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Idiopathic thrombocytopenic purpura
Idiopathic thrombocytopenic purpura
P. H. B. B o l t o n - M a g g s
sudden onset (usually a day or 2). While the appearance is impressive, the child is well, and other types of bleeding are rare. Minor epistaxis may occur but major bleeding from mucous membranes is less common. On examination mucosal purpura may be seen, the fundi are normal, there are no other signs of illness and there is no organomegaly. A full blood count is normal apart from an isolated thrombocytopenia which is often less than 20 x 109/1 in a child with symptoms. Many children have a history of a recent viral infection (but so do many normal children) or vaccination (within the last 2-3 weeks), e.g. rubella (or varicella). In the typical case no further investigations are required, and no therapy is indicated. The parents need an explanation of the condition with emphasis on the benign nature and good outlook (preferably with written material2). Sensible advice should be given relating to management including what to do in the event of an injury. The child who presents only with skin bruising needs neither bed rest nor admission to hospital, which is neither quiet nor necessarily safer than being at home. It is important not to cause undue anxiety by focussing too closely on the low platelet count 3 (Table 1). In the typical case the diagnosis is not difficult. The pitfalls and differential diagnoses are considered in Table 2. In young children careful consideration must be given to a congenital cause, otherwise such diagnoses will be missed:
Thrombocytopenia in childhood has a variety of causes. A mild asymptomatic reduction in platelet count is not unusual in a child with a viral infection and may cause unnecessary anxiety when picked up as an incidental finding now that most automated machines produce a platelet count as part of the package. Severe thrombocytopenia as an isolated finding is usually (but not invariably) due to idiopathic thrombocytopenic purpura (ITP). In children this is a benign disorder usually associated with few significant symptoms and a very good prognosis, and is significantly different from the ITP in adult life. Originally described in 1735 by Werlhof in a young woman with a self-limiting bleeding disorder, ITP is caused by immune-mediated platelet destruction. Some stimulus (usually an infection) triggers an inappropriate immune response with antibody production against platelet membrane glycoproteins leading to a markedly reduced platelet lifespan. This was first demonstrated in 1950 by Harrington who infused himself with plasma from a patient with ITP, producing a profound thrombocytopenia. Numerous studies have since confirmed the theory of antibody mediated platelet destruction. 1 The marrow increases the output (identified by increased megakaryocytes in the bone marrow aspirate and trephine) but this is not sufficient to maintain the peripheral count. ITP is not a common condition and the incidence in children is probably about 1 in 25 000 of the population.
• Bernard-Soulier syndrome (BSS) - a recessively Clinical presentation and diagnosis
inherited disorder with giant platelets and bleeding more severe than the platelet count would suggest. Platelet function tests show reduced aggregation to the antibiotic ristocetin which is due to reduction or absent glycoprotein lb on the platelets.
The typical child is less than 10 years of age and presents with bruising and purpura with a relatively Paula H.B. Bolton-Maggs MRCP, MRCPath, Consultant
• Wiskott-Aldrich syndrome (WAS) - small platelets, associated with eczema and immune deficiency.
Paediatric Haematologist, Royal Liverpool Children's NHS Trust, Alder Hey, Eaton Road, Liverpool L12 2AP. Correspondence and requests for offprints to PHBB-M.
Current Paediatrics (1995)5, 181-185 © 1995PearsonProfessionalLtd
181
182 CURRENT PAEDIATRICS
Table 1 Prevention of anxiety in ITP3 Give the family information about
Benign nature of the disease Irrelevance of platelet counts High rate of spontaneous recovery Extreme rarity of intracranial bleeding
Doctors should avoid
Prolonged hospitalisation of the child Unnecessary diagnostic tests Unnecessary treatment
'Some physicians who are not seeing ITP patients frequently.., are overly impressed by the extent of the cutaneous manifestations and tend to convey this to the patient or parent. Considerable psychological morbidity is generated by conveying the impression that the well-being of the child rises and falls with the platelet count. Most parents and patients can live quite comfortably with petechiae and low platelets, awaiting spontaneous remission, provided their physician can. ,3
T h e bleeding c o m p l i c a t i o n s a n d infections can be life-threatening, a n d these patients m a y be candidates for b o n e m a r r o w t r a n s p l a n t a t i o n . These i n h e r i t e d d i s o r d e r s have quite different implications for genetic counselling a n d m a n a g e m e n t . I n I T P the b o n e m a r r o w is o f n o r m a l o r increased cellularity with a n increase in the m e g a k a r y o c y t e s . T h e r e is p e r i p h e r a l platelet d e s t r u c t i o n w i t h a c o m p e n s a t o r y increase in m a r r o w activity. T h e a p p e a r a n c e s o f the m a r r o w will exclude o t h e r m o r e serious p a t h o l o g y such as acute l e u k a e m i a , t u m o u r infiltration a n d aplastic a n a e m i a . T h e a p p e a r a n c e is n o t d i a g n o s t i c o f ITP, b u t only indicates t h a t the cause o f the t h r o m b o c y t o p e n i a is p e r i p h e r a l destruction r a t h e r t h a n failure o f p r o d u c t i o n . I f o t h e r d i s o r d e r s such as BSS o r W A S have n o t been t h o u g h t of, the m a r r o w will n o t suggest the diagnosis. W h i l e the m a j o r i t y o f children u n d e r 10 years o f age will have isolated acute ITP, o l d e r sufferers are m o r e likely to be female, to have a chronic course, a n d a n u n d e r l y i n g p a t h o l o g y a n d need to be investigated accordingly. Table 2 Differential diagnosis of ITP 1. Could it be a congenital thrombocytopenia? • Is the history life-long? • Is the bleeding worse than the count suggests? • Is there a family history? • Are there any physical congenital abnormalities? 2. What other differential diagnoses must be considered? • Are there additional laboratory abnormalities In the WBC - abnormal cells, neutropenia? In the red cells - - macrocytosis, fragmentation? • Are there additional clinical features? Lymphadenopathy, splenomegaly? Bone pain, limping? Sick child? • In the presence of these, consider marrow examination. 3. Underlying disorders • Systemic lupus erythematosis Autoantibody screen - ANF and dsDNA • Antiphospholipid syndrome Evidence of anticardiolipin antibodies Lupus anticoagulant • HIV infection
Fig. 1--Child with ITP who sustained a head injury, and needed treatment.
Management of acute ITP Who to treat? M o s t children with I T P d o n o t need any t r e a t m e n t at all. I n the p a s t the desire to treat has been g o v e r n e d b y the fear o f i n t r a c r a n i a l h a e m o r r h a g e . I n d e e d , a m a j o r review o f 1TP does n o t m e n t i o n ' n o t r e a t m e n t ' as a n o p t i o n . 1 It is n o w generally agreed t h a t the risk o f serious bleeding in children has been overstated. Recently L i l l e y m a n 4 c a r r i e d o u t a n a t i o n w i d e survey b y q u e s t i o n n a i r e to find all cases o f i n t r a c r a n i a l h a e m o r r h a g e ( I C H ) in c h i l d h o o d I T P between 1974-1994. F o u r t e e n cases h a d o c c u r r e d in the
Table3 Classification of childhood ITP by severity of symptoms Mild • Bruising and petechiae; occasional minor epistaxis Very little or no interference with daily living Moderate • More severe skin manifestations with some mucosal lesions and more troublesome epistaxis or menorrhagia Severe • Bleeding episodes (epistaxis, melaena and/or menorrhagia) requiring hospital admissions and/or blood transfusions symptoms seriously interfering with quality of life.
IDIOPATHIC THROMBOCYTOPENIC PURPURA
Alder Hey patients - 24 patients
183
Other hospitals - 17 patients
-1 21
I•IVIG
~Steroids
F-INotreatment
There was a large difference in treatment not related to differences in bleeding tendency. Why is this so? Is there such variation between paediatricians nationally? A national audit is in progress by the BPA
Fig. 2~Differencesin the managementof ITP betweenhospitalsin MerseyRegion.
20 years, 6 children surviving without important sequelae. In 7 cases the ICH occurred within a week of onset of the ITP, but in 5 it was more than 2 months from diagnosis. Four children had underlying causes 2 had head injuries and 2 had AV malformations. Extrapolating from the incidence of ITP in Sheffield, Lilleyman calculates that the incidence of ICH is about 0.1% of all children with ITR This is substantially less than the 1% usually quoted. No other instances of serious haemorrhage were reported in this survey. It should be noted that the risk of ICH is not restricted to the days surrounding diagnosis, but remains a risk for as long as the platelet count remains very low. The child should be assessed by symptoms, and not by the platelet count alone, according to the scheme in Table 3. Treatment should only be considered for those classed as 'moderate' or 'severe', who will be the minority of children. In our experience over the past 2 years only 3 out of 23 children presenting with ITP required any treatment. Another reason for treatment would be a child with a low count who has an accident (e.g. Fig. 1) or who requires surgery such as dental extractions. The natural history of ITP shows that most children will remit spontaneously, sometimes within a very short time (a few days), and the majority (90%) within 9-12 weeks. 5 Oral steroids or intravenous immunoglobulin?
Treatment with oral steroids is favoured by many whether this is of any clinical benefit is disputed. 6 Possibly adolescents with very low counts may be more likely to bleed, and therefore warrant therapy. 6 Steroids do not have to be given in large doses - 0.25 mg/kg may well be enough, and should only be given for a clearly defined period (e.g. 2-3 weeks).
Intravenous immunoglobulin (IVIG) is sometimes used to treat uncomplicated ITP, perhaps because it produces a rapid response in the platelet count; therefore in the hospital where normal practice has been to keep a child in hospital until an 'acceptable' platelet count is reached (usually >20 x 109/1), such treatment may well shorten the hospital stay, thereby reducing cost. As discussed above, this approach is based on the false premise that a low count carries a significant morbidity, and that hospitalisation is necessary. Neither of these assumptions is true. IVIG is invasive, expensive, can have side effects, and has (rarely) been associated with transmission of hepatitis C, a potentially life-threatening infection. 7 These different approaches to management have been clearly highlighted in a recent audit in Mersey Region which shows less treatment given in the tertiary centre (Fig. 2), in spite of there being no differences in the characteristics of the children presenting with ITR Figure 3 shows the outcome of 20 cases of ITP seen at Alder Hey over the past 2 years who have not required any treatment. Very helpful guidelines for the management of ITP have recently been published 5 - the major recommendations are highlighted in Table 4. Marrow examination before treatment: If treatment is given, then marrow examination must be performed first to exclude other pathology including rare congenital disorders (such as Fanconi anaemia) where isolated thrombocytopenia may be the only feature. 8 We have seen one child whose isolated thrombocytopenia had been treated with IVIG before marrow examination, with no response - the thrombocytopenia was the first clue to acute lymphoblastic leukaemia. The use of oral steroids in such a case might have induced a remission, the child then only presenting with first 'relapse' when the chance of a
184
CURRENT PAEDIATRICS
cure would have been jeopardised by his earlier inappropriate treatment. 100 -
-
8O
6O Cumulative % 40 telets >50 x 109/I t Platelets >100 x 10~/l
2O
0 20
40
60
80
100
120
140
Days
Fig. ~ T i m e to remission in 20 untreated children with ITP, either to platelet count of 50 or 100 x 10911.
Table 4 Guidelines for the m a n a g e m e n t of childhood ITP (Eden and Lilleyman on behalf o f the British Paediatric Haematology Forum) s • • • • •
• •
Treatment is not necessary for children presenting with bnlising alone Hospital admission and/or enforced rest is not necessary Marrow examination is not m a n d a t o r y unless treatment is planned Oral steroids: a dose o f 0.25 mg/kg m a y be as effective a n d safer than higher doses IVIG should be reserved for: - The emergency treatment of patients who present with active bleeding and who do not spontaneously remit or respond to steroids - Cover for essential surgery and dental extractions Chronic ITP does not necessarily need treatment and should be discussed with the regional paediatric haematologists Platelet transfusions are only indicated for life-threatening haemorrhage
Remissions may occur spontaneously many years after diagnosis (even 10-20 years) and the predicted spontaneous remission rate is 61% after 15 years, l° Children over the age of 10 and girls are more likely to have a chronic course and an underlying disease (Fig. 4) and need work-up to exclude other diagnoses such as SLE. In the absence of bleeding symptoms children with chronic ITP need advice about their lifestyle (to avoid contact sports and non-steroidal anti-inflammatory drugs), and may need occasional therapy to cover dental extractions or trauma. Children without significant symptoms should not be maintained indefinitely on steroids nor given repeated courses of IVIG; clinicians must beware of titrating therapy against the platelet count without consideration of the symptoms (or lack of them). Which children with chronic ITP need treatment?: A platelet count of >30 x 109/1 usually gives rise to no serious bleeding problems. The most worrying patients are those with Lilleyman's 'chronic severe ITP' who have low counts and troublesome bleeding manifested usually by repeated epistaxis or menorrhagia. ]1 Such individuals are very rare (estimated at 5-10 in the whole of the UK in a year) H, and therefore should be referred to a specialist? These are probably the only children in whom splenectomy should be contemplated. W I G or pulses of methylprednisolone produce usually a temporary remission and although this can be repeated some children show progressively less response. Several other agents have been tried] I but experience with any one is limited, and such therapy should be initiated only by an experienced haematologist. Splenectomy and precautions needed
Platelet transfusions are not indicated for the management of bleeding in ITR Since the pathology is platelet consumption, transfused platelets are unlikely to be effective unless given in mega-doses, and expose the child to unnecessary risks. The only exception to this is in the very rare situation of life threatening haemorrhage where a 'belt and braces' approach is reasonable - IVIG, steroids and large numbers of platelets (e.g. 20 donor units)?
Splenectomy was commonly performed for children with chronic ITR However, these are two major drawbacks: splenectomy only produces remission in about two thirds of cases, and is not without risk. Splenectomy should not be performed for a low
E~Acute ITP ==Chronic ITP 6 5
The management of chronic ITP Chronic ITP is arbitrarily but conventionally defined as thrombocytopenia persisting beyond 6 months from diagnosis. A longer history of bruising or bleeding symptoms at diagnosis is predictive of a more chronic course? Chronic ITP does not necessarily need any specific treatment if giving rise to no symptoms, and is not of itself an indication for splenectomy. If a marrow examination has not been done it is reasonable to do it in order to exclude other diagnoses even if no specific therapy is planned. 8
Number of cases (total 43)
4
iii~l
3 2 1
[
0 <01
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Age (Years)
Fig. 4 - - A g e at presentation of cases of ITP at Alder Hey - 5-year retrospective analysis with a total of 43 children. 13 (30%) were below 2 years, furthermore those over 10 years were more likely to have chronic ITP and an underlying disease.
IDIOPATHIC THROMBOCYTOPENIC PURPURA
185
Table 5 Information for patients undergoing splenectomy (Department of Health, March 1995)
platelet c o u n t alone, b u t only in p a t i e n t s w i t h significant s y m p t o m s w h o are m o r e t h a n 6 m o n t h s f r o m diagnosis. 5,H A s p l e n i c i n d i v i d u a l s are at increased risk o f serious sepsis f r o m e n c a p s u l a t e d o r g a n i s m s w h i c h are n o r m a l l y cleared b y the spleen, i.e. p n e u m o c o c c u s , a n d Haemophilus influenzae. T h e m o r t a l i t y in different series is 1.4-1.6%, which is greater t h a n the risk o f d y i n g f r o m h a e m o r r h a g e due to t h r o m b o c y t o p e n i a ) 1 T h e risk o f p o s t s p l e n e c t o m y sepsis is p r o b a b l y greatest in b u t certainly n o t c o n f i n e d to c h i l d h o o d . 12 R e c e n t discussions o f the late m o r t a l i t y f r o m infection following s p l e n e c t o m y 13,14 have resulted in guidelines for the m a n a g e m e n t o f s p l e n e c t o m y 15 (Table 5) t o g e t h e r with a c a r d t h a t patients can c a r r y in case o f e m e r g e n c y (Fig. 5). W h i l e discussion continues over the n a t u r e a n d d u r a t i o n o f a n t i b i o t i c prophylaxis, the m o s t i m p o r t a n t feature is p r o b a b l y a d e q u a t e e d u c a t i o n o f the p a t i e n t to r e p o r t early for m e d i c a l help in the face o f any infectious episode.
limiting within a few weeks, a n d often requires no specific therapy. W h e n the c o n d i t i o n is chronic, lasting m o r e t h a n 6 m o n t h s , p r o v i d i n g there are n o significant s y m p t o m s , n o specific t h e r a p y is indicated. U n d e r l y i n g d i s o r d e r s s h o u l d be s o u g h t in these children.
Conclusion
Acknowledgement
C h i l d h o o d I T P is a n u n c o m m o n disorder. A l t h o u g h the low platelet c o u n t m a y frighten the m e d i c a l attendants, the patients rarely have significant s y m p t o m s . T h e d i s o r d e r is u s u a l l y b e n i g n a n d self-
The author is grateful to Professor John Lilleyman for his helpful comments.
Fig, ~-Department of Health card for asplenic individuals.
* Ensure that medical attendants are aware that you have no spleen • Vaccinations pre-splenectomy - pneumococcal vaccine Hib vaccine - meningococcal vaccine under some circumstances (travel to certain countries) • Daily antibiotics until at least the age of 16 or a course to keep at home for use at onset of illness • Consult doctor immediately if ill • Special precautions may be needed when travelling abroad * Animal bites must be treated promptly including a course of antibiotics
References 1. Karpatkin S. Autoimmune thrombocytopenic purpura. Semin Hematol 1985; 22: 260-288. 2. Chessells J, Hann I. Idiopathic thrombocytopenic purpura (ITP) - some notes for parents. Published by Great Ormond Street Hospital for Children NHS Trust, 1995. 3. Dickerhoff R. Experience with 74 ITP patients - comparison of different management policies. In: Sutor AH, Thomas KB, eds. Thrombocytopenia in Childhood. Stuttgart and New York: Schattauer, 1994: 121-127. 4. Lilleyman JS. Intracranial haemorrhage in idiopathic thrombocytopenic purpura. Arch Dis Child 1994; 71: 251-253. 5. Eden OB, Lilleyman JS. Guidelines for the management of idiopathic thrombocytopenic purpura. Arch Dis Child 1992; 67: 1056-1058. 6. Buchanan GR. The nontreatment of childhood idiopathic thrombocytopenic purpura. Eur J Pediat 1987; 146:107-112. 7. Bjoro K, Froland SS, Yun Z, Samdal I-IH, Haaland T. Hepatitis C infection in patients with primary hypogammaglobulinaemia after treatment with contaminated immune globulin. N Engl J Med 1994; 331: 1607-1611. 8. Chessells J. Chronic idiopathic thrombocytopenic purpura: primum non nocere. Arch Dis Child 1989; 64: 1326-1328. 9. Robb LG, Tiedeman K. Idiopathic thrombocytopenic purpura: predictors of chronic disease. Arch Dis Child 1990; 65: 502-506. 10. Reid MM. Chronic idiopathic thrombocytopenic purpura: incidence, treatment and outcome. Arch Dis Child 1995; 72: 125-128. 11. Lilleyman JS. The therapeutic challenge of chronic severe ITP in children. In: Sutor AH, Thomas KB, eds. Thrombocytopenia in Childhood. Stuttgart: Schattauer, 1994: 141-148. 12. Evans DIK. Post splenectomy sepsis 10 years or more after operation. J Clin Pathol 1985; 38: 309-311. 13. McMullin M, Johnston G. Long term management of patients after splenectomy. B M J 1993; 307: 1372~1373. 14. Deodhar HA, Marshall R J, Barnes JN. Increased risk of sepsis after splenectomy. B M J 1993; 307: 1408-1409. 15. Department of Health. Information about splenectomy for patients. Leaflets and cards available from HMSO, Oldham Broadway Business Park, Broadgate, Chadderton, Oldham, OL9 0JA.
P. H. B. B o l t o n - M a g g s
sudden onset (usually a day or 2). While the appearance is impressive, the child is well, and other types of bleeding are rare. Minor epistaxis may occur but major bleeding from mucous membranes is less common. On examination mucosal purpura may be seen, the fundi are normal, there are no other signs of illness and there is no organomegaly. A full blood count is normal apart from an isolated thrombocytopenia which is often less than 20 x 109/1 in a child with symptoms. Many children have a history of a recent viral infection (but so do many normal children) or vaccination (within the last 2-3 weeks), e.g. rubella (or varicella). In the typical case no further investigations are required, and no therapy is indicated. The parents need an explanation of the condition with emphasis on the benign nature and good outlook (preferably with written material2). Sensible advice should be given relating to management including what to do in the event of an injury. The child who presents only with skin bruising needs neither bed rest nor admission to hospital, which is neither quiet nor necessarily safer than being at home. It is important not to cause undue anxiety by focussing too closely on the low platelet count 3 (Table 1). In the typical case the diagnosis is not difficult. The pitfalls and differential diagnoses are considered in Table 2. In young children careful consideration must be given to a congenital cause, otherwise such diagnoses will be missed:
Thrombocytopenia in childhood has a variety of causes. A mild asymptomatic reduction in platelet count is not unusual in a child with a viral infection and may cause unnecessary anxiety when picked up as an incidental finding now that most automated machines produce a platelet count as part of the package. Severe thrombocytopenia as an isolated finding is usually (but not invariably) due to idiopathic thrombocytopenic purpura (ITP). In children this is a benign disorder usually associated with few significant symptoms and a very good prognosis, and is significantly different from the ITP in adult life. Originally described in 1735 by Werlhof in a young woman with a self-limiting bleeding disorder, ITP is caused by immune-mediated platelet destruction. Some stimulus (usually an infection) triggers an inappropriate immune response with antibody production against platelet membrane glycoproteins leading to a markedly reduced platelet lifespan. This was first demonstrated in 1950 by Harrington who infused himself with plasma from a patient with ITP, producing a profound thrombocytopenia. Numerous studies have since confirmed the theory of antibody mediated platelet destruction. 1 The marrow increases the output (identified by increased megakaryocytes in the bone marrow aspirate and trephine) but this is not sufficient to maintain the peripheral count. ITP is not a common condition and the incidence in children is probably about 1 in 25 000 of the population.
• Bernard-Soulier syndrome (BSS) - a recessively Clinical presentation and diagnosis
inherited disorder with giant platelets and bleeding more severe than the platelet count would suggest. Platelet function tests show reduced aggregation to the antibiotic ristocetin which is due to reduction or absent glycoprotein lb on the platelets.
The typical child is less than 10 years of age and presents with bruising and purpura with a relatively Paula H.B. Bolton-Maggs MRCP, MRCPath, Consultant
• Wiskott-Aldrich syndrome (WAS) - small platelets, associated with eczema and immune deficiency.
Paediatric Haematologist, Royal Liverpool Children's NHS Trust, Alder Hey, Eaton Road, Liverpool L12 2AP. Correspondence and requests for offprints to PHBB-M.
Current Paediatrics (1995)5, 181-185 © 1995PearsonProfessionalLtd
181
182 CURRENT PAEDIATRICS
Table 1 Prevention of anxiety in ITP3 Give the family information about
Benign nature of the disease Irrelevance of platelet counts High rate of spontaneous recovery Extreme rarity of intracranial bleeding
Doctors should avoid
Prolonged hospitalisation of the child Unnecessary diagnostic tests Unnecessary treatment
'Some physicians who are not seeing ITP patients frequently.., are overly impressed by the extent of the cutaneous manifestations and tend to convey this to the patient or parent. Considerable psychological morbidity is generated by conveying the impression that the well-being of the child rises and falls with the platelet count. Most parents and patients can live quite comfortably with petechiae and low platelets, awaiting spontaneous remission, provided their physician can. ,3
T h e bleeding c o m p l i c a t i o n s a n d infections can be life-threatening, a n d these patients m a y be candidates for b o n e m a r r o w t r a n s p l a n t a t i o n . These i n h e r i t e d d i s o r d e r s have quite different implications for genetic counselling a n d m a n a g e m e n t . I n I T P the b o n e m a r r o w is o f n o r m a l o r increased cellularity with a n increase in the m e g a k a r y o c y t e s . T h e r e is p e r i p h e r a l platelet d e s t r u c t i o n w i t h a c o m p e n s a t o r y increase in m a r r o w activity. T h e a p p e a r a n c e s o f the m a r r o w will exclude o t h e r m o r e serious p a t h o l o g y such as acute l e u k a e m i a , t u m o u r infiltration a n d aplastic a n a e m i a . T h e a p p e a r a n c e is n o t d i a g n o s t i c o f ITP, b u t only indicates t h a t the cause o f the t h r o m b o c y t o p e n i a is p e r i p h e r a l destruction r a t h e r t h a n failure o f p r o d u c t i o n . I f o t h e r d i s o r d e r s such as BSS o r W A S have n o t been t h o u g h t of, the m a r r o w will n o t suggest the diagnosis. W h i l e the m a j o r i t y o f children u n d e r 10 years o f age will have isolated acute ITP, o l d e r sufferers are m o r e likely to be female, to have a chronic course, a n d a n u n d e r l y i n g p a t h o l o g y a n d need to be investigated accordingly. Table 2 Differential diagnosis of ITP 1. Could it be a congenital thrombocytopenia? • Is the history life-long? • Is the bleeding worse than the count suggests? • Is there a family history? • Are there any physical congenital abnormalities? 2. What other differential diagnoses must be considered? • Are there additional laboratory abnormalities In the WBC - abnormal cells, neutropenia? In the red cells - - macrocytosis, fragmentation? • Are there additional clinical features? Lymphadenopathy, splenomegaly? Bone pain, limping? Sick child? • In the presence of these, consider marrow examination. 3. Underlying disorders • Systemic lupus erythematosis Autoantibody screen - ANF and dsDNA • Antiphospholipid syndrome Evidence of anticardiolipin antibodies Lupus anticoagulant • HIV infection
Fig. 1--Child with ITP who sustained a head injury, and needed treatment.
Management of acute ITP Who to treat? M o s t children with I T P d o n o t need any t r e a t m e n t at all. I n the p a s t the desire to treat has been g o v e r n e d b y the fear o f i n t r a c r a n i a l h a e m o r r h a g e . I n d e e d , a m a j o r review o f 1TP does n o t m e n t i o n ' n o t r e a t m e n t ' as a n o p t i o n . 1 It is n o w generally agreed t h a t the risk o f serious bleeding in children has been overstated. Recently L i l l e y m a n 4 c a r r i e d o u t a n a t i o n w i d e survey b y q u e s t i o n n a i r e to find all cases o f i n t r a c r a n i a l h a e m o r r h a g e ( I C H ) in c h i l d h o o d I T P between 1974-1994. F o u r t e e n cases h a d o c c u r r e d in the
Table3 Classification of childhood ITP by severity of symptoms Mild • Bruising and petechiae; occasional minor epistaxis Very little or no interference with daily living Moderate • More severe skin manifestations with some mucosal lesions and more troublesome epistaxis or menorrhagia Severe • Bleeding episodes (epistaxis, melaena and/or menorrhagia) requiring hospital admissions and/or blood transfusions symptoms seriously interfering with quality of life.
IDIOPATHIC THROMBOCYTOPENIC PURPURA
Alder Hey patients - 24 patients
183
Other hospitals - 17 patients
-1 21
I•IVIG
~Steroids
F-INotreatment
There was a large difference in treatment not related to differences in bleeding tendency. Why is this so? Is there such variation between paediatricians nationally? A national audit is in progress by the BPA
Fig. 2~Differencesin the managementof ITP betweenhospitalsin MerseyRegion.
20 years, 6 children surviving without important sequelae. In 7 cases the ICH occurred within a week of onset of the ITP, but in 5 it was more than 2 months from diagnosis. Four children had underlying causes 2 had head injuries and 2 had AV malformations. Extrapolating from the incidence of ITP in Sheffield, Lilleyman calculates that the incidence of ICH is about 0.1% of all children with ITR This is substantially less than the 1% usually quoted. No other instances of serious haemorrhage were reported in this survey. It should be noted that the risk of ICH is not restricted to the days surrounding diagnosis, but remains a risk for as long as the platelet count remains very low. The child should be assessed by symptoms, and not by the platelet count alone, according to the scheme in Table 3. Treatment should only be considered for those classed as 'moderate' or 'severe', who will be the minority of children. In our experience over the past 2 years only 3 out of 23 children presenting with ITP required any treatment. Another reason for treatment would be a child with a low count who has an accident (e.g. Fig. 1) or who requires surgery such as dental extractions. The natural history of ITP shows that most children will remit spontaneously, sometimes within a very short time (a few days), and the majority (90%) within 9-12 weeks. 5 Oral steroids or intravenous immunoglobulin?
Treatment with oral steroids is favoured by many whether this is of any clinical benefit is disputed. 6 Possibly adolescents with very low counts may be more likely to bleed, and therefore warrant therapy. 6 Steroids do not have to be given in large doses - 0.25 mg/kg may well be enough, and should only be given for a clearly defined period (e.g. 2-3 weeks).
Intravenous immunoglobulin (IVIG) is sometimes used to treat uncomplicated ITP, perhaps because it produces a rapid response in the platelet count; therefore in the hospital where normal practice has been to keep a child in hospital until an 'acceptable' platelet count is reached (usually >20 x 109/1), such treatment may well shorten the hospital stay, thereby reducing cost. As discussed above, this approach is based on the false premise that a low count carries a significant morbidity, and that hospitalisation is necessary. Neither of these assumptions is true. IVIG is invasive, expensive, can have side effects, and has (rarely) been associated with transmission of hepatitis C, a potentially life-threatening infection. 7 These different approaches to management have been clearly highlighted in a recent audit in Mersey Region which shows less treatment given in the tertiary centre (Fig. 2), in spite of there being no differences in the characteristics of the children presenting with ITR Figure 3 shows the outcome of 20 cases of ITP seen at Alder Hey over the past 2 years who have not required any treatment. Very helpful guidelines for the management of ITP have recently been published 5 - the major recommendations are highlighted in Table 4. Marrow examination before treatment: If treatment is given, then marrow examination must be performed first to exclude other pathology including rare congenital disorders (such as Fanconi anaemia) where isolated thrombocytopenia may be the only feature. 8 We have seen one child whose isolated thrombocytopenia had been treated with IVIG before marrow examination, with no response - the thrombocytopenia was the first clue to acute lymphoblastic leukaemia. The use of oral steroids in such a case might have induced a remission, the child then only presenting with first 'relapse' when the chance of a
184
CURRENT PAEDIATRICS
cure would have been jeopardised by his earlier inappropriate treatment. 100 -
-
8O
6O Cumulative % 40 telets >50 x 109/I t Platelets >100 x 10~/l
2O
0 20
40
60
80
100
120
140
Days
Fig. ~ T i m e to remission in 20 untreated children with ITP, either to platelet count of 50 or 100 x 10911.
Table 4 Guidelines for the m a n a g e m e n t of childhood ITP (Eden and Lilleyman on behalf o f the British Paediatric Haematology Forum) s • • • • •
• •
Treatment is not necessary for children presenting with bnlising alone Hospital admission and/or enforced rest is not necessary Marrow examination is not m a n d a t o r y unless treatment is planned Oral steroids: a dose o f 0.25 mg/kg m a y be as effective a n d safer than higher doses IVIG should be reserved for: - The emergency treatment of patients who present with active bleeding and who do not spontaneously remit or respond to steroids - Cover for essential surgery and dental extractions Chronic ITP does not necessarily need treatment and should be discussed with the regional paediatric haematologists Platelet transfusions are only indicated for life-threatening haemorrhage
Remissions may occur spontaneously many years after diagnosis (even 10-20 years) and the predicted spontaneous remission rate is 61% after 15 years, l° Children over the age of 10 and girls are more likely to have a chronic course and an underlying disease (Fig. 4) and need work-up to exclude other diagnoses such as SLE. In the absence of bleeding symptoms children with chronic ITP need advice about their lifestyle (to avoid contact sports and non-steroidal anti-inflammatory drugs), and may need occasional therapy to cover dental extractions or trauma. Children without significant symptoms should not be maintained indefinitely on steroids nor given repeated courses of IVIG; clinicians must beware of titrating therapy against the platelet count without consideration of the symptoms (or lack of them). Which children with chronic ITP need treatment?: A platelet count of >30 x 109/1 usually gives rise to no serious bleeding problems. The most worrying patients are those with Lilleyman's 'chronic severe ITP' who have low counts and troublesome bleeding manifested usually by repeated epistaxis or menorrhagia. ]1 Such individuals are very rare (estimated at 5-10 in the whole of the UK in a year) H, and therefore should be referred to a specialist? These are probably the only children in whom splenectomy should be contemplated. W I G or pulses of methylprednisolone produce usually a temporary remission and although this can be repeated some children show progressively less response. Several other agents have been tried] I but experience with any one is limited, and such therapy should be initiated only by an experienced haematologist. Splenectomy and precautions needed
Platelet transfusions are not indicated for the management of bleeding in ITR Since the pathology is platelet consumption, transfused platelets are unlikely to be effective unless given in mega-doses, and expose the child to unnecessary risks. The only exception to this is in the very rare situation of life threatening haemorrhage where a 'belt and braces' approach is reasonable - IVIG, steroids and large numbers of platelets (e.g. 20 donor units)?
Splenectomy was commonly performed for children with chronic ITR However, these are two major drawbacks: splenectomy only produces remission in about two thirds of cases, and is not without risk. Splenectomy should not be performed for a low
E~Acute ITP ==Chronic ITP 6 5
The management of chronic ITP Chronic ITP is arbitrarily but conventionally defined as thrombocytopenia persisting beyond 6 months from diagnosis. A longer history of bruising or bleeding symptoms at diagnosis is predictive of a more chronic course? Chronic ITP does not necessarily need any specific treatment if giving rise to no symptoms, and is not of itself an indication for splenectomy. If a marrow examination has not been done it is reasonable to do it in order to exclude other diagnoses even if no specific therapy is planned. 8
Number of cases (total 43)
4
iii~l
3 2 1
[
0 <01
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Age (Years)
Fig. 4 - - A g e at presentation of cases of ITP at Alder Hey - 5-year retrospective analysis with a total of 43 children. 13 (30%) were below 2 years, furthermore those over 10 years were more likely to have chronic ITP and an underlying disease.
IDIOPATHIC THROMBOCYTOPENIC PURPURA
185
Table 5 Information for patients undergoing splenectomy (Department of Health, March 1995)
platelet c o u n t alone, b u t only in p a t i e n t s w i t h significant s y m p t o m s w h o are m o r e t h a n 6 m o n t h s f r o m diagnosis. 5,H A s p l e n i c i n d i v i d u a l s are at increased risk o f serious sepsis f r o m e n c a p s u l a t e d o r g a n i s m s w h i c h are n o r m a l l y cleared b y the spleen, i.e. p n e u m o c o c c u s , a n d Haemophilus influenzae. T h e m o r t a l i t y in different series is 1.4-1.6%, which is greater t h a n the risk o f d y i n g f r o m h a e m o r r h a g e due to t h r o m b o c y t o p e n i a ) 1 T h e risk o f p o s t s p l e n e c t o m y sepsis is p r o b a b l y greatest in b u t certainly n o t c o n f i n e d to c h i l d h o o d . 12 R e c e n t discussions o f the late m o r t a l i t y f r o m infection following s p l e n e c t o m y 13,14 have resulted in guidelines for the m a n a g e m e n t o f s p l e n e c t o m y 15 (Table 5) t o g e t h e r with a c a r d t h a t patients can c a r r y in case o f e m e r g e n c y (Fig. 5). W h i l e discussion continues over the n a t u r e a n d d u r a t i o n o f a n t i b i o t i c prophylaxis, the m o s t i m p o r t a n t feature is p r o b a b l y a d e q u a t e e d u c a t i o n o f the p a t i e n t to r e p o r t early for m e d i c a l help in the face o f any infectious episode.
limiting within a few weeks, a n d often requires no specific therapy. W h e n the c o n d i t i o n is chronic, lasting m o r e t h a n 6 m o n t h s , p r o v i d i n g there are n o significant s y m p t o m s , n o specific t h e r a p y is indicated. U n d e r l y i n g d i s o r d e r s s h o u l d be s o u g h t in these children.
Conclusion
Acknowledgement
C h i l d h o o d I T P is a n u n c o m m o n disorder. A l t h o u g h the low platelet c o u n t m a y frighten the m e d i c a l attendants, the patients rarely have significant s y m p t o m s . T h e d i s o r d e r is u s u a l l y b e n i g n a n d self-
The author is grateful to Professor John Lilleyman for his helpful comments.
Fig, ~-Department of Health card for asplenic individuals.
* Ensure that medical attendants are aware that you have no spleen • Vaccinations pre-splenectomy - pneumococcal vaccine Hib vaccine - meningococcal vaccine under some circumstances (travel to certain countries) • Daily antibiotics until at least the age of 16 or a course to keep at home for use at onset of illness • Consult doctor immediately if ill • Special precautions may be needed when travelling abroad * Animal bites must be treated promptly including a course of antibiotics
References 1. Karpatkin S. Autoimmune thrombocytopenic purpura. Semin Hematol 1985; 22: 260-288. 2. Chessells J, Hann I. Idiopathic thrombocytopenic purpura (ITP) - some notes for parents. Published by Great Ormond Street Hospital for Children NHS Trust, 1995. 3. Dickerhoff R. Experience with 74 ITP patients - comparison of different management policies. In: Sutor AH, Thomas KB, eds. Thrombocytopenia in Childhood. Stuttgart and New York: Schattauer, 1994: 121-127. 4. Lilleyman JS. Intracranial haemorrhage in idiopathic thrombocytopenic purpura. Arch Dis Child 1994; 71: 251-253. 5. Eden OB, Lilleyman JS. Guidelines for the management of idiopathic thrombocytopenic purpura. Arch Dis Child 1992; 67: 1056-1058. 6. Buchanan GR. The nontreatment of childhood idiopathic thrombocytopenic purpura. Eur J Pediat 1987; 146:107-112. 7. Bjoro K, Froland SS, Yun Z, Samdal I-IH, Haaland T. Hepatitis C infection in patients with primary hypogammaglobulinaemia after treatment with contaminated immune globulin. N Engl J Med 1994; 331: 1607-1611. 8. Chessells J. Chronic idiopathic thrombocytopenic purpura: primum non nocere. Arch Dis Child 1989; 64: 1326-1328. 9. Robb LG, Tiedeman K. Idiopathic thrombocytopenic purpura: predictors of chronic disease. Arch Dis Child 1990; 65: 502-506. 10. Reid MM. Chronic idiopathic thrombocytopenic purpura: incidence, treatment and outcome. Arch Dis Child 1995; 72: 125-128. 11. Lilleyman JS. The therapeutic challenge of chronic severe ITP in children. In: Sutor AH, Thomas KB, eds. Thrombocytopenia in Childhood. Stuttgart: Schattauer, 1994: 141-148. 12. Evans DIK. Post splenectomy sepsis 10 years or more after operation. J Clin Pathol 1985; 38: 309-311. 13. McMullin M, Johnston G. Long term management of patients after splenectomy. B M J 1993; 307: 1372~1373. 14. Deodhar HA, Marshall R J, Barnes JN. Increased risk of sepsis after splenectomy. B M J 1993; 307: 1408-1409. 15. Department of Health. Information about splenectomy for patients. Leaflets and cards available from HMSO, Oldham Broadway Business Park, Broadgate, Chadderton, Oldham, OL9 0JA.