HEME-ONC STEP 3 REVIEWBy James K. Rustad, M.D.

Copyright © 2009 All Rights Reserved

OUTLINE Anemia Iron Deficiency Anemia Beta and Alpha

Thalassemia Vitamin B12 deficiency

and Schilling test Hemolytic Anemia

(Autoimmune, Hereditary Spherocytosis, Drug-Induced, and Microangiopathic)

G6PD Deficiency Sickle cell Anemia

Blood Transfusion Reactions

Neutropenia ITP Heparin Induced

Thrombocytopenia Coagulation tree,

abnormalities, and testing

Oncology: Leukemias and Lymphomas

Multiple Myeloma

ANEMIA

ANEMIA

What to do? Check CBC and Retic Count If Retic index > 2.5 OR Absolute retic count >

75000 ----- likely Hemolysis or Hemorrhage

MEAN CORPUSCULAR VOLUME (MCV)

Measure of average RBC volume (size) Microcytic anemia < 80 (Iron Deficiency) Normocytic/Normochromic 80-95: chronic

disease, renal failure, hypothyroidism Macrocytic > 95 (B12, Folate deficiency).

Remember “hypersegmented (lobed) neutophils”

IRON DEFICIENCY ANEMIA VS. ACD

Lab Value IRON Deficiency Anemia of Chronic Disease

Iron Decreased Decreased

TIBC Increased Decreased

Ferritin Decreased Normal or Elevated

CLINICAL CASE SCENARIO

CBC suggests Microcytic Anemia (low MCV), Next step?

Iron Studies. If normal, what is next step? Hb electrophoresis. If normal, what is

diagnosis? Alpha-Thalassemia Trait, which is a

Diagnosis of Exclusion

CLINICAL NUGGETS OF KNOWLEDGE

Retic Count will increase one week after starting oral iron.

Take iron 2 hours before and 4 hours after calcium/antacids (decreases absorption).

If not tolerating Ferrous sulfate (abdominal cramps), switch to Ferrous gluconate.

BETA THALASSEMIA

Normal Minor Major

HbA 97-99% 90% 0-10%

HbA2 1-3% 4-8% 4-10%

HbF 0% 1-5% 90-96%

BETA THALASSEMIA MAJOR (COOLEY’S ANEMIA) Homozygous Severe anemia: patient

cannot survive without transfusion! To Diagnose?

Hb electrophoresis On Peripheral Smear: Target cells (also

present in sickle cell, S.C. disease)

Basophilic stippling (also present in alcohol abuse, lead poisoning)

BETA THALASSEMIA

Extramedullary and Intramedullary erythropoiesis

Chipmunk facies Hair on end

appearance in skull x-ray due to marrow expansion.

Treatment: Blood transfusion, allogenic bone marrow transplant.

ALPHA THALASSEMIA

There are four alpha globin genes.

One deleted: silent carrier, normal.

Two deleted: Thalassemia minor or Alpha Thalassemia Trait. Low Hct with very low MCV.

Three deleted: HbH disease. Severe hemolytic anemia, increased Retic count, Hb Electrophoresis shows HbH. Tx: repeated transfusion. Poor prognosis.

Four deleted: Hydrops Fetalis (Hb Electrophoresis shows Hb Bart): Death in utero.

SCHILLING TEST

To differentiate the cause of Vitamin B12 deficiency:

Decreased intake Decreased

production of intrinsic factor

Decreased absorption

Vitamin B12 IM to saturate plasma level then radio-labeled B12 administered orally.

ALGORITHM STEP ONE: 24 HOUR URINE TEST

If normal (7% of oral dose in urine), cause is decreased intake.

If abnormal, give Radio-labeled B12 and Intrinsic Factor.

ALGORITHM STEP TWO: RADIO-LABELED B12 AND IF

Normal: Intrinsic Factor Deficiency caused by Pernicious anemia or Gastrectomy

Abnormal: Cause is decreased absorption of B12 caused by Blind Loop syndrome, Crohn’s or Ileal Resection.

SUSPECTED BLIND LOOP SYNDROME

Treat with antibiotics and repeat testing. If normal: blind loop syndrome.

If still abnormal: caused by Crohn’s or ileal resection.

SCHILLING TEST ALGORITHM

NML:7% of

oral dose

in urine

24 hour urine

ABNL: Give B12

and IF

NML: I.F. DeficientPerniciousAnemia or

Gastrectomy

AABNL: Decreased absorption

If improved after ABX: Blind loop

syndrome.Otherwise: Crohn’s or ileal resection

HEMOLYTIC ANEMIA

Anemia and jaundice

Increased: retic index, LDH, indirect bilirubin

Decreased: haptoglobin

AUTOIMMUNE HEMOLYTIC ANEMIA

Warm antibody induced

Cold antibody induced

Antibody IgG against Rh antigen

IgM against I antigen

Causes Idiopathic, drug induced, lymphoma, leukemia

Idiopathic, mycoplasma, mono, Waldenstrom’s macroglobulinemia

Coomb’s Test + IgG or IgG and C3

- IgG Only C3 +

Cold agglutinin Negative Positive

Treatment Steroid, Splenectomy. If treatment refractory: immunosuppressive!Cyclophosphamide or Cyclosporin.

No Steroid or Splenectomy. Immunosuppressive treatment!! Cyclophosphamide or Chlorambucil.

INCREASED MHC AND SPHEROCYTES MHC: Mean corpuscular

hemoglobin Two causes: Autoimmune hemolytic

anemia (Coombs test positive)

Hereditary Spherocytosis (Coombs test negative)

Spherocytes are hyperchromic; they have no area of central pallor (normal red blood cells do!)

CLINICAL SCENARIO Child with anemia,

icterus, jaundice and splenomegaly on exam.

Spherocytes in peripheral smear.

Retic count and MCHC increased.

Coombs test negative.

Most likely diagnosis? Hereditary

spherocytosis!

HERIDITARY SPHEROCYTOSIS

Confirmatory test: Osmotic Fragility Test

Treatment: Splenectomy

You may also give Folic Acid.

DRUG INDUCED HEMOLYTIC ANEMIA

Alpha-Methyldopa Type

Penicillin Type

Quinidine Type

Direct Coomb’s

IgG+ C3+ IgG+ C3+ IgG negativeC3+

Indirect Coomb’s

Positive without adding Drug

Positive ONLY when adding drug

Positive ONLY when adding drug

CLINICAL CASE

30 year old pregnant patient with anemia. On Methyldopa for Hypertension and started

on Penicillin for recent UTI. On exam: pallor. Labs: increased retic count, increased LDH,

spherocytes present on smear. Direct Coombs + for IgG and C3.

Indirect Coombs positive ONLY when drug added.

Most likely cause of anemia? PENICILLIN

MICROANGIOPATHIC HEMOLYTIC ANEMIA

Fragmented RBC’s Schistocytes (black

arrows) Helmet cells (red

arrows) Causes: TTP HUS DIC Prosthetic Heart Valve HELLP syndrome in

pregnancy

THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP)

Microangiopathic hemolytic anemia

Neuro: change in mental status (confusion waxes and wanes in minutes)

May have renal insufficiency

PT, PTT normal Cause: unknown Treatment:

plasmapheresis

HEMOLYTIC UREMIC SYNDROME

Causes: unknown OR diarrhea with E. Coli O157: H7, Shigella, Salmonella.

G6PD DEFICIENCY X-linked recessive

(usually male) Usually in Black

Americans G6PD Deficiency can

cause hemolytic anemia.

Common precipitants include:

Infection Drugs such as Dapsone,

Quinine, Sulfonamide, Primaquin, Quinidine, Nitrofurantoin

Bite cells

SICKLE CELL ANEMIA

Valine replaces glutamic acid at position 6 of beta chain

Sickle Hb forms polymer when dehydrated Hb electrophoresis HbS positive RBC containing HbF does not sickle (fewer

crises) Chronic hemolysis: RUQ pain secondary to

calcium bilirubinate gallstone Spleen not palpable Poorly healing ulcers of the lower extremity

SICKLE CELL ANEMIA (SS) VS. SICKLE CELL TRAIT (SA)

Sickle cell anemia (SS): Sickle cell trait (SA)

HbS: 75%-95%HbF: 2%-20%HbA2: 2-4%

HbS: 40%HbA: 60%

Factors precipitating sickling: Hypoxia, dehydration, acidosis, hypothermia

Crisis only w/ severe hypoxia: Examples include mountaineering and skiing. Hematuria more frequent than in SS.

CLINICAL CASE

Patient with sickle cell anemia complains of SOB, weakness. CBC shows hemoglobin of 5 (baseline 9-10)

Next study? Retic count to differentiate between

Hemolytic Crisis (Retic count high) secondary to splenic sequestration or co-existent G6PD deficiency vs. Aplastic crisis (Retic count low).

Treatment of sequestration is splenectomy. On exam of patient with splenic

sequestration: spleen palpable whereas it was not palpable on prior exams.

CLINICAL CASE

Patient with sickle cell complains of weakness.

Hematocrit 20 and low Retic index at 0.8. History of febrile illness and skin rash one

week ago. Most likely diagnosis? Aplastic crisis secondary to PARVOVIRUS.

CLINICAL CASE

Patient with sickle cell comes to ER with cough and chest pain worse on inspiration and lying down.

CXR shows infiltration and patient started on IV fluids and antibiotics.

In 48 hours NO clinical improvement, severe chest pain continues. Diagnosis and next step in management?

Acute Chest Pain Syndrome; arrange for Exchange Transfusion

BLOOD TRANSFUSION REACTIONSClinical Case Scenarios

CLINICAL CASE SCENARIO

Patient with anemia receives blood transfusion and develops chills/fever/chest and flank pain. Most likely diagnosis?

ABO incompatibility Treatment: Stop

transfusion and start IV hydration to prevent Acute Tubular Necrosis!

CASE SCENARIO Patient underwent

complete compatibility testing, receives blood transfusion and four hours later develops fever, chills. What happened?

Leukoagglutinin reaction (not secondary to hemolysis).

Treatment? Acetaminophen and

Diphenhydramine

CASE SCENARIO

Patient with lymphoma (immuno-compromised) needs blood transfusion. What to do?

Transfuse GAMMA Radiated Blood to prevent Graft vs. Host Disease.

CASE SCENARIO

History of Febrile Reaction with Blood Transfusion. Needs to be transfused again --- what to do?

Leukocyte depletion filter.

CASE SCENARIO

A blood transfusion leads to hives and bronchospasm caused by plasma proteins. If another transfusion is necessary, what is the next step?

Transfuse WASHED (“like the laundry”) packed RBC’s!

NEUTROPENIA18 y.o. black male, WBC

2000, Polymorphs

38%, asymptomatic

Repeat CBC in 3-4

weeks, if WBC same = Benign

neutropenia with no risk

infection

If after 3-4 weeks, WBC increased,

repeat again in 3-4 weeks. If WBC goes

down, Cyclic Neutropenia. Increased risk of

infection and treat with Granulocyte

Macrophage Colony Stimulating Factor!

IDIOPATHIC THROMBOCYTOPENIA (ITP)

Case: Young Female Patient with Platelets 8000. Started on Prednisone 40 mg. After 4 weeks, platelet count 150,000. When Prednisone tapered to 20 mg, platelet count drops below 20,000. Next step?

Plan for Splenectomy as patient needs high dose Prednisone to maintain platelet counts.

HEPARIN INDUCED THROMBOCYTOPENIA (HIT)

Type I usually mild and self limited; Type II (immune) is of clinical concern.

Type II occurs 5-15 days after starting therapy.

Increased risk of Thrombosis due to heparin induced platelet aggregation.

HIT II DIAGNOSIS

Diagnosis: 14C serotonin release assay; antiheparin/platelet factor 4 antibody.

Treatment: Stop all forms of heparin even the flush for the IV line.

HIT II TREATMENT

If anticoagulation needed use Danaproid, Lepirudin, Hirudin, or Argatroban. These have no Antidote!

Remember, “if you’ve got the poison (Heparin), then I’ve got the remedy (Protamine sulfate).”

CLINICAL CASE Patient in hospital

received heparin for DVT prophylaxis. Returned home and then after one week came back to ER in severe abdominal pain; on exam abdomen mildly tender in peri-umbilical area (subjective greater than objective pain).

Labs: WBC count and Lactic Acid high, Platelets law.

Most likely diagnosis?

Acute Mesenteric Ischemia secondary to HIT II.

COAGULATION TREE Coagulation Abnormalities and Testing

COAGULATION CASCADE

Intrinsic (PTT)

12

11

9

8

Factor 10 (changes Prothrombin to

Thrombin)

Extrinsic (PT)

TF

7

COAGULATION CASCADE (CONTINUED)

Fibrinogen to Fibrin

Monomer via

Thrombin

Monomer to Polymer

Polymer to Cross linked

fibrin via Factor 13

VON WILLENBRAND’S DISEASE

Deficiency of vWF Most common

inherited bleeding disorder. Autosomal dominant.

Functions: Bridge for platelet adhesion and aggregation. Carrier for factor 8 (increases half life by five-fold).

Prolonged bleeding time despite normal platelet count.

Treatment? Desmopressin in

mild bleeding. Factor 8 concentrate

for severe bleeding or prior to surgery or if patient is still bleeding after desmopressin.

COAGULATION TESTS

Prolonged PTT and Normal PT

No bleeding: Factor 12 deficienc

y

Mild or rare bleeding: Factor 11 deficiency

Frequent and severe bleeding:

Factor 9 or 8 deficiency!!

HEMOPHILIA A VS. HEMOPHILIA B

Hemophilia A Hemophilia B

Affects only male Affects only male

Low factor 8 coagulation activity

Low factor 9 coagulant activity

Prolonged PTT (normal PTT on mixing study), normal PT

Prolonged PTT (normal PTT on mixing study), normal PT

Family history Family history

Spontaneous bleeding in the joints

Spontaneous bleeding in the joints

Treatment: Factor 8 concentrate

Treatment: Factor 9 concentrate

Normal Factor 8 antigen

COAGULATION TESTS

Prolonged PT, normal

PTT

Primary Factor 7 deficienc

y

Early Vitamin K deficiency (Vit K

dependent 2,7,9,10) due to

diet, broad spectrum ABX which kill gut

bacteria

Coumadin

COAGULATION TESTING

Both PTT and PT prolonged? Defect in common pathway DIC, Liver Disease, Vitamin K deficiency

MIXING STUDIES

Patient bleeding with platelets, PT,

bleeding time normal but PTT

elevated

Mixing Study with normal plasma: PTT

normal.

Factor 8 or 9 level

(deficiency?)

Tx: FFP

Mixing Study: PTT not corrected due to Lupus anticoagulant (not bleeding in

Lupus: hypercoagulable

state)

Mixing Study: PTT

not corrected

due to circulating anticoagulant Factor 8 antibody

(bleeding)

Patient with history of recurrent abortion

and stroke, increased PTT

CLINICAL CASE SCENARIO After a dental extraction,

patient develops severe bleeding. Normal platelets, bleeding time, PT, PTT. Most likely diagnosis?

Factor 13 deficiency (problem with forming cross-linked fibrin)

Diagnosis: Clot solubility in 5M urea

Treatment: FFP

ONCOLOGYLeukemia and Lymphoma

ACUTE LEUKEMIA In children: 80% acute leukemia: ALL In adults 80% acute leukemia: AML S/Sx: fatigue, gum bleeding, epistaxis, ecchymosis,

purpura, petechiae, bone pain, recurrent infection. On exam: hepatosplenomegaly, lymphadenopathy

non tender, firm, rubbery (especially ALL). Labs: decreased platelet, decreased RBC and Hb/Hct,

increased WBC with 90% blast cell in peripheral smear (patients have leukopenia but due to blast cells total count increases).

Bone marrow: hypercellular with > 30% blast cells

ACUTE LEUKEMIA

AML cells have granules, Auer Rods, histochemical stain suggests myeloid enzyme such as peroxidase.

Worst prognosis: Monosomy 5 and 7

Treatment: Cytarabine and Daunorubicin. After remission consider Bone Marrow Transplant.

ALL cells have surface marker TdT (terminal dexy nucleotidal transferase).

Worst prognosis: t (9:22) and t (4:11)

Treatment: Vincristine, Prednisone, Daunorubicin, L-Asperginase – after remission CNS prophylaxis with intrathecal Methotrexate and cranial irradiation; also consider Bone Marrow Transplant.

AML ALL

CHRONIC MYELOGENOUS LEUKEMIA

Hallmark: WBC > 100,000

Most cells mature (less than 5% blast cells)

Low leukocyte Alk. phos.

: fatigue, night sweats, low grade fever

On exam: splenomegaly, sternal tenderness

Drug of choice: Imatinib mesylate (inhibit tyrosine kinase activty of bcl/abl oncogene).

Bone marrow transplant (only curative treatment < 60 year old with HLA matched sibling).

CML (PHILADELPHIA CHROMOSOME)

Philadelphia chromosome negative CML has poorer prognosis than Philadelphia chromosome positive.

CHRONIC LYMPHOCYTIC LEUKEMIA

Hallmark: lymphocytosis

WBC usually greater than 20,000 (75-95% of cells are mature lymphocytes)

Usually CD19 is a marker of B and CD5 of T lymphocyte.

Usually patient will be >65 yr of age.

If Anemia + Thrombocytopenia: IV Fludrabine (IV), Chlorambucil. Refractory CLL: Alemtuzumab

HODGKIN’S LYMPHOMA

Commonly presents as painless cervical lymphadenopathy in young children.

To diagnose? Lymph node biopsy

“Reed-Sternberg” cells

HODGKIN’S LYMPHOMA

Most common: nodular sclerosing type.

Staging: I: one lymph node II: two or more lymph

nodes on one side of diaphragm

III: both sides of diaphragm

IV: disseminated disease

A: No constitutional symptoms

B: fever, night sweats

Treatment: IA and IIA: radiation.

Others: chemotherapy

ABVD: Adriamycin, Bleomycin, Vincristine, Dacarbazine

BURKITT’S LYMPHOMA B-cell lymphoma Translocation of

protooncogene C-myc from Chromosome 8 to 14

Presentation: abdominal pain/fullness

Retroperitoneal or pelvic lymphadenopathy

Treatment: low risk – chemotherapy and high risk – autologous stem cell transplant

Dx: lymph node biopsy (uniform small cells with scant cytoplasm), “starry sky”

MULTIPLE MYELOMA Age > 65 Anemia, bone pain,

renal failure, increased calcium, proteinuria

Plasma cell malignancy (paraproteins produced)

Dx: SPEP, UPEP Bence Jones protein in

urine Dipstick (detects

albumin, intact globulin) will be negative, urine protein quantitation will have proteinuria

Monoclonal spike in beta or gamma globulin region. IgG – 60%, IgA – 25%, light chain – 15%

Bone x-ray with lytic lesion Bone marrow infiltrated

with plasma cells Treatment: Combination

chemo with VAD (Vincristine, Adriamycin, Dexamethasone). If not tolerated: Thalidomide + Dexamethasone

< 70 yo: consider autologous stem cell transplant.

THANK YOU FOR YOUR ATTENTION

Questions?