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Management of Purpura in Children
Management of Purpura in Children STEPHEN D. MILLS
is a symptom that is encountered frequently in medical practice. It may be caused either by vascular defects or by abnormalities in the blood itself, such as deficiency of platelets or other defects of coagulation. Successful management of the condition depends primarily on ascertaining the causative factor and removing it. PURPURA
CATEGORIES OF PURPURA
It has been oommon practice to divide the purpuras into two main categories depending upon the absence or presence of normal numbers of platelets in the circulating blood. These categories are designated "thrombopenic" and "nonthrombopenic" respectively. Either may be the result of infection, especially in childhood when the acute exanthemata and infections of the respiratory tract so frequently precede the appearance of purpura. N onthrombopenic purpura probably occurs more frequently than does the thrombopenic variety, and it'usually is not as serious. Bleeding may occur into the skin, joints, intestinal mucosa or kidneys or into different combinations of these sites, in which the capillaries are presumed to be the target areas of an allergic type of reaction to some drug, chemical or foreign protein, usually bacterial. This condition has also been known as anaphylactoid purpura or Sch6nlein-Henoch purpura when it involves the joints or intestinal mucosa. Treatment consists of removal of the causative agent, drug or chemical, control of infection, use of supportive therapy including blood transfusion and, in some cases, administration of steroid hormones and antihistamine drugs. Thrombopenic purpura is encountered more frequently in hospital practice, as it is the more severe of the two varieties and hence often requires treatment in a hospital. One hundred and five of the 187 children (less than 15 years of age) with purpura of all varieties seen at the Clinic in the decade immediately preceding the year 1955 had the thrombopenic type, while only 82 had the nonthrombopenic type. Even though the physician knows that the thrombopenic type of purpura may result from infection, toxic agents such as drugs and chemicals, or a blood dyscrasia, he may find it impossible to assign a cause in the majority of 1197
Step hen D. M ills
1198
patients, in which event the purpura is called "idiopathic." It is in idiopathic purpura that one is unable to predict what form of treatment will benefit a particular patient. Patients with acute idiopathic purpura, which is defined arbitrarily as purpura of not more than 2 months' duration and which represents a significant proportion of all cases of thrombopenic purpura in children, are reported by several writers to recover spontaneously, so that only supportive treatment is required. However, three of our patients with this diagnosis died of uncontrolled hemorrhage, which has caused us to feel less optimistic about handling children with acute purpura by conservative measures. The majority of patients with thrombopenic purpura are classified in the chronic idiopathic group. In a subsequent section of the paper this group of patients in particular will be discussed in the light of present-day methods of treatment to prevent the possibility of intracranial hemorrhage, menorrhagia or uncontrolled and generalized bleeding, which have been the most serious complications of purpura. DIAGNOSIS
Great enlargement of the spleen is unusual in purpura of any variety and its presence should suggest other diagnostic possibilities such as congestive splenomegaly or one of the blood dyscrasias. Clinical evidence of splenomegaly was recorded in 21 children with thrombopenic and in 10 with nonthrombopenic purpura in the series of 187 children with purpura previously mentioned, but in only nine was the degree of enlargement considered significant; at splenectomy more than half the spleens were definitely overweight for the age and size of the patient, but the overweight was not great. Laboratory Tests
The results of laboratory tests are of definite aid in differential diagnosis. The concentration of hemoglobin and the erythrocyte, leukocyte and differential counts are normal unless there has been infection or severe bleeding. The blood smear is helpful in disclosing purpura due to leukemia or aplastic anemia. The number of platelets is decreased (usually less than 50,000 per cubic millimeter) in thrombopenic purpura and normal (100,000 to 250,000) in the nonthrombopenic type. There is poor correlation between the platelet count and the tendency to bleed. After splenectomy the platelet count usually increases precipitously, less often is slow to increase and, in a few patients, does not respond at all. Increase of the platelet count to 1,000,000 or more in children is not an indication for anticoagulant therapy. Examination of the bone marrow should be carried out in all who undergo splenectomy and others in whom the diagnosis is uncertain. Here again, one can usually detect leukemia, aplastic anemia, metastasis of a malignant lesion to the marrow, and granulomatous disease. Megakaryo-
Management of Purpura in Children
1199
cytes are almost always present but they may not split off platelets in normal fashion. Bleeding time is often prolonged more than 30 minutes in patients with thrombopenic purpura and the clot fails to retract in 24 hours, both meaning some platelet deficiency. Coagulation time is normal. Thc RumpelLeede or cuff test gives positive results in many of the patients with thrombopenic purpura and in a few of those who have nonthrombopenic purpura. This test is a measure of capillary fragility and correlates betteI with the patient's tendency to bleed than does the platelet count. COMPLICATIONS
The most dreaded complication is intracranial hemorrhage. This occurred in five of 187 children with purpura of all types, of whom two had acute purpura that proved fatal, two became blind and had a severe mental defect, and one had fatal cerebral hemorrhage following severe drug intoxication; all five had purpura of the thrombopenic variety. Menorrhagia is not uncommon in thrombopenic purpura. It was found in five adolescent girls in the series just mentioned. Vaginal bleeding occurred in three young children. One patient required hysterectomy to control her bleeding when splenectomy failed. Hematuria was noted in 17 of the patients with anaphylactoid purpura and in seven with thrombopenic purpura. Chronic nephritis resulted in only one instance of the former type. PROGNOSIS
The outlook for recovery in most patients is good, especially with nonthrombopenic purpura. Recent reports 1• S indicate that acute purpura in children is a self-limited disease with favorable outcome and that splenectomy is not needed in most cases. There were 11 deaths in the Mayo Clinic group of 187 children. All who died had thrombopenic purpura, and in seven of these the disease was secondary to other causes. Three died from the toxic effect of x-rays or drugs on their bone marrow, one of toxoplasmosis, one of meningococcemia with adrenal hemorrhage, one of sepsis and intestinal obstruction and one of toxic hepatitis and nephritis. Four deaths were in the idiopathic thrombopenic group; three of these patients had acute fulminating purpura and one had chronic purpura and uncontrolled menorrhagia despite treatment with steroid hormones and splenectomy. TREATMENT
In the secondary types of purpura, whether thrombopenic or nonthrombopenic, one should search for the underlying condition and treat it; this entails removal of the offending drug or chemical and treatment of the responsible infection with suitable antibiotics or other agents.
1200
Stephen D. Mills
Fresh whole blood is used to provide platelets, which deteriorate rapidly in stored blood. Transfusions of platelets may be offered if suitable facilities are available, but repeated transfusions may be less effective owing to sensitization of the patient to transfused platelets. Use of silicone technique is said to be helpful in preserving platelets from destruction during transfusion of blood or platelets. Hormone Therapy
Continued experience with steroid-hormone therapy has shown it to be helpful in the control of bleeding, though the mechanism that is responsible is not well understood. An intravenous drip of corticotropin (ACTH) given in either dextrose or saline solution in doses of 25 to 40 mg. daily over a period of 8 to 12 hours may be helpful when bleeding is acute and severe. In the series of 187 children mentioned previously, 27 were treated with steroid hormones at the Clinic or elsewhere; 18 of these had thrombopenic and nine had nonthrombopenic purpura, and all were given cortisone except five who were given corticotropin. Dosage was varied according to the form of steroid employed and the size of the child. For cortisone, the dose varied from 50 to 200 mg. a day; for corticotropin, it varied from 20 to 40 mg. a day. It was impossible to obtain accurate figures for dosage on five of the patients treated elsewhere, and a review of the records of children treated at the Clinic indicates that the doses used may have been too small and the course of treatment too brief in the light of present-day knowledge. All but three of the patients who were treated with steroid hormones for thrombopenic purpura finally underwent splenectomy with benefit when it seemed apparent that hormone therapy had not helped them. Of the three who did not undergo splenectomy, one died of intracranial hemorrhage on the fifth day of treatment, one gradually improved, and one remained unimproved. If larger doses of either hormone should be employed in handling these patients and the hormone should be given for longer periods in order to control bleeding, the results might be complicated by the appearance of symptoms of hypercortisonism. Perhaps the use of the newer preparations, such as prednisone, in handling purpura would avoid the unfavorable side effects of therapy with cortisone or corticotropin. Splenectomy
For severe or prolonged bleeding, splenectomy has been the treatment of choice. Stroebel and co-workers found a good response to splenectomy in 85 per cent of 59 adults and in 90 per cent of 20 children with idiopathic thrombopenic purpura. A recent review of Clinic experience with thrombopenic purpura from all causes in 105 children shows that 54 were splenectomized for purpura of the idiopathic type. Follow-up over the decade prior to 1955 shows
Management of Purpura in Children
1201
that of 50 patients traced 1 to 10 years after splenectomy, 37 were completely well, eight were somewhat improved (so that 90 per cent were benefited), three were unimproved and two died postoperatively. Of the patients treated medically in the same decade, 15 were well, one was improved, one was unimproved and two had died of their disease, so that 84 per cent responded favorably to medical management. Of the two deaths following splenectomy, one was that of an ll-yearold boy with only a 2-day history of severe bleeding from the nose and generalized purpura. His platelets numbered 33,000 on admission, and the results of blood and marrow studies wete consistent with a diagnosis of acute idiopathic thrombopenic purpura. He was given 100 mg. of cortisone daily for 2 days and then splenectomy was done. Despite transfusions of fresh whole blood, he continued to bleed and died 1 day postoperatively. No cause for his bleeding in the peritoneal cavity and small bowel was found at postmortem examination. The other postoperative death was that of a 14-year-old girl with menorrhagia of 5 months' duration and with generalized purpura of the skin following measles. The platelets numbered 46,000 and she was somewhat anemic. Examination of blood smears and bone marrow showed decreased platelet formation in a hypocellular marrow. Cortisone was given orally, 200 mg. a day for 8 days, without benefit. She then underwent splenectomy and transfusion of whole blood. Treatment with cortisone was continued postoperatively, but bleeding into the skin and from the uterus persisted and the girl died 8 days postoperatively. Again no cause for the bleeding could be found at necropsy. The splenic pedicle was intact and a large intraperitoneal hemorrhage was found. These two fatalities among 54 splenectomized children represent a mortality rate of less than 4 per cent, which is not excessive in view of the severity or chronicity of the illness in many patients. The indications for splenectomy in idiopathic thrombopenic purpura have been (1) prolonged or severe bleeding unresponsive to other measures, (2) severe menorrhagia in young adolescent girls and (3) recurring episodes of purpura sufficient in degree or extent to limit the activities of the child because of the danger from trauma. There seems to be no reason for splenectomy in (1) nonthrombopenic purpura, (2) symptomatic or secondary purpura and (3) purpura whose nature is not clear. SUMMARY AND CONCLUSIONS
Proper handling of the child with purpura depends basically on classification of the purpura as to the causative agent and treatment of the underlying cause whenever possible. The frequency with which infections precede the appearance of purpura in children is noteworthy. The outlook for recovery may be good with conservative management, including hlood transfusion, use of antibiotic drugs and, in some cases, use of steroid hormones. In the Clinic series, most of the patients were 6 years
Stephen D. Mills
1202
of age or less. Splenectomy was performed on 54 of 78 patients with idiopathic thrombopenic purpura, with two deaths. The risk of intracranial bleeding and the continuance of purpura into adult life or into the menstrual age in girls should be considered in determining the treatment to be used. REFERENCES l. Clement, D. H. and Diamond, L. K.: Purpura in Infants and Children: Its
Natural History. A.M.A. Am. J. Dis. Child. 85:259-278 (March) 1953. 2. Komrower, G. M. and Watson, G. H.: Prognosis in Idiopathic Thrombocytopenic Purpura of Childhood. Arch. Dis. Childhood. 29:502-506 (Dec.) 1954. 3. Newton, W. A. Jr. and Zuelzer, W. W.: Idiopathic Thrombocytopenic Purpura in Childhood. New England J. Med. 245:879-885 (Dec. 6) 1951. 4. Stroebel, C. F., Campbell, D. C. and Hagedorn, A. B.: Problem of Essential Thrombocytopenic Purpura. M. CLIN. NORTH AMERICA. 33:1027-1046 (July) 1949.
is a symptom that is encountered frequently in medical practice. It may be caused either by vascular defects or by abnormalities in the blood itself, such as deficiency of platelets or other defects of coagulation. Successful management of the condition depends primarily on ascertaining the causative factor and removing it. PURPURA
CATEGORIES OF PURPURA
It has been oommon practice to divide the purpuras into two main categories depending upon the absence or presence of normal numbers of platelets in the circulating blood. These categories are designated "thrombopenic" and "nonthrombopenic" respectively. Either may be the result of infection, especially in childhood when the acute exanthemata and infections of the respiratory tract so frequently precede the appearance of purpura. N onthrombopenic purpura probably occurs more frequently than does the thrombopenic variety, and it'usually is not as serious. Bleeding may occur into the skin, joints, intestinal mucosa or kidneys or into different combinations of these sites, in which the capillaries are presumed to be the target areas of an allergic type of reaction to some drug, chemical or foreign protein, usually bacterial. This condition has also been known as anaphylactoid purpura or Sch6nlein-Henoch purpura when it involves the joints or intestinal mucosa. Treatment consists of removal of the causative agent, drug or chemical, control of infection, use of supportive therapy including blood transfusion and, in some cases, administration of steroid hormones and antihistamine drugs. Thrombopenic purpura is encountered more frequently in hospital practice, as it is the more severe of the two varieties and hence often requires treatment in a hospital. One hundred and five of the 187 children (less than 15 years of age) with purpura of all varieties seen at the Clinic in the decade immediately preceding the year 1955 had the thrombopenic type, while only 82 had the nonthrombopenic type. Even though the physician knows that the thrombopenic type of purpura may result from infection, toxic agents such as drugs and chemicals, or a blood dyscrasia, he may find it impossible to assign a cause in the majority of 1197
Step hen D. M ills
1198
patients, in which event the purpura is called "idiopathic." It is in idiopathic purpura that one is unable to predict what form of treatment will benefit a particular patient. Patients with acute idiopathic purpura, which is defined arbitrarily as purpura of not more than 2 months' duration and which represents a significant proportion of all cases of thrombopenic purpura in children, are reported by several writers to recover spontaneously, so that only supportive treatment is required. However, three of our patients with this diagnosis died of uncontrolled hemorrhage, which has caused us to feel less optimistic about handling children with acute purpura by conservative measures. The majority of patients with thrombopenic purpura are classified in the chronic idiopathic group. In a subsequent section of the paper this group of patients in particular will be discussed in the light of present-day methods of treatment to prevent the possibility of intracranial hemorrhage, menorrhagia or uncontrolled and generalized bleeding, which have been the most serious complications of purpura. DIAGNOSIS
Great enlargement of the spleen is unusual in purpura of any variety and its presence should suggest other diagnostic possibilities such as congestive splenomegaly or one of the blood dyscrasias. Clinical evidence of splenomegaly was recorded in 21 children with thrombopenic and in 10 with nonthrombopenic purpura in the series of 187 children with purpura previously mentioned, but in only nine was the degree of enlargement considered significant; at splenectomy more than half the spleens were definitely overweight for the age and size of the patient, but the overweight was not great. Laboratory Tests
The results of laboratory tests are of definite aid in differential diagnosis. The concentration of hemoglobin and the erythrocyte, leukocyte and differential counts are normal unless there has been infection or severe bleeding. The blood smear is helpful in disclosing purpura due to leukemia or aplastic anemia. The number of platelets is decreased (usually less than 50,000 per cubic millimeter) in thrombopenic purpura and normal (100,000 to 250,000) in the nonthrombopenic type. There is poor correlation between the platelet count and the tendency to bleed. After splenectomy the platelet count usually increases precipitously, less often is slow to increase and, in a few patients, does not respond at all. Increase of the platelet count to 1,000,000 or more in children is not an indication for anticoagulant therapy. Examination of the bone marrow should be carried out in all who undergo splenectomy and others in whom the diagnosis is uncertain. Here again, one can usually detect leukemia, aplastic anemia, metastasis of a malignant lesion to the marrow, and granulomatous disease. Megakaryo-
Management of Purpura in Children
1199
cytes are almost always present but they may not split off platelets in normal fashion. Bleeding time is often prolonged more than 30 minutes in patients with thrombopenic purpura and the clot fails to retract in 24 hours, both meaning some platelet deficiency. Coagulation time is normal. Thc RumpelLeede or cuff test gives positive results in many of the patients with thrombopenic purpura and in a few of those who have nonthrombopenic purpura. This test is a measure of capillary fragility and correlates betteI with the patient's tendency to bleed than does the platelet count. COMPLICATIONS
The most dreaded complication is intracranial hemorrhage. This occurred in five of 187 children with purpura of all types, of whom two had acute purpura that proved fatal, two became blind and had a severe mental defect, and one had fatal cerebral hemorrhage following severe drug intoxication; all five had purpura of the thrombopenic variety. Menorrhagia is not uncommon in thrombopenic purpura. It was found in five adolescent girls in the series just mentioned. Vaginal bleeding occurred in three young children. One patient required hysterectomy to control her bleeding when splenectomy failed. Hematuria was noted in 17 of the patients with anaphylactoid purpura and in seven with thrombopenic purpura. Chronic nephritis resulted in only one instance of the former type. PROGNOSIS
The outlook for recovery in most patients is good, especially with nonthrombopenic purpura. Recent reports 1• S indicate that acute purpura in children is a self-limited disease with favorable outcome and that splenectomy is not needed in most cases. There were 11 deaths in the Mayo Clinic group of 187 children. All who died had thrombopenic purpura, and in seven of these the disease was secondary to other causes. Three died from the toxic effect of x-rays or drugs on their bone marrow, one of toxoplasmosis, one of meningococcemia with adrenal hemorrhage, one of sepsis and intestinal obstruction and one of toxic hepatitis and nephritis. Four deaths were in the idiopathic thrombopenic group; three of these patients had acute fulminating purpura and one had chronic purpura and uncontrolled menorrhagia despite treatment with steroid hormones and splenectomy. TREATMENT
In the secondary types of purpura, whether thrombopenic or nonthrombopenic, one should search for the underlying condition and treat it; this entails removal of the offending drug or chemical and treatment of the responsible infection with suitable antibiotics or other agents.
1200
Stephen D. Mills
Fresh whole blood is used to provide platelets, which deteriorate rapidly in stored blood. Transfusions of platelets may be offered if suitable facilities are available, but repeated transfusions may be less effective owing to sensitization of the patient to transfused platelets. Use of silicone technique is said to be helpful in preserving platelets from destruction during transfusion of blood or platelets. Hormone Therapy
Continued experience with steroid-hormone therapy has shown it to be helpful in the control of bleeding, though the mechanism that is responsible is not well understood. An intravenous drip of corticotropin (ACTH) given in either dextrose or saline solution in doses of 25 to 40 mg. daily over a period of 8 to 12 hours may be helpful when bleeding is acute and severe. In the series of 187 children mentioned previously, 27 were treated with steroid hormones at the Clinic or elsewhere; 18 of these had thrombopenic and nine had nonthrombopenic purpura, and all were given cortisone except five who were given corticotropin. Dosage was varied according to the form of steroid employed and the size of the child. For cortisone, the dose varied from 50 to 200 mg. a day; for corticotropin, it varied from 20 to 40 mg. a day. It was impossible to obtain accurate figures for dosage on five of the patients treated elsewhere, and a review of the records of children treated at the Clinic indicates that the doses used may have been too small and the course of treatment too brief in the light of present-day knowledge. All but three of the patients who were treated with steroid hormones for thrombopenic purpura finally underwent splenectomy with benefit when it seemed apparent that hormone therapy had not helped them. Of the three who did not undergo splenectomy, one died of intracranial hemorrhage on the fifth day of treatment, one gradually improved, and one remained unimproved. If larger doses of either hormone should be employed in handling these patients and the hormone should be given for longer periods in order to control bleeding, the results might be complicated by the appearance of symptoms of hypercortisonism. Perhaps the use of the newer preparations, such as prednisone, in handling purpura would avoid the unfavorable side effects of therapy with cortisone or corticotropin. Splenectomy
For severe or prolonged bleeding, splenectomy has been the treatment of choice. Stroebel and co-workers found a good response to splenectomy in 85 per cent of 59 adults and in 90 per cent of 20 children with idiopathic thrombopenic purpura. A recent review of Clinic experience with thrombopenic purpura from all causes in 105 children shows that 54 were splenectomized for purpura of the idiopathic type. Follow-up over the decade prior to 1955 shows
Management of Purpura in Children
1201
that of 50 patients traced 1 to 10 years after splenectomy, 37 were completely well, eight were somewhat improved (so that 90 per cent were benefited), three were unimproved and two died postoperatively. Of the patients treated medically in the same decade, 15 were well, one was improved, one was unimproved and two had died of their disease, so that 84 per cent responded favorably to medical management. Of the two deaths following splenectomy, one was that of an ll-yearold boy with only a 2-day history of severe bleeding from the nose and generalized purpura. His platelets numbered 33,000 on admission, and the results of blood and marrow studies wete consistent with a diagnosis of acute idiopathic thrombopenic purpura. He was given 100 mg. of cortisone daily for 2 days and then splenectomy was done. Despite transfusions of fresh whole blood, he continued to bleed and died 1 day postoperatively. No cause for his bleeding in the peritoneal cavity and small bowel was found at postmortem examination. The other postoperative death was that of a 14-year-old girl with menorrhagia of 5 months' duration and with generalized purpura of the skin following measles. The platelets numbered 46,000 and she was somewhat anemic. Examination of blood smears and bone marrow showed decreased platelet formation in a hypocellular marrow. Cortisone was given orally, 200 mg. a day for 8 days, without benefit. She then underwent splenectomy and transfusion of whole blood. Treatment with cortisone was continued postoperatively, but bleeding into the skin and from the uterus persisted and the girl died 8 days postoperatively. Again no cause for the bleeding could be found at necropsy. The splenic pedicle was intact and a large intraperitoneal hemorrhage was found. These two fatalities among 54 splenectomized children represent a mortality rate of less than 4 per cent, which is not excessive in view of the severity or chronicity of the illness in many patients. The indications for splenectomy in idiopathic thrombopenic purpura have been (1) prolonged or severe bleeding unresponsive to other measures, (2) severe menorrhagia in young adolescent girls and (3) recurring episodes of purpura sufficient in degree or extent to limit the activities of the child because of the danger from trauma. There seems to be no reason for splenectomy in (1) nonthrombopenic purpura, (2) symptomatic or secondary purpura and (3) purpura whose nature is not clear. SUMMARY AND CONCLUSIONS
Proper handling of the child with purpura depends basically on classification of the purpura as to the causative agent and treatment of the underlying cause whenever possible. The frequency with which infections precede the appearance of purpura in children is noteworthy. The outlook for recovery may be good with conservative management, including hlood transfusion, use of antibiotic drugs and, in some cases, use of steroid hormones. In the Clinic series, most of the patients were 6 years
Stephen D. Mills
1202
of age or less. Splenectomy was performed on 54 of 78 patients with idiopathic thrombopenic purpura, with two deaths. The risk of intracranial bleeding and the continuance of purpura into adult life or into the menstrual age in girls should be considered in determining the treatment to be used. REFERENCES l. Clement, D. H. and Diamond, L. K.: Purpura in Infants and Children: Its
Natural History. A.M.A. Am. J. Dis. Child. 85:259-278 (March) 1953. 2. Komrower, G. M. and Watson, G. H.: Prognosis in Idiopathic Thrombocytopenic Purpura of Childhood. Arch. Dis. Childhood. 29:502-506 (Dec.) 1954. 3. Newton, W. A. Jr. and Zuelzer, W. W.: Idiopathic Thrombocytopenic Purpura in Childhood. New England J. Med. 245:879-885 (Dec. 6) 1951. 4. Stroebel, C. F., Campbell, D. C. and Hagedorn, A. B.: Problem of Essential Thrombocytopenic Purpura. M. CLIN. NORTH AMERICA. 33:1027-1046 (July) 1949.