Idiopathic Thrombocytopenic Purpura

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 Fc 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 ABs 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 patients 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.

Contd
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.

Contd
In 6.9% cases, ITP occured after vaccinations, particularly the MMR vaccination (DTP, Oral polio, Hepatitis A & B).

Contd
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.

Contd
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 g/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 g/kg anti-D, 75 g/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 .

Contd
A single 75 g/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 ????

Contd
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.

Pediatr Blood Cancer 2006 ;47 Childrens 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).

ITP in children

Contd
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 ???

Contd
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 83.9 yrs.

Contd
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.

Contd
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.

Contd
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.

Contd
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.

Contd
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 contd
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 g/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.

Contd
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.