Understanding Complete Blood Counts The ABCs of CBCs

1. Understanding Complete Blood Counts The ABCs of CBCs Robert Miceli, MD MetLife

2. The Good, The Bad, and The Ugly For Financial Professional Use Only

3. What Are the Major Components of Blood? • Red Blood Cells (also called erythrocytes) • White Blood Cells (also called leukocytes) • Platelets (also called thrombocytes) • Plasma For Financial Professional Use Only

4. Fancy Words for High and Low For Financial Professional Use Only

5. Symptoms For Financial Professional Use Only

6. Hematology Tests • Specialized tests • Bone Marrow aspiration and biopsy • All of the formed elements of the blood are produced primarily in the bone marrow • They are produced by progenitor cells – cells which grow and differentiate into mature formed elements • This test can detect the lack or overabundance of these progenitor cells, and can find other problems such as cancer For Financial Professional Use Only

7. How Are Blood Cells Formed? For Financial Professional Use Only

8. Red Blood Cells (RBCs) • Largest cellular component of blood, about 40-45% of blood volume • Comprised mostly of hemoglobin • Transport oxygen • Red blood cells normally last about 120 days before they are removed by the spleen For Financial Professional Use Only

9. Hemoglobin • Red pigment molecule which gives RBCs (and blood) its color • Contains 4 molecules of heme and 4 of globin (2 alpha chains and 2 beta chains) • Each molecule of heme contains one iron ion For Financial Professional Use Only

10. White Blood Cells • There are several types of White Blood Cells • They are all involved in immunity but in somewhat different ways • Granulocytes (neutrophils, PMNs, polymorphonuclear leukocytes, or “polys”) – involved in acute infections with bacteria. Immature form is called a “band” • Lymphocytes – involved in many types of infection, especially viruses -Produce antibodies and “memory cells” - Are further divided into T-cells and B-cells • Eosinophils – involved in parasitic infections and allergies • Basophils – involved in parasitic infections and allergies • Monocytes – involved in bacterial and parasitic infections For Financial Professional Use Only

11. White Blood Cells (WBCs) • Neutrophils – also called a variety of other names on CBC reports, including: • polys • PMNs • segs • grans • Lymphocytes • Monocytes • Eosinophils • Basophils For Financial Professional Use Only

12. Platelets • Really more of a fragment of a cell • They are broken off from a very large cell in the bone marrow called a megakaryocyte • Primary function is to aid in blood clotting • Lifetime in the blood is 7-10 days after which they are destroyed in the spleen • Their clotting function is permanently inhibited by aspirin For Financial Professional Use Only

13. Plasma • Plasma is the liquid component of blood • Comprised mostly of water, but also includes: • Protein (albumin, globulin, fibrinogen) • Lipids (cholesterol, triglycerides) • Dissolved salts and minerals (sodium, calcium, potassium) • Glucose For Financial Professional Use Only

14. Case # 1 • 32 yo female applying for $1 million whole life • Insurance labs show elevations of total cholesterol at 240 and alkaline phosphatase at 170, other labs are normal • Medical records include CBC from 1 month prior to application, done during routine office visit. • Paramedical exam: currently pregnant For Financial Professional Use Only

15. “Anemia” of Pregnancy • During pregnancy, the volume of red blood cells increases by about 20%, but the plasma volume increases by 45%. • Net result is ≈ 15% decrease in hemoglobin and hematocrit. For Financial Professional Use Only

16. Complete Blood Count (CBC) For Financial Professional Use Only

17. Red Blood Count and RBC Indices For Financial Professional Use Only

18. Measuring RBCs (and the “Rule of Threes”) • Hematocrit (HCT) is the percent of a volume of whole blood occupied by intact red blood cells. Measured in percent. • Normal range for women: 36 - 46% • Normal range for men: 41 - 53% • Hemoglobin (HGB) measures the concentration of hemoglobin expressed as grams of hemoglobin per deciliter (100 ml) of whole blood. • Normal range for women: 12 - 16 g/dL • Normal range for men: 13.5 - 17.5 g/dL • RBC count is the number of red blood cells per microliter of whole blood. Measured in millions of RBCs per microliter of whole blood. • Normal range for women: 4.0 - 5.2 x106/mm3 • Normal range for men: 4.5 - 5.9 x106/mm3 For Financial Professional Use Only

19. Red Blood Cell Indices • Mean Corpuscular Volume (MCV) is the average size of red blood cells. • Normal range: 80-100 fL • Low = “microcytic” (“too small”) High = “macrocytic” (“too big”) Normal = “normocytic” (“just right”) • Red Cell Distribution Width (RDW) measures the variability in the size of red blood cells. • Normal range: 11.5-14.5% • On a peripheral blood smear, high RDW is described as “anisocytosis” • Mean Corpuscular Hemoglobin (MCH) is the amount of hemoglobin in an average red blood cell. • Normal range: 26-34 pg/cell • Mean Corpuscular Hemoglobin Concentration (MCHC) is the average concentration of hemoglobin in an average RBC. • Normal range: 31-37 g/dL • “Hypochromic” = “too pale” “Normochromic” = “just right” For Financial Professional Use Only

20. Red Blood Cell Indices • Mean Corpuscular Volume (MCV) is the average size of red blood cells. • Normal range: 80-100 fL • Low = “microcytic” (“too small”) High = “macrocytic” (“too big”) Normal = “normocytic” (“just right”) • Red Cell Distribution Width (RDW) measures the variability in the size of red blood cells. • Normal range: 11.5-14.5% • On a peripheral blood smear, high RDW is described as “anisocytosis” • Mean Corpuscular Hemoglobin (MCH) is the amount of hemoglobin in an average red blood cell. • Normal range: 26-34 pg/cell • Mean Corpuscular Hemoglobin Concentration (MCHC) is the average concentration of hemoglobin in an average RBC. • Normal range: 31-37 g/dL • “Hypochromic” = “too pale” “Normochromic” = “just right” For Financial Professional Use Only

21. Red Blood Cell Indices • Mean Corpuscular Volume (MCV) is the average size of red blood cells. • If anemia is present, MCV is a useful tool to guide further testing • If anemia is not present, MCV is of little value: • Low MCV without anemia suggests thalassemia minor (trait) • High MCV without anemia can be caused by certain medications (Dilantin, oral contraceptives, methotrexate) and is a “soft” marker of possible alcohol overuse • Red Cell Distribution Width (RDW) measures the variability in the size of red blood cells. • Not useful in the absence of anemia For Financial Professional Use Only

22. Classification of Anemias Using MCV and RDW For Financial Professional Use Only

23. Descriptive Terms Used on Peripheral Smears • Anisocytosis: marked variation in RBC sizes (visual counterpart of increased RDW) • Hypochromia or hypochromasia: RBCs are paler than normal because they contain less hemoglobin (visual counterpart of decreased MCH) • Macrocytosis: increased number of large RBCs (visual counterpart of increased MCV) • Microcytosis: increased number of small RBCs (visual counterpart of decreased MCV) • Poikilocytosis: marked variation in the shape of RBCs For Financial Professional Use Only

24. Reticulocyte Count • Reticulocytes are “young” red blood cells that were recently released from the bone marrow. • Normally, reticulocytes comprise 0.5 - 2.5% of all red blood cells. • Increased reticulocytes (reticulocytosis) is a normal response to blood loss or anemia. Since reticulocytes are larger, the MCV (and RDW) may be elevated. • The combination of anemia with a low or normal reticulocyte count indicates that the bone marrow is unable to respond normally, either due to lack of essential ingredients (iron deficiency, vitamin B12 or folate deficiency), bone marrow disease, or chronic disease. For Financial Professional Use Only

25. Anemia • Low RBCs – two ways to get there: Too little production, or increased destruction • Low production • Aplastic anemia (no production) • Iron Deficiency Anemia • Increased Destruction • Hemolytic anemia • Spherocytosis • Hemoglobin disorders (thalassemia, sickle cell, others) • Hemorrhage (blood loss) • Hypersplenism (an overactive spleen which destroys formed elements prematurely) • Regardless of the type of anemia, once the level of hemoglobin/hematocrit gets sufficiently low, mortality may result • Mortality Concerns • Severe anemia may cause a critical lack of oxygen to the brain or heart • Less severe anemia may still worsen chronic heart or lung conditions For Financial Professional Use Only

26. Iron deficiency/hemorrhagic anemia • The oxygen-carrying protein heme contains iron, and gives blood its red color • If iron levels are low, RBCs cannot be produced fast enough to match losses • Iron-deficiency anemia is the most common form of anemia world-wide • May be due to poor intake of iron or chronic loss of blood • Blood is lost most commonly from the GI tract • The most important factor to consider when underwriting this condition is – What is the cause? • Possibilities include • Stomach ulcers • Colon cancer • Vascular malformations in the GI tract • Endometrial cancer • Recent surgery or trauma • Multiple blood donations • Can be treated with iron supplements, blood transfusion and/or eradication of the cause For Financial Professional Use Only

27. Case # 2 • 57 yo male applying for $250,000 whole life • Paramedical exam: mild type 2 diabetes, controlled on oral medications, HbA1c 6.1% • APS: routine follow-up for diabetes, no complications, CBC done as routine test For Financial Professional Use Only

28. Case # 2 (continued) • Serum vitamin B12 and folate levels were normal • Iron studies showed low serum ferritin and a low transferrin saturation, consistent with iron deficiency • Colonoscopy was normal • Upper endoscopy showed moderate gastritis and esophagitis with no evidence of active bleeding • Hemoglobin improved with administration of iron Iron-poor RBCs are pale and small (low MCV and MCH) For Financial Professional Use Only

29. Megaloblastic Anemia • A diverse group of anemias, all of which show elevated MCV on the blood count • May be caused by: • Vitamin deficiency (usually B12 or folic acid) • Alcohol intake (moderately high levels) • Leukemia (WBCs would be abnormal, too) • Certain medications • Pernicious anemia – vitamin B12 deficiency caused by an inability to absorb the vitamin from the GI tract. May cause neuropathy, weakness, or even psychiatric problems • Usually treated by • Determining and eliminating the cause • Correcting the vitamin deficiency (if any) • May require injections of vitamin B12 if the cause is pernicious anemia • Mortality concerns – determined by the underlying cause and severity of anemia For Financial Professional Use Only

30. Autoimmune Hemolytic Anemia • A condition where the immune system attacks and destroys red blood cells • Two forms: • Warm antibody • Cold Agglutinin disease • Both cause: • Normocytic anemia with antibodies against red blood cells (positive Coomb’s test) • Mortality concerns • Severity of anemia (hemolytic crises may be fatal) • Presence of an underlying cause (such as infection or rheumatologic disease – like rheumatoid arthritis) • Need for side-effect prone treatments such as steroids, immunosuppressants, or frequent blood transfusions For Financial Professional Use Only

31. Hereditary Spherocytosis/Elliptocytosis • A disorder of red cell shape where the misshapen cells are taken up by the spleen and destroyed prematurely • Leads to anemia and splenomegaly • Splenectomy will normalize the blood count and resolve the anemia, but the cells will still be misshapen • Mortality Concerns: • Severity of hemolysis or anemia • Overwhelming infection after splenectomy For Financial Professional Use Only

32. Anemia of Chronic Disease • Also known as anemia of chronic inflammation • May occur in association with a wide variety of chronic diseases, especially inflammatory conditions, chronic infection, liver disease, congestive heart failure, diabetes, and cancer. • Anemia is usually mild (Hgb 9-12, Hct 27-35), but can be lower in about 20% of cases. • MCV is usually normal or low normal • Platelets may be elevated, especially if inflammation is prominent For Financial Professional Use Only

33. Hemoglobin Disorders • These are various, largely genetic, disorders which affect hemoglobin • Those which affect globin: • Thalassemias • Sickle cell and related disorders • Those which affect heme: • Porphyrias For Financial Professional Use Only

34. Thalassemias • Inherited disorders of the globin gene leading to low levels of alpha or beta globin chains • Fatalities are unusual in all but the most severe forms • Alpha Thalassemia: Beta Thalassemia major • Hemoglobin H disease • Alpha Thalassemia Trait • Beta Thalassemia: • Beta Thalassemia major • Beta Thalassemia intermedia • Beta Thalassemia minor (trait) • Prevalence as high as 10% in Mediterranean, African, and Southeast Asian populations • Typically mild anemia with marked microcytosis • Can coexist with other hemoglobin abnormalities, with increased severity of the anemia and increased mortality concern, but true beta-thalassemia minor (trait) has no excess mortality concerns For Financial Professional Use Only

35. Case # 3 • 47 yo female applying for $1.5 million term • Paramedical exam: all questions answered “no” • Insurance labs normal • Medical records: routine gynecologic visits, CBC done as part of routine exam last year For Financial Professional Use Only

36. Underwriting Tip: Identifying β-thalassemia minor For Financial Professional Use Only

37. Sickle Cell Disease • Forms of hemoglobin: • “A” – adult normal hemoglobin • “S” – sickle cell hemoglobin • “C” – mutant hemoglobin, but with a different result • Since each person has 2 genes, several combinations are possible • “SA” – Sickle trait, may have minimal sickle cell formation, but otherwise is basically a carrier • “SS” – affected with sickle cell disease can be mild to severe • “SC” – similar to SS but milder • “CC”- similar to SS but quite a bit milder Sickle Cell Disease: • When oxygen level is low, RBCs assume a sickle shape, and block capillaries, leading to severe bone pain, and infarctions in various organs • Death can occur from infection, severe anemia, stroke or heart attack For Financial Professional Use Only

38. Porphyria • A large variety of genetic disorders which affect the biosynthesis of heme • All are rare • May cause episodes of severe abdominal pain, sensitivity to sunlight, even psychiatric problems or paralysis • Mortality Concerns • Fatalities are quite rare, may occur in the most severe case For Financial Professional Use Only

39. White Blood Count with Differential For Financial Professional Use Only

40. Absolute Neutrophil Count 5.2 x 1000 = 5200 5200 x .401 = 2085 For Financial Professional Use Only

41. Underwriting Tip • If the total white blood count (WBC) is normal, the red cells and platelets are normal, and your applicant is otherwise healthy, don’t worry about the differential white blood count, especially if the absolute counts are normal. • The percentage of neutrophils, lymphocytes, etc. often fluctuate in response to an infection; this is not a big underwriting concern. For Financial Professional Use Only

42. Types of White Blood Cells - What’s the Diff? • Neutrophils – also called a variety of other names on CBC reports, including: • polys • PMNs • segs • bands or stabs (immature neutrophils indicate acute infection) • Lymphocytes • Monocytes • Eosinophils • Basophils For Financial Professional Use Only

43. WBC Differential: Neutrophils For Financial Professional Use Only

44. Leukocytosis • An elevated WBC count is termed “leukocytosis” • Normal level is 4,400 to 10,000 WBC per mm3 • This can result from many causes, principally infections, inflammatory disorders, and medications • Cancer and myeloproliferative disorders can also cause high, sometimes extremely high, WBC counts • Treatment is aimed at the underlying cause • Death may result from the underlying cause such as severe infection or cancer (leukemia) For Financial Professional Use Only

45. Neutropenia • The relative lack of neutrophils (the most common type of WBC, also called granulocytes) • Normally humans have at least 1500 neutrophils/mm3 • Severe neutropenia (almost no neutrophils) is “agranulocytosis” • May be cause by gene defects, various drugs, or medical conditions • Treatment is usually aimed at the underlying cause • Some may require antibiotics to prevent infection or medications to stimulate production of neutrophils • Death may occur due to overwhelming infection Chronic Benign Neutropenia: • Overall risk of infection is low, usually asymptomatic • Two forms – familial and non-familial • Key features from underwriting perspective are the absence of significant infections and stability over time For Financial Professional Use Only

46. Case # 4 • 44 yo male applying for $2,000,000 whole life • Paramedical exam: rotator cuff injury to right shoulder, getting physical therapy, elevated cholesterol on Lipitor • Insurance labs are normal • Medical records only included labs, no office notes. Total WBC x % Neutrophils = ANC 2800 x 50.2% = 1406 For Financial Professional Use Only

47. Case # 4: Additional Information • Office notes arrive for review with no history of recurrent or serious infections, and WBC has been stable in 2.5 - 4.0 range for the past 5 years. Absolute neutrophil counts are always greater than 1000. For Financial Professional Use Only

48. WBC Differential: Lymphocytes For Financial Professional Use Only

49. WBC Differential: Monocytes For Financial Professional Use Only

50. WBC Differential: Eosinophils For Financial Professional Use Only