Transcript Childhood Immune Thrombocytic Purpura January

David H. Rubin, MD
Chairman and Program Director
Department of Pediatrics SBH
Professor of Clinical Pediatrics
Albert Einstein College of Medicine
INTRODUCTION
 Immune 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….
INTRODUCTION
 Splenic 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
INTRODUCTION
 ITP classified by
 Age: childhood versus adult
 Duration 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
EPIDEMIOLOGY
 Annual incidence of ITP 5/100,000 children and
2/100,000 adults
 Accurate 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/MORTALITY
 Hemorrhage: the primary cause of long-term
morbidity and mortality in patients with ITP
 Intracranial hemorrhage - most frequent cause of
death associated with ITP is spontaneous or accidental
trauma induced IC bleeding
 Most cases of hemorrhage occur in patients with platelet
counts < 10 x 103/L
 Not predictable
 Occurs in 0.5 -1% of children; 50% fatal (Segal JB, J Thromb
Haemost. 2006)
 17% of children experience major hemorrhage
MORBIDITY/MORTALITY
 Treatment 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
PATHOPHYSIOLOGY
 Loss of self tolerance leads to production of autoantiboodies
directed against platelet antigens
 IgG autoantibodies act specifically against platelet specific
antigens, glycoproteins IIb/IIIa, Ib/IX
 Detection of autoantibodies difficult, not routinely available
 Indirect 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
PATHOPHYSIOLOGY
 Increased 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/SYMPTOMS
 Abrupt onset (childhood ITP)
 Gradual onset (adult ITP)
 Purpura
 Menorrhagia
 Epistaxis
 Gingival bleeding
 Recent live virus immunization (childhood ITP)
 Recent viral illness (childhood ITP)
 Bruising tendency
CLINICAL SIGNS/SYMPTOMS
 50-60% of children have febrile illness preceding discovery of
thrombocytopenia
 Associated illnesses with ITP
 Rubella
 Varicella
 Mumps
 Rubeola
 EBV
 Also: MMR vaccination
 Mucocutaneous 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 DIAGNOSIS
 Psuedothrombocytopenia – 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 DIAGNOSIS
 diGeorge syndrome – thymic hypoplasia (often
variable), susceptibility to infections, low IgA,
thrmbocytopenia
 Infections – HIV, hepatitis C
 Wiskott 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 consultation
 Bone 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),
splenectomy
 Target: RE of spleen
 Problem: development and production of anti platelet
antibodies with T and B cell involvement
 Therapy: prednisone, immunosuppressive agents
 Problem: impaired platelet production and antibody
effects on normal development
 Therapy: 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/L
 British guidelines: treat if <30,000/L or > 30,000/L
with symptoms
 5 year mortality rate for counts < 30,000/L:
 2.2% for patients < 40 years of age
 48% for patients > 60 years of age
ST
1
LINE THERAPY: IVIG
 Improves thrombocytopenia
 Transient effect: 3-4 weeks
 Quicker return to normal platelet counts
when used with steroids and/or anti-D
 Important side effects (in 75% of patients)
 Headaches, aseptic meningitis
 Nausea, vomiting, fever
1ST LINE THERAPY: CORTICOSTEROIDS
 Used 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
ITP
 Bone marrow examination therefore used prior to
treatment of children with ITP with corticosteroids
1ST LINE THERAPY: CORTICOSTEROIDS
 Various 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 antiCD 20 (rituximab) and cyclophosphamide have all
been used in patients with chronic or refractory
ITP
 Success rates with these drugs variable
 Most frequently used agent is anti-CD 20
(rituximab)
2nd LINE THERAPY:
IMMUNOSUPPRESSION/RITUXIMAB
 Rituximab: 375 mg/m² IV once/weekly for four weeks
 Response seen during treatment and up to six weeks after




the last dose
Response rates in children have been variable
24 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: SPLENECTOMY
 Splenectomy 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: SPLENECTOMY
 Need to be concerned about significant risks of developing




overwhelming sepsis
Asplenic 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 ANTAGONISTS
 Thrombopoietic agents: romiplostin (AMG 531) and
eltrombopag
 TPO 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