Unit 3 - Pictures Hematology Rbc Disorders

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Normal PB smear and schematic of mature RBC
Note that RBCs are a biconcave disc. Since less Hb is concentrated in the area of depression in the membrane, it appears pale when flat on a slide, hence the central area of pallor. If the central area of pallor expands, then there is a problem with Hb synthesis, which implicates one of the microcytic anemias. If the cell is a spherocyte, there is no central area of pallor. If there is excess membrane, there is a bulge in the center of the cell collecting more Hb, hence the appearance of a target cell. Mature RBCs do not have mitochondria and use glucose for a fuel (anaerobic glycolysis).

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Asymptomatic patient
This is a normal smear. Note the uniformity of the RBCs, the normal amount of central pallor, and the compression pallor induced by platelets sitting on top of the RBC membrane. This can be confused with malarial ring forms.

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Supravital stain of RBCs in an asymptomatic person
Two reticulocytes are present in the slide. Reticulocytes are RBCs that within 24 hours will be changed into a mature biconcave disc by macrophages in the spleen. The supravital stain identifies RNA filaments, indicating that the cell is still synthesizing Hb. The reticulocyte count is the most important test to order after identifying an anemia since it tells the clinician how the bone marrow is responding to the anemia.

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Reticulocyte stain
Note the RNA filaments in these young RBCs.

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PB in a 9 year old child with b-thalassemia major and a severe microcytic anemia and elevated reticulocyte count
The arrow points to a marrow reticulocyte or shift cell, which, unlike a peripheral blood reticulocyte, requires 48-72 hours before it becomes a mature RBC and has a bluish discoloration (polychromasia). In severe thalassemia, the excess production of a-chains are toxic to RBCs causing a hemolytic anemia. Stimulation of marrow erythropoiesis causes the release of polychromasia cells as well as nucleated RBCs. In a reticulocyte count, the count must first be corrected for the degree of anemia and then further corrected (divide by 2) if polychromasia is present, since they have RNA filaments like PB reticulocytes and would falsely increase the reticulocyte count.

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Normal bone marrow
Note the proportion of cells to fat is ~70 cells to 30 fat. Large cells are megakaryocytes. Cells with round nuclei are either nucleated RBCs or young neutrophils (myelocytes, etc). Cells with "squiggly" nuclei are segmented neutrophils and bands. The normal myeloid to erythroid ratio is usually 3/1 indicating more WBCs than RBCs in the marrow.

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Patient with anemia and jaundice
What is the most likely diagnosis?

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This child most likely has sickle cell disease. Note the pallor of the lips, scleral icterus, and chipmunk facies (prominent zygomatic bones) due to marrow expansion from excessive erythropoiesis. Sickle cells are removed by macrophages, hence releasing large amounts of unconjugated bilirubin.

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Skull x-ray from a child with sickle cell disease
Note the expansion of the marrow cavity in the skull giving it a "hair on end" appearance. Frontal bossing and prominence of the zygomatic bone is also noted. These changes occur owing to massive erythropoiesis in the bone marrow and indicate a severe hemolytic anemia (e.g., sickle cell disease, thalassemia major)

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Patient with a severe anemia. What is the most likely diagnosis?

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She has a classic chipmunk face from prominence of her zygomatic bones. This indicates expansion of the marrow space by a brisk erythropoiesis. Since she is black, the most likely diagnosis is HbSS disease.

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PB in an asymptomatic patient who had his spleen removed 10 years ago following its rupture in a car accident
The arrow points to a spherocyte. In the background are target cells (cells with a bullseye center). Both types of RBCs are commonly seen post-splenectomy. Unlike spherocytes, which have too little membrane ("skinny RBC"), hence forming a sphere rather than a biconcave disc, target cells have excessive membrane ("obese RBC"), hence forming a bulge in the middle that collects more Hb. Howell Jolly bodies and reticulocytes, and siderocytes may also be present in the PB.

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PB from a patient with sickle cell disease
Note the nucleated RBC (NRBC), sickle cells, and target cells, which are markers of a hemoglobinopathy. NRBCs are commonly seen when patients are briskly hemolyzing and overtaxing the bone marrow.

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PB in an asymptomatic patient who had a surgical scar in the LUQ
The arrow is pointing to a target cell containing a remnant of nucleus called a Howell Jolly body. The patient had a ruptured spleen after a car accident and had his spleen removed. Note the increase in target cells. Target cells are increased after splenectomy, in hemoglobinopathies, and in alcoholics with liver disease.

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PB demonstrating rouleaux and agglutination
Rouleaux (stack of coins) is associated with an increase in IgG or fibrinogen, while agglutination seen with an increase in IgM, which owing to its pentameric configuration is able to bridge the negative charge around RBCs and agglutinate them. Cold agglutinins contain IgM antibodies, which clump RBCs in digital vessels in cold weather and produce Raynaud’s phenomenon.

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Patients fingers: there is a history of craving for eating ice chips and a severe microcytic anemia

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The nails exhibit spooning or koilonychia, a characteristic feature of iron deficiency.

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Patient with a severe microcytic anemia and dysphagia for solids (not liquids)

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Note the cracking at the angles of the mouth (cheilosis, stomatitis). With a history of a microcytic anemia, and dysphagia for solids, the patient probably has the Plummer Vinson syndrome with iron deficiency producing an esophageal web, glossitis, cheilosis, and achlorhydria.

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PB from a 4 year old child with a microcytic anemia and an increase in the RDW. What is the most likely diagnosis?

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The cells are hypochromic. The most likely cause is iron deficiency secondary to GI blood loss, most often a bleeding Meckel’s diverticulum

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What are two of the important types of glutamate receptor?

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Inotropic receptors (ligand-gated ion channels): including the NDMA (R)

Metabotropic receptors, which are coupled to ion channels via heterotrimeric G proteins

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PB in a patient with b-thalassemia minor and a mild microcytic anemia
Note the tear drops cells, and cells with a fine stippled appearance, the latter representing persistence of ribosomes (basophilic stippling). This is a nonspecific finding in any anemia with a defect in Hb synthesis, which characterizes the microcytic anemias. Thalassemias characteristically have an elevation in the RBC count.

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BM with a Prussian blue stain in an alcoholic with a microcytic anemia
The patient has a sideroblastic anemia. The ringed sideroblast in the slide represents a nucleated RBC with iron trapped in the damaged mitochondria (alcohol is a mitochondrial poison). Damage to the mitochondria interferes with normal heme synthesis. Siderocytes with iron (Pappenheimer bodies) often accompany sideroblastic anemias. Alcohol is the most common cause of acquired sideroblastic anemia. Pyridoxine deficiency and Pb poisoning are additional causes

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PB from the alcoholic with microcytic anemia
Note the irregular dark inclusions in the RBCs. These are clumps of hemosiderin in the cytosol called Pappenheimer bodies and the cells are called siderocytes (sideroblasts are NRBCs in the bone marrow). These are present in iron overload diseases, in this case, alcohol induced sideroblastic anemia.

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BM with Prussian blue stain in a patient taking INH for an active case of TB who has a microcytic anemia.
What is the most likely diagnosis?

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Iron stores are increased and ringed sideroblasts are present indicating a defect in heme synthesis. INH produces deficiency of pyridoxine (B6), which is a cofactor in the reaction between glycine and succinyl CoA to form D ALA. Iron enters the mitochondria but cannot exit the mitochondria, so it accumulates in mitochondria located around the nucleus and produces the ringed sideroblast (ring around the collar).

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X-ray of hand of 9 month old black child with dactylitis and sickle cell disease
Note the white out of the bones owing to infarction and the densities in the epiphyses of the digits, the latter indicating lead poisoning. Pb is the only heavy metal that deposits in the epiphyses

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PB from the 9 month old child with severe microcytic anemia and a history of eating paint chips from his crib

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The PB exhibits classic coarse basophilic stippling owing to denaturation of ribonuclease by Pb. Basophilic stippling is due to persistence of ribosomes (Pb denatures ribonuclease). Note also the hypochromic microcytic cells owing to a defect in heme synthesis (ferrochelatase and ALA dehydrase are denatured by Pb). There is an increase in RBC protoporphyrin and d ALA

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PB finding in a 35 year old man with epigastric distress, dark stools, and a microcytic anemia. What is the most likely diagnosis?

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The smear shows marked microcytosis and hypochromasia and the history suggests GI blood loss, most likely from a bleeding duodenal ulcer.

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Physical diagnostic finding
You would expect what type of anemia in the patient?

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Koilonychia is present which suggests iron deficiency.

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Physical diagnostic finding
Playing odds, what anemia would you expect in this patient?

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Iron deficiency anemia. Note the pale conjunctiva.

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Physical findings in a patient compared to a normal hand

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The patients nail beds are pale and the palmar creases are pale compared to normal indicating anemia.

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PB in a 35 year old alcoholic with a macrocytic anemia. What is the most likely diagnosis?

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The slide exhibits a hypersegmented neutrophil (pathognomonic of B12 or folate deficiency) and a mature lymphocyte. The RBCs are macroovalocytes (egg shaped). The most likely origin is folate deficiency owing to only a 3-4 supply of folate in the liver. Alcohol also blocks the reabsorbtion of folate in the jejunum. Serum folate, RBC folate, and B12 levels should be ordered.

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Gallstones removed from a 22 year old female with a chronic hemolytic anemia. What is the most likely diagnosis?

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The stones are calcium bilirubinate stones, which indicate the presence of increased generation of unconjugated bilirubin from extravascular hemolysis in a chronic hemolytic state such as congenital spherocytosis or sickle cell disease. The excess amount of conjugated bilirubin that will be generated from metabolism of the unconjugated bilirubin will combine with calcium to form these small, jet black stones.

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PB from a patient with a brisk hemolytic anemia. What is the most likely diagnosis?

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Note the presence of spherocytes and polychromasia, the latter indicating a pronounced erythropoiesis in the bone marrow, which is common in hemolytic anemias like congenital spherocytosis or autoimmune hemolytic anemia.

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PB from a patient with jaundice and a mild normocytic anemia with an increased corrected reticulocyte count. What is the most likely diagnosis?

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The arrows point to spherocytes in a patient with congenital spherocytosis (AD disease). A lymphocyte is present in the center of the slide. Jaundice is due to extravascular hemolysis by macrophages and increased production of unconjugated bilirubin.

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Hb electrophoresis patterns in various hemoglobinopathies

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Note the normal migration sites for a normal person with HbA, HbA2, and HbF. Patients with HbSA (trait) have ~40% HbS, with the remainder representing A, A2 and F. In HbSS (disease), there is no HbA and varying amounts of HbF, the latter a potent inhibitor of sickling (the more the better). b-Thal major has a proportionately greater concentration of HbF than all the other types, while b-thal minor has a slightly increased amount of F and A2.

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PB from a 9 month old black child with painfully swollen hands and feet

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The patient has sickle cell disease and is presenting with dactylitis (infarctions in the bones of the digits). Note the sickle cells and the target cells in the background. HbS is the substitution of valine for glutamic acid in the sixth position of the b-chain

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Hands from the 9 month old black child with sickle cell disease and dactylitis, the first manifestation of sickle cell disease

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HgF protects the child from this complication for the first few months by inhibiting sickling.

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Two year old child with sickle cell disease: What does the RBC finding signify in this patient?

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Note the single RBC with a Howell Jolly body (nuclear remnant). This indicates that the patient's spleen is non-functional.

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PB in a 22 year old black man with chest pain. What is the most likely diagnosis?

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The patient has sickle cell disease (note sickle cells and the background of target cells) and the acute chest syndrome. The latter is associated with fever, hypoxemia, a pulmonary infiltrate, and pleuritic chest pain. It is treated with oxygen and blood transfusion.

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PB in a 67 year old woman with a macrocytic anemia

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The arrow points to a tear drop cell, which may be seen in patients with B12 deficiency, myelofibrosis, and thalassemia. The other RBCs are macroovalocytes. The patient has pernicious anemia.

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PB from a patient with Crohns disease and a macrocytic anemia
What is the most likely diagnosis?

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The WBC is hypersegmented indicating either B12 or folate deficiency. Since the terminal ileum is involved in 80% of cases of CD, the most likely diagnosis is B12 deficiency, since it is absorbed in the terminal ileum.

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PB in an alcoholic with alcoholic hepatitis and a macrocytic anemia
What are these cells called?

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Note the round, macrocytic target cell. Alcohol increases the cholesterol in the RBC membrane resulting in excess membrane and target cell formation. Hypersegmented neutrophils are not present in this type of macrocytic anemia.

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PB findings in a woman on birth control pills who has a mild macrocytic anemia

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What is the most likely diagnosis? Note the 2 hypersegmented neutrophils indicating B12 and/or folate deficiency. Birth control pills inhibit the uptake of the monoglutamate form of folate in the jejunum, hence producing a folate deficiency.

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PB finding in a patient with celiac disease, a normocytic anemia, and an increased RDW

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Note the two populations of RBCs (dimorphic), both small and large cells, the former representative of iron deficiency and the latter folate/B12 deficiency secondary to malabsorption in celiac disease. Since the MCV is a mean of the average size of the RBCs, the MCV is normal, however, the RDW, which detects size variations is increased. Malabsorption and the myelodysplastic syndrome are common causes of dimorphic RBC populations.

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BM finding in a patient.
What would you expect the CBC to show?

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The patient has an aplastic anemia, hence one would expect pancytopenia.

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Schematic of the nonincubated and incubated osmotic fragility test for congenital spherocytosis and pyruvate kinase (not discussed)

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Note that in spherocytosis, the cells lyse more easily than normal cells in hypotonic salt solutions because they have less membrane than normal RBCs and no extra space to contain water and salt. Note that incubation makes the defect more pronounced.

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PB from a 26 year old woman with acute cholecystitis and a mild normocytic anemia with an increased corrected reticulocyte count

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The patient has hereditary elliptocytosis, an AD disease, with either a defect in spectrin (similar to spherocytosis) or protein 4.1 in the RBC membrane. Increased extravascular hemolysis by macrophages in the spleen increases the release of unconjugated bilirubin, which increases the amount of bilirubin metabolized in the liver and excreted in the bile, hence predisposing to calcium bilirubinate stones.

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PB from a 27 year old with splenomegaly and a mild normocytic anemia with an elevated corrected reticulocyte count

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The patient has congenital spherocytosis, an AD disease with a defect in spectrin in the cell membrane causing the cell to lose membrane ("skinny RBC") and form a sphere rather than a biconcave disc. Spherocytes are trapped and removed by macrophages in the cords of Billroth (extravascular hemolysis). Osmotic fragility testing confirms the diagnosis.

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PB on the left and special supravital stain on the right in a black man who developed a hemolytic anemia when he took primaquine for malaria.

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The patient has G6PD deficiency, or Heinz body anemia. The absence of the enzyme reduces the amount of glutathione synthesized which is necessary to neutralize peroxide in the RBC when infections occur or oxidizing drugs are used. Peroxide damages the Hb producing Heinz bodies and damages the sulfhydryl groups in the RBC membrane, producing a predominantly intravascular hemolysis. The Heinz body prep is best to diagnose the disease in the active stage of hemolysis, while the enzyme assay confirms the diagnosis when hemolysis has subsided and new RBCs are synthesized that are either deficient in the enzyme or contain a defective enzyme that degrades as the RBC matures.

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BM finding in a patient with a hemolytic anemia and positive direct Coombs test

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The arrow points to a macrophage that has phagocytosed a number of RBCs (erythrophagocytosis) that are coated by IgG and C3 for which the macrophages have receptors. In the direct Coombs test, rabbit anti-human IgG and C3 antibodies crosslink RBCs coated by IgG and C3 causing them to visibly clump under the microscope. Extravascular hemolysis is the most common mechanism of RBC destruction in autoimmune hemolytic anemias. The end-product of the RBC destruction is unconjugated bilirubin. The iron and amino acids are recycled.

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PB in a patient with severe calcific aortic stenosis and a mild normocytic anemia with an increased corrected reticulocyte count. What is the most likely diagnosis?

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Note the increased number of schistocytes that have traumatized by the calcified valve. This is a microangiopathic anemia. Haptoglobin levels would be low and hemosiderin present in the urine sediment. Iron deficiency and thrombocytosis commonly occur in chronic cases.

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Peripheral blood from a missionary with spiking fever: What is the most likely diagnosis?

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The patient has falciparum malaria. Note the ring forms in many of the RBCs. Some are multiply infected, which is a characteristic of falciparum malaria. Only ring forms and gametocytes are present in the peripheral blood in this type of malaria. Fever corresponds with rupture of the RBCs (intravascular hemolysis).

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Peripheral smear from a 3 year old boy with recurrent infections

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Arrow points to neutrophil with giant lysosomes of Chediak Higashi syndrome. AR disease with a membrane defect in transferring lysosomal enzymes into phagocytic vacuoles. Since the lysosomes have never been emptied, they are markedly enlarged. Patients also have severe neutropenia

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Borrelia recurrentis spirochetes in peripheral blood:
Borrelia recurrentis is the cause of relapsing fever. It is relapsing owing to the emergence of new antigen types, similar to what is seen in African sleeping sickness. Ticks and lice may transmit the disease. Note the loosely wound spirochetes in the blood

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Multiple ring forms in RBCs in patient with Plasmodium falciparum infection:
Plasmodium species are sporozoans. Falciparum malaria only has ring forms and gametocytes in the peripheral blood. Multiple infestation of RBCs by ring forms is a characteristic finding of this type of malaria. Fever and hemoglobinuria coincide with intravascular rupture of the RBCs. Extravascular hemolysis by macrophages also occurs.

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Peripheral blood with ring forms and multiple infestation of RBCs- Plasmodium falciparum:
Multiple infestation of RBCs by ring forms is a characteristic finding of this type of malaria.

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Peripheral blood with a banana-shaped gametocyte of Plasmodium falciparum:
No ring forms are noted in the slide. Note that the gametocyte is not located within an RBC.

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Fever patterns of Plasmodium species:
Fever coincides with intravascular hemolysis of the RBCs. Plasmodium falciparum (left side of the schematic) has a quotidian pattern, which refers to daily spikes of fever that persist for a few days and occasionally break every couple of days. Plasmodium vivax or ovale have a tertian pattern (middle of the schematic), which is fever q. 48 hrs. Plasmodium malariae has a quartan pattern (right of the schematic), which occurs q. 72 hrs.

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Trypanosomal form in blood in African sleeping sickness due to Trypanosoma brucei gambiense (hemoflagellate):
Only the extracellular form (trypanosomes) are present in this disease. The vector is the tsetse fly. Prominent posterior cervical lymphadenopathy is called Winterbottom's sign. Similar to relapsing fever due to Borrelia recurrentis, there is antigen variation. Death is by starvation.

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Romana's sign in girl- Chagas disease due to Trypanosoma cruzi: Note the periorbital edema due to rubbing the eye when the Reduvid bug defecates in this area. Both trypanosomes (extracellular) and leishmanial forms (intracellular) are present in the disease. Xenodiagnosis is where a sterile Reduvid bug is allowed to bite the patient and then the bug is examined for the organism.

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Gram positive yeasts in a monocyte in peripheral blood- Candida albicans sepsis:
The patient had a catheter in the subclavian vein. The fungus commonly produces metastatic abscesses and is a vessel invader that produces infarctions.