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Immune Mediated Thrombocytopenic
Purpura
 ITP is defined as isolated thrombocytopenia with no
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clinically apparent associated conditions or other
causes of thrombocytopenia
ITP is a high prevalence disease 16 to 27 per million
per year
Incidence increases with age
Female predominance under the age of 60 but not
over the age of 60
It can have an abrupt onset or insidious onset. It is
generally abrupt in onset with children
Classification
Acute ITP
Chronic ITP
Mostly children
Acute onset
Mostly adults
Usaully gradual onset
Spontaneous
remission frequent
Spontaneous remission rare
Chronic recurrent course
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Aetiology in children
Often after infection (viral or bacterial)
Theories:
*antibody cross-reactivity
*H. pylori
*bacterial lipopolysaccharides
Pathogenesis of ITP
ITP is an autoimmune disease during which pt.
body’s immune system attacks and destroys
his platelets.
The body releases auto-antibodies which
chemically tag its’ own cells as foreign
ITP is mediated by IgG autoantibodies.
Glycoprotein IIb/IIIa, Ib/Ix, Ia/IIa, IV and V ...
Accelerated clearance through Fcү receptors that are
expressed by tissue macrophages (spleen & liver).
This causes a rapid drop in the level of platelets
in a person’s body
100 cases per 1 milion persons per year.
About half of these cases occur in children.
Primary vs Secondary .
Acute vs Chronic ( >6 months).
Affected children are young (peak age ~ 5 yrs) and
previously healthy, and they typically present with the
sudden onset of petechiae or purpura a few days or
weeks after an infectious illness.
Boys and girls are equally affected.
Presentation
 Petechiae, purpura, and easy bruising - very
common
 Epistaxis, gingival bleeding, and menorrhagia common
 Overt gastrointestinal bleeding and gross
hematuria are rare
 Intracranial hemorrhage - very rare
In more than 70% of children, the illness resolves within
six months, irrespective of whether they receive
therapy.
By contrast, ITP in adults is generally chronic.
Evaluation of ITP
 Features consistent with the diagnosis of ITP
 Thrombocytopenia with normal or slightly large
platelets
 Normal RBC morphology and number (may have
associated iron def or thallasemia etc.)
 Normal white cell number and morphology
 Splenomegaly rare
 Features not consistent with the diagnosis of ITP
 Giant platelets
 RBC abnormalities ie schisotocytes
 Leukocytosis or Leukopenia
Diagnosis (of Exclusion)
 Rule out other causes:
*lab error / PLT clumping
*drug / medication interaction
*infections (HIV, Hepatitis C)
*destructive / consumptive processes
(TTP/HUS)
*bone marrow disease (leukemias, MDS)
The diagnosis of ITP remains one of exclusion.
Secondary forms of the disease occur in association
with SLE, the antiphospholipid syndrome,
immunodeficiency states (IgA deficiency and
common variable hypogammaglobulinemia),
Lymphoproliferative disorders (CLL, Large
granular lymphocytic leukemia, and lymphoma),
infection with HIV and hepatitis c virus, and
therapy with drugs such as heparin and
quinidine.
To Marrow or Not to Marrow?
 Bone marrow aspiration & biopsy if…
 Patient 60 yrs. or older
 Poorly responsive to tx
 Unclear clinical picture
The bone marrow in patients with ITP
contains normal or increased numbers of
megakaryocytes.
There is consensus, that bone marrow examination is
not necessary in children if management involves
observation or IVIG.
Although it is not mandatory, many pediatric
hematologists recommend that an aspiration be
performed before starting corticosteroids to rule out
the rare case of acute leukemia.
Anti-Platelet Antibody Testing
 NOT recommended by ASH Practice Guidelines
 Poor positive/negative predictive values, poor
sensitivity with all current testing methods…
 …and doesn’t change the management!
General Principles of Therapy
The decision to treat ITP is based on the platelet
count, the degree of bleeding, and the patient’s
lifestyle
 Major bleeding rare if PLT > 10,000
 Goal = get PLT count to safe level to prevent
bleeding…
“Safe” Platelet Counts
 “moderately” = 30-50,000
 Probably safe if asymptomatic
 Caution with elderly (CNS bleeds)
The incidence of intracranial hemorrhageis ~ between
0.2-1%.
Almost all intracranial hemorrhages occur at platelet
counts below 20.000/mm3, and generally below
10.000/mm3.
Risk factors : head trauma and exposure to
antiplatelet drugs.
Most intracranial hemorrhagrs occur within four weeks
after presentation with ITP, often within the first
week.
Most children with typical acute ITP recover
completely within a few weeks without treatment
and that there is no proof that therapy prevents
intracranial hemorrhage.
ITP in many children – certainly those without
hemorrhage –is managed on an outpatient basis with
minimal investigation, short-term therapy in select
cases, and the avoidance of activities that predispose
the patient to trauma and of medications that impair
platelet function.
American Society of Hematology
(ASH) recommends drug therapy for
children with platelet counts of less
than 10.000/mm3 with little or no
purpura.
The UK guidelines state : only patients
who experience significant mucous
membrane bleeding receive treatment.
TREATMENT
Watch & Wait strategy.
Corticosteroids (high, standard or low dose).
IVIG (high or low dose, 2 day or 1 day).
IV anti-D immunoglobulin in Rh(D) positive patients
(high or low dose).
Randomized clinical trials have demonstrated that therapy with
IVIG shortens the duration of severe thrombocytopenia ( platelet
< 20.000 /mm3) .
Adverse reactions : headache, fever, nausea, and aseptic
meningitis.
The response to IVIG is more rapid than the response to IV anti-D.
The average decrease in the hemoglobin level is 1.3 g per deciliter,
and intravascular hemolysis is rare.
Urgent Treatment
Neurologic symptoms, internal bleeding, or emergency
surgery demands immediate intervention.
IV.Methylprednisone (30 mg/Kg/d; max 1 gr/d for 2-3
days) / 20-30min + IVIG (1 gr/kg/d for 2-3 days) +
infusion of platelets that is 2-3 times the usual amount
infused; Vincristine may be considered.
Splenctomy should be considered if it has not yet been
performed.
Plasmapheresis is of limited benefit.
Antifibrinolytic therapy (e.g. Aminocaproic acid) may
reduce mucosal bleeding, and recombinant factor VIIa
should be considered.
Management of first Relapse
Approximately 25% of children with ITP have a relapse
after initial treatment.
One third of children have spontaneous remission and
only 5% still have severe thrombocytopenic requiring
therapy one year after diagnosis.
Guidelines from the American Society of Hematology
recommended that splenctomy be considered for
children who have had ITP for at least one year with
symptomatic, severe thrombocytopenia.
In children, the rate of complete remission after
splenectomy is 70-80%.
Bacterial sepsis ( ~ 3%) !!!!
Chronic Refractory ITP
Achallenge is posed by the occasional symptomatic child in whom
splenectomy fails or is containdicated and in whom the platelet
count cannot be sustained with acceptable doses of
corticosteroids, anti-D immune globulin.
American Soceity of Hematology guidelines recommend treatment
for such children if they have symptomatic thrombocytopenia
and platelet counts of less than 30.000/mm3.
No regimen is universally effective.
Vincristine, azathioprine, cyclophosphamide or cyclosporine.
Splenectomy in children with
chronic ITP
The aim of the study was to determine whether the
response to splenectomy is related to the response to
previous treatments ???
Should the Patient be Hospitalized?
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ITP Practice Guideline – American Society of
Hematology
 Patients with platelet counts >20,000 should not be
hospitalized if they are either asymptomatic or
have only minor purpura.
 Hospitalization is appropriate for patients with
platelet counts <20,000 who have significant
mucous membrane bleeding.
Options for Treatment
Steroids
IVIG
Anti-D
Splenectomy
Rituximab
Thrombopoietin receptor agonists
Others: danazol, cyclophosphomide, azathioprine,
vincristine, cyclosporine A, dapsone.
Does the Pt need to be treated?
 ASH Guideline
 Patients with counts >50,000 do not routinely require
treatment
 However, treatment is indicated in patients with platelet
counts <20,000 to 30,000, and those with counts <50,000
and significant mucous membrane bleeding (or risk
factors for bleeding, such as hypertension, peptic ulcer
disease, or a vigorous lifestyle).
 When ITP symptoms persist after primary treatment
(glucocorticoid) and splenectomy, further therapy is
recommended in patients with platelet counts <30,000
who have active bleeding.
Initial Therapy
 Prednisone 1 mg/kg/day
*usually response within 2 weeks
 Taper off after PLT response
 Duration of use = controversial
Second-Line Therapy
 IV Immune Globulin (IVIg)
1 gram/kg/day x 2 days
 WinRho (anti-D) – if pt is Rh+
50-75 mcg/kg/day
Anti-D as effective as IVIG in Rh+, non- •
spelectomized patients; response rate – 70%
Anti-D infusion time is 5 - 10 minutes instead of
several hours over 2 – 5 days
Treatment Side-Effects
 Steroids
*bone density loss
*muscle weakness
*GI effects
*weight gain
 IVIG/anti-D
*hypersensitivity *headache
*renal failure
*nausea/vomiting
*alloimmune hemolysis
Emergency Therapy – serious bleeding
Long term prognosis excellent in children with
acute ITP
In adults 12-25% will require chronic or recurrent
therapies .
5% or less will develop “chronic refractory ITP”
Splenectomy
 Predictors of response – younger age found to
correlate with response but this finding is not
consistent
 Durability – while there are reports of late relapses,
“analysis of 21 case series with follow-up of more
than 5 years, suggest that the response to
splenectomy is durable.”
 Toxicity: operative mortality 0.2 – 1%, complications
9 – 13% (? Related to willingness to operate on older
patients?); fatal asplenic sepsis 0.73 per 1000 pt yrs
Splenectomy
“ Splenectomy remains the single best
option to convert a patient with ITP into a
“nonpatient,” that is, one who is unlikely to
need frequent monitoring or intervention,
and it minimizes interference with a normal
lifestyle.”
Chronic Refractory ITP
 Persistent > 3 months
 PLT < 50,000
 Failure to respond to splenectomy
When all else fails…
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Steroids
IVIg / anti-D
Rituximab (anti-CD20)
Cyclophosphamide
Danazol
Accessory splenectomy
H. pylori eradication
Rituximab
 Anti CD20 monoclonal antibody targeting B-cells
 Many uncontrolled trials showing response rates (Plts
> 50K) from 40 – 60%.
 Time to response is 3-7 weeks.
 Follow up is short (median in one systematic review
9.5 mos) though one study of unsplenectomized
patients found 33% still responding at 2 yrs.
 Toxicities: Infusion reactions; rare cutaneous,
pulmonary and infectious events described (In rare
cases fatal), reactivation of hepatitis B