Karen Nina Ocampo, MD

10 January 20088 am Ledesma Hall, MMC

Learning Objectives: To present a case of chronic ITP To discuss the presentation of chronic ITP To discuss the pathogenesis, diagnosis and

management of chronic ITP To discuss updates on diagnosis and

management of ITP

GENERAL DATA

V.A. 65 year old Female Filipino Roman Catholic

2 weeks PTA patient noted to have hematomas over left shoulder and left arm Denies history of fever nor trauma, intake of medications (+) petechiae lower extremities no consult was done

One day PTA

(+) right leg pain, weakness,Persistence of hematomas ER consult

ADMISSION

History of Present Illness

Review of SystemNo weight loss, anorexiaNo headache, blurring of visionNo dyspnea, orthopneaNo chest pain, palpitationsNo abdominal pain, diarrhea, vomitingNo hematuria, dysuria No arthralgia, edema

5

Past Medical HistoryNo hypertension, diabetes mellitus, asthma

Family HistoryNo hypertension, diabetes mellitus, asthma

Patient recalled similar symptoms among third degree relatives

Personal and Social Historynon smoker and non alcoholic beverage drinker

OB and Gynecologic History

8

She had menarche at age 16, regular lasting for 5 days consuming about 3 pads a day.

She is a G4P4(4004), all were normal deliveries assisted by midwife, denies any miscarriages nor any other pregnancy related complications. Patient is menopause 

PHYSICAL EXAMINATION General survey : conscious & coherent not in

distress

Admitting vital signs BP 150/80 mmHg , HR 89 bpm , RR 16 cpm ,

T 37 C

SHEENT: (+)hematoma, petechiae, ecchymoses on both upper and lower extremities , pinkish palpebral conjunctivae, anicteric sclerae,

HEART: Adynamic precordium, normal rate regular rhythm, apex beat at 5th ICS, LMCL, no murmur

PHYSICAL EXAMINATION CHEST and LUNGS: Symmetrical chest

expansion, no retractions, clear breath sounds

ABDOMEN: flabby, soft, normal active bowel sounds, no tenderness non palpable liver and spleen

EXTREMITIES: no edema, no cyanosis, full and equal pulses

SALIENT FEATURES 65 year old female menopauseno history of trauma/intake of any medicine no melena, hematochezia, hemoptysis no feverhematomas, eccymoses, and petechiae on all

extremitiesNo splenomegaly

INITIAL IMPRESSION Bleeding disorder, to consider coagulopathy versus thrombocytopenia

COURSE IN THE WARDS:HEMATOLOGY SERVICE

On admission CBC showed severe thrombocytopenia (platelet count 10, 000).

Initially transfused with 4 units platelet concentrate.

Started on Solucortef IVBMA done

Slightly hypecellular bone marrow 40% with megakaryocyticErythroid Hyperplasia and relative increase in eosinophils 13.7%

Morphologic findings consistent with peripheral consumption of plateletsBone marrow diff count

blast 2%granulocytic 32.6%eosinophils 13.7%basophils 0%lymphocytes 12.1%plasma cells 1.1%

15

Noted to have episodes of gum bleeding and hematuria,

Aside from platelet concentrate, FFP and PRBC was also transfused

Almost 40 units platelet concentratewas transfused,development of platelet antibodies considered.

Given IV Ig

Started on cyclophophamide 1 gm in 250cc D5W

Transfused with plasma pheresis

Azathioprine 50mg started

16

Hematology sheetCBC 10/20

D110/21 D2

10/22 D3

10/23 D4

10/24 D5

10/25D6

10/26D7

6H post BT

10/27D8

10/27D9

10/28D10

Hemoglobin 12.6 11.4 11.2 10.7 9 8.6 10.9 10.4 11.1

Hematocrit 37 36.1 35.7 34.8 28.9 27.8 34.1 33 33.5

RBC 5.5 5.5 5.3 5.1 4.4 4.2 5 4.8 5

WBC 5400 6050 6320 4930 6280 5770 5360 9140 8980 8620

Eosinophils 8 2 1 1 1 1 1 2 1

Stabs 0 1

Segmenters 42 73 63 62 66 50 54 63 37 65

Lymphocytes 44 18 32 32 30 40 40 33 57 27

platelet count 10T 6T 14T 10T 8T 6T 7T 5T 10T 10T 4T

Platerlet conc transfused

4units 8units 4units 4units

18

CBC 11/1 D12

11/4D15

11/6D17

11/8D19

11/9D20

11/10D21

11/11D22

11/12D23

11/13D24

11/14D25

11/15D26

Hemoglobin 11.1 8.8 11.2 11.4 8.9 9 9.6 7.6 10.7 10.2 9.7

Hematocrit 33.6 27.4 34.3 33 27.3 28.5 29.7 24.3 33.1 31.7 30.3

RBC 5 3.9 4.7 4.8 3.9 4 4.2 3.4 4.4 4.2 4

WBC 9100 8470 9140 10830 4980 4200 8930 7710 9350 6210 4930

Eosinophils 2 3 2 2

Stabs 0

Segmenters 72 67 50 60 79 85 75 78 83 80 70

Lymphocytes 20 21 43 34 16 12 17 15 13 14 20

platelet count 7T 5T 10T 10T 7T 16T 5T 5T 9T 6T 4T

11/16D27

11/21 11/24

9.7 10.7 11.8

31.3 34 35

3.9 4.5 4.5

3660 4680 5150

83 85 85

83 85 85

10 7 10

9T 3T 5T

NeurologyProblem 2 Right lower leg painInitial Impression was Transient Ischemic

attack LMCA branchGiven somazine initiallyCT scan of lumbar spine showed spinal

canal stenosis L4 – S1Lyrica was given, no other interventions done

and was treated symptomatically

CardiologyProblem 3 HypertensionPatient on admission noted to have elevated

BP 150/100, highest of which is 190/110 ECG showed non specific ST-T wave changes Started on amlodipine 5 mg 1 tab OD,

Clonidine 75mcg BID, Candesartan

1. 1. Drug use history Drug use history-quinidine, quinine, -quinidine, quinine,

sulfonamides, sulfonamides, rifampin rifampin && heparin heparin

2.HyperslenismOn UTZ no splenomegaly noted

3. Infection Infectious mononucleosisHIV --Patients with HIV infection frequently

develop an immunologic form of thrombocytopenia

DHFRubella

4. DIC5.ITP

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Final DiagnosisImmune Thrombocytopenic Purpura

Essential HypertensionDegenerative disc disease

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IImmunemmune Thrombocytopenic Thrombocytopenic PurpuraPurpura (ITP)(ITP)

IncidenceIncidence 1.1. 1 10000/ , Population 1 10000/ , Population 2.2. 15 50Children (age < yr.) % 15 50Children (age < yr.) %

1 1Girl : Boy = : 1 1Girl : Boy = : - 0.5 1.5% - 0.5 1.5%

3.3. - (20 40 .) 50% - (20 40 .) 50% - 34 1Female : Male = : - 34 1Female : Male = : MMMMMMMMM MMMMMMMMMMMMM MMMM

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DefinitionDefinition

1.1.MMMMMMMMMMMMMM 2.2.MMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMM

-- MMMMMMMMMMMM MM MMMMMMMMMMMMMMMMMMMM MM MMMMMMMM-- MMMMM MM MMMMMMMM MM MMM

3.3. M MMMMMM& M MMMMMM&

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EtiologyEtiology .. ITP is a disease of increased peripheral ITP is a disease of increased peripheral

MMMMMMMMMMMM. MMMMMMMMMMMM. .. MMMM MMMMMMMM MMMMMMM MMMM-MMMMMMMMMM MMMM MMMMMMMM MMMMMMM MMMM-MMMMMMMMMM MM MMMMMMMM MMMMMMMM MMMMMMMMMM MMMMMMMM MMMMMMMM MMMMMMMM MM MMMMMMMMMMMMMMMMMMMMMMMM..

.. Most patients have either normal or incr Most patients have either normal or incr MMMMMMMM MMMMMMMMMM MM MMM. MMMMMMMM MMMMMMMMMM MM MMM.

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Clinical ManifestationsClinical Manifestations 1.1.MMMMMMM MMMMMMM

-- PetechiaePetechiae

-- MMMMMMMMMMMMMMMMMMMM

2.2.MMMMMMMMMMMMMMMMMMMM

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Clinical AppearanceClinical Appearance 1.1. Acute ITP (children) Acute ITP (children)

2.2. Chronic ITP (adults) Chronic ITP (adults)

3.3. MMMMMMM MMMMM MMMMMMMMM() MMMMMMM MMMMM MMMMMMMMM()

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ClassificationClassification

Mostly children Mostly children

Male/FemaleMale/Female = = 1111

Acute onset Acute onset

MMMMM MMMMMM. MMMMM MMMMMM. 20000< , /mm20000< , /mm33

Spontaneous Spontaneous

remission frequent remission frequent

- Mortality : 0.5 1.5 - Mortality : 0.5 1.5%%

Mostly adults Mostly adults

Male/FemaleMale/Female = = -134 -134

MMMMMMM MMMMMMM MMMMMMMMMMMM MMMMMMM MMMMM MMMMM . MMMMM . 22 만만 –– 55 만만 //33

Spontaneous remission r Spontaneous remission rMMMMMM

MMMMMMM MMMMMMMMM MMMMMMMMMMMMM MMMMMMMMM MMMMMM

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M MMMM MMMM MMMM MMM M MMMMMM MMMM MMMMMM MMM

Common Signs and SymptomsCommon Signs and Symptoms

1.1.MMMMMMMMMMMMMM 2.2.MenorrhagiaMenorrhagia

3.3.EpitaxisEpitaxis

4.4. Gingival bleeding Gingival bleeding

5.5. MMMMMMMMMMMM MMMMMM MMMM() MMMMMMMMMMMM MMMMMM MMMM() 6.6. Recent viral illness Recent viral illness (acute ITP) (acute ITP)

7.7. Bruising tendency Bruising tendency

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Role of SpleenRole of Spleen 1. - Auto antibody production

2.MMMMMMMM MMMMMMMMMMM

3.MMMMMMMM MMMMMMM

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1.1. Evaluate the type and the severity of Evaluate the type and the severity of

MMMMMMMMMMMMMMMM 2.2. Try to exclude other causes of Try to exclude other causes of

MMMMMMMMMMMMMMMM 3.3. Seek evidence of Seek evidence of

-- MMMMM MMMMMMMMMMMM MMMMMMM -- thrombosisthrombosis

-- autoimmune diseases and autoimmune diseases and

-- infection, particularly HIV infection, particularly HIV

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Physical Examination Physical Examination

Common Physical FindingsCommon Physical Findings

MMMMMMMMMMM MMMMMMMMMMMMMMMMM MMMMMMMMMMMM

HemorrhageHemorrhage

MMMMMMMMMMMMMMMMMMMMMM MMMMMMMMMMMMMMMM MMMMMMMM

Signs of GI bleedin Signs of GI bleedinMM

Spontaneous bleedi Spontaneous bleedi 100ng ( plt. < , 100ng ( plt. < ,

00 /mm 00 /mm33))

MenorrhagiaMenorrhagia

MMMMMMM MMMMMMMMMMMMMMMMM MMMMMMMMMM Evidence of intracran Evidence of intracran

MMM MMM MMMMMMMMMM MMM MMMMMMM Nonpalpable spleen Nonpalpable spleen

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Mortality/MorbidityMortality/Morbidity 1.1. Hemorrhage represents the most serious Hemorrhage represents the most serious

complicationcomplication

2.2. Mortality rate from hemorrhage is Mortality rate from hemorrhage is

approximately 1% in children and 5% in ad approximately 1% in children and 5% in adultult

3.3. Increase risk of severe bleeding in adult I Increase risk of severe bleeding in adult ITPTP

4.4. Spontaneous remission Spontaneous remission

: : occure in more than 80 % in children occure in more than 80 % in children

: : uncommon in adults uncommon in adults36

Laboratory ExaminationLaboratory Examination

1.1.Complete Blood Cell Count (CBC)Complete Blood Cell Count (CBC)

-- Isolated thrombocytopenia Isolated thrombocytopenia

-- MPV & MPV & PDW PDW increase ( increase (Automate)Automate)

2.2. Bone Marrow Examination Bone Marrow Examination

--MeMe gakaryocyte, Megakaryoblast & gakaryocyte, Megakaryoblast &

-- Promegakaryocyte > increase/nor -- Promegakaryocyte > increase/normalmal

-- -- Other cellular component > normal -- Other cellular component > normal

3.3. Platelet Platelet Auto-antibodyAuto-antibody

--PAIgG PAIgG -(non specific)-(non specific)

-- GP specific antibod GP specific antibodyy37

38

Fewer Platelets than normal. Fewer Platelets than normal.

39

Two mature megakaryocytes; one with a Two mature megakaryocytes; one with a very high N/C ratio, the other with a very very high N/C ratio, the other with a very low N/C ratio. low N/C ratio.

40

Mature megakaryocyte containing an NRBC Mature megakaryocyte containing an NRBC (Emperipolis). (Emperipolis).

The mature red cell may be superimposed on The mature red cell may be superimposed on thethe

megakaryocyte. megakaryocyte.

41

Two bare megakaryocyte nuclear massesTwo bare megakaryocyte nuclear masses

Platelet Auto-antibodiesPlatelet Auto-antibodiesPAIgGPAIgG

PBIgGPBIgG

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Platelet Antigens Platelet Antigens

M M MMM M MM //IXIXGPIIb/IIIaGPIIb/IIIaGPIa/IIaGPIa/IIaEtc.Etc.

Laboratory FindingsLaboratory Findings

1.1. Isolated thrombocytopenia Isolated thrombocytopenia

2.2. No splenomegaly No splenomegaly

3.3. Increase megakaryocytes in BM Increase megakaryocytes in BM

4.4. No other cause of thrombocytopenia No other cause of thrombocytopenia

5.5. - Platelet auto antibody found - Platelet auto antibody found

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Differential DiagnosisDifferential Diagnosis 1.1. Drugs induced thrombocytopenia Drugs induced thrombocytopenia

-- Drug use history Drug use history

--quinidine, quinine, quinidine, quinine, sulfonamides, sulfonamides,

rifampin rifampin && heparin heparin

2.2. Low platelet production Low platelet production

-- Bone marrow failure Bone marrow failure

-- Leukemia/LymphomaLeukemia/Lymphoma

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3.3. Over platelet destruction Over platelet destruction

-Hypersplenism, TTP, SLE -Hypersplenism, TTP, SLE && DIC, DIC, InfInf ection ection

-HIV, DHF, Rubella, -HIV, DHF, Rubella, Infectious MononucleosisInfectious Mononucleosis-Leptospirosis-Leptospirosis-Malaria-Malaria

4.Others : 4.Others : CLL, CLL, HypogammaglobulinemiaHypogammaglobulinemia

Treatment & PrognosisTreatment & PrognosisAcute ITPAcute ITP

1.1. 80Self remission % 80Self remission %2.2.Platelet transfusion Platelet transfusion MM MM severe severe bleedingbleeding

3.3.CCorticosteroid orticosteroid MMMMMMM M MMMMMMMMMMM M MMMM - 3 4n weeks - 3 4n weeks

4.4.No response to No response to corticosteroidcorticosteroid > 6 ( 1 > 6 ( 1

5 5 %) %) consider Splenectomyconsider Splenectomy

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Chronic ITPChronic ITP1.1. -102Complete remission ( -102Complete remission (

M M 0 M M 0

2.2.CCorticosteroid therapy orticosteroid therapy to r to rMMMMM MMMMM phagocytic activity phagocytic activity MMMM RE system RE system MMMMMMMM & MMMMMMMM &antibody production antibody production 3.3. Consider Splenectomy : Consider Splenectomy :

-- MM MMMMMMMM MM MMMM MMMM MM MMMMMMMM MM MMMM MMMM steroid steroid -Cerebral hemorrhage-Cerebral hemorrhage

Adults: first line therapyPlatelets >30 x 109/L

Observe

Or treat if: BleedingPlanned procedure

likely to induce bleeding

Platelets >30 x 109/L

Observe

Or treat if: BleedingPlanned procedure

likely to induce bleeding

Platelets <30 x 109/L

Observe

Treat if Platelets <10 x 109/LClinical problemsPlanned procedure

Prednisolone 1mg/kg/day x 2/52 then ¯

IVIg (effective in 75% but not sustained)

Platelets <30 x 109/L

Observe

Treat if Platelets <10 x 109/LClinical problemsPlanned procedure

Prednisolone 1mg/kg/day x 2/52 then ¯

IVIg (effective in 75% but not sustained)

Adults: second line therapy - drugsHigh dose steroids

DexamethasoneMethylprednisolone

High dose IVIg

IV anti-D

Danazol

Azathioprine

Cyclosporin

Vincristine, combination chemoRx, dapsone, etc.

High dose steroidsDexamethasoneMethylprednisolone

High dose IVIg

IV anti-D

Danazol

Azathioprine

Cyclosporin

Vincristine, combination chemoRx, dapsone, etc.

Adults: second line therapy - splenectomy2/3 will respond

Need platelets >30 x 109/L for splenectomy

VaccinationPneumovax, Hib, Meningococcal C2 weeks pre-op

Other prophylaxisPenicillin 250-500mg bd (or equivalent) ?for

life ?2 yearsAnnual flu vaccine + Pneumovax booster 5

yearly

2/3 will respondNeed platelets >30 x 109/L for splenectomy

VaccinationPneumovax, Hib, Meningococcal C2 weeks pre-op

Other prophylaxisPenicillin 250-500mg bd (or equivalent) ?for

life ?2 yearsAnnual flu vaccine + Pneumovax booster 5

yearly

Cines, D. B. et. al. N Engl J Med 2002;346:995-1008

Mechanisms of Action of Therapies for Immune Thrombocytopenic Purpura

Options for severe refractory ITP

25% adults

Intermittent IVIg, combination chemoRx

RecommendRituximabMycophenolate mofetilCampath-1H

25% adults

Intermittent IVIg, combination chemoRx

RecommendRituximabMycophenolate mofetilCampath-1H

ITP: therapy in adultsFirst lineFirst linePrednisolonePrednisoloneIVIgIVIg

First lineFirst linePrednisolonePrednisoloneIVIgIVIg

Second lineSecond lineObserveObserveDexamethasoneDexamethasoneMethylprednisoloneMethylprednisoloneHigh dose IVIgHigh dose IVIgAnti-DAnti-DDapsoneDapsoneAzathioprineAzathioprineCyclosporinCyclosporinCyclophosphamideCyclophosphamideCombination Combination chemoRxchemoRxVinca alkaloidsVinca alkaloids

Second lineSecond lineObserveObserveDexamethasoneDexamethasoneMethylprednisoloneMethylprednisoloneHigh dose IVIgHigh dose IVIgAnti-DAnti-DDapsoneDapsoneAzathioprineAzathioprineCyclosporinCyclosporinCyclophosphamideCyclophosphamideCombination Combination chemoRxchemoRxVinca alkaloidsVinca alkaloids

Fail 1st & 2ndFail 1st & 2ndObserveObserveIntermittent Intermittent

IVIg/steroidsIVIg/steroidsCombination Combination

chemoRxchemoRx

ExperimentalExperimentalMycophenolateMycophenolateRituximabRituximabCampathCampath

Fail 1st & 2ndFail 1st & 2ndObserveObserveIntermittent Intermittent

IVIg/steroidsIVIg/steroidsCombination Combination

chemoRxchemoRx

ExperimentalExperimentalMycophenolateMycophenolateRituximabRituximabCampathCampath

SplenectomySplenectomy

Experimental Treatment1. Stem Cell TransplantationIn patients with chronic ITP who have:

(1) failed to respond to all forms of standard therapy (2) who have severe thrombocytopenia with associated mucosal bleeding (nosebleeds, bleeding from the stomach or bowel, etc.), consideration may be given to stem cell transplantation.

2.Thrombopoetin stimulating receptors

.

3. AMG 531given SQstimulates platelet production No being tested in phase III clinical trial of ITP patients with base line platelet count <30000

4. Elthrombopag oral medicationalso stimulates platelet productionAn ITP phase III study is starting

5. AKR 501oral medication stimulates platelet productionan ITP phase II study is ongoing

Guidelines on Platelet Transfusion

INDICATIONSFOR PLATELET TRANSFUSION

BLEEDING DUE TOTHROMBOCYTOPAENIAFUNCTIONALLY ABNORMAL PLATELETSThrombocytopenia does not equal Platelet

Transfusion

1. THROMBOCYTOPENIAMarrow suppressive chemotherapyConsumptive coagulopathyRarely in situations of rapid platelet

destructionITP ( Immune Thrombocytopenia)TTP (Thrombotic Thrombocytopenic Purpura)

Contraindicated in Heparin induced thrombocytopenia

2. FUNCTIONALLY ABNORMAL PLATELETS

Haematological disorders:Myeloproliferative DiseaseMyelodysplastic Disease

Aspirin and other anti-platelet drugs

Acquired Platelet Dysfunction

Clinical Practice Guidelines Platelets

Likely to be appropriate<10 with no risks or <20 risk factorsmaintain > 50 during surgery or

proceduresinherited/drug induced defectsbleeding and thrombocytopenia50 and massive transfusionhigher counts in neurosurgical/

ophthalmological procedures

Thank you