acute lymphob (2)
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leukemialeukemia
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What is leukemia?What is leukemia? Cancer of the white blood cells
Acute or Chronic
Affects ability to produce normal blood cells
Bone marrow makes abnormally large number
of immature white blood cells calledblasts
Cancer of the white blood cells
Acute or Chronic
Affects ability to produce normal blood cells
Bone marrow makes abnormally large number
of immature white blood cells calledblasts
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H
istoryH
istory Means white blood in Greek
Discovered by Dr. Alfred Velpeau in France,1827
Named by pathologist Rudolf Virchow in
Germany, 1845
Means white blood in Greek
Discovered by Dr. Alfred Velpeau in France,1827
Named by pathologist Rudolf Virchow in
Germany, 1845
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Main TypesMain Types Acute Lymphocytic Leukemia (ALL)
Acute Mylogenous Leukemia (AML) Chronic Lymphocytic Leukemia (CLL)
Chronic Mylogenous Leukemia (CML)
Acute Lymphocytic Leukemia (ALL)
Acute Mylogenous Leukemia (AML) Chronic Lymphocytic Leukemia (CLL)
Chronic Mylogenous Leukemia (CML)
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Acute lymphoblastic
leukemia (ALL)
Acute lymphoblastic
leukemia (ALL)-most common malignancy diagnosed in children
-, one third of all pediatric cancers.
-a peak incidence in children aged 2-5 years.-Although a few cases are associated with
inherited genetic syndromes,the cause of ALL remains largely unknown .
-most common malignancy diagnosed in children
-, one third of all pediatric cancers.
-a peak incidence in children aged 2-5 years.-Although a few cases are associated with
inherited genetic syndromes,the cause of ALL remains largely unknown .
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Normal human blood
White Cell Red Cell
Platelet
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Blood with
leukemia
BlastsRed Cell
Platelet
White Cell
Normal human blood
White Cell Red Cell
Platelet
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- a fast-growing cancer of the white blood cells.
- In ALL, the bone marrow makes lots of
unformed cells called blasts that normally would
develop into lymphocytes
-However, the blasts are abnormal. They
do not develop and cannot fight infections..
- a fast-growing cancer of the white blood cells.
- In ALL, the bone marrow makes lots of
unformed cells called blasts that normally would
develop into lymphocytes
-However, the blasts are abnormal. They
do not develop and cannot fight infections..
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The number of abnormal cells (or leukemia
cells) grows quickly.
They crowd out the normal red blood cells,white blood cells and platelets the body needs
The number of abnormal cells (or leukemia
cells) grows quickly.
They crowd out the normal red blood cells,white blood cells and platelets the body needs
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Development of Leukemia in the
Bloodstream
Development of Leukemia in the
Bloodstream
Stage 1- Normal Stage 2- Symptoms Stage 3- Diagnosis
Stage 4- Worsening
Stage 5a- Anemia
Stage 5b- Infection
Legend
White Cell
Red Cell
PlateletBlast
Germ Sources from Leukemia, by D. Newton and D. Siegel
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Possible risk factors for ALL include thefollowing:
Having a brother or sister with leukemia .
Being white .Being exposed to x-rays before birth .
Being exposed to radiation .
Past treatment with chemotherapy or other drugs thatweaken the immune system .
Having certain genetic disorders, such as Down syndrome .
Possible risk factors for ALL include thefollowing:
Having a brother or sister with leukemia .
Being white .Being exposed to x-rays before birth .
Being exposed to radiation .
Past treatment with chemotherapy or other drugs thatweaken the immune system .
Having certain genetic disorders, such as Down syndrome .
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Clinical pictureClinical picture
Appears 2-6weeks before diagnosis
Variable &nonspecific:
1-Generalised weakness and fatigue
2 -anemia3-Frequent or unexplained feverand infections
4-Weight loss and/or loss of appetite
5-Excessive and unexplained bruising
6-bone pain,joint pain (caused by the spread of "blast" cellsto the surface of the bone or into the joint from the marrowcavity)
7-breathlessness
8-Enlarged lymph nodes,liver&or spleen
Appears 2-6weeks before diagnosis
Variable &nonspecific:
1-Generalised weakness and fatigue
2 -anemia3-Frequent or unexplained feverand infections
4-Weight loss and/or loss of appetite
5-Excessive and unexplained bruising
6-bone pain,joint pain (caused by the spread of "blast" cellsto the surface of the bone or into the joint from the marrowcavity)
7-breathlessness
8-Enlarged lymph nodes,liver&or spleen
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Less commonly :
Vomiting
Headache
Respiratory distress
rash
Less commonly :
Vomiting
Headache
Respiratory distress
rash
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Physical examinationPhysical examination
Fever
Tachycardia
Irritability
Pallor
Ecchymosis
Periorbital edemaPapilledema
Epistaxis
Fever
Tachycardia
Irritability
Pallor
Ecchymosis
Periorbital edemaPapilledema
Epistaxis
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Hepatomegaly
Splenomegaly
Testicular enlargement
Bone pressure on pressure
Cranial nerve palsy
Hepatomegaly
Splenomegaly
Testicular enlargement
Bone pressure on pressure
Cranial nerve palsy
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Skin lesions uncommon
(leukemia cutis)Discrete
Cover face trunk &eventually all body
Individual lesions slightly nodular erythematous& purpuric eventually necrotic
Skin lesions uncommon
(leukemia cutis)Discrete
Cover face trunk &eventually all body
Individual lesions slightly nodular erythematous& purpuric eventually necrotic
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Only 4 % present with CNS manifestations
5-10% with testicular affection
Only 4 % present with CNS manifestations
5-10% with testicular affection
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classificationclassification
Mathe & colleagues were among the first to
propose amorphological classifications of ALL
Drawbacks: subjective as it depends on
morphological features (cell size cytoblasmic
basophilia.
Mathe & colleagues were among the first to
propose amorphological classifications of ALL
Drawbacks: subjective as it depends on
morphological features (cell size cytoblasmic
basophilia.
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FAb classificationFAb classification
ALL-L1: smalluniform cells
ALL-L2: large varied cells
ALL-L3: large varied cells with vacuoles
(bubble-likefeatures
ALL-L1: smalluniform cells
ALL-L2: large varied cells
ALL-L3: large varied cells with vacuoles
(bubble-likefeatures
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Depending on cell size ,nuclear chromatin
pattern ,shape ,prominence of nucleoli,
cytoblasmic characterestics,amount ofbasophilia& vacuolization
Labs agreed that fab was prognostic
&L1 carriedmorefavourable prognosis
Depending on cell size ,nuclear chromatin
pattern ,shape ,prominence of nucleoli,
cytoblasmic characterestics,amount ofbasophilia& vacuolization
Labs agreed that fab was prognostic
&L1 carriedmorefavourable prognosis
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WHO classificationWHO classification
1- Acute lymphoblastic leukemia/lymphomaSynonyms:Former Fab L1/L2
i.precursor Bacutelymphoblasticleukemia/lymphoma. Cytogenetic subtypes:[18] t(12;21)(p12,q22) TEL/AML-1
t(1;19)(q23;p13) PBX/E2A
t(9;22)(q34;q11) ABL/BCR
T(V,11)(V;q23) V/MLL
ii. Precursor T acute lymphoblastic
leukemia/lymphoma 2- Burkitt's leukemia/lymphoma Synonyms:Former
FAB L3
3- Biphenotypic acute leukemia
1- Acute lymphoblastic leukemia/lymphomaSynonyms:Former Fab L1/L2
i.precursor Bacutelymphoblasticleukemia/lymphoma. Cytogenetic subtypes:[18] t(12;21)(p12,q22) TEL/AML-1
t(1;19)(q23;p13) PBX/E2A
t(9;22)(q34;q11) ABL/BCR
T(V,11)(V;q23) V/MLL
ii. Precursor T acute lymphoblastic
leukemia/lymphoma 2- Burkitt's leukemia/lymphoma Synonyms:Former
FAB L3
3- Biphenotypic acute leukemia
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It depends on immunophenotyping
using monoclonal antibodies against surface&
cytoplasmic differentiation antigens
It depends on immunophenotyping
using monoclonal antibodies against surface&
cytoplasmic differentiation antigens
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Laboratory StudiesLaboratory Studies
o obtaina CBC. peripheralsmearforthe presenceand
morphologyoflymphoblasts.
o Anelevatedleukocyte countof>10 X 109/L (>10 X103/L) occursinonehalfofpatients with ALL.
o Thedegreeofleukocytic elevation(blasts) atdiagnosis
remains the most important predictor of the patient's
prognosis.o Neutropenia,anemia,andthrombocytopeniamaybe
observedsecondarytoinhibitionofnormal
hematopoiesisbyleukemic infiltration. Rare casesof
ALL mayinitiallymanifest with pancytopenia.
o obtaina CBC. peripheralsmearforthe presenceand
morphologyoflymphoblasts.
o Anelevatedleukocyte countof>10 X 109/L (>10 X103/L) occursinonehalfofpatients with ALL.
o Thedegreeofleukocytic elevation(blasts) atdiagnosis
remains the most important predictor of the patient's
prognosis.o Neutropenia,anemia,andthrombocytopeniamaybe
observedsecondarytoinhibitionofnormal
hematopoiesisbyleukemic infiltration. Rare casesof
ALL mayinitiallymanifest with pancytopenia.
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oVarious metabolic abnormalities
o may include increased serum levels of uric acid,potassium, phosphorus, and calcium, and lactatedehydrogenase (LDH).
o The degree of abnormality reflects the leukemic
cell burden and destruction (lysis). Although notuniversally performed, coagulation studies can behelpful, including tests of the prothrombin time(PT), activated partial thromboplastin time (aPTT),fibrinogen level, and D-dimer level to assess for
disseminated intravascular coagulation; thesestudies are particularly important in a child who isacutely toxic.
oVarious metabolic abnormalities
o may include increased serum levels of uric acid,potassium, phosphorus, and calcium, and lactatedehydrogenase (LDH).
o The degree of abnormality reflects the leukemic
cell burden and destruction (lysis). Although notuniversally performed, coagulation studies can behelpful, including tests of the prothrombin time(PT), activated partial thromboplastin time (aPTT),fibrinogen level, and D-dimer level to assess for
disseminated intravascular coagulation; thesestudies are particularly important in a child who isacutely toxic.
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ImmunophenotypingImmunophenotyping
Complete morphologic, immunologic, and
genetic examination of the bone marrow is
necessary to establish the diagnosis of ALL
Complete morphologic, immunologic, and
genetic examination of the bone marrow is
necessary to establish the diagnosis of ALL
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Approximately 80% of childhood ALLs involve
lymphoblasts with phenotypes that correspond
to those of B-cell progenitor
T-cell ALL is identified by the expression of T-
cellassociated surface antigens, of whichcytoplasmic CD3 is specific
Approximately 80% of childhood ALLs involve
lymphoblasts with phenotypes that correspond
to those of B-cell progenitor
T-cell ALL is identified by the expression of T-
cellassociated surface antigens, of whichcytoplasmic CD3 is specific
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Cytogenetic and molecular
diagnosis
Cytogenetic and molecular
diagnosis In more than 90% of ALLs, specific genetic
alterations can be found in the leukemic blasts.
These alterations include changes in
chromosome number (ploidy) and structure;
about half of all childhood ALLs involve
recurrent translocations.
In more than 90% of ALLs, specific genetic
alterations can be found in the leukemic blasts.
These alterations include changes in
chromosome number (ploidy) and structure;
about half of all childhood ALLs involve
recurrent translocations.
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molecular techniquesmolecular techniques
, including fluorescence in situ hybridization
(FISH), reverse transcriptase-polymerase chain
reaction (RT-PCR), and Southern blot analysishelp improve diagnostic accuracy.
, including fluorescence in situ hybridization
(FISH), reverse transcriptase-polymerase chain
reaction (RT-PCR), and Southern blot analysishelp improve diagnostic accuracy.
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Imaging StudiesImaging StudiesChest radiography: Evaluateforamediastinalmass.In
general,nootherimagingstudiesarerequired. However,ifthe physicalexaminationrevealsenlargedtestes, performultrasonographytoevaluatefortesticularinfiltration.
Testicular ultrasonography: Performtesticularultrasonographyifthetestesareenlargedon physicalexamination.
Renal ultrasonography: Some clinicians prefertoevaluateforleukemic kidneyinvolvementtoassesstheriskoftumor
lysissyndrome.Echocardiography and ECG: Obtainanechocardiogramand
an ECG beforeanthracyclinesareadministered
Chest radiography: Evaluateforamediastinalmass.Ingeneral,nootherimagingstudiesarerequired. However,ifthe physicalexaminationrevealsenlargedtestes, performultrasonographytoevaluatefortesticularinfiltration.
Testicular ultrasonography: Performtesticularultrasonographyifthetestesareenlargedon physicalexamination.
Renal ultrasonography: Some clinicians prefertoevaluateforleukemic kidneyinvolvementtoassesstheriskoftumor
lysissyndrome.Echocardiography and ECG: Obtainanechocardiogramand
an ECG beforeanthracyclinesareadministered
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ProceduresProcedures
Bonemarrow aspirateandbiopsy: The results
confirm the diagnosis of ALL. In addition, special
stains (immunohistochemistry), immunophenotyping,
cytogenetic analysis, and molecular analysis help inclassifying each case.
Lumbar puncture with cytospinmorphologic
analysis: These tests are performed before systemic
chemotherapy is administered to assess for CNS
involvement and to administer intrathecal
chemotherapy
Bonemarrow aspirateandbiopsy: The results
confirm the diagnosis of ALL. In addition, special
stains (immunohistochemistry), immunophenotyping,
cytogenetic analysis, and molecular analysis help inclassifying each case.
Lumbar puncture with cytospinmorphologic
analysis: These tests are performed before systemic
chemotherapy is administered to assess for CNS
involvement and to administer intrathecal
chemotherapy
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Histologic FindingsHistologic Findings
Although it is not correlated with the immunophenotypic andcytogenetic classification information, the FAB system isgenerally well accepted and used. According to this system,ALL is classified into 3 groups based on morphology.
L1: Cells are usually small, with scant cytoplasm andinconspicuous nucleoli. L1 accounts for 85% of all cases ofchildhood ALL.
L2: Cells are larger, than in L1. The cells demonstrate considerableheterogeneity in size, with prominent nucleoli, and abundant
cytoplasm. L2 accounts for 14% of all childhood ALLs.L3: Cells are large and notable for their deep cytoplasmic
basophilia. They frequently have prominent cytoplasmicvacuolation and are morphologically identical to Burkittlymphoma cells. L3 accounts for 1% of childhood ALLs
Although it is not correlated with the immunophenotypic andcytogenetic classification information, the FAB system isgenerally well accepted and used. According to this system,ALL is classified into 3 groups based on morphology.
L1: Cells are usually small, with scant cytoplasm andinconspicuous nucleoli. L1 accounts for 85% of all cases ofchildhood ALL.
L2: Cells are larger, than in L1. The cells demonstrate considerableheterogeneity in size, with prominent nucleoli, and abundant
cytoplasm. L2 accounts for 14% of all childhood ALLs.L3: Cells are large and notable for their deep cytoplasmic
basophilia. They frequently have prominent cytoplasmicvacuolation and are morphologically identical to Burkittlymphoma cells. L3 accounts for 1% of childhood ALLs
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treatmenttreatment
Chemotherapy:
3 chemotherapy phases: induction,consolidation or intensification, and
maintenance
The earlier acute lymphocytic leukemia is
detected, the more effective the treatment .
Chemotherapy:
3 chemotherapy phases: induction,consolidation or intensification, and
maintenance
The earlier acute lymphocytic leukemia is
detected, the more effective the treatment .
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Treatment of Recurrent ALLTreatment of Recurrent ALL
Much of the treatment strategy depends on how
soon the leukemia returns after the first
treatment. The shorter the time interval, thegreater will be the need for newer and more
aggressive chemotherapy .
Much of the treatment strategy depends on how
soon the leukemia returns after the first
treatment. The shorter the time interval, thegreater will be the need for newer and more
aggressive chemotherapy .
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The most commonly used chemotherapy drugs are
vincristine, L-asparaginase, anthracyclines
(doxorubicin, daunorubicin), cyclophosphamide,cytarabine (ara-C), and epipodophyllotoxins
(etoposide, teniposide). Your child will also receive a
steroid (prednisone or dexamethasone) and vincristine
unless he or she is known to be resistant to thesemedications. Intrathecal chemotherapy will also be
given .
The most commonly used chemotherapy drugs are
vincristine, L-asparaginase, anthracyclines
(doxorubicin, daunorubicin), cyclophosphamide,cytarabine (ara-C), and epipodophyllotoxins
(etoposide, teniposide). Your child will also receive a
steroid (prednisone or dexamethasone) and vincristine
unless he or she is known to be resistant to thesemedications. Intrathecal chemotherapy will also be
given .
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Cure Rates for ALL
The chance of being cured of low-risk ALL is
about 85% to 95%, standard-risk is about 65%to 85%, and high-risk ALL is about 60% to
65% .
Cure Rates for ALL
The chance of being cured of low-risk ALL is
about 85% to 95%, standard-risk is about 65%to 85%, and high-risk ALL is about 60% to
65% .
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AgentsDiscriptionphase
Combination of
Prednisoloneordexamethasone ) in
children (,
vincristine ,
asparaginase ,anddaunorubicin
)used in Adult
ALL) is used to
induce remission .
to rapidly kill most tumor
cellsThis is defined as the
presence of less than 5%
leukemic blasts in the
bone marrow, normalblood cells and absence of
tumor cells from blood,
and absence of other signs
and symptoms of thedisease .
induction
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Typical
intensificationprotocols use
vincristine ,
cyclophosphami
de ,cytarabine ,daunorubicin ,
etoposide ,
thioguanineor
mercaptopurinegiven as blocks
in different
combinations
high doses of intravenous
multidrug chemotherapy tofurther reduce tumor
burden
most protocols include
delivery of chemotherapy
into the CNS fluid
multiple lumbar punctures
Ommaya reservoir
Intensification
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daily oral mercaptopurine,
once weekly oral
methotrexate, once monthly
5-day course of intravenous
vincristine and oral
corticosteroids are usually
used. The length of
maintenance therapy is 3
years for boys, 2 years for
girls and adults.
The aim ofmaintenance
therapy is to kill any
residual cell that was not
killed by remission
induction, and
intensification regimens.
Although such cells are
few, they will cause relapse
if not eradicated .
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Whereas B-cell ALL istreated witha 2- to 8-
month courseofintensivetherapy,achieving
acceptable cureratesfor patients with B-precursorandT-cell ALL requires
approximately 2-2.5yearsofcontinuation
therapy.
Attemptstoreducethistimeresultinhighrelapseratesaftertherapyisstopped .
Whereas B-cell ALL istreated witha 2- to 8-
month courseofintensivetherapy,achieving
acceptable cureratesfor patients with B-precursorandT-cell ALL requires
approximately 2-2.5yearsofcontinuation
therapy.
Attemptstoreducethistimeresultinhighrelapseratesaftertherapyisstopped .
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Central nervous system relapse is treated with
intrathecal administration ofhydrocortisone
methotrexate, and cytarabine
Central nervous system relapse is treated with
intrathecal administration ofhydrocortisone
methotrexate, and cytarabine
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Treatment of Residual
Disease
Treatment of Residual
Disease All these treatment plans may change if the
leukemia hasn't completely disappeared
treatment may be intensified or prolonged
All these treatment plans may change if the
leukemia hasn't completely disappeared
treatment may be intensified or prolonged
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Bone marrow or cord blood transplant (also
called a BMT) a transplant (discussed further
below) offers some patients the best chance fora long-term remission of their disease. Because
transplants can have serious risks, this treatment
is used for patients who are less likely to reach along-term remission with chemotherapy alone .
Bone marrow or cord blood transplant (also
called a BMT) a transplant (discussed further
below) offers some patients the best chance fora long-term remission of their disease. Because
transplants can have serious risks, this treatment
is used for patients who are less likely to reach along-term remission with chemotherapy alone .
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RadiationtherapyRadiationtherapy
Radiation therapyor radiotherapy) is used onpainful bony areas,in high disease burdens, or aspart of the preparations for abone
marrow transplant ) total body irradiation). Radiation in the formof whole brain radiation is also used for central nervous system
prophylaxis, to prevent recurrence of leukemia in the brain.Whole brain prophylaxis radiation used to be a common methodin treatment of childrens ALL. Recent studies showed that CNS
chemotherapy provided results as favorable but with lessdevelopmental side effects. As a result, the use of whole brainradiation has been more limited.
Radiation therapyor radiotherapy) is used onpainful bony areas,in high disease burdens, or aspart of the preparations for abone
marrow transplant ) total body irradiation). Radiation in the formof whole brain radiation is also used for central nervous system
prophylaxis, to prevent recurrence of leukemia in the brain.Whole brain prophylaxis radiation used to be a common methodin treatment of childrens ALL. Recent studies showed that CNS
chemotherapy provided results as favorable but with lessdevelopmental side effects. As a result, the use of whole brainradiation has been more limited.
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Recent data suggest that leukemia arises from
the stem cell that acquires features of
differentiated cells. Although this observationmay appear to be a subtle difference, it is
important because it implies the need to
eradicate the leukemic stem cell, and not just the
differentiated blasts, to achieve a cure .
Recent data suggest that leukemia arises from
the stem cell that acquires features of
differentiated cells. Although this observationmay appear to be a subtle difference, it is
important because it implies the need to
eradicate the leukemic stem cell, and not just the
differentiated blasts, to achieve a cure .
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Chemotherapy withstem
celltransplant
Chemotherapy withstem
celltransplant
Stem cell transplant is a method of giving chemotherapy andreplacing blood-forming cells destroyed by the cancer treatment.
Stem cells (immature blood cells) are removed from the blood orbone marrow of a donor and are frozen and stored. After thechemotherapy is completed, the stored stem cells are thawed andgiven back to the patient through an infusion. These reinfusedstem cells grow into (and restore) the body's blood cells. A stem
cell transplant using stem cells from a donor who is not relatedto the patient is being studied in clinical trials
Stem cell transplant is a method of giving chemotherapy andreplacing blood-forming cells destroyed by the cancer treatment.
Stem cells (immature blood cells) are removed from the blood orbone marrow of a donor and are frozen and stored. After thechemotherapy is completed, the stored stem cells are thawed andgiven back to the patient through an infusion. These reinfusedstem cells grow into (and restore) the body's blood cells. A stem
cell transplant using stem cells from a donor who is not relatedto the patient is being studied in clinical trials
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New typesoftreatmentNew typesoftreatment
arebeingtestedin clinicaltrials. Theseincludethe
following:
High-dose chemotherapyOtherdrugtherapy
Imatinibmesylate(Gleevec) isatypeofanticancer
drug calledatyrosinekinaseinhibitor.Itblocksthe
enzyme,tyrosinekinase,that causesstem cellstodevelop intomore whiteblood cells(granulocytesor
blasts) thanthebodyneeds.
arebeingtestedin clinicaltrials. Theseincludethe
following:
High-dose chemotherapyOtherdrugtherapy
Imatinibmesylate(Gleevec) isatypeofanticancer
drug calledatyrosinekinaseinhibitor.Itblocksthe
enzyme,tyrosinekinase,that causesstem cellstodevelop intomore whiteblood cells(granulocytesor
blasts) thanthebodyneeds.
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^ Harrison's Principles of Internal Medicine, 16th Edition,
Chapter 97. Malignancies of Lymphoid Cells. Clinical Features,
Treatment, and Prognosis of Specific Lymphoid Malignancies. ^ Finding Cancer Statistics Cancer Stat Fact Sheets Chronic
Lymphocytic Leukemia National Cancer Institute
^ Colvin GA, Elfenbein GJ (2003). "The latest treatment advances for acute
myelogenous leukemia". Med Health R I86 (8): 2436. PMID 14582219.
^ Patients with Chronic Myelogenous Leukemia Continue to Do Well onImatinib at 5-Year Follow-Up Medscape Medical News 2006
^ Updated Results of Tyrosine Kinase Inhibitors in CML ASCO 2006
Conference Summaries
^ Harrison's Principles of Internal Medicine, 16th Edition,
Chapter 97. Malignancies of Lymphoid Cells. Clinical Features,
Treatment, and Prognosis of Specific Lymphoid Malignancies. ^ Finding Cancer Statistics Cancer Stat Fact Sheets Chronic
Lymphocytic Leukemia National Cancer Institute
^ Colvin GA, Elfenbein GJ (2003). "The latest treatment advances for acute
myelogenous leukemia". Med Health R I86 (8): 2436. PMID 14582219.
^ Patients with Chronic Myelogenous Leukemia Continue to Do Well onImatinib at 5-Year Follow-Up Medscape Medical News 2006
^ Updated Results of Tyrosine Kinase Inhibitors in CML ASCO 2006
Conference Summaries
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Thank youThank you
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DisordersofplateletsDisordersofplatelets
Plateletsareanimportant componentinthe
first phaseofhemostasis-platelet plugformation.When plateletsarereducedin
numberordefectiveinfunction,bleeding
mayoccur.Bleedingtypicallyinvolvesskinandmucous
Plateletsareanimportant componentinthe
first phaseofhemostasis-platelet plugformation.When plateletsarereducedin
numberordefectiveinfunction,bleeding
mayoccur.Bleedingtypicallyinvolvesskinandmucous
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Idiopathic(Autoimmune)Thromboc
ytopenic purpura
Idiopathic(Autoimmune)Thromboc
ytopenic purpura
Definition
Idiopathic thrombocytopenic purpura(ITP) isa syndrome characterizedby:
1- Thrombocytopenia( Platelet countlessthan 100.000/mm)
2- Shortened plateletsurvival
3- PresenceofantiplateletantibodyinthePlasma
4- Increasedmegakaryocytesinthebonemarrow
Definition
Idiopathic thrombocytopenic purpura(ITP) isa syndrome characterizedby:
1- Thrombocytopenia( Platelet countlessthan 100.000/mm)
2- Shortened plateletsurvival
3- PresenceofantiplateletantibodyinthePlasma
4- Increasedmegakaryocytesinthebonemarrow
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This conditionmaybeacute, chronic,orrecurrent.Inthe acuteform,the
platelet countreturnstonormal
(>150,000/mm) within 6 monthsafterdiagnosisandrelapsedoesnotoccur.
This conditionmaybeacute, chronic,orrecurrent.Inthe acuteform,the
platelet countreturnstonormal
(>150,000/mm) within 6 monthsafterdiagnosisandrelapsedoesnotoccur.
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In the chronic form, the platelet countremains low beyond 6 months. In the
recurrent form, the platelet count decreases
after having returned to normal levels.
In the chronic form, the platelet countremains low beyond 6 months. In the
recurrent form, the platelet count decreases
after having returned to normal levels.
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Possible pathophysiologyofimmune
thrombocytopenia
Possible pathophysiologyofimmune
thrombocytopenia
A N T I B O D Y
Antigen-antibody
complex
Platelet
sensitization
?Megakaryocytes
injury
Impaired platelet
function
Increased platelet
production
Accelerated plateletdestruction
? Deficient platelet
production
Megakaryocytichyperplasia Thrombocytopenia DEFCTIVE HEMOSTASISThrombocytopenia
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Pathophysiological classificationof
thrombocytopenic states
1. Increased platelt destuction ( normal or increased
megakaryocytes in the marrow-megakaryocytic
thrombocytopenia)
A. Immune thrombocytopenias
1. Idiopathic
a. Idiopathic thrombocytopenic
Purpura
Pathophysiological classificationof
thrombocytopenic states
1. Increased platelt destuction ( normal or increased
megakaryocytes in the marrow-megakaryocytic
thrombocytopenia)
A. Immune thrombocytopenias
1. Idiopathic
a. Idiopathic thrombocytopenic
Purpura
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2. Secondary
a.Infection induced (e.g.,viral- HIV,CMV,EBV
Varicella, rubella,rubeola, mumps,parvovirus
B19; bacterial-tuberculosis, typhoid)
b. Drug induced ( see Table 10-5)
c. posttransfusion purpura
d. Autoimmune hemolytic anemia (Evans
syndrom)
2. Secondary
a.Infection induced (e.g.,viral- HIV,CMV,EBV
Varicella, rubella,rubeola, mumps,parvovirus
B19; bacterial-tuberculosis, typhoid)
b. Drug induced ( see Table 10-5)
c. posttransfusion purpura
d. Autoimmune hemolytic anemia (Evans
syndrom)
S i l hS i l h
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e.Systemic lupuserythematosus
f. Hyperthyroidism
g. Lymphoproliferativedisoordersh. Allergy,anaphylaxis
3- Neonatalimiunethrombocytopeniasa.Neonatalimiunethrombocytopenias
b.Neonatalalloimmunethrombocytopenias
c.Erythroblastosisfetalis-Rhincompatibility
e.Systemic lupuserythematosus
f. Hyperthyroidism
g. Lymphoproliferativedisoordersh. Allergy,anaphylaxis
3- Neonatalimiunethrombocytopeniasa.Neonatalimiunethrombocytopenias
b.Neonatalalloimmunethrombocytopenias
c.Erythroblastosisfetalis-Rhincompatibility
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B.NonimmunethrombocytopeniasB.Nonimmunethrombocytopenias
1. Due to platelet consumptiona. Microangiopathic hemolytic anemia
b. Disseminated intravascular coagulation
c. Chronic relapsing schistocytichemolytic anemia
1. Due to platelet consumptiona. Microangiopathic hemolytic anemia
b. Disseminated intravascular coagulation
c. Chronic relapsing schistocytichemolytic anemia
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d. Thrombotic thrombocytopenic
purpura
e. Thrombotic thrombocytopenic purpura
f. Kasabach-Merrittsyndrome(giant
hemangioma)g. Cyanotic heartdisease
d. Thrombotic thrombocytopenic
purpura
e. Thrombotic thrombocytopenic purpura
f. Kasabach-Merrittsyndrome(giant
hemangioma)g. Cyanotic heartdisease
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2.Dueto plateletdestruction2.Dueto plateletdestruction
a.Drugs(e.g.,ristocetin, protaminesulfate,
bleomycin)
b. Left ventricularoutflow obstruction
c.Infections
d. Cardiac (e.g., prosthetic heart valves,
repairofintracardiac defects)
e. Malignanthypertension
a.Drugs(e.g.,ristocetin, protaminesulfate,
bleomycin)
b. Left ventricularoutflow obstruction
c.Infections
d. Cardiac (e.g., prosthetic heart valves,
repairofintracardiac defects)
e. Malignanthypertension
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II.Disordersofplateletdistributionor poolingII.Disordersofplateletdistributionor pooling
A. Hypersplenism (e.g., portal
hypertension,Gauchers disease, cyanotic
congenital heart disease, neoplastic, infectious )
B. Hypothermia
A. Hypersplenism (e.g., portal
hypertension,Gauchers disease, cyanotic
congenital heart disease, neoplastic, infectious )
B. Hypothermia
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III.Decreased platelet production-deficient
thrombopoiesis
III.Decreased platelet production-deficient
thrombopoiesis
(decreasedorabsentmegaka-ryocytesinthe
marrow-amegakaryocytic thrombocytopenia)
A. Hypooplasiaorsuppressionof
megakaryocytes
1.Drugs(e.g., chlorthiazides,estrogenic
hormones,ethanol,tolbutamide)
2. Constitutional
(decreasedorabsentmegaka-ryocytesinthe
marrow-amegakaryocytic thrombocytopenia)
A. Hypooplasiaorsuppressionof
megakaryocytes
1.Drugs(e.g., chlorthiazides,estrogenic
hormones,ethanol,tolbutamide)
2. Constitutional
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a. Thrombocytopeniaabsentradii- TAR
syndrome.
b. Congenitalmegakaryocytic hypoplasia
withoutanomalies
c. Congenitalhypoplastic thrombocytopeniawith
microcephly .
a. Thrombocytopeniaabsentradii- TAR
syndrome.
b. Congenitalmegakaryocytic hypoplasia
withoutanomalies
c. Congenitalhypoplastic thrombocytopeniawith
microcephly .
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d. Rubellasyndrome
e. Trisomy 13,18
f. Fanconisanemia
d. Rubellasyndrome
e. Trisomy 13,18
f. Fanconisanemia
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4.Disordersofcontrolmechanism4.Disordersofcontrolmechanism
a. Thrombopoietindeficiency
b. Tidal plateletdysgenesis
c.
Cyclic thrombocytopenias
a. Thrombopoietindeficiency
b. Tidal plateletdysgenesis
c.
Cyclic thrombocytopenias
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5. Metabolic disorders5. Metabolic disorders
a. Methylmalonic acidemia
b. Ketotic glycinemia
c. Holocarboxylasesynthetase
deficiency
d.Isovaleric acidemia
e.Idiopathic hyperglycinemiaf.Infantsborntohypothyroid
mothers
a. Methylmalonic acidemia
b. Ketotic glycinemia
c. Holocarboxylasesynthetase
deficiency
d.Isovaleric acidemia
e.Idiopathic hyperglycinemiaf.Infantsborntohypothyroid
mothers
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Hereditary plateletdisordersHereditary plateletdisorders
a. Bernard-Souliersyndrome
b. May Hegglinanomaly
c.Wiskott-Aldrichsyndrome
d. Puresexlinkedthrombocytopenia
e. Mediterraneanthrombocytopenia
a. Bernard-Souliersyndrome
b. May Hegglinanomaly
c.Wiskott-Aldrichsyndrome
d. Puresexlinkedthrombocytopenia
e. Mediterraneanthrombocytopenia
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7- Acquiredaplastic disorders7- Acquiredaplastic disorders
a. Idiopathic
b. Druginduced(e.g.,doesrelated:anticanceragents;benzene,organic
andinorganic arsenicals,Mesanthoin, Tridione,antithyroids,antidiabetics,antihis-tamines,
phenylbutazone,insecticides,goldcompounds;idiosyncrasy: chloram-phenicol)
a. Idiopathic
b. Druginduced(e.g.,doesrelated:anticanceragents;benzene,organic
andinorganic arsenicals,Mesanthoin, Tridione,antithyroids,antidiabetics,antihis-tamines,
phenylbutazone,insecticides,goldcompounds;idiosyncrasy: chloram-phenicol)
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c. Radiationinduced
d. Viralinfections(e.g.,hepatitis, HIV,EBV)
B.
Marrow infiltrative processes1- Benign
a. Osteopetrosis
b.Storagediseases
c. Radiationinduced
d. Viralinfections(e.g.,hepatitis, HIV,EBV)
B.
Marrow infiltrative processes1- Benign
a. Osteopetrosis
b.Storagediseases
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2- Malignant
a. Denovo-leukemias,myelofibrosis,langerhans cellhistiocytosis,
histiocytic medullary
reticulosis
b. Secondary-lymphomas,
neuroblastoma,othersolidtumormetastases
2- Malignant
a. Denovo-leukemias,myelofibrosis,langerhans cellhistiocytosis,
histiocytic medullary
reticulosis
b. Secondary-lymphomas,
neuroblastoma,othersolidtumormetastases
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A bonemarrow biopsy,inadditiontomarrowaspiration,shouldalwaysbe carriedoutto
avoidsam-plingerrorsandtoestablishthe
presenceofadecreasednumberof
megakaryocyocytes inthemarrow.
These conditionsareassociated withnormalor
increasedbonemarrow megakaryocytes.
A bonemarrow biopsy,inadditiontomarrowaspiration,shouldalwaysbe carriedoutto
avoidsam-plingerrorsandtoestablishthe
presenceofadecreasednumberof
megakaryocyocytes inthemarrow.
These conditionsareassociated withnormalor
increasedbonemarrow megakaryocytes.
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Inadults,the chronic formismore common,
whereasin children,theacuteformismore
common. The clinicalfeaturesofacuteandchronic ITP arelistedintable 10-2.
Incidence
ThetrueincidenceofITP isunknownBecausethediseaseis
oftentransient. Theesti-matedincidenceis
about 1 in 10.000 people peryear.
Inadults,the chronic formismore common,
whereasin children,theacuteformismore
common. The clinicalfeaturesofacuteandchronic ITP arelistedintable 10-2.
Incidence
ThetrueincidenceofITP isunknownBecausethediseaseis
oftentransient. Theesti-matedincidenceis
about 1 in 10.000 people peryear.
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Pathogenesis
PlateletsurvivalPlateletsurvivalisgreatlyshortened.
Chromium-51 (51Cr) labeled plateletshave
alifespanof1-4hourstoafew minutes.
Pathogenesis
PlateletsurvivalPlateletsurvivalisgreatlyshortened.
Chromium-51 (51Cr) labeled plateletshave
alifespanof1-4hourstoafew minutes.
Pl t l t A tib diPl t l t A tib di
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Platelet AntibodiesPlatelet Antibodies
Increasedquantitiesofimmunoglobulin(
IgG)
Havebeendemonstratedonthe plateletsurface
andtherateofplateletdestructionin TTP is
proportionaltolevelsofsuch platelt-associated
IgG (PALgG). Recently,targetantigensof
autoantibodieshavebeenshown: Platelet
glycoprotein(Gp) IIb/IIIa, Gp Ib/Ix,and Gpv .
Increasedquantitiesofimmunoglobulin(
IgG)
Havebeendemonstratedonthe plateletsurface
andtherateofplateletdestructionin TTP is
proportionaltolevelsofsuch platelt-associated
IgG (PALgG). Recently,targetantigensof
autoantibodieshavebeenshown: Platelet
glycoprotein(Gp) IIb/IIIa, Gp Ib/Ix,and Gpv .
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Host FactorsHost Factors
There is a higher incidence than expectedof human leukocyte antigens (HLA) B8
and B12 in patients. Persone with this
specific phenotype run a higher risk of
devel-oping thedisease, if exposed to
precipitating factors.
There is a higher incidence than expectedof human leukocyte antigens (HLA) B8
and B12 in patients. Persone with this
specific phenotype run a higher risk of
devel-oping thedisease, if exposed to
precipitating factors.
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Clinical FeaturesClinical Features
1- Age: Thegreatestfrequencyofoccurrenceisbetweenages 2 and 8years.
Infantsless
Than 2 yearsold(infantileITP) havethefollowing clinicalfeatures:
a- More abrupt onset
1- Age: Thegreatestfrequencyofoccurrenceisbetweenages 2 and 8years.
Infantsless
Than 2 yearsold(infantileITP) havethefollowing clinicalfeatures:
a- More abrupt onset
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b- Moresevere clinical course
C- Platelet countgenerallyless than
20.000/mmm3
D- Poorresponsetotreatment
e- Higherincidentofchronicity
(30%)
b- Moresevere clinical course
C- Platelet countgenerallyless than
20.000/mmm3
D- Poorresponsetotreatment
e- Higherincidentofchronicity
(30%)
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2- sex: Bothsexesareequally
affected.
3- Predisposingfactors: A historyofprecedinginfection,usually viral,isnoted
withinthe preceding 3weeksin50-80% of
cases.
2- sex: Bothsexesareequally
affected.
3- Predisposingfactors: A historyofprecedinginfection,usually viral,isnoted
withinthe preceding 3weeksin50-80% of
cases.
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Nonspecific upperrespira-tory
infectionsarethemost commoninpostinfectious cases.Inabout 20%
ofcases,aspecific infection canbe
duetosmallpoxorlivemeasles
vaccination.
Nonspecific upperrespira-tory
infectionsarethemost commoninpostinfectious cases.Inabout 20%
ofcases,aspecific infection canbe
duetosmallpoxorlivemeasles
vaccination.
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SymptomsSymptoms
Petechiae, purpura,andecchymoses
(bruising) arethesymptoms
associated withstratesanapproachbasedonbleedingtime.
Petechiae, purpura,andecchymoses
(bruising) arethesymptoms
associated withstratesanapproachbasedonbleedingtime.
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Skin
Echymosesor purpuraareusuallyfoundontheanteriorsurfaceofthew lowerex-tremities
andoverbony prominences,suchastheribs
scapula,legs,and pubic area. Symptomsare
mildin50% ofcases withfew bruisesonthe
legsortrunk.
Skin
Echymosesor purpuraareusuallyfoundontheanteriorsurfaceofthew lowerex-tremities
andoverbony prominences,suchastheribs
scapula,legs,and pubic area. Symptomsare
mildin50% ofcases withfew bruisesonthe
legsortrunk.
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Mucous MembranesMucous Membranes
Petechiaemaybefoundinthesub conjunctivae,buccalmucosa,soft palate,andskin. Bleeding
fromthenose,gums,mucousmembranes,
gastrointinaltract,orkidneysisnotuncommon,especiallyattheonestofdisease.
Menorrhagiamayoccurandmaybesever.
Hematemesisandmelenaareinfrequent.
Petechiaemaybefoundinthesub conjunctivae,buccalmucosa,soft palate,andskin. Bleeding
fromthenose,gums,mucousmembranes,
gastrointinaltract,orkidneysisnotuncommon,especiallyattheonestofdisease.
Menorrhagiamayoccurandmaybesever.
Hematemesisandmelenaareinfrequent.
I l OI l O
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Internal OrgansInternal Organs
Bleedingmayoccurintothefollowingorgans :1- Centralnervoussystem-aserious complication,
usually precededbyheadacheanddizziness
andacutebleedingmanifestationselsewhere2- Retinalhemorrhage
Bleedingmayoccurintothefollowingorgans :1- Centralnervoussystem-aserious complication,
usually precededbyheadacheanddizziness
andacutebleedingmanifestationselsewhere2- Retinalhemorrhage
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3- Middleear-uncommon;leadstohearing
impairment
4- Deep musclehematomateand
hemarthrosis-rare; characteristic ofplasma
conagulationfactordisorders;seenafterintramuscularinjectionor significant
trauma.
3- Middleear-uncommon;leadstohearing
impairment
4- Deep musclehematomateand
hemarthrosis-rare; characteristic ofplasma
conagulationfactordisorders;seenafterintramuscularinjectionor significant
trauma.
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PLATELET COUNT
NORMALLOW
VASCULAR Platelet Dysfunction
Congenital AcquiredCongental Acquired
Hemorrhagic telangiectasia
Ehlers- Danlos syndrome
Henoch-Schonlein purpura
Purpura factitia purpura
Fulminans vasculitis(e.g., SLE
Clinical approach to nonthrombocytopenic purpuraClinical approach to nonthrombocytopenic purpura
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Clinical approach to nonthrombocytopenic purpura
based on bleeding time
Clinical approach to nonthrombocytopenic purpura
based on bleeding time
Normal Platelet Count
Normal Ab
Normal Platelet Count
Normal Ab
PetechiaePurpuraEcchymoses
Bleeding Time
Henich- Schonlein
Purpura
Purpura factitia
Fvlll activity
Fvlll antigen
Vwf
Fvlll activity
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Normal Abn Normal Abn
Fvlll activity
Fvlll antigen
Vwf
Platelet aggregation(ADP, epinephrine
Collagen, ristocetin
Von Willebrandsdisease
Adhesion defects
Aggregation defects
Defects in release
Congenital vascular
disorders hemorrhagic
Telangiectasia
Ehlers-danlos syndrome
Abnormal Normal
Normal Abn
Abnormal
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Signs :-
Withtheexceptionofhemorrhagicmanifestation,the physicalexaminationis
notsignificant. Pallorisusuallyabsent
unlesstherehasbeensignificantbleeding.Thetip ofthespleenis palpableinfewer
than 10% ofpatients.
Signs :-
Withtheexceptionofhemorrhagicmanifestation,the physicalexaminationis
notsignificant. Pallorisusuallyabsent
unlesstherehasbeensignificantbleeding.Thetip ofthespleenis palpableinfewer
than 10% ofpatients.
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Thefindingofsplenomegalysuggeststhe
probabilityofleukemia,systemiclupuserythematosus(SLE),infectious,
mononucleosis,orhypersplenism.
Cervicallymphadenopathyisnot present
unlessthe precipitatingfactorisa viralillness.
Thefindingofsplenomegalysuggeststhe
probabilityofleukemia,systemiclupuserythematosus(SLE),infectious,
mononucleosis,orhypersplenism.
Cervicallymphadenopathyisnot present
unlessthe precipitatingfactorisa viralillness.
Laboratory FindingsLaboratory Findings
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Laboratory FindingsLaboratory Findings
1-Platelet counta- Always less than 100.000/mm3
b-Often less than 200.000/mm3 in
patients with severe generalized
hemorrhagic
1-Platelet counta- Always less than 100.000/mm3
b-Often less than 200.000/mm3 in
patients with severe generalized
hemorrhagic
Platelet Diseases Based onPlatelet Diseases Based on
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Platelet Diseases Based on
PlateletSize
Platelet Diseases Based on
PlateletSize
Macrothrombocytes(MPV)
ITP orany condition withincreased
plateletturnover(e.g.,DI
C)Bernard-Souliersyndrome
May Hegglinanomaly
Alportsyndrome
Macrothrombocytes(MPV)
ITP orany condition withincreased
plateletturnover(e.g.,DI
C)Bernard-Souliersyndrome
May Hegglinanomaly
Alportsyndrome
S i h l t l t d M t lS i h l t l t d M t l
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Swiss cheese plateletsyndrome Montreal
plateletsyndrome
Gray plateletsyndrome Various
mucopolysaccharidoses
Normalsize(MPVnormal)
Swiss cheese plateletsyndrome Montreal
plateletsyndrome
Gray plateletsyndrome Various
mucopolysaccharidoses
Normalsize(MPVnormal)
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conditionsin whichmarrow is
hypocellularorinfiltrated withmalignantdisease
Microthrombocytes(MPV decreased)
Wiskott AldrichsyndromeTARsyndrome
Somestorage pooldiseases
Iron- deficiencyanemia
conditionsin whichmarrow is
hypocellularorinfiltrated withmalignantdisease
Microthrombocytes(MPV decreased)
Wiskott AldrichsyndromeTARsyndrome
Somestorage pooldiseases
Iron- deficiencyanemia
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Notes:-
MPV,mean platelet volume
(asdeterminedbyautomatedelectronic
counters);
normal,8.9 1.5um3 ,ITP,idiopathic
Notes:-
MPV,mean platelet volume
(asdeterminedbyautomatedelectronic
counters);
normal,8.9 1.5um3 ,ITP,idiopathic
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thrombocytopenic purpura;disseminated
intravascular coagulation; TAR,
thrombocytopenic absentradii.
C- Mean platelet volume(MPV)increased(on
automated
countingequipment);normal,8.9 1
.5um
3
thrombocytopenic purpura;disseminated
intravascular coagulation; TAR,
thrombocytopenic absentradii.
C- Mean platelet volume(MPV)increased(on
automated
countingequipment);normal,8.9 1
.5um
3
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2- Blood smear2- Blood smear
a- Bloodsmearnormal,aprtfrom
thrombocytopenia(ifactiveinfection,in-
creasedneutrophils,lymphocytes,oratypical
mononuclear cellsmaybe present)
b- Mildeosinophilia( 25% ofpatients)
c- Anemia presentonlyin proportionto
amountofbloodloss
a- Bloodsmearnormal,aprtfrom
thrombocytopenia(ifactiveinfection,in-
creasedneutrophils,lymphocytes,oratypical
mononuclear cellsmaybe present)
b- Mildeosinophilia( 25% ofpatients)
c- Anemia presentonlyin proportionto
amountofbloodloss
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3-Bone marrow3-Bone marrow
a- Increased megakaryocytes, often immatureand with absence of budding
b-Normal erythriod and myeloid cells
c- Increased eosinophils (25% of patients)
a- Increased megakaryocytes, often immatureand with absence of budding
b-Normal erythriod and myeloid cells
c- Increased eosinophils (25% of patients)
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d- Erythroidhyperplasiaifsignificantbloodloss.
(marrow findingsarediagnostic ofITP onlywhenconsistent withthe clinicalstateand
presenceofalow platelet countand when
other causes
d- Erythroidhyperplasiaifsignificantbloodloss.
(marrow findingsarediagnostic ofITP onlywhenconsistent withthe clinicalstateand
presenceofalow platelet countand when
other causes
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Ofsecondarythrombocytopeniaareexcluded. Themain purposeof
performingabonemarrow
examinationistoexcludeotherhematologic disorders,e.g.,leukemia.)
Ofsecondarythrombocytopeniaareexcluded. Themain purposeof
performingabonemarrow
examinationistoexcludeotherhematologic disorders,e.g.,leukemia.)
4 C l ti fil4 C l ti fil
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4- Coagulation profile4- Coagulation profile
a- Bleedingtime usuallyabnormal
b- Clotretraction poortoabsent
c- Prothrombintime(PT),activated partial
thromboplastintime(APTT),andfibrinogenlevel normal
d- Prothrombin consumptiontest defective
utilizationofprothrombin
a- Bleedingtime usuallyabnormal
b- Clotretraction poortoabsent
c- Prothrombintime(PT),activated partial
thromboplastintime(APTT),andfibrinogenlevel normal
d- Prothrombin consumptiontest defective
utilizationofprothrombin
5- Investigations in patients with5- Investigations in patients with
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5- Investigations in patients with
purpura
5- Investigations in patients with
purpura
a- Completeblood count(CBC),including
bloodsmearand platelet count
b- Bonemarrow aspirationc- Antinuclearantibody
(ANA),C3,C4,CH50,andanti-ds-DNA
d- Coombstest
a- Completeblood count(CBC),including
bloodsmearand platelet count
b- Bonemarrow aspirationc- Antinuclearantibody
(ANA),C3,C4,CH50,andanti-ds-DNA
d- Coombstest
A fib i l l d li dA fib i l l d li d
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e- PT,APTT,fibrinogenlevel,andsplit products
offibrinogen(SPF)
f-Liverfunctiontests withbloodureanitrogen
(BUN) and creatinine
f- Monospottestand/or Epstein-Barr
virus(EBV),humanimmunodeficiency virus
(HIV) ,parvovirustiters
h- Exciusionofsecondary causesof
thrombocytopenia
e- PT,APTT,fibrinogenlevel,andsplit products
offibrinogen(SPF)
f-Liverfunctiontests withbloodureanitrogen
(BUN) and creatinine
f- Monospottestand/or Epstein-Barr
virus(EBV),humanimmunodeficiency virus
(HIV) ,parvovirustiters
h- Exciusionofsecondary causesof
thrombocytopenia
DiagnosisDiag
nosis
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DiagnosisDiagnosis
Criteriforthediagnosisareasfollows:
1- Clinicalexamination-purpura with
anotherwiseessentiallynormal
physicalexamination, withno
significantsplenomegalyandno
lymphadenopathy
Criteriforthediagnosisareasfollows:
1- Clinicalexamination-purpura with
anotherwiseessentiallynormal
physicalexamination, withno
significantsplenomegalyandno
lymphadenopathy
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2- Platelet countandbloodssmears-
thrombocytopeniaonly, withno
evidenceofred cellor whitebloodcellabnormalities
2- Platelet countandbloodssmears-
thrombocytopeniaonly, withno
evidenceofred cellor whitebloodcellabnormalities
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3- Bonemarrow-normaltoincreasednumberofmegakaryocytes with
normalmyeloidanderythroid
elements
3- Bonemarrow-normaltoincreasednumberofmegakaryocytes with
normalmyeloidanderythroid
elements
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4- Exclusionofsecondary causesofthrombocytopenia,suchas
hypersplenismmicroangiopathic
hemolytic anemia,disseminatedintravascular coagulation(DIC),drug-
inducedthrombocytopenia(Tabe 10-
5
), SLE,infectionssuchas EBV, HI
V,and parvovirus.
4- Exclusionofsecondary causesofthrombocytopenia,suchas
hypersplenismmicroangiopathic
hemolytic anemia,disseminatedintravascular coagulation(DIC),drug-
inducedthrombocytopenia(Tabe 10-
5
), SLE,infectionssuchas EBV, HI
V,and parvovirus.
TreatmentTreatment
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TreatmentTreatment
Notreatmentisrequired whenthe platelet countisgreaterthan 35.000/mm3 andthe patientis
asymptomatic (mildbruisingbutnoevidence
ofmucousmembranebleeding).Contactsportsshouldbeavoided.
Notreatmentisrequired whenthe platelet countisgreaterthan 35.000/mm3 andthe patientis
asymptomatic (mildbruisingbutnoevidence
ofmucousmembranebleeding).Contactsportsshouldbeavoided.
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Depo-Proveraoranyotherlong-acting
progesteroneisusefulinsuspending
menstruationforseveralmonths,to
preventexcessivemenorrhagiain
menstuatingfemales.
Depo-Proveraoranyotherlong-acting
progesteroneisusefulinsuspending
menstruationforseveralmonths,to
preventexcessivemenorrhagiain
menstuatingfemales.
Steroid therapySteroid therapy
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Steroid therapySteroid therapy
1- Rationala.Inhibits phagocytosisofantibody-
coated plateletsinthespleen and prolongs
plateletsurvival
b.Improves capillaryresistanceand
therebyimproves plateleteconomy
c.Inhibits plateletantibody production
1- Rationala.Inhibits phagocytosisofantibody-
coated plateletsinthespleen and prolongs
plateletsurvival
b.Improves capillaryresistanceand
therebyimproves plateleteconomy
c.Inhibits plateletantibody production
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2- Indications2- Indications
a. Bleedingfrommucousmembranes
b. Extensive purpuraandbruising,especially
ofheadandneck
c. Progressive purpurad. Persistentthrombocytopenia
( beyond 3 weeks)
e. Recurrentthrombocytopenia
f. Platelet countlessthan 30,000/mm3
a. Bleedingfrommucousmembranes
b. Extensive purpuraandbruising,especially
ofheadandneck
c. Progressive purpurad. Persistentthrombocytopenia
( beyond 3 weeks)
e. Recurrentthrombocytopenia
f. Platelet countlessthan 30,000/mm3
3. Does and duration3. Does and duration
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3.Doesandduration
a. Acourseofprednisone, 60 mg/day,isgiven
individeddoses(40 mg/dayfor childrenunder 2 yearsofage ) . Prednisoneisreduced
inastepwisefashionto40 mg, 30 mg,and 10
mg/dayat5-7dayintervals,irrespectiveofthepolatelte count,andisstoppedattheendof
the course,regardlessoftheresponse.
3.Doesandduration
a. Acourseofprednisone, 60 mg/day,isgiven
individeddoses(40 mg/dayfor childrenunder 2 yearsofage ) . Prednisoneisreduced
inastepwisefashionto40 mg, 30 mg,and 10
mg/dayat5-7dayintervals,irrespectiveofthepolatelte count,andisstoppedattheendof
the course,regardlessoftheresponse.
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b.Ifthereisnoresponseorifthe platelet
countresponseandfallsagainasthesteroidsarediscontinued,arepeat
4-weekcourseshouldbegivenafteramonth
orso.
c.Insever cases,methylprednisolone
( Solumedrol ) 500mg/m2/dayfor5days
producesamorerapidresponsethan
conventionalsteroids.
b.Ifthereisnoresponseorifthe platelet
countresponseandfallsagainasthesteroidsarediscontinued,arepeat
4-weekcourseshouldbegivenafteramonth
orso.
c.Insever cases,methylprednisolone
( Solumedrol ) 500mg/m2/dayfor5days
producesamorerapidresponsethan
conventionalsteroids.
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d. Prolongeduseofsteroidsin TTP is
undesirable. Largedoesor prolonged
steroidusagemay perpetuatethe
thrombocytopeniaanddepress platelet
production.
d. Prolongeduseofsteroidsin TTP is
undesirable. Largedoesor prolonged
steroidusagemay perpetuatethe
thrombocytopeniaanddepress platelet
production.
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High-DoseIntravenous GammaglobulinHigh-DoseIntravenous Gammaglobulin
1- Rationale for high-dose intravenous gamma globulin
(IVGG) (Table10-6)
a. Reticuloendothelial fc-receptor blockade
b. Decrease in autoantibody synthesis
c. Protection of platelets and/ or megakaryocytes from
platelet antibody
d. Clearance of persistent viral infection byInfusion of specific antibody
1- Rationale for high-dose intravenous gamma globulin
(IVGG) (Table10-6)
a. Reticuloendothelial fc-receptor blockade
b. Decrease in autoantibody synthesis
c. Protection of platelets and/ or megakaryocytes from
platelet antibody
d. Clearance of persistent viral infection byInfusion of specific antibody
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2.IndicationsinacuteITP
a.Neonatalsymptomatic immune
thrombocytopeniaandinfantslessthan 2years
ofage whoaregenerallymorerefractoryto
steroidtreatmentb. Validalternativetherapyto corticosteroid
therapy
3. Available products(see Table 10-7)
2.IndicationsinacuteITP
a.Neonatalsymptomatic immune
thrombocytopeniaandinfantslessthan 2years
ofage whoaregenerallymorerefractoryto
steroidtreatmentb. Validalternativetherapyto corticosteroid
therapy
3. Available products(see Table 10-7)
4 Dosage4 Dosage
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4.Dosage
a. Acute ITP: a total does of 2g/kg body weigh
given as follows:
(1) 0.4g/kg IVGG per day for 5 days or
(2) 1g / kg per day for 2 days.
In infants less than 2 years old, 5-day protocol is
better tolerated
4.Dosage
a. Acute ITP: a total does of 2g/kg body weigh
given as follows:
(1) 0.4g/kg IVGG per day for 5 days or
(2) 1g / kg per day for 2 days.
In infants less than 2 years old, 5-day protocol is
better tolerated
b. Chronic ITPb. Chronic ITP
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(1) InitialIVGG doesof1g/kgbody weight
dailyfor 2days,followedby pe-riodic
singleinfusions(0.4-1g/kg- dependingon
response) tomaintain platelet countatasafe
level(>30.000/mm3
)(2) Alternate-day corticosteroidsuseful
adjunctivetherapy whenIVGG isused
(1) InitialIVGG doesof1g/kgbody weight
dailyfor 2days,followedby pe-riodic
singleinfusions(0.4-1g/kg- dependingon
response) tomaintain platelet countatasafe
level(>30.000/mm3
)(2) Alternate-day corticosteroidsuseful
adjunctivetherapy whenIVGG isused
5. Response5. Response
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a. AcuteITP : 80% rsepondinitially
(1) Fewerdaysofbleedingepisodescomparedtosteroidtreatment;fasterresponse
(2) Morerapidincreasein platelet counts
comparedtosteroidtreatment.
a. AcuteITP : 80% rsepondinitially
(1) Fewerdaysofbleedingepisodescomparedtosteroidtreatment;fasterresponse
(2) Morerapidincreasein platelet counts
comparedtosteroidtreatment.
6.IVGG toxicity6.IVGG toxicity
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a. AnaphylaxisinIgA- deficient patientsbecause
ofpreexistingIgA antibodiesthatreact withsmallamountsof IgA presentin commercially
availablegam-maglobulin
b. Postinfusionheadachein 20% ofpatients;
transientand possiblysevere(insevere cases,
administer postinfusiondexamethasone 0.15-
0.3mg/kgIV)
a. AnaphylaxisinIgA- deficient patientsbecause
ofpreexistingIgA antibodiesthatreact withsmallamountsof IgA presentin commercially
availablegam-maglobulin
b. Postinfusionheadachein 20% ofpatients;
transientand possiblysevere(insevere cases,
administer postinfusiondexamethasone 0.15-
0.3mg/kgIV)
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c. Feverand chillsin 1-3%ofpatients;
prophylactic asetaminophen(10-15mg/kg,4hourly,asrequired) and
diphenhydramine(1mg/kg, 6-8 hourly,as
required ) toreducetheincidenceandseverity
c. Feverand chillsin 1-3%ofpatients;
prophylactic asetaminophen(10-15mg/kg,4hourly,asrequired) and
diphenhydramine(1mg/kg, 6-8 hourly,as
required ) toreducetheincidenceandseverity
d. Coombs-positivehemolytic anemiabecauseofd. Coombs-positivehemolytic anemiabecauseof
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the presenceofbloodgroup antibodies(anti-A,
anti-B,anti- D) presentinIVGG
e. Hepatitis C virus(HCV) infectionreportedin
patientsreceivingIVGG;however,noreportsofHIV infection withanylicensed preparation
intheunitedstates
the presenceofbloodgroup antibodies(anti-A,
anti-B,anti- D) presentinIVGG
e. Hepatitis C virus(HCV) infectionreportedin
patientsreceivingIVGG;however,noreportsofHIV infection withanylicensed preparation
intheunitedstates
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CombinationsteroidsandIntravenous
Gammaglobulin
A patient with the following clinical findings
should be treated with both steroids and high-
dosage IVGG until he or she is clinically
improved and is asymptomatic and the platelet
count is greater than 30.000/mm3 :
CombinationsteroidsandIntravenous
Gammaglobulin
A patient with the following clinical findings
should be treated with both steroids and high-
dosage IVGG until he or she is clinically
improved and is asymptomatic and the platelet
count is greater than 30.000/mm3 :
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Bleedingfrommucousmembranesextensive
Petechiae, purpura,andecchymoses
symptomsand/orsignsofinternalhemorrhage,especilllyintracranial
hemorrhsge
Bleedingfrommucousmembranesextensive
Petechiae, purpura,andecchymoses
symptomsand/orsignsofinternalhemorrhage,especilllyintracranial
hemorrhsge
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This combinationelevatesthe platelet countmore
rapidlytohigherlevelsthaneitheralone.Itisveryuseful whenitis crucialtoincreasethe
platelet countrapidlyorin preparationfor
surgery.
High-dosesolumedrol500mg/m2 canbeusedas
thesteroidinemergencysituation.
This combinationelevatesthe platelet countmore
rapidlytohigherlevelsthaneitheralone.Itisveryuseful whenitis crucialtoincreasethe
platelet countrapidlyorin preparationfor
surgery.
High-dosesolumedrol500mg/m2 canbeusedas
thesteroidinemergencysituation.
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Anti-RhD Therapy
InfusionofIV anti-RhDimmunoglobulinto
individuals with RhD-positiveerythrocytes
causesatransienthemolytic anemiainthe
recipient. Coincident withimmune clearanceof
Anti-RhD Therapy
InfusionofIV anti-RhDimmunoglobulinto
individuals with RhD-positiveerythrocytes
causesatransienthemolytic anemiainthe
recipient. Coincident withimmune clearanceof
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theantibody-coatedautologousredblood cells,
thereis prolongedsurvivalofplateletsin
patients withITP. Themechanismforthe
beneficialeffectofIV anti- RhDinITP is
blockadeofthefc receptorsofreticuloendothelial cells
theantibody-coatedautologousredblood cells,
thereis prolongedsurvivalofplateletsin
patients withITP. Themechanismforthe
beneficialeffectofIV anti- RhDinITP is
blockadeofthefc receptorsofreticuloendothelial cells
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6. Theincreasein platelet countoccursafter48
hours;therefore,thistherapyisnot
appropriateforemergencytreatment.
Patients whohavenotappropriatefor
emergencytreatment. Patients whohavenotundergonesplenectomyaremorlikelyto
respondtoIV anti-RhDthanare
splenectomized patients.
6. Theincreasein platelet countoccursafter48
hours;therefore,thistherapyisnot
appropriateforemergencytreatment.
Patients whohavenotappropriatefor
emergencytreatment. Patients whohavenotundergonesplenectomyaremorlikelyto
respondtoIV anti-RhDthanare
splenectomized patients.
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Win Rho,anti-D,isa plasma-dervedgamma
immuneglobulin containingahightiterof
antibodiesto Rh0 antigensoftheredblood cells
(RBC) (anti-D) forIV injection.
Win Rho SDF (Nabi, Boca Raton, FL, USA) hasbeenlicensedinthe Unitedstates, canada,and
Ireland.
Win Rho,anti-D,isa plasma-dervedgamma
immuneglobulin containingahightiterof
antibodiesto Rh0 antigensoftheredblood cells
(RBC) (anti-D) forIV injection.
Win Rho SDF (Nabi, Boca Raton, FL, USA) hasbeenlicensedinthe Unitedstates, canada,and
Ireland.
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Prerequisiteforuse
The patientmustbe RhD positiveforthismode
oftherapytobebeneficial.
Dose
Win Rho SDF 50Mg/IV infusionovera 3-5
minute period. The platelet countand
hemoglobinlevelsshouldbe checked
approximately 1 weeklater,butnosoonerthan 3-4davs.
Prerequisiteforuse
The patientmustbe RhD positiveforthismode
oftherapytobebeneficial.
Dose
Win Rho SDF 50Mg/IV infusionovera 3-5
minute period. The platelet countand
hemoglobinlevelsshouldbe checked
approximately 1 weeklater,butnosoonerthan 3-4davs.
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Ifthe platelet counthasincreased,thanthe
patient canbere-treatedifthe platelt count
fallsto 30.
000/MI.
I
fthehemoglobinleveldecreaseis
1 g/dlorless,thedose canbeincreasedup to
70-80 Mg/ Kgdose.
Ifthe platelet counthasincreased,thanthe
patient canbere-treatedifthe platelt count
fallsto 30.
000/MI.
I
fthehemoglobinleveldecreaseis
1 g/dlorless,thedose canbeincreasedup to
70-80 Mg/ Kgdose.
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Repeatanti-RhDtreatmentat 3-8 week
intervals,maintaininga platelet countof
morethan 30.000/mm3.
Repeatanti-RhDtreatmentat 3-8 week
intervals,maintaininga platelet countof
morethan 30.000/mm3.
VincristineVincristine
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VincristineVincristine
Dose: 0.02 mg/kg(maximum,2mg) IV, weekly4In patients whorespondto vincristine
and vinblastine,there isa promptrisein
platelet count,oftentonormalrange.
Mostchildrenrequirerepeateddosesat 2-3 week
intervalstomaintainasafe platelet count.If
thereisnoresponseafter4 weeks,further
treatmentisnotindicated.
Dose: 0.02 mg/kg(maximum,2mg) IV, weekly4In patients whorespondto vincristine
and vinblastine,there isa promptrisein
platelet count,oftentonormalrange.
Mostchildrenrequirerepeateddosesat 2-3 week
intervalstomaintainasafe platelet count.If
thereisnoresponseafter4 weeks,further
treatmentisnotindicated.
DanazolDanazol
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DanazolDanazol
Danazolisanandrogen;ithasbeenshowntoincreasethe platelet countinsome patients
withrefractoryITP.
Does
300-400 mg/m2 /dayorallyfor 2-3 months.
Danazolisanandrogen;ithasbeenshowntoincreasethe platelet countinsome patients
withrefractoryITP.
Does
300-400 mg/m2 /dayorallyfor 2-3 months.
SideeffectsSideeffects
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*Acne * Hirsutism
*Weightgain * Livertoxicity
Vinblastineanddanazolhavebeenused
withsomesuccessin combination.
*Acne * Hirsutism
*Weightgain * Livertoxicity
Vinblastineanddanazolhavebeenused
withsomesuccessin combination.
CyclophosphamidC
yclophosphamid
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The action of cycloposphamide is similar to thatof azatghioprine (see below)
The action of cycloposphamide is similar to thatof azatghioprine (see below)
A responseusuallyoccurs 2-10 weeksaftertheA responseusuallyoccurs 2-10 weeksafterthe
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p y
initiationoforaltherapy
Sideeffects
Bonemarrow suppression
Alopecia
Hepatic toxicity
Hemorrhagic cystitis
Leukemia(Long-term complication)
p y
initiationoforaltherapy
Sideeffects
Bonemarrow suppression
Alopecia
Hepatic toxicity
Hemorrhagic cystitis
Leukemia(Long-term complication)
Azathioprine
Immunosuppression withazathioprine
Azathioprine
Immunosuppression withazathioprine
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u osupp ess o w op e
Hasbeenbeneficialin patients withsome
autoimmunediseases(e.g.,autoimmune
hemolytic anemia,ITP)
u osupp ess o w op e
Hasbeenbeneficialin patients withsome
autoimmunediseases(e.g.,autoimmune
hemolytic anemia,ITP)
- Interferon- Interferon
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Platelettransfusions
Plasmapharoin
Splenectomy:- SplenectomyisindicatedforseveracuteITP withacutelife-threateningbleeding,whichisnonresponsivetomedicaltreatment
Platelettransfusions
Plasmapharoin
Splenectomy:- SplenectomyisindicatedforseveracuteITP withacutelife-threateningbleeding,whichisnonresponsivetomedicaltreatment
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