HOW I TREAT IDIOPATHIC THROMBOCYTOPENIC PURPURA

INTRODUCTION
TO SET FORTH APROACH TO MANAGING ADULTS PRIMARY (AUTOIMMUNE) ITP FROM ASH & THE BRITISH COMMITTEE FOR STANDARDS IN HAEMATOLOGY GENERAL HAEMATOLOG Y TASK FORCE : 1.WHO DEVELOPS ITP ? 2.HOW DIAGNOSIS ITP ? 3.WHO WE TREAT ITP 4.ITP AND PREGNANCY
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WHO DEVELOPS ITP ?

TYPICAL ITP : ADULT WOMAN AGE : BETWEEN 18 AND 40 YEARS TWO PUBLICATION HAVE QUESTIONED THIS PERCEPTION : DENMARK (SURVEY) -THE FEMALE-MALE RATIO =1. 7 : 1 -MEDIAN AT DIAGNOSIS 56 YEARS

ENGLAND (PROSPECTIVE COHORT) (PLATELET (PLT) < 50.000X109/L -THE FEMALE-MALE RATIO =1.2 : 1 -HIGHEST >60 YEARS
Frederiksen H, Schmidt. The Incidence of Idiophatic Thrombocytopenic Purpura in Adult Increase with age. ASH 1999: 909-913 (1)

Cines D.B. Blanchette V.S. Immune Thrombocytopenic. N Engl J Med. March,2002:995-1008 George JN, el Harake MA, Aster RH. Thrombocytopenia due to enhanced platelet destruction By immunologic mechanism, in Beutler E, Litchmann MA, Coller BS, Kipps TJ. (eds):

HOW WE DIAGNOSE ITP

- DIAGNOSIS OF EXCLUSION - ESSENSIAL ELEMEN : ISOLATED THROMBOCYTOPENIA, PERIFERAL SMEAR (UNREMARKABLE), - PHYSICAL EXAMINATION (BLEEDING CONSISTENT WITH PLT COUNT)

Stasi R, Provan D. Management of Immune Thrombocytopenic Purpura in Adult Mayo Clin Proc. 2004;79:504-522

- BMP (RUTINE) > TYPICAL PATIENT >60 YEARS > DON`T SHOW A ROBUST RESPONSE (PLT>50.000) > PRIOR SPLENECTOMY > EVALUATION OF RESPONSE IVIG, anti-D > POOR RESPONSE TREATMENT

WHO WE TREAT
PLT <20.000/MM3 WITH BLEEDING MANIFESTATION OR NOT 10-YEAR STUDY OF 310 PT (PLT<30.000) 1 HEMORRHAGIC DEATH

META-ANALYSIS OF 17 STUDIES, THE AGE ADJUSTED RISK OF FATAL HEMORHAGE WITH PLT <30.000
<40 Y 0,4%, 40-60 Y 1,2%, >60 Y 13% 5Y MORTALITY 2,2 TO 47,8%

TREATMENT AT PRESENTATION
PRINCIPLES OF MANAGEMENT PLT<20.000, WITH PETECHIAE OR PURPURA, THE ONSET MORE OFTEN INSIDIOUS THAN PREVIOUSLY PLT<10.000, SEVERE CUTANEOUS BLEEDING,PROLONGE EPISTAXIS, GINGGIVA BLEEDING, OVERT HEMATURIA, OR MENORRHAGIA PLT COUNTS : 10.000-20.000, 30.000 TO 50.000, >50.000, SPONTANEOUS BLEEDING MAY NOT EASY BRUISING DISCOVERED INCIDENTALLY

PLT COUNT : 30.000 INITIAL GOAL OF TREATMENT PLT 20.000 TO 50.000 IMMIDIATE TH/ IS NOT REQUIRED. IN ABSENCE OF BLEEDING OR PREDISPOSING COMORBID UNCONTROLED HT, ACTIVE PEPTIC ULCER DISEASE , ANTICOAGULATION, RECENT SURGERY OR HEAD TRAUMA. PLT 40.000 TO 50.000, RECOMMENDED, REQUIRING ASPRIN, NSAID, WARFARIN, OR ATHER ANTITHROMBOTICS.

Cines D.B. Blanchette V.S. Immune Thrombocytopenic. N Engl J Med. March,2002:995-1008

Cines D.B. Blanchette V.S. Immune Thrombocytopenic. N Engl J Med. March,2002:995-1008

HOSPITALIZATION AND EMERGENCY THERAPY

HOSPITALIZED : 1.PROFOUND MUCUCUTANEOUS OR INTERNAL BLEEDING 2.PLT 20.000 BLEEDING & HISTORY OF SIGNIFICANT COMPLIANCE RESPON TH/ HAS NOT BEEN ESTABLISHED

REDUCE RISK OF BLEEDING (GENERAL): -CESSATION OF DRUG THAT IMPAIR PLT FUNCTION -CONTROL BP -MINIMIZE TRAUMA

-REDUCE MUCOSAL BLEEDING E-AMINOCAPROIC ACID ( 100mg/KB LOADING DOSE UP TO MAX OF 5 gr IV OVER 30-60 MNT FOLLOW UP BY 5 gr EVERY 6 H IV OR ORALLY (MAX DOSE=24 gr/DAY)
TRANEXAMIC ACID DESMOPRESSIN ACETAT (DDAVP; 0,3 ug/KB)

INITIAL THERAPY FOR NONEMERGENT INDICATIONS

THERE IS NO CONSENSUS OPTIMAL DURATION OF CORTICOSTEROID CONTINUE FULL DOSE FOR 3 to 4 WEEKS TAPERRING PREDNISON SLOWLY, ONCE DOSES OF 10 MG/DAY ARE REACHED RESPON RATE 50-90% STABEL REMISI 10-30%

PERSISTEN ITP THROMBOCYTOPENIA RECURS WHEN CORTICOSTEROID ARE TAPERED TARGET PLT > 20.000 to 30.000

MAYOR DECISION : SPLENECTOMY

SPLENECTOMY
BEST OPTION TIMING OF THE PROCEDURE DEPENS ON : -DISEASE SEVERITY, -RESPONSIVNES AND SIDE EFFECT OF THERAPY -RISK OF THE TRAUMA AND OF THE PROCEDURAL AND PATIENT AND DOCTOR PREFERENCE.

RECOMMENDED :
ANY THERAPY (PREDNISON >10mg/D) FAILURED (PLT <30.000) (3 to 6 MO) PLT <20.000 or DIFFICULT TO CONTROPL BLEEDING DISEASE DO NOT ABATE BY 1 YEAR AFTER DIAGNOSIS DO NOT SHOW DURABLE RESPONSE INTOLERAN OF THERAPY

HOW ABAUT THE APROACH ? A 75 Y-OLD ASYMPTOMATIC, PLT<18.000, A LIFE EXPENTANCY OF 8 to 12 Y, SIGNIFICANS RISK FROM SURGERY. ACTIVE YOUNG ADULT WITH EASY BRUISING OR SIGNIFICANS MENORRHAGIA , PLT 20.000 to 30.000, LIFE EXPENTANCY 50 to 60 Y, AND NO SIGNS OF ABATING

BEFORE SPLENECTOMY : IV IG, IV ant-D or PULSE DOSE OF CORTICOSTEROID AFTER SPLENECTOMY : 85% HEMOSTATIC RESPONSE 2/3 DURABLE RESPONSE. INCIDENSSE RELAPSES 15 to25% WITH IN 10 Y MORTALITY RATE FOR OPEN AND LAPAROSCOPIC SPLENECTOMY ARE 1,0 % and 0,2%

LONG TERM RISK SPLENECTOMY : BACTERIAL SEPSIS <1% IMMUNIZE WITH VACCINES AT LEAST 2 WEEK PRIOR -POLYVALENT PNEUMOCOCCAL, -H INFLUENZA Type b, -QUADRIVALENT MENINGOCOCAL POLYSACCHARIDA REVACCINATION PNEUMOCCOCAL EVERY 5 t0 10 Y

THE EXPERIENCE : MOST PTS RESPOND TO VACCINATION GIVEN MORE THAN 6 WEEK AFTER SURGERY DO NOT RECOMMENDED LIFE LONG USE OF : -PHENNOXYMETHYL-PENICILLIN (250-500 mg PO/12H) -ERYTHROMYCIN (500 mg PO TWICE DAILY)

TREATMENT OF CHRONIC ITP

PRINCIPLES OF TREATMENT PLT <50.000 AFTER SPLENECTOMY (30-40%) DI NOT RESPON OR RELAPSE

FIRST-LINE THERAPY

SYMPTOMATIC RELAPSES OR SEVERE RECURRENT THROMBOCYTOPENIA IN THE SAME WAY AS AT INITIAL PRESENTATION CORTICOSTEROID OR IV IG OR EMERGENT MEASURES (HOSPITALISASI AND EMERGENCY THERAPY)E .

Anti-CD20 (RITIXIMAB 375 mg/m2 IV EVERY WEEK FOR 4 WEEK RESPONSES : 4 8 week (4 MO) COMPLET OR PARTIAL REMISSION 25-50% MANY COMPLET RESPONSES ARE DURABLE (>1Y) NO RESPON RITUXIMAB TWO AGENT TO AVOID INDUCING MULTIPLE DRUG RESISTANCE GENES (DANAZOLE, AZATHIOPRINE or MYCOPHENOLATE MOFETIL TREAT 4 to 6 MO (FULL EFECT) RESPONS CORTICOSTEROID TAPPERED AND IVIG STOP

AZATHIOPRIN 2mg/kg PO DAY DANAZOLE 10 -15mg/ kg/DAY (600-800mg PER DAY) RESPON OCCURS 3-4 MO CONTINUE AT FULL DOSE FOR >12 MO AND DISCONTINUE GRADUALLY REMISION : 20-40%
DAPSON : 75-100 mg PO SIMILAR DANAZOLE (avoid if G6PD def) MYCOPHENOLATE MOFETIL 500 mg PO TWICE A DAY INCREASE to 1000 to 1500 PO TWICE A DAY AFTER 2 WEEKS. .

TREATMENT OF CHRONIC ITP

SECOND-LINE THERAPY

CYCLOPHOSPHAMIDE : INTRAVENA 500-1000 mg /m2 (2 OR 3 COURSE) AT 3-4 WEEK INTERVAL, Or PO 1-2 mg/kg DAILY (RESPONSE 1-3 MO) CsA 1,25 2,5 mg/kg/ DOSE PO EVERY 12 HOURS

TREATMENT OF CHRONIC REFRACTORY ITP

DEFINE CHRONIC REFRACTORY ITP AS FAILURE OF ANY MODALITY TO KEEP PLT >20.000 (5%) CsA 1,25 2,5 MG/KG/ DOSE PO EVERY 12 HOURS CYCLOPHOSPHAMIDE 1.0-1,5 G/M2 IV (4 WEEK INTERV)

EXPERIMENTAL THERAPY
THROMBOPOETIC FACTOR
STUDY PEGYLATED RECOMBINAT HUMAN MEGAKARYO CYTE 2 OF 4 PTS DEVELOPED TEMPORARY THROMBOCYTOSIS STUDY 2 PLACEBO-CONTROL TRIAL AMG-531 (MOLECUL THROMBOPOIETIN RECEPTOR) (DOSE >3,0 ug/Kg) 8 OF 12 PTS AND 7 OF 8 PTS SHOWED TEMPORARY BUT SUBSTANTIAL INCREASES PLT
Nomura S, Dan K, Hotta T, Fujimura K, Ikeda Y. Effects of pegylated recombinat human mega Karyocyte growth and development factor inpatients with idiopathic thrombocytopenic purpura. Blood. 2002;100:728-730 Emmons V.B, Reid D.M, Cohen R.L, et all. Human Thrombopoietin levels are high when Thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet Destruction. Blood 1996;87:4068-71

AUTOLOGOUS STEM CELL TRANSPLANT : REPORTED 14 PTS REFRACTORY ITP MORE THAN 6 MO AFTER TRANSPLANT SIX PTS STABLE PLT (>100.000), AND 2 PTS PARTIAL , ( 9 42 MO) THERE WERE NO PROCEDURAL DEATHS SEPSIS UNCOMMON TWO OF 6 PTS COMPLET RESPON DIED WITHIN YEAR

Huhn RD, Forgaty PF, Nakamura R. et all. High-dose cyclophosphamide with autologus Lymphocyte depleted periperal blood (PBSC) support for treatmeny of refractory niimune Thrombocytopenia.Blood. 2002;101:71-77

ITP AND PREGNANCY

CONSULT TO THE PHYSICIAN : -SAFE PREGNANCY -DIAGNOSIS -DIFFRENTIAL DX: HELL SYNDROME (pregnancy induced hypertension and related condition such as hemolysis,elevated liver enzyms, and low PLT count) -OBSTETRIC CAUSE of DIC, -MICROANGIOPATHIC HEMOLYTIC PROCESSES, -GESTATIONAL THROMBOCYTOPENIA.

-INCIDENCE : 1 per 1.000 to 10.000 PREGNANCY MILD THROMBOCYTOPENIA : PLT < 70.000 (95%) -NO IMPACT ON MATERNAL & FETAL DEATH -NORMAL 2 MO OF DELIVERY ITP (SUSPECT) PLT <50.000 ( trimester 2) ABSENCE OF SYMPTOM OR TREATMENTMONITOR PLT : -at least monthly through the first trimester 2 -biweekly in the third -weekly as term or more if indicated

PLT (ideal) > 20.000 THROUGHT PREGNANCY > 50.000 NEAR TERM PLT(higher) Epidural anasthesi
THERAPY : INITIAL CORTICOSTEROID PREDNISON (low dose) : 20 mg every day IVIG IV anti-D (safe and efective) (limited experience) AZHATHIOPRIN possible exception for Renal Transplant

DELIVERY IS BASED ALMOST ENTIRY PPH IS UNCOMMON EVEN WITH SEVERE THROMBOCYTOPENIA NEONATUS BORN : > ITP NEONATES BORN (4%) PLT<20.000 >SEVERITY d1 to d3 >No ANTENATAL MATERNAL MEASURE PREDICT NEONATAL PLT >MEASURE PLT cord; FIRST WEEK POST PARTUM DECREASED ONSET OF THROMBOCYTOPENIA >PLT<50.000 SONOGRAPHY : CT SCANNING, MRI

CONCLUSION

THE INCIDENCE ITP INCREASED WITH INCREASE AGE DIAGNOSIS ITP PEREXCLUSION TREATMENT ITP; EMERGENCY AND NONEMERGENCY TREATMENT WHEN PLT <20.000/MM3 AND TARGET PLT >30.000/MM3 MINIMAL EMERGENT THERAPY INCLUDE IV METHYLPREDNISOLONE AND IVIG. THERAPHY MINIMUM 3 MO AND MAXIMUM 12 MO SPLENECTOMY:SINGLE BEST OPTION FOR PERSISTEN ITP