A Hematology Case Study
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Transcript of A Hematology Case Study
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Dr. Wael Lotfy Heikal
M.B.B.CH, MSC Clinical Pathology
Pathologist Khasab Hospital Laboratory
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A football player who had dropped
from the teamA 35 year-old man was dropped from the
football team.
He admitted to the coach that he had beenfeeling unusually tired for the last 6 monthsand had occasional episodes of sweating,
especially at night.He went to his family doctor.
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The only additional symptom that he mentionedwas occasional discomfort in his left upper
abdomen.
He didn't smoke and he consumed 20 units ofalcohol weekly . He had never been in hospital ,was taking no medication and denied the use ofrecreational drugs.
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What might be causing his symptom?
y Fatigue could be caused by anaemia
or depression ,
and " sweating" could be
a manifestation of infection.
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What should be done next?
yA full physical examination.
y The man appeared healthy.
y There was no evidence of weight loss and the onlyabnormal finding was an enlarged spleen, palpable4cm below the left costal margine on quietinspiration.
y There was no lymphadenopathy & his chest was
clinically clear.
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Where is the spleen in a healthy individual?
y The spleen lies between the 9th and 11th ribs posteriorly.
y It is not normally palpable.
y Occasionally in a very thin individual you may be able topalpate the tip of the spleen on deep inspiration.
y In this case the spleen was easily palpable on quietinspiration and, therefore, is significantly enlarged.
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What diseases might cause an enlarged spleen in
an otherwise healthy looking young man?
A palpable spleen in an otherwise healthy lookingyoung man suggests either a hematological disorderor an increase in blood flow through the spleen,causing it to enlarge( e.g. portal hypertension).
In tropical areas infections such as malaria &schistosomiasis may cause a large spleen.
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y It is reliable for anexperienced examiner.
yHowever, in obeseindividuals it may bevery difficult to feel aslightly enlarged spleen.
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What investigations will define the size of the spleen?
Ultrasound examination
of the abdomen is
a reliable, non-invasive,inexpensive test.
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What investigations might help to find the cause of the
enlarged spleen?
yA full blood count, blood film, reticulocyte count
and a biochemical screen.
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Normal range (male)Patient's results
13.5-18.0 g/dl14.0 g/dlHb
4.0-11.0x109/l (103/l)55.0x 109 /lWBC
140-450x 109/l (103/l)600x109 /lPlatelets
20-100x109/l (0.2-1.5%)6.4%Reticulocyte count
Full blood & reticulocyte count
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The blood film
y There was a marked
increase in the white
cell count.y White cell precursors
including
metamyelocytes,
myelocytes, andpromyelocytes were
present
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basophil blast
neutrophils
and
precursors promyelocyte
CML
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What do these blood results indicate?
y The Hb is normal and the white cell count is elevated.
y White cell precursors are present.,These cells are normally foundin the bone marrow and not in the peripheral blood.
y The platelet count is also elevated.
y This suggests that the bone marrow is overactive and releasing
white cells and platelets prematurely into the circulation.
y The results of these tests therefore suggest a sever disturbance ofthe bone marrow, not an infectious disease.
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What should be done next?
y He should be referred to a hematologist because hehas significant haematological disorders.
y The patient received an appointment to see ahaematologist 2 days later.
y He was adviced not to play football and to avoidstrenuous exercise.
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Why was this advice given?
y It is possible to rupture an enlarged spleenfollowing trauma.,This could lead to life
threatening intra-abdominal bleeding.
y He was interviewed and examined by thehematologist,who repeated the blood count and
blood film and received the results of thebiochemical screen & ultrasound examination.
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How would the hematologist interpret the
blood finding?
y The most likely diagnosis in a young man with a large spleenand with this blood picture is chronic myeloid leukaemia(CML).
y It is possible in sever infections or when there are marrowmetastases to have an elevated white cell count and to see whitecell and red cell precursors in the blood ( a leucoerythroblasticblood picture) .
y There are a number of possible causes of large spleen, such aschronic infection with malaria, liver disease with portalhypertension, non-Hodgkin's lymphomas and chroniclymphocytic leukaemia, but none of these conditions will havethe peripheral finding as described in this patient.
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Normal rangePatient's result
230-450IU/l850 IU/lLactic dehydrogenase(LDH)
150-470 mol/l
(3-8mg/dl)
600mol/lUrate(uric acid)
Lactic dehydrogenase andurate( uric acid) results:
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How are the biochemical results explained?
y The elevated LDH reflects cell death and is non-specific.
y It could be elevated following myocardialinfarction, liver damage or premature death ofblood cells.,In this case it reflects death of whiteblood cells.
y Similarly the elevated uric acid level in the plasmareflects increased cell turnover.
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What should be done next?
yA bone marrow examination was arranged since aserious hematological disorder was suspected.
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From which site was the bone marrow
aspirated?
yThe posterior iliac crest. It is the
least painful site for the patient
and almost completely without
hazard.
yCare should be taken to make
sure that adequate local
analegesia is given and there isno bleeding after the procedure.
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What investigations would the hematologist
request on the sample of bone marrow?
y Slides for microscopic examinations.
yA sample should be also sent to the genetics
department for a karyotypic (cytogenetic) analysis
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How does the bone marrow aspirate help to confirm the
suspected diagnosis?
The slides revealed:1- a very cellular specimen withincreased numbers of white blood cellE/G ratio: 1:4 1: 10 and,
2- increased number of plateletprecursors( megakaryocytes),
3-variable fibrosis, increase in reticulin.,
suggesting increased marrow activity or
reduced cell death ( apoptosis).
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How should the patient be managed?
y The probable diagnosis should be explained to the patient.
y If he has a partner she should be invited, with the
patients permission, to come back in a few days to discussthe result of the result of the outstanding tests.
y The patient should be assured that there is no immediatedanger, but he advised to remain off work and refrain from
contact sports until the diagnosis is clarified.
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What medications would the hematologist prescribe?
y Allopurinol, a competitive inhibitor of xanthine oxidase.,This drugwill reduce urate(uric acid) in plasma and decrease the risk of gout andrenal damage.
y The patient and his partner were given the results 3 days later.
y The cytogenetic analysis revealed a normal number ofchromosomes but a small chromosome number 22.
y This was due to translocation of a portion of chromosome 9 tochromosome 22 and a reciprocal ( reverse) transfer of a portion ofchromosome from chromosome 22 to chromosome 9.
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Philadelphia chromosome. A piece of chromosome 9 and a piece of chromosome 22 break off and trade places. The bcr-abl gene is formed on
chromosome 22 where the piece of chromosome 9 attaches. The changed chromosome 22 is called the Philadelphia chromosome.
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Figure, The abnormally small chromosome22, the Philadelphia chromosome
y Molecular consequence ofthe t(9;22) is the fusionprotein BCRABL, whichhas increased in tyrosinekinase activity
y BCR-ABL proteintransform hematopoieticcells so that their growthand survival become
independent of cytokinesy It protects hematopoietic
cells from programmed celldeath (apoptosis)
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Figure, FISH analysis( fluorescent in situ hybridization) of bone marrow cells showing
fusion of BCR/ABL.(F).
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Why is this small chromosome 22 called the Philadelphia
chromosome and what is its significance?
y The small, abnormal chromosome 22 was firstdescribed by two scientists in patients with CML inPhiladelphia.
y This translocation was the first non-random,reproducible chromosome abnormality to bedescribed in a human cancer.
y It is always present in the bone marrow cells ofpatients with CML.,
y It is very significant in our understanding of thepathogenesis of CML.
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y When portions of different chromosomes come together theproduction of an abnormal gene product(protein) occurs.
y In the case of CML the abnormal gene product influences celldivision and programmed cell death (apoptosis).
y The fusion gene on chromosome 22 is called BCR/ABL.
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Key point:
y The abnormal chromosome found in CML
causes the malignant phenotype i.e. makes the cells
behave in a cancerous way.
y In very recent times this knowledge has
stimulated the development of drugs whichspecifically inhibit these abnormalities and induceapoptosis of the leukemia cells.
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What is the long term outlook for the patient?
y The only definitive treatment is a stem cell transplant from a HLA
compatible sibling.
y As this patient has no siblings he will be treated medically.
y A search for a HLA compatible volunteer donor should be carried out
( there are over 6 million donors on the international panel).
y If as suitable donor is found, consideration should be given to a stem
cell transplant, depending to his response to medical treatment.
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Can you construct an algorithm for investigations of a patient with ahigh white cell count and a large spleen?
A patient who has minor symptoms is found to havean elevated white blood cell count
Complete physical examination
Enlarged spleen
white cell precursors in blood film
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Confirmation of enlarged spleen
Marrow for morphological examination and cytogeneticanalysis
Normal chromosome number but small chromosome 22.
Philadelphia' chromosome
Diagnosis: chronic myeloid leukaemia
Medical treatment initially and consideration for stemcell transplantation
u come:
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u come:
y Imatinibmesylate, a new agent capable ofinducing apoptosis in the leukaemia cells, was
prescribed.
y He returned to work a few days and was ableto resume a normal life.
y He is seen in the hematology clinic atmonthly intervals.
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Thank you