The Top Ten Anemias to Know for Boards A Quick Qu ick Revie Re view w of HighHigh-Yield Yield Anem Anemias ias
Kristine Krafts, M.D. 2nd Edition
Table of Conte Contents nts Introduction ............................................................................3 Important basic stuff ...............................................................4 Iron-Deficiency Iron-Defic iency Anemia ..........................................................9 Megaloblastic Megaloblas tic Anemia ...........................................................10 Hereditary Spherocy Spherocytosis tosis ......................................................11 G6PD Deficiency ..................................................................12 Sickle-Cell Anemia ................................................................13 Thalassemia...........................................................................14 Autoimmune Hemolytic Anemia ..........................................15 Microangiopath Microa ngiopathic ic Hemolytic Anemia...................................17 Anemia of Chron Chronic ic Disease ..................................................18 Aplastic Anemia ...................................................................19 Preview: The Complete Hematopathology Hematopathology Guide ...............20
Introduction Thanks for downloading The Top Ten Anemias to Know for Boards. This short study guide covers the anemias most often covered on board exams (and on pathology course exams). It quickly summarizes the most high-yield points about pathogenesis, morphology and treatment for each anemia, and gives you a nice image of each type. We'll also take a quick look at some important clinical features of anemias, and we'll discuss the meaning of CBC indices as well as how to look at a blood smear.
Getting Started You can click on any of the anemia titles in the table of contents to go straight to that anemia. Or just read the whole thing straight through - it should only take 15 - 20 minutes.
If you like this book… You might find some of our other guides useful. Here's a summary of Pathology Student stuff: The Complete (But Not Obsessive) Hematopathology Guide A concise but thorough review of benign and malignant hematopathology. Clot or Bleed: A Painless Guide for People Who Hate Coag Coag made understandable! Covers basic mechanisms and bleeding and thrombotic diseases. Path Bites Anthology: A Collection of Short, Easy and Strangely Fun Pathology Lessons Over 500 quick, high-yield essays that cover all major areas in general and systemic pathology. Anatomic Pathology Compendium A collection of our best Pathology Student essays on difficult anatomic pathology topics. Hematopathology Compendium A collection of our best Pathology Student essays on hematopathology. General Pathology Compendium A collection of our best Pathology Student essays on general pathology topics. Neuropathology Mini-Course A 4-week course that covers 12 high-yield neuropath topics, with memory strategies you can put to use right away.
Important basic stuff Clinical Information Anemia (from an-, without, and -emia, blood) is a reduction below normal in hemoglobin or red blood cell number. Patients with anemia can present in different ways, depending on what kind of anemia they have and how severe it is. The general signs and symptoms of anemia relate to the underlying lack of oxygencarrying capacity: fatigue, weakness, dizziness, tachycardia, pallor of skin and mucous membranes. It’s important to remember that if an anemia is fairly mild, symptoms will not be present. Also, if the anemia is chronic and slowly progressive, the cardiovascular system adjusts to the new diminished level of oxygen, and symptoms will only appear when the anemia becomes quite severe. In addition to the general symptoms of anemia, some specific findings may be present. If the anemia is hemolytic, the patient may be jaundiced. Patients with iron-deficiency anemia may show spoon-shaped nails (koilonychia), a smooth tongue, or pica (a craving to eat dirt and other non-food items). And patients with megaloblastic anemia may develop a big, beefy tongue.
The Complete Blood Count The CBC is comprised of a bunch of different indices. You get all of these on every report, whether you ask for them specifically or not (that’s just the way the machine does it!). Some of these indices are really useful (like the hemoglobin, MCV and RDW), and some of them are rarely if ever used (like the mean platelet volume). You should know what each one measures, and be able to recognize the normal range.
Red blood cell count (RBC) •
Total number of red blood cells in blood
•
Normal ranges: male 4.5-6.0 x 1012/L, female 3.8-5.2 x 10 12/L
Hemoglobin (Hgb) •
Concentration of hemoglobin in blood
•
Normal ranges: male 13-18 g/dL; female 12-16 g/dL
•
Hgb below normal = anemia
Hematocrit (Hct) •
Volume of “packed” red blood cells.
•
In the old days, was performed by spinning a tube of blood and estimating the amount of total blood volume taken up by the red cells (not a great method – because if the cells are of unusual shape, they may not pack as well as normal red cells, producing an artificially elevated Hct)
•
Now calculated by machine (MCV x RBC)
•
Normal ranges: male 40-52%, female 35-47%
Mean red blood cell volume (MCV) •
Average size of red blood cells
•
Normal range: 80-100 fL (1 fL = 10 -15 L)
•
Differentiates between microcytic (MCV < 80), normocytic (MCV 80-100) and macrocytic (MCV > 100) anemias
Mean cell hemoglobin (MCH) •
Weight of Hgb in the average red blood cell
•
Normal range: 26-34 pg (1 pg = 10 -12 g)
•
Not a frequently used parameter
Mean cell Hgb concentration (MCHC) •
Concentration of Hgb in the average red blood cell
•
Normal range: 32-36 g/dL
•
Calculated by machine (Hgb/Hct)
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Differentiates between hypochromic (MCHC < 32) and normochromic (MCHC 32-36) anemias
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There is no such thing as a hyper chromic red cell (you can’t put excess hemoglobin into a cell, or it would burst!)
•
You can see this nicely on a blood smear: normochromic cells have a “zone of central pallor” (that white dot in the middle of the cell) that is no more than 1/3 the diameter of the red cell. Hypochromic red cells have just a thin rim of hemoglobin.
Red cell distribution width (RDW) •
Standard deviation of the MCV
•
Tells you how much the red blood cells differ from each other in size . If they are all pretty similar in size, the RDW is low. If some cells are little and some are big, the RDW is high.
•
Normal range = 12-13.5%
•
Differentiates between anemias with minimal anisocytosis (difference in cell size) (RDW = 12-13.5%) and those with increased anisocytosis (RDW > 13.5%).
White blood cell count (WBC) •
Total number of leukocytes in blood
•
Normal ranges: adult: 4.5-11 x 109/L, newborn: 9-30, child over 1: 5.0-17.0
•
A high WBC is seen in many conditions. Some are benign, such as infection and inflammation. Others are malignant, such as leukemia.
Differential (“diff ”) •
Amounts of each white blood cell type in blood
•
Normal ranges:
Platelet count (Plt) •
Total number of platelets in blood
•
Normal range = 150-450 x 109/L
•
Causes of a low platelet count are numerous and include splenomegaly, idiopathic thrombocytopenic purpura, disseminated intravascular coagulation, and bone marrow failure.
•
Causes of a high platelet count are also numerous, and include reactive thrombocytosis (as seen in iron-deficiency anemia) and essential thrombocythemia.
MPV (mean platelet volume) •
Average size of platelets
•
Normal range depends on the platelet count! (Normally, if the platelet count falls, the body compensates a little by trying to make bigger platelets.)
•
Not used all that often.
The Blood Smear There are three main things you need to look at when you’re faced with a blood smear: the red cells, the white cells, and the platelets. It helps if you have a plan that you follow every time, kind of like radiologists do when they look at imaging studies. That way you’re not tempted to just start looking at the exciting stuff and forget about all the other stuff. Here’s your plan for the red cells. 1. Estimate number (just eyeball it; make sure there aren’t a lot of “holes” between the cells). 2. Look for variation in size (anisocytosis). • • •
Oval macrocytes (B12/folate deficiency) Microcytes (iron deficiency anemia, thalassemia) The size range can often help you narrow down which type of anemia is present (for example, in iron-deficiency anemia, there is usually a big range of sizes)
3. Look for variation in shape (poikilocytosis). • • • • • •
Schistocytes (microangiopathic hemolytic anemia) Spherocytes (hemolytic anemia, hereditary spherocytosis) Teardrop cells or dacryocytes (myelofibrosis or myelophthisic processes) Target cells or codocytes (hemoglobinopathies, thalassemias, liver disease) Sickle cells (sickle cell anemia) Echinocytes and acanthocytes (liver disease)
4. Estimate the average amount of hemoglobin in each cell (chromasia). • •
Normochromic (zone of central pallor = 1/3 of the cell diameter) Hypochromic (zone of central pallor >1/3 of the cell diameter)
5. Estimate number of reticulocytes (polychromatophilic cells). • •
Normal: one or two polychromatophilic cells per field. The lower the Hgb, the higher the reticulocyte count should be.
6. Look for anything else weird. • •
Nucleated red blood cells Inclusions (Howell-Jolly bodies, Pappenheimer bodies, bugs)
Iron-Deficiency Anemia Pathogenesis Blood loss (e.g., GI bleed or heavy menses) or really bad diet (rare).
Morphology The red cells are hypochromic and microcytic. There is increased anisocytosis (each successive wave of new red cells is smaller, because there's less and less iron around!) and poikilocytosis (elliptocytes are often present). Reticulocytes are decreased, because the lack of iron leads to decreased red cell production. The platelet count is often increased, for some reason.
IDA: hypochromic red cells and anisocytosis
Iron studies •
! serum iron
•
" TIBC (total iron binding capacity)
•
! ferritin
Treatment Figure out why patient is iron deficient (don't just treat the anemia, or you might miss something really important, like a GI bleed due to colon cancer). Then give oral iron supplements.
Megaloblastic Anemia Pathogenesis Vitamin B12 and/or folate deficiency (from bad diet, absorption problems, folateantagonist drugs) makes it hard to make DNA (you need both B 12 and folate to make DNA). RNA production runs smoothly though. So the nucleus (full of DNA) lags behind the cytoplasm (full of RNA) in development, and the cell divides more slowly (because it’s waiting for signals from the slow-moving nucleus).
Morphology Blood The red cells are macrocytic, and you often see great big oval macrocytes. Hypersegmented neutrophils (with more than 6 nuclear lobes) are also present.
Megaloblastic anemia: hypersegmented neutrophil Bone marrow The bone marrow shows "megaloblastic" cells: giant red cell or neutrophil precursors with nuclear-cytoplasmic asynchrony (mature cytoplasm, immature nucleus).
Treatment Treatment depends on the cause of the anemia. You can’t (or shouldn’t) just replace the B12 and/or folate without knowing what’s wrong with the patient.
Hereditary Spherocytosis Pathogenesis Patients with HS have defects in the membrane cytoskeleton (in spectrin, ankyrin, band 3, or band 4.2). The red cell membrane is unstable, leading to increased fragility and the formation of spherocytes, which get eaten by macrophages.
Morphology The red cells are normochromic and normocytic, and depending on the patient's particular genetic defect, there may be a ton of spherocytes (which look smaller than normal red cells, and lack central pallor) or just a few.
HS: moderate amount of spherocytes
Treatment If the disease is mild, patients don’t need treatment. In severe cases, splenectomy can be useful (because that’s where the red cells get destroyed).
G6PD Deficiency Pathogenesis Glucose-6-phosphate dehydrogenase (G6PD) helps reduce nasty free radicals made during cell metabolism. Patients who have a deficiency of G6PD are usually okay until they encounter some sort of oxidizing substance (like a drug, or fava beans). Without enough G6PD around, free radicals attack the molecular bonds between heme and globin, and globin becomes denatured, forming a little blob called a Heinz body. The spleen bites out these Heinz bodies, leaving what look like actual bite marks in the cell.
Morphology Without exposure to offending agents, most patients have no anemia. After exposure, though, patients get an acute hemolytic episode, with cell fragments, microspherocytes, and bite cells (caused by recent pitting of Heinz bodies). Supravital staining reveals Heinz bodies (these decrease in number as Hgb bottoms out, because younger cells have greater G6PD activity).
G6PD deficiency: bite cell
Treatment Avoid exposure to known oxidants. Usually the hemolysis is self-limiting, with spontaneous resolution in a week or so.
Sickle-Cell Anemia Pathogenesis Sickle cell anemia is a type of hemoglobinopathy (a group of diseases of hemoglobin characterized by point mutations in a globin chain gene). The abnormal hemoglobin in sickle cell anemia changes shape when it releases oxygen, causing it to polymerize, which distorts the red cell into a sickle shape. Sickle cells are fragile, and they stick together in small vessels, leading to ischemia. Tiny, repeated infarcts in the spleen lead to fibrosis and eventual "autosplenectomy" (the spleen becomes a small, fibrotic lump that doesn't work well at all).
Morphology During times of decreased oxygenation ("crises"), sickle cells are present in the blood. Also, after autosplenectomy occurs, you can see a "post-splenectomy blood picture," which includes things the spleen normally removes, like nucleated red blood cells, Howell-Jolly bodies, and Pappenheimer bodies.
Sickle cell anemia: lots of sickle cells
Treatment It’s important to prevent triggers (things that makes the red cells want to give up oxygen, like infection). Vaccination against encapsulated bugs is given in patients who have undergone autosplenectomy.
Thalassemia Pathogenesis The thalassemias are quantitative diseases of hemoglobin. They are characterized by a decrease in amount of one of the hemoglobin chains. In "-thalassemia there is a decreased amount of α chains. In #-thalassemia, there is a decreased amount of ,
β chains. You end up with a two-fold problem: 1. Decreased hemoglobin production (due to decreased globin chains) 2. Excess unpaired " chains (in # thal) or #, $, and % chains (in " thal), which form tetramers and lead to premature red cell destruction.
Morphology In mild thalassemia, patients have a mild microcytic, hypochromic anemia. Sometimes there are target cells, or cells with basophilic stippling. Patients with severe thalassemia have a whopping anemia marked anisocytosis and poikilocytosis.
Moderate thalassemia: target cells, anisocytosis and poikilocytosis
Treatment Patients with mild thalassemia don’t require treatment. Patients with severe anemia may need repeated red cell transfusions or even bone marrow transplantation.
Autoimmune Hemolytic Anemia Pathogenesis There are two flavors of autoimmune hemolytic anemia, warm and cold. In warm autoimmune hemolytic anemia (WAIHA), the patient makes IgG anti-red-cell antibodies which bind best at 37º C (“warm”). Splenic macrophages think these antibody-coated red cells are yummy, and they nibble on them (or gobble them up entirely). In cold autoimmune hemolytic anemia (CAIHA), the patient makes IgM anti-redcell antibodies that bind best at temperatures <37º C (“cold”). This means they bind in distal body parts but fall off in warm body parts. Because the antibodies are IgM in nature, they bind a bunch of red cells together, forming clumps. In addition, complement binds to the red cells, causing intravascular hemolysis.
Morphology In WAIHA, the blood smear shows prominent spherocytosis. In CAIHA, if you make the blood smear at a cool temperature, you can see nice big red blood cell agglutinates (clumps).
CAIHA: red cell agglutinates
Important lab test Direct antiglobulin test (DAT) Also called the Coombs test. Mix patient's red cells with anti-human globulin (an antibody against human immunoglobulins). If the red cells are coated with antibodies (as they are in some immune processes), the anti-human globulin will attach to those antibodies, bridging the red cells and making them clump together. So if you see red cell clumping, that means the patient's red cells are coated with antibodies, and the patient's hemolysis is probably immune-related.
Treatment Treat underlying cause, if there is one. In WAIHA, steroids can be useful, and if all else fails, splenectomy might be necessary. In CAIHA, it’s helpful to keep the patient warm.
Microangiopathic Hemolytic Anemia Pathogenesis Red cells are ripped apart by physical trauma (fibrin strands snag them or mechanical devices bash them). There are a ton of possible causes, including disseminated intravascular coagulation, hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, malignancies (especially adenocarcinoma), sepsis, trauma, and artificial heart valves.
Morphology The blood smear shows schistocytes, which are small, pointy red cell fragments.
MAHA: schistocyte
Treatment The important thing is to figure out what’s causing the MAHA and then treat that. Schistocytes are never normal - so if you see them, you have to seek out an underlying cause!
Anemia of Chronic Disease Pathogenesis Anemia of chronic disease happens in a ton of different diseases, from infections to inflammatory conditions to malignancies. There is a complex disturbance in iron metabolism which prevents iron from making it into normoblasts.
Morphology The blood shows a normochromic, normocytic anemia with minimal anisocytosis and poikilocytosis (it’s a “bland-looking” anemia). Some cases (about 25%) are microcytic, but the MCV rarely gets below 72 fL.
Anemia of chronic disease: pretty normal-looking blood smear
Iron studies •
! serum iron
•
! TIBC
•
!
ferritin (ferritin is an acute phase reactant - so it goes up in the types of conditions that cause ACD)
Treatment ACD is usually so mild that no treatment of the anemia is required. The underlying disease is the focus of the patient’s treatment.
Aplastic Anemia Pathogenesis In aplastic anemia, there are very few hematopoietic precursor cells in the bone marrow (and therefore, decreased numbers of red cells, white cells, and platelets in the blood). The potential causes are numerous (like drugs, viruses, or hereditary conditions), but in many cases, no specific cause can be identified.
Morphology The blood is pancytopenic, meaning that the red cells, white cells, and platelets are all decreased. The bone marrow is markedly hypocellular, or "empty".
Aplastic anemia: "empty" bone marrow
Treatment Treatment includes transfusion of blood components as needed, drug therapy to stimulate hematopoiesis and suppress the immune system, and if necessary, bone marrow transplant.
Preview: The Complete Hematopathology Guide Everything you need to know about hematopathology, illustrated with tons of nice photos and easy ways to remember what you learn. “The only reason I did well in hemepath in medical school is because of you." Richard, Medical Student
Chronic Leukemias Chronic leukemias are very different from acute leukemias. Chronic leukemias are for the most part diseases of older adults (acute leukemias occur in both children and adults). They appear in an insidious fashion and have a relatively good prognosis (as opposed to acute leukemias, which have a stormy onset and poor prognosis). In addition, chronic leukemias are composed of fairly mature-appearing hematopoietic cells (as opposed to acute leukemias, which are composed of blasts). There are two kinds of chronic leukemias: myeloid and lymphoid. Instead of being reasonable, and calling them “chronic myeloid leukemias” and “chronic lymphoid leukemias,” the powers that be dubbed the two divisions “chronic myeloproliferative disorders” and “chronic lymphoproliferative disorders.” These names are not so great, in my opinion, since these are not just “disorders” – they are real leukemias!
Pathophysiology Chronic leukemias are malignant, monoclonal proliferations of mostly mature myeloid or lymphoid cells in the bone marrow (and blood). These leukemias progress more slowly than acute leukemias. So early on, the marrow is involved – but not totally replaced – by malignant cells. Still, it is hard for the normal white cells to function properly. The lymphoid cells, in particular, have a hard time making normal immunoglobulin in certain chronic lymphoproliferative disorders.
One of the major causes of mortality in these patients is infection. As chronic leukemias evolve, more and more of the marrow is replaced by tumor, and eventually there is little room for normal white cells to grow.
Clinical Features Chronic leukemias present in over a period of weeks or months. Patients might have splenomegaly (which shows up as a dragging sensation or fullness in the left upper quadrant of the abdomen), lymphadenopathy, or a general feeling of malaise and fatigue. Some patients are asymptomatic at diagnosis, and the disease is picked up on a routine blood smear or CBC. Likewise, the clinical course is different in chronic leukemia. In many cases of chronic leukemia, patients can live for years without treatment at all.
Chronic Myeloproliferative Disorders Chronic myeloproliferative disorders are malignant clonal proliferations of a pluripotent stem cell that lead to excessive proliferation of myeloid cells in the blood and bone marrow. What that means in plain English is that a stem cell somewhere way back (before it’s even committed to the neutrophil line, or red cell line) goes bad and starts proliferating like crazy – so you wind up with a marrow packed with cells from all the myeloid lineages (the official name is “panhyperplasia”). Usually, one particular myeloid lineage predominates in this growth fest – so you’ll see a ton of all the myeloid cells, but the majority are neutrophils, or red cells, or megakaryocytes. So the chronic myeloproliferative disorders have been divided into four types according to what is proliferating most: •
Chronic myeloid leukemia (tons of neutrophils and precursors)
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Polycythemia vera (tons of red cells and precursors)
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Essential thrombocythemia (tons of platelets and megakaryocytes)
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Chronic myelofibrosis (tons of everything…then nothing! See below.)
We’ll consider each of these separately because they are very different clinically and morphologically. But they do have some common features: all of them have a high white count with a left shift, a hypercellular marrow, and splenomegaly.
Chronic Myeloid Leukemia Chronic myeloid leukemia (CML) is a chronic myeloproliferative disorder characterized by a marked proliferation of neutrophils (and precursors) in the bone marrow and blood. All cases have a t(9;22), also known as the Philadelphia chromosome (it’s the 22 that’s officially the Philadelphia chromosome).
Clinical Features CML frequently occurs in patients who are around 40 or 50. It does not occur in children (though there is a separate disease similar to CML, called juvenile CML, that does occur in kids). Usually, the onset is slow, with a long asymptomatic period, followed by fevers, fatigue, night sweats and abdominal fullness. On physical exam, patients usually have an enlarged spleen. Hepatomegaly and lymphadenopathy may also be present. There are three clinical stages, or phases, of CML: chronic phase, accelerated phase and blast crisis. Patients generally present in chronic phase and then progress to one or both of the other phases.
Chronic phase • • • •
High but stable number of neutrophils and precursors. Stable hemoglobin and platelet count. Easily controlled by therapy. With traditional treatment (not imatinib, see below), usually lasts 3-4 years; is then followed by accelerated phase and/or blast crisis.
Accelerated phase • • • •
Characterized by a change in the patient's previously stable state. Usually see increasing leukocytosis, decreasing hemoglobin and platelet count. May terminate in this stage, or may progress to blast crisis. Usually fatal within several months.
Blast crisis • •
Characterized by a marked increase in blasts (myeloblasts or lymphoblasts). Usually fatal within a few weeks or months.
Morphology Blood The blood smear shows a marked neutrophilia with a left shift. The left shift is a little weird in that it is not evenly distributed between all the neutrophil stages. There are tons of neutrophils at all stages of development, but there are relatively more myelocytes and segmented neutrophils (and relatively less of the other stages). There are a few myeloblasts around (which you don’t see in normal blood, of course) but they don’t number more than 2 or 3%.
CML, blood: leukoc tosis with le t shi t Here’s an interesting thing: patients with CML almost always have a basophilia. That’s actually one of the first things that happens in the development of the disease! There are few if any other reasons for a basophilia. So if you see this in a patient, even if they don’t have the typical findings of CML (big white count with lots of neutrophils and precursors), you should rule out CML! The platelet count may be increased (because of all the megakaryocytes around in the bone marrow).
Bone marrow The bone marrow is hypercellular, with a pan-myeloid hyperplasia (all the myeloid cells are increased – neutrophils and precursors, red cell precursors, and megakaryocytes). However, if you look closely, you’ll see that the neutrophils and precursors make up the bulk of the cells. Later in the course of the disease, the marrow may become fibrotic. You can detect this using a reticulin stain. This is not a good sign.
CML, bone marrow: hypercellular
Pathophysiology All cases of CML have a translocation between chromosomes 9 and 22, resulting in what’s commonly known as the Philadelphia chromosome (Ph). This designation refers to the new chromosome 22 that results from the translocation. Nobody talks about poor chromosome 9. The translocation places the c- abl proto-oncogene on chromosome 9 next to the bcr gene on chromosome 22. A new, fusion gene is created: the bcr-abl gene. The bcr-abl gene encodes a protein called p210, which is a super-powerful tyrosine kinase that drives the cells to grow like crazy.
Here’s a weird fact: the Philadelphia chromosome is found not only in the myeloid cells in CML, but also in some B lymphocytes! That’s weird, considering that this is a myeloid lesion with no morphologic changes in the lymphoid cells. This probably means that the initial bad cell (the one that became malignant) was a very early stem cell, one that hadn’t even committed itself to myeloid or lymphoid lineage yet - so the Philadelphia chromosome is present in all the descendants of that cell. Further supporting this idea is the fact that when patients enter blast crisis, the blasts are sometimes lymphoid!
Treatment and Prognosis In the old days, CML was treated with myelosuppressive agents like hydroxyurea, and then if the patient had a match and could tolerate it, allogeneic bone marrow transplant was performed. That was the only hope for a cure. Not long ago, a new drug called imatinib (or Gleevec) was developed. This drug targets the bcr-abl gene product, preventing it from exerting its massive tyrosinekinase-mediated growth stimulation. It has been like a miracle for many patients – even patients in the later stages of the disease. In fact, we don’t even know what the typical prognosis of CML is anymore, because these patients are still living with the disease. This drug has turned CML into a chronic but treatable disease, like diabetes, for many patients. It’s one of the happiest leukemia research stories ever.
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