1. Hemolytic Anemia Part I FJ Albert, DO, DTM&H Hospital Medicine Lexington Medical Center West Columbia, SC Associate Professor Clinical Internal Medicine Edward Via College of Osteopathic Medicine Carolinas Campus

2. Topic Summary Anemia Hemolytic Anemia Hereditary Spherocytosis (HS) Elliptocytosis Paroxysmal Nocturnal Hemoglobinuria (PNH) Pyruvate Kinase Deficiency

3. Topic Summary Glucose-6-Phosphate Dehydrogenase Deficiency (G6PD) Thalassemias Sickle Cell Disease Disseminated Intravascular Coagulation (DIC) Malaria Henoch-Schonlein Purpura (HSP)

4. Anemia Defined by hemoglobin value Hemoglobin <13.5 g/dL in women Hemoglobin <12 g/dL in men

5. Anemia Mean Corpuscular Volume (MCV) –Size of a red blood cell –Normal 80-100 fL –Microcytic vs Macrocytic Mean Corpuscular Hemoglobin Concentration (MCHC) –Concentration of hemoglobin within a red blood cell –Normal 32-36 g/dL –Hypochromic vs Hyperchromic

6. Anemia Workup Serum iron Serum Total Iron Binding Capacity (TIBC) Serum ferritin Reticulocyte percentage/CBC smear –Normal reticulocyte percentage 0.5-1.5%

7. Anemia Workup Iron deficiency anemia –Low serum iron and high TIBC –Low serum ferritin Anemia of chronic disease –Low serum iron and low TIBC –Normal or high serum ferritin

8. Hemolytic Anemia Elevated reticulocyte percentage Elevated serum LDH Elevated serum bilirubin (indirect predominance) Low plasma haptoglobin

9. Haptoglobin RBC destruction releases hemoglobin in plasma Free hemoglobin binds to haptoglobin Hemoglobin-haptoglobin complex removed by liver Plasma haptoglobin, therefore, markedly reduced with hemolytic anemia

10. Red Blood Cells Average survival is 110 to 120 days Two modes of destruction –Increasing RBC age –Hemolysis due to processes independent of RBC age

11. Hereditary Spherocytosis Characterized by anemia, jaundice, and splenomegaly Family history of hemolytic anemia

12. Hereditary Spherocytosis Alterations in genes that encode proteins responsible for unifying RBC inner membrane to the outer lipid bilayer Spectrin deficiency most common protein deficiency seen in HS Passage of RBCs through spleen  progressive loss of RBC lipid layer  acquired spheroid shape  ultimate RBC hemolysis

13. Spherocytosis Complete Blood Count (CBC) –Anemia –Reticulocytosis –Low Mean Corpuscular Volume (MCV) –Increased Mean Corpuscular Hemoglobin Concentration (MCHC) –Increased Red Cell Distribution Width (RDW) –Spherocytes seen on CBC smear

14. Spherocytosis Direct and Indirect Antiglobulin (Coombs) serology is NEGATIVE with spherocytosis POSITIVE Direct and Indirect Antiglobulin (Coombs) tests are associated with autoimmune hemolytic anemias

15. Normal RBCs

16. Spherocytes

17. Presence of spherocytes seen in –Hereditary Spherocytosis (HS) –Glucose-6-phosphate deficiency (G6PD) –Snake bites –Sepsis secondary to Clostridium –Microangiopathic hemolytic anemia

18. Confirming Diagnosis of Hereditary Spherocytosis Serologic testing –Eosin-5-maleimide binding test –Acidified glycerol lysis time or the cryohemolysis test (either one in combination with the Eosin-5-maleimide binding test)

19. Hereditary Spherocytosis Treatment RBC transfusions for symptomatic anemia Folic acid (1 mg/day orally), to support erythropoiesis Consideration of splenectomy –Eliminate hemolysis and anemia Early splenectomy reduces risk of bilirubin gallstone formation  reduces need for cholecystectomy later in life

20. Splenectomy ALL patients who undergo splenectomy (regardless of reason), are at increased risk for infections/sepsis from encapsulated bacteria Proper immunization and/or antibiotic considerations for splenectomized patients –Hemophilus Influenzae B –Streptococcus Pneumoniae –Neisseria Meningitidis

21. Elliptocytosis Also known as hereditary ovalocytosis Autosomal dominant transmission Inherited disorder of one or more red blood cell membrane proteins

22. Elliptocytosis Spectrum of disease from asymptomatic (most cases) to life-threatening Normal individuals have up to 5% elliptical RBC forms Hereditary Elliptocytosis associated with 15-100% elliptical RBC forms

23. Elliptocytosis Diagnosed by peripheral smear abnormalities and other specialized laboratory tests and DNA testing Treatment –Folic acid (1mg/day) orally –Red blood cell transfusions –Splenectomy for severe disease

24. Paroxysmal Nocturnal Hemoglobinuria (PNH) Defect in the glycosylphosatidyl-inositol (GPI) anchor of hemoglobin, due, in turn, to a genetic abnormality (PIG-A gene) Clinical manifestations relate to hematopoietic function abnormalities

25. Paroxysmal Nocturnal Hemoglobinuria (PNH) Hemolytic anemia –Especially after viral or bacterial infections Hypercoagulable state –Venous thrombosis, especially hepatic or other intraabdominal venous system Bone marrow hypoplasia/aplasia Progression to myelodysplastic syndrome (MDS) or acute leukemia

26. Pyruvate Kinase Deficiency Most common congenital NON- SPHEROCYTIC hemolytic anemia Most common congenital NON- SPHEROCYTIC hemolytic anemia Autosomal recessive transmission Autosomal recessive transmission Deficiency of erythrocyte Pyruvate Kinase enzyme  hemolysis Deficiency of erythrocyte Pyruvate Kinase enzyme  hemolysis Mechanism of hemolysis not clear Mechanism of hemolysis not clear

27. Pyruvate Kinase Deficiency Pyruvate Kinase Deficiency Severity of disease is highly variable Severity of disease is highly variable Some have life-threatening, transfusion requiring, hemolytic anemia from onset at birth Some have life-threatening, transfusion requiring, hemolytic anemia from onset at birth Some have fully compensated disease with minimal hemolysis Some have fully compensated disease with minimal hemolysis

28. Pyruvate Kinase Deficiency Intrauterine PRBC transfusions in affected fetuses with severe anemia Intrauterine PRBC transfusions in affected fetuses with severe anemia Phototherapy, in addition to possible PRBC transfusions, for severe hyperbilirubinemia during neonatal period Phototherapy, in addition to possible PRBC transfusions, for severe hyperbilirubinemia during neonatal period

29. Pyruvate Kinase Deficiency Oral folic acid (1 mg/day) is common Oral folic acid (1 mg/day) is common Splenectomy for severe disease Splenectomy for severe disease –Reduces symptoms –Reduces frequency of PRBC transfusions Hematopoietic cell transplantation if no benefit from splenectomy Hematopoietic cell transplantation if no benefit from splenectomy

30. Glucose-6-phosphate dehydrogenase deficiency (G6PD) Glucose-6-phosphate dehydrogenase deficiency (G6PD) Most common enzyme disorder of red blood cells in humans Most common enzyme disorder of red blood cells in humans X-linked transmission X-linked transmission Mostly asymptomatic, except following exposure to agents that cause hemolysis Mostly asymptomatic, except following exposure to agents that cause hemolysis

31. G6PD Deficiency G6PD Deficiency Glucose-6-phosphate dehydrogenase catalyzes first step of the hexose monophospate (HMP) shunt Glucose-6-phosphate dehydrogenase catalyzes first step of the hexose monophospate (HMP) shunt HMP shunt protects RBCs from oxidative injury via NADPH production HMP shunt protects RBCs from oxidative injury via NADPH production Enzyme deficiency results in RBC oxidative injury Enzyme deficiency results in RBC oxidative injury

32. G6PD Deficiency G6PD Deficiency List of more commonly used medications to avoid with known G6PD deficiency List of more commonly used medications to avoid with known G6PD deficiency –Dapsone –Nalidixic Acid –Nitrofurantoin –Primaquine –Sulfamethoxazole (TMP-SMX; Bactrim/Septra)

33. G6PD Deficiency G6PD Deficiency Foods notorious for hemolysis in G6PD deficiency Foods notorious for hemolysis in G6PD deficiency –Fava beans Others that MAY cause hemolysis with G6PD deficiency (individualized based on mutations) Others that MAY cause hemolysis with G6PD deficiency (individualized based on mutations) –Red wine, legumes, blueberries, tonic water –Henna (tattoo ink)

34. Fear the Fava!

35. Thalassemia Thalassemia The major hemoglobin in NORMAL adults is hemoglobin A, consisting of one pair of alpha globin chains and one pair of beta globin chains The major hemoglobin in NORMAL adults is hemoglobin A, consisting of one pair of alpha globin chains and one pair of beta globin chains

36. Thalassemia Thalassemia Thalassemia refers to a spectrum of diseases characterized by reduced or absent production of these pairs of alpha or beta globin chains Thalassemia refers to a spectrum of diseases characterized by reduced or absent production of these pairs of alpha or beta globin chains Definitive diagnosis of ALL thalassemias is by hemoglobin electrophoresis Definitive diagnosis of ALL thalassemias is by hemoglobin electrophoresis Microcytic, hypochromic anemia Microcytic, hypochromic anemia –Low MCV and low MCHC, respectively

37. Beta Thalassemia Beta thalassemia is due to impaired production of beta globin chains Associated with relative excess of alpha globin chains

38. Beta Thalassemia Beta Thalassemia Beta thalassemia minor Beta thalassemia minor –Majority are asymptomatic –Ninety percent of hemoglobin is Hgb A Beta thalassemia intermedia Beta thalassemia intermedia Beta thalassemia major Beta thalassemia major –Absent or markedly reduced beta chains –Hemoglobin A absent or markedly reduced –Only hemoglobin F and A2 present –Severe hemolytic anemia

39. Alpha Thalassemia Alpha thalassemia is due impaired production of alpha globin chains Associated with relative excess of beta globin chains

40. Alpha Thalassemia Alpha Thalassemia A normal individual possesses four functional alpha globin genes A normal individual possesses four functional alpha globin genes Alpha thalassemia reflects a loss of one, two, three, or four of these genes Alpha thalassemia reflects a loss of one, two, three, or four of these genes

41. Alpha Thalassemia Alpha Thalassemia Alpha thalassemia minima Alpha thalassemia minima –Three normal alpha globin chain genes –Asymptomatic, with normal blood counts Alpha thalassemia trait Alpha thalassemia trait –Two normal alpha globin chain genes –Mild anemia (microcytic, hypochromic)

42. Alpha Thalassemia Alpha Thalassemia Hemoglobin H disease Hemoglobin H disease –One normal/functional alpha globin chain gene –Symptomatic at birth –Neonatal jaundice and life long hemolytic anemia Hydrops fetalis and hemoglobin Barts Hydrops fetalis and hemoglobin Barts –No inherited normal alpha globin chain genes –Not compatible with extrauterine life

43. Sickle Cell Disease Sickle Cell Disease Homozygous for hemoglobin S (HbSS) Homozygous for hemoglobin S (HbSS) –Most severe form of disease –Results from substitution of valine, for glutamic acid, as the sixth amino acid of the beta globin gene

44. Sickle Cell Disease Sickle Cell Disease Heterozygous for both hemoglobin S and hemoglobin C (HbSC) Heterozygous for both hemoglobin S and hemoglobin C (HbSC) Heterozygous for hemoglobin S (HbS) Heterozygous for hemoglobin S (HbS) –Sickle cell trait –Asymptomatic

45. Sickle Cell Disease Sickle Cell Disease Clinical hallmarks of disease Clinical hallmarks of disease –Vaso-occlusive processes (sickle cell pain crisis) –Red blood cell destruction via hemolysis

46. Sickle Cell Disease Sickle Cell Disease Exacerbations of disease usually occur secondary to some type of physiologic stressor Exacerbations of disease usually occur secondary to some type of physiologic stressor –Infection –Volume depletion –Emotional stress/sleep deprivation

47. Sickle Cell Disease Sickle Cell Disease Clinical manifestations of disease Clinical manifestations of disease –Anemia (hemolytic) –Reticulocytosis (3-15 reticulocyte %) –Unconjugated hyperbilirubinemia –Elevated serum LDH –Low serum haptoglobin –Sickled RBCs on peripheral smear –Howell-Jolly bodies on peripheral smear Reflects hyposplenia from splenic infarctions Reflects hyposplenia from splenic infarctions

48. Sickle Cell Anemia Sickle Cell Anemia

49. Sickled RBCs and Howell Jolly Bodies Sickled RBCs and Howell Jolly Bodies

50. Sickle Cell Disease Treatment Sickle Cell Disease Treatment Acute pain crisis treatment Acute pain crisis treatment –Determine possible source of infection –Supplemental oxygenation –IVF with hypotonic fluid (e.g. ½ NS) is preferred –Pain control (narcotics are first line)

51. Sickle Cell Disease Sickle Cell Disease Chronic disease management Chronic disease management –Folic acid (1mg/day) orally –Hydroxyurea –Multivitamin (MVI) –Calcium with vitamin D supplementation

52. Sickle Cell Disease Sickle Cell Disease Chronic disease management Chronic disease management –Vaccination against encapsulated bacteria (Streptococcus pneumoniae, Hemophilus influenzae (HIB), and Neisseria meningitidis) –Vaccination against Hepatitis B, seasonal influenza, and H1NI influenza