Scand J Haematol (1975) 14, 286-294
Thrombotic Thrombocytopenic Purpura in Childhood Results of a Survey and Re-Examination of the Literature NOLAN BERMAN, M.D.
&
JERRYZ. FINKLESTEIN, M.D.
Harbor General Hospital, Department of Pediatrics (Chief, Joseph W . St. Geme, Jr.), Torrance, California, USA
A survey was conducted among 46 pediatric institutions in the United States and Canada t o evaluate the presentation, therapy and survival of children with thrombocytopenic purpura (TTP) seen since 1960. TTP is an uncommon disease in the pediatric age group, and the clinical and pathologic findings in adults and children are almost identical. It can be distinguished from haemolytic uraemic syndrome in that it usually occurs in older children, the renal disease is milder, and the central nervous system symptoms appear to be related to vascular occlusive disease, and not to the complications of severely compromised kidneys. Appropriate biopsy specimens which reveal typical widespread hyaline occlusion of arterioles may confirm the diagnosis. Combinations of corticosteroids, splenectomy, and heparin have been used as therapy. Prognosis has improved, and is probably related to improved supportive care. K e y words: TTP - therapy - splenecto'my - survival - childhood
Accepted for publication February 28, 1975 Correspondence to: Dr. Jerry Z. Finklestein, Departmelnt of Pediatrics, Harbor General Hospital, 1000 West Carson Street, Torrance, California 90509, USA
An 11-year-old Black male recently entered our institution with an acute illness characterized clinically by fever, purpura, disorientation and stupor. He had microangiopathic haemolytic anaemia, thrombocytopenia and azotemia. Clinical diagnosis of thrombotic thrombocytopenic purpura (TTP) was confirmed by histologic examination of splenic tissue following therapeutic splenectomy. To aid in our management of this patient, the literature was reviewed to determine the natural history of TTP in the pediatric age group. It soon became evident,
however, that TTP had not been clearly distinguished from haemolytic uraemic syndrome (HUS), and therapeutic guidelines for the management of children with TTP could not be adequately evaluated. Since Moschowitz' description of TTP (1925), close to 300 cases have been reported in the medical literature. Although TTP is usually considered a disease of adults, cases have occurred in the pediatric age group. A review by MacWhinney et a1 (1962) of TTP in childhood summarized 19 histologically-confirmed cases. In 1966,
TTP IN CHILDHOOD
Amorisi & Ultman reviewed the world literature and found 271 cases with 39 affected children. The latter authors admit, however, that since many of the cases included in their review preceded Gasser’s (1955) original description of HUS, their statistics were probably inaccurate, and that many cases actually represented instances of HUS and not TTP. The relationship between HUS and TTP remains controversial. Patients with either disease may present with thrombocytopenia, microangiopathic haemolytic anaemia, purpura, and evidence of central nervous system (CNS) and renal involvement. Differentiation of one disorder from the other is often difficult if only clinical observations are available. Gasser (1955) stated that the severe renal disease of HUS distinguished it from TTP. Lieberman et a1 (1966) and Lieberman (1972) analyzed their patients with HUS and also concluded that TTP and HUS could be distinguished on the basis of characteristic clinical and pathologic patterns. Other authors have suggested that the two entities may simply be agemodified manifestations of the same basic disease process (Shumway et a1 1964, Taub et a1 1964, Mettler 1969). The TTP literature was therefore reexamined to determine whether a characteristic clinical picture and essential diagnosis criteria for TTP could be established. In addition, by means of a questionnaire, the current experiences of physicians in the United States and Canada were surveyed to more accurately assess the frequency of TTP and to document the effectiveness of present day therapy. This paper reports the results of the literature search and of the questionnaire survey.
287
MATERIALS AND METHODS The pediatric cases of TTP in the English language literature were reviewed. Those cases which were marked by acute renal failure and histopathology primarily affecting the kidney were considered to be examples of HUS and thus excluded from this report (Brunson & Davis 1955, Symmers & Belf 1956, Wile & Sturgeon 1966, Allison 1957, Robinson et a1 1958, Lorber & Emerg 1959, Brain et a1 1962, Bukowski & Koblenzer 1962, Monens & Retera 1967). One case was excluded because histopathologic confirmation was lacking (Rubinstein et a1 1959), and another case was excluded because the clinical description was too brief for evaluation (Frick & Hitzig 1960). These arbitrary criteria permitted assurance that only well-documented, histologigally-proven cases were included. The positive clinical and laboratory findings of the remaining cases were then tabulated in order to establish common diagnostic criteria (Moschowitz 1925, Baehr et a1 1936, Engle et a1 1947, Singer et al 1947, Muirhead et al 1948, Wile & Singer 1948, Adelson et al 1954, Clinical Conference 1954, Craig & Gitlin 1957, Killelea 1961, Swaiman et a1 1962, Clinicopathological Conference 1968). The findings (thrombocytopenia, fever, purpura, anaemia, renal abnormalities, CNS dysfunction and characteristic histopathologic specimens) established by the literature survey, were then utilized as the basis of a questionnaire which was forwarded to 140 university-affiliated pediatric departments in the United States and Canada. Cooperating physicians were asked to use these diagnostic criteria and to report their cases of TTP seen since 1960, in children 16 years of age and under. Cases were then evaluated in regard to the duration of illness, impact of therapy, and outcome. Our own patient was also included in the survey. RESULTS OF LITERATURE REVIEW
13 of the 37 cases reviewed met the diagnostic criteria for TTP (Table I). Identifying data. The ages ranged from 20 months to 16 years; only 1 patient was less than six years of age. The ratio of females to males was 3:1. 7 patients were
36 % related to renal failure
92 %
(i) 10 patients:
Thrombotic Thrombocytopenic Purpura in Childhood Results of a Survey and Re-Examination of the Literature NOLAN BERMAN, M.D.
&
JERRYZ. FINKLESTEIN, M.D.
Harbor General Hospital, Department of Pediatrics (Chief, Joseph W . St. Geme, Jr.), Torrance, California, USA
A survey was conducted among 46 pediatric institutions in the United States and Canada t o evaluate the presentation, therapy and survival of children with thrombocytopenic purpura (TTP) seen since 1960. TTP is an uncommon disease in the pediatric age group, and the clinical and pathologic findings in adults and children are almost identical. It can be distinguished from haemolytic uraemic syndrome in that it usually occurs in older children, the renal disease is milder, and the central nervous system symptoms appear to be related to vascular occlusive disease, and not to the complications of severely compromised kidneys. Appropriate biopsy specimens which reveal typical widespread hyaline occlusion of arterioles may confirm the diagnosis. Combinations of corticosteroids, splenectomy, and heparin have been used as therapy. Prognosis has improved, and is probably related to improved supportive care. K e y words: TTP - therapy - splenecto'my - survival - childhood
Accepted for publication February 28, 1975 Correspondence to: Dr. Jerry Z. Finklestein, Departmelnt of Pediatrics, Harbor General Hospital, 1000 West Carson Street, Torrance, California 90509, USA
An 11-year-old Black male recently entered our institution with an acute illness characterized clinically by fever, purpura, disorientation and stupor. He had microangiopathic haemolytic anaemia, thrombocytopenia and azotemia. Clinical diagnosis of thrombotic thrombocytopenic purpura (TTP) was confirmed by histologic examination of splenic tissue following therapeutic splenectomy. To aid in our management of this patient, the literature was reviewed to determine the natural history of TTP in the pediatric age group. It soon became evident,
however, that TTP had not been clearly distinguished from haemolytic uraemic syndrome (HUS), and therapeutic guidelines for the management of children with TTP could not be adequately evaluated. Since Moschowitz' description of TTP (1925), close to 300 cases have been reported in the medical literature. Although TTP is usually considered a disease of adults, cases have occurred in the pediatric age group. A review by MacWhinney et a1 (1962) of TTP in childhood summarized 19 histologically-confirmed cases. In 1966,
TTP IN CHILDHOOD
Amorisi & Ultman reviewed the world literature and found 271 cases with 39 affected children. The latter authors admit, however, that since many of the cases included in their review preceded Gasser’s (1955) original description of HUS, their statistics were probably inaccurate, and that many cases actually represented instances of HUS and not TTP. The relationship between HUS and TTP remains controversial. Patients with either disease may present with thrombocytopenia, microangiopathic haemolytic anaemia, purpura, and evidence of central nervous system (CNS) and renal involvement. Differentiation of one disorder from the other is often difficult if only clinical observations are available. Gasser (1955) stated that the severe renal disease of HUS distinguished it from TTP. Lieberman et a1 (1966) and Lieberman (1972) analyzed their patients with HUS and also concluded that TTP and HUS could be distinguished on the basis of characteristic clinical and pathologic patterns. Other authors have suggested that the two entities may simply be agemodified manifestations of the same basic disease process (Shumway et a1 1964, Taub et a1 1964, Mettler 1969). The TTP literature was therefore reexamined to determine whether a characteristic clinical picture and essential diagnosis criteria for TTP could be established. In addition, by means of a questionnaire, the current experiences of physicians in the United States and Canada were surveyed to more accurately assess the frequency of TTP and to document the effectiveness of present day therapy. This paper reports the results of the literature search and of the questionnaire survey.
287
MATERIALS AND METHODS The pediatric cases of TTP in the English language literature were reviewed. Those cases which were marked by acute renal failure and histopathology primarily affecting the kidney were considered to be examples of HUS and thus excluded from this report (Brunson & Davis 1955, Symmers & Belf 1956, Wile & Sturgeon 1966, Allison 1957, Robinson et a1 1958, Lorber & Emerg 1959, Brain et a1 1962, Bukowski & Koblenzer 1962, Monens & Retera 1967). One case was excluded because histopathologic confirmation was lacking (Rubinstein et a1 1959), and another case was excluded because the clinical description was too brief for evaluation (Frick & Hitzig 1960). These arbitrary criteria permitted assurance that only well-documented, histologigally-proven cases were included. The positive clinical and laboratory findings of the remaining cases were then tabulated in order to establish common diagnostic criteria (Moschowitz 1925, Baehr et a1 1936, Engle et a1 1947, Singer et al 1947, Muirhead et al 1948, Wile & Singer 1948, Adelson et al 1954, Clinical Conference 1954, Craig & Gitlin 1957, Killelea 1961, Swaiman et a1 1962, Clinicopathological Conference 1968). The findings (thrombocytopenia, fever, purpura, anaemia, renal abnormalities, CNS dysfunction and characteristic histopathologic specimens) established by the literature survey, were then utilized as the basis of a questionnaire which was forwarded to 140 university-affiliated pediatric departments in the United States and Canada. Cooperating physicians were asked to use these diagnostic criteria and to report their cases of TTP seen since 1960, in children 16 years of age and under. Cases were then evaluated in regard to the duration of illness, impact of therapy, and outcome. Our own patient was also included in the survey. RESULTS OF LITERATURE REVIEW
13 of the 37 cases reviewed met the diagnostic criteria for TTP (Table I). Identifying data. The ages ranged from 20 months to 16 years; only 1 patient was less than six years of age. The ratio of females to males was 3:1. 7 patients were
36 % related to renal failure
92 %
(i) 10 patients:
