Hematology Review 2009

Kim Auriemma, MSN, APRN-BC, AOCN Nurse Practitioner Georgia Cancer Specialists

Complete Blood Count

CBC or Hemogram: one of the most commonly ordered lab tests. It assesses: White blood cells (WBC) Red blood cells (RBC) Platelets (PLT) WBC Differential

The Complete Blood Cell Count

TABLE 1 The Complete Blood Cell Count
Parameter Hemoglobin Normal adult range Male: 14.0 17.4 mg/dL Female: 12.0 16.0 mg/dL Male: 42% 52% Female: 35% 48% Male: 4.5 5.5 x 106/L Female: 4.0 5.0 x 106/L 5.0 10.0 x 103/L Indications Low: Anemia High: Polycythemia Low: Anemia High: Polycythemia Low: Anemia High: Polycythemia Low: Leukopenia High: Leukocytosis Low: Thrombocytopenia High: Thrombocytosis Low in anemia: Low marrow output High: RBC loss

Hematocrit

RBC count

WBC count

Platelet count

140 400 x 103/L 0.5% 1.5% 25 85 x 103/L

Reticulocyte count

RBC, red blood cell; WBC, white blood cell. Data extracted from: Fischbach FT. A Manual of Laboratory and Diagnostic Tests. Philadelphia, Pa: Lippincott Williams & Wilkins; 2003:47.

Blood cells

Blood
Blood makes up about 7% of a bodys weight An average adult has 14-18 pints of blood Four main blood types: A, O, B, AB Rh positive or negative Universal Donor: OUniversal Recipient: AB +

Red Blood Cells

Red blood cells transport oxygen from the lungs to the organs and peripheral tissues, then return to the lungs carrying carbon dioxide to be exhaled. RBCs are pliable and designed to traverse the small capillary beds. RBCs contain the oxygen carrying protein Hemoglobin (HGB). Hematocrit measures the % of RBC mass in 100ml blood. Normal RBC life span = 120 days

Red Blood Cells

Reticulocytes: immature RBCs Number helps to determine causes of anemia. Normal retic count is 1.0-2.0% Low retic <1%= decreased marrow production of RBCs causing anemia Elevated Retic > 2% = indicates anemia caused by RBC loss

Normal RBC

Red Cell Morphology

TABLE 2 Red Cell Morphology
Possible findings Burr cells Spur cells Stomatocyte Spherocyte Schistocyte, helmet Elliptocyte, ovalocyte Teardrop cells Sickle cells Target cells Parasites Basophilic stippling Bite cells Significance Uremia, low potassium, artifact, stomach cancer, peptic ulcer disease Liver disease, abetalipoproteinemia Hereditary condition, alcoholic liver disease Hereditary condition, immune hemolytic anemia, water dilution, posttransfusion Thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, vasculitis, myelophthisic glomerulonephritis, prosthetic heart valve Hereditary, iron deficiency, megaloblastic anemias Iron deficiency, myelophthisic, megaloblastic anemias Sickle cell disease Postsplenectomy thalassemia, hemoglobinopathy Malaria, babesiosis Thalassemia, lead toxicity G6PD deficiency

G6PD, glucose-6-phosphate dehydrogenase. Data extracted from: Fischbach FT. A Manual of Laboratory and Diagnostic Tests. Philadelphia, Pa: Lippincott Williams & Wilkins; 2003:84-86.

Anemia of Decreased Marrow Production

When the marrow slows production due to insufficient erythropoietin (EPO), lack of other vital elements in RBC production including iron, folate, B12, or attack on the bone marrow by a virus, toxin or cancer. The mean corpuscular volume (MCV) is the most useful parameter to evaluate a low retic count anemia

Anemia
Microcytic anemias have low MCV (< 80) most common type of anemia encountered in primary care Differential diagnosis: Iron deficiency anemia, thalassemia, anemia of chronic disease/inflammation, sideroblastic anemia

Microcytic Anemia
TABLE 3 Laboratory Findings in Microcytic Anemias
Red cell morphology Serum iron level Decreased Total iron-binding capacity Increased Percent saturation Serum ferritin level

Iron deficiency anemia

Anemia of chronic inflammation Sideroblastic anemia Thalassemia

Microcytic, hypochromic
Normocytic, microcytic Microcytic, hypochromic Microcytic, target cells

< 16%

Decreased

Decreased

Decreased

10% 20%

Increased

Increased Normal or increased

Normal

50% 100% 30% 100%

Increased

Normal

Normal or increased

Data extracted from: Massey. Med Clin North Am. 19929; Adamson JW. Iron deficiency and other hypoproliferative anemias. In: Kasper DL, Braunwald E, Fauci A, et al, eds. Harrisons Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill Professional; 2004:660-666.

Iron Deficiency Anemia

Definition: anemia occurs when body iron stores are depleted by prolonged bleeding without replacement. Other causes can include inadequate iron stores due to poor dietary intake and or poor absorption or utilization Incidence: common, seen in up to 20% of women, 50% of pregnant women and 3% of men Lab findings: anemia, low retic, low MCV and low MCHC low ferritin, low % iron saturation, elevated TIBC, possible thrombocytosis Signs and Symptoms: fatigue, pallor, pica, blood loss Exam findings: pallor, pale conjunctiva, koilonychia, angular stomatitis, glossitis. More severe anemia may see tachycardia, tachypnea

Iron deficiency anemia

Management: first must identify etiology GI bleeding Menorrhagia Pregnancy Poor intake Lack of absorption

Iron deficiency anemia

Repletion of iron Oral Iron Ferrous Sulfate 320mg bid-tid (most common, GI side effects) Ferrous Gluconate 325 mg bid-tid(better tolerated) Niferex 150 mg qd Repliva 1 po qd (taken 21 of 28 days) Vitamin C aids absorption of iron. Milk/calcium products hamper absorption * Will need 3-6 months of oral iron to replete stores. If no response, or unable to tolerate or absorb, refer to hematology for intravenous iron therapy (Infed, Ferrlicit, Venofur)

Iron deficiency anemia

hypochromic

Hemolytic anemia
Hemolytic anemia occurs when the bone marrow is unable to make up for premature destruction of red blood cells by increasing their production. Hemolysis can be triggered by infection, medications, autoimmune responses, inherited disorders (hemoglobinopathies)

Treatment depends on cause

Folate (folic acid) is used in all hemolytic anemias to help stabilize the RBC membrane and decrease destruction

Hemolytic Anemia
Auto-immune hemolytic anemia - Cause is often unknown Signs and Symptoms: usually very acute and serious with sudden rapid drop in Hgb leading to fatigue, weakness, SOB. Patient is usually hospitalized Exam findings: pallor, tachycardia, tachypnea, jaundice, splenomegaly Labs: low Hgb/Hct, + direct Coombs, elevated bilirubin, elevated LDH, low serum haptoglobin, elevated retic count Diff Dx: anemia secondary to blood loss, hemoglobinopathy

Auto-Immune Hemolytic anemia

Treatment: Steroids, usually Prednisone at high dose (1mg/kg) to help suppress the immune system. Gradual taper over weeks to months. Splenectomy is often considered followed by other types of immune modulation if hemolysis is not improving. Blood transfusions can be used to off set severe anemia however there is increased risk for antibody development and reactions This can be a chronic relapsing disease

Hemoglobinopathies
Hemoglobinopathy: defined as a genetic defect that results in an abnormal structure of one or both of the globin chains of the hemoglobin molecule These disorders are hereditary and some such as sickle cell trait and G6PD deficiency once offered an evolutionary advantage over time by providing immunity to malaria There are hundreds of types of hemoglobinopathies and most are not clinically apparent

Thalassemia Syndromes
Definition: inherited genetic disorders that cause decreased production of normal Hgb A. Three types: Beta Thalassemia major Beta Thalassemia minor Alpha Thalassemia Incidence: In b thalassemia can be as high as 1 in 10 in certain Mediterranean populations. In the US approx 2 million people have some form of thalassemia trait or disease. Thalassemia is the most common genetic disorder worldwide.

 Thalassemia Major
Most severe form. Also known as Cooleys anemia. Lab findings: Hgb electropheresis would show increase in Hgb A2 and F with no normal Hgb A Signs and symptoms usually present in infants prior to 6 months of age including irritability, poor feeding, pallor Physical findings: severe anemia, jaundice and hepatosplenomegaly, as well as growth retardation Management includes life long chronic blood transfusions to replace abnormal Hgb with normal Hgb. Chronic transfusions lead to iron overload which must be removed from the body with chelation therapy (Desferol, Exjade) to avoid liver and heart failure.

 Thalassemia Minor
Definition: less severe form of thalassemia whereby pt does produce some normal Hgb A Labs: Hgb electropheresis shows decreased Hgb A and increased Hgb A2 and F. Peripheral smear often shows target cells and basophilic stippling. Iron studies are normal Signs and Symptoms are usually absent Physical exam: normal or may have splenomegaly Management: no specific therapy is required. Iron supplements are not recommended unless iron studies confirm iron deficiency with low ferritin

 Thalassemia
Definition: Genetic disorder of the A-globin chain. 4 loci of alpha globin and severity of disease depends on number of alpha globin chains genetically affected. Incidence: Most common thalassemia with highest incidence in those of Southeast Asian, Mediterranean and African decent. Labs: Microcytic RBC, with or without anemia. May have elevated RBC count. Hgb electropheresis may be normal Signs and Symptoms: none to mild symptoms of anemia including pallor, fatigue to most severe form causing fetus with hydrops fetalis and stillbirth.

 Thalassemia
Physical findings: none to more severe form of disorder causing splenomegaly to most severe form in which all 4 alpha globin chains are affected. This is not compatible with life

Management: most often there is no specific therapy. Genetic counseling recommended for families with history of thalassemias prior to pregnancy

RBC Target Cells

Target Cells

Sickle cell anemia

Sickle cell anemia genetic disorder whereby red blood cells in a stressful environment become abnormally shaped like a sickle and cause hemolysis, anemia and veno-occlusion. This leads to end-organ damage in the spleen, kidneys and liver. Incidence: More than 70,000 Americans have sickle cell disease. About 2 million Americans, 1 in 12 African Americans - have sickle cell trait Ethnic groups with sickle cell anemia are usually African descendants although those of Mediterranean decent can also be affected. Labs: CBC shows anemia, adult sickle cell anemia patients usually have elevated WBC and platelet count, elevated retic, elevated bilirubin, Hgb electropheresis shows abnormal Hgb SS (more severe disease) or Hgb SC or S-beta thalassemia

Sickle cell anemia

Signs and symptoms: anemia occurs as abnormal RBC have a shortened life span of only about 15 days compared to the usual 120 days. The RBCs are also fragile and lack flexibility leading to veno-occlusion and resulting pain crises, as well as risk for CVA and priapism. Sickle cell veno-occlusive crises can be triggered by infection, dehydration, temperature changes and other stressors to the body. Exam findings: scleral icteris, jaundice, splenomegaly in children (adults usually have either required splenectomy in childhood or have infarcted the spleen causing loss of spleneic function by adult age).

Sickle cell disease

Normal adult spleen is 11cm in craniocaudal length. This picture illustrates a spleen that has infarcted due to sickle cell disease and shrunk to 4.5cm in length. This spleen would not be functional.

Auto-splenectomy

Sickled red blood cells

Pathophysiology of sickle cell disease

Parasite

Sickle cell anemia

Diff Dx: other hemoglobinopathies Treatment: no cure for sickle cell disease other than allogeneic bone marrow transplant which carries significant risk for morbidity and mortality. Management of this chronic disease includes avoidance of known triggers of veno-occlusive crisis, daily folic acid. Analgesics for painful crisis patients are often hospitalized for pain crisis for IV narcotic analgesics, hydration with D5W (need free water), anti-inflammatories.

Sickle cell disease

Hydrea is sometimes used to treat sickle cell disease and decrease frequency of pain crises and hospitalizations in adult sickle cell patients. Thought to work by increasing fetal hgb and decreasing tendency for RBC to sickle. Vaccination with pneumococcal vaccine q5 years in adults is recommended since spleneic function is impaired. Blood transfusions with exchange transfusion is used in serious cases of acute chest syndrome or priapism and are also used in children with sickle cell disease as prophylaxis to reduce risk of CVA.

G6PD deficiency
Glucose-6-phosphate dehydrogenase deficiency a hereditary enzyme deficiency that leads to hemolysis when certain drugs are ingested that induce oxidant stress on RBCs. Incidence - Most common human enzyme deficiency affecting 400 million people worldwide. X-linked recessive disorder with more males affected than females. Occurs more often in blacks Signs and symptoms: none unless hemolysis occurs causing anemia with fatigue, SOB, dark urine

G6PD deficiency
Exam findings: none specific unless having active hemolysis Drugs to be avoided with G6PD def: Elitec (rasburicase), Methylene blue, Pyridium, Sulfacetamide, Sulfasalazine, Isobutyl nitrite, Nitrofuratoin, Primaquine, Sulfamethoxazole (Bactrim), Toluidine blue *G6PD deficient patient are also allergic to fava beans

G6PD deficiency
Labs: show evidence of hemolysis Elevated bilirubin levels Elevated serum LDH Low serum haptoglobin Hemoglobinuria Elevated retic count Low RBC count and hemoglobin Heinz bodies present on examination of the peripheral blood smear using special stains Methylene blue test Methemoglobin reduction test used for diagnosis

Anemia of Chronic Disease

Definition: anemia caused by inflammatory processes occurring due to long-standing infection, neoplastic disease and other inflammatory disorders including rheumatoid arthritis, SLE. These processes block iron transportation from storage sites to the bone marrow factory. Can also be associated with renal failure and decreased erythropoietin production

Incidence: second most common anemia behind iron deficiency anemia

Lab findings: CBC showing anemia, low or normal MCV, normal iron studies or low % iron saturation with normal to low TIBC, elevated CRP or sed rate, elevated BUN/creatinine

Anemia of Chronic Disease

Signs and Symptoms: fatigue, pallor or asymptomatic if patient has long standing history of RA, SLE, other inflammatory disease, chronic renal failure Physical findings: none specific

Management: Treat underlying disease

If unable to determine causative factor, refer to hematology for bone marrow biopsy

Sideroblastic Anemia
Definition: anemia characterized by ringed-sideroblasts. Caused by an enzyme disorder in which the body has adequate iron but is unable to incorporate it into hemoglobin. Iron enters the developing red blood cell where iron accumulates in the mitochondria giving a ringed appearance to the nucleus (ie: ringed sideroblast). Can be caused by genetic defect, toxin exposure or idiopathic. Lab findings: microcytic anemia, basophilic stippling on peripheral smear, usually normal iron studies. Bone marrow biopsy needed if this anemia is suspected based on presentation and peripheral smear. Check blood ETOH, lead levels

Sideroblastic anemia

Sideroblastic anemia
Signs and Symptoms: depend on cause. May have history of ETOH abuse, have altered mental status, abdominal pain or neuropathy, history of treatment for TB, fatigue, pallor, family history Physical findings: pallor, abnormal neuro exam with decreased sensory perception, tender abdomen, evidence of ETOH, enlarged spleen or liver, cardiac arrhythmia Management: refer to hematology for management. Sometimes treated as a Myelodysplastic syndrome with epo growth factors. May progress to aplastic anemia requiring bone marrow transplant

Macrocytic Anemias
Definition: macrocytosis or megaloblastic anemia is characterized by anemia with elevated MCV Incidence: fairly common, seen more in the elderly and those with history of GI pathology or surgeries Differential Dx:B12 deficiency, folate deficiency, history of GI disorder or surgery, chemotherapy, chronic alcoholism, hypothyroidism, liver disease (hepatitis), splenectomy (loss of filtration through spleen leads to larger RBCs)

Macrocytic RBC

B12 deficiency anemia

Definition: anemia caused by inadequate B12. Can be due to inadequate dietary intake in vegans or more commonly as a result of loss of intrinsic factor which leads to inability to absorb B12 (pernicious anemia) Lab findings: anemia on CBC, MCV elevated usually > 95. Normal or low serum B12 with elevated methylmalonic acid, normal or elevated homocysteine, anti-intrinsic factor antibodies

B12 deficiency
Signs and Symptoms: fatigue, pallor, neuropathy, dizziness, hair loss, memory loss/dementia in elderly, history including chronic gastritis, bariatric surgery, auto-immune disorder. Physical findings: pallor, tachycardia, abnormal sensory neuro exam, tachypnea Management: Cyanocobalamin 1000mcg IM weekly x 4 then monthly usually for life

B12 is poorly absorbed by the oral route

Folate Deficiency anemia

Definition: macrocytic anemia caused by lack of folic acid. Common in alcoholics Lab findings: CBC with anemia, macrocytic with MCV > 95. Elevated homocysteine with low or normal serum folate Signs and Symptoms: fatigue, pallor, unusual diet (no uncooked fruits and vegetables), alcoholism Physical exam: none specific Management: Folic Acid 1mg po qd Repeat homocysteine in 3 months and if remains elevated, may increase folic acid to 2mg daily. Treatment usually long term.

Increased marrow production

Elevated blood cells due to over production in the marrow. Can see overproduction of RBC, WBC, Platelets

Erythrocytosis
Definition: Over production of red blood cells in the bone marrow. Possible causes are: Polycythemia Vera (PV) myeloproliferative disorder which leads to over production of red blood cells (possibly also in WBC and Platelets) in the bone marrow. Incidence in the US: PV is relatively rare, occurring in 0.6-1.6 persons per million. Occurs more in men. Work up should be triggered for Hgb > 15 in women and > 17 in men

Polycythemia

Polycythemia Vera
Lab tests would include RBC mass, serum erythropoietin levels (usually decreased), ABG, bone marrow biopsy usually performed, JAK 2 mutation analysis (JAK genes play important role in hematopoesis) History and Exam findings: splenomegaly, red complexion (plethora), fatigue, headache, dizziness, assess for clotting Diff Dx: elevated RBC from smoking, chronic cardiac or lung disease, high altitude, dehydration Treatment therapeutic phlebotomy 500ml weekly until Hct < 45%, then usually maintenance phlebotomy every 1-3 months. May require replacement IV fluids to avoid hypotension

Secondary Erythrocytosis
Definition: elevated RBC count without other blood cell abnormality. Most common causes are smoking, dehydration and environment of chronic hypoxia Lab findings: Elevated RBC with otherwise normal WBC, platelet count. Bone marrow biopsy would show normal erythrocyte precursors, normal epo level Diagnosis is often one of exclusion if polycythemia is ruled out Signs and symptoms depending on cause. May have symptoms of chronic hypoxia, SOB, oxygen requirement, current tobacco use. High altitude living Management: treat underlying cause

Thrombocytosis
Definition: elevated platelet count > 500,000 Diff Dx includes: bone marrow myeloproliferative disorder as in essential thrombocythemia (ET) or secondary to iron deficiency, splenectomy, infection, malignancy or inflammatory disease Incidence: little data Lab findings: CBC showing elevated platelet count. Iron studies may show iron deficiency. JAK 2 mutation analysis can be helpful Signs and Symptoms: often asymptomatic and found on routine CBC. ET patient may experience headaches, TIAs

Thrombocytosis
Physical findings: eval for evidence of infection, lymphadenopathy, bleeding, thrombosis Bone marrow needed to evaluate for ET Usually referred to hematology for work up Management: treat underlying cause as applicable For ET: usually no treatment unless patient is symptomatic with headaches, TIAs, thrombosis. Treatment usually consists of Anagrelide and or Hydroxyurea. May consider at least ASA for asymptomatic patient with platelet count > 1 million.

Platelets

Thrombocytopenia
Definition: platelet count < 100,000. Differential Dx: bone marrow dysfunction, malignancy, auto-immune response, medication, chemotherapy, acute bleeding, acute thrombosis, DIC, HIT, lab error Incidence: ITP: 100 cases per million people per year with children accounting for half of those. Females more likely to be affected. Lab/diagnostic studies: check CBC for other cytopenias, HIT assay, platelet aggregation studies, anti-platelet antibodies, bleeding time, bone marrow biopsy would show elevated megakaryocytes (platelet precursors) in destruction problem however low megakaryocytes in bone marrow production disorder. Check DIC panel. Check cultures of blood, CSF if evidence of infection. Radiographic studies for evidence of DVT/PE. Spleneic ultrasound to eval for sequestration

Thrombocytopenia
Signs and symptoms: bruising, bleeding, infectious symptoms, abd pain, fever, recent history of heparin, medication use including recent chemo, thiazides, ethanol, estrogen, sulfonamides, quinine, quinidine, methyldopa, anti-epileptics Physical findings: ecchymoses, bleeding, splenomegaly with LUQ pain, SOB, hemoptysis (with PE), unilateral lower ext edema, + homans sign (with DVT), erythema, swelling or other evidence of infection, petechiae Management: depending on cause For ITP (idiopathic thrombocytopenia purpura) need to suppress immune system since this is an autoimmune response. Usually treat with Prednisone 1mg/kg qd until platelet count back to normal range then slowly taper. Often have relapse. Can also use IVIG, Monoclonal ab therapy with Rituxan. N-Plate

Thrombocytopenia
For HIT (heparin induced thrombocytopenia) must discontinue all Heparin use (considered Heparin allergic). This response causes patient to be hypercoagulable despite low platelet count so patient must be anti-coagulated with Refludan/Argatroban in hospital setting and then Warfarin as out patient for 3-6 months under care of hematologist For medication related drop discontinue offending medication and platelets should recover rapidly. May be an expected drop post chemotherapy if being treated for cancer For consumption from acute thrombosis, patient needs to be anti-coagulated and platelets should recover

Thrombocytopenia
Lab Error: can have platelet clumping due to EDTA tube this may cause platelet count to appear falsely low peripheral smear examination can confirm normal platelet count. Blood can be collected in NA citrate tube and re-run to confirm normal count For TTP (thrombotic thrombocytopenia purpura) this rare disorder of the anticoagulation system will cause patient to require plasmapheresis to remove inhibitors of VW factor. Give pt FFP (fresh frozen plasma) to replace normal VW factor. This is a rare but serious disease that requires care under hematologist. May see RBC schistocytes on smear

Bleeding Disorders
Hemophilia Definition: genetic disorder characterized by lack of blood clotting factors. Hemophilia A: lack of factor VIII (most common). Sex linked occurring in 1:10,000 males Hemophilia B: lack of factor IX (Christmas factor) occurring in 1:100,000 males Labs/diagnostic testing: diagnosed by checking factor activity levels, CBC, PT/PTT, bleeding time Signs and symptoms: easy bruising, prolonged bleeding, painful joints due to hemarthrosis. Older hemophiliacs likely to be infected with HIV due to receiving contaminated factor products

Hemophilia
Physical findings: Ecchymoses, bleeding, edematous painful joints Management: Patients with hemophilia require replacement of factor when bleeding occurs or sometimes daily based on severity of disease.

Bleeding Disorders
Von Willebrand disease (VWD) Definition: bleeding disorder caused by lack of Von Willebrand factor which interferes with platelet function thereby increasing risk for bleeding. Most forms of VWD are mild Incidence: most common blood clotting disorder occurring in 1 in 800-1000 people Labs: normal CBC, bleeding time (prolonged), Von Willebrand factor assay (reduced), platelet aggregation study (reduced), Ristocetin co-factor (reduced)

Von Willebrand Disease

Signs and symptoms: easy bruising, prolonged bleeding after surgery, dental procedure, menorrhagia, epistaxis Physical findings: may be normal or may see ecchymoses, petechiae, bleeding

Management: Desmopressin (DDAVP) nasal spray helps to increase factor VIII and VW factor in the blood Fresh frozen plasma/cryoprecipitate in acute bleeding or surgery

White blood cells

Definition: blood cells that fight infection. Produced in the bone marrow. Elevated = leukocytosis Decreased = leukopenia.

Leukopenia
Definition: total WBC < 4,300

Differential Dx: Infection including bacterial or viral, chemotherapy, other medications (anti-epileptics, penicillins, sulfonamides, cephalosporins, thiazides, cimetidine, ethanol, immunosuppressants), hematologic malignancy, aplastic anemia, hypersplenism, auto-immune disorders, Feltys syndrome. Low WBC can be normal in certain populations
Lab studies/diagnostic testing: CBC, differential, CMP, bone marrow biopsy

Leukopenia
Signs and Symptoms: maybe none, symptoms of infection, fever, lymphadenopathy, weight loss, night sweats. Check medications Physical findings: lymphadenopathy, splenomegaly, may be asymptomatic Management: determine underlying cause Blacks can have asymptomatic leukopenia as baseline

Leukocytosis
Definition: WBC > 10,800

Differential Dx: Infection, Chronic inflammation, Medications (steroids), Recovery post chemotherapy, WBC growth factors (Neupogen, Leukine, Neulasta) used in cancer therapies, hematologic malignancy (leukemia) or bone marrow dysfunction
Lab/diagnostic tests: CBC with diff, UA/cx if urinary symptoms, CXR if resp symptoms, blood cultures, LAP (leukocyte alkaline phosphotase elevated in leukomoid reaction, decreased in leukemias)

Leukocytosis
Signs and Symptoms: may be asymptomatic, fever, infectious symptoms, cough, SOB, dysuria, skin infection/abcess, rash, weight loss, fatigue, night sweats Physical findings: may be none. Erythema, edema, skin rash, lymphadenopathy, cachexia, hepatosplenomegaly, abnormal heart sounds, adventitious lung sounds Management: determine underlying cause. If unable to determine cause or if leukocytosis persists or is rising after treating for infection, hematology consult for bone marrow biopsy

Leukemia
Definition: hematologic malignancy of the bone marrow whereby abnormal immature cells crowd out normal cells. WBC can be elevated or decreased in leukemia. RBC and platelets can be normal or decreased Types of leukemia: most common Acute Myelogenous Leukemia Acute Lymphocytic Leukemia Chronic Myelogenous Leukemia Chronic Lymphocytic Leukemia

Acute Leukemia
Incidence: about 7000 cases per year in US. 80% are AML, 20% ALL Etiology is unknown for the most part. Risk factors include exposure to benzene, radiation exposure and prior treatment with cytotoxic chemotherapy Lab findings: CBC can show elevated, normal or low WBC count. Often see anemia at presentation as well as thrombocytopenia. Differential often shows circulating blasts (very immature WBCs). Elevated LDH usually seen. Bone marrow biopsy diagnostic Signs and Symptoms: pallor, fatigue, fever, anorexia, weight loss, weakness, palpitations, dyspnea on exertion, infection, rash, bleeding, bruising

Acute Leukemia
Physical findings: Ecchymoses, bleeding, pallor, tachycardia, tachypnea, hepatosplenomegaly, petechiae, scleral hemorrhage Management: Rapid recognition of symptoms as those of leukemia is crucial in acute leukemia as patients can decline rapidly and die from infectious complications or hemorrhage. Referral to hematologist for work up and chemotherapy

Acute Leukemia

Bone Marrow Biopsy

Chronic Leukemia
Definition: differs from acute leukemia in that symptoms have lasted more than 3 months. For CML, the natural history of the disease usually includes a chronic phase lasting 2-4 yrs. Accelerated phase can then occur leading to progressive leukocytosis, anemia and thrombocytopenia. Eventually a blast crisis may ensue in which the disease may behave more like AML requiring aggressive therapy and having a poor prognosis Incidence: 4000 cases in US per year for CML

Chronic Leukemia
Lab/diagnostic testing: CBC with diff shows elevated WBC often with basophilia. Anemia often present. Platelets may be normal or low. Usually no peripheral blasts. Marrow blasts elevated or normal. LDH increased. With very high WBC may see hyperkalemia and hypoglycemia. Ultrasound of spleen often done as well as CT scans to help differentiate between leukemia and lymphoma Signs and Symptoms: may be subtle easy fatigability, malaise, anorexia, abd discomfort and early satiety from enlarged spleen. Physical findings: may be none, or hepatosplenomegaly, pallor, ecchymoses Diagnosis made with bone marrow biopsy

Chronic Leukemia
Management: CLL: many times a watch and wait approach is taken and only treated if WBC doubling time is < 6m or pt becomes symptomatic with progressive abnormal blood counts. At that point chemotherapy would be offered, usually IV therapy depending on pts age and performance status CML: Most cases of CML have a genetic 9:22 translocation (termed Philadelphia Chromosome). This type of CML is treated at this time with an oral targeted chemotherapy agent called Gleevec taken daily. There are also new agents being studied for CML that work similar to Gleevec if Gleevec fails.

Lymphoma
Definition: Hematologic malignancy involving lymphadenopathy as well as possible bone marrow and other solid organ involvement. Types: Hodgkins Lymphoma and Non-Hodgkins Lymphoma (NHL) Incidence: About 8000 new cases of Hodgkins disease are diagnosed each year. Usually occurring in young adults. NHL has an incidence of up to 90,000 new cases per year Differential Dx: infections causing lymphadenopathy, cat scratch fever, viral infections (HIV), auto-immune disorders, endocrine disorders, sarcoidosis Lab/diagnostic testing: CBC with diff, CMP, LDH, Beta 2 microglobulin, lymph node biopsy, bone marrow biopsy, CXR, CT scans, PET scan

Lymphoma
Risk factors for development of lymphoma: EBV, HHV8, HTLV-1 viruses have a strong association with development of lymphoid tumors. h.Pylori is a risk factor for development of gastric MALT (mucosa associated lymphoid tissue) lymphoma. Inherited or acquired immunodeficiency disorders also predispose individuals to lymphoma. Increase incidence of NHL in farmers and meat workers. Increased Hodgkins disease in wood workers. Signs and symptoms: Painless adenopathy, fever, night sweats, weight loss, fatigue (B-symptoms) Physical findings: lymphadenopathy in one or more lymph node chains, hepatosplenomegaly, pallor

Lymphoma
Staging: based on number of lymph node chains involved and location above and or below diaphragm, bone marrow status, extra nodal sites of disease, absence or presence of B-symptoms Stages from IA-IVB

Histiologic subtypes also important in determining aggressiveness of disease which guides treatment plan offered to patient
Less aggressive NHL: follicular center cell More aggressive NHL: diffuse large cell

Lymphoma
Management: Based on stage, and subtype for Hodgkins disease usually IV chemotherapy +/- radiation therapy NHL treatment can range from watch and wait approach to very strong IV chemotherapy for the aggressive subtypes. Bone marrow transplant is sometimes needed if patient fails initial chemotherapy for aggressive NHL.

WBC Differential
Five subtypes of WBC noted in differential include: Neutrophils (segs + bands) AKA granulocytes these are immature WBC. Important in fighting bacterial infections. Elevated neutrophils can be caused by acute infection, chemotherapy, stress reaction, burns, tissue necrosis, chronic inflammatory disorders. Decreased neutrophils = neutropenia. Increased risk for infection if neutrophils < 1000. Severe risk for infection if < 500. Lymphocytes elevated or decreased levels can be caused by infection bacterial or viral, most common cause of increased level >10,000 is CLL. Lymphopenia can be caused by acute stressful illness (MI, pneumonia) as well as steroid therapy and lymphoma

WBC Differential
Monocytes increased in infection, granulomatous disease (sarcoid), collagen vascular disease. Decreased in acute stress reaction, pt on steroids, leukemia, chemo and immunosuppressant therapies Eosinophils Increased in allergic diseases, parasitic infections, collagen vascular diseases, from certain medications, leukemia. Decreased in acute stressful illness, steroids Basophils Increased in allergic diseases, CML, chronic inflammatory disorders.

WBC differential cells

Case Studies

Case Study #1
History 11 year old male. Presented in emergency room with recent onset of easy bruising, bleeding gums, and persistent epistaxis. Previously in excellent health. Mother stated he was "never sick before in his entire life." No history of recent viral infection, and no family history of bleeding disorders

Case Study #1
CBC (with microscopic differential) RBC 4.52 x 1012/L HGB 13.4 g/dL HCT 37.2 % MCV 82.3 fL MCH 29.6 pg MCHC 35.9 g/dL RDW 12.1 WBC 5.3 x 109/L N 44 % L 39 M 14 E 1 B 2 PLT <5 x 109/L MPV 10.9 fL

Case Study #1
Morphologic Alterations Results of the blood smear exam were: RBC morphology: Normocytic, normochromic WBC morphology: Within normal limits (one lymphocyte shown here) PLT morphology: Appear increased in size

Case Study #1
1 giant platelet seen

Case Study #1
Further Laboratory Studies Bone marrow biopsy: Aspirate: Erythrocyte and granulocyte maturation within normal limits. Megakaryocytes appear normal in number and morphology. Sections: Slightly hypocellular for his age, with abundant megakaryocytes. Coagulation: INR 0.91 (RI 0.85-1.15)PTT 24.8 sec (RI 23-34)TT 15.8 sec (RI 13-18)

Case Study #1
Physical Exam Bleeding from the left nostril. Numerous petechiae and purpura; mostly on the extremities. No organomegaly.

Case Study #1

What is the most likely diagnosis?

Case Study #1
Diagnosis Immune thrombocytopenic purpura (ITP)

Case Study #1
Clinical Course The patient was given standard therapy for ITP for more than a month, but failed to respond. His platelet counts did not improve and he continued to have severe nosebleeds. Because the patient's ITP was refractory to treatment, it was decided to perform a splenectomy. During the procedure, he received several units of platelets, and tolerated the surgery well. His platelet count gradually recovered; after six months it was 289 x 109/L. He is followed in Hematology Clinic, and continues to do well.

Case Study #2
33 year old female. Immigrated to the United States from Laos four years prior to admission. History obtained through an interpreter. Multiple transfusions and splenectomy two years prior to admission. Reason and/or diagnosis unclear to patient. Presented with flu-like symptoms of fever, malaise, epigastric discomfort and nonproductive cough.

Case Study #2
CBC
(with microscopic differential) RBC 4.15 x 10[12]/L HGB 8.1 g/dL HCT 28.6 % MCV 68.9 fL MCH 19.5 pg MCHC 28.2 g/dL RDW 22.3 WBC (corrected) 8.0 x 10[9]/L N 51 % L 36 M 7 E 4 B 2 NRBC/100 WBC 83 PLT 540 x

Case Study #2

Case Study #2
Morphologic Alterations Results of the blood smear exam were: RBC morphology: 3+ hypochromasia 1+ polychromasia 2+ anisocytosis 3+ target cells occ spherocytes and fragments Howell Jolly bodies present WBC morphology: Within normal limits PLT morphology: Within normal limits

Case Study #2
Hemoglobin electrophoresis: Hemoglobin E 80 % Hemoglobin F 5 % Other hemoglobins* 15 % *Identified as hemoglobin A2, hemoglobin Barts and a hemoglobin H mutant. Iron studies: Serum ferritin 3234 ng/mL (RI 12-86) Serum iron 140 g/dL (RI 65-175) TIBC 152 g/dL (RI 250-410) Saturation 92 % (RI 20-55)

Case Study #2
Diagnosis Homozygous hemoglobin E disease and alpha thalassemia Clinical course The patient's flu-like symptoms subsided; they were presumed to be viral in origin. She was referred to the Hematology Clinic, and placed on iron chelation therapy. After 18 months, her serum ferritin had fallen to 114 ng/mL. Her hemoglobin remained in the 7 to 9 g/dL range. Chelation was discontinued, with plans to monitor the ferritin level every six months and resume treatment when needed.

Case Study #3
History 39 year old female. History of fibrocystic breast disease. Seen for routine work-up prior to breast biopsy. Physical Exam Moderate splenomegaly. No other organomegaly.

Case Study #3
(with microscopic differential) RBC 4.28 x 10[12]/L HGB 13.4 g/dL HCT 41.2 % MCV 96.3 fL MCH 31.3 pg MCHC 32.5 g/dL WBC 133.6 x 10[9]/L N seg 56 % N band 15 N meta 13 N myelo 4 N pro 3 L 3 M 4 E 1 B 1 PLT 417 x 10[9]/L

CBC

Case Study #3

Case Study #3
Morphologic Alterations Results of the blood smear exam were: RBC morphology: Normocytic, normochromic WBC morphology: Mature stages and precursors all within normal morphologic limits PLT morphology: Within normal limits

Case Study #3
Bone marrow biopsy: Aspirate differential (1000 cells): Erythroblasts 9.9% Myeloblasts 1.1N promyelocytes 1.4N and precursors 71.7L 2.0M 2.8E and precursors 2.2B and precursors 8.9 Sections: Markedly hypercellular with increased megakaryocytes.

Case Study #3
Cytochemistry: Leukocyte alkaline phosphatase[LAP] score: 3 (RI 64-176) Cytogenetics: 46,XX,t(9;22)(q34;q11)[Philadelphia chromosome]seen in all marrow cells analyzed.

Case Study #3
Diagnosis: Chronic Myeloid Leukemia (CML)

Clinical Course Following the standard preparatory regimen, the patient received an allogeneic bone marrow transplant. The donor was her HLAmatched brother. Her post-transplant course went well, and 28 days later, her hemoglobin was 11.9 g/dL, WBC 2.0 x 10[9]/L, and PLT 84 x 10[9]/L. Her marrow showed evidence of good engraftment in all three cell lines. Cytogenetics showed 46,XY normal karyotype in all marrow cells analyzed. No 46,XX cells and no cells with a Philadelphia chromosome were seen. This patient continues to be followed in Hematology Clinic. At her last visit, ten years post-transplant, she was still doing well and had no evidence of recurrent disease. Molecular diagnostic studies performed at that time were negative for BCR-abl transcripts.

Case Study #4
18 year old male student from Nigeria. Came to the emergency room with symptoms of fever, shaking chills, nausea, and generalized malaise; occurring intermittently over the past five days. Physical Exam Fever of 103.3F. Tachycardia with a heart rate of 122. Otherwise within normal limits

Case Study #4
CBC (with microscopic differential) RBC 5.85 x 10[12]/L HGB 13.3 g/dL HCT 41.8 % MCV 71.5 fL MCH 22.7 pg MCHC 31.8 g/dL RDW 12.1 WBC 6.2 x 10[9]/L N 89 % L 8 M 2 E 1 B 0 PLT 102 x 10

Case Study #4

Case Study #4
Morphologic Alterations Results of the blood smear exam were: RBC morphology: Normochromic Numerous red cells contain intraerythrocytic organisms. Infected RBCs are enlarged; some are oval shaped, others appear somewhat "fimbriated." Doubly infected cells are present, and several morphologic stages can be found, including ring forms, mature schizonts, and gametocytes. WBC morphology: Within normal limits (one lymphocyte shown here)

Case Study #4
PLT morphology: normal RBC enzyme: G6PD (RI 4.6-13.5) 11.7 U/g Hgb

Case Study #4
Diagnosis - Malaria Upon further questioning, the patient stated that he had arrived in the United States from Nigeria approximately six months prior to this visit. Shortly after his arrival, he had experienced a similar illness that was diagnosed as malaria. Medication was prescribed, but once he felt better he did not continue to take it. Based on the blood smear morphology, the periodic pattern of his fever and chills, and his travel history, the causative organism was identified as Plasmodium ovale.

Case Study #4
Clinical Course The patient was hydrated with normal saline, and started on appropriate treatment for the erythrocytic stages of malaria. Several days later he began a second course of therapy to eliminate the exoerythrocytic (hepatic) forms of the organism. He completed the course of therapy, and on subsequent visits was asymptomatic. Note: On the basis of his low MCV, his relatively high RBC count, and his ethnic background, it is likely that this patient also has alpha thalassemia trait.

Case Study #5
History: 70 year old female. Symptoms of dyspnea on exertion, easy fatigability, and lassitude for past 2 to 3 months. Denied hemoptysis, GI, or vaginal bleeding. Claimed diet was good, but appetite varied. Physical Exam: Other than pallor, no significant physical findings were noted. Occult blood was negative.

Case Study #5
CBC (with microscopic differential)
RBC HGB HCT MCV MCH MCHC RDW WBC N L M E B PLT 3.71 x 10[12]/L 5.9 g/dL 20.9 % 56.2 fL 15.9 pg 28.3 g/dL 20.2 5.9 x 10[9]/L 82 % 13 1 4 0 383 x 10[9]/

Case Study #5

Case Study #5
Morphologic Alterations Results of the blood smear exam were: RBC morphology: 2+ hypochromasia 3+ microcytosis 2+ anisocytosis 2+ elliptocytes and target cells occ teardrops and fragments WBC morphology: Within normal limits (one lymphocyte shown here) PLT morphology: Within normal limits

Case Study #5
Iron studies were performed, and results were: serum ferritin <10 ng/mL (RI 12-86) serum iron 24 g/dL (RI 65-175) TIBC 729 g/dL (RI 250-410) saturation 3% (RI 20-55)

Case Study #5
Diagnosis Iron deficiency anemia Clinical Course Diagnostic procedures included upper GI endoscopy, colonoscopy, and small bowel biopsy. All were negative. The patient received packed RBC transfusions and was started on iron therapy. She refused any further laboratory testing or other procedures, and was discharged at her own request. She was lost to follow-up. The etiology of her iron deficiency anemia could not be determined, but it was most likely nutritional.

Case Study #6
History 75 year old male. Symptoms of severe headache and generalized pruritis. Physical Exam Spleen palpable 10 cm. below left costal margin. Liver palpable 3 cm. below right costal margin. The rest of the exam was within normal limits.

Case Study #6
CBC (with microscopic differential) RBC 7.70 x 10[12]/L HGB 17.3 g/dL HCT 54.3 % MCV 97.1 fL MCH 32.2 pg MCHC 33.2 g/dL RDW 16.4 WBC 18.3 x 10[9]/L N seg 79 % N myelocyte 5 % L 9 M 4 E 0 B 3 PLT 484 x 10

Case Study #6

Case Study #6
Morphologic Alterations Results of the blood smear exam were: RBC morphology: Essentially normocytic, normochromic WBC morphology: Within normal limits PLT morphology: Within normal limits

Case Study #6
Further Laboratory Studies Bone marrow biopsy: Aspirate differential: Within normal limits Sections: Markedly hypercellular for age. Cytogenetics: 46,XY. No numerical or structural chromosome abnormalities detected. Pulmonary function: Oxygen saturation: 97% (RI 94-100)

Case Study #6
Diagnosis Polycythemia vera Clinical Course The patient is being followed by his local physician, and treated with periodic phlebotomy.

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