CK Li

Idiopathic Thrombocytopenic Purpura (ITP) is the commonest bleeding disorder in children. It is also known as "Primary Immune Thrombocytopenic Purpura". There is a great variation in the incidence of ITP, from 10 to 125 per million population. Probably due to the under diagnosis of many mild cases. ITP is defined as condition with isolated thrombocytopenic with no other clinically apparent associated conditions or causes of thrombocytopenia. Some of the common causes of thrombocytopenia are: SLE, myelodysplasia, haematological or non-haematological malignancy, lymphoproliferative disorders, HIV infection, alloimmune thrombocytopenia, congenital or hereditary nonimmune thrombocytopenia ... etc. However, there are no specific diagnostic criteria for ITP, the diagnosis is made by exclusion of other causes. History and physical examination are important in making accurate diagnosis of ITP. Details of the bleeding symptoms such as severity, type and duration of bleeding should be noted. Systemic symptoms enquiry especially recent viral illnesses within past six weeks should be asked. Recent immunization, medications and risk factor for HIV infections may give hint to the underlying causes of thrombocytopenia. Family history of bleeding disorders may suggest hereditary type of thrombocytopenia. The life style of the patient should also be enquired since this is important in the management of the child. Bleeding signs should be checked for during the examination, especially the mucosal and the retinal hemorrhage. Significant mucosal bleeding is associated with a higher chance of intracranial haemorrhage. Hepatosplenomegaly and lymphadenopathy may suggest underlying malignancy or some form of infection. For hereditary thrombocytopenias; dysmorphic features such as skeletal anomalies (absent radius), short stature, hyperpigmentation may be present. A complete blood count with careful examination of the blood smear is mandatory for making the diagnosis. In ITP, the red cell and white cell morphology should be normal. There may be some giant platelets, but it should not be in consistent way. Platelet clumps should also be looked for which may give rise to psueudothrombocytopenia. Bone marrow examination is usually not necessary if the patient has typical history, examination and normal blood count except isolated thrombocytopenia. Bone marrow examination may be necessary if the patient has persistent thrombocytopenia for more than six months, or no response to the IVIG treatment. Anti-nuclear antibody and direct antiglobulin test may be performed before splenectomy. HIV antibody should be checked for patients with risk factor. Platelet antigen specific antibody is not very helpful in diagnosis as this is not very specific.

There are different types of treatment modalities for ITP, however there is problem of assessing efficacy of each type of treatment due to:

1. Poor correlation of platelet count and clinical bleeding;
2. lack of controlled studies;
3. lack of comparison of benefits and harms of each type of treatment.

Anyway, platelet count is still the most useful surrogate for outcome. If the patient is having platelet count more than 10 x 10⁹/L and asymptomatic, or only with minor purpura, the patient is not required hospitalization. The different types of treatment are discussed in the following.

1. Observation:

About 80% of patients without specific treatment had complete remission by six months. However, there was no large prospective study on comparing "observation" with other types of specific treatment. In the reported series, 0.9% of patients had fatal bleeding, mainly intracranial haemorrhage (ICH). 40% of the ICH occurred within the first two weeks after the diagnosis, but ICH could occur even up to 5 years after diagnosis. In those who had complete remission, the platelet count normalized in 2-8 weeks time, about 1/2 to 2/3 within 4 weeks. The reported cases of ICH mostly occurred before the IVIG or steroid era. In patients with platelet more than 20 x 10⁹/L and being asymptomatic, they may be observed for a course to see whether they have spontaneous remission.

2. Steroid treatment:

There are several regimens of steroid treatment:

1. Prednisone 1-2 mg/kg or 60 mg/m² per day for 2-4 weeks and tapered.
2. Prednisone 4 mg/kg/day for 7 days and then tapered to 21 days.
3. IV or oral methylprednisolone 10-50 mg/kg/day for 3-7 days.

It was shown that steroid treated patients had more rapid platelet recovery as compared to observation group, 4 days versus 16 days to achieve platelet count more than 50 x 10⁹/L. In patients received high dose steroid, the platelet recovery might be as rapid as that of IVIG. It was recommended to give high dose steroid treatment in patients with life threatening bleeding. Due to the side-effects of steroid, most people recommended treatment should be limited to 21 days.

3. IV immunoglobulin (IVIG):

80 - 90% of the patients had good response to IVIG treatment. The initial treatment regimen was 0.4 mg/ kg/day for 5 days, total of 2 gin. However, the regimen of lower doses had been tried with success, such as 1 gm/kg for 1 day, 0.4 mg/kg/day for 2 days, 0.8 mg/kg/day for 1 days. Our practice is to give 1 dose of 0.4 mg/kg and observe for platelet recovery, if the platelet count increase to more than 20 x 10⁹/kg without active bleeding, no further doses of IVIG will be given. The response of IVIG usually occurred within one to three days. The degree of response and duration of response depends on dosage of IVIG, usually higher dosage will achieve more rapid response with longer duration. About 15-75% of patients received IVIG had some form of side-effects, but mostly were mild such as headache, backache, nausea, fever. There might be rare complications of IVIG treatment such as aseptic meningitis, alloimmune haemolysis and hepatitis. One of the major disadvantage of IVIG is the expensive cost of the treatment.

4. Anti-Rh (D) immunoglobulin:

Intravenous anti-Rh (D) immunoglobulin for treatment of ITP had been recently introduced and was found to be effective in about 80% of cases. The dose was recommended to be 25-50 ug/kg IV given either as single dose or divided doses over 2 days. The time to response after anti-Rh (D) may be slightly longer than WIG. The side-effect of anti-Rh (D) included chills, headache and fever. However the major limiting factor is the alloimmune haemolysis, there is a mean maximum drop of haemoglobin of 1.7 gm/dl, 3.7% of patients may have a drop of haemoglobin more than 4 g/dl. Even though most patients did not require blood transfusion, anti-Rh (D) is not recommended as the first line treatment for ITP because of the above side-effects.

5. Splenectomy:

Splenectomy had been shown to be effective to achieve complete remission in about 72% of patients. However, with other less invasive treatment available, splenectomy is now seldom performed during the acute phase. It is reserved as emergency treatment for life threatening bleeding or in patients who had refractory symptomatic and severe chronic ITP. The response of platelet recovery usually occurred within days after operation. The complications of splenectomy included pen-operative morbidity and mortality. The long term risk of fatal bacterial infection is the major disadvantage, sepsis occurred in about 2% of patients and mortality had been reported to be 1%. However the above complication rates were mainly from the era before routine pre-splenectomy immunization and the post-splenectomy penicillin. Before doing splenectomy, IVIG ± parenteral steroid may be given so as to raise the platelet count, and thus reduce the operation risk. The patient should also receive the following vaccines at least 2 weeks before the operation polyvalent pneumococcal vaccine, haemophilus influenzae type B vaccine ±meningococcal vaccine.

6. Alternative treatment:

Cytotoxic agents such as vincristine, azathioprine, cyclophosphamide had been tried with some success. Danazol, vitamin C and cyclosporine A had also been reported to be useful in occasional patients. Protein-A immunoadsorption and plasma exchange had been reported in some adult series to be successful. However the alternative treatment are seldom required in paediatric practice.

7. Emergency treatment:

In patients who had life threatening bleeding, they would require combined treatment to increase the platelet count as quickly as possible. High dose steroid (30 mg/kg/day methylprednisolone for 3 days) + IVIG + platelet transfusion and splenectomy is recommended.

Since there was no lack of randomised trials for acute ITP, it is difficult to give firmed and evidence-based recommendation for treatment. However there are consensus of opinion on the following situation:

1. Platelet count more than 30 x 10⁹/L: if the patients is asymptomatic oronly having minor purpura, no treatment is required.
2. Platelet count less than 20 x 10⁹/L: the patient should be treated with specific treatment if that is associated with significant mucosal bleeding.
3. Platelet count less than 10 x 10⁹/L: the patient should be treated even he/she only has minor purpura.

For neonates born to mothers with ITP are as risk of developing thrombocytopenia. About two third of these neonates had decreased platelet counts, and 83% will reach the nadir of thrombocytopenia by 1 to 2 days, and 100% by day 6. The platelet count will begin to rise or stabilized by day 7. The platelet count at birth may not be the lowest value, therefore the platelet count should be repeated for at least 3-4 days after birth. If the baby has platelet count less than 50 x 10⁹/L, ultrasound of the brain is indicated. However there is no contraindication for breast feeding in mothers with ITP. If the platelet count is less than 20 x 10⁹/L, IVIG should be given, there is intracranial hemorrhage, IVIG combined with steroid may give better response.