Send letter to journal:
Re: Evidence calls for paradigm shift towards non aggressive approach in immune thrombocytopenic purpura

Dear Editor,

The Nordic Study on Childhood ITP does provide valuable data on the initial management of children with acute idiopathic/immune thrombocytopenic purpura (ITP). Treutiger et al have rightly concluded that aggressive treatment of such children neither reduces the morbidity nor decreases the risk for developing chronic ITP.[1] However, the two most striking observations from this study are the obvious inconsistencies in management among different centres and the noticeably high rate of interventions. Whereas some centres treated as many as 89% of children, a few others followed the watch and wait policy and restricted interventions to just 14% of patients. It must be noted that the sample population was unselected and hence identical at all the study centres. Out of a total of 98 treatment centres, 43 treated more than two thirds of newly diagnosed children, with a pooled treatment rate as high as 87%. The overall rate of interventions across all centres was 61%, which accounted for a significant proportion of the entire study population.

Absence of an international consensus statement is perhaps the single most important factor for the wide variations in clinical practice. The two popular paediatric guidelines currently in use are those from the American Society of Hematology (ASH) in 1996 and the British Society for Haematology (BSH) in 2003.[2,3] The former recommends aggressive measures to keep the platelet count above a ‘safe’ level of 20x109/L whereas the latter specifically advises against treatment solely based on the platelet count. A noteworthy point here is the fact that the ASH guideline is now eleven years old. During this period, a considerable number of articles have been published, providing a better understanding of the pathogenesis and natural history of ITP.[4-7] Observations from such studies do question the role of aggressive management of ITP with respect to morbidity and mortality.

Despite the fact that there are region specific discrepancies in management guidelines, there seems to be sufficient evidence based recommendations in favour of the non pharmacological approach. A well child with typical clinical and laboratory features does not require a bone marrow aspirate and can be managed expectantly irrespective of the severity of thrombocytopenia (grade B recommendation).[3] Treatment should be on the basis of symptoms in addition to cutaneous bleeds and not on platelet count alone (level IIb evidence, grade B recommendation).[3] Corticosteroids are indicated when a child has extensive cutaneous bleeds along with mucosal haemorrhage (level Ib evidence, grade A recommendation). Intravenous immunoglobulin (IVIG) should be reserved for emergency treatment of serious bleeding and surgical procedures likely to induce blood loss (level Ib evidence, grade A recommendation).[3] Platelet transfusions should only be given in presence of life threatening bleeding along with steroids or IVIG (grade C recommendation).[3]

The toxicity profile of corticosteroids in children is well recognised. IVIG is a pooled blood product, with inherent risks of blood product transfusion and has even been shown to transmit hepatitis C virus infection.[8] A randomised trial demonstrated that 75% of children treated with IVIG had experienced significant side effects.[9] Over the past decade, many studies have provided varying levels of evidence in favour of the expectant policy of management in acute ITP.[5-7] No scientific study has come up with evidence to the effect that a conservative approach in severely thrombocytopenic well children without life threatening features increases the risk for morbidity or mortality. Some reports have shown that early treatment with steroids and/or IVIG have failed to prevent intracranial haemorrhage and hence cannot be considered as an absolute protective measure.[10]

To select the best therapeutic approach when multiple options are available, the ideal way forward is to subject them to multicentric randomised controlled trials (RCTs). However, due to the reasons listed above, it will be an extremely challenging task to obtain ethical approval and conduct the ideal RCT comparing conservative and aggressive therapeutic approaches. From a risk versus benefit perspective, the use of pharmacological measures upfront in all children with severe thrombocytopenia simply cannot be justified. Hence the existing controversy regarding the best management practice in acute ITP remains unique in that randomisation does not seem to be a feasible option. It may therefore be reasonable to accept the available levels of evidence and grades of recommendation, thus shifting the current practice to a standardised watch and wait mode of non pharmacological management.

References

1.Treutiger I, Rajantie J, Zeller B et al. Does treatment of newly diagnosed idiopathic thrombocytopenic purpura reduce morbidity? Arch Dis Child 2007; 92 : 704-7.

2.George JN, Woolf SH, Raskob JE et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996; 88(1) : 3-40.

3.British Committee for Standards in Haematology General Haematology Task Force. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol 2003; 120(4) : 574-96.

4.Bolton-Maggs PH, Dickerhoff R, Vora AJ. The non-treatment of childhood ITP (or "the art of medicine consists of amusing the patient until nature cures the disease"). Semin Thromb Hemost 2001; 27(3) : 269-75.

5.Dickerhoff R, von Ruecker A. The clinical course of immune thrombocytopenic purpura in children who did not receive intravenous immunoglobulins or sustained prednisone treatment. J Pediatr 2000; 137(5) : 629-32.

6.Tarantino MD. The treatment of immune thrombocytopenic purpura in children. Curr Hematol Rep 2006; 5(1) : 89-94.

7.Roganovic J, Letica-Crepulja M. Idiopathic thrombocytopenic purpura: a 15 year natural history study at the Children’s Hospital, Rijeka, Croatia. Pediatr Blood Cancer 2006; 47(5 Suppl) : 662-4.

8.Duhem C, Dicato MA, Ries F. Side effects of intravenous immunoglobulins. Clin Exp Immunol 1994; 97 : 79-83.

9.Blanchette VS, Luke B, Andrew M et al. A prospective, randomized trial of high-dose intravenous immune globulin G therapy, oral prednisone therapy, and no therapy in childhood acute immune thrombocytopenic purpura. J Pediatr 1993; 123(6) : 989-95.

Send letter to journal:
Re: Evidence calls for paradigm shift towards non aggressive approach in immune thrombocytopenic purpura

Dear Editor,

The Nordic Study on Childhood ITP does provide valuable data on the initial management of children with acute idiopathic/immune thrombocytopenic purpura (ITP). Treutiger et al have rightly concluded that aggressive treatment of such children neither reduces the morbidity nor decreases the risk for developing chronic ITP.[1] However, the two most striking observations from this study are the obvious inconsistencies in management among different centres and the noticeably high rate of interventions. Whereas some centres treated as many as 89% of children, a few others followed the watch and wait policy and restricted interventions to just 14% of patients. It must be noted that the sample population was unselected and hence identical at all the study centres. Out of a total of 98 treatment centres, 43 treated more than two thirds of newly diagnosed children, with a pooled treatment rate as high as 87%. The overall rate of interventions across all centres was 61%, which accounted for a significant proportion of the entire study population.

Absence of an international consensus statement is perhaps the single most important factor for the wide variations in clinical practice. The two popular paediatric guidelines currently in use are those from the American Society of Hematology (ASH) in 1996 and the British Society for Haematology (BSH) in 2003.[2,3] The former recommends aggressive measures to keep the platelet count above a ‘safe’ level of 20x109/L whereas the latter specifically advises against treatment solely based on the platelet count. A noteworthy point here is the fact that the ASH guideline is now eleven years old. During this period, a considerable number of articles have been published, providing a better understanding of the pathogenesis and natural history of ITP.[4-7] Observations from such studies do question the role of aggressive management of ITP with respect to morbidity and mortality.

Despite the fact that there are region specific discrepancies in management guidelines, there seems to be sufficient evidence based recommendations in favour of the non pharmacological approach. A well child with typical clinical and laboratory features does not require a bone marrow aspirate and can be managed expectantly irrespective of the severity of thrombocytopenia (grade B recommendation).[3] Treatment should be on the basis of symptoms in addition to cutaneous bleeds and not on platelet count alone (level IIb evidence, grade B recommendation).[3] Corticosteroids are indicated when a child has extensive cutaneous bleeds along with mucosal haemorrhage (level Ib evidence, grade A recommendation). Intravenous immunoglobulin (IVIG) should be reserved for emergency treatment of serious bleeding and surgical procedures likely to induce blood loss (level Ib evidence, grade A recommendation).[3] Platelet transfusions should only be given in presence of life threatening bleeding along with steroids or IVIG (grade C recommendation).[3]

The toxicity profile of corticosteroids in children is well recognised. IVIG is a pooled blood product, with inherent risks of blood product transfusion and has even been shown to transmit hepatitis C virus infection.[8] A randomised trial demonstrated that 75% of children treated with IVIG had experienced significant side effects.[9] Over the past decade, many studies have provided varying levels of evidence in favour of the expectant policy of management in acute ITP.[5-7] No scientific study has come up with evidence to the effect that a conservative approach in severely thrombocytopenic well children without life threatening features increases the risk for morbidity or mortality. Some reports have shown that early treatment with steroids and/or IVIG have failed to prevent intracranial haemorrhage and hence cannot be considered as an absolute protective measure.[10]

To select the best therapeutic approach when multiple options are available, the ideal way forward is to subject them to multicentric randomised controlled trials (RCTs). However, due to the reasons listed above, it will be an extremely challenging task to obtain ethical approval and conduct the ideal RCT comparing conservative and aggressive therapeutic approaches. From a risk versus benefit perspective, the use of pharmacological measures upfront in all children with severe thrombocytopenia simply cannot be justified. Hence the existing controversy regarding the best management practice in acute ITP remains unique in that randomisation does not seem to be a feasible option. It may therefore be reasonable to accept the available levels of evidence and grades of recommendation, thus shifting the current practice to a standardised watch and wait mode of non pharmacological management.

References:

1. Treutiger I, Rajantie J, Zeller B et al. Does treatment of newly diagnosed idiopathic thrombocytopenic purpura reduce morbidity? Arch Dis Child 2007; 92 : 704-7.

2. George JN, Woolf SH, Raskob JE et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996; 88(1) : 3-40.

3. British Committee for Standards in Haematology General Haematology Task Force. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol 2003; 120(4) : 574-96.

4. Bolton-Maggs PH, Dickerhoff R, Vora AJ. The non-treatment of childhood ITP (or "the art of medicine consists of amusing the patient until nature cures the disease"). Semin Thromb Hemost 2001; 27(3) : 269-75.

5. Dickerhoff R, von Ruecker A. The clinical course of immune thrombocytopenic purpura in children who did not receive intravenous immunoglobulins or sustained prednisone treatment. J Pediatr 2000; 137(5) : 629-32.

6. Tarantino MD. The treatment of immune thrombocytopenic purpura in children. Curr Hematol Rep 2006; 5(1) : 89-94.

7. Roganovic J, Letica-Crepulja M. Idiopathic thrombocytopenic purpura: a 15 year natural history study at the Children’s Hospital, Rijeka, Croatia. Pediatr Blood Cancer 2006; 47(5 Suppl) : 662-4.

8. Duhem C, Dicato MA, Ries F. Side effects of intravenous immunoglobulins. Clin Exp Immunol 1994; 97 : 79-83.

9. Blanchette VS, Luke B, Andrew M et al. A prospective, randomized trial of high-dose intravenous immune globulin G therapy, oral prednisone therapy, and no therapy in childhood acute immune thrombocytopenic purpura. J Pediatr 1993; 123(6) : 989-95.