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Idiopathic Thrombocytopenic Purpura in Adults
Idiopathic Thrombocytopenic Purpura in Adults DONALD C. CAMPBELL
A NUMBER of classifications of the thrombocytopenic purpuras have been used by various workers in the field. One of the broadest utilizes the status of the megakaryocytes as determined by aspiration of bone marrow, and separates the group into amegakaryocytic and megakaryocytic. Thrombocytopenia caused by failure of bone marrow, such as occurs in aplastic anemia, or caused by invasion of the bone marrow, such as occurs in leukemia or lymphoblastoma, is associated with reduced numbers of megakaryocytes and is classified as "amegakaryocytic." In idiopathic thrombocytopenia, on the other hand, the megakaryocytes usually are present in normal or increased numbers; hence, this form is included in the megakaryocytic group. Other types of thrombocytopenia also are included in this megakaryocytic category. They include those consequent to the use of certain drugs, such as quinine and sedative agents (Sedormid), and those which are associated with a number of disease states, some of which are acute exanthemas, sarcoidosis and disseminated lupus erythematosus. Establishment of the diagnosis of idiopatbic thrombocytopenic purpura must be accomplished by exclusion of known etiologic conditions in this megakaryocytic group. TYPICAL OBSERVATIONS
When it has been established that the condition of the patient is in the category of id:opathic thrombocytopenic purpura, certain findings will be expected to be present. The peripheral blood, of course, will be characterized by thrombocytopenia. Examination of the bone marrow ordinarily will show a normal or increased number of megakaryocytes. As a rule, it will be noted that there is little platelet formation, and in some instances there may be many degenerative changes in the megakaryocytes. Sometimes an increase will be noted in the less mature forms of megakaryocytes. It should be mentioned, however, that some hematologists feel that the chief contribution of examination of the bone marrow in this group is to exclude leukemia and aplastic anemia. Diggs and Hewlett, in a study of the bone marrow of 36 patients with idiopathic thrombo1187
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cytopenic purpura, found no correlation between (1) the number of megakaryocytes in smears of marrow during the acute phase of the disease, and (2) the prognosis, whether or not splenectomy was done. Splenomegaly probably will not be present, although there are occasional exceptions to this. Generally, a tourniquet test will demonstrate an increase in capillary fragility. The bleeding time usually will be prolonged, but the coagulation time will be normal. There is a wide variation in the clinical manifestations in this group of patients. Some complain only of easy bruising or spontaneous ecchymosis. Others display these signs in addition to generalized petechiae and frank bleeding. Unfortunately, the response of these patients to various therapeutic programs also exhibits a wide variability, and efforts to predict the final outcome in any patient have not been successful. PREVIOUS STUDIES
In 1949 several of us reported our experience in a study of 150 patients who had idiopathic thrombocytopenic purpura. 9 In this group 59 of the adult patients were treated with splenectomy, and 84.7 per cent of them obtained a satisfactory immediate response. Steroid therapy was not available at the time of this study, but both cortisone and corticotropin have been widely used in recent years in the management of patients with idiopathic thrombocytopenic purpura. In an effort to evaluate our experience with steroid therapy in this condition, we have reviewed the records of the patients for whom this diagnosis was made during the years 1952 through 1954. In a few instances a given patient also had been seen by us at an earlier date, so that occasionally the total period of observation actually is more than 3 years. TWO FORMS OF THE DISEASE
Much has been written about the separation of idiopathic thrombocytopenic purpura into the acute and ehronic types. Persons who have the aeute type are predominantly children. In them the onset of bleeding into the skin and from mucous membranes is acute. In many instances a history of preceding infection can be obtained. Our experience with this category is limited, and among the 50 adult persons seen during the past 3 years there were only two who were classified as having the acute type of disease. Except to describe these two patients briefly, we shall not discuss our experience with acute idiopathic thrombocytopenic purpura in this paper. Physicians with a wide experience in the management of patients who have acute idiopathic thrombocytopenic purpura have, however, emphasized that it is very often a self-limited disease, and their program of management has been to keep the patient at complete rest in bed, to treat the infection, when it was present, to administer steroids when the condition was sufficiently severe, and to observe. Clement and Diamond, in their report involving a group of 96 children, noted that 38
Idiopathic Thrombocytopenic Purpura in Adults
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were symptom-free within 6 weeks after the onset of their illness. All of these 38 children were classified as having acute thrombocytopenic purpura. Our study is predominantly that of chronic idiopathic thrombocytopenic purpura. Since it is based upon the study of patients seen within a recent 3-year period, we have not been able to obtain protracted followup information in many instances, but we have obtained some follow-up data in 46 cases. We know that occasionally persons who apparently achieve an excellent result after splenectomy will experience a recurrence of thrombocytopenic purpura several years later. STEROID THERAPY
Observations on the response of patients with idiopathic thrombocytopenia to steroid therapy were made as early as 1950 by Robson and Duthie and by Meyers, Miller and Bethell. Most physicians who have been interested in this problem have noticed that often there is an improvement in the vascular component of this disease without a corresponding increase in thrombocytes. Lozner has discussed his experience with patients who had idiopathic thrombocytopenic purpura. He found that after hormonal treatment most patients obtained complete remission of the increased capillary fragility, whereas perhaps only half obtained satisfactory remission of thrombocytopenia. After discontinuance of hormone therapy, both the capillary fragility and the thrombocytopenia usually quickly return to previous abnormal states. Bethell's results with cortisone or corticotropin among such patients have been more favorable. He and his colleagues observed 23 patients who were so treated, and complete clinical and hematologic remissions were achieved for all but seven. The remissions of nine of the patients were sustained for 6 to 40 months. Bethell and his associates used cortisone in a dose of 300 mg., generally given orally and in fractional doses of 75 mg. every 6 hours. When they used corticotropin the dose as a rule was 25 units, administered intramuscularly every 6)ours. Stefanini and Dameshek in general used smaller doses of cortisone and corticotropin than did Bethell. They wrote that in their experience sustained increases in platelets were exceptional, although they were impressed with the manner in which the agent produced prompt and effective control of the bleeding manifestations of the disease. They did point out, however, the possibility that larger doses of the hormone might be more effective in producing sustained remissions. TRANSFUSION OF PLATELETS
Before any discussion of the results of therapy with cortisone, corticotropin and splenectomy among the patients whose records we have recently reviewed, a word should be said about the transfusion of platelets. Much work has been done in the development of this technique and
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Stefanini, who has contributed much information to this field, has emphasized some of the practical difficulties encountered in the preparation and supply of platelet suspensions. Stefanini believes that the transfusion of platelets should be limited to those patients in whom control of bleeding cannot be accomplished by any other measure. In general, the transfusion of platelets or of platelet-rich blood with the use of special techniques, such as entire plastic systems or a system made water-repellent by coating it with silicone, is most effective against the amegakaryocytic type of thrombocytopenic purpura. In idiopathic thrombocytopenic purpura a platelet-destructive mechanism often is present, which means that transfused platelets would be much less effective. It is not feasible to try to control bleeding over any extended period by means of transfusion of platelets, and the chief use of that measure in idiopathic thrombocytopenic purpura is to attempt to control severe bleeding or to prepare a patient for splenectomy. Platelet transfusion was not employed for any of the patients whom we are discussing. SALIENT FEATURES OF PRESENT STUDY
Of the 50 patients 16 years of age or older whom we are including in this study, 34 were females and 16 were males. The incidence according to sex, with a predominance of females, has been noted in most similar studies. Only two patients of this group had acute idiopathic thrombocytopenia, and 21 of the group gave a history of purpura that antedated treatment with either steroids or splenectomy by at least a year. Five of the group (four females and one male) experienced spontaneous remissions. Two (one female and one male) were having minimal hemorrhagic manifestations and, because of other medical problems, were not treated for the hematologic disorder. Both were seen 3 years later and, although their platelet counts were still less than 50,000, neither had experienced difficulties secondary to the thrombocytopenia. The remaining 41 patients (all of whom had chronic idiopathic thrombocytopenia) were treated with one of the steroid preparations or splenectomy or both. ACUTE IDIOPATHIC THROMBOCYTOPENIC PURPURA
Both of the patients classified as having acute idiopathic thrombo:. cytopenic purpura were treated with splenectomy and without steroids. Ordinarily, steroid therapy would be considered for patients in this group but there were reasons for not using it when we saw these patients early in 1952. One was a young man 17 years old whose purpura and epistaxis were severe and had been present for less than a week. The response of the platelets after splenectomy was slow; they increased from 10,000 to 94,000 on the Iilixth postoperative day. Gradual reduction of the platelet count followed, but tliere was no bleeding. Two months after splenectomy the patient had a cerebral hemorrhage, and when he returned to the Clinic his platelet count was 33,000. He improved spontaneously,
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however, and a month later his platelet count was 123,000. Four months later the count was 284,000. His father wrote that the son was entirely well 472 years postoperatively. The other patient who had idiopathic thrombocytopenic purpura classified as acute was a woman 22 years old. Within a few hours after she had been admitted to the hospital she had a cerebral hemorrhage and became stuporous. As soon as the diagnosis of idiopathic thrombocytopenic purpura had been established, it was decided to do splenectomy. Unfortunately, the patient never regained consciousness, and died 6 hours postoperatively. CHRONIC IDIOPATHIC THROMBOCYTIC PURPURA
Initial TreatIllent with Steroids
Twenty-one patients received cortisone or corticotropin as their initial therapy. Nineteen of these 21 subsequently underwent splenectomy. Results in this group can be listed in five rather general categories. Complete and Sustained Remissions. Two of these 21 patients apparently obtained complete and sustained remissions after steroid therapy alone. One of them was a man 52 years old who had experienced recurrent purpura, gingival bleeding and epistaxis for 6 months. When he took 25 mg. of corticotropin every 6 hours for 2 months, his symptoms completely subsided and his platelet count increased from 25,000 to 433,000. He did experience further difficulty 8 months later, with some degree of gingival bleeding, and the number of platelets decreased to 70,000. He then received 25 mg. of cortisone twice daily, and his symptoms subsided within 48 hours, and the number of platelets increased to 182,000. He was entirely well, without having received additional therapy, 10 months later. The other patient, a woman 31 years old, was treated by her family physician with 75 mg. of hydrocortisone daily. She was well, and her platelet count had increased from 23,000 to 138,000, 5 months after the treatment had been discontinued. It is, of course, impossible to know whether or not these persons experienced spontaneous remissions. It can be said only that remissions followed steroid therapy. No Response to Steroid Therapy. Three of the 21 patients seemed to show no response to steroid therapy. Our data in one instance are entirely inadequate, for we do not know the dose of cortisone that was administered at home. The physician of this patient did report that the patient failed to respond. The patient was a 54-year-old woman with a history of some degree of purpura and epistaxis that had been present for 15 months. She obtained an excellent result from splenectomy, and was well 3Yz months later. Another woman, 49 years old, failed to show any response, but she had been receiving only 37.5 mg. of cortisone daily. She had received this dose of cortisone for 2 months before we saw her. She gave a history of
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purpura that had been present for a year, and she obtained an excellent immediate response from splenectomy. We were unable to obtain any follow-up information. The third patient was a man 57 years old who said that purpura and epistaxis had been present in varying degrees for a year, but that more bleeding had occurred during the month preceding his admission to the Clinic. He did not improve, and there was no response, in respect to platelets, to the administration of 25 units of ACTH every 6 hours for 2 weeks. Moreover, he did not improve after splenectomy. He received 200 mg. of cortisone daily during the postoperative period, and this measure at first seemed to reduce the bleeding, but he died 3 weeks postoperatively in the presence of a generalized hemorrhagic picture. ~ Control of Bleeding and Platelet Response, but with Relapse When Treatment was Discontinued. Five of these 21 patients obtained responses from the standpoint of increases in platelets and complete control of bleeding. Two received 200 mg. of cortisone daily, two received 100 mg. of cortisone daily, and one received 80 units of ACTH daily. All experienced a relapse each time treatment was discontinued, and all underwent splenectomy. The four patients previously treated with cortisone responded well to splenectomy. The single patient who had obtained a favorable response from ACTH achieved a good immediate response from splenectomy, but relapse intervened 2 months later. The bleeding at that time was controlled with additional steroid therapy. She was clinically well 331 years postoperatively, but the platelet counts remained low. She was not receiving steroid therapy at the time of our last report. Control of Bleeding but Lack of Platelet Response. Eight of these 21 patients achieved control of the purpura and bleeding, but there was no increase in the platelet counts. Three of them received a daily dose of 200 mg. of cortisone, one received 150 mg. daily, three received 100 mg. daily, and one received 75 mg. daily. All underwent splenectomy, and the results were satisfactory for six patients. Two patients did not respond favorably to splenectomy. The first patient who did not respond to splenectomy was a man 76 years old who had failed to respond to a dose of 100 mg. of cortisone daily. His condition was chronic, with the presence of petechiae and bleeding for 131 years. The bleeding had increased during the month prior to his admission to the Clinic, and he had noted melena of some degree. Splenectomy was carried out, with a satisfactory immediate response, but with a relapse 2 months later. His physician wrote that this patient died 9 months postoperatively. The cause of death was not determined. The other patient who did not respond favorably to splenectomy was a man 65 years old who had been receiving a daily dose of 75 mg. of cortisone at home. This medication had not increased his platelet count, but it had controlled bleeding for 6 months. At the end of that time he
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began to notice more petechiae, and some gross bleeding. Splenectomy was carried out, but it did not abate his symptoms. Bleeding was well controlled during the postoperative period by means of 100 mg. of cortisone administered daily. The patient died 4 months postoperatively, however, of a cerebral hemorrhage. Steroid Therapy at Home, with Reduction of Bleeding but Inadequate Data as to Steroid Dosage. Three other patients in this group of 21 had received steroid therapy at home, and we could not be sure of either the dosage or the platelet counts. Each of them felt that the bleeding and purpuric manifestations had been ameliorated by the use of steroids. A man 57 years old had obtained complete relief after each of eight courses of cortisone, only to have petechiae and epistaxis recur when the use of the agent was stopped. The platelet count failed to increase after splenectomy, but he did not have any symptoms of hemorrhage. Reports have been received from his physician 7 months and 2 years postoperatively. In each report it was said that the patient was well and that his platelet count was normal. The second patient in this group was a woman 26 years old who had been treated for 3 months with varying doses of ACTH. Control of bleeding had been incomplete and it was said that the platelets failed to increase. When we saw her, the platelet count was 19,000, and the patient had recently noted hematuria. She had experienced little difficulty with bleeding after splenectomy, but the platelet count failed to increase. She received no medication postoperatively, and her physician 8 months later wrote that she was well, and that her platelet count was normal. The third patient of this group was a woman 25 years old who obtained an excellent immediate postoperative response to splenectomy, but concerning whom we have not been able to get follow-up information. Initial Treatment with Splenectomy
Twenty patients with chronic idiopathic thrombocytopenic purpura were treated with splenectomy as an initial procedure. This group also can be subdivided according to the results of therapy. Satisfactory Clinical and H ematologic Response. Fourteen patients (11 females and 3 males) obtained satisfactory postoperative responses and did not require any other treatment. We were not able to obtain followup information about two patients in this group of 14, but the remainder were well 3 months to 3Y2 years later. Failure of Splenectomy, but Control of Bleeding with Cortisone Postoperatively. The condition of four patients agrees with this category in varying degrees: Two of them were first seen by us after splenectomy had been carried out at home. Both of these patients, a woman 23 years old and a man 54 years old, were maintained by means of cortisone administered periodi-
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cally during the postoperative period, and they were progressing satisfactorily when last seen 3 years after splenectomy. A third patient in this group was a man 48 years old whose condition failed to respond to splenectomy but whose episodes of bleeding postoperatively were controlled satisfactorily with cortisone during a followup period of 22 months. The fourth patient was a woman 18 years old. She said that petechiae and easy bruising had been noted since the age of 5 years, and that menorrhagia had developed after menstruation started. The status of the bone marrow was typical, and moderate eosinophilia was detected in the marrow. At the time of operation, however, a number of granulomas were found in the spleen, suggesting that the thrombocytopenia may have been secondary to some chronic disease. The condition of this patient did not respond to splenectomy, and petechiae and vaginal bleeding recurred over the next 4 years. In 1954 the bleeding was controlled by the administration of 50 mg. of cortisone daily, and hysterectomy was performed. The patient was not experiencing bleeding or petechiae a month later, but she was still receiving 50 mg. of cortisone daily. Relapse After Splenectomy, with Spontaneous Recovery. The condition of only one patient would be suitable for this category, and his clinical picture was somewhat atypical, since there was some reduction in megakaryocytes in the aspirated bone marrow. He was 63 years old, and had experienced some degree of purpura and epistaxis over an 18-month period. He had a malignant lesion of his hand secondary to irradiation. The platelet count increased from 25,000 to 130,000 after splenectomy and an operation for the lesion on his hand had been accomplished satisfactorily. Within a month the number of platelets had returned to the figure obtaining before splenectomy, and there was a recurrence of petechiae and some degree of epistaxis. The administration of 100 mg. of cortisone daily for 10 days did not ameliorate the bleeding or increase the platelet count. We have heard from this patient, who is a physician, on two occasions since he was dismissed: once 10 months postoperatively and once 3Y2 years postoperatively. On both occasions he was well and his platelet counts were normal. Failure of Splenectomy, Cortisone and Corticotropin. The condition of the final patient in this study unfortunately must be given this classification. She was a woman 29 years old who said that purpura had been present for 2 years, with episodes of epistaxis and menorrhagia. When she was first seen by us this patient also was experiencing gingival bleeding. She did not improve after splenectomy, and cortisone administered in a dose of 50 mg. every (3 hours, or 60 to 80 mg. of ACTH administered daily, seemed to have little effect. Blood was administered to her a total of 91 times. A report from the hospital in which she died indicated that
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death was caused by a cercbral hemorrhage, and that no accessory spleens could be found. SUMMARY
The records of 50 adult patients who received the diagnosis of idiopathic thrombocytopenic purpura and who were seen at the Mayo Clinic during a 3-year period have been reviewed. Only two patients had acute idiopathic thrombocytopenic purpura, and one died after splenectomy preceded by a cerebral hemorrhage. Forty-eight patients had chronic idiopathic thrombocytopenic purpura. The ratio of females to males was 2: 1. Nine patients in this group did not undergo splenectomy. Five of the nine obtained spontaneous remissions, two had symptoms which were not severe and were observed for several years, during which thrombocytopenia persisted, and two obtained remissions after steroid therapy. The initial treatment of 19 patients was the use of steroids, but these 19 subsequently underwent splenectomy. In some instances the dose of steroids was too small. No patient received doses as large as those used by Bethell and his associates. Thirteen patients, however, received doses of 100 to 200 mg. of cortisone or 80 units of corticotropin daily. In this particular group reduction of bleeding, with or without an increase in platelets, was oh served in 12, but relapse ensued when treatment was stopped. When splenectomy was carried out in this group of 19 patients, 13 achieved satisfactory clinical and hematologic responses. Two failed to gain any increase in platelets, but suhsequently they were well, perhaps as a result of spontaneous remissions. Two patients obtained clinical improvement and an increase in platelets after splenectomy, but relapse supervened 2 months later. The condition of one of the two was controlled by means of steroid therapy postoperatively, whereas the other died 9 months postoperatively. Of the other patients for whom treatment did not avail, onc died 3 weeks and one 4 months postoperatively. The initial treatment of 20 patients was splenectomy. Fourteen of these responded well and required no other treatment. One achieved an initial response, but thrombocytopenia and hleeding recurred after a month. A suhsequent remission seemed to be spontaneous. The condition of four patients did not respond to splenectomy, but did respond to steroids admil!istered postoperatively. One patient obtained no improvement from either splenectomy or steroids, and died several months postoperatively. It is an estahlished fact that steroid therapy is an important part of the management of many patients who have idiopathic thrombocytopenic purpura. For many patients with the chronic: form of the disease, however, splenectomy is the treatment most likely to"'succeed. Nevertheless, there are still no criteria available whereby the~physician can be assured that any specific program of treatment will result in cure of the disease for a given patient.
Donald C. Campbell
1196 REFERENCES
1. Bethell, F. H.: Blood Diseases and Malignancy. In Lukens, F. D. W.: Medical Uses of Cortisone: Including Hydrocortisone and Corticotropin. New York. The Blakiston Company, 1954, pp. 464~492. 2. Clement, D. H. and Diamond. L. K.: Purpura in Infants and Children: Its Natural History. A.M.A. Am. J. Dis. Child. 85:259~27S (March) 1953. 3. Diggs, L. W. and Hewlett, J. S.: Study of Bone Marrow from Thirty-six Patients with Idiopathic Hemorrhagic (Thrombopenic) Purpura. Blood. 3:1090~1104 (Oct.) 1948. 4. Lozner, E. L.: Thrombocytopenic Purpuras. Bull. New York Acad. Med. 30:1S4~ 194 (March) 1954. 5. Meyers, Muriel C., Miller, Stanley and Bethell, F. H.: Administration of ACTH in Hypersplenic Syndromes (Abstr.) ..T. Lab. & Clin. Med. 36:965~966 (Dec.) 1950. 6. Robson, H. N. and Duthie, J. J. R.: Capillary Resistance and Adrenocortical Activity. Brit. M. J. 2:971~977 (Oct. 2S) 1950. 7. Stefanini, Mario: Management of Thrombocytopenic States. A.M.A. Arch. Int. Med. 95:543~556 (April) 1955. S. Stefanini, Mario and Dameshek, William: Hemorrhagic Disorders: Clinical and Therapeutic Approach. New York, Grune & Stratton, Inc., 1955, pp. S8-142. 9. Stroebel, C. F., Campbell, D. C. and Hagedorn, A. B.: Problem of Essential Thrombocytopenic Purpura. M. Cr,rN. NORTH AMERICA. 33:1027-1046 (July) 1949.
A NUMBER of classifications of the thrombocytopenic purpuras have been used by various workers in the field. One of the broadest utilizes the status of the megakaryocytes as determined by aspiration of bone marrow, and separates the group into amegakaryocytic and megakaryocytic. Thrombocytopenia caused by failure of bone marrow, such as occurs in aplastic anemia, or caused by invasion of the bone marrow, such as occurs in leukemia or lymphoblastoma, is associated with reduced numbers of megakaryocytes and is classified as "amegakaryocytic." In idiopathic thrombocytopenia, on the other hand, the megakaryocytes usually are present in normal or increased numbers; hence, this form is included in the megakaryocytic group. Other types of thrombocytopenia also are included in this megakaryocytic category. They include those consequent to the use of certain drugs, such as quinine and sedative agents (Sedormid), and those which are associated with a number of disease states, some of which are acute exanthemas, sarcoidosis and disseminated lupus erythematosus. Establishment of the diagnosis of idiopatbic thrombocytopenic purpura must be accomplished by exclusion of known etiologic conditions in this megakaryocytic group. TYPICAL OBSERVATIONS
When it has been established that the condition of the patient is in the category of id:opathic thrombocytopenic purpura, certain findings will be expected to be present. The peripheral blood, of course, will be characterized by thrombocytopenia. Examination of the bone marrow ordinarily will show a normal or increased number of megakaryocytes. As a rule, it will be noted that there is little platelet formation, and in some instances there may be many degenerative changes in the megakaryocytes. Sometimes an increase will be noted in the less mature forms of megakaryocytes. It should be mentioned, however, that some hematologists feel that the chief contribution of examination of the bone marrow in this group is to exclude leukemia and aplastic anemia. Diggs and Hewlett, in a study of the bone marrow of 36 patients with idiopathic thrombo1187
Donald C. Campbell
1188
cytopenic purpura, found no correlation between (1) the number of megakaryocytes in smears of marrow during the acute phase of the disease, and (2) the prognosis, whether or not splenectomy was done. Splenomegaly probably will not be present, although there are occasional exceptions to this. Generally, a tourniquet test will demonstrate an increase in capillary fragility. The bleeding time usually will be prolonged, but the coagulation time will be normal. There is a wide variation in the clinical manifestations in this group of patients. Some complain only of easy bruising or spontaneous ecchymosis. Others display these signs in addition to generalized petechiae and frank bleeding. Unfortunately, the response of these patients to various therapeutic programs also exhibits a wide variability, and efforts to predict the final outcome in any patient have not been successful. PREVIOUS STUDIES
In 1949 several of us reported our experience in a study of 150 patients who had idiopathic thrombocytopenic purpura. 9 In this group 59 of the adult patients were treated with splenectomy, and 84.7 per cent of them obtained a satisfactory immediate response. Steroid therapy was not available at the time of this study, but both cortisone and corticotropin have been widely used in recent years in the management of patients with idiopathic thrombocytopenic purpura. In an effort to evaluate our experience with steroid therapy in this condition, we have reviewed the records of the patients for whom this diagnosis was made during the years 1952 through 1954. In a few instances a given patient also had been seen by us at an earlier date, so that occasionally the total period of observation actually is more than 3 years. TWO FORMS OF THE DISEASE
Much has been written about the separation of idiopathic thrombocytopenic purpura into the acute and ehronic types. Persons who have the aeute type are predominantly children. In them the onset of bleeding into the skin and from mucous membranes is acute. In many instances a history of preceding infection can be obtained. Our experience with this category is limited, and among the 50 adult persons seen during the past 3 years there were only two who were classified as having the acute type of disease. Except to describe these two patients briefly, we shall not discuss our experience with acute idiopathic thrombocytopenic purpura in this paper. Physicians with a wide experience in the management of patients who have acute idiopathic thrombocytopenic purpura have, however, emphasized that it is very often a self-limited disease, and their program of management has been to keep the patient at complete rest in bed, to treat the infection, when it was present, to administer steroids when the condition was sufficiently severe, and to observe. Clement and Diamond, in their report involving a group of 96 children, noted that 38
Idiopathic Thrombocytopenic Purpura in Adults
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were symptom-free within 6 weeks after the onset of their illness. All of these 38 children were classified as having acute thrombocytopenic purpura. Our study is predominantly that of chronic idiopathic thrombocytopenic purpura. Since it is based upon the study of patients seen within a recent 3-year period, we have not been able to obtain protracted followup information in many instances, but we have obtained some follow-up data in 46 cases. We know that occasionally persons who apparently achieve an excellent result after splenectomy will experience a recurrence of thrombocytopenic purpura several years later. STEROID THERAPY
Observations on the response of patients with idiopathic thrombocytopenia to steroid therapy were made as early as 1950 by Robson and Duthie and by Meyers, Miller and Bethell. Most physicians who have been interested in this problem have noticed that often there is an improvement in the vascular component of this disease without a corresponding increase in thrombocytes. Lozner has discussed his experience with patients who had idiopathic thrombocytopenic purpura. He found that after hormonal treatment most patients obtained complete remission of the increased capillary fragility, whereas perhaps only half obtained satisfactory remission of thrombocytopenia. After discontinuance of hormone therapy, both the capillary fragility and the thrombocytopenia usually quickly return to previous abnormal states. Bethell's results with cortisone or corticotropin among such patients have been more favorable. He and his colleagues observed 23 patients who were so treated, and complete clinical and hematologic remissions were achieved for all but seven. The remissions of nine of the patients were sustained for 6 to 40 months. Bethell and his associates used cortisone in a dose of 300 mg., generally given orally and in fractional doses of 75 mg. every 6 hours. When they used corticotropin the dose as a rule was 25 units, administered intramuscularly every 6)ours. Stefanini and Dameshek in general used smaller doses of cortisone and corticotropin than did Bethell. They wrote that in their experience sustained increases in platelets were exceptional, although they were impressed with the manner in which the agent produced prompt and effective control of the bleeding manifestations of the disease. They did point out, however, the possibility that larger doses of the hormone might be more effective in producing sustained remissions. TRANSFUSION OF PLATELETS
Before any discussion of the results of therapy with cortisone, corticotropin and splenectomy among the patients whose records we have recently reviewed, a word should be said about the transfusion of platelets. Much work has been done in the development of this technique and
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Donald C. Camp bell
Stefanini, who has contributed much information to this field, has emphasized some of the practical difficulties encountered in the preparation and supply of platelet suspensions. Stefanini believes that the transfusion of platelets should be limited to those patients in whom control of bleeding cannot be accomplished by any other measure. In general, the transfusion of platelets or of platelet-rich blood with the use of special techniques, such as entire plastic systems or a system made water-repellent by coating it with silicone, is most effective against the amegakaryocytic type of thrombocytopenic purpura. In idiopathic thrombocytopenic purpura a platelet-destructive mechanism often is present, which means that transfused platelets would be much less effective. It is not feasible to try to control bleeding over any extended period by means of transfusion of platelets, and the chief use of that measure in idiopathic thrombocytopenic purpura is to attempt to control severe bleeding or to prepare a patient for splenectomy. Platelet transfusion was not employed for any of the patients whom we are discussing. SALIENT FEATURES OF PRESENT STUDY
Of the 50 patients 16 years of age or older whom we are including in this study, 34 were females and 16 were males. The incidence according to sex, with a predominance of females, has been noted in most similar studies. Only two patients of this group had acute idiopathic thrombocytopenia, and 21 of the group gave a history of purpura that antedated treatment with either steroids or splenectomy by at least a year. Five of the group (four females and one male) experienced spontaneous remissions. Two (one female and one male) were having minimal hemorrhagic manifestations and, because of other medical problems, were not treated for the hematologic disorder. Both were seen 3 years later and, although their platelet counts were still less than 50,000, neither had experienced difficulties secondary to the thrombocytopenia. The remaining 41 patients (all of whom had chronic idiopathic thrombocytopenia) were treated with one of the steroid preparations or splenectomy or both. ACUTE IDIOPATHIC THROMBOCYTOPENIC PURPURA
Both of the patients classified as having acute idiopathic thrombo:. cytopenic purpura were treated with splenectomy and without steroids. Ordinarily, steroid therapy would be considered for patients in this group but there were reasons for not using it when we saw these patients early in 1952. One was a young man 17 years old whose purpura and epistaxis were severe and had been present for less than a week. The response of the platelets after splenectomy was slow; they increased from 10,000 to 94,000 on the Iilixth postoperative day. Gradual reduction of the platelet count followed, but tliere was no bleeding. Two months after splenectomy the patient had a cerebral hemorrhage, and when he returned to the Clinic his platelet count was 33,000. He improved spontaneously,
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however, and a month later his platelet count was 123,000. Four months later the count was 284,000. His father wrote that the son was entirely well 472 years postoperatively. The other patient who had idiopathic thrombocytopenic purpura classified as acute was a woman 22 years old. Within a few hours after she had been admitted to the hospital she had a cerebral hemorrhage and became stuporous. As soon as the diagnosis of idiopathic thrombocytopenic purpura had been established, it was decided to do splenectomy. Unfortunately, the patient never regained consciousness, and died 6 hours postoperatively. CHRONIC IDIOPATHIC THROMBOCYTIC PURPURA
Initial TreatIllent with Steroids
Twenty-one patients received cortisone or corticotropin as their initial therapy. Nineteen of these 21 subsequently underwent splenectomy. Results in this group can be listed in five rather general categories. Complete and Sustained Remissions. Two of these 21 patients apparently obtained complete and sustained remissions after steroid therapy alone. One of them was a man 52 years old who had experienced recurrent purpura, gingival bleeding and epistaxis for 6 months. When he took 25 mg. of corticotropin every 6 hours for 2 months, his symptoms completely subsided and his platelet count increased from 25,000 to 433,000. He did experience further difficulty 8 months later, with some degree of gingival bleeding, and the number of platelets decreased to 70,000. He then received 25 mg. of cortisone twice daily, and his symptoms subsided within 48 hours, and the number of platelets increased to 182,000. He was entirely well, without having received additional therapy, 10 months later. The other patient, a woman 31 years old, was treated by her family physician with 75 mg. of hydrocortisone daily. She was well, and her platelet count had increased from 23,000 to 138,000, 5 months after the treatment had been discontinued. It is, of course, impossible to know whether or not these persons experienced spontaneous remissions. It can be said only that remissions followed steroid therapy. No Response to Steroid Therapy. Three of the 21 patients seemed to show no response to steroid therapy. Our data in one instance are entirely inadequate, for we do not know the dose of cortisone that was administered at home. The physician of this patient did report that the patient failed to respond. The patient was a 54-year-old woman with a history of some degree of purpura and epistaxis that had been present for 15 months. She obtained an excellent result from splenectomy, and was well 3Yz months later. Another woman, 49 years old, failed to show any response, but she had been receiving only 37.5 mg. of cortisone daily. She had received this dose of cortisone for 2 months before we saw her. She gave a history of
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purpura that had been present for a year, and she obtained an excellent immediate response from splenectomy. We were unable to obtain any follow-up information. The third patient was a man 57 years old who said that purpura and epistaxis had been present in varying degrees for a year, but that more bleeding had occurred during the month preceding his admission to the Clinic. He did not improve, and there was no response, in respect to platelets, to the administration of 25 units of ACTH every 6 hours for 2 weeks. Moreover, he did not improve after splenectomy. He received 200 mg. of cortisone daily during the postoperative period, and this measure at first seemed to reduce the bleeding, but he died 3 weeks postoperatively in the presence of a generalized hemorrhagic picture. ~ Control of Bleeding and Platelet Response, but with Relapse When Treatment was Discontinued. Five of these 21 patients obtained responses from the standpoint of increases in platelets and complete control of bleeding. Two received 200 mg. of cortisone daily, two received 100 mg. of cortisone daily, and one received 80 units of ACTH daily. All experienced a relapse each time treatment was discontinued, and all underwent splenectomy. The four patients previously treated with cortisone responded well to splenectomy. The single patient who had obtained a favorable response from ACTH achieved a good immediate response from splenectomy, but relapse intervened 2 months later. The bleeding at that time was controlled with additional steroid therapy. She was clinically well 331 years postoperatively, but the platelet counts remained low. She was not receiving steroid therapy at the time of our last report. Control of Bleeding but Lack of Platelet Response. Eight of these 21 patients achieved control of the purpura and bleeding, but there was no increase in the platelet counts. Three of them received a daily dose of 200 mg. of cortisone, one received 150 mg. daily, three received 100 mg. daily, and one received 75 mg. daily. All underwent splenectomy, and the results were satisfactory for six patients. Two patients did not respond favorably to splenectomy. The first patient who did not respond to splenectomy was a man 76 years old who had failed to respond to a dose of 100 mg. of cortisone daily. His condition was chronic, with the presence of petechiae and bleeding for 131 years. The bleeding had increased during the month prior to his admission to the Clinic, and he had noted melena of some degree. Splenectomy was carried out, with a satisfactory immediate response, but with a relapse 2 months later. His physician wrote that this patient died 9 months postoperatively. The cause of death was not determined. The other patient who did not respond favorably to splenectomy was a man 65 years old who had been receiving a daily dose of 75 mg. of cortisone at home. This medication had not increased his platelet count, but it had controlled bleeding for 6 months. At the end of that time he
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began to notice more petechiae, and some gross bleeding. Splenectomy was carried out, but it did not abate his symptoms. Bleeding was well controlled during the postoperative period by means of 100 mg. of cortisone administered daily. The patient died 4 months postoperatively, however, of a cerebral hemorrhage. Steroid Therapy at Home, with Reduction of Bleeding but Inadequate Data as to Steroid Dosage. Three other patients in this group of 21 had received steroid therapy at home, and we could not be sure of either the dosage or the platelet counts. Each of them felt that the bleeding and purpuric manifestations had been ameliorated by the use of steroids. A man 57 years old had obtained complete relief after each of eight courses of cortisone, only to have petechiae and epistaxis recur when the use of the agent was stopped. The platelet count failed to increase after splenectomy, but he did not have any symptoms of hemorrhage. Reports have been received from his physician 7 months and 2 years postoperatively. In each report it was said that the patient was well and that his platelet count was normal. The second patient in this group was a woman 26 years old who had been treated for 3 months with varying doses of ACTH. Control of bleeding had been incomplete and it was said that the platelets failed to increase. When we saw her, the platelet count was 19,000, and the patient had recently noted hematuria. She had experienced little difficulty with bleeding after splenectomy, but the platelet count failed to increase. She received no medication postoperatively, and her physician 8 months later wrote that she was well, and that her platelet count was normal. The third patient of this group was a woman 25 years old who obtained an excellent immediate postoperative response to splenectomy, but concerning whom we have not been able to get follow-up information. Initial Treatment with Splenectomy
Twenty patients with chronic idiopathic thrombocytopenic purpura were treated with splenectomy as an initial procedure. This group also can be subdivided according to the results of therapy. Satisfactory Clinical and H ematologic Response. Fourteen patients (11 females and 3 males) obtained satisfactory postoperative responses and did not require any other treatment. We were not able to obtain followup information about two patients in this group of 14, but the remainder were well 3 months to 3Y2 years later. Failure of Splenectomy, but Control of Bleeding with Cortisone Postoperatively. The condition of four patients agrees with this category in varying degrees: Two of them were first seen by us after splenectomy had been carried out at home. Both of these patients, a woman 23 years old and a man 54 years old, were maintained by means of cortisone administered periodi-
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cally during the postoperative period, and they were progressing satisfactorily when last seen 3 years after splenectomy. A third patient in this group was a man 48 years old whose condition failed to respond to splenectomy but whose episodes of bleeding postoperatively were controlled satisfactorily with cortisone during a followup period of 22 months. The fourth patient was a woman 18 years old. She said that petechiae and easy bruising had been noted since the age of 5 years, and that menorrhagia had developed after menstruation started. The status of the bone marrow was typical, and moderate eosinophilia was detected in the marrow. At the time of operation, however, a number of granulomas were found in the spleen, suggesting that the thrombocytopenia may have been secondary to some chronic disease. The condition of this patient did not respond to splenectomy, and petechiae and vaginal bleeding recurred over the next 4 years. In 1954 the bleeding was controlled by the administration of 50 mg. of cortisone daily, and hysterectomy was performed. The patient was not experiencing bleeding or petechiae a month later, but she was still receiving 50 mg. of cortisone daily. Relapse After Splenectomy, with Spontaneous Recovery. The condition of only one patient would be suitable for this category, and his clinical picture was somewhat atypical, since there was some reduction in megakaryocytes in the aspirated bone marrow. He was 63 years old, and had experienced some degree of purpura and epistaxis over an 18-month period. He had a malignant lesion of his hand secondary to irradiation. The platelet count increased from 25,000 to 130,000 after splenectomy and an operation for the lesion on his hand had been accomplished satisfactorily. Within a month the number of platelets had returned to the figure obtaining before splenectomy, and there was a recurrence of petechiae and some degree of epistaxis. The administration of 100 mg. of cortisone daily for 10 days did not ameliorate the bleeding or increase the platelet count. We have heard from this patient, who is a physician, on two occasions since he was dismissed: once 10 months postoperatively and once 3Y2 years postoperatively. On both occasions he was well and his platelet counts were normal. Failure of Splenectomy, Cortisone and Corticotropin. The condition of the final patient in this study unfortunately must be given this classification. She was a woman 29 years old who said that purpura had been present for 2 years, with episodes of epistaxis and menorrhagia. When she was first seen by us this patient also was experiencing gingival bleeding. She did not improve after splenectomy, and cortisone administered in a dose of 50 mg. every (3 hours, or 60 to 80 mg. of ACTH administered daily, seemed to have little effect. Blood was administered to her a total of 91 times. A report from the hospital in which she died indicated that
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death was caused by a cercbral hemorrhage, and that no accessory spleens could be found. SUMMARY
The records of 50 adult patients who received the diagnosis of idiopathic thrombocytopenic purpura and who were seen at the Mayo Clinic during a 3-year period have been reviewed. Only two patients had acute idiopathic thrombocytopenic purpura, and one died after splenectomy preceded by a cerebral hemorrhage. Forty-eight patients had chronic idiopathic thrombocytopenic purpura. The ratio of females to males was 2: 1. Nine patients in this group did not undergo splenectomy. Five of the nine obtained spontaneous remissions, two had symptoms which were not severe and were observed for several years, during which thrombocytopenia persisted, and two obtained remissions after steroid therapy. The initial treatment of 19 patients was the use of steroids, but these 19 subsequently underwent splenectomy. In some instances the dose of steroids was too small. No patient received doses as large as those used by Bethell and his associates. Thirteen patients, however, received doses of 100 to 200 mg. of cortisone or 80 units of corticotropin daily. In this particular group reduction of bleeding, with or without an increase in platelets, was oh served in 12, but relapse ensued when treatment was stopped. When splenectomy was carried out in this group of 19 patients, 13 achieved satisfactory clinical and hematologic responses. Two failed to gain any increase in platelets, but suhsequently they were well, perhaps as a result of spontaneous remissions. Two patients obtained clinical improvement and an increase in platelets after splenectomy, but relapse supervened 2 months later. The condition of one of the two was controlled by means of steroid therapy postoperatively, whereas the other died 9 months postoperatively. Of the other patients for whom treatment did not avail, onc died 3 weeks and one 4 months postoperatively. The initial treatment of 20 patients was splenectomy. Fourteen of these responded well and required no other treatment. One achieved an initial response, but thrombocytopenia and hleeding recurred after a month. A suhsequent remission seemed to be spontaneous. The condition of four patients did not respond to splenectomy, but did respond to steroids admil!istered postoperatively. One patient obtained no improvement from either splenectomy or steroids, and died several months postoperatively. It is an estahlished fact that steroid therapy is an important part of the management of many patients who have idiopathic thrombocytopenic purpura. For many patients with the chronic: form of the disease, however, splenectomy is the treatment most likely to"'succeed. Nevertheless, there are still no criteria available whereby the~physician can be assured that any specific program of treatment will result in cure of the disease for a given patient.
Donald C. Campbell
1196 REFERENCES
1. Bethell, F. H.: Blood Diseases and Malignancy. In Lukens, F. D. W.: Medical Uses of Cortisone: Including Hydrocortisone and Corticotropin. New York. The Blakiston Company, 1954, pp. 464~492. 2. Clement, D. H. and Diamond. L. K.: Purpura in Infants and Children: Its Natural History. A.M.A. Am. J. Dis. Child. 85:259~27S (March) 1953. 3. Diggs, L. W. and Hewlett, J. S.: Study of Bone Marrow from Thirty-six Patients with Idiopathic Hemorrhagic (Thrombopenic) Purpura. Blood. 3:1090~1104 (Oct.) 1948. 4. Lozner, E. L.: Thrombocytopenic Purpuras. Bull. New York Acad. Med. 30:1S4~ 194 (March) 1954. 5. Meyers, Muriel C., Miller, Stanley and Bethell, F. H.: Administration of ACTH in Hypersplenic Syndromes (Abstr.) ..T. Lab. & Clin. Med. 36:965~966 (Dec.) 1950. 6. Robson, H. N. and Duthie, J. J. R.: Capillary Resistance and Adrenocortical Activity. Brit. M. J. 2:971~977 (Oct. 2S) 1950. 7. Stefanini, Mario: Management of Thrombocytopenic States. A.M.A. Arch. Int. Med. 95:543~556 (April) 1955. S. Stefanini, Mario and Dameshek, William: Hemorrhagic Disorders: Clinical and Therapeutic Approach. New York, Grune & Stratton, Inc., 1955, pp. S8-142. 9. Stroebel, C. F., Campbell, D. C. and Hagedorn, A. B.: Problem of Essential Thrombocytopenic Purpura. M. Cr,rN. NORTH AMERICA. 33:1027-1046 (July) 1949.