ANEMIAS OBJECTIVES. What is Anemia. A Narrow Exploration Mainly Involving Anemia Studies

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1 A Narrow Exploration Mainly Involving Anemia Studies ANEMIAS OBJECTIVES Definition of Anemia What Causes Anemia Signs and Symptoms Types of Anemia Case Studies What is Anemia Derived from the ancient Greek word Anaimia = lack of blood Basic Definitions: 1. Decrease in the amount of RBCs in the blood 2. Decrease in concentration of Hemoglobin in the blood 3. Lower ability of the blood to carry oxygen 1

2 How Hemoglobin Works HOW LONG DOES IT TAKE FOR AN RBC TO TRAVEL FROM THE HEART THROUGH THE BODY AND BACK? Only 20 seconds! 2

3 How Common is Anemia? Anemia is the most common disorder of the blood Anemia affects approximately ¼ of all people in the world Almost 3.5 million Americans are affected by anemia Anemia is extremely common in developing countries, especially in very poor areas where malnutrition is a factor Causes of Anemia The causes of anemia are numerous, however, most can be grouped into three major categories Blood Loss (Excessive Bleeding) Inadequate Production of RBCs Excessive Destruction of RBCs Blood Loss Chronic Excessive Bleeding Heavy menstrual bleeding Hemorrhoids Nosebleeds Ulcers Bladder tumors GI cancer Kidney cancer Polyps 3

4 Blood Loss Sudden Excessive Bleeding Childbirth Surgery Injury / Trauma Ruptured Blood Vessel Inadequate Production of RBC S (Compromised Bone Marrow) Aplastic Anemia Folate Deficiency Iron Deficiency Leukemia Lymphoma Metastatic Cancer Myelodysplasia Myelofibrosis Multiple Myeloma Vitamin B12 and Vitamin C deficiencies Excessive Destruction of RBCs Autoimmune Reactions Enlarged Spleen G6PD Deficiency Spherocyte Hemoglobin C Disease Hereditary Elliptocytosis Hereditary Spherocytosis Mechanical Damage to RBCs Paroxysmal Nocturnal Hemoglobinuria (PNH) Sickle Cell Disease Thalassemia Sickle Cell 4

5 Signs and Symptoms of Anemia Fatigue Decreased energy Weakness Shortness of breath Lightheadedness Palpitations (feeling of heart racing) Pale skin Black or tarry stools Low blood pressure Enlargement of the spleen (in some cases) Symptoms in Severe Anemia Chest pain / Angina / Even heart attack Dizziness Fainting Rapid heart rate Jaundice Hematuria Confusion A Few Basic Facts About Anemia Anemia is actually a sign of a disease process rather than a disease itself Anemia is classified as either chronic or acute There are three major types of anemia, classified according to the size of the RBCs Microcytic smaller than normal Normocytic normal size Macrocytic larger than normal 5

6 Microcytic Anemia Hemoglobin synthesis failure / insufficiency RBCs are smaller than normal MCV < 80 fl Microcyte Major causes: Iron Deficiency low levels of iron Anemia of Chronic Disease Globin Synthesis defects Thalassemia inherited disorders of hemoglobin synthesis Normocytic Anemia RBCs are normal in size but low in numbers Major causes: Acute blood loss Aplastic anemia (bone marrow failure) Hemolytic anemia Anemia associated with kidney disease Macrocytic Anemia RBCs are larger than normal MCV > 100 fl Major causes: Deficiency of B12, folic acid or both (inadequate intake or insufficient absorption) Pernicious anemia lack of intrinsic factor which is needed to absorb B12 from food Myelodysplastic Syndrome Anemia related to alcoholism 6

7 Taking a Closer Look at Some of the Most Common Anemias Anemia from active bleeding Iron deficiency anemia Anemia of chronic disease Anemia related to kidney disease Anemia related to pregnancy Anemia related to poor nutrition Pernicious anemia Sickle cell anemia Thalassemia Anemia associated with alcoholism Bone marrow related anemia Aplastic anemia Hemolytic anemia Anemia from Active Bleeding Loss of blood through any kind of bleeding such as menstrual, childbirth, trauma, nose bleed, ulcers, cancers and many more Blood is lost at a such a rapid rate that the bone marrow is unable to keep up with production Symptoms go away quickly once blood loss is prevented Can be life threatening depending on severity Bone Marrow 7

8 Iron Deficiency Anemia Iron deficiency causes approximately half of all anemia cases world wide More prevalent in women than men Hemoglobin is reduced due to lack of iron needed for its production Iron deficiency can be due to numerous reasons 1. Insufficient dietary intake 2. Insufficient absorption 3. Loss of iron from bleeding 4. Parasitic infections 5. Pregnancy (increased iron needed to serve mother s increased blood volume plus supply hemoglobin for the fetus). Rare for newborn to be iron deficient baby takes mom s iron during pregnancy Oxygen Binds to Iron 8

9 Laboratory Findings in Iron Def Anemia A Simple Test You Can Take at Home Betanin the pigment found in beets is decolorized by ferric ions. If you are iron deficient, your urine will be red in color after eating beets! 9

10 Think twice before ordering tea with your meal Tea with a meal interferes with iron absorption Tea is an iron chelator that is, it binds with the iron in the food and then the iron passes out through the intestine instead of being absorbed Anemia of Chronic Disease Any long term medical condition can lead to anemia of chronic disease usually mild anemia Chronic inflammation (Rheumatoid arthritis, Lupus, Crohns) Chronic immune activation (HIV, Hepatitis B and C) Malignancy (Lymphoma, Hodgkin s, Lung Ca, Breast Ca) 1. Massive elevation of Interleukin 6 in response to inflammatory cytokines 2. Stimulates hepcidin production & released from the liver 3. Results in reduced iron carrier protein, ferroportin 4. Prevents release from iron stores locks up iron 5. Decreased ability of bone marrow to respond to erythropoietin 10

11 Essential Factors involved in Erythropoiesis and Anemia of Chronic Disease Bone Marrow Prussian Blue Stain Peripheral Blood Wrights Stain Anemia Related to Kidney Disease Kidneys detect the level of Oxygen in the RBCs Kidneys produce a hormone called Erythropoietin Erythropoietin stimulates the stem cells to produce more RBCs In Kidney disease and in end stage renal disease, the production of erythropoietin is diminished Anemia tends to worsen as CKD progresses There is also blood loss from on going hemodialysis. This depletes iron stores which in turn leads to iron deficiency anemia with CKD anemia How Erythropoietin Works 11

12 When There is Kidney Disease Anemia Related to Pregnancy Water weight and fluid gain during pregnancy dilute the blood which may then appear to be anemia Also it is common during pregnancy to have other deficiency anemias such as iron deficiency, B12 deficiency and folate deficiency (demand is higher in order to supply both mom and fetus) Morning sickness contributes to loss of vitamins/minerals Lack of B12 and Folate can lead to birth defects Anemia can also be a direct result of blood loss during and after delivery 12

13 Causes of Anemia in Pregnancy Maternal Anemia 13

14 Anemia Related to Poor Nutrition Many vitamins and minerals are required to make RBCs Iron, Folic acid and Vitamin B12 are needed for proper production of hemoglobin Vitamin C, Riboflavin and Copper are also required in small amounts for proper RBC production Riboflavin is found in eggs, milk, nuts and fortified cereal Vitamin C is found in fresh fruits and vegetables Copper is obtained from consuming shellfish, seafood nuts, seeds and soybeans A diet high in processed foods will not provide the needed nutrients to make RBCs A lack of food, experienced by many poor, results in anemia Foods That Promote RBC Production You are What You Eat Many of today s health issues are caused by poor food choices, nutritional deficiencies and lack of exercise 14

15 But For Some It s Not a Choice Pernicious Anemia Vitamin B12 (Cobalamin) Deficiency Most common in older adults Decrease # s of RBCs plus RBCs are macrocytic B12 is found in liver, meats, milk and legumes During digestion, B12 attaches to intrinsic factor (IF) IF is produced by parietal cells which line the stomach The B12 intrinsic factor complex enters the intestine where the B12 is absorbed into the bloodstream In fact, B12 can only be absorbed when attached to IF In pernicious anemia, the parietal cells stop producing intrinsic factor which makes the intestine completely unable to absorb B12 Oval Macrocytes 15

16 Peripheral Smear in Pernicious Anemia Hyper segmented Neutrophil Oval Macrocyte > 5% of neutrophils with 5 lobes or > 1% of neutrophils with 6 lobes is a diagnostic indicator of Pernicious Anemia Taking a look at the Pathology 16

17 Causes of B12 Deficiency Intrinsic Factor Production Problems Surgical removal of the stomach Corrosive substance damage to the stomach lining B12 Usage Issues Structural defect of the intestinal system can result in an overgrowth of bacteria which in turn absorb the B12 for themselves Infection with intestinal worms (fish tapeworms) uses the B12 resulting in anemia Intestine (the ileum) absorption complications Certain diseases and conditions cause the ileum to not function properly so it is unable to absorb B12 Disorders include tropical sprue, Whipple disease, Crohns disease and tuberculosis Vitamin B12 Deficiency Anemia Vitamin B12 or extrinsic factor is essential for DNA synthesis and cell proliferation The main dietary source of vitamin B12 are meat (especially liver), eggs and dietary supplements B12 is stored in the liver Only use 3 ug/day (3000 ug of B12 is stored in the liver) 17

18 Unexplained neurological abnormalities, think B12 Deficiency Sickle Cell Anemia Autosomal dominant, chronic form of hemolytic anemia Most common in persons of African and Mediterranean descent RBCs have reduced life span, are rigid and crescent in shape Shape is the result of an abnormality in the hemoglobin Sickle shape of the RBC makes it difficult for the cells to pass through small arterioles and capillaries Cells clump together and occlude blood vessels It is believed that the sickle cell mutation developed as a defense against Malaria. Malarial parasites have decreased survival in erythrocytes containing Hb S Carriers of Hb S have a survival advantage in areas where malaria is prevalent 18

19 Mutation in the DNA Sequence Clinical Manifestations in Sickle Cell Disease Problems in sickle cell disease typically begins around 5 to 6 months of age Average life expectancy in the developed world is 50 years old Most episodes of sicklecell crisis last 5 to7 days Long term and worsening pain as people get older A small number of people with sickle cell disease can be cured by bone marrow transplant 19

20 Sickle Cells Thalassemia A group of recessively inherited disorders characterized by reduced or absent amounts of hemoglobin resulting in anemia Many types that range in severity from mild to life threatening Beta Thalassemia (most common), caused by a change in the gene for the beta globin component of hemoglobin Alpha Thalassemia caused by changes in the gene for the alpha globin component of hemoglobin Most common in African, Mediterranean and Asian Alpha thalassemia Diminished synthesis of alpha chains of Hgb 1. Loss of one gene: 2. Loss of two genes: 3. Loss of three genes: 4. Loss of four genes: 20

21 Beta thalassemia Homozygous form is called thalassemia major Hgb A is completely absent, appears in the newborn period and is marked by hemolytic, hypochromic, microcytic anemia. Also, hepatosplenomegaly, skeletal deformation, mongoloid face and cardiac enlargement Heterozygous form is called thalassemia minor Usually asymptomatic but can show a mild anemia The Genetics of Beta Thalassemia 21

22 Marrow Expansion = Skeletal Deformities Anemia Associated with Alcoholism Alcohol can be toxic to the bone marrow resulting in suppression of RBC production Abnormalities in membrane phospholipids Interference with folate utilization RBC s are large and structurally abnormal Defective RBCs are destroyed prematurely Alcoholism can be associated with poor nutrition and vitamin deficiencies which also lead to anemia Abstinence can reverse many of alcohol s effects on hematopoiesis and blood cell functioning How Much is Too Much? Toxic effect on hematopoiesis occurs when daily alcohol consumption equals Four 12 ounce beers 22

23 Bone Marrow Related Anemia Anemia caused by diseases that are directly related to the bone marrow Leukemia, Lymphoma and Myeloma can alter the production of RBCs in the marrow Bone cancer may be the result of a malignant tumor of the bone itself or cancer that has metastasized from another area of the body to the bone. Bone cancer can destroy bone marrow tissue and the body s ability to manufacture red blood cells, thereby causing anemia Myelodysplastic syndrome (MDS): something goes wrong at the stem cell level resulting in decreases in all cell lines PNH: abnormal stem cells in the bone marrow produce defective red blood cells resulting in anemia Aplastic Anemia Aplastic anemia is the medical term for bone marrow failure to produce erythrocytes Characterized by reduction or depletion of hematopoietic precursor cells It is a rare but serious disorder. It can develop suddenly or slowly and tends to get worse over time Most common in adolescents, young adults, and the elderly Life threatening and without treatment will result in death 3 basic categories: acquired, hereditary and idiopathic 23

24 Acquired Toxins, such as pesticides, arsenic, and benzene Radiation and chemotherapy Medicines Infectious diseases, such as hepatitis, Epstein Barr virus, cytomegalovirus, parvovirus B19, and HIV Autoimmune disorders, such as lupus and rheumatoid arthritis Hereditary Fanconi anemia, Shwachman Diamond syndrome, dyskeratosis congenita, and Diamond Blackfan anemia Idiopathic In 60% of the cases the cause of the disorder is unknown Aplastic Anemia Under the Microscope 24

25 Hemolytic Anemia Caused by the increased destruction of erythrocytes (RBCs) RBCs are destroyed prematurely Three main categories 1. Inherited RBC production abnormality such as hereditary spherocytosis and elliptocytosis 2. Acquired Exposure to environmental agents such as medications, toxins, poisons, infections Mismatched blood transfusions Rh incompatibility between mom and fetus 3. Mechanical Microvascular or valvular abnormalities Causes of Hemolysis by Site of Abnormality Under the Microscope Spherocyte Schistocyte Spherocyte 25

26 Making the Correct Diagnosis Medical history Physical exam Blood tests Detailed information: symptoms diet medications alcohol intake ethnic background Common Laboratory Testing in Anemia Work up CBC (including peripheral smear review) Reticulocyte Count (including IRF and RET He) Iron / Iron Binding Capacity B12 Folate Direct Coombs LDH Haptoglobin Bilirubin Urinalysis 26

27 A Closer Look at the Importance of the Reticulocyte Test Retic profile includes Reticulocyte (% and #) Immature Reticulocyte Fraction (IRF) Reticulocyte Hemoglobin (RET He) Reticulocyte counts on hematology analyzers have been around for some time IRF and RET He are new advances that provide a great deal of additional information regarding the patient s hematological picture Immature Reticulocyte Fraction IRF is a direct cellular measurement of erythropoiesis. It is useful to the clinician in the management of anemia and in the use of erythropoietic stimulating agents (ESA) such as Procrit. High IRF means the bone marrow is producing RBCs and sending them out of the marrow in response to anemia. Reticulocyte is an immature red cell; Immature Retic Fraction is even a younger stage. 3 stages of Retic maturation shown by low, medium and high fluorescence. The IRF is made up of the Medium (MFR) and High (HFR) fluorescing Retics. Male with Mild Anemia HGB = 11.5 Slightly increased IRF = 16.2 (Normal IRF = ) Bone marrow is compensating 27

28 Male with Severe Anemia HGB = 8.0 Very high IRF = 30.0% Bone marrow is compensating Male with Anemia HGB = 9.4 IRF= 0.0 % Bone marrow is not compensating Patient will most likely need transfusion in the near future Reticulocyte Hemoglobin Equivalent RET He direct measurement of the incorporation of iron into the reticulocyte hemoglobin. Lack of iron availability in the bone marrow is the primary cause of decreased RET He. Retics have a limited life span of 1 2 days If they are released from the marrow low in iron, they will have a decreased quantity of hemoglobin. RBCs normally circulate for 120 days If they are deficient in iron and hemoglobin they will remain so for their entire lifetime. 28

29 RET He RET He Normal Range: = pg Low RET He results trigger the provider to begin iron therapy much earlier. Patient s experience with iron deficiency can be better managed and anemic period decreased And isn t this who it is all about? Female with Iron Deficiency Anemia Low HGB = 11.8 Low RET He RET He = 27.1 (nl = ) Iron therapy is indicated Low RET He Female with Anemia Not due to Iron Deficiency Low HGB = 9.6 Normal RET He RET He =33.7 Iron therapy is not indicated Normal RET He 29

30 Quick Case Study 73 year old man with stomach cancer is put on a phase one clinical trial after he failed with conventional treatment Clinical trial calls for numerous lab tests to be run each week including a CBC and Reticulocyte count Hemoglobin was slightly low at 12.8 g/dl and the RET He was also slightly decreased at 27.7 pg Results were given to physician and physician ordered iron studies Iron studies confirmed diagnosis of iron deficiency anemia and patient was started on oral iron Lab Results Follow up The following week the patient again had the required lab tests for the clinical trial Hemoglobin dropped to 8.5g/dl but now the Ret He was normal at 30.5pg Why was the RET He normal when the Hemoglobin dropped significantly? And the week before the IRF was normal at 7.1% but now increased at 19.2% 30

31 High IRF Conclusion The patient most likely has a bleed or a hemolysis process going on The high IRF indicates the bone marrow is working and producing RBCs pushing them out quickly to make up for the loss in the peripheral blood The normal RET He is because the patient doesn t have as many RBCs (remember he has lost over a million) for hemoglobinization Although the amount of iron the man has is still the same it is spread out over less RBCs so the remaining RBCs have a normal Reticulocyte Hgb level The Added Benefit of RET He Low RET He is an early predictor of iron deficiency anemia and iron therapy can begin sooner BUT IN ADDITION On the reverse side, a normal RET He of 32 pg/cell or higher rules out iron deficiency with a negative predictive value of 98.5% This allows the clinician to move on quickly to the next step of diagnosing the cause of the patient s anemia 31

32 Additional Procedures Sometimes blood and urine tests are not enough to fully diagnose the underlying cause or the severity of the anemia Additional diagnostic procedures that can be helpful : Upper endoscopy Colonoscopy Biopsies especially of the GI tract Bone Marrow Biopsy Cat Scan MRI Bone Marrow Biopsy Treatment of Anemia Treatment for anemia depends on the type, cause, and severity of the condition Treatments may include dietary changes or supplements, transfusions, medicines, or surgical procedures to treat blood loss Treatment plan is to increase oxygen carrying capacity of the blood This is done by raising the hemoglobin level in the RBCs 32

33 Treatment of Anemia Based on Underlying Cause Dietary changes Life style changes Iron supplements / infusions B12 / Folate Procrit Vitamin C Antibiotics Hormones Blood transfusions Bone marrow transplant Case Studies in Anemia Case #1 35 year old male, airline pilot, married no children Stage IV colorectal cancer with metastases to lung, liver and mediastinum Family history of cancer: breast cancer (maternal grandmother), colon cancer (paternal grandfather), lymphoma (mother) Past treatment for his colorectal cancer includes 7 cycles of chemotherapy plus radiation and surgery Patient begins another round of chemotherapy with FOLFOX and Oxaliplatin which is standard treatment for metastatic colorectal cancer 33

34 Complications Following Treatment Immediately following his treatment patient complains of coca cola colored urine Urinalysis is positive for large amount of blood on the dipstick but no RBCs seen on the microscopic LDH is slightly increased at 290 and Haptoglobin is on the low side of normal at 35 Patient returns the following day for repeat labs. LDH high at 420, Haptoglobin low at <10, Hgb slightly decreased at 12.3 and direct coombs is positive Drop in hemoglobin at a rate of approximately a gram a day with numerous spherocytes seen on the peripheral smears CBC Results Drop in Hemoglobin Autoimmune Hemolytic Anemia Suspect drug related, most likely oxaliplatin as there have been case reports of this in the literature Patient given prednisone to treat the hemolytic anemia Oxaliplatin will not be given to him in the future Hemoglobin stabilized and then returned to normal in about two weeks time 34

35 Case #2 29 year old female, married and mother of four children all under the age of 7 Patient complains of extreme fatigue, headaches and shortness of breath Patient has a history of heavy menstruation along with bleeding episodes between periods Patient has taken minimal dose of oral iron in the past but doesn t take it regularly due to complications of constipation and upset stomach Lab tests including CBC, Reticulocyte, Ferritin, Iron/IBC, B12 and Folate are drawn Low HgB CBC Results copy from Low below MCV from 7/16 High Platelet? 35

36 Iron Deficiency Anemia Significant anemia consistent with iron deficiency anemia Strongly recommend a GYN consultation and possible hysterectomy as it is believed the heavy menses is the underlying cause of the deficiency IV iron infusion given to patient Weekly CBC s to monitor anemia status Case #3 64 year old divorced man presents with severe anemia Complication include positive for Hepatitis C Known history of alcoholism Also, notable for iatrogenic iron overload due to numerous blood transfusions Lab tests done include CBC with smear review, direct coombs, CMP, Ferritin, B12, Folate and Haptoglobin Bone Marrow Biopsy performed 36

37 Bone Marrow Biopsy Results 64 year old male with hepatitis C and cirrhosis along with bone marrow failure. Decreased hematopoiesis without evidence of myelodysplasia or lymphoid neoplasms. Leukopenia and neutropenia without granulocytic dysplasia, circulating blasts or overtly atypical lymphoid cells. Severe thrombocytopenia with normal platelet morphology. Normocytic anemia. Markedly hypocellular bone marrow (approximately 10% cellular) with trilineage hematopoietic maturation Aplastic Anemia 37

38 Case # 4 45 year old woman with history of sickle cell anemia Increasing number of pain crises Frequent headaches Chronic numbness and tingling in extremities Extreme fatigue Excessive bruising Progressive drop in hemoglobin requiring more blood transfusions (Hgb was in the low to mid 8 s now in the low to mid 7 s) Lab Results Significance of the High Ferritin Ferritin reflects the total iron stores in the body Iron is one of the most common elements in nature In the body, Iron is essential in oxidative energy production, oxygen transportation & much more Patients receiving frequent blood transfusions add 1 mg of iron to their body with every ml of PRBCs There is no natural mechanism for the excretion of excess iron in humans The simplest and easiest method for iron removal is therapeutic phlebotomy but in an anemia patient it is impractical and counterproductive 38

39 Iron Loading Anemia Significantly higher mortality rate Liver fibrosis, can lead to liver cirrhosis / liver cancer Also associated with cardiac failure Increased risk of diabetes mellitus Treatment Patient found to be non compliant with the use of her drug, Exjade Exjade is an iron chelating drug Binds with iron then iron is excreted from the body in the urine and stool Patient states she didn t like the adverse reactions she was having to the drug Nausea, vomiting, diarrhea, hearing loss, rash and it tasted bad Also, expensive for her $150 / day Iron Loading Anemia due to non compliance 39

40 And Now Everyone May Inquire About Stuff ANEMIAS 40