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-Hgb electrophoresis, iron studies, hyperbilirubinemia, increased LDH
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Q: What happens with long term transfusions in patients with beta-thalassemia major?
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-hemochromatosis
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Q: What is a differential diagnosis for microcytic, hypochromic anemia?
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-iron deficiency anemia and thalassemia, sideroblastic anemia, anemias of chronic diseases
-all of these can be microcytic, hypochromic anemias |
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Q: How can one zone in on thalassemia with microcytic, hypochromic anemias?
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-Sideroblastic anemias: cells can be micro, norma, and macrocytic depending on the cause
-With iron deficiency anemia and anemias of chronic disease, there is a period of time where patients are normachromic, normacytic, it is progressive -Tentative diagnosis: thalassemia because patients with thalassemia have high red cell count |
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Q: What is the mensor index?
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-RBC/MCV, if less than 13, probably thalassemia
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Q: What are the two types of thalassemias?
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-alpha and beta
-Alpha thalassemias are deletions, betas are point mutations with no residual effects, just anemia |
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Q: Describe the components of the alpha globulin molecule and which deletions cause what effects.
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-1 deletion (slight anemia but no other residual effects)
-2 deletions – probably has anemia, but rarely hemolytic anemia -3 deletions – probably have hemoglobin H disease (HbH), Tetramer of beta chains, not compatible with life -4 deletions – hemoglobin Barts (Hb-Barts) disease, Tetramer of gamma chains, All 4 genes are affected, incompatible with life, no alpha chains so no Hb made |
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Q: What are the lab findings with alpha thalassemia minor?
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-alpha thal minor is from 1 or 2 deletions
-In alpha thalassemia minor, get no abnormal Hb produced, just less alpha chains -HbA (2 alphas, 2 betas), HbA2, and HbF (2alphas, 2gammas) are produced in normal proportions |
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Q: What is the use of Hb electrophoresis?
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-When look at an Hb electrophoresis, proportionally they all look the same, so cannot diagnose alpha thalassemia this way, it is just a way of eliminating it as a potential
-is used to identify beta thalassemias which show abnormal Hb |
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Q: Describe beta thalassemias.
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-Involve point mutations, show abnormal Hb so can identify disease by Hb electrophoresis, shows abnormality in production of beta Hb chain
-get less beta chain which means less Hb A which leads to the body to compensate by producing more Hb A2 and F (elevated) -3 forms: minor, intermediate, and major |
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Q: In terms of the symptoms for beta-thalassemia, what does it depend on?
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-Symptoms are based upon how much normal beta chain is being produced
-Amount of compensation depends on how much beta chain is being produced and consequently Hb A being produced |
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Q: Describe major beta-thalassemia.
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-Very little production of Hb A (25-30%), also called Cooley’s Anemia, These patients have a tough time because treatment is transfusions and after time, one complication is iron overload disease.
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Q: Describe the problem with repeated transfusion in patients with major beta-thalassemia.
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-Because introducing all these red cells and body doesn’t get rid of iron very well and so red cell is broken down, iron gets stored in all the various tissues, organs, macrophages, and if there is more iron that macrophages can handle, it goes into paranchymal cells. This leads to tissue dysfunction. Heart disease is a common problem due to cirrhosis of liver and deposits in the liver. This is called hemochromatosis (inherited disease of absorbing more iron than normal and storage in tissues.
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Q: What is hemolytic anemia?
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-Hemolytic anemia: get elevation in total bilirubin or indirect (unconjugated) fraction. Seen in patients with transfusion reactions, autoimmune hemolytic anemias or drug induced, or as a result of beta thalassemia major and severe megaloblastic anemias
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Q: What happens with sever beta thalassemia major?
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-If beta thalassemia major gets severe enough, it can be categorized as a hemolytic anemia (like megaloblastic anemia). But in these two cases, red cells are being destroyed in the bone marrow, not peripherally in the blood stream.
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Q: Describe minor or intermediate beta thalassemia?
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-just varying degrees of how bad the disease can become
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Q: Can RDW be used to differentiate between iron deficiency and thalassemia?
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-YES, Iron Deficient Patient will have an elevated RDW (micro, macro, or normacytic cells) while Thalassemia patients have a normal RDW (this is a genetically inherited disease, and all the cells are microcytic )
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Q: When looking at a blood smear of beta-thalassemia major, what do you see?
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-Microcytic cells, MCV is 68-70, hypochromic, target cells, nucleated red cells (see Hb in cytoplasm of cell, should NOT be seen in peripheral blood smear)
-Bone marrow puts out the more mature cells first and then goes backwards, so if see nucleated reds, think severe anemias, because bone marrow is really trying to pump out blood cells to compensate. |
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Q: What does the presence of basophilic stippling suggest in beta thalassemia major?
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-presence suggests abnormal heme synthesis, seen in thalassemias, iron deficiencies, lead poisoning
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Q: What is the problem with lead poisoning?
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-Lead interferes with ALA synthestase and ferrochetalase in the heme pathway, so get accumulation of the first compound. So don’t get incorporation of iron, and don’t go beyond the first component of that pathway.
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Q: How do you diagnose anemias?
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-see elevation in bilirubin and indirect fraction
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Q: What should be seen in every case of beta thalassemia?
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-should see basophilic stippling, though this can be difficult
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Q: What does it mean to be B0 or B+?
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-gene beta, if 0 that means gene is dysfunctional and not producing any beta globulin, if +, then normal and is producing beta chain, but just don’t know how much
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Q: Describe sickle cell anemia.
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-Inherited condition, abnormality, have valine for glutamic acid in the #6 position at the amino terminal on chromosome 11
-Test used for diagnosing sickle cell is Hb electrophoresis (Hb S migrates slower than normal Hb (due to lack of charge on Hb S for valine), Hb G and HbD also migrate in the same position as HbS) -Do a citric acid test to separate these 3 |
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Q: Describe sickledex.
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-screening test for sickle cell
-Solubility test can also separate Hb S -use organic buffer, have sodium dithinite, which reduces oxygen tension and has a lysing agent to release the Hb -Take the red cell, HbS is released by the lysing agent and will be insoluble in the solution, normal Hb is soluble in the solution (solution would be clear). -HbS solution would look hazy, and how hazy it is depends on how much HbS is there, from here go to Hb electrophoresis -HbD and HbG are soluble in the test, so can make the differentiation that way as well |
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Q: What are the two categories of sickle cell anemia?
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-heterozygous SCA and homozygous SCA
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Q: Describe heterozygous SCA.
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-Most people don’t know they have it until they are put under stress of reduced oxygen tension. This is the sickle cell trait
-Sickle Cell Crisis: red cells sickle and occlude some of the small vessels in the kidneys (or somewhere in kidneys) |
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Q: Describe homozygous SCA.
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-More severe than hetero, patients know they have it because ANY reduction in oxygen tension gives them occluded vessels
-Consequence is that depends on which vessel is occluded: can get stroke (from brain), liver (jaundice), kidney (pain during urination) etc. |
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Q: Which organs are most susceptible to vessel occlusion?
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-Organs most susceptible are spleen, kidney, and bone marrow because venous blood flow through these organs is very slow and cells will sickle
-Head of the femur is also affected and can get necrosis due to lack of arterial flow, aseptic necrosis to the femoral head -Can also end up with sequestration in the spleen, which leads to autosplenectomy giving clogs, ischemia, and total infarction of the spleen |
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Q: What is osteomyelitis?
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-infection, inflammation of the bone
-Salmonella is most often isolated with osteomyelitis and sickle cell anemia |
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Q: When having a patient who you feel may have sickle cell anemia, what do you do first?
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-sickledex (screening test), can get false positive too though (sulf-Hb), run isoelectric point assay to make sure
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Q: What is a sickle cell crisis?
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-pain where the occlusion is, due to lack of oxygen
-can occur in kidney leading to back pain |
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Q: What is seen in patients with autosplenectomoy with sickle cell anemia patients?
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-Howell-Jolly bodies
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Q: What happens if have changes in one or 2 alpha genes?
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-usually asymptomatic
-no test available to identify thalassemia individuals, is a diagnosis of exclusion -can get quantitative analysis of alpha and beta chain to nail diagnosis, but very expensive and time consuming (wait 1-2 months), not necessary |
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Q: What is the difference between hemosiderosis and hemochromatosis?
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-hemosiderosis-iron overload, but iron is engulfed by macrophages, no tissue damage
-hemochromatosis-macrohpage space taken up, so much iron that it is now in tissue cells with eventual tissue damage |
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Q: Why is iron toxic to the cell?
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-fenton reaction, forms free radicals
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Q: What are some different causes of hypoxia?
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-ischemia (caused by occlusion of arteries, embolis or mass compressing vessel) <NEWELINE -abnormal Hb (Hb S, Hb H, Methemoglobin, Carboxyhemoglobin, DEC Hb synthesis)
-bone marrow (fatty bone marrow (cells that look like fatty cells but is not generally fat)), myelofibrosis, kidney disease (not enough erythropoietin) -DEC oxidative phophorylation (cyanide poisoning) |
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Q: What is the composition of normal Hb and what types are found in humans?
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-tetrameric protein composed of two like pairs of globin chains each with its own heme group
-normal adult red cells contain mainly HbA (alpha2beta2) along with small amounts of HbA2 (alpha2delta2) and fetal hemoglobin (alpha2gamma2) -clinically significant Hbopathies result from mutations in the beta-globin gene |
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Q: What percent of Hb is HbS in patients with sickle cell?
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-if homozygous almost all the Hb is HbS (alpha2betasickle2), in heterozygeots only about 40% of the Hb in HbS, the remainder being normal Hb
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Q: Describe the pathogenesis of Sickle cell disease.
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-when deoxygenated, HbS molecules undergo aggregation and polymerization, the red cell cytosol converts from a freely flowing liquid to a viscous gel as HbS aggregates form
-with continued deoxygnation aggregated HbS molecules assemble into long needle-like fibers within red cells, producing a distorted sickle or holly-leaf shape -is reversible w/ oxygenation, but if repeated can lead to membrane damage and permanent sickling, precipitated HbS fibers also cause oxidant damage not only in irreversible sickeled cells but also in normal appearing cells |
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Q: Why is MCHC elevated in HbS patients?
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-with membrane injury, red cells become loaded with Ca2+, this activates a K+ channel leading to the efflux of K+ and water, INC MCHC
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