Anemias
to Know for Boards Kristine Krafts, M.D. PathologyStudent.com
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Table of Contents
Iron-deficienc y anemia Megaloblasti c anemia Hereditary spherocytosis Glucose-6-phosphate-dehydrogenase deficiency Sickle cell anemia Thalassemia Autoimmune hemolytic anemia Microangiopa thic hemolytic anemia Anemia of chronic disease Aplastic anemia
Introduction Clinical stuff 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 (CBC) 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.
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Total number o f red blood cel ls in blood Normal ranges: male 4.5-6.0 x 1012 /L, female 3.8 -5.2 x 1012 /L
Concentration of hemoglobin in blood Normal ranges: male 13-18 g/dL; female 12-16 g/dL Hgb below normal = anemia
The most useful red cell indices are the hemoglobin, MCV and RDW.
Volume of “pac ked” red blood cel ls. 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%
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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
Weight of Hgb in the average red blood cell Normal range: 26-34 pg (1 pg = 10-12 g) Not a frequently used parameter
Concentration of Hgb in the average red blood cell Normal range: 32-36 g/dL Calculated by machine (Hgb/Hct) Differentiates between hypochromic (MCHC < 32) and normochromic (MCHC 32-36) anemias 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 thi s nicel y on a blood smear: no rmochromic cells have a “zone of central pallor” (t hat 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.
Standard deviation of the MCV Tells yo u how much the red blood cells di ffer from each ot her in size. If they are all pretty similar in size, the RDW is low. If some 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%).
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Total number of leukocytes in blood Normal ranges: adult: 4.5-11 x 109 /L, newborn: 9 -30, child o ver 1: 5.0-17 .0 A high WBC is seen in many condition s. Some are benign, such as infection and inflammation . Others are malignant, such as leukemia.
Amounts of e ach white blo od cell type i n blood Normal ranges: Neutrophils Lymphocytes Monocytes Eosinophils Basophils
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Percentage of WBC 45-75 20-50 1-8 0-6 0-1
Absolute (x 1 09 /L) 2-8 1-4 0.1-0.8 0-0.5 0-0.3
Total number of platelets i n 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.
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. (just eyeball it; make sure there aren’t a lot of “holes” between the cells).
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Oval macrocytes (B12 /folate deficie ncy) 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) 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) Normochromic (zone of central pallor comprises ! 1/3 of the cell diameter) Hypochromic (zone of central pallor comprises >1/3 of the cell diameter)
Normal: one or two polychromatophilic cells per field. The lower th e Hgb, the hi gher the retic ulocyte cou nt should be. • •
Nucleated red blood cells Inclusions (Howell-Jolly bodies, Pappenheimer bodies, bugs)
When looking at blood smears, it helps to follow the same plan every time.
Reticulocytes vs. polychromatic cells “Reticulocyte” and “polychromatophilic cell” are two names for the same thing – immature red cells that still contain a little ribosomal RNA. When you do a supravital stain on a blood smear, the RNA stains blue, and the cells are called “reticulocytes”. When you do a normal WrightGiemsa stain, the cells look big and slightly basophilic, and they are called “polychromatophilic cells.” This is one of those fine points that, when casually mentioned on rounds your third or fourth year, will make you look very smart.
One. Iron-Deficiency Anemia Blood loss (e.g., GI bleed or menses) or really bad diet (rare)
Iron-deficiency anemia is a
microcytic, hypochromic anemia with increased anisocytosis and poikilocytosis.
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Hypochromic, microcytic anemia Increased anisocytosis (some little cells, some bigger cells) Increased poikilocytosis (elliptocytes are present, for some reason) Decreased reticulocyte number (because there’s not enough iron around!) Platelet count usually increased for some reason
" serum iron # TIBC (total iron binding capacity) " ferritin
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 iron (orally).
Two. Megaloblastic Anemia Vitamin B12 and/or folate deficiency (from bad diet, absorption problems, folate-antagonist drugs) makes it hard to make DNA (you need both B12 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 slowmoving nucleus).
Megaloblastic anemia is a
macrocytic anemia with oval macrocytes • • •
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Macrocytic anemia (MCV >100) Oval macrocytes. Hypersegmented (more than 5 lobes) neutrophils.
and hypersegmented neutrophils.
“Megaloblastic” cells: giant red cell or neutrophil precursors with nuclear-cytoplasmic asynchrony (mature cytoplasm, immature nucleus).
Treatment depends on th e 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.
Three. Hereditary Spherocytosis 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.
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Mild normochromic, normocytic anemia. Numerous spherocytes.
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).
Hereditary spherocytosis: Lots of spherocytes due to a spectrin defect .
Four. G6PD Deficiency 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 G6PD, 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.
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).
Avoid exposure to known oxidants. Usually the hemolysis is self-limiting, with spontaneous resolution in a week or so.
Without G6PD, free radicals accumulate and Heinz bodies form.
Five. Sickle-Cell Anemia Sickle cell anemia is a type of hemoglobinopathy (diseases with point mutations in one of the globin chain genes). The abnormal hemoglobin (called HbS) in sickle cell anemia changes shape when it releases oxygen. The HbS molecules then aggregate and polymerize, forming the cell into a fragile, non-deformable, sickle shape. Sickle cells bust open more easily; they also stick together in small vessels, leading to ischemia (often occurring in hands, feet, lungs, and spleen). The spleen may undergo massive enlargement (due to red cell sequestration) in early childhood. By early adulthood, however, the spleen is reduced to a small, fibrotic remnant (due to recurrent hemorrhage and fibrosis); this is called “autosplenectomy”.
In the blood, particularly during crises, sickle cells are present. After autosplenectomy occurs, there is what’s called a "post-splenectomy blood picture": nucleated red blood cells, targets, HowellJolly bodies, Pappenheimer bodies, and a slightly increased platelet count (the platelets love to hang out in the spleen, so when you take away their little home, they have no choice but to hang out in the blood).
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.
Sickle cell anemia is a
qualitative abnormality of hemoglobin
Six. Thalassemia The th alassemias are chara cterized by a quant itative decrease i n one of the hemoglobin chains. In $-thalassemia there is a decreased amount of $ chain. In %-thalassemia, there is a decreased amount of % chain. You end up with a two-fold problem: 1. Decreased hemoglobin production (because of the decrease in globin chains) 2. Excess unpaired $ chains (in % thalassemia) or %, &, and ' chains (in $ thalassemia), which form tetramers and lead to premature red cell destruction.
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.
Patients with mild thalassemia don’t require treatment. Patients with severe anemia may need repeated red cell transfusions or even bone marrow transplantation.
Thalassemia is a
quantitative abnormality of hemoglobin
Seven. Autoimmune Hemolytic Anemia 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 37° C (“warm”). Macrophages think these antibody-coated red cells are yummy, and they nibble them up (or gobble them whole). In cold autoimmune hemolytic anemia (CAIHA), the patient makes IgM anti-red-cell antibodies that bind best at temperatures <37° 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.
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)!
Also called the Coombs test. Mix pat ient's red cel ls wi th a nti-human globulin (an antibody against human immunoglobulins). If the red cells are coated with antibodies (as they are in some immune processes, see later), the anti-human globulin will attach to those antibodies, bridging the red cells and making them clump together. So, a positive result (red cell clumping) means the patient's red cells are coated with antibodies, and the hemolysis is probably immune-related.
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.
WAIHA :
IgG spleen spherocytes
CAIHA : IgM/complement intravascular hemolysis agglutination
Eight. Microangiopathic Hemolytic Anemia
If a patient has MAHA, you must find out why!
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, and artificial heart valves.
The blood sme ar shows schisto cytes, which are small, poin ty red cell fragme nts.
The important thing is to figure out wh at’s causing the MAHA and t hen treat th at.
Nine. Anemia of Chronic Disease Anemia of c hronic disease happens in a ton of di fferent diseases, from in fections, to i nflammatory conditions, to malignancies. There is a complex disturbance in iron metabolism which prevents iron from making it into normoblasts.
The blood s hows a normo chromic, normo cytic anemia with minimal anisocytosis and poikilo cytosis (it’s a “bland-looking” anemia). Some cases (about 25%) are microcytic, but the MCV rarely gets below 72 fL.
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" serum iron " TIBC # ferritin (ferritin is an acute phase reactant! It goes up in the types of conditions that cause ACD)
ACD is usually so mild that no treatment of the anemia is required. The underlying disease is the focus of the patient’s treatment.
ACD is bland-looking
Ten. Aplastic Anemia In aplastic anemia, there is a 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 causes are numerous (like drugs, viruses, or hereditary conditions), but in most cases, no specific cause can be identified.
The blood is pancytopenic, meaning tha t the red cells , white cell s, and platelet s are all decrease d. The bone marrow is markedly hypoce llular, or "empty" .
Treatment includes transfusion of blood components as needed, drug therapy to stimulate hematopoiesis and suppress the immune system, and if necessary, bone marrow transplant.
pancytopenia and an empty marrow
Preview: The Complete (But Not Obsessive) Hematopathology Guide Everything you need to know about hematopathology, illustrated with tons of nice photos. “I’m a first year pathology resident and would not have made it through my heme rotation without your hematopathology study guide.”
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 matureappearing hematopoietic cells (as opposed to acute leukemias, which are composed of blasts). There are two kinds o f ch ronic leukemias: myeloid and l ymphoid. Instead of be ing 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! But no one asked me.
The chronic leukemias are malignant, monoclona l 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 the 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.
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 The ch ronic mye loproliferative disorders are malignant clonal proliferation s of a pluripo tent st em 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) Polycythemia vera (tons of red cells and precursors) Essential thrombocythemia (tons of platelets and megakaryocytes) 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 myeloproliferative disorders:
CML, PV, ET, and chronic myelofibrosis
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).
CML has a t(9;22). 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. • • • •
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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. 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. Characterized by a marked increase in blasts (myeloblasts or lymphoblasts). Usually fatal within a few weeks or months.
Chronic myeloid leukemia:
marked neutrophilia, left shift, and basophilia
Blood The bl ood smea r shows a marked neutrophilia with a left s hift. T he le ft shift is a little weird in that i t 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%. 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 hyperce llular, with a pan-myeloid hyperplasia (all the myeloid cells are i ncreased – neutrophils and precursors, red cell precursors, 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.
All cases of CML have a translocatio n 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 increases tyrosine kinase activity and disrupts the cell cycle. Here’s a weird fact: the Philadelphia chromosome is found not only in the myeloid cells, but also in some B lymphocytes! That’s weird, considering that this is a myeloid lesion with no apparent 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, and the Philadelphia chromosome is present in all the descendents of that cell. Further supporting this idea is the fact that when patients enter blast crisis, the blasts can be lymphoid!
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. Recently, a new drug called imatinib (or Gleevec) was developed that targets the messed-up tyrosine kinase receptor activity in CML. 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.