Pathology-Red Cell Disorders Pathology Flashcards
What are hypoxic symptoms that present in patients with anemia?
Weakness, fatigue, dyspnea, pale conjunctiva & skin, headache, lightheadedness and angina.
What is a situation where a patient would have an abnormal Hb, Hct and not be truly anemic?
Pregnancy. More blood volume = diluted RBC concentration.
What is a situation where a patient would have a normal Hb, Hct but actually be anemic?
Bleeding out from a gunshot wound. RBC concentration remains the same, but total blood volume is decreased. Hct and Hgb will show anemia once fluid loss has been replaced.
Lab definition of anemia>
Hb < 13.5g/dL in males. < 12.5g/dL in females.
What defines normocytic anemia?
MCV = 80-100. < 80 = microcytic anemia. > 100 = macrocytic anemia.
What is responsible for the RBCs being small in microcytic anemia?
RBC generation starts with a large erythroblast. The erythroblast divides into smaller cells until the RBC has the desired concentration of Hb. When there is decreased production of Hb, the RBC divides again to maintain the correct concentration, thus creating a smaller RBC.
What is hemoglobin?
Heme (Fe2+ & Protoporphyrin) + Globin.
How can Fe2+ cause a microcytic anemia?
Nutritional Fe2+ deficiency = less heme = less Hgb = more RBC divisions to maintain proper Hgb concentration. Chronic inflammatory state = Fe2+ locked away in macrophages = less heme = less Hgb = more RBC divisions to maintain proper Hgb concentration.
How can protoporphyrin cause a microcytic anemia?
Sideroblastic anemia = low protoporphyrin levels = less heme = less Hgb = more RBC divisions to maintain proper Hgb concentration.
How can globin cause microcytic anemia?
Thalassemia = decreased production of the globin chain = decreased Hgb = more RBC divisions to maintain proper Hgb concentration.
What type of iron is more readily absorbed in the duodenum?
Heme iron (meat derived).
How is iron absorbed by the intestines and put into the blood?
Enterocyte absorbs Fe from gut lumen -> Ferroportin transports Fe from enterocyte to blood -> Transferrin transports Fe in blood to liver and bone marrow macrophages -> Fe is stored intracellularly by bound ferritin.
What 4 laboratory tests should you use to consider the iron status of a patient?
How much iron is in blood = serum iron, how many transferrin molecules are in the blood = TIBC, how many transferrin molecules are bound by iron = % saturation, how much iron is stored in bone marrow macrophages and liver = serum ferritin
What are common causes of anemia in infants? Children? Adult men? Adult women? Elderly in Western world? Elderly in 3rd world?
Infants: breast feeding (no Fe in breast milk); Children: poor diet; Adult men: peptic ulcer disease; Adult women: menorrhagia or pregnancy; Elderly: colon polyps/ colon carcinoma in Western world, hookworm (Necator and Ancylostoma)
Why are celiac patients at risk for Fe-deficiency anemia?
Destruction of the duodenal villi caused malabsorption of iron.
Why are patients with a gastrectomy at risk for Fe-deficiency anemia?
Stomach acid maintains the Fe2+ state and it is more readily absorbed. Decreased acid in patients with a gastrectomy have more Fe3+ that is not as readily absorbed.
What are the stages of iron deficiency anemia?
1) Body depletes stored iron = decreased serum ferritin, increased TIBC. 2) Serum iron is depleted = serum iron decreases, % saturation decreases. 3) Bone marrow recognizes there is less iron = makes fewer RBCs = Normocytic anemia. 4) Bone marrow pumps out smaller cells w/less Hgb = Microcytic and hypochromic (increased central area of pallor) anemia.
What happens to TIBC when ferritin goes down?
It goes up. This makes sense because depletion of storage iron (serum ferritin) causes the liver to send out more transferrin to look for more iron to bring back from the blood (TIBC)
What is the normal % saturation?
Typically 1/3 transferrin molecules are bound by Fe, so 33%. This goes down when you are anemic because now maybe 1/6 are bound by iron.
What is the early stage of iron deficiency anemia?
Normocytic anemia
What are the clinical features of iron-deficiency anemia?
1) Anemia 2) Koilonychia (spoon-shaped nails) 3) Pica (chewing on things like dirt or ice)
Why do you see an increased RDW in iron-deficiency anemia?
The anemia starts with a normocytic anemia and progresses to a microcytic anemia. This creates a population of RBCs that vary widely in their sizes.
What lab value changes would you expect to see in a patient with iron deficiency anemia? Peripheral blood smear, MCV, RDW, ferritin, TIBC, serum iron, % saturation & FEP?
Peripheral blood: hypochromic RBCs, MCV: decreased, RDW: increased, ferritin: decreased, TIBC: increased, serum iron: decreased, % saturation: decreased, FEP:
What lab value will be elevated as a direct result of Fe-deficiency and inability to form heme?
Free Erythrocyte Protoporphyrin (FEP). Note that heme consists of protoporphyrin and iron. If there is not enough iron to make heme, there will be increased free erythrocyte protoporphyrin.
What about this blood smear makes you think this patient has iron-deficiency anemia?
Microcytic (many RBCs that are actually smaller than a lymphocyte’s nucleus) and hypochromic anemia.
How do you treat iron-deficiency anemia?
Supplemental iron (ferrous sulfate) and uncover the underlying cause of anemia and treat if possible.
A patient presents with anemia, dysphagia and a beefy red tongue. Why does this patient have dysphagia?
The patient has the classic triad of Plummer-Vinson syndrome: anemia, an esophageal web (causing dysphagia) and atrophic glossitis.
What is the most prevalent type of anemia you will see in hospitals? How does this happen?
Microcytic anemia of chronic disease. Chronic disease results in release of the acute phase reactant, hepcidin. Hepcidin locks iron in its storage sites away from bacteria to prevent replication. Preventing Fe release from macrophages to erythroid precursors causes microcytic anemia. Hepcidin also suppresses EPO production.
A patient in the hospital is battling an invasive brain tumor. He is not losing any blood from the tumor, but is anemic. What would you expect to see on lab values: ferritin, TIBC, serum iron, % saturation and FEP?
This patient most likely has anemia of chronic disease from release of hepcidin. Ferritin levels will increase because hepcidin prevents Fe release from macrophages. TIBC will decrease because storage levels are high. Serum iron will decrease because it will be depleted and hepcidin inhibits Fe release. % saturation will be decreased because there is less serum iron available to bind to transferrin. FEP will increase because there is less iron available to pair with protoporphyrin and form heme.
A patient in the hospital is battling an invasive brain tumor. He is not losing any blood from the tumor, but is anemic. Ferritin is increased, TIBC is decreased, serum iron is decreased, % saturation is decreased and FEP is increased. How do you treat this patient?
1) Treat the underlying cause to get hepcidin out of the picture and free stored iron for usage 2) Administration of exogenous EPO in especially helpful in patients with cancer.
What enzyme is responsible for the final step in heme synthesis?
Ferrochelatase combines Fe2+ with protoporphyrin in the mitochondria of the erythroid precursor.
What is the rate limiting step in the production of protoporphyrin? How is this clinically relevant?
Succinyl CoA -> ALA by the enzyme ALAS (ALA synthase). This is clinically significant because the reaction can be impaired if someone has B6 deficiency.
What reaction follows the conversion of succinyl CoA to ALA by the enzyme ALAS?
ALA -> porphobiliinogen by the enzyme ALAD (ALA dehydrogenase)
Where does iron go after it is release from the bone marrow macrophages in its quest to form heme? What happens if the patient has sideroblastic anemia?
The mitochondria of the erythroid precusor. There it meets up with protoporphyrin and forms heme. If the patient has sideroblastic anemia, there is no protoporphyrin in the mitochondria for Fe to react with. The mitochondria become iron-laiden and form a ring around the nucleus of the erythroid precursor (forming a ringed sideroblast).
What is the most common cause of congenital sideroblastic anemia?
The rate-limiting enzyme of protoporphyrin synthesis: ALAS. This is the enzyme that catalyzes the reaction succinyl CoA -> ALA.
What are common causes of acquired sideroblastic anemia?
ALCOHOLISM: mitochondrial poison that damages production of protoporphyrin. LEAD POISONING: lead can denature the enzymes ALAD (ALA -> porphobiliinogen) and ferrochelotase (Fe + protoporphyrin -> heme). B6 DEFICIENCY: succinyl CoA -> ALA by the enzyme ALAS requires vitamin B6.
When do patients typically present with a sideroblastic anemia from B6 deficiency?
Isoniazid therapy
A patient presents who is anemic. He works at a pistol range cleaning up shells and has been there over 30 years. Peripheral blood smear shows ringed sideroblasts. What would you expect to see on labs ferritin, TIBC, serum iron and % saturation?
Sideroblastic Anemia generally presents in an iron-overloaded state because iron-laiden erythroid precursors die and iron leaks out of the cell. Bone marrow macrophages eat the leaked iron = increased ferritin and decreased TIBC. Iron leaks into blood = increased serum iron and increased % saturation. Note that hemochromatosis will share similar laboratory findings.
What is the difference between a thalassemia and sickle cell anemia?
Thalassemias arise from decreased synthesis of globin chains. Sickle cell anemia has normal globin synthesis, but the globin chain is mutated.
What disease are carriers of inherited thalassemia, sickle cell mutations and people with G6PD deficiency protected from?
Plasmodium falciparum malaria
What are the normal types of hemoglobin found in the human body?
HbF (fetal) : alpha2gamm2. HbA: alpha2beta2. HbB: alpha2delta2. Note that the alpha chain is used by each hemoglobin.
Why does a single deletion on the locus for the alpha hemoglobin chain not cause thalassemia? What does it take for someone to become symptomatic with alpha-thalassemia?
There are 4 alpha alleles on chromosome 16 (2 on each chromosome). People become mildly anemic with alpha-thalassemia when 2 genes are deleted.
Why is thalassemia not as bad in African compared to Asia?
The cis 2 gene deletion is more common in Asia, which is the more severe deletion. The trans 2 gene deletion is more common in Africa.
A mother has a child with severe anemia. There were no symptoms of anemia during pregnancy. Hgb electrophoresis reveals HbH. What is causing the baby’s anemia?
3 alpha hemoglobin genes have been deleted. In utero, the baby was utilizing HbF, where the single alpha gene was sufficient to have normal Hgb. When the child was born, decreased alpha chain causes beta chain tetramers to form, which are HbH. These tetramers damage RBCs and cause anemia.
An asian couple comes to the clinic because of infertility problems. The wife has had multiple miscarriages and is currently a few weeks pregnant. What test do you want to do on fetal blood?
Electrophoresis for Hb Barts. Asians are prone to have the cis 2 gene deletion. If each parent gives a chromosome with 2 cis gene deletions on each chromosome the child will have 4 genes deleted, which is lethal and called hydrops fetalis. It is lethal because the defect in alpha chains causes formation of gamma tetramers (Hb Barts) instead of HbF
Why are beta-thalassemia symptoms so much more variable than those of alpha-thalassmia?
Although there are only two beta genes on chromosome 11, there are 3 possibilities for each gene: normal beta chain, beta null (beta globin chain is absent) and beta + (diminished production of beta-globin chain). The combination of these makes for a wide spectrum of disease.
A 22 year old army recruit comes in for his blood work. He reports no symptoms of any illness. Labs reveal increased RBC count, microcytic anemia and peripheral blood smear is shown below. What genetic mutation is likely causing his condition?
Beta thalassemia minor (Beta/Beta +). Note the hypochromic cells and target cells in the peripheral blood smear. Target cells appear when there is decreased Hgb in the RBC cytoplasm, allowing for a bleb to protrude from the center of the RBC in the normal area of pallor. Note that this is the mildest form of beta-thalassemia and usually is asymptomatic.
A 22 year old army recruit comes in for his blood work. He reports no symptoms of any illness. Labs reveal increased RBC count, microcytic anemia and peripheral blood smear shows hypochromic cells and target cells. What is the key lab finding for this condition?
When people have beta thalassemia minor they present without symptoms and microcytic, hypochromic cells with target cells and an isolated increase in HbA2 on Hgb electrophoresis.
A mother has a 2 month old baby with severe anemia. There were no symptoms of anemia during pregnancy. Hgb electrophoresis reveals increased HbA2 & HbF and no HbA. What is causing the baby’s anemia?
The baby has beta-thalassemia major. This is from beta null/beta null mutations that presents with severe anemia after birth because in utero the child is utilizing HgF, which is composed of alpha2/gamma2 subunits, not using a single beta subunit. HgF is protective for a few months until the body begins to rely on alpha2/beta2 Hgb.
Why do babies with beta-thalassemia major develop massive erythroid hyperplasia?
The absence of beta subunits (beta null/beta null) causes alpha tetramers to form. These tetramers damage RBCs as they are being produced so you get ineffective erythropoiesis. The spleen also recognizes the alpha tetramers so you get extra vascular hemolysis of RBCs if they make it out of the marrow. This puts the marrow on overdrive for RBC production.
What clinical signs give you a high index of suspicion for beta-thalassemia major?
Severe anemia, “crew-cut” sign on x-ray from expansion of hematopoiesis into marrow of skull, a “chipmunk face” from expansion of hematopoiesis into the marrow of the facial bones and hepatosplenomegaly from extramedullary hematopoiesis.
Aside from macrocytic RBCs, what else might give you a hint that a patent has megaloblastic anemia on a peripheral blood smear?
Hypersegmented neutrophils (5+ lobes).
What is your next test to do if a patient has a normocytic anemia?
Reticulocyte count to determine if they are hyperproliferative or hypoproliferative. (Note the reticulocyte shown below with the bluish cytoplasm from residual RNA). If the corrected reticulocyte count > 3%, you know there is good marrow response and the problem is likely due to peripheral destruction. If the corrected reticulocyte count < 3%, you know the marrow is responding poorly and there is underproduction of red cells.
A 20 year old man presents with splenomegaly, gallstones and jaundice. Labs reveal an increased unconjugated bilirubin, RDW and MCHC and normocytic anemia. Peripheral blood smear is shown below. Osmotic fragility test. What is causing this patient’s condition?
The patient has hereditary spherocytosis. This is due to inherited defect in cytoskeleton membrane tethering proteins: most commonly spectrin, ankyrin or band 3.1. Note the spherocytes with loss of central pallor, increased RDW from splenic macrophage consumption of RBC blebs, increased MCHC from increased RBC [Hgb] due to decreased cytoplasm, splenomegaly from hypertrophy of macrophages due to eating of spherocytes and jaundice from hemolysis.
A 20 year old man presents with splenomegaly, gallstones and jaundice. Labs reveal an increased unconjugated bilirubin, RDW and MCHC and normocytic anemia. Peripheral blood smear is shown below. Osmotic fragility test is positive. What condition would be life threatening to this patient?
Parvovirus B19 infection of erythroid precursors, resulting in aplastic crisis. This is because there is already limited production of RBCs by the bone marrow due to early termination of spherocytes.
A 20 year old man presents with splenomegaly, gallstones and jaundice. Labs reveal an increased unconjugated bilirubin, RDW and MCHC and normocytic anemic. Peripheral blood smear is shown below. Osmotic fragility test is positive. How do you treat this patient?
Splenectomy. Spherocytes will persist, but anemia will resolve because macrophages are no longer terminating them early in their lifecycle.
What do you know about this patient?
This is a Howell-Jolly body. This indicates that the patient has had a splenectomy because there is persistent DNA inside of the RBC that is normally removed by the splenic macrophages.
A mother brings in her 6 month old girl who has jaundice and chipmunk facies. Physical exam reveals hepatomegaly. Labs reveal elevated unconjugated bilirubin and normocytic anemia. Peripheral blood smear is shown below. What is causing the child’s symptoms?
This patient has sickle cell anemia. This is an AR mutation in the beta chain of Hgb that replaces hydrophilic Glu with hydrophobic Val. In order to have sickle cell DISEASE, you must have 2 abnormal beta genes; this will result in > 90% HbS in RBCs.
A mother brings in her 6 month old girl who has jaundice and chipmunk facies. Physical exam reveals hepatomegaly. Labs reveal elevated unconjugated bilirubin and normocytic anemia. Peripheral blood smear is shown below. What condition would pose a major threat to this child’s life?
Aplastic crisis with parvovirus B19 infection of erythroid precursors.
A mother brings in her 6 month old girl who has jaundice and chipmunk facies. Physical exam reveals hepatomegaly. Labs reveal elevated unconjugated bilirubin and normocytic anemia. Peripheral blood smear is shown below. What physical exam finding would you expect to see if the child’s RBCs were undergoing irreversible sickling?
Vascular occlusion and infarction. The common presenting sign in infants is dactylitis: swollen hands and feet from vaso-occlusive infarcts of the bones.
A mother brings in her 6 month old girl who has jaundice and chipmunk facies. Physical exam reveals hepatomegaly. Labs reveal elevated unconjugated bilirubin and normocytic anemia. Peripheral blood smear is shown below. What is the most common cause of death in children due to this condition?
Vascular occlusion and infarction from irreversible sickling of RBCs in sickle cell disease causes the spleen to become shrunken and fibrotic. Autosplenectomy increases risk of infection by encapsulated organisms (because it is main site of antibody production) and is the most common cause of death in children. There is also increased risk of salmonella paratyphi osteomyelitis.
A 25 year old man comes to see you who has jaundice and chipmunk facies. He complains of chest pain and shortness of breath that has persisted since he had pneumonia a few days ago. Physical exam reveals hepatomegaly. Labs reveal elevated unconjugated bilirubin, normocytic anemia and pulmonary infiltrates. Peripheral blood smear is shown below. What is the most common cause of death in adults due to this condition? What other presentations are related to this?
The most common cause of death from sickle cell disease in adults is acute chest syndrome from vaso-occlusion of pulmonary microcirculation. Vaso-occlusion of bone can also cause pain crisis, vaso-occlusion of renal arteries causes renal papillary necrosis (presents with gross hematuria and proteinuria).
How does Hb electrophoresis differ in sickle cell disease vs. sickle cell trait?
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A patient presents with a mild normocytic anemia. Peripheral blood smear is shown below. What is your diagnosis?
Note the Hgb C crystal, the patient has Hemoglobin C. This is an AR mutation in the beta chain of hemoglobin that replaces Glu with Lys. Note that this is less common than sickle cell disease.
A 37 year old man presents with dark urine and back pain after having a severe bout of the pneumonia. He was given sulfa drugs to treat the infection and symptoms began shortly thereafter. Labs reveal a normocytic anemia and elevated unconjugated bilirubin. Peripheral blood smear is shown below. What is likely causing this man’s symptoms?
This patient has G6PD deficiency. This is an X-linked recessive disorder causing a reduced half-life of G6PD. Hours after oxidative stress hitting the RBC, Hbg precipitates as a Heinz body, which is removed by splenic macrophages, causing formation of bite cells. This leads some extravascular hemolysis, but predominant intravascular hemolysis. Intravascular hemolysis presents with hemoglobinuria and back pain because Hgb is nephrotoxic.
A 37 year old man presents with dark urine and back pain after having a severe bout of the pneumonia. He was given sulfa drugs to treat the infection and symptoms began shortly thereafter. Labs reveal a normocytic anemia and elevated unconjugated bilirubin. Peripheral blood smear is shown below. What are other factors that could cause him to present this way?
Causes of oxidative stress include infections, drugs (primaquine, sulfa and dapsone) and fava beans. All of these can result in hemolytic crisis from G6PD deficiency.
How do you screen for G6PD deficiency?
Heinz preparation, highlights the precipitated Hgb within the RBC. G6PD deficiency is confirmed by enzymatic studies once the episode resolves (because all the RBCs w/o G6PD are dead during the acute episode.
A patient presents with shortness of breath, angina and tachycardia. Labs reveal schistocytes. What condition are these schistocytes a hallmark of?
The patient has microangiopathic hemolytic anemia. This happens as a result of intravascular pathology (usually a microthrombus) that shears RBCs as they pass through circulation, making schistocytes.
A 22 year old service member presents with fatigue, daily fevers, shortness of breath and dark colored urine. She spent a year working in Africa recently. Physical exam reveals splenomegaly. Peripheral blood smear is shown below. What is causing the symptoms in this patient?
Note the small malarial organisms within the RBCs. This patient has malaria from a mosquito bite (anopheles) that transmits plasmodium and it infects RBCs and the liver. This causes intravascular hemolysis from the plasmodium life cycle that causes cyclical fever. Note that there will be some extravascular hemolysis from splenic macrophages eating infected cells and this will cause splenomegaly.
Classic biopsy finding of aplastic anemia
Empty, fatty bone marrow
