PASS Anemia PDF

Chapter Seven: Anemias The key to understanding anemias is organization. PASS teaches how to understand why a patient is anemic and how to organize hematology. With about 25% of the world’s population suffering from anemia, it makes sense that it is one of the most common presenting problems clinica...

Chapter Seven: Anemias The key to understanding anemias is organization. PASS teaches how to understand why a patient is anemic and how to organize hematology. With about 25% of the world’s population suffering from anemia, it makes sense that it is one of the most common presenting problems clinically. The definition of anemia sounds deceptively simple — a decrease in the number of circulating red blood cells — but it results in some big problems for the human body. Those missing RBCs contained millions of hemoglobin molecules that were supposed to be carrying oxygen to the tissues. Without the red pigment in the hemoglobin, the patient starts to become pale. Without the oxygen, the patient starts to have fatigue. This cascade effect — with a decrease in red blood cells, meaning a decrease in hemoglobin, meaning a decrease in the amount of oxygen getting to the tissue — illustrates why anemia can be the cause of so many problems and this also illustrates why anemia is never normal. There are two ways to approach Anemias: Inadequate Production: Bone marrow has problems making RBCs Excessive Destruction: Too many RBCs are being destroyed in the body Levels of Anemia Normal level of Hemoglobin (Hg): Male: 13 – 17 g/dL Female: 11 – 15 g/dL REMEMBER Q: How to estimate the patients Hematocrit (Hct) level? RBC mass over volume Grades of Anemia: Mild: < 11 (or Hct of 33) Moderate: < 9 (or Hct 27) Severe: < 7 (or Hct 21) Hypoxia Hypoxia is defined as low levels of p02 and the Hg is less than 7 g/dL REMEMBER Normal pO2 60-100 mm Hg 197 Anemias Oxygen Content = SaO2 (oxygen bound to Hg) + pO2 (dissolved oxygen) Acute Hypoxia is a Low Energy State (always make the PASS connection!) Chronic Hypoxia will cause 3 adaptations: • Increase erythropoietin production (kidney parenchyma) to stimulate the bone marrow • Increase mitochondria density in the skeletal muscle • Angiogenesis which leads to digital clubbing Cyanosis Dusky blue discoloration of skin and mucous membranes. This blue color is due to the increased amount of deoxygenated hemoglobin (deoxyhemoglobin) in the blood vessel; this does not necessarily mean a decrease in amount of hemoglobin. Cyanosis occurs when 5g of Hg are fully desaturated of O2 Cyanosis, like anemia, is associated with hypoxia. However, cyanosis cannot be used to evaluate anemia, as the dusky blue discoloration becomes less evident as anemia worsens. Two Types of Cyanosis (Central VS. Peripheral): Central • Decreased systemic arterial oxygen saturation • Less oxygen being sent to tissue • Seen when oxygen saturation ≤ 5 percent • When 5g/dL of Hb are fully desaturated of O2 Peripheral • More oxygen being taken out by tissues • Have normal systemic oxygen saturation, but tissues taking too much oxygen out of blood. Can get acrocyanosis, which is a symmetrical, painless, and persistent blue discoloration of hands or feet. In anemic patients, much more profound decreases in tissue oxygen levels are required to see this blue discoloration. 198 Anemias REMEMBER Q: Which type of cyanosis is worse? A: Central cyanosis Example: Patient A has a normal Hb of 17 g/dL and Patient B is anemic with a Hb of g/d For cyanosis to appear, a patient must have 5 g/dl or more of deoxyhemoglobin in capillary blood. Patient A: 5 g/dL of deoxyhemoglobin / 17 g/dL of total hemoglobin = 29% of Hb must desaturate before cyanosis appears Patient B 5 g/d of deoxyhemoglobin / g/d of total hemoglobin = 63% of Hb must desaturate before cyanosis appears Patient A has greater risk of cyanosis even though his baseline Hb was much higher than Patient B. • • • To measure Hg: check Protein Electrophoresis To measure saturation of oxygen: check Pulse Oximetry To measure pO2: check Arterial Blood Gases (ABG) There are 2 major ways to approach anemias 1st. Check Reticulocyte count • • • Reticulocyte count can be included on Complete Blood Count (CBC). Reticulocytes are big, immature RBCs without a nucleus that develops. All RBCs start out as reticulocytes in the bone marrow. They stay in the marrow for three days, then circulate in the bloodstream for about 24 hours before becoming a mature RBC. Normally account for 1% of the total RBCs in circulation. Reticulocytes first show up on day 4 and peak on day 7 199 Anemias Figure 7. 1 Anemia Classification based on Reticulocyte Count Low Reticulocyte Count • Low reticulocyte count in blood due to decreased RBC production • It may be a hypo-proliferative bone marrow problem - biopsy shows fat in place of bone marrow • Other causes include: • Renal failure, which leads to decreased production erythropoietin. Erythropoietin is a hormone released by kidneys that increases the production rate of RBCs in response to decreased oxygen in the tissues. Treat with Procrit, Epogen, or Darbepoetin. • Hypothyroidism - If thyroid hormone is not present, erythropoietin cannot work as thyroid hormones are permissive and required for the overall functioning of the body. Treat with Levothyroxine. • Aplastic anemia - MCC is infection with Parvovirus B19. Second MCC is drugs, chemicals and chemotherapy with Chloramphenicol, Benzene, AZT, Vinblastine (“blasts the marrow”) • Metastatic cancers can replace the normal bone marrow. • Fanconi Anemia: pure RBC aplasia, hereditary or secondary to a Thymoma 200 Anemias • Diamond Blackfan Syndrome: RBC aplasia plus finger abnormalities like triphalangeal thumb High Reticulocyte Count Increased number of reticulocytes in the blood means the bone marrow is trying to make more RBCs for the body to use, which means that there is peripheral destruction in progress. Therefore, we know the cause of Anemia in this patient is: A) Not a bone marrow problem B) A hyperproliferative anemia We must ask ourselves, why is the bone marrow working in over-drive and producing more immature RBCs (reticulocytes) and therefore trying to make more over all mature RBCs? The bone marrow does this because there is increased RBC destruction happening somewhere in our body’s periphery. Now, we must determine where these RBCs are being destroyed. • Two choices: intravascular (in the bloodstream) VS. extravascular (in the spleen & liver) • Hemolytic anemia is most commonly extravascular REMEMBER Vasculitis: • Schistocytes (torn platelets and RBCs) • Burr cells • Helmet cells • Haptoglobin (protein that binds free Hg) Extravascular Patient will have splenomegaly & jaundice (increased levels of unconjugated bilirubin) Diseases: • Hereditary Spherocytosis • Glucose-6-Phosphate Dehydrogenase Deficiency (also has intravascular characteristics) 201 REMEMBER Hereditary Elliptocytosis • Autosomal Dominant • Structural damage of the RBC Anemias • • • Sickle Cell Anemia Hemoglobin C Disease Pyruvate Kinase Deficiency Intravascular Patient will have hemoglobinuria, hemoglobinemia (free hemoglobin in the blood plasma), and decreased serum haptoglobin. Haptoglobin binds free hemoglobin from lysed RBCs and brings it to the spleen for removal. Intravascular hemolytic anemia can be immune or non-immune. REMEMBER Hereditary Spherocytosis • Autosomal Dominant • Defect in Spectrin/Ankyrin • Osmotic fragility test: quick lysis when placed in hypotonic saline Use Coombs Test to detect antibodies that attack RBCs Direct Coombs Test • Detects antibodies DIRECTLY on the surface of RBC • Used to detect Warm (IgG) and Cold (IgM) Agglutinin disease • Used to screen babies for hemolytic disease of the newborn Indirect Coombs test • Detects antibodies IN the plasma • Used to screen for antibodies in blood transfusion • Used to screen mom in hemolytic disease of the newborn Immune hemolytic anemias (also called autoimmune hemolytic anemia) • • Positive Direct Coombs Test Warm agglutinin disease - most common type of autoimmune hemolytic diseases. Happens at body temperature. IgG antibodies attack the RBCs. 202 REMEMBER Drugs that cause Hemolytic Anemia: • • • • • • • Penicillins Cephalosporins Sulfa drugs Alpha-Methyldopa PTU Antimalarials Dapsone Drug induced Lupus: • • • • • Hydralazine INH Procainamide Penicillamine Phenytoin Ethusuximide (“H.I.P.P.P.E”) Anemias • Cold agglutinin disease - produced in response to infection or neoplasm. IgM antibodies attack RBCs. RBCs clump together in the bloodstream when patient is exposed to cold ambient air. Non-immune hemolytic anemias • • • • Paroxysmal nocturnal hemoglobinuria Glucose-6-Phosphate Dehydrogenase Deficiency (also has extravascular characteristics) Microangiopathic Hemolytic Anemia Malaria Some RBCs speak. All you have to do is listen. Here is what they have to say... • • • • • • • • • Reticulocyte o Immature RBCs. These cells signify that the bone marrow is healthy and functioning. Howell Jolly Bodies o Remains of the nucleus in the RBC that is normally removed by the spleen. Think hemolytic anemia and splenectomy. Spherocytosis o MCC: Aged RBC; Hereditary Spherocytosis Elliptocytosis o MCC: Hereditary Elliptocytosis Schistocytes o Sheared platelets and RBC damage. Think vasculitis. Tear Drop Cells o RBCs gets squeezed out of BM. They look like a Hershey’s kiss. o MCC: Hemolytic anemia, Cancer in the BM Target Cells o More clear area in the center, so less Hg than normal o MCC: Iron Deficiency Anemia. Also seen in Thalassemia. Heinz Body o Precipitated or oxidized protein (hemoglobin) stuck to the sides of the RBC o MCC: G6PD Deficiency Basophilic stippling o There are too many Heinz bodies o MCC: Lead poisoning 203 Anemias • • • Acanthocytes o RBC coated with lipid o MCC: Hyperlipidemias (familial), obesity, nephrotic syndrome, renal failure, pregnancy Anisocytosis o Different cell sizes Poikilocytosis o Different cell shapes REMEMBER Malabsorption: • MCC in Children: o Cystic Fibrosis o Celiac sprue • MCC in Adults: o Crohn’s Disease 204 Anemias 2nd Approach: Order a CBC with Differential • • • MCV (Mean Corpuscular Volume) MCH (Mean Corpuscular Hemoglobin) MCHC (Mean Corpuscular Hemoglobin Concentration) = MCH /MCV Figure 7.2 Anemia Classification based on MCV Microcytic Hypochromic • Most common • Low MCV/Low MCH • Impaired Hemoglobin Production • Target cells seen on smear • Reticulocyte count is low Iron Deficiency: • Serum Fe is low • Ferritin (90% in mucosal cells) is low • Transferrin (equivalent to TIBC) is HIGH • MCC until 21 y/o: poor intake, middle age: IBD, after 40 y/o: mucosal bleeding (Male-Colon, Female-Endometrial) • Rx: Ferrous Iron with Vitamin C 205 Anemias Late Chronic Disease • Any disease that lasts more than 3 weeks, the body will shut down bone marrow. RBCs die in 60-90 days because of hepcidin. Hepcidin also interferes with transferrin ability to absorb iron. • Serum Fe is low • Ferritin is normal or increased • TIBC is decreased Lead Poisoning • Blocks Delta ALA Dehydratase and Ferrochetolase • High free erythrocyte protoporphyrin (FEP) • Basophilic stippling • MCC: eating peeling paint from old buildings Hemoglobinopathies Thalassemia: Alpha: 4 gene copies: 1 deletion is normal; 2 deletions causes microcytic anemia with/without symptoms, 3 deletions causes microcytic anemia with symptoms, Hg H = β4; 4 deletions cause Hydrops Fetalis (Hemoglobin Bart) Beta: 2 gene copies: 1 deletion causes an increase in Hg A2 and Hg F with/without symptoms; 2 deletions leads to having only Hg A2 and Hg F and hypoxia at 6 months of age Hemoglobin S Sickle Cell Disease: Homozygous, Glu to Val on position 6 of the Beta Chain; vasoocclusion leads to necrosis of various tissues; dactylitis (painful fingers and toes) is usually the initial presentation; protects against malaria. Sickle Cell Trait: Heterozygous; can present as painless hematuria; cells may sickle with extreme hypoxia. Sideroblastic anemia • Hereditary. Positive family history • Sideroblasts are macrophages with iron stippled thru them. • Use Prussian Blue Stain to diagnose. 206 Anemias Microcytic Hyperchromic • Low MCV • High MCHC • High Reticulocytes • High Bilirubin • Hyperkalemia Hereditary Spherocytosis: This is the only disease in this category Normocytic Normochromic • Normal MCV • Normal MCH • Nothing is wrong with the RBC; you just don't have enough of them. Acute hemorrhage Less than 4 days, before reticulocytes show up Chronic disease early 1st 60 days of a disease process Renal Failure Lack of Erythropoietin. Treat with Procrit, Epogen, or Darbepoetin Hypothyroidism If thyroid hormone is not present, erythropoietin cannot work Aplastic anemia: • MCC is Parvovirus B19 which attacks the BM. The BM is always replicating DNA and RNA therefore it is unable to synthesize RBCs. Bone marrow is replaced with fat. • Drugs are the second cause. (e.g. Chloramphenicol, Benzene, AZT, Vinblastine) • Myelofibrosis – Cancer of the BM in which the BM becomes fibrotic. • Fanconi Anemia: Pure RBC aplasia, hereditary or secondary to a Thymoma • Diamond Blackfan Syndrome: RBC aplasia plus finger abnormality (triphalangeal thumb) 207 Anemias Macrocytic Anemia Increase MCV Defective nuclear division Vitamin B12 Deficiency: • Vit. B12 is a cofactor for Malonyl-CoA Mutase and Homocysteine Methyl Transferase • MCC: Type A Gastritis (Pernicious Anemia) Folate Deficiency: • First vitamin that runs out with rapid cellular division • MCC: overcooked veggies Hypothyroidism: Aforementioned, thyroid hormones are permissive. Without them, the body cannot carry out its day-to-day functions. Alcohol: Denatures all proteins; impairs nuclear division Chemotherapy drugs: Damage the DNA and stop nuclear replication Anti-convulsive drugs: • Block Ca (microtubules need Ca) and/or folate • Phenytoin: blocks calcium and folate • Ethosuximide: blocks calcium • Valproic acid: blocks sodium, calcium, and folate • Carbamazepine: blocks sodium and calcium Paroxysmal Nocturnal Hemoglobinuria (PNH)-an intravascular non-immune hemolytic anemia • Rare, acquired, life-threatening disease of the blood • Gene mutation causes an anchor for proteins that attach to the outside of RBC cell membrane to be absent • Missing protein anchor is called glycosyl-phosphatidylinositol (GPI). Without GPI, complement tags cell for destruction. • First described in military recruits Symptoms • Fatigue out of proportion to the degree of anemia • Jaundice and pink/red urine • Hemoglobinuria may happen at night, as the disease name indicates, or it may happen during the day 208 Anemias • • Patients can also present with thrombosis in unusual sites, such as a vein in the abdomen or brain, possibly due to complement fixing over time, causing inflammation in the vessels — aka vasculitis. This can predispose the patient to developing a clot. Patients may die from MI and stroke. To Diagnose • Previously used the Hams Test: o Involved putting RBCs on a petri dish then adding complement. If nothing happened, then they would add acid. If patient had PNH, RBCs would lyse. o This test has a low sensitivity and specificity which is why it is now rarely used. • Now we use Flow Cytometry (CD55 and CD59 detected on surface): • Cell components are fluorescent labeled then put through a laser, which causes them to emit specific wavelengths of light. Rx: C5 Blockers • Eculizumab • Mepolizumab • Reslizumab • Benralizumab (blocks C5 receptor) 209