acute lymphob (2)

8/6/2019 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


62/143

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


63/143

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


64/143

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


65/143

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


66/143

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


67/143

a. Thrombocytopeniaabsentradii- TAR

syndrome.

b. Congenitalmegakaryocytic hypoplasia

withoutanomalies

c. Congenitalhypoplastic thrombocytopeniawith

microcephly .

a. Thrombocytopeniaabsentradii- TAR

syndrome.

b. Congenitalmegakaryocytic hypoplasia

withoutanomalies

c. Congenitalhypoplastic thrombocytopeniawith

microcephly .


68/143

d. Rubellasyndrome

e. Trisomy 13,18

f. Fanconisanemia

d. Rubellasyndrome

e. Trisomy 13,18

f. Fanconisanemia


69/143


70/143

4.Disordersofcontrolmechanism4.Disordersofcontrolmechanism

a. Thrombopoietindeficiency

b. Tidal plateletdysgenesis

c.

Cyclic thrombocytopenias

a. Thrombopoietindeficiency

b. Tidal plateletdysgenesis

c.

Cyclic thrombocytopenias


71/143

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


72/143

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


73/143

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)


74/143

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


75/143

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


76/143

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.


77/143

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.


78/143

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


79/143

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 .


80/143

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.


81/143

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


82/143

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%)


83/143

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.


84/143

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.


85/143

SymptomsSymptoms

Petechiae, purpura,andecchymoses

(bruising) arethesymptoms

associated withstratesanapproachbasedonbleedingtime.


(bruising) arethesymptoms

associated withstratesanapproachbasedonbleedingtime.


86/143

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.


87/143

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


88/143

Internal OrgansInternal Organs

Bleedingmayoccurintothefollowingorgans :1- Centralnervoussystem-aserious complication,

usually precededbyheadacheanddizziness

andacutebleedingmanifestationselsewhere2- Retinalhemorrhage

Bleedingmayoccurintothefollowingorgans :1- Centralnervoussystem-aserious complication,

usually precededbyheadacheanddizziness

andacutebleedingmanifestationselsewhere2- Retinalhemorrhage


89/143

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.


90/143

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


91/143

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


92/143

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


93/143

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.


94/143

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


95/143

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


96/143

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


97/143

Swiss cheese plateletsyndrome Montreal

plateletsyndrome

Gray plateletsyndrome Various

mucopolysaccharidoses

Normalsize(MPVnormal)

Swiss cheese plateletsyndrome Montreal

plateletsyndrome

Gray plateletsyndrome Various

mucopolysaccharidoses

Normalsize(MPVnormal)


98/143

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


99/143

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


100/143

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


101/143

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


102/143

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)


103/143

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


104/143

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


105/143

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


106/143

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


107/143

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


108/143

DiagnosisDiagnosis

Criteriforthediagnosisareasfollows:

1- Clinicalexamination-purpura with

anotherwiseessentiallynormal

physicalexamination, withno

significantsplenomegalyandno

lymphadenopathy

Criteriforthediagnosisareasfollows:

1- Clinicalexamination-purpura with

anotherwiseessentiallynormal

physicalexamination, withno

significantsplenomegalyandno

lymphadenopathy


109/143

2- Platelet countandbloodssmears-

thrombocytopeniaonly, withno

evidenceofred cellor whitebloodcellabnormalities

2- Platelet countandbloodssmears-

thrombocytopeniaonly, withno

evidenceofred cellor whitebloodcellabnormalities


110/143

3- Bonemarrow-normaltoincreasednumberofmegakaryocytes with

normalmyeloidanderythroid

elements

3- Bonemarrow-normaltoincreasednumberofmegakaryocytes with

normalmyeloidanderythroid

elements


111/143

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


112/143

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.


113/143

Depo-Proveraoranyotherlong-acting

progesteroneisusefulinsuspending

menstruationforseveralmonths,to

preventexcessivemenorrhagiain

menstuatingfemales.

Depo-Proveraoranyotherlong-acting

progesteroneisusefulinsuspending

menstruationforseveralmonths,to

preventexcessivemenorrhagiain

menstuatingfemales.

Steroid therapySteroid therapy


114/143

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


115/143

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


116/143

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.


117/143

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.


118/143

d. Prolongeduseofsteroidsin TTP is

undesirable. Largedoesor prolonged

steroidusagemay perpetuatethe

thrombocytopeniaanddepress platelet

production.

d. Prolongeduseofsteroidsin TTP is

undesirable. Largedoesor prolonged

steroidusagemay perpetuatethe

thrombocytopeniaanddepress platelet

production.


119/143

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


120/143

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


symptomsand/orsignsofinternalhemorrhage,especilllyintracranial

hemorrhsge

Bleedingfrommucousmembranesextensive


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

acute lymphob (2)

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