Immune thrombocytopenia (ITP)

 Immune thrombocytopenia is an acquired thrombocytopenia caused by autoantibodies against

platelet antigens
 It is characterized by an isolated thrombocytopenia (platelet count <100 * 10^9/l).
 It was previously called idiopathic thrombocytopenic purpura and immune thrombocytopenic
purpura.

Epidemiology

 The most common cause of acute onset of thrombocytopenia in an otherwise well child
 Estimated about 1 in 20,000 children
 A recent history of viral illness is described in 50-65% of cases of childhood ITP
 1 - 4 wk after exposure to a common viral infection
 The peak age is 1-4 yr.
 ITP seems to occur more often in late winter and spring after the peak season of viral
respiratory illness.

Pathophysiology

 Anti-platelet antibody (usually IgG), a plasma-derived factor, is the main culprit in ITP pathogenesis
 The trigger for production of these autoantibodies is unknown.
 The major antigenic targets of these autoantibodies are platelet glycoproteins (GPs) IIb/IIIa and
Ib/IX
 After binding of the antibody to the platelet surface, circulating antibody-coated platelets are
recognized by the Fc receptor on splenic macrophages, ingested, and destroyed hence the drop in
platelet count

ITP is not only a disease of platelet destruction but also a disease of platelet underproduction, whereby
megakaryopoiesis is inversely correlated with the concentration of anti-platelet antibodies in the blood

 CD8+ cytotoxic T-lymphocytes in patients with ITP cause apoptosis of platelets and decrease
production of platelets in the bone marrow by attacking megakaryocytes

Other mechanisms of platelet destruction involving cell-mediated immunity include

 regulatory T-cell (CD4+, CD25+,FOXp3+) dysfunction and secondarily impaired peripheral immune
tolerance.

regulatory T-cells (CD4+, CD25+,FOXp3+) are decreased and dysfunctional in ITP patients and that ITP
therapies that normalize the platelet count partly do so by increasing regulatory T-cell levels back to normal.

Based on the above, the hallmark of the pathogenesis of ITP is loss of tolerance to platelet surface
glycoproteins.

divided the immune tolerance defects in ITP into three categories:

(1) peripheral tolerance defects arising in the setting of immune stimulation,

(2) differentiation blocks with skewed peripheral B-cell subsets, and

(3) central tolerance defects arising during development or later on in the bone marrow
  Reduced production of TPO.

TPO, a glycoprotein hormone produced by the liver and kidneys, is the main endogenous regulator of
platelet production. TPO increases platelet counts by promoting the maturation of megakaryocytes into
platelet-producing cells.

Normal patients with thrombocytopenia are expected to have high TPO levels due to loss of feedback
inhibition, but ITP patients seem to have extremely low levels of TPO suggesting that ITP truly is also a
disease of platelet production

 Most common viruses have been described in association with ITP, including Epstein-Barr virus
 In some patients ITP appears to arise in children infected with Helicobacter pylori or rarely following
the measles, mumps, rubella vaccine

Classification of ITP based on duration

Newly diagnosed – 1 - 3 months

Persistent – between 3 - 12 months

Chronic - > 12 months

Can also be classified as:

Primary – due to autoimmune mechanisms leading to platelet destruction and platelet underproduction
that is not triggered by an apparent associated condition.

Secondary – associated with another condition such as autoimmune disorders, adverse drug reactions, or
intoxications, infections, lymphoproliferative diseases.

Clinical Manifestations

 The classic presentation of ITP is a previously healthy 1-4 yr old child who has sudden onset of
generalized petechiae and purpura
  bleeding from the gums and mucous membranes, particularly with profound thrombocytopenia
(platelet count <10 × 109/L).
 history of a preceding viral infection 1-4 wk before the onset of thrombocytopenia
 physical examination is normal, other than the finding of petechiae and purpura

Classification system Depending on the basis of symptoms and signs, but not platelet count; ITP is classified
as:

 Class 1: No symptoms
 Class 2. Mild symptoms: –Bruising and petechiae –Occasional minor epistaxis –Very little
interference with daily living
 Class 3. Moderate: – More severe skin and mucosal lesions – More troublesome epistaxis and
menorrhagia
 Class 4. Severe: – Bleeding episodes—menorrhagia, epistaxis, melena—requiring transfusion or
hospitalization - Symptoms interfering seriously with the quality of life

The presence of abnormal findings such as hepatosplenomegaly, bone or joint pain, or remarkable
lymphadenopathy suggests other diagnoses

Laboratory Findings

 Severe thrombocytopenia (platelet count <20 × 109/L) is common, and platelet size is normal or
increased, reflective of increased platelet turnover
 In acute ITP, the hemoglobin value, white blood cell (WBC) count, and differential count should
be normal.
 Bone marrow examination shows normal granulocytic and erythrocytic series, with
characteristically normal or increased numbers of megakaryocytes

Indications for bone marrow aspiration/biopsy include:

1. An abnormal WBC count or differential

2. Unexplained anemia

3. Findings on history and physical examination suggestive of a bone marrow failure syndrome or
malignancy.

Other laboratory tests should be performed as indicated by the history and physical examination

 A direct antiglobulin test (Coombs) should be done If there is unexplained anemia to rule out Evans
syndrome (autoimmune hemolytic anemia and thrombocytopenia) and Before instituting therapy
with IV anti-D

Diagnosis/ Differential Diagnosis

Autoimmune thrombocytopenia may be an initial manifestation of :

1. SLE

2. HIV infection

3. Common variable immunodeficiency

4. Lymphoma(rarely)

Treatment

Platelet transfusion in ITP is usually contraindicated unless life-threatening bleeding is present (Antiplatelet
antibodies bind to transfused platelets as well as they do to autologous platelets)

• Initial approaches to the management of ITP include the following:

1. No therapy other than education and counseling of the family and patient for patients with minimal,
mild, and moderate symptoms, as defined earlier.
• This approach is:
- Far less costly
- Side effects are minimal

2. Prednisone at dose of 1-4 mg/kg/24 hr

- Corticosteroid therapy is usually continued for 2- 3 wk or until a rise in platelet count to >20 ×
109/L has been achieved, with a rapid taper
- long-term side effects: 1. Growth failure 2. Diabetes mellitus 3. Osteoporosis

3. Intravenous immunoglobulin (IVIG) at a dose of 0.8- 1.0 g/kg/day for 1-2 days.
- Induces a rapid rise in platelet count (usually >20 × 109/L) in 95% of patients within 48 hr.
- IVIG induces a response by downregulating Fc-mediated phagocytosis of antibody-coated
platelets.
- IVIG therapy is:
1.) Expensive;
2.) Time-consuming to administer;
3.) After infusion, there is a high frequency of headaches and vomiting, suggestive of IVIG-
induced aseptic meningitis.

4. Intravenous anti-D therapy for Rh positive patients:

- IV anti-D at a dose of 50-75 μg/kg causes a rise in platelet count to >20 × 109/L in 80-90% of
patients within48-72 hr.

Intracranial hemorrhage Multiple modalities should be used, including: 1. Platelet transfusion 2. IVIG 3.
High-dose corticosteroids 4. Prompt consultation by neurosurgery and surgery

The role of splenectomy in ITP should be reserved for 1 of 2 circumstances.

 1. The older child (≥4 yr) with severe ITP that has lasted >1 yr (chronic ITP) whose symptoms are not
easily controlled with therapy
2. Life-threatening hemorrhage (intracranial hemorrhage) complicates acute ITP when Platelet count
cannot be corrected rapidly with transfusion of platelets and administration of IVIG and
corticosteroids

Prognosis

 Severe bleeding is rare (<3% of cases)

 In 70-80% of children who present with acute ITP, spontaneous resolution occurs within 6 mo
 Fewer than 1% of patients develop an intracranial hemorrhage.
 Approximately 20% of children who present with acute ITP go on to have chronic ITP
 The outcome/prognosis may be related more to age, as:
- ITP in younger children is more likely to resolve
- The development of chronic ITP in adolescents approaches 50%.

ASH GUIDELINES FOR THE MANAGEMENT OF ITP

Management of children with newly diagnosed ITP

1. a.) Outpatient management for patients with a platelet count of <20 × 109/L who have no or mild
bleeding

b.) Outpatient management of patients with a platelet count of ≥20 × 109/L who have no or mild
bleeding

2. Observe rather than initiation of corticosteroids patients who have no or minor bleeding

3. Observe rather than IV immunoglobulin children who have no or minor bleeding

4. Observe rather than anti-D immunoglobulin children who have no or minor bleeding

Corticosteroid duration and type.

5. Corticosteroids for 7 days or shorter for children with non–life-threatening mucosal bleeding and/or
diminished HRQoL

6. prednisone (2-4 mg/kg per day; maximum, 120 mg daily, for 5-7 days) rather than dexamethasone
(0.6 mg/kg per day; maximum, 40 mg per day for 4 days) in children with non–life-threatening mucosal
bleeding and/or diminished HRQoL

7. Corticosteroids rather than anti-D immunoglobulin in children with non–life-threatening mucosal

bleeding and/or diminished HRQoL

8. either anti-D immunoglobulin or IVIG in children with non–life-threatening mucosal bleeding and/or
diminished HRQoL

9. Corticosteroids rather than IVIG In children with non–life-threatening mucosal bleeding and/or
diminished HRQoL
Management of children with ITP who do not have a response to first-line treatment

Second-line therapies: splenectomy, TPO-RA, and rituximab compared 1 against the other.

10. TPO-RAs > rituximab in children with ITP who have non–life-threatening mucosal bleeding and/or
diminished HRQoL

11. TPO-RAs > splenectomy In children with ITP who have non–life-threatening mucosal bleeding
and/or diminished HRQoL

12. Rituximab > splenectomy In children with ITP who have non–life-threatening mucosal bleeding
and/or diminished HRQoL

Good practice statement.

The treating physician should ensure that the patient has appropriate immunizations prior to splenectomy
and that they receive counseling regarding antibiotic prophylaxis following splenectomy. The treating
physician should educate the patient on prompt recognition and management of fever and refer to current
recommendations on pre- and post-splenectomy care.

References

1. Nelson’s text book of paediatrics 21st edition

2. UptoDate: Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis
3. Author:James B Bussel, MDSection Editor:Sarah O'Brien, MD, MScDeputy Editor:Carrie Armsby, MD,
MPH
4. Hassan M. Moukhadder, Bachar F. Chaya, Abdul-Hamid A. Bazarbachi & Ali T. Taher (2016) Immune
thrombocytopenia: a comprehensive review from pathophysiology to promising treatment
modalities, Expert Opinion on Orphan Drugs, 4:12, 1217-1227, DOI:
10.1080/21678707.2016.1247691
5. American Society of Hematology 2019 guidelines for immune thrombocytopenia