David H. Rubin, MDChairman and Program DirectorDepartment of Pediatrics SBHProfessor of Clinical Pediatrics

Albert Einstein College of Medicine

INTRODUCTIONImmune thrombocytopenic purpura (ITP) -

clinical syndrome with decreased number of circulating platelets

Clinical bleeding tendency with bruising or extravasation of blood from capillaries to skin and mucous membranes

Platelets coated with autoantibodies to platelet membrane antigens results in….

INTRODUCTIONSplenic sequestration and phagocytosis

by mononuclear macrophages (#1)Shortened lifespan of platelets in

circulation (#2)Incomplete compensation by increased

platelet production by bone marrow (#3)Final Result

Decreased platelet count

INTRODUCTIONITP classified by

Age: childhood versus adultDuration of illness: newly diagnosed,

persistent (3-12 m), chronic (>12m)Thrombocytopenia: platelet count < 150

x 103/L) > 12 months defines chronic form of disease

Presence of an underlying disorder

EPIDEMIOLOGYAnnual incidence of ITP 5/100,000

children and 2/100,000 adultsAccurate data difficult to obtain because

most cases of childhood ITP self-limited and may not come to medical attention

Age-adjusted prevalence of immune ITP was reported as 9.5/100,000 people (Siegel et al, J Thromb Haemost Nov 2006)Prevalence peaks at 1-6 years

MORBIDITY/MORTALITYHemorrhage: the primary cause of long-term

morbidity and mortality in patients with ITPIntracranial hemorrhage - most frequent

cause of death associated with ITP is spontaneous or accidental trauma induced IC bleedingMost cases of hemorrhage occur in patients with

platelet counts < 10 x 103/LNot predictableOccurs in 0.5 -1% of children; 50% fatal (Segal JB, J

Thromb Haemost. 2006)17% of children experience major hemorrhage

MORBIDITY/MORTALITYTreatment related morbidity

To maintain platelet count in safe range in patients with chronic resistant ITP, long-term course of corticosteroids and immunosuppressive medications or splenectomy may be required

Morbidity and mortality may be related to complications with corticosteroids or splenectomy

PATHOPHYSIOLOGYLoss of self tolerance leads to production of

autoantiboodies directed against platelet antigensIgG autoantibodies act specifically against platelet

specific antigens, glycoproteins IIb/IIIa, Ib/IXDetection of autoantibodies difficult, not routinely

availableIndirect free plasma autoantibody tests inferior to

direct tests; direct tests detect platelet bound autoantibodies but only 80% accurate; thus negative test does not exclude ITP

Platelet antibody not recommended as part of routine testing

PATHOPHYSIOLOGYIncreased platelet destruction and impaired

platelet production Spleen is key organ in pathophysiology

Platelet autoantibodies formed in the white pulp

Macrophages in the red pulp destroy immunoglobulin coated platelets

Autoantibody coated platelets induce Fc receptor-mediated phagocytosis by mononuclear macrophages

Proposed mechanism of action of antibody-coated liposomes in ITP. (A) Platelets and RBCs in healthy individuals. (B) Anti-platelet antibody coated platelets are destroyed by FcγR-mediated and complement-mediated phagocytosis. (C) Antibody coated RBCs compete with antibody-coated platelets for FcγR after anti-D treatment. (D) Antibody-coated liposomes compete with antibody-coated platelets for FcγRs and complement receptors (CR1) 

CLINICAL SIGNS AND SYMPTOMS

CLINICAL SIGNS/SYMPTOMSAbrupt onset (childhood ITP)Gradual onset (adult ITP)PurpuraMenorrhagiaEpistaxisGingival bleedingRecent live virus immunization (childhood ITP)Recent viral illness (childhood ITP)Bruising tendency

CLINICAL SIGNS/SYMPTOMS50-60% of children have febrile illness preceding discovery

of thrombocytopeniaAssociated illnesses with ITP

RubellaVaricellaMumpsRubeolaEBV

Also: MMR vaccinationMucocutaneous bleeding seen (range from nothing (77% in

1 series) to purpura, petechiae, epistaxis)

PRESENTING FEATURES IN CHILDREN WITH ITP (Blanchette, 2010)

DIFFERENTIAL DIAGNOSIS

L. Nesbitt, D. Waxman, J. Cruz, Z. Reyes-Taucher & A. Sharathkumar: A Newborn with Petechiae and Bruising. The Internet Journal of Pediatrics and Neonatology. 2010 Volume 12 Number 2

INHERITED THROMBOCYTOPENIAS CLASSIFIED BY PLATELET SIZE

Baren JL et al. Ped Emerg Med, 2008

Rudolph, A. et al. Pediatrics, 2010

DIFFERENTIAL DIAGNOSISPsuedothrombocytopenia – platelet clumping

with anticoagulant EDTA; test with sample collected in tube with 3.8% Na citrate

Evan’s syndrome – immune mediated RBC destruction (severe anemia) with chronic ITP; poor prognosis

Kasabach Merritt syndrome – rapidly enlarging vascular anomaly, microangiopathc hemolytic anemia and thrombocytopenia

Bernard Soulier syndrome – congenital bleeding disorder, thrombocytopenia, huge platelets, and very prolonged bleeding time

DIFFERENTIAL DIAGNOSISdiGeorge syndrome – thymic hypoplasia

(often variable), susceptibility to infections, low IgA, thrmbocytopenia

Infections – HIV, hepatitis CWiskott Aldrich syndrome – X linked,

thrombocytopenia, small platelets, eczema, and recurrent infections due to immune deficiency

Grey platelet syndrome – caused by absence of platelet granules resulting in grey color on Wright stain; absent platelet aggregation

(Baren JL et al. Ped Emerg Med, 2008)

MANAGEMENT

SUGGESTED WORKUP OF PATIENT WITH POTENTIAL ITP

MANAGEMENT(Fleisher et al, Peds Emerg Med 6th ed, 2010)

Controversy regarding treatment of newly diagnosed patient with ITP with no serious bleeding; no available data to support or reject “watch and wait” strategy (Pels, 2010)

Usual benign disease v side effects and cost of management??Therapy deferred?? > 1 year of age, no active bleeding,

close follow-up guaranteed observation, avoid ASA and NSAIDS with platelet issues

Therapy initiated for patients with Moderate/severe anemia Severe thrombocytopenia (<10,000/L) for 2-3 weeks < 1 year of age Followup care uncertain Physical activity difficult to control

MANAGEMENT(Fleisher et al, Peds Emerg Med 6th ed, 2010)

Obtain hematology consultationBone Marrow biopsy/aspiration on every patient is also

controversial Commonly used therapies

Prednisone: 4 mg/kg/day (4 day course) watch for gastritis, emotional lability, hypertension, hyperglycemia

Anti-D: antibody directed against D antibody of RBC; 50-75 g/kg IV Rh+ patients, not significantly anemic and have their spleens Antibody coated erythrocytes are sacrificed to the reticuloendothelial

system so that antibody coated platelets are allowed to circulate Results in mild hemolytic anemia with decreased Hg of `1-1.5 grams

IVIG: 0.8-1.0 gram/kg with 2nd dose after 24 hrs if platelet count < 40-50,000/L Side effect is headache; watch for allergic and transfusion

reactions

RATIONALE FOR THERAPY (Pels, 2011)

Presumed cause of ITP: antibody mediated destruction of platelets by macrophages in RE of spleen….Therapy: IVIG, antiRhD immunoglobulin (anti-D),

splenectomyTarget: RE of spleen

Problem: development and production of anti platelet antibodies with T and B cell involvementTherapy: prednisone, immunosuppressive agents

Problem: impaired platelet production and antibody effects on normal developmentTherapy: thrombopoietic agents

(Pels, Semin Thromb Hemost, 2011)

1ST LINE THERAPY: EXPECTANT MANAGEMENT

ITP usually benign disease – yet lack of “no treatment” arm in most RCTs

1996 Amer Soc Heme: treat if asymptomatic and platelet count >20,000/L

2003 European Soc Heme: treat if <50,000/LBritish guidelines: treat if <30,000/L or >

30,000/L with symptoms5 year mortality rate for counts < 30,000/L:

2.2% for patients < 40 years of age48% for patients > 60 years of age

1ST LINE THERAPY: IVIGImproves thrombocytopeniaTransient effect: 3-4 weeksQuicker return to normal platelet counts

when used with steroids and/or anti-DImportant side effects (in 75% of

patients) Headaches, aseptic meningitisNausea, vomiting, fever

1ST LINE THERAPY: CORTICOSTEROIDSUsed worldwide as first-line therapy in acute

ITP due to lower costs and greater availability compared with IVIG

In US, steroids used for children who do not respond to initial therapy with IVIG

Theoretical risk of misdiagnosis of acute leukemia as ITPBone marrow examination therefore used prior

to treatment of children with ITP with corticosteroids

1ST LINE THERAPY: CORTICOSTEROIDSVarious regiments of corticosteroids have been used

for the treatment of child ITP; prednisone 60 mg/m² for 21 days, 1 to 2 mg/kilogram per day for 21 days or 4 mg/kilo/day for 4 to 21 days

Initial studies using prednisone 60 mg/m² for the treatment of ITP resulted in 90% of children with platelet counts >30,000/L either by 10 days

Higher dose of steroids 4 mg/kg/day achieved similar results; 88 8% of patients had platelet counts >20,000 after 1 week

Side effects are significant; dependent on dose and length of treatment Weight gain, facial swelling, hypertension, cataracts,

gastric irritation, and osteoporosis

1ST LINE THERAPY: ANTI-D IMMUNOGLOBULIN

Anti-RhD immunoglobulin or anti-Dhas effectively used in RhD+ nonsplenectomized patients with ITP in 1980s

In one study 83% of patients with ITP achieved platelet counts > 20,000/L (Scaradavou,, 1997)

Review of patients (Kane et al, 2010) who received high-dose anti-D (75 µg/kg) showed similar efficacy to IVIG (1 g/kg) – although there were higher incidence of side effects in the anti-D group (chills rigors and hemolysis resulting in anemia requiring diffusion)

1ST LINE THERAPY: ANTI-D IMMUNOGLOBULIN

Side effects of anti-D usually mild with infusion reactions occurring in 3.2% of patients

Most common reported reactions include headache, nausea, vomiting, and fever

Hemolysis mild with a decrease of hemoglobin between 0.8 and 1.7 g/dL

However reports of severe hemolysis requiring transfusion and even DIC after receiving anti-D

2nd LINE THERAPY: IMMUNOSUPPRESSION

Immunosuppressive drugs (e.g. azathioprine, cyclosporine A, mycophenylate mofetil and anti-CD 20 (rituximab) and cyclophosphamide have all been used in patients with chronic or refractory ITP

Success rates with these drugs variableMost frequently used agent is anti-CD 20

(rituximab)

2nd LINE THERAPY: IMMUNOSUPPRESSION/RITUXIMAB

Rituximab: 375 mg/m² IV once/weekly for four weeksResponse seen during treatment and up to six weeks

after the last doseResponse rates in children have been variable24 children treated with rituximab; 62% achieved

platelet counts > 150,000/L; responses lasted an average of 13 months (Wang J 2005)

Other studies have not been as successful response rates in other studies shown only 31% improvement

Side effects reported teaches that is similar: urticaria headache and serum sickness were the most common

2nd LINE THERAPY: SPLENECTOMYSplenectomy considered only when treatment

with first and second line agents such as steroids and IVIG has failed

With splenectomy for chronic ITP, 73 to 86% show increases in platelets usually after the first 72 hours after surgery

Long-term studies of children show response rate is anywhere from 45-65%; relapses occur first year after surgery - but may occur years later

2nd LINE THERAPY: SPLENECTOMYNeed to be concerned about significant risks of

developing overwhelming sepsisAsplenic patients susceptible to infection with

encapsulated organisms such as pneumococcus, Haemophilus influenza and meningococcus

Patients immunized 2 weeks pre-splenectomy and receive booster immunizations every five years along with antibiotic prophylaxis

Postsplenectomy mortality rates due to sepsis are 3% in children with ITP

Complications from splenectomy: perioperative bleeding

TPO RECEPTOR ANTAGONISTSThrombopoietic agents: romiplostin (AMG 531)

and eltrombopagTPO is the platelet specific growth factor

known to stimulate its receptor on the surface of human megacaryocytes and enhance platelet production

These drugs are usually used for the treatment of chronic ITP

Pediatric data on these drugs are minimal yet several ongoing studies have been presented with promising early results

Baren JL et al. Ped Emerg Med, 2008

Fleischer et al, Ped. Emerg. Med, 6th ed. 2010

SUMMARY (Liebman et al, 2011)

ITP is a heterogeneous autoimmune disorder characterized by isolated thrombocytopenia with peripheral blood platelet counts of less than 100,000/L in the absence of any obvious initiating work on the cause; essentially this is a diagnosis of exclusion

The peak age of presentation of ITP in children between five and six years with 70% of cases presenting between the ages of one and 10 years

A presumptive diagnosis of ITP is made by a careful history, physical exam, complete blood count and review of the blood smear

SUMMARY (Liebman et al, 2011)

Response to the initial treatment with corticosteroids IVIG or anti-RhD supports the diagnosis

Bone marrow examination has been recommended in patients refractory to ITP therapy or who relapse after initial remission, in patients with systemic symptoms or atypical physical findings, and in patients before splenectomy

Treatment protocols involve first and second line therapy