indianff. Pediatr. ' i 4 : ~'tq.3, 197",
CHRONIC IDIOPATHIC
I"HRONII~OCYTOPENIC PURPURA* A Case R e p o r t
S.K. KALRA, V. VATWAm, P.K. SARKAR aND R. NATH Ptlrle
The term "idiopathic thronmocytopenic p u r p u r a " (ITP) has traditionally been used to define an acquired haemorrhagic state due to a m a r k e d reduction of the circulating platelet count in the presence of a normal m a r r o w and the absence of associated systemic disease. Continuing observations have indicated the validity of identifying two major groups: (1) acute I T P , characterized by an abrupt onset and a very high rate of rapid, complete, and permanent recovery, occurring primarily in children (Lusher and Znelzer 1966) and (2) chronic I T P , characterized by a relatively insidious onset and a very low rate of spontaneous recovery, occurring primarily in adults (Baldini 1966). T h e finding, by recently developed techniques, that the majority of individuals with chronic ITP, have demonstrable antiplateIet antibodies (Karpatkin and Strick 1972) has suggested that this group should no longer be designated as "idiopathic" but rather diagnosed as having " a u t o i m m u n e thrombocytopenic p u r p u r a " ( K a r p a t k i n 1971). At present immunologic data relating to I T P in childhood are insufficient to warrant such a designation. Moreover, while studies of large groups of children with I T P have provided firm statistics concerning prognosis, it is not possible to predict in the individual child, at the onset of the disease, *'From the Department of Pune- I. Received on August 24, 1977.
Paediatrics,
A.F.M.C.,
whether the disorder will follow the acute or chronic course. The definition of when I T P in childhood should be designated as chronic is, at best, arbitrary. At least 85 to 90 per cent of children will recover completely within a year, and the disease is traditionally classified as chronic after that time. However, although spontaneous recovery after one year is relatively rare, instances of complete cure as long as 3} years after onset have been reported (David et al. 1974). We report here a case of chronic I T P in a child which is u n c o m m o n in paediatric practice and is usually found in adults.
R e p o r t o f A Case R.H., a 12-year-old, Muslim girl, was admitted on31.12.76 with the complaints of easy bruising and the sudden spontaneous development of cutaneous petechiae and ecchymoses of bizarre distribution, for three years. She had had two episodes each of melaena and epistaxis during this period. There was no history of haemarthrosis, skin ailments, allergic manifestations or exposure to drugs known to cause bone marrow suppression. There was no history of similar illness in the family. Physical examination revealed extensive confluent ecchymotic patches over the buttocks, thighs and shoulder regions. Lesions were non-itching and there was no associated urticaria. There was no pallor. None of her joints was swollen or tender
344
INDIAN JOURNAL OF PEDIATRICS
and she had no deep haematomas. The liver, spleen or lymphnodes were not enlarged. The fundus was normal. No abnormality was detected in other systems. Investigations revealed blood indices including bleading time, clotting time and prothrombin time within normal limits. The tourniquet test and LE cell phenomenon were negative. Pe,ipheral blood smear revealed gross t h r o m b o c y t o p a e n i a - platelet count being 8000/cu m m and platelet adhesion 25Yo ( N = 2 5 - 3 9 % ) . Bone marrow examination showed a normoblastic picture with increased number and size of megakaryocytes, most containing peripheral vacuoles and lacking platelet budding. Antiplatelet antibodies were detected in the patient's serum. Splenectomy was performed on 15.4.77 and two months after splenectomy, she continued to be asymptomatic. Her platelet count inereased up and was maintained around 600,000/ram 3. Discussion
I T P is characterized by a greatly reduced platelet survival, from a few days to a few minutes, as a result of an immunologic process (Aster and Keene 1969, H a r k a r 1970). In I T P t h e p r e s e v e e o f a c i r c u l a t i n g antiplatelet substance, an IgG globulin formed in the spleen (Karpatkin 1971, K a r p a t k i n and Strick 1972, K a r p a t k i n 1972) was clearly shown in the cross transfusion studies of H a r m i n g t o n et al. (1951). Platelets that are sensitised by a high level of antibody in the spleen (Aster 1972) are destroyed predominantly in the spleen (Aster and Jaudl 1964). 'With greater sensitisation they are sequestrated in the liver. This ' I T P factor' may also affect megakaryocytes and inhibit platelet produe-
VOL.
,t4,
No. 358
tion (Aster and Jaudl 1964, Mckenna an~! Pisciotta 1962) since platelets and megakaryocytes share the same antigen (Corn and Upshow, 1962 Saner and Von Loughem 1954, SiLber 1960, Vasquez and Lewis 1960). Thus tile megakaryocyte hyperplasia in bone marrow represents an ineffective thrombocytopoiesis, Oestrogens induce and corticosteroids inhibit the sequestration in tile .spleen and at other sites of the reticuloendothelial system, hence the high incidence of chronic I T P in women of the child bearing age and fl-equent relapses at periods of hormonal disbalance (Doan 1960). Chronic I'FP has a fluctuating clinical course and m a y last for m a n y years. It has a peak incidence in adults 20-40 years of age, an insidious onset with a long history of easy bruising with relatively mild bleeding manifestations, a m o d e r a t e lowering of the platelet count to 40,00@ to 80,O00/mma, a platelet survival indicating increased platelet destruction of moderate to severe degree, no significant anaemia or leucopenia and no significant splenomegaly. Remissions and relapses belong to the natural history of chronic form. Episodes of bleeding may last a few days or a few weeks, and may be intermittent or even cyclical. Relapses in some cases a p p e a r to be associated with v a e d n a t i o n s and exposure to insecticides. Dt,rii:g remissions the platelet count does not usually return to completeh,' normal levels but remains at 1 to 89of the normal value and platelet life .~span improves considerably remaining however, shorter than normal (Hirsch and Damashek 1951 ). For majority of patients with persistence o t t h r o m b o e y t o p e n i a one year after onset, splenectomy remains the ultimate therapeutic measure of choice. In 50-88% cases
K A L R A E T A I . . - - C H R O N I C I D I O P A T H I C THI~OMBOGYTOPI~NIC P U R P U R A
complete and sustained remissions have followed splenectomy (Wilde 1967). In many of the remaining patients, some increase in platelet number and amelioration of bleeding manifestations have been observed. The effectiveness ofsplenectomy in I T P presumably is the result of the removal of the organ that is mainly responsible for the sequestration of antibody sensitized platelcts. Even when this procedure eventuates in a complete remission, evidence of increased platelet production and decreased platelet survival may persist. In such cases, spleneetomy appears to convert a "decompensated" state of platelet destructiol,1 into a " c o m p e n s a t e d " one, in which platelet production can keep up with continuing destruction. Fhe indications for splenectomy in I T P could be summarised as 1.
Failure of spontaneous remission after six or more months of observation in patients whose clinical manifestations are moderate to severe.
2.
~:ailure to respond to steroid therapy.
3.
Relapse after decreasing the dosage or discontinuation of steroid therapy.
4.
Requirement of high doses of steroids for maintenance of a clinical status free of serious haemorrhage.
5.
When adequate follow up of a case cannot be assured.
6.
When over-riding contraindications to the use of steroids are present.
7.
When growth, development, social or economic status is uniquely impaired by the effects of steroid therapy or by recurrences of bleeding.
345
Following splenectomy a post.operative rise in platelet count is seen in virtually every patient, with the peak rise occurring in 4 to 14 days. Patients whose platelet count reach 500,0(}0/mma in the post-operative period lend to have a better likelihood of permanent benefit than those whose maximum rise fails to reach this level. Some children may develop a post-operative thrombocytosis exceeding one million per mm 3, but this is transient and anticoagulatlon is not needed. The risk of post-splenectomy sepsis and meningitis is very low in I T P and routine prophylaxis with penicillin is not recommended. However, febrile illnesses in the splenectomized child must be observed and treated promptly and alertness to the possibility of septicaemia and meningitis, predominantly pneumococcal, must be maintained. The mainstay in the treatment of patients who have failed to respond to splenectomy is corticosteroids. T h e dosage should be titrated against the severity of the haemorrhagic manifestations rather than the platelet count. Immunosuppressive thetapy has been used in tile treatment of children whose thrombocytopenia persists despite splenectomy and corticosteroid therapy (Finch I974). Most trials have utilized azathioprine and corticosteroids in combination, and approximately one-third of children so treated were considered to have shown benefit. Other drugs like Actinomycin C, cyclophosphamide (Laros and Penner 1971) and most recently, Vinblasline (Marmont and Damasio 1971) have been tried in the treatment of chronic I T P refractory to splenectomy, with some benetit reported with each.
346
VOL. 44, N o . 358
INDIAN JOURNAL OF PEDIATRICS
Regerenees Aster, R.H. (1972). Platelet sequestration studies in man. Br. 07. Haemat. 22, 259. Aster, R.tt. and Jaudl, J.H. (1964). Platelet sequestration in man II, immunological arid clinical studies. 07. Clin. Invest. 43, 856, Aster, R.H. and Keene, W.R. (1969). Sites of platelet destruction in ITP. Br. 7. Haemat. 15, 61. Baldini, M. (1966). Idiopathic thrombocytopenic purpura. New Engl. 07. Med. 274, : 1245, 1302, 1360. Corn, M., Upshow, J.D. (1962). Evaluation of platelet antibodies in ITP. Arch. Inter. Med 109, 157. Doan, C.A. (1960). Idiopathic and secondary thrombocytopenic purpura. Clinical study and evaluatiorJ of 381 cases over a period of 28 years. Ann Int. Med. 35, 968. Finch. S.C. (1974). Immm:osuppressi'~'e therapy of chronic ITP. Amer. 07. Med. 56, 4. Harkar, L.A. (1970). Thromboklaetics in ITP. Brit. 07. Haemat. 19, 95. Harmington, W.J., .'vlinich, V., Hollingsworth, J.W. and Moore, C.\". (1951). Demonstration of a thrombocytopenie factor in the blood of patients with thr0r~!b0cytoper, ic purpura. 7. Lab. Clin. Med. 38, I. Hirsch, E.O. ~nd Damashek, W. (1951). Idiopathic thrombocytopenia Review of 89 cases with particular reference to differentiation and treatment of acute self limited and chronic type. Arch. Int. Med. 88, 701. Karpa~kin, S. (1971). Autoimmune thrombocytopenic purpura. Amer. 07. ~ted, 261, 127.
Karpatkin, S., Strick, N. (1972). Cumulative experience in the detection of antiplatelet antibody in 234 patients with ITP lupus erythernatosis and other clinical disorders. Amer..~. Med. 52, 776. Karpatkin, S. (1972). Detection of splenic antiplatelet antibody synthesis in idiopathic autoimmune thrombocytopenic purpura. By. 07. Naemat. 23, 167. Laros, A.K. and Penner, J.A. (1971). 'Refractory' thrombocytopenic purpura treated successfully with cyclophosphamidc. 07.A.M.A. 215, 445. Lusher, J.M., Znelzer, W.W. (1966). Idiopathic thrombocytopenic purpura in childhood. 07. Paediatr, 6B, 971. Marmont, A.M., Damasio, E.E. (1971). Vinblastine sulphate in idiopathic thrombocytopenic purpura. Lancet, 2, 94. Mckenna, J.L. and Pisciotta, A.V: (1962). Fluorescence of megakaryocyles in ITP stained with fluorescent antiglobulln serum. Blood 19, 664. Saner, A.]. Von Loughem, J.J. (1954). A study of occurrence of platelet auto antibodies. Sang 4, 120. Silber, R. [1960). The application of fluorescent antibody methods to the study of platelet.~. Blood 16,958. Vazquez, J.J. and Lewis, J.H. (1960). Immunocytochemical studies on platelets. The demonstration of common antigen in human platelets and megakaryoeytes. Blood 16, 968. Wilde, R.C. (1967). Splenectomy for chronic ITP. Arch. Surg. 95, 344.
CHRONIC IDIOPATHIC
I"HRONII~OCYTOPENIC PURPURA* A Case R e p o r t
S.K. KALRA, V. VATWAm, P.K. SARKAR aND R. NATH Ptlrle
The term "idiopathic thronmocytopenic p u r p u r a " (ITP) has traditionally been used to define an acquired haemorrhagic state due to a m a r k e d reduction of the circulating platelet count in the presence of a normal m a r r o w and the absence of associated systemic disease. Continuing observations have indicated the validity of identifying two major groups: (1) acute I T P , characterized by an abrupt onset and a very high rate of rapid, complete, and permanent recovery, occurring primarily in children (Lusher and Znelzer 1966) and (2) chronic I T P , characterized by a relatively insidious onset and a very low rate of spontaneous recovery, occurring primarily in adults (Baldini 1966). T h e finding, by recently developed techniques, that the majority of individuals with chronic ITP, have demonstrable antiplateIet antibodies (Karpatkin and Strick 1972) has suggested that this group should no longer be designated as "idiopathic" but rather diagnosed as having " a u t o i m m u n e thrombocytopenic p u r p u r a " ( K a r p a t k i n 1971). At present immunologic data relating to I T P in childhood are insufficient to warrant such a designation. Moreover, while studies of large groups of children with I T P have provided firm statistics concerning prognosis, it is not possible to predict in the individual child, at the onset of the disease, *'From the Department of Pune- I. Received on August 24, 1977.
Paediatrics,
A.F.M.C.,
whether the disorder will follow the acute or chronic course. The definition of when I T P in childhood should be designated as chronic is, at best, arbitrary. At least 85 to 90 per cent of children will recover completely within a year, and the disease is traditionally classified as chronic after that time. However, although spontaneous recovery after one year is relatively rare, instances of complete cure as long as 3} years after onset have been reported (David et al. 1974). We report here a case of chronic I T P in a child which is u n c o m m o n in paediatric practice and is usually found in adults.
R e p o r t o f A Case R.H., a 12-year-old, Muslim girl, was admitted on31.12.76 with the complaints of easy bruising and the sudden spontaneous development of cutaneous petechiae and ecchymoses of bizarre distribution, for three years. She had had two episodes each of melaena and epistaxis during this period. There was no history of haemarthrosis, skin ailments, allergic manifestations or exposure to drugs known to cause bone marrow suppression. There was no history of similar illness in the family. Physical examination revealed extensive confluent ecchymotic patches over the buttocks, thighs and shoulder regions. Lesions were non-itching and there was no associated urticaria. There was no pallor. None of her joints was swollen or tender
344
INDIAN JOURNAL OF PEDIATRICS
and she had no deep haematomas. The liver, spleen or lymphnodes were not enlarged. The fundus was normal. No abnormality was detected in other systems. Investigations revealed blood indices including bleading time, clotting time and prothrombin time within normal limits. The tourniquet test and LE cell phenomenon were negative. Pe,ipheral blood smear revealed gross t h r o m b o c y t o p a e n i a - platelet count being 8000/cu m m and platelet adhesion 25Yo ( N = 2 5 - 3 9 % ) . Bone marrow examination showed a normoblastic picture with increased number and size of megakaryocytes, most containing peripheral vacuoles and lacking platelet budding. Antiplatelet antibodies were detected in the patient's serum. Splenectomy was performed on 15.4.77 and two months after splenectomy, she continued to be asymptomatic. Her platelet count inereased up and was maintained around 600,000/ram 3. Discussion
I T P is characterized by a greatly reduced platelet survival, from a few days to a few minutes, as a result of an immunologic process (Aster and Keene 1969, H a r k a r 1970). In I T P t h e p r e s e v e e o f a c i r c u l a t i n g antiplatelet substance, an IgG globulin formed in the spleen (Karpatkin 1971, K a r p a t k i n and Strick 1972, K a r p a t k i n 1972) was clearly shown in the cross transfusion studies of H a r m i n g t o n et al. (1951). Platelets that are sensitised by a high level of antibody in the spleen (Aster 1972) are destroyed predominantly in the spleen (Aster and Jaudl 1964). 'With greater sensitisation they are sequestrated in the liver. This ' I T P factor' may also affect megakaryocytes and inhibit platelet produe-
VOL.
,t4,
No. 358
tion (Aster and Jaudl 1964, Mckenna an~! Pisciotta 1962) since platelets and megakaryocytes share the same antigen (Corn and Upshow, 1962 Saner and Von Loughem 1954, SiLber 1960, Vasquez and Lewis 1960). Thus tile megakaryocyte hyperplasia in bone marrow represents an ineffective thrombocytopoiesis, Oestrogens induce and corticosteroids inhibit the sequestration in tile .spleen and at other sites of the reticuloendothelial system, hence the high incidence of chronic I T P in women of the child bearing age and fl-equent relapses at periods of hormonal disbalance (Doan 1960). Chronic I'FP has a fluctuating clinical course and m a y last for m a n y years. It has a peak incidence in adults 20-40 years of age, an insidious onset with a long history of easy bruising with relatively mild bleeding manifestations, a m o d e r a t e lowering of the platelet count to 40,00@ to 80,O00/mma, a platelet survival indicating increased platelet destruction of moderate to severe degree, no significant anaemia or leucopenia and no significant splenomegaly. Remissions and relapses belong to the natural history of chronic form. Episodes of bleeding may last a few days or a few weeks, and may be intermittent or even cyclical. Relapses in some cases a p p e a r to be associated with v a e d n a t i o n s and exposure to insecticides. Dt,rii:g remissions the platelet count does not usually return to completeh,' normal levels but remains at 1 to 89of the normal value and platelet life .~span improves considerably remaining however, shorter than normal (Hirsch and Damashek 1951 ). For majority of patients with persistence o t t h r o m b o e y t o p e n i a one year after onset, splenectomy remains the ultimate therapeutic measure of choice. In 50-88% cases
K A L R A E T A I . . - - C H R O N I C I D I O P A T H I C THI~OMBOGYTOPI~NIC P U R P U R A
complete and sustained remissions have followed splenectomy (Wilde 1967). In many of the remaining patients, some increase in platelet number and amelioration of bleeding manifestations have been observed. The effectiveness ofsplenectomy in I T P presumably is the result of the removal of the organ that is mainly responsible for the sequestration of antibody sensitized platelcts. Even when this procedure eventuates in a complete remission, evidence of increased platelet production and decreased platelet survival may persist. In such cases, spleneetomy appears to convert a "decompensated" state of platelet destructiol,1 into a " c o m p e n s a t e d " one, in which platelet production can keep up with continuing destruction. Fhe indications for splenectomy in I T P could be summarised as 1.
Failure of spontaneous remission after six or more months of observation in patients whose clinical manifestations are moderate to severe.
2.
~:ailure to respond to steroid therapy.
3.
Relapse after decreasing the dosage or discontinuation of steroid therapy.
4.
Requirement of high doses of steroids for maintenance of a clinical status free of serious haemorrhage.
5.
When adequate follow up of a case cannot be assured.
6.
When over-riding contraindications to the use of steroids are present.
7.
When growth, development, social or economic status is uniquely impaired by the effects of steroid therapy or by recurrences of bleeding.
345
Following splenectomy a post.operative rise in platelet count is seen in virtually every patient, with the peak rise occurring in 4 to 14 days. Patients whose platelet count reach 500,0(}0/mma in the post-operative period lend to have a better likelihood of permanent benefit than those whose maximum rise fails to reach this level. Some children may develop a post-operative thrombocytosis exceeding one million per mm 3, but this is transient and anticoagulatlon is not needed. The risk of post-splenectomy sepsis and meningitis is very low in I T P and routine prophylaxis with penicillin is not recommended. However, febrile illnesses in the splenectomized child must be observed and treated promptly and alertness to the possibility of septicaemia and meningitis, predominantly pneumococcal, must be maintained. The mainstay in the treatment of patients who have failed to respond to splenectomy is corticosteroids. T h e dosage should be titrated against the severity of the haemorrhagic manifestations rather than the platelet count. Immunosuppressive thetapy has been used in tile treatment of children whose thrombocytopenia persists despite splenectomy and corticosteroid therapy (Finch I974). Most trials have utilized azathioprine and corticosteroids in combination, and approximately one-third of children so treated were considered to have shown benefit. Other drugs like Actinomycin C, cyclophosphamide (Laros and Penner 1971) and most recently, Vinblasline (Marmont and Damasio 1971) have been tried in the treatment of chronic I T P refractory to splenectomy, with some benetit reported with each.
346
VOL. 44, N o . 358
INDIAN JOURNAL OF PEDIATRICS
Regerenees Aster, R.H. (1972). Platelet sequestration studies in man. Br. 07. Haemat. 22, 259. Aster, R.tt. and Jaudl, J.H. (1964). Platelet sequestration in man II, immunological arid clinical studies. 07. Clin. Invest. 43, 856, Aster, R.H. and Keene, W.R. (1969). Sites of platelet destruction in ITP. Br. 7. Haemat. 15, 61. Baldini, M. (1966). Idiopathic thrombocytopenic purpura. New Engl. 07. Med. 274, : 1245, 1302, 1360. Corn, M., Upshow, J.D. (1962). Evaluation of platelet antibodies in ITP. Arch. Inter. Med 109, 157. Doan, C.A. (1960). Idiopathic and secondary thrombocytopenic purpura. Clinical study and evaluatiorJ of 381 cases over a period of 28 years. Ann Int. Med. 35, 968. Finch. S.C. (1974). Immm:osuppressi'~'e therapy of chronic ITP. Amer. 07. Med. 56, 4. Harkar, L.A. (1970). Thromboklaetics in ITP. Brit. 07. Haemat. 19, 95. Harmington, W.J., .'vlinich, V., Hollingsworth, J.W. and Moore, C.\". (1951). Demonstration of a thrombocytopenie factor in the blood of patients with thr0r~!b0cytoper, ic purpura. 7. Lab. Clin. Med. 38, I. Hirsch, E.O. ~nd Damashek, W. (1951). Idiopathic thrombocytopenia Review of 89 cases with particular reference to differentiation and treatment of acute self limited and chronic type. Arch. Int. Med. 88, 701. Karpa~kin, S. (1971). Autoimmune thrombocytopenic purpura. Amer. 07. ~ted, 261, 127.
Karpatkin, S., Strick, N. (1972). Cumulative experience in the detection of antiplatelet antibody in 234 patients with ITP lupus erythernatosis and other clinical disorders. Amer..~. Med. 52, 776. Karpatkin, S. (1972). Detection of splenic antiplatelet antibody synthesis in idiopathic autoimmune thrombocytopenic purpura. By. 07. Naemat. 23, 167. Laros, A.K. and Penner, J.A. (1971). 'Refractory' thrombocytopenic purpura treated successfully with cyclophosphamidc. 07.A.M.A. 215, 445. Lusher, J.M., Znelzer, W.W. (1966). Idiopathic thrombocytopenic purpura in childhood. 07. Paediatr, 6B, 971. Marmont, A.M., Damasio, E.E. (1971). Vinblastine sulphate in idiopathic thrombocytopenic purpura. Lancet, 2, 94. Mckenna, J.L. and Pisciotta, A.V: (1962). Fluorescence of megakaryocyles in ITP stained with fluorescent antiglobulln serum. Blood 19, 664. Saner, A.]. Von Loughem, J.J. (1954). A study of occurrence of platelet auto antibodies. Sang 4, 120. Silber, R. [1960). The application of fluorescent antibody methods to the study of platelet.~. Blood 16,958. Vazquez, J.J. and Lewis, J.H. (1960). Immunocytochemical studies on platelets. The demonstration of common antigen in human platelets and megakaryoeytes. Blood 16, 968. Wilde, R.C. (1967). Splenectomy for chronic ITP. Arch. Surg. 95, 344.
