6. Intro to Anemia and Hemolytic Anemias

Question 1

lifespan of a RBC

Answer 1

120 days

Question 2

Anemia (overall definition)

Answer 2

reduction in the total circulating red cell mass below normal limits (normal limits depends on the person: eg sea level vs high altitude; dx by reduction in [hemoglobin] and hematocrit)

Question 3

hemoglobin concentration

Answer 3

normal is 14 g/dL (whole blood) (low in chronic anemia or increased EC volume)

Question 4

hematocrit

Answer 4

normal is 42%; % packed red cells (Packed cell volume/PCV) per volume of whole blood (low in chronic anemia or increased EC volume)

Question 5

clinical features of anemia

Answer 5

history (weakness/fatigue and dyspnea on exertion); physical exam (pallor and tachycardia); long term fatty changes in liver, myocardium and kidney

Question 6

4 major differentials for hemolytic anemia

Answer 6

inherited genetic defects (eg hereditary pherocytosis, G6PD defic, PNH, sickle cell disease and thalessemias), antibody-mediated destruction (eg hemolytic disease of the newborn, transfusion reactions, drug induced), mechanical trauma (eg heart valves, marathon running, bongo drumming), infections of RBCs (eg malaria, babesiosis)

Question 7

4 major differentials for decreased RBC production

Answer 7

inherited genetic defects, nutritional deficiencies, primary hematopoietic neoplasms, infections of red cell progenitors

Question 8

signs and symptoms of hypoxia re: anemia

Answer 8

CNS: headache, dimness of vision and faintness CV: angina due to ischemic cardiac muscle Skeletal muscle: claudication due to ischemic skeletal muscle *with acute blood loss and shock, renal hypoperfusion may result in oliguria and/or anuria

Question 9

factors determining clinical severity of anemia

Answer 9

degree of anemia rapidity of onset effectiveness of compensatory mechanisms oxygen requirements (pts w/long term anemia can withstand hemoglobin of 6g/dL without tachycardia)

Question 10

anemia re: acute blood loss (cause, clinical effects, treatment, and crit findings)

Answer 10

cause: trauma clinical effects of hypovolemia and decreased tissue perfusion: tachycardia, hypotension, decreased urine output, if massive can lead to cardiovascular collapse, shock and death treatment: restore extracellular volume with acellular fluids (electrolyte solutions, colloids like albumin or dextran) +/- RBCs depending on degree of bloodloss (platelets and plasma too perhaps) crit: normal after acute bloodloss but hypovolemic, low after treated with acellular fluids but no longer hypovolemic

Question 11

chronic anemia vs defective production - how do you differentiate?

Answer 11

look at reticulocytes (see if the body is responding to the anemia appropriately) - non-nucleated RBC precursors with some rRNA - visualize with supravital stains or flow cytometry - count is increased in hemolytic anemias - takes 5-7 days to manifest - normal mean is 1.5% - % may be misleading in anemic patients given a percentage of fewer number of reticulocytes per microliter of blood - absolute reticulocyte count = %retic/100 X total red cells/mcL (normal is 75,0000/microliter)

Question 12

what factors decrease hemoglobin affinity for Oxygen, making it easier to unload oxygen at the tissue level?

Answer 12

increased temperature, increased 2-3 DPG, increased [H+]

Question 13

what are the body’s steps to compensating for anemia?

Answer 13

1. increased levels of 2-3DPG (from intermediate of glycolytic pathway, binds to hgb to reduce its affinity for O2, max to 1.5-2X normal levels to increase O2 delivery by 30%, compensation for anemia with crit down to 30%) 2. heart increses CO by increasing HR and stroke rate 3. kidneys release EPO (stim bone marrow, takes weeks to impact crit)

Question 14

treatment of chronic anemia

Answer 14

treat root cause (patient not lab value), red cell transfusion when indicate (pt is symptomatic or at risk), epo analogs if chronic renal failure, patients on chemo, or some elective surgeries prophylactically

Question 15

EPO analogs

Answer 15

• Many formulations § Epogen/procrit - epoetin alpha § Aranesp- darbepoietin alpha - Used for treating patients with chronic renal failure and cancer patients on chemo § Or prophylactically in some pre surgery □ Patients with mild anemia (hgb = 10-13 g/dL) □ Scheduled for elective non-cardiac, non-vascular sugery with a significant anticipated blood loss who are likely to be transfused ® ~2+ units of RBCs □ Start pre-surgery (1.5-3 weeks) □ Iron supplements - Not approved yet uses: § Cancer pts not on chemo § Anemia of premature infants § Preoperative autologous blood donation § Chronic inflammatory disease § ICU Patients - Other EPO effects: § EPO receptors present on non-erythroid cells, including some neoplastic cells § Inhibits apoptosis § Stimulates vascular endothelial cell prolif & angiogenesis - EPO and iron stores § Response is limited by availability of iron for hemoglobin synthesis § Monitor Fe stores before and during tx □ Most pts require Fe supplements - Adverse effects of EPO § Hypertension □ Seen more often in pts with renal failure □ Caused by increased crit § Thrombotic events □ Increased risk at serious thrombotic events in pts with higher hemogic targets (CRF, malignancy) □ MI, DVT, PE, stroke § Cancer progression □ Increased tumor recurrence and decreased survival when EPO is dosed to increase hemoglobin >12 g/dL

Question 16

hemolytic anemia overall features

Answer 16

premature destruction of RBCs (lifespan

Question 17

diagnostic eval of hemolytic anemia, history

Answer 17

○ Onset/duration (Hereditary vs acquired) ○ History of fatigue ○ History of jaundice ○ Abdominal pain/cholelithiasis (hemolysis and bilirubin stones) ○ Medications (some drugs are oxidants) ○ Foreign travel (parasites) ○ Infection (sick contacts) ○ vascular/cardiac surgery ○ Blood loss or sequestratino ○ Discolored urine Complete family history (jaundice, anemia, etc)

Question 18

Diagnostic eval of hemolytic anemia, physical exam

Answer 18

○ Pallor ○ Tachycardia ○ Increased temperature (helps O2 dissoc) ○ Jaundice ○ Distended neck veins, S3 gallop ○ Click of mechanical valves splenomegaly

Question 19

• Diagnostic eval of hemolytic anemia, laboratory

Answer 19

○ Hgb and crit ○ Mean cell volume (MCV) (less than 80/100 = microcytic) ○ RBC distribution witdth (RDW) § Reticulocytes large so skew curve to be wider ○ Morphologic eval of peripheral smear ○ Reticulocyte count ○ Bilirubin § Indirect = unconjugated § Serum and urine ○ Coombs test § DAT to detect RBC antibodies ○ Other special testing Osmotic fragility, sucrose hemolysis, hemoglobin electrophoresis, flow cyto, etc

Question 20

extravascular vs intravascular hemolysis

Answer 20

extravascular: - Common - Destruction of RBCs occurs within phagocytes, mostly in spleen - Varying degree of splenomegaly ○ Patients may benefti from splenectomy - Jaundice intravascular: - Less common - May be caused by complement fixation, mechanical injury, or intracellular parasites - Hemoglobinemia - Hemoglobinuria - Hemosiderinuria ○ Brown urine (hgb is rel from RBCs into bloodstream in excess of binding capacity of heptaglobin, excess is filtered by kidney) - Jaundice

Question 21

re: intravascular hemolysis, what happens to plasma and urine hemoglobin, haptoglobin, and urine hemosiderin?

Answer 21

hemoglobin: rise initially (less than 1 day) haptoglobin: falls as free hgb is bound (1-3 days) hemosiderin: increases later with breakdown (3-10 days)

Question 22

three types of immunohemolytic anemias

Answer 22

1. warm antibody type (IgG Abs active at 37*C): primary (idiopathic), secondary (autoimmune distorders like lupus, drugs, lymphoid neoplasms) 2. cold agglutinin type (IgM Abs active below 37*C): acute due to infection like mononucleosis, chronic (idiopathic, lymphoid neoplasms) 3. cold hemolysin type (IgG Abs active below 37*C): rare, kids following viral infecs

Question 23

hemolytic disease of the newborn (HDN) and hyrops fetalis

Answer 23

• Antigen negative mom sensitized to antigen positive fetus by fetomaternal hemorrhage or previous pregnancy • Mother’s Abs cross placenta and cause fetal anemia • Previously most often seen during 2nd pregnancy with Abs to Rh • With routine RhDIg prophylaxis, now most commonly seen with ABO antibodies, which can occur at first pregnancy

Question 24

malaria

Answer 24

stats: - 247 million infections - 655,000 deaths in 2010 (98% africa) peripheral smear: - intraerythrocytic rings - multiple in falciparum, or double chromatin dots - gametocytes (some species like banana gametocyte in falicparum) paroxysmal symptoms: - shaking chills - fatigue - anemia and splenomegaly with longstanding infec - fever depending on species - falciparum: malignant tertian - malariae: quartan - ovale and vivax: benign tertian - knowlesi: quotidian

Question 25

Hereditary spherocytosis

Answer 25

type of hemolytic anemia - renders RBCs less deformable and vulnerable to splenic sequestration/destruction - mutations that lead to insufficient membrane skeletal components: (pathophysiology) — band 3, ankyrin, band 4.2, or spectrin (lipid bilayer to cytoskeleton_ - severity varies: —20-30% asymptomatic, chronic hemolytic anemia, some presents super severe at birth and need transfusions, and life threatening aplastic crisis possible triggered by acute parvovirus infection (it infects red cell precursors and leads to aplastic crisis) - symptoms and smear — spherocytosis distinctive but not pathognomic —splenomegaly from congestion at cords of billroth —-coleliethiasis occurs in 40-50% affected - OSMOTIC FRAGILITY TESTING — RBCS abnormally sensitive to osmotic lysis when incubated in hypotonic salt solutions (influx of water and burst) - Treatment —folate due to high red cell turnover and splenectomy if excessive or anemia is stunting growth

Question 26

G6PD deficiency

Answer 26

hexose monophosphate shunt deficiency, inherited enzyme disorder leading to hemolytic anemia - impaired enzyme function reduces ability of RBCs to protect themselves vs oxidative injuries that lead to hemolysis - x-linked recessive - hundreds of variants known (most asymptomatic) —– 10% american blacks, mild version with oxidative exposure hemolyses older RBCs —– 50% kurdish jews which is severe and life threatening, high freq perhaps due to protection vs plasmodium falciparum - episodic intra and extravascular hemolysis caused by exposures that gen oxidant stress ——not chronic hemolysis (no splenomeg or cholelithiasis) ——due to infections, drugs like anti-malarials or sulfonamides, or foods like fava beans (favism) - testing —–heinz bodies with supravital stains (fava beans with heinz ketchup) —–bite cells in smear thanks to spleen —–testing after acute hemolytic episode only will show normal cells thanks to killing of primary older cells, so wait 6 weeks to test via genetic testing —–recovery phase has reticulocytosis

Question 27

paroxysmal noctural hemoglobinuria (PNH)

Answer 27

results from acquired mutations in the PIGA gene (x-linked and subject to lyonization) –> causative mutation in hematopoietic stem cell, so all clonal progeny are deficient - intravascular hemolysis related to complement activation - chronic hemolysis more typical (paroxysmal nocturnal only 25 % perhaps due to low night pH) - thrombosis leading cause of related death (40% of patients suffer venous thrombosis thanks to platelet dysfunction and free hgb absorption of nitrous oxide) - 5-10% pts develop AML or MDS - dx by flow cytometry (deficient in CD55, CD59, or CD8 and DAF so heightened sensitivity to complement and alternate complement pathway), test with sucrose hemolysis testing