Transcript Immune Thrombocytopenic Purpura

Idiopathic Thrombocytopenic Purpura
‫הצגת מקרה‬
‫• נ‪.‬ד ילדה בת ‪ 10‬שנים שהתקבלה עקב פריחה‬
‫פטכיאלית בגוף‪ ,‬לציין שסבלה מדלקת גרון כעשרה‬
‫ימים טרם קבלתה‪.‬‬
‫• בבדיקה בקבלה ‪ :‬אכימוזות ופטכיות מפושטות על‬
‫פני הגוף‪ ,‬שאר הבדיקה תקינה ללא הגדלת בלוטות‬
‫לימפה וללא אורגנומגליה‪.‬‬
‫• בדיקות מעבדה ‪ :‬מס' טסיות – ‪ 10.600‬ללא דיכוי‬
‫של שאר השורות‪.‬‬
‫• הושלמה בדיקת פונדוסים ושתן לכללית – תקינים‪.‬‬
‫המשך‪...‬‬
‫• לאור ההתייצגות הקלינית והמעבדתית סוכמה שקרוב‬
‫לוודאי ‪. ITP‬‬
‫• הילדה שוחררה להמשך מעקב אמבולטורי ללא טיפול‬
‫תרופתי‪.‬‬
‫• כעבור שנה מהאבחנה עדיין מס ‘ טסיות נמוך סביב‬
‫‪ , 9700‬טופלה בקורס של ‪ IVIG‬שגרם לתגובה קצרת‬
‫טווח‪ ,‬שבהמשך הופסק לאור הופעת כאבי ראש‬
‫חזקים‪.‬‬
‫המשך‪....‬‬
‫• נשלחו נוגדנים נגד טסיות לרמב"ם ???‬
‫• לאור תמונה של ‪ Chronic ITP‬נשלח בירור שכלל‬
‫‪Anti ds DNA , Anti cardiolipin, ANA :‬‬
‫המשך‪...‬‬
‫•‬
‫•‬
‫•‬
‫•‬
‫כעבור שנתיים מהאבחנה לאור טרומבוציטופניה סביב‬
‫‪ 7000‬הוחלט להתחיל טיפול בסטירואידים (פרדנזון של‬
‫‪ 60‬מ"ג ליום)‪.‬‬
‫טרם התחלת הסטירואידים בוצעה בדיקת לשד עצם‬
‫שהראתה ריבוי מגקריוציטים ‪.‬‬
‫לאחר התחלת סטירואידים היתה עלייה במספר הטסיות‬
‫ל ‪. 40.000‬‬
‫הבעייתיות היתה תלות מלאה בטיפול ותגובה שחלפה עם‬
‫הורדת המינון‪.‬‬
‫המשך‪....‬‬
‫• בשנת ‪ 2004‬היה ניסיון עם ‪ Rituximab‬ללא‬
‫הטבה (טסיות נשארו סביב ‪.) 7000‬‬
‫• ב ‪ 07.2004‬הועלתה אפשרות של ‪Splenectomy‬‬
‫• מאז ‪ 07.2001‬טסיות סביב ‪20.000 – 5000‬‬
‫• ס"ד אחרונה ב ‪ – 04.2006‬מספר טסיות סביב‬
‫‪12.000‬‬
ITP
100 cases per 1 milion persons per year.
About half of these cases occur in children.
Primary vs Secondary .
Acute vs Chronic ( >6 months).
The etiology is still unknown and the
pathogenesis is complex and possibly
depends on disturbed antigen presentation, T
cell activation and signaling, disregulated B
cell stimulation and antibodies, unbalanced
activation / suppression of complement.
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.
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.
The bone marrow in patients with ITP
contains normal or increased numbers of
megakaryocytes.
Pathophysiology
ITP is mediated by IgG autoantibodies.
Glycoprotein IIb/IIa, Ib/Ix, Ia/IIa, IV and V
...
Accelerated clearance through Fcү receptors
that are expressed by tissue macrophages
(spleen & liver).
Genetics
Monozygotic twins.
An increased prevalence of HLA-DRw2 and
DRB1*0410 alleles.
HLA-DR4 and DRB1*0410 alleles have been
associated with unfavorable and favorable
response to corticosteroids, respectively.
Diagnosis
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.
The guidelines of the American Society of
Hematology state that a bone marrow
examination is not required in adults
younger than 60 yrs of age if the
presentation is typical but is appropriate
before splenectomy is performed.
Marrow examination is necessary in the
presence of atypical features (e.g., those
with additional cytopenias, protracted fever,
bone or joint pain, unexplained macrocytosis
), or in patients who do not have a brisk or
robust response to therapy.
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.
The direct assay for the measurement of
platelet-bound AB’s has an estimated
sensitivity of 49-66%, an estimated
specificity of 78-92%, and an estimated
PPV of 80-83%.
The decision to treat ITP is based on the
platelet count, the degree of bleeding, and
the patient’s lifestyle
.
Management
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.
Childhood ITP in the nordic countries
Acta paediatrica 2005;94
A prospective registration 1998 – 2000.
Ninety eight paediatric departments.
506 children with newly ITP aged 0-14 yr and
at least one platelet count <30.000 .
423 of the children followed for 6 months.
The platelet count < 10.000 in 58%.
Chronic ITP developed in 25% :
thrombocytopenia < 150.000 persisting after
6 months.
Cont’d
Most cases in the winter months from October
to March.
About 57.7% of the children have various
infections in the 4 wk preceding diagnosis.
The majority had viral URI, flu-like diseases or
unspecified fever.
Some patients developed ITP following a
bacterial infection like sinusitis, otitis media or
tonsillitis.
Cont’d
In 6.9% cases, ITP occured after vaccinations,
particularly the MMR vaccination (DTP, Oral
polio, Hepatitis A & B).
Cont’d
Factors associated with chronic ITP :
Insidious onset of symptoms.
A bsence of preceding infection and/or
vaccination.
Age 8-14 yrs.
Female gender.
Treatment soon after diagnosis did not
appear to influence the risk of developing
chronic disease.
The frequency of mucosal bleeding was
related to the initial platelet count (<15000).
3/15 patients with severe haemorrhage had
platelet count between 16 – 24.000 .
Corticosteroids versus IVIG for the treatment
of acute ITP in children
J Pediatr 2005; 147
A systematic review and meta-analysis of
randomized controlled trials comparing
corticosteroids with IVIG.
10 studies were included.
The primary outcome was the number of
patients with a platelet count >20.000, 48
hrs after treatment initiation.
Cont’d
25% of patients treated with corticosteroids
and 18% of patients treated with IVIG
developed chronic ITP.
Children treated with corticosteroids for acute
ITP are 26% less likely to have a platelet
count > 20.000 after 48 hrs of therapy,
when compared with children treated with
IVIG.
Single dose of anti-D immune globulin at 75 µg/Kg is as
effective as intravenous immune globulin.
The journal of pediatrics .April 2006.
Randomised prospective trial of immune globulin
treatments for 105 Rh+ children with newly
diagnosed ITP and a platelet count<20.000.
Nine study sites in the USA.
Age range 1-16 yrs.
Patients received either a single IV dose of 50 µg/kg
anti-D, 75 µg/kg anti-D, or 0.8 g/kg IVIG.
By 24 hrs after treatment 50%, 72%, 77% of patients
in the anti-D50, anti-D75, and IVIG groups,
respectively, had achieved a platelet count >
20.000 .
Cont’d
A single 75 µg/kg dose of anti-D raised the
platelet count in children with newly
diagnosed immune thrombocytopenia more
rapidly than standard dose anti-D and as
effectively as IVIG.
The presence of wet purpura at study entry •
affected the response to treatment, in all •
and
in each group. •
Rituximab treatment for symptomatic chronic
ITP. Pediatr blood cancer 2006;47
Monoclonal antibody against CD20+ B cells.
Rapid depletion of B-cells for 6-12 months.
Mechanism in ITP ????
Cont’d
About 1/3 of children has acontiuous
response.
Side effects : chills, fever, urticaria and
serum sickness (12%).
The time to platelet counts> 50.000 ranged
from 1 – 7 weeks.
No increased frequency of infections.
ITP in children
Pediatr Blood Cancer 2006 ;47
Children’s hospital “Bambino Gesu” Rome.
Jan 1995 – Dec 2005.
265 children with ITP.
Diagnosis was made, excluding other haematological
disorders by BM aspirate showing normal to
increased megakaryocytes.
None of the 265 children had been pretreated or
received any steroid treatment for at least 2 months
before the observation.
Children with a platelet count >= 10.000 and no
significant cutaneous or mucosal bleeding have
been observed without any treatment (wait & see).
Cont’d
208 out of 265 children were treated.
CR – persistent plt count >= 100.000 for at
least 3 months without further therapy.
PR – a plt count 30-100.000 for at least 3
months.
Splenectomy in children with
chronic ITP
Pediatr Blood Cancer 2006;47
The aim of the study was to determine
whether the response to splenectomy is
related to the response to previous
treatments ???
Cont’d
Retrospective study.
90 children that were splenctomized for
chronic ITP in 11 Italian centers and
previously treated with several treatments
including IVIG.
Chronic ITP – PLT count < 50.000 persistng
for a minimum of 6 months.
The mean age was 8±3.9 yrs.
Cont’d
The mean follow up after splenectomy was 2.4
yrs.
Plt count were constantly > 50.000 in 75% of
patients.
The success of splenectomy was strongly
correlated with a good response to previous
treatment.
A negative response to any of the prior
treatments had no predictive value.
AMG 531 For chronic ITP
NEJM OCT 19:2006
AMG 531 – Amgen : Thrombopoiesis-Stimulating
Protein.
There is evidence that platelet production is
suboptimal in a substantial proportion of patients
with ITP.
Cont’d
Thrombocytopenia occurs in patients with ITP
when the rate of plt destruction exceeds the
ability of the bone marrow to increase platelet
production.
Kinetic data show that plt production, as measured
by plt turnover, is reduced in 2/3 of patients with
ITP.
Plasma level of endogenous thrombopoietin are
not elevated in patients with ITP, as they are in
patients with thrombocytopenia due to
chemotherapy or aplastic anemia.
Cont’d
9 U.S. Centers enrolled patients with chronic ITP in
two sequential trials.
Inclusion criteria :
Age 18 - 65 yrs.
A history of ITP for at least 3 months.
One or more prior treatments for ITP.
A mean platelet count < 30.000/mm3 for patients not
receiving corticosteroids or < 50.000 /mm3 for
patients receiving corticosteroids.
Cont’d
The following intervals since the last
administration of therapy for ITP were
required : 2 weeks for IVIG, 8 weeks for
alkylating agents, 16 weeks for rituximab,
and 4 weeks for all other treatments.
Cont’d
Exclusion criteria :
Any known risk factor for thromboembolic
events, a history of cardiovascular disease,
active cancer, and a history of a bone
marrow disorder.
This study was a multicenter, trial consisting of two phases,
with no overlap between patients in phase 1 and those
in phase 2.
Phase 1 (July 2002 - Oct 2003) :
Safety and tolerability of two injections of AMG 531 in .1
patients with ITP.
The dose that would result in platelet count that was within
the targeted range (50.000 to 450.000/mm3)
Phase 1 cont’d
AMG 531 was administered by SC. Injection on day 1,
followed by 14 days of observation.
Health status, CBC, and blood chemical values were
monitored throughout the study.
Assays to detect anti-AMG 531 antibodies were performed
before treatment, at the end of treatment, and at the
end of the study.
If plt <50.000 on day 15, a second identical dose was
administered. If plt>=50.000 on day 15, the second
dose was delayed until day 22, if plt>=50.000 the
second dose was not given.
Follow up for 8 weeks after the study.
Phase 2
Oct 2003 – June 2004.
Double blind, placebo controlled.
Patients were randomly assigned to receive
AMG 531 at one of three doses (1,3 or 6
µg/kg) or placebo once a week for 6
weeks.
Doses were withheld if plt > 350.000/mm3.
Follow up for 6 weeks after the last dose.
Cont’d
AMG 531 does not appear to affect the
ongoing rate of platelet destruction; in all
patients receiving the drug, the platelet
count returned to the baseline value after
the discontinuation of short term
treatment.