Ye Seventeenth of JulyTwo Thousand and Fourteen

Vince Herrin

Hematology Board Review

A 45 year old woman presents with fatigue and nausea. She has occasional palpitations and SOB with minimal exertion. Her cardiac and pulmonary exams are normal but she has spooning of her nails.

Question #1

Which of the following should be true?

A) Low iron, low IBC, low ferritinB) Low iron, high IBC, high ferritinC) Low iron, low IBC, high ferritinD) Low iron, high IBC, low ferritin

#1

Your iron studies are nondiagnostic for a diagnosis of Iron deficiency. Which of the following would you order next?

a) Soluble transferrin receptorb) Beta 2 microglobulinc) RBC massd) ESR

#1 cont

However, remember the gold standard for proving Iron deficiency anemia is……

?????

#1

Treatment for iron deficiency is best accomplished with……

a) IV iron replacement weeklyb) IV iron replacement c) IM iron replacement d) PO iron replacement

#1

by indicesmicrocytic/low MCV normocytic/normal MCV iron deficiency -anemia of chronic

disease thalassemia lead poisoning

macrocytic/high MCV B12/folate deficiency hemolysis liver disease

Classification of Anemia:

by RDW normalIncreased

by reticulocyte responsenormalincreased

hemolysis

Classification of Anemia

A 38 yo male patient is referred to you for recommendations regarding their microcytic anemia. The patient has no systemic symptoms.

The CBC shows: WBC 5.7 (normal differential), RBC 5.8, Hgb 12, HCT 37.1, platelets 340. MCV is 71 and RDW is 15.

Ferritin is 50, iron 50, TIBC 300. Hemoglobin electrophoresis is normal.

#2

Your recommendation should be:

A. Referal for EGD and colonoscopyB. Iron infusion with a goal of replacing

1000 mg storage ironC. Reassurance and a discussion about DNA

testing testingD. Iron absorption assay followed by 6 months

of PO iron supplementation

#2

Know other anemias…..

#2

Anemia of chronic diseaseHemoglobinopathiesAplastic anemiaHemolytic anemias

AIHACold antibodiesmicroangiopathic

Other types of anemia

Anemia of inflammationUnable to utilize available storage ironMediated by inflammatory cytokines such as

TNF, IL 1, and IFN betaUsually associated with a decreased

erythropoietin state or reduced responsiveness to erythropoietin

ANEMIA OF CHRONIC DISEASE

Clues for diagnosis

Usually normochromic normocytic RBCs

Occasionally may be hypochromic microcytic

Decreased reticulocyte count

ANEMIA OF CHRONIC DISEASE

Comparison: Fe deficiency ACD

Fe Low Low

TIBC High Low

Transferrin Saturation

Low Low/Normal

Ferritin Low Normal/High

Differentiate with neurological symptomsCheck vitamin levelsCheck antibodiesSuspect diagnosis but vitamin levels

normal……Check MMA and Homocystine

B12/folate deficiency

WARMIgG antibodiesAssociated with lymphoproliferative and

collagen vascular diseasesCOLDIgM antibodiesHemolysis is via the complement pathwayAssociated with lymphoproliferative diseases

or infection

Warm and cold auto antibodies

CIGAR/PENCIL SHAPES

MACROOVALOCYTES

SPHEROCYTES

SCHISTOCYTES

RBC “CLUES”

BITE CELLS

BURR CELLS

SPUR CELLS

TARGET CELLS

TEARDROP CELLS

RBC “CLUES”

Primary platelet vs. coagulopathy can be differentiated by the type of bleeding

Primary platelet bleeding is mucosal with petechia, epistaxis, gum bleeding and GI tract bleeding

Coagulation cascade bleeds are generally joint and soft tissue bleeds

BLEEDING DISORDERS

A 42 year old female with complaints of epistaxis and easy bruising for 2 weeks is seen in the ER. She has the following CBC:

HGB 10 WBC 6200HCT 30 PLTS 38,000MCV 72 normal differential

CASE

A differential diagnosis includes:A) Systemic LupusB) HepatitisC) Drug effectD) ITPE) All of the above

CASE

Decreased platelets result from

Decreased IncreasedProduction Destruction

Sequestration

THROMBOCYTOPENIA

As a general rule, if platelets above 20,000 the risk of spontaneous bleeding is small. When the count goes below 10,000 then the risk increases substantially and transfusions should be considered.

THROMBOCYTOPENIA

Not always idiopathic30-30-30-10 rule

IdiopathicDrugsDisease states such as lymphoma, CLL,

collagen vascular diseasesViral illnesses such as HCV, HIV

ITP

Treatment options:Platelets > 30,000---observationPlatelets< 30,000---treatment

Steroids IVIGSplenectomy

Up to 80% improved with these maneuvers

ITP

You are evaluating a 40 yo female patient who fell at home. She has no known significant medical history. She is awake but lethargic and has the following test results of concern:

HCT 27, platelets 45, schistocytes on peripheral smear

BUN 40, creatinine 1.8, LDH 800

Coags are within normal limits; tox screen negative

Question

Your next move after completing your assessment should be:A. Send an ADAMTS13 and consult

Hematology for urgent plasmapheresisB. Order a d-dimer to rule out early DICC. One unit random-donor apheresed

irradiated plateletsD. CT Chest/Abdomen/Pelvis to look for occult

injury or PE

Question

DIAGNOSTIC PENTADFeverNeurological signsMicroangiopathic hemolytic anemiaThrombocytopeniaRenal dysfunction

THROMBOTIC THROMBOCYTOPENIC PURPURA

Newly determined genetic determinant for TTPADAMTS13 gene defect found in many

patientsEncodes for a vW antigen protease responsible

for cleaving unusually large vW multimersThis syndrome is considered a medical

emergency and treatment should be instituted immediately

TTP

Affects about 3% of patients treated with heparin

Less risk with porcine heparin Less risk with LMWHs

Occurs 5-8 days after starting heparin therapy unless there has been prior exposure

Amnestic response after prior exposure and can develop thrombocytopenia within 1-2 days

If platelet count falls by 50% or falls below 100,000 should immediately stop heparin

HEPARIN INDUCED THROMBOCYTOPENIA

You are doing a pre-op physical on a healthy 55 yo man who injured his knee. He has a history of nosebleeds as a child and his mother was a “free-bleeder” but had no major episodes and died of an MI at age 74. He tells you he was once tested for von-Willebrands, but that it was negative.

His CBC is entirely normal, as are his chemistries.

His coags reveal a PT of 12.5 and a PTT of 40.

Question

You ordered a repeat PTT with a 1:1 mix, which corrected. Your next step will be:

A. Reassurance and clearance for surgery.B. Repeat testing for von Willebrand’s diseaseC. Order a bleeding time and clear the patient

for surgery if the result is normal.D. Recommend FFP prior to surgery at a dose

of 15 mg/kg to cover whatever coagulation abnormality he has.

Question

Most common inherited bleeding disorderAutosomal dominant inheritanceAffected individuals are heterozygousBleeding ranges from mild to severe and

spontaneousProlonged PT/PTT, BT, abnl platelet

aggregation with ristocetin

VON WILLEBRAND DISEASE

Von Willebrand factor is a multimeric protein with two functions

Platelet adhesion---links platelet receptors to exposed subendothelium

Carrier protein for factorVIIIType I – quantitative defectType 2 – qualitative defects

2b – thrombocytopenia associatedType 3 – no protein detectable

vWD

Also called the giant platelet syndromeGlycoprotein Ib platelet defectUnable to bind vWF which is important for

adhesion to the endotheliumHave abnormal ristocetin aggregationHave mild thrombocytopenia

BERNARD-SOULIER SYNDROME

Autosomal recessive inheritanceMucosal bleedingGlycoprotein IIb-IIIa defectUnable to crosslink fibrinogen which is

important for aggregationHave abnormal ADP and EPI aggregation

GLANZMANN’S THROMBASTHENIA

1:1 mix of patient and normal plasmaWill detect a factor deficiency---should see

correction with mix Will allow detection of an inhibitor---doesn’t

correct with mixingMay need to do a 2 hour incubation to reveal an

inhibitor--- may correct initially put prolong with incubation if a weak (slow) inhibitor is present

Hemophilia A and B most common

EVALUATION OF PROLONGED PT OR PTT

Third most commonAutosomal recessive inheritanceCorrelation between factor level and bleeding

tendency is poorLess spontaneous bleedingTreat with FFP

FACTOR XI

Deficiency is very rareAcquired deficiency occurs with

amyloidosis****Treat with FFP

FACTOR X

XII is also known as the Hageman factorHave very prolonged PTTNo evidence of clinical bleeding and have

normal hemostasis

FACTOR XII

A healthy 50 yo female has followed with your for several years and comes in with right leg swelling that has been present for about 3 weeks. She is on no medications except amlodipine. She has not injured herself, been ill lately, or been on any trips. Her BMI is 24.

You are suspicious based on the exam and order a Doppler which reveals subacute nearly occlusive clot in the right superficial femoral vein.

Question

Her CBC, chemistries, and coags are all wnl. Your recommendation to her is:

A. Take aspirin, use warm soaks and wear support hose because this is superficial thrombophlebitis.

B. Admit to the hospital for tPA infusion to prevent varicose vein formation.

C. Order a JAK-2 analysis to assess occult myeloproliferative disease

D. Recommend at least 6 months of anticoagulation, initiating LMW heparin and warfarin today.

E. 3 months of anticoagulation beginning with Lovenox for a week and then warfarin loading at 10mg per day for 3 days

Question

Hypercoaguable states result in unprovoked thrombosis

Generally there is a family history of thrombosis

Most are undefined but there are several deficiencies of the natural occurring anticoagulants that are described

THROMBOTIC DISORDERS

Protein may be decreased or dysfunctionalCheck level prior to initiation of HeparinPROTEIN C DEFICIENCYShould measure prior to the initiation of

Warfarin therapyPROTEIN S DEFICIENCYFunctions as a cofactor with Protein CShould measure prior to the initiation of

Warfarin therapy

ANTITHROMBIN III DEFICIENCY

Mutation in factor V resulting in resistance to Activated Protein C

Most common cause is Factor V Leiden mutation

Most common inherited hypercoaguable defect

Found in up to 25% of patients with recurrent thrombosis

Additive to other risk factors (OCPs, pregnancy, other defects)

APC RESISTANCE

Prolonged PTT

Paradoxical clottingmay be venous or arterial

Recurrent spontaneous fetal loss

ANTIPHOSPHOLIPID ANTIBODY SYNDROME

A 72 year old man presents with fatigue and bruising. He has been noted to be mildly pancytopenic with a CBC as follows:

Hgb 9.4 WBC 2300 segs 35HCT 28 Plt ct 65,000 monos 45MCV 102 Retic 0.4% lymphs 20His peripheral smear shows basophilic

stippling and a dimorphic population.

CASE

The best diagnosis for this case would be:A) Lymphoma with a leukemic phase B) Sickle Cell diseaseC) Evans syndromeD) MyelodysplasiaE) Chronic lymphocytic leukemia

CASE

Peripheral smear and lab findings suggestive of a MDS state includeDimorphic RBC populationMacrocytic RBC’s Pseudo Pelger-Huet anomalyLarge agranular plateletsDecreased reticulocyte count

MDS

CytogeneticsPrimarily see abnormalities of chromosomes

5,7,or 8Trisomy 8 very common5q- syndrome has a more favorable

prognosis and is usually found in females with thrombocytosis

Abnormalities of chr 11 with secondary MDS

MDS

A 45 year old woman presents with fatigue, early satiety and bruising. She has noted some night sweats and a 10 pound weight loss over the last 6 weeks. Her PE is remarkable for splenomegaly and large ecchymosis. Her CBC is as follows:

HGB 10 WBC 250,500HCT 31 Plts 675,000MCV 78

CASE

What would you like to see next?A) Platelet aggregationsB) Coagulation studiesC) Iron studiesD) WBC differential

CASE

What is the most likely diagnosis?A) Chronic Myeloid LeukemiaB) Polycythemia veraC) Acute Myeloid LeukemiaD) Chronic Lymphocytic Leukemia

CASE

Polycythemia vera

Essential Thrombocytosis

Myelofibrosis

Chronic Myeloid Leukemia

MYELOPROLIFERATIVE DISORDERS

Peripheral blood looks like marrowBasophilia/EosinophiliaDecreased LAPPhiladelphia chromosome -- t(9,22)

Moves the abl proto-oncogene on chr 9 to the bcr region on chr 22

Results in production of an abnormal tyrosine kinase

CML

Natural disease progression CHRONIC PHASE

ACCELERATED PHASE

BLAST CRISIS

CML

Imatinib , et alPrototype in the class of drugs designed to

take advantage of the t(9,22) abnormalityA tyrosine kinase inhibitorMany patients with cytogenetic remissions

but duration unknownFew side effects—N/V/D, cytopenias

CML

Diagnosis requires exclusion of secondary causes of erythrocytosisGaisbock’s syndromeHypoxic statesRenal diseaseMalignancy

Polycythemia Vera

VERALOW ERYTHROPOIETIN levelsJAK-2 associationTREAT with PHLEBOTOMYLEUKEMIA/MYELOFIBROSIS

SECONDARYHYPOXIAPHLEBOTOMYNO LEUKEMIA risk

POLYCYTHEMIA

By definition - thrombocytosis sustained over 6 months that is unexplained

May be associated with splenomegaly but not usually massive

No clear diagnostic tests exist

ESSENTIAL THROMBOCYTOSIS

Must rule out other causes for “reactive” thrombocytosis

Iron deficiency anemiaMalignancyCollagen vascular diseaseInfectionPostsplenectomy stateOther MPDs

ET

Characterized by a myelophthisic picture on peripheral smearTeardrop-shaped RBC’sNRBC’sLeft shifted WBC series

AnemicLAP nondiagnostic

MYELOFIBROSIS

Clues on peripheral smearBlasts==Acute leukemia Auer rods == myeloid blastsMature cells==Chronic leukemia Mature lymphocytes==CLLMature segs==CML

HEMATOLOGIC MALIGNANCIES

Work up includesA bone marrow aspirate and biopsySpecial stains on marrow or peripheral bloodFlow cytometry on marrow or peripheral bloodCytogenetic studies on marrow

ACUTE LEUKEMIA

AMLM0 UNDIFFERENTIATEDM1 WITHOUT MATURATIONM2 WITH MATURATIONM3 PROMYELOCYTICM4 MYELOMONOCYTICM5 MONOCYTICM6 ERYTHROIDM7 MEGAKARYOCYTIC

M2With t(8,21) has a good prognosis

M4With inverted 16 and associated eosinophilia

is a good prognostic category

AML

M3Associated with t(15,17) Translocation involving the retinoic acid

receptor geneGood prognosis categoryProminent Auer rodsCommonly associated with DIC

AML

M5Commonly associated with skin and soft

tissue diseaseGingival hyperplasiaCNS disease may occur

AML

Treatment scheme:Induction chemotherapy—designed to take a

patient to aplasia with recovery of “normal” hematopoiesis and a remission state

Consolidation chemotherapy– designed to reinforce the remission obtained. Usually multiple cycles given

AML

Treatment for APL is differentBased on the translocation of the retinoic acid

receptorUses All Trans Retinoic Acid (ATRA) as a

maturational agentMust also include chemotherapy with at least

an anthracyclineHeparin usually not necessary

AML

Primarily occurs in childrenLymphadenopathy and splenomegaly occur in

50%An anterior mediastinal mass is common with

the T-cell subtypesCNS disease is common

ACUTE LYMPHOCYTIC LEUKEMIA

ALLL1 CHILDHOOD

L2 ADULT

L3 BURKITT’S

Treatment schemeInduction chemotherapy with multi-drug

regimens Consolidation chemotherapy with multi-

drug regimens for multiple cyclesimportant drugs include Vincristine,

prednisone and anthracyclines

ALL

Treatment scheme contMaintenance chemotherapy is an important

part of ALL treatment and lasts for several cycles

CNS prophylaxis is also necessary with chemotherapy +/- radiation therapy

ALL

An 80 year old woman is seen for her yearly check up. She feels well. A screening CBC is done and has the following values.

Hgb 7 WBC 55,000 lymphs 98%HCT 20 Plts 40,000

Her physical exam is remarkable for 2 cm lymphadenopathy in the cervical chain. Her peripheral smear looks like this:

CASE

What is this disease?A) CMLB) CLLC) HCLD) PLL

CASE

Which of the following statements is true? A) She has stage IV diseaseB) She should be observed rather than treated

at this stageC) Her life expectancy from this leukemia is

less than 6 monthsD) This is a leukemoid reaction

CASE

The most common leukemia in the western countries

Typically a disease of older individualsFlow cytometry is usually diagnostic

Typically a B cell disorder CD19,CD20,CD23 PositiveCD5 Positive

CHRONIC LYMPHOCYTIC LEUKEMIA

RAI staging system Survival

O Lymphocytosis > 10 yrs I Lymphadenopathy 6-7 yrsII Splenomegaly 6-7 yrsIII Anemia 2-3 yrsIV Thrombocytopenia 2-3 yrs

CLL

Treatment options includeObservation –many patients have no

indication for therapy at the time of presentation

Indications for treatment include Symptomatic disease Rapid doubling of the WBC count Anemia Thrombocytopenia

CLL

Complications includeHypogammaglobulinemia

Treatment with IVIG may be of benefitAutoimmune disorders such as AIHA or ITP

Treat with high dose steroids Treat disease as well

Commonly associated with second malignanciesLung cancerHead and neck cancer

CLL

B cell phenotype-- CD 19,CD20 Positivealso CD 11C, CD 25, and CD 103 PositiveIncreased risk for infectionsAffects males 4:1 over females

Usual presentation is PancytopeniaLarge splenomegalyInaspirable bone marrow

HAIRY CELL LEUKEMIA

A 24 year old girl presents with painless lymphadenopathy in her cervical chain that measures up to 3 cm. She is asymptomatic and has not had any recent URI symptoms.

Physical exam is pertinent for the lymph nodes mentioned as well as several small inguinal nodes measuring 2-3 cm.

She has an FNA of an inguinal node that is nondiagnostic.

CASE

The next step should beA) CT scan of chest, abdomen and pelvisB) ObservationC) Fine needle aspiration of the cervical nodesD) Excisional biopsy of a cervical node

CASE

Her pathology returns diffuse large cell lymphoma. After discussion of her diagnosis with her, the next most appropriate step in her management would be:

CASE

A) Referral to general surgery for debulking of all disease

B) Check a GHS and begin chemotherapy with ABVD

C) Check a b2MG, LDH, and ESRD) CT scan of chest, abdomen, and pelvis

CASE

Her CT scan returns with a mediastinal mass that measures 12 cm as well as many nodes in her abdomen, the largest being 3 cms.

She has a bone marrow that is negative for disease.

What is the stage of her disease?

CASE

A) IIBB) IIIBEC) IIBXD) IIIAXE) IV

CASE

Staging systemAnn Arbor

Stage I 1 node or groupStage II 2 or more lymph node

groups, same side of the diaphragmStage III Spans the diaphragmStage IV Disseminated disease

LYMPHOMA

Subscripts with the staging system include A --B symptoms absentB --B symptoms presentX --Bulky disease --defined as any

mass >10 cms or a mass > 1/3 the diameter of the chest

E –Extranodal disease

Lymphoma

You have now determined that your patient has stage IIIAX disease. She asks your advice concerning treatment options. You should tell her:

CASE

A) She does not yet need treatment B) She should not agree to treatment as there

is none with proven efficacyC) She should receive radiation therapy to her

mediastinal mass followed by rituxanD) Multiagent chemotherapy will offer her a

chance for cure

CASE

Bimodal age distributionOften see the “B” symptoms

Fever Night sweatsWeight loss

Pruritus is commonUnusual complaint of pain with alcohol

ingestion

HD

Classification includesLymphocyte PredominantMixed CellularityNodular SclerosingLymphocyte Depleted

Prognosis is most closely linked to stage of diseaseStage IA with survival rate of >90%Stage IV with survival rate of >60%

HODGKIN DISEASE

Long term complications after treatment for Hodgkin Disease are common and include

HypothyroidismInfertilitySecondary malignancy including

MDS/AMLSolid tumors such as Breast and Lung

HD

Most are B cell in origin

Incidence is increasing in Western countries

Many associated with immunodeficiency states

NON-HODGKIN’S LYMPHOMA

Burkitt’s lymphoma==L3 Endemic Epidemic

African variety USJaw mass Abdominal massEBV +++ EBV +/-

NHL

Lymphoblastic lymphoma ==ALLTypically young adults and childrenFrequently a mediastinal mass at

presentationOften Stage IV at presentationCNS involvement is common

NHL –specific types

H PYLORI ASSOCIATEDMALT

EBV ASSOCIATEDPOST TRANSPLANT NHL

HTLV-1 ASSOCIATEDATLL

OTHER NHL’S

A 72 year old man is seen for routine check up. He has no complaints and his physical exam is benign. Screening lab is as follows:Hgb 12.0 Tprot 10HCT 37 Alb 2.0WBC 3300 AST 67Plts 460,000 ALT 80

CASE

Work up should include which of the following?A) Liver biopsyB) Bone marrow aspirate and biopsyC) SPEP/UPEPD) Beta-2-Microglobulin

CASE

MULTIPLE MYELOMAClues include A low anion gapRouleaux on

peripheral smearAn elevated globulin

fraction (TP-Alb)

95% will have an abnormal protein on SPEP or UPEP

The M spike is most commonly IgG followed by IgA, light chain disease,and IgD

<5% will be non-secretory and have no evidence of protein secretion

MM

GAMMOPATHY

MGUS<10%

PLASMA CELLS

< 3 GRAMS PROTEIN

NO LYTIC LESIONS

MM>30%

PLASMA CELLS

>3.5 GRAMS PROTEIN

+/- LYTIC LESIONS

Affects about 5% of patients over 70About 25% will progress to MM over about

10 yearsNo treatment requiredFollow lab studies every 6 monthsMULTIPLE MYELOMATreat for progressive diseaseBMT accepted treatment for MM Solitary plasmacytoma becomes MM in most

patients over time

MGUS

Increased IgM levelsMore common in older menPresentation is usually with

Lymphadenopathy/organomegalyPurpuraNeuropathyHyperviscosity syndrome

Cells best described as “plasmacytoid lymphocytes”

WALDENSTROM’s MACROGLOBULINEMIA

Pluripotent cells found in the bone marrowRare (less than 1 in 100,000 cells)No identifiable morphological characteristicsCD 34 + (stem cell antigen)Can be induced to circulate

in the peripheral bloodNeed 2.0–5.0 x 106 CD 34 + cells/kg

of recipient body weight

STEM CELLS

Cell sources:

HPSCT

BONE MARROW PBSC

HEMATOPOIETIC STEM CELL TRANSPLANTATION

Types of transplants:

HPSCT

AUTOLOGOUS ALLOGENEIC

HPSCT

Use patient’s own cellsHas less acute mortalityHigher relapse rateSome accepted indications for autologous

transplant include: Lymphoma including NHL and HD Leukemia including AML and ALL in CR Multiple Myeloma Breast cancer is controversial Testicular cancer for

relapsed disease

AUTOLOGOUS TRANSPLANT

Related donor or unrelated donor(NMDP)Has a higher acute mortality rateLess relapse risk Some accepted indications

for allogeneic transplantChronic leukemia including CML and CLLRelapsed acute leukemia including

AML and ALLMyelodysplasiaMultiple myeloma (VIC)

ALLOGENEIC TRANSPLANT

GVHD—a unique toxicity to allogeneic transplant—higher risk with unrelated donor source; may be fatal; acute looks like fever, skin rash, GI track involvement; chronic looks like scleroderma

GV“T”—a benefit of GVHD is graft vs. tumor effect, which may decrease relapse rate—mediated by T lymphocytes

TOXICITY