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NR507 Week 2 – EDAPT Study Guide
Hematological Disorders
- What is anemia?
- Microcytic Anemias
- Macrocytic Anemias
- Normocytic Anemias
- Hemoglobinopathies Iron deficiency anemia is a microcytic, hypochromic anemia. The site of blood cell formation, a process known as hematopoiesis, varies with age The MCV is the index that measures the average size of RBCs. Bradycardia is not characteristic of anemia. Tachycardia is present due to hypoxemia. Anemia can be cause by impaired RBC production, excessive blood loss, and increased RBC production What is Anemia? Anemia is a hematological disorder characterized by a reduction in the total number of circulating red blood cells (RBCs) and/or a decrease in hemoglobin (Hb) amount or function. Anemia stems from the Greek meaning of “without blood” and refers to the condition whereby the capacity of blood to transport oxygen to the tissues is reduced. Anemia can be caused by 1) impaired RBC production, 2) excessive blood loss, 3) increased RBC destruction OR any combination of the three. In order to recognize and differentiate the type of anemia that is present, it is important to understand the components that make up the complete blood count (CBC). For the purposes of this content, we will discuss only the components that relate to red blood cells and their production. Red blood cells (RBC): The number of erythrocytes in 1 cubic mm of whole blood.
- Normal for men is 4.7-6.1 mcL.
- Normal in women is 4.5-5.2 mcL. Hemoglobin (Hb): The oxygen-carrying pigment of red cells.
- Normal for men is 13.5-17.5 g/dL.
- Normal for women is 12.0-15.5 g/dL. Hematocrit (Hct):
The volume of cells as a percentage of the total volume of cells and plasma in whole blood. Normal for men is 42-45%.
- Normal for women is 37-48%. Reticulocyte: Immature RBCs. Used to assess bone marrow function.
- Normal in adults is approximately 3%. Mean Cell Volume (MCV): This measures the average size of the RBC.
- Normal is 80-100 fL. Mean Corpuscular Hemoglobin (MCH): Average weight of hemoglobin per red cell.
- Normal is 27-33 pg. Mean Corpuscular Hemoglobin Concentration (MCHC): Average concentration of hemoglobin per erythrocyte.
- Normal is 32-36%. Red cell Distribution Width (RDW): This index is a quantitative estimate of the uniformity of individual cell size.
- Normal is 11.5-14.5% Microcytic (M CV< fL) Normocytic (MCV 80- 99 fL ) Macrocytic (MCV>1 00 fL) Iron deficiency Anemia of inflammation and chronic disease B12 deficiency (pernici ous anemia) Sideroblastic Hereditary spherocytosis Folate deficiency
Iron deficiency is categorized as a microcytic and hypochromic anemia. Iron deficiency anemia (IDA) is the most common type of anemia, affecting almost 20%
E.S. is a 20-year old female who reports to the primary care office complaining of fatigue. Her history is significant for heavy menstrual cramping and prolonged bleeding. She indicates that her menses lasts for more than 5 day with heavy bleeding and that she has had to stay home from work for the last two days due to the presence of fatigue and headache. She denies a family history of fatigue. The NP obtains a diet history from E.S. where she reports that she is a busy college student, taking a full load of classes, and works part time as an accounting clerk. Therefore, although not intentional, she finds herself skipping one or two meals a day. She also reports eating fast food because it accommodates her busy schedule. While the physical exam is normal, the NP considers the patient’s history of the world population. The most common problem contributing to this is the insufficient amount of iron availability. Causes of IDA include:
- Inadequate dietary intake.
- Chronic and or occult bleeding: hemorrhage, colitis, cirrhosis, GI ulcers, esophageal lesions, or menorrhagia; note that it only takes 2-4 mL (about 1 tsp) of blood loss per day to lose 1-2 mg of iron).
- Decreased ability to utilize Fe for heme synthesis (e.g. transferrin deficiencies and mitochondrial defects). These are a less common cause of IDA. The pathophysiology of IDA is very simple: insufficient Fe levels or inability for mitochondria to utilize Fe effectively leads to decreased Hb synthesis and the formation of smaller, paler cells. Let’s review a case of a 20-year old female who presents with iron deficiency anemia. Lab Patie nt Resul ts Referen ce Range WBC 8.5 (billion cells/L)
(billion cells/L) RBC 4.1 (mcL) 4.7-6. (mcL)
Understanding the types of anemia and corresponding lab values are integral for primary care providers. The RBC indices provide many clues as to the source of an anemia, when present. Your knowledge of the anemia types and their characteristics will most certainly be evaluated on your national board certification exam. When iron stores are depleted, the cell’s mitochondria are unable to utilize iron effectively. Transferrin saturation checks how many places on transferrin that can hold iron. Normal values are 20% to 50%. In severe cases of iron-deficiency anemia, this number may fall below 10% The pathophysiology of IDA is that insufficient Fe levels or inability for mitochondria to utilize Fe effectively leads to decreased Hb synthesis and the formation of smaller, paler cells. Liver disease causes a non-megaloblastic anemia. Folate (folic acid) is an essential vitamin for RNA and DNA synthesis within the maturing erythrocyte. The lack of intrinsic factor results in pernicious anemia (vit B). Macrocytic Anemias As you should recall, macrocytic anemias result from conditions whereby the RBCs are large (MCV>100 dL). Macrocytic anemias are categorized as megaloblastic and non-megaloblastic:
- Megaloblastic: Folate deficiency and vitamin B12 deficiency
- Non-megaloblastic: Liver disease, myelodysplastic syndrome, increased reticulocyte count (hemorrhage) In this section, we will explore the macrocytic, hypochromic, megaloblastic anemias which are caused from folate and vitamin B12 deficiencies. Key Differences in Laboratory Findings Between Pernicious Anemia and Folate Deficiency Laboratory Parameter Normal Range Pernicious Anemia Folate Deficiency Findings Serum Vitamin B- 12 200- 900 pg/mL Low (< pg/mL) Normal Serum Folate 3-20 ng/mL Normal or low Low (<3 ng/mL)
Key Differences in Laboratory Findings Between Pernicious Anemia and Folate Deficiency Laboratory Parameter Normal Range Pernicious Anemia Folate Deficiency Findings Mean Corpuscular Volume (MCV) 80-100 fl High (> fl) High ( > 100 fl) Mean Corpuscular Hemoglobin Concentration (MCHC) 32-26 g/dL Normal Normal Reticulocyte count 0.5-1.5% Low Normal or elevated or low Serum Iron 60- μg/dL Normal or increased Normal or decreased Folate and cobalamin (vitamin B12) are required for red blood cell DNA synthesis; therefore, a deficiency in either results in impaired DNA replication of the RBC. This causes the erythroblasts to continue to increase in size (macrocytic) instead of undergoing cell division. The following table highlights the key differences in laboratory findings between pernicious anemia and folate deficiency. B12 Deficiency (Pernicious Anemia) Pernicious anemia (PA) results from the autoimmune destruction of the gastric parietal cells which decreases the secretion of intrinsic factor. Intrinsic factor, as you probably recall, binds to B12 in the stomach and travels through the small intestine. When the complex reaches the ileum, it is broken and B12 is absorbed into the blood. Why is this important? Because B12 is needed for DNA maturation and condensation. As a result, a deficiency leads to immature RBCs, lack of functional hemoglobin, and decreased nerve cell myelination. This genetically induced autoimmune condition is especially prevalent in individuals of English, Irish or Scandinavian ancestry. Additional causes of B12 deficiency include insufficient dietary intake, gastritis, H. pylori infections and advanced age. PA may also result from gastrectomy procedures whereby absorption of B12 is decreased. The increase in number of
anemia are two conditions where the RBCs are normal in size, but the reticulocyte counts are high. In aplastic anemia, the RBCs are normal in size, but the reticulocyte counts are low.
Hemolytic anemia means literally the “lysis” of red blood cells. It can be caused by the following:
- Infection: this includes parasitic and helminthic organisms and certain hemolytic toxin-producing strains of the bacterium, Escherichia coli, that is found as a common cause of food poisoning outbreaks.
- Transfusion Reaction: this occurs from an incorrect or incompatible blood product. Relate this cause to our Module 1 concept, hypersensitivity reactions. Our clinical application for the Type 2- Cytotoxic reaction involved the delayed transfusion reaction where the individual responded to an incompatible blood type received.
- Hemolytic disease of the newborn (Rh incompatibility issue occurring in Rh- mothers and their Rh+ fetus): This condition also links back to our Module 1 discussion on the Type 2 Cytotoxic hypersensitivity reaction. Refer to the clinical application case under Module 1, Type 2 Cytotoxic reaction to review the underlying pathophysiology occurring with hemolytic anemia. Regardless of the cause of the hemolysis, the underlying pathophysiology does not change.
- Autoimmune reactions: these can be either congenital or idiopathic in nature.
- Drug-induced: note that drugs are chemicals and they autoxidize (self- destruct, especially over time and/or with exposure to heat, moisture) to form H 2 O 2 (hydrogen peroxide, a free radical) which causes Fe +2^ to oxidize to form Fe +3; and as mentioned earlier, this form of iron cannot bind O 2 as well. In addition, hydrogen peroxide can also attack and oxidize cell membranes to weaken them. In any of the above situations, there is a premature destruction/lysis of RBCs due to enzymes or toxins produced by the infectious agent, chemical release mediated by own immune system, or because of certain chemicals/drugs. Note that circulating blood contains Vitamin C and RBCs contain glutathione, both of which are natural antioxidants to help protect cells. Blood loss anemia In situations where the number of RBCs lost is greater than number of RBCs produced due as the direct result of blood loss is considered blood loss anemia. Blood loss anemia can be acute or chronic. Acute blood loss anemia is usually associated with acute GI bleeding, severe trauma, surgical or labor and delivery complications. Chronic blood loss anemia is commonly associated with chronic GI bleeding. Chronic blood loss will deplete iron stores and also produce iron-deficiency anemia. A normal, healthy young adult can lose 500-1000mL (10-20%) of blood with minimal effects. Compensation and recovery begin within 24 hours for losses up to 1500 mL of blood. Sudden, severe hemorrhage can induce hypovolemic shock, cardiovascular failure, and death. Diagnosis and management of a blood loss anemia must take into account the reason behind the loss, the rate and amount of blood loss, and the capacity of the patient to compensate for both volume losses and anemia.
The Reticulocyte count is low in aplastic anemia. The MCV is normal in hemolytic anemia.
There are 2 genes (alpha 1 and alpha 2) involved in encoding synthesis of the alpha protein chains for Hb. The pathology of sickle cell anemia involves a single amino-acid change on the beta-chain. Cells that contain abnormal types of hemoglobin are more resistant to infection by the parasite that causes malaria. Thalassemia may have many possible genetic mutations. The abnormal RBCs in Sickle cell anemia can occlude cerebral, splenic and glomerular blood vessels and create a high risk for stroke. Inherited Disorders of Erythrocytes: Hemoglobinopathies Individuals may inherit a disorder of the erythrocytes called hemoglobinopathies. There are four genes involved in encoding synthesis of the alpha protein chains for Hb. These genes are located on chromosome number 16. There are two genes involved in encoding synthesis of the beta protein chains for Hb. These genes are located on chromosome number 11. From these six different genetic loci, over 300 different Hb gene defects have been documented. The two most common examples include sickle- cell anemia and thalassemia. Sickle-Cell Anemia Sickle-cell anemia is an inherited autosomal recessive genetic disorder. As discussed in the Basics of Human Genetics recorded presentation, autosomal recessive disorders develop as the result of inheriting two abnormal genes, one from each parent. If the individual inherits a normal Hb gene from one parent and an abnormal Hb gene from the other parent, that individual would have “sickle cell trait” and be an asymptomatic carrier. They could pass on the abnormal gene to their offspring, but they themselves would experience minimal, if any signs and symptoms of the condition. The pathophysiology of sickle cell anemia involves a single amino acid change on the beta-chain (the amino acid valine replaces glutamic acid). This simple change results in the formation of elongated, “sickled” Hb molecules (designated HbS) which does not bind oxygen as readily. Oxidative stress (such as occurs with hypoxia), anxiety, fever, cold, and dehydration further decrease oxygen binding to Hb and increases sickling tendencies of the Hb. The sickling of millions of hemoglobin molecules causes distortion of RBCs that house those molecules. This weakens the RBCs and they rupture after only 10-15 days in circulation. This is a type of hemolytic anemia and presents with the classic anemia signs and symptoms in addition to other serious complications. The lysis of large amounts of RBCs put the individual at risk for circulatory iron-overload The abnormal RBCs also occlude cerebral, splenic and glomerular blood vessels and create a high
especially prevalent. Therefore, many sickle-cell individuals are asplenic by adulthood. Thalassemia The thalassemia(s) are a group of related inherited autosomal recessive genetic disorders. Similar to sickle cell anemia, the affected individual must inherit an abnormal Hb gene from both parents. However, unlike sickle cell anemia, thalassemia is characterized by many different possible genetic mutations. These mutations cause single or multiple amino acid changes on alpha- and/or beta-chains resulting in synthesis of Hb with abnormal chains, or even missing alpha- and beta- chains. Depending on the mutation, there can be varying degrees of distortion and dysfunction of the RBC. Because of the number of different possible genetic mutations, thalassemia can present in a variety of forms from minor to major and be asymptomatic in the mildest forms and lethal in the most severe forms, such as Cooley’s thalassemia. Sickle Cell Anemia and Thalassemia Review the list of statements concerning Sickle Cell Anemia and Thalassemia. Identify the appropriate anemia for each. Consult your McCance textbook as needed on these anemias. Sickle Cell Anemia Collectively, sickle cell anemia and the different forms of thalassemia represent the most common genetically inherited disorders. It is estimated that over 300 million people worldwide have one of these conditions and many millions more are carriers of these genetic traits. Furthermore, these conditions are more prevalent in individuals from certain geographic regions. Specifically, genetic mutations for these conditions are found in people of African, Mediterranean, and Southeast Asian descent. The name “thalassemia” literally translates from “thalassa” – the Greek word for sea. The reason that the genetic mutations for these hemoglobinopathies persisted in the human gene pool through the centuries is an advantage. It turns out that cells that contain abnormal types of hemoglobin are more resistant to infection by the parasite that causes malaria. This is a disease that happens to be endemic in the same parts of the world where these types of anemias are also prevalent. Not only are the abnormal RBCs more resistant to infection, but their shortened lifespan in circulation is not long Sickle Cell Anemia Thalassemia Involves a single amino acid change on the beta-chain May have many possible genetic mutations Increased red blood cell (RBC) hemoglobin S concentration, RBC dehydration, acidosis, and hypoxemia Characterized by acute painful episodes Ineffective erythropoiesis Occurs primarily in persons from southeast Asia and
enough to allow the malaria parasite to complete its reproduction cycle. This allowed our ancestors who carried these
