Understanding Complete Blood Counts the Abcs of Cbcs

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Understanding Complete Blood Counts The ABCs of CBCs

Robert Miceli, MD MetLife

The Good, The Bad, and The Ugly

Common Abnormal but • Mild iron deficiency anemia in pre-menopausal women Benign CBCs • Beta thalassemia minor

(CBC may be accepted without • Chronic benign neutropenia repeat CBC or clinical evaluation) • Reactive thrombocytosis

• Iron deficiency anemia in men or post-menopausal women Abnormal / Worrisome CBCs • Mild or moderate anemia, not fully evaluated

(may require additional follow-up • Unexplained thrombocytopenia or thrombocytosis or clinical evaluation) • Mild abnormalities involving all 3 cell lines (red cells, white cells, and platelets), mild pancytopenia

• Leukemia Markedly Abnormal CBCs • Severe anemia • Severe leukopenia or severe pancytopenia

For Financial Professional Use Only 2 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 3 Fancy Words for High and Low

Cell Type Too High Too Low Erythrocytosis or Red Blood Cells (Erythrocytes) Anemia Polycythemia Thrombocytosis or Platelets (Thrombocytes) Thrombocytopenia Thrombocythemia

White Blood Cells (Leukocytes) Leukocytosis Leukopenia

Neutrophils Neutrophilia Neutropenia

Lymphocytes Lymphocytosis Lymphopenia

Eosinophils Eosinophilia ---

Monocytes Monocytosis ---

Basophils Basophilia ---

For Financial Professional Use Only 4 Symptoms

Factor Too Much Too Little

Shortness of breath RBCs Clots, strokes (dyspnea), hypoxia, fatigue, pallor

WBCs Clots, strokes Infections

Platelets Clots, strokes Bleeding

For Financial Professional Use Only 5 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 6 How Are Blood Cells Formed?

For Financial Professional Use Only 7 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 8 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 9 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 10 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 11 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 12 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 13 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.

TEST RESULT UNITS REF RANGE WBC 10.8 x 1000/mm3 3.9 - 11.1 RBC 3.73 L x 106/mm3 4.00 - 5.20 HGB 10.8 L g/dL 12.0 - 16.0 HCT 32.4 L % 38.5 - 49.0 MCV 84 fl 80 - 97 MCH 31.0 pg 27.5 - 33.5 MCHC 33.3 % 32.0 - 36.0 PLT 310 x 1000/mm3 150 - 350

• Paramedical exam: currently pregnant

For Financial Professional Use Only 14 “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 15 Complete Blood Count (CBC)

TEST RESULT UNITS REF RANGE WBC 5.2 x 1000/mm3 3.9 - 11.1 RBC 3.81 L x 106/mm3 4.20 - 5.70 HGB 14.5 g/dL 13.2 - 16.9 HCT 41.2 % 38.5 - 49.0 MCV 98 H fl 80 - 97 MCH 33.7 H pg 27.5 - 33.5 MCHC 35.3 % 32.0 - 36.0 RDW 11.8 % 11.0 - 15.0 PLT 172 x 1000/mm3 140 - 390 MPV 7.6 fl 7.5 - 11.5 NEUT % 40.1 % 38.0 - 80.0 LYMPH % 46.1 % 15.0 - 49.0 MONO % 12.9 % 0.0 - 13.0 EOS % 0.6 % 0.0 - 8.0 BASO % 0.3 % 0.0 - 2.0 NEUT, ABS 2085 cells/mm3 1650 - 8000 LYMPH, ABS 2397 cells/mm3 1000 - 3500 MONO, ABS 671 cells/mm3 40 - 900 EOS, ABS 31 cells/mm3 30 - 600 BASO, ABS 16 cells/mm3 0 - 125 For Financial Professional Use Only 16 Red Blood Count and RBC Indices

• 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 18 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 19 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 21 Classification of Anemias Using MCV and RDW

Low MCV Normal MCV High MCV (Microcytic) (Normocytic) (Macrocytic)

Low RDW Thalassemia minor (low variability)

Anemia of chronic Thalassemia minor Aplastic anemia disease Normal RDW Anemia of chronic Myelodysplastic Hereditary disease syndrome spherocytosis

Early deficiency of B12 or folate High RDW Iron deficiency iron, B12, or folate deficiency (high variability) Sickle cell anemia Hemolytic anemia

For Financial Professional Use Only 22 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 23 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 24 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 25 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 26 Case # 2

TEST RESULT UNITS REF RANGE WBC 7.5 x 1000/mm3 3.9 - 11.1 • 57 yo male applying for RBC 3.46 L x 106/mm3 4.60 - 6.20 $250,000 whole life HGB 10.1 L g/dL 14.0 - 18.0 HCT 29.6 L % 40.0 - 54.0 • Paramedical exam: mild type 2 MCV 85.6 fl 80 – 94 MCH 29.3 pg 27 - 33 diabetes, controlled on oral MCHC 34.2 % 32.0 - 36.0 medications, HbA1c 6.1% RDW 13.9 % 11.0 - 15.0 PLT 222 x 1000/mm3 140 - 390 NEUT % 58.0 % 40 - 79 • APS: routine follow-up for LYMPH % 29.5 % 15 - 45 diabetes, no complications, MONO % 7.0 % 0 - 11 EOS % 5.2 % 0 - 6 CBC done as routine test BASO % 0.3 % 0 - 3 NEUT, # 4.4 x103 uL 1.8 - 8.7 LYMPH, # 2.2 x103 uL 0.7 - 5.0 MONO, # 0.5 x103 uL 0.0 - 1.2 EOS, # 0.4 x103 uL 0.0 - 0.7 BASO, # 0 x103 uL 0.0 - 0.3

For Financial Professional Use Only 27 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 Iron-poor RBCs are pale and small (low MCV and MCH) active bleeding • Hemoglobin improved with administration of iron

For Financial Professional Use Only 28 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 29 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 30 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 31 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 32 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 33 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 34 Case # 3

TEST RESULT UNITS REF RANGE • 47 yo female applying for $1.5 million term WBC 4.7 x 109/L 4.4 - 11.3

12 • Paramedical exam: all RBC 5.6 x 10 /L 4.7 - 6.1 questions answered “no” HGB 10.5 L g/dL 12.3 - 15.3 • Insurance labs normal HCT 31.6 L % 35.9 - 44.6 • Medical records: routine MCV 65.8 L fL 80 - 96 gynecologic visits, CBC done MCH 19.9 L pg 27.5 - 33.2

as part of routine exam last MCHC 26.7 L % 33.4 - 35.5 year RDW 13.0 % 11.5 - 14.5

PLT 249 x 109/L 100 - 450

For Financial Professional Use Only 35 Underwriting Tip: Identifying β-thalassemia minor

Beta-Thalassemia Minor Iron Deficiency Anemia

• RBC count normal or high- • RBC count low-normal or low, normal, usually over 5 almost always less than 5

• Violates “Rule of 3s” • Usually follows “Rule of 3s” (hemoglobin is less than 3 times (hemoglobin is roughly 3 times the the RBC count) RBC count)

• MCV usually quite low (60-70) • MCV doesn’t become that low even when anemia is mild unless anemia is quite severe

• RDW is usually normal or low • RDW is often high

For Financial Professional Use Only 36 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,For Financial severe Professional anemia, Use Only stroke or heart attack 37 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 38 White Blood Count with Differential

TEST RESULT UNITS REF RANGE WBC 5.2 x 1000/mm3 3.9 - 11.1 RBC 3.81 L x 106/mm3 4.20 - 5.70 HGB 14.5 g/dL 13.2 - 16.9 HCT 41.2 % 38.5 - 49.0 MCV 98 H fl 80 - 97 MCH 33.7 H pg 5.2 27.5x 1000 - 33.5 = 5200 MCHC 35.3 % 32.0 - 36.0 RDW 11.8 % 5200 11.0 x - .40115.0 = 2085 PLT 172 x 1000/mm3 140 - 390 MPV 7.6 fl 7.5 - 11.5 NEUT % 40.1 % 38.0 - 80.0 LYMPH % 46.1 % 15.0 - 49.0 MONO % 12.9 % 0.0 - 13.0 EOS % 0.6 % 0.0 - 8.0 BASO % 0.3 % 0.0 - 2.0 NEUT, ABS 2085 cells/mm3 1650 - 8000 LYMPH, ABS 2397 cells/mm3 1000 - 3500 MONO, ABS 671 cells/mm3 40 - 900 EOS, ABS 31 cells/mm3 30 - 600 BASO, ABS 16 cells/mm3 0 - 125 For Financial Professional Use Only 40 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 41 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 42 WBC Differential: Neutrophils

Possible Causes of Possible Causes of Neutrophilia: Neutropenia:

Common: chronic benign Common: bacterial infections, neutropenia (some forms are inflammatory disorders, stress, familial), chemotherapy certain drugs (especially prednisone), pregnancy Uncommon: systemic lupus erythematosus, immunodeficiency Rare: leukemias states

For Financial Professional Use Only 43 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 44 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 45 Case # 4

TEST RESULT UNITS REF RANGE • 44 yo male applying for WBC 2.8 L x 1000/mm3 3.9 - 11.1 RBC 5.02 x 106/mm3 4.20 - 5.70 $2,000,000 whole life HGB 14.9 g/dL 13.2 - 16.9 HCT 45.2 % 38.5 - 49.0 • Paramedical exam: rotator cuff MCV 95 fl 80 - 97 MCH 34.0 H pg 27.5 - 33.5 injury to right shoulder, getting MCHC 35.1 % 32.0 - 36.0 physical therapy, elevated RDW 13.8 % 11.0 - 15.0 cholesterol on Lipitor PLT 212 x 1000/mm3 140 - 390 NEUT % 50.2 % 38.0 - 80.0 LYMPH % 36.0 % 15.0 - 49.0 • Insurance labs are normal MONO % 13.3 % 0.0 - 13.0 • Medical records only included EOS % 0.3 % 0.0 - 8.0 labs, no office notes. BASO % 0.2 % 0.0 - 2.0 Total WBC x % Neutrophils = ANC 2800 x 50.2% = 1406 For Financial Professional Use Only 46 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 47 WBC Differential: Lymphocytes

Possible Causes of Possible Causes of Lymphocytosis: Lymphopenia:

Common: viral infections Uncommon: systemic lupus Uncommon: inflammatory bowel erythematosus, immunodeficiency disease states Rare: chronic lymphocytic Rare: aplastic anemia, Hodgkin’s leukemia, vasculitis disease For Financial Professional Use Only 48 WBC Differential: Monocytes

Possible Causes of Decreased Levels: Monocytosis: Common: recovery phase after infections Uncommon: certain infections (TB, malaria), inflammatory bowel disease - - - Rare: myeloproliferative disorders including myeloid metaplasia, polycythemia vera, certain forms of leukemia and lymphoma

For Financial Professional Use Only 49 WBC Differential: Eosinophils

Possible Causes of Decreased Levels: Eosinophilia:

Common: allergic disorders (including drug reactions) Uncommon: parasite infection, lupus, rheumatoid arthritis - - - Rare: hypereosinophilic syndrome, diffuse skin diseases, some forms of leukemia and lymphoma, Löffler’s endocarditis

For Financial Professional Use Only 50 Case # 5

TEST RESULT UNITS REF RANGE • 45 yo female applying for $1 WBC 8.2 x 1000/mm3 3.9 - 11.1 million term RBC 4.5 x 106/mm3 4.2 - 5.7 HGB 13.0 g/dL 12.0 - 16.0 • Paramedical exam: asthma, HCT 40.5 % 36.0 - 46.0 usually well-controlled with MCV 94 fl 80 - 97 inhalers MCH 28.0 pg 27.5 - 33.5 MCHC 34.0 % 32.0 - 36.0 • Insurance labs: normal RDW 13.4 % 11.0 - 15.0 PLT 372 x 1000/mm3 140 - 390 • Medical records: records from NEUT % 45.1 % 38.0 - 80.0 primary care physician confirm LYMPH % 37.6 % 15.0 - 49.0 that asthma is generally well- MONO % 5.3 % 0.0 - 13.0 controlled, although she did EOS % 12.0 H % 0.0 - 8.0 BASO % 0.0 % 0.0 - 2.0 require short-term prednisone in NEUT, ABS 3698 cells/mm3 1650 - 8000 2007. Also followed by a LYMPH, 3083 cells/mm3 1000 - 3500 dermatologist for atopic ABS dermatitis. Records include CBC MONO, ABS 435 cells/mm3 40 - 900 3 from 9/08. EOS, ABS 984 H cells/mm 30 - 600 BASO, ABS 0 cells/mm3 0 - 125

For Financial Professional Use Only 51 Case # 6

TEST RESULT UNITS REF RANGE • 45 yo male applying for $1 million WBC 9.2 x 1000/mm3 3.9 - 11.1 term RBC 4.2 x 106/mm3 4.20 - 5.70 HGB 13.3 g/dL 13.2 - 16.9 • Paramedical exam: has seen HCT 40.2 % 38.5 - 49.0 personal physician for cold and MCV 96 fl 80 - 97 cough, last visit 1 month ago MCH 32.0 pg 27.5 - 33.5 MCHC 35.3 % 32.0 - 36.0 • Insurance labs: normal RDW 11.8 % 11.0 - 15.0 • Medical records: seen in January, PLT 390 x 1000/mm3 140 - 390 March, and August of this year NEUT % 40.1 % 38.0 - 80.0 complaining of non-productive cough LYMPH % 29.5 % 15.0 - 49.0 since December 2008. Chest x-ray MONO % 9.5 % 0.0 - 13.0 showed questionable vague infiltrates EOS % 20.1 H % 0.0 - 8.0 in both lung bases. Did not improve BASO % 0.9 % 0.0 - 2.0 with 2 courses of antibiotics or NEUT, ABS 3689 cells/mm3 1650 - 8000 therapeutic trial of asthma inhalers. LYMPH, 2714 cells/mm3 1000 - 3500 ABS Upper GI series and upper endoscopy MONO, ABS 874 cells/mm3 40 - 900 showed no evidence of GERD. On EOS, ABS 1850 H cells/mm3 30 - 600 August visit, also noted fatigue and BASO, ABS 83 cells/mm3 0 - 125 diarrhea. For Financial Professional Use Only 52 WBC Differential: Basophils

Possible Causes of Basophilia: Decreased Levels:

Rare: leukemias, myeloid - - - metaplasia, Hodgkin’s disease

For Financial Professional Use Only 53 Platelet Count

• “Young” platelets, recently released from the bone marrow, are typically slightly larger • Often elevated in immune or idiopathic thrombocytopenic purpura (ITP) • In an individual with low platelet count (thrombocytopenia): – Increased MPV indicates normal bone marrow response – Decreased or low normal MPV may indicate impaired bone marrow response

For Financial Professional Use Only 55 Selected Causes of Abnormal Platelet Counts

Possible Causes of Possible Causes of Thrombocytosis: Thrombocytopenia: Common: “Reactive” thrombocytosis related to acute trauma, surgery, Common: spurious lab result blood loss, iron deficiency, chronic caused by platelet clumping, infections (osteomyelitis), idiopathic or immune-mediated inflammatory diseases including thrombocytopenia (ITP), rheumatoid arthritis and ulcerative medications, viral infection colitis, splenectomy Uncommon: hemolytic-uremic Uncommon: polycythemia vera, syndrome, leukemia, sepsis, essential thrombocytosis (plt count hypersplenism over 600,000), some cancers

For Financial Professional Use Only 56 Case # 7

• 28 yo female applying for TEST RESULT UNITS REF RANGE $100,000 term WBC 10.9 x 1000/mm3 3.9 - 11.1 RBC 4.4 x 106/mm3 4.20 - 5.70 • Paramedical exam: car HGB 13.5 g/dL 13.2 - 16.9 accident 3 months ago HCT 41.3 % 38.5 - 49.0 MCV 96 fl 80 - 97 • Insurance labs: normal MCH 33.6 H pg 27.5 - 33.5 MCHC 34.9 % 32.0 - 36.0 RDW 11.8 % 11.0 - 15.0 • Medical records: MVA 3 PLT 481 H x 1000/mm3 140 - 390 months ago with airbag MPV 11.3 fl 7.5 - 11.5 deployment, two broken ribs and fractured foot.

For Financial Professional Use Only 57 Idiopathic Thrombocytopenic Purpura (ITP)

• Although there are many causes of low platelet counts, including medications, infections, and hypersplenism, the term “ITP” is reserved for the autoimmune destruction of platelets; “Immune thrombocytopenic purpura” • Immune system attacks and destroys platelets faster than they can be produced; red rash (purpura) and bleeding • Some cases will remit with this alone and never recur • If more severe, can usually be cured with splenectomy, but some will still have low platelets after splenectomy • Prognosis depends on the current platelet count and the mode of treatment • Mortality Concerns – Fatalities may occur due to severe bleeding or due to overwhelming infection after splenectomy

For Financial Professional Use Only 58 Bone Marrow Disorders • All formed elements of the blood are made primarily in the bone marrow • There is particular concern if all 3 cell lines are abnormal (RBCs, WBCs, and platelets), especially if: – the applicant is over age 50 and/or – there is an increased percentage of monocytes • This suggests the possibility of diseases involving the bone marrow, and many of these diseases have very significant mortality concerns. • Aplastic Anemia: diminished-absent precursor cells (pancytopenia) • Myeloproliferative disorders: bone marrow cells grow too rapidly with over-production of blood cells and/or platelets – If this acceleration continues it may transform into cancer (usually leukemia) – Myeloproliferative disorders include: • Essential thrombocytosis • Polycythemia vera • Myelofibrosis (possible pancytopenia) • Myelodysplastic syndromes: ineffective blood cell production (pancytopenia)

For Financial Professional Use Only 59 Aplastic Anemia

• A disorder where the bone marrow stops producing blood cells (pancytopenia - all lines – RBC, WBC and platelets) • Can be congenital (Fanconi anemia), or acquired • Acquired form brought on by certain infections or drugs • Prognosis depends on severity – most cases pose a very high mortality risk unless spontaneously remitted long ago • Mortality Concerns: – The aplastic crisis may result in death due to infection, bleeding, or severe anemia – Complications of bone marrow transplant (graft vs. host disease) For Financial Professional Use Only 60 Essential Thrombocytosis (ET)

• Also called essential thrombocythemia • Megakaryocytes in the bone marrow produce too many platelets, which may be misshapen or may function poorly • They may become so numerous as to cause clotting (risk of stroke) • Platelet count at least 600k up to 1.5 million per mm3 • Prognosis depends on frequency of bleeding/clotting complications • Also, increased risk for developing leukemia, especially chronic myelogenous leukemia (CML)

For Financial Professional Use Only 61 Polycythemia (rubra) vera

• Red cell progenitors start to lose control over their growth • Can be treated with phlebotomy (removing blood) or marrow-suppressing medications • Mortality Concerns –Fatalities can occur due to clotting, or due to malignant transformation

For Financial Professional Use Only 62 Myelofibrosis

• A condition where the bone marrow becomes fibrotic (scarred) • Can cause low counts of all cell lines (pancytopenia) • Spleen and liver may become enlarged as they begin to serve as back-up producers of formed elements (extramedullary hematopoesis) • Mortality Concerns: Decreasing counts of all formed elements may lead to death from infection, severe anemia, or bleeding

For Financial Professional Use Only 63 Myelodysplasia

• A bone marrow disorder of older individuals, where there is ineffective production of red blood cells, eventually may also involve the WBC and platelet lines (pancytopenia) • Can be a precursor to leukemia • Several subtypes, e.g., refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) • Treatment is supportive – transfusions and antibiotics • Prognosis is generally poor • Mortality Concerns: malignant transformation, severe anemia, infection, or bleeding

For Financial Professional Use Only 64 Case # 8

76 yo male applying for $2 million UL • MD exam: type 2 diabetes, on Avandia • Insurance labs: glucose 118, hemoglobin A1c 7.9% • Medical records: mild anemia, normal iron studies, B12 and folate levels normal, no history of alcohol excess TEST 7/08 RESULT 1/10 RESULT 8/10 RESULT UNITS REF RANGE WBC 7.0 5.4 4.7 L K/µL 4.8 - 10.8 RBC 4.37 L 3.97 L 3.82 L x 106/mm3 4.40 - 5.70 HGB 13.7 L 11.8 L 11.5 L g/dL 14.0 - 18.0 HCT 42.1 35.4 L 34.4 L % 42.0 - 52.0 MCV 96.9 101.2 H 102.2 H fl 80 - 97 MCH 33.0 33.6 H 33.1 pg 27.5 - 33.5 MCHC 33.2 33.0 32.9 % 32.0 - 36.0 RDW 13.8 14.9 14.3 % 11.0 - 15.0 PLT 241 199 129 L K/µL 140 - 390 MPV 8.9 9.0 8.3 L fl 8.6 - 11.7 NEUT % 55.0 61.0 55.6 % 30.0 - 75.0 LYMPH % 34.8 27.7 31.7 % 10.0 - 50.0 MONO % 7.2 9.2 11.2 H % 2.0 - 10.0 EOS % 2.5 1.6 1.1 % 0.0 - 6.0 BASO % 0.5 For0.5 Financial Professional 0.4 Use Only % 0.0 - 2.0 65 Case # 8: CBCs dated 7/08, 1/10, 8/10

TEST 7/08 RESULT 1/10 RESULT 8/10 RESULT UNITS REF RANGE WBC 7.0 5.4 4.7 L K/µL 4.8 - 10.8 RBC 4.37 L 3.97 L 3.82 L x 106/mm3 4.40 - 5.70 HGB 13.7 L 11.8 L 11.5 L g/dL 14.0 - 18.0 HCT 42.1 35.4 L 34.4 L % 42.0 - 52.0 MCV 96.9 101.2 H 102.2 H fl 80 - 97 MCH 33.0 33.6 H 33.1 pg 27.5 - 33.5 MCHC 33.2 33.0 32.9 % 32.0 - 36.0 RDW 13.8 14.9 14.3 % 11.0 - 15.0 PLT 241 199 129 L K/µL 140 - 390 MPV 8.9 9.0 8.3 L fl 8.6 - 11.7 NEUT % 55.0 61.0 55.6 % 30.0 - 75.0 LYMPH % 34.8 27.7 31.7 % 10.0 - 50.0 MONO % 7.2 9.2 11.2 H % 2.0 - 10.0 EOS % 2.5 1.6 1.1 % 0.0 - 6.0 BASO % 0.5 0.5 0.4 % 0.0 - 2.0

For Financial Professional Use Only 66 Q&A

For Financial Professional Use Only 67 Life insurance products are issued by MetLife Investors USA Insurance Company, Metropolitan Life Insurance Company and in New York only, by First MetLife Investors Insurance Company. All guarantees are based on the claims-paying ability and financial strength of the issuing insurance company. Variable products are distributed by MetLife Investors Distribution Company (MetLife Investors), Irvine, CA. September 2012

L0911208105[exp0912][All States][DC,GU,MP,PR,VI]

For Financial Professional Use Only 68