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Therapeutic considerations in childhood idiopathic thrombocytopenic purpura
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T H E R A P E U T I C CONSIDERATIONS IN C H I L D H O O D IDIOPATHIC THROMBOCYTOPENIC PURPURA Authors:
Russell Ware Thomas R. Kinney Division of Hematology/Ontology Department of Pediatrics Duke University Medical Center Durham, North Carolina
Referee:
Campbell W, McMillan Department of Pedlatr[cs Univershyof North Carolina School of Medicine;and North Carolln~,Memorial Hospital Chapel Hill, North Carolina
I. INTRODUCTION Idiopathic thrombocytopenic purpura (ITP) in childhood is characterized by isolated thrombocytopenia, normal to increased numbers of megakaryocytes on bone marrow aspirate, and absence of other etiologies such as connective-tissue disease, sepsis, disseminated intravascular coagulation, drug reaction, and malignancy. In ITP, the thrombocytopenia is immune-medlated; platelets are sensitized by antibody, complement, and/or immune complexes and are destroyed by the reticuloendothelial system (RES). In children, 1TP generally follows one of three clinical courses: acute, chronic, or acute recurrent. Morbidity from ITP arises from the tendency to bleed. Bleeding into the gastrointestinal tract occurs in 2 to 8% of patients, hematuria in
2. 3.
Reducethe incidence and/or mortality of ICH. This goal is difficult to assess in a clinical trial, because of the low incidence of ICH. Assuming an incidence of 1% for ICH in childhood ITP, approximately 14,000 patients would have to enter a randomized trial in order to detect a 50% reduction in the incidence of ICH. ~ Shorten the disease course of acute 1TP. This is a self-limited illness, but therapy could minimize the duration of thrombocytopenia and hemorrhagic symptoms. Induce remission in chronic ITP. There are several therapeutic choices for chronic ITP, with varying efficacy and side effects. The risk/benefit ratio for any therapy must be assessed for each patient.
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In a previous monograph, the clinical course and pathophysiology of childhood ITP have been discussed.' In this monograph, current therapy for acute and chronic ITP is described. Efficacy, mechanisms of action, and side effects of corticosteroids, splcnectomy, and intravenous immunoglobulin (1Ylg) will be presented. Next, alternative therapeutic modalities will be mentioned. Finally, guidelines for the management of a child with ITP will be presented. II. C O R T I C O S T E R O I D S A. Efficacy The use of corticosteroids in acute childhood ITP is an area of intense controversy. Until recently, all clinical studies were flawed because they were retrospective, involved small patient numbers, and/or had nonrandom treatment regimens. The first well designed study was by MeWilliams and Maurer,' in which 13 children were randomized to receive either Preduisone 2 mg/kg/day orally for 3 weeks or no corticosteroid therapy. They showed that the median time to normalization of platelet count was significantly shorter in the treated group. In a recently published larger trial from Europe,' 73 children were randomized to receive either Prednisolone 60 mg/m2/day orally for 3 weeks or placebo. The treated group had significantly shorter duration of platelet counts less than 30 x 10"/1 and platelet counts less than I00 x 109/1 as well as a shorter duration of a prolonged bleeding time. These data suggest that corticosteroids accelerated the rise in platelet count and improved the capillary resistance. Both of these effects would decrease hemorrhagic symptoms. The opposite viewpoint is championed by Lusher and co-workers. ~'9 They reported that in 465 consecutive cases of childhood ITP, no child less than 13 years old has ever had an ICH. In addition, their study of corticosteroid usage suggests that r,orticosteroids slightly prolonged the duration of thrombocytopenia and could cause rebound or withdrawal thrombocytopenia. A recent controlled prospective study by Buchanan et al.'~ failed to show a significant benefit from Prednisone therapy. The efficacy of corticosteroid therapy in chronic ITP is well accepted. T M The response rate of chronic ITP to corticosteroids has been estimated to be 50% .'~ Despite an initial response with normalization of platelet count, rarely can this remission be sustained off therapy. Low-dose therapy, even alternate-day therapy, however, may be adequate to maintain hemostasis. Only if the hemorrhagic symptoms continue or the side effects of corticosteroids become intolerable, should other therapies be considered. B. Mechanisms of Action Even though there is an abundance of literature on the Use of corticosteroids in childhood ITP, the precise mechanisms of action are not fully understood. The data show that corticosteroids have many effects upon the immune system, several of which may be important in ITP. At present, there appears to be at least four possible mechanisms by which corticosteroids act in the treatment of ITP. I. Decreased Binding of Antibody to Platelets Thi~ effect can be shown best if platdet-associated l e g (PAIgG) levels are measured before and during corticosteroid therapy. Data supporting this mechanism of action first appeared in the paper of Dixon, Rosse, and Ebbed," in which the first quantitative antiglobulin consumption (QAC) assay for PAIgG was described. They showed that response to corticosteroids was associated with a decrease in direct PAIgG, but correlation with indirect or serum PAIgG was poor. This effect was not immediate,
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FIGURE 1. Seria]platelet counts and PAlgG levelsin a patient with acute ITP. for both the rise in platelet count and fall in direct PAIgG took several weeks. A change in antibody production could explain these findings as well. The same laboratory carefully studied a 15-year-old male with acute ITP, using serial blood samples during treatment with corticosteroids. 's The data on this patient are shown in Figure I. The direct PAIgG, representing IgG on the platelet surface, returned to normal by 2 weeks. The indirect or serum PAIgG level transiently rose before returning to normal. The platelet count rose to 50 x 109/1 by 2 weeks, and was normal by 4 weeks. This anecdotal report suggests that the effect of corticosteroids on autoantibody binding is fairly rapid. It is tempting to postulate that the costicosteroids release the IgG from the platelet surface, causing the temporary rise in the indirect (serum) PAIgG level. Serial measurement of direct and indirect PAIgG, using an accurate direct-labeled assay, needs to be done on a group of patients before, during, and aft~,'r therapy with eorticosteroids. Only then can the effect of corticosteroids on antibody binding to the platelet surface be elucidated. 2. Decreased Platelet Phagocytosis by the R E S
The recognition and ingestion of sensitized platelets by phagocytosis is a major aspect of clearance in childhood [TP. The theory that cnrticosternid therapy interferes with RES clearance is supported by several studies. Over 30 years ago, Harrington and co-workers demonstrated that infusion of plasma from patients with ITP will cause thromboeytopenia in normal recipients. 's" Over a decade later, Shulman verified this finding, '~ but then modified the experiment. When the volunteers were given corticosteroids prior to the infusion, the resulting thrombocytopenia was partially inhibited. This protective effect of corticosteroids was the same if given 3 days or 3 hr before infusion the ITP plasma, but continued administration was necessary to assure effectiveness. If corticosteroids were stopped 1 or 2 days after the infusion of ITP plasma, thrombocytopenia would occur. Because splenectomized
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individuals did not develop thromboeytopenia from transfusion of plasma from patients with ITP, the protection afforded by eotticosteroids seen in normal volunteers was attributed to interference with RES clearance. In 1974, Branehog and Weinfeld .2 used platelet-labeling techniques to show that the piatelet life span in patients with ITP is prolonged after corticosteroids are instituted. The proposed mechanism is a change in RES clearance, specifically by altering the spleen/liver clearance ratio. That same year, MeMillan et al.*l described an in vitro assay using splenic leukocytes to phagoeytose normal platelets. They found that splenic leukocytes from patients with resistant ITP were more phagocytic than those from patients with ITP sensitive to corticosteroids or from normal controls. They postulated that the corticosteroids affect the ability of the splenic leukocytes to phagocytose platelets. Handin and Stossel" used another in vitro test to study the effects of cortleosteroids. Their assay measured phagocytosis of antibody coated platelets by peripheral lenkocytes. High-dose corticostcroids decreased the ability of peripheral blood monoeytes and granulocytes to phagocytose sensitized platelets, either by affecting the number or the affinity of leukocyte Fc receptors.
3. Altered Vascular Permeability and Improved Capillary Integrity Without platelets to repair microvaseular injury, thrombocytopenic patients have easy bruisability and spontaneous petechiae and purpura. In addition to vascular repair, however, platelets somehow support the integrity of the vascular endothelium. '~ Thrombocytopenia from irradiation, immune destruction, or chemotherapy results in well documented changes in the vascular endothelium, z~with fenestrations and microvascular thinning. Using a rabbit model, Kitchens2. has shown that corticosteroids reverse the endothelial lesions which accompany thrombocytopenia. The capillary integrity and therefore hemostasis may therefore be improved. Similarly, Senyi and co-workers22 have reported that corticosteroids improve the bleeding times of thrombocytopcnlc rabbits. It is unclear at this time whether or not these findings are applicable to childhood ITP or human thromboeytopeqia in general. g. Decreased Autoantlbody Production This mechanism of action could account for the long-term remissions that are observed with chronic eorticosteroid use. There are several reports which support this proposed effect. In 1973, Butler and Rossen2'." used normal human volunteers to show that a brief course of methylprednisolone caused a signficaat decrease in serum igG. In their study, the nadir occurred in the 3rd week following therapy. Clearance of radiolabeled IgG suggested that this decrease was largely attributable to decreased synthesis of leG, and not increased catabolism. They found that corticosteroids had no affect upon the ability to mount a primary or secondary antibody response to antigens given during the drug-treatment period, but did seem to inhibit ongoing antibody synthesis. These findings support the idea that cortieosteroids can change specific antibody production. Soon after, MeMillan r al) g studied the effects of eorticosteroids on IgG synthesis in patients with lTD. Using bone marrow and splenic tissue from these patients, they showed that splenic production of IgG was not affected by corticosteroids, but the larger mari-ow production was greatly decreased. Marrow IgG production began to decrease 3 weeks after starting corticosteroid therapy and reached 25~ of pretreatment production rates after 6 weeks. They hypothesized that the corticosteroids affect a lymphocyticeffector ceil important for the normal marrow humoral immune response.
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Table 1 SIDE EFFECTS RESULTING FROM CORTiCOSTEROID USE Fluid and electrolytes Sodium retention/waterretention Hypokalcmicalkalosis Hyperglycemia G~strointestinal Pancreatitis Felatic ulceration Masculoskeletal Osteoporosis Myo0athy Growthsuppression Skin Cutaneous thinning Ecehymoses Ache Hirsutism
Cushing's Habitus "Moon face" "Buffaio hump" Supraclar fat pads Trunca] obesity Striae CiqS Psychosis Psychiatricdisturbances Hematological
Hypercoagulabillty Miscellaneous Increasedrisk of infection Hypertension Cataracts
C. Dose A typical initial corticosteroid preparation and dose prescribed for childhood ITP is Prednisone,'2,mg/kg/day (maximum 60 mg daily) orally for 3 weeks. The Prednisone is gradually discontinued over I to 2 additional weeks. There are no data to justify longer therapy for treatment of acute ITP. If the thrombocytopenia recurs and is accompanied by significant bleeding, Prednisone may be reinstituted at the lowest possible dose to minimize bleeding if the thrombocytopenia is responsive to steroids. If prolonged steroid therapy is required, attempts should be made to utilize an alternateday schedule to reduce side effects. D. Side Effects The iist of side effects from corsticosteroids is long, and includes mineraio- and glucocorticoid effects. Most of the side effects are related to the dose, frequency, and duration of therapy. The principal complications resulting from corticosteroid use are listed in Table 1.26 Ili. S P L E N E C T O M Y A. Introduction The majority of children diagnosed with ITP will achieve normal platelet count within a few months of diagnosis. In the small percentage of children who remain thrombocytopenic, become corticosteroid dependent, or have life-threatening hemorrhagic symptoms, splenectomy is usually recommended. The spleen is a significant source of antibody production as well as the potential site of platelet destruction in ITP. There a~'~ .~zveral reports on the use of splenectomy in childhood ITP.
B. Efficacy The actual percentage of children who willachieve normal plateletcount aftersplenectomy varies,but is usually reported to be from 55 to 88%. 2,,.',~BAnother I0 to 20070 more will have less bleeding despite persistent thrombocytopenia. The typical response to splenectomy is an immediate rise in platelet count, often within hours after surgerY~ The plg,teiet count may rise to 1000 to 2000 • 10".1"1after splenectomy. Thrombotic complications from this thrombocytosis have not been reported. Most children
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will have a relatively high platelet count (500 to 1000 x iON/I) for several weeks, which will usually return to normal values by 6 months. 2 It is difficult to predict which children will respond to splenectomy. Some authors have associated a previous response to corticosteroids with a subsequent response to splenectomy, t0,~9'3~while others do not find such a correlation. 2'z7 The precise predictive value of a response to corticosteroids is not known, but a lack of response does not contraindicate splenectomy. Theoretically, patients who have massive platelet destruction in the spleen should respond well to splenectomy. In a recent study of platelet kinetics and splenectomy in ITP, the authors used S~Cr-labeled platelets to determine the pattern of platelet sequestration. ~j They found that children and adult patients with a splenic or splenohepatic sequestration (75~ were much more likely to have a good response to splenectomy than those patients with hepatic or diffuse patterns of platelet sequestration. Studies of platelet kinetics and sequestration may be useful in predicting response to splenectomy, but at this time their efficacy has not been established. In some patients with ITP who achieve remission after splenectomy, there is recurrence of thrombocytopenia. ~2 In a retrospective study involving 177 patients (59 children) with chronic ITP who underwent splenectomy, 145 (82070)had immediate remission after surgery and 14 (8%) more achieved remission later. Of the patients in remission, 32 (200/o) had recurrence of thrombocytopenia, most frequently between 6 and 48 months postsplenectomy. Of the 32 patients with relapse, 13 had transient thrombocytopenia associated with a viral illness, and 12 had recurrence from accessory spleens found at repeat surgery. The prevalence of one or more accessory spleen is reported to be 16~ in children undergoing splenectomy) ~ These data point to the importance of searching vigorously for accessory spleens at the time of original splenectomy. C. Mechanisms of Action As previously noted, the spleen is an important site of antibody production in 1TP. Its removal is usually associated with normalization of the PAIgG level, as well as normalization of the platelet count. '~ The spleen is also an important site of platelet destruction in ITP. Its active RES, high antibody concentration, abundant platelet pool, and slow circulation provide a unique environment for platelet destruction. As the platelets slowly traverse the splenic cords, they are in prolonged contact with platelet antibody and phagocytic cells. The value of spleneetomy is therefore more than simple removal of a large RE cell population; rather it is the removal of the entire milieu conducive to platelet destruction. The small percentage of children who undergo splenectomy for ITP and do not achieve remission probably have other mechanisms or sites of platelet destruction. As noted in an earlier section, the liver, bone marrow, and other lymphoid tissue may be a site of destruction for platelets in ITP. ~.~(.a~Alternatively, as detailed in our previous monograph, platelet destruction may be mediated by complement, immune complexes, or cellular immune mechanisms? D, Side Effects The most significant danger after splenectomy results from the loss of a major part of the immune system. Beyond the morbidity and mortality of surgery, there is now awareness of an increased chance of postsplenectomy infection and sepsis. In a review of splenectomy and postsplenectomy sepsis, Dickerman ~' noted the importance of the spleen for a competent immune system. After splenectomy) patients have an increased susceptibility to sepsis from encapsulatedorganismssuch as Streptococcus pneumoniae and Haemophilus influenzae. In ~addition, splenectomy c a n
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cause impaired clearance of bacteria in the bloodstream; decreased amplified T cell function; ~' low serum lgM levels;~'~ decreased immunologic response to some antigens, including perhaps the switch from lgM to lgG synthesis;4~ and altered complement function. '~.'2 The use of the pneumococcal polysaccharide vaccine and prophylactic penicillin may reduce the risk of postsplenectomy sepsis. In an attempt to quantitate the riks of splenectomy, a nationwide survey was conducted by the surgical section of the American Academy of Pediatrics. a3 Of 1413 children who had undergone splenectomy, 765 (54%) had a hematologic disease (e.g., ITP, autoimmuue hemolytic anemia, hereditary spherocytosis) in which the spleen was the primary site of cell destruction, and 265 (18%) of the children had 1TP. The overall hospital mortality was 47 patients (3.3%), but only 4 (0.3%) died from overwhelming infection. There were three hospital deaths in the 265 children with ITP, all due to intracranial bleeding. In two, the intracranial bleeding was related to thrombocytopenia persisting after spleneetomy. Of the patients available for follow-up (541), 34 (6%) died of infection. Of these 34 deaths from sepsis, 16 were in children less than 2 years of age at splenectomy. The authors state that for patients with ITP, overalI mortality from elective sptenectomy should be < 1%. In summary, splenectomy is a very effective treatment for childhood ITP, although not invariably successful. Splenectomy should be considered successful if the platelet count achieved allows normal activity and symptomatic control, regardless of the actual number. Splenectom!, should never be considered early in the course of the disease, unless there are life-threatening hemorrhagic symptoms. Splenectomy carries the risk of postoperative infection and sepsis. This risk may be reduced by the pneumococcal vaccine, prophylactic penicillin, and heightened clinical suspicion of sepsis when the asplenic patient presents with fever. 1V. IVIg In the past few years, the use of intravenous immunoglobulin (IVIg) has become popular in the treatment of ITP. Although its true potential is not yet clear, IVig promises to be both a tool for the study of the immune system, plus a useful therapeutic modality fur autoimmune diseases including ITP. A. Efficacy In 1965, Shulman and co-workers t6 published their landmark article on the role of the RES in ITP. They studied the effects of corticosteroids on RES clearance, but also noted another form of RES inhibition, in patients with "autoerythrocyte sensitization" prior infusion of red cell stroma partially inhibited the thrombocytopenia resulting from infusion of ITP plasma. This was probably the first demonstration of RES blockade, and the authors anticipated the efficacy st RES blockade in lTP. Many years passed, however, before their foresight was realized. In 1981 ]mbach et al. '3~4 published two reports on the use of intravenous immunnglobulin (IVIg) in childhood ITP. They had been using the IVIg preparation in a group of patients with congenital or acquired agammag[obullnemia and hypogammaglobullnemia, in two such patients with severe thrombocytopc'nia, they noted a resolution of the thrombocytopenia after IVlg administration. These observations prompted the use of IVIg on a patient with refractory ITP, and the results were very impressive. In their first report on four of four children with refractory ITP, the platelet count rose to 300 to 650 x I&/! within 5 to 10 days of IVIg infusion. In two of two children with idiopathic aplastic anemia, however, there was no response. Their second report provided data on seven children with chronic or intermi:tent ITP and six with acute ITP. In all pa-
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tients the platelet count rose sharply within 5 days, but the initial resonse and subsequent course varied. Additional reports on the efficacy of IVlg in ITP quickly followed. In 1982, Fehr et al. (~ reported the use of high-dose IVIg in four adults with ITP, none of whom had undergone splenectomy. All patients had a transient rise in the platelet count within 4 to 5 days of administration, but the duration of response was much shorter than that reported in children. Bussel and co-workers4~ used IVIg on 12 consecutive children with chronic 1TP, and reported that nine had responses which postponed splenectomy. Of these nine with good responses, four required booster doses of [VIg every 4 to 10 weeks, while five required no further therapy. In 1983, literature appeared on the use of IVlg for "neonatal I T P " , 47-~~which is congenital thrombocytopenia in an infant born to a mother with ITP, secondary to transplacental passage of platelet antibodies. The benefits of ante- and postnatal IVIg were reported. In the largest series reported to date, Uchino eta[. ~j reported the use of high-dose IVlg in 177 cases of ITP with 102 children and 75 adults. Overall, 87% of the patients had a rise in platelet count during the first week of therapy, but in the majority of cases the platelet count was back to the pretreatment level within 1 month. A shorter duration of ITP at the time of evaluation was associated with better results, but previous response so corticosteroids or presence of spleen did not affect the results of IVlg administration. Because IVlg is a relatively new therapeutic modality for the treatment of ITP, few follow-up data are available. Imbach52 recently reported on 17 children with ITP, all followed from 18 to 27 months. All had initial responses to IVlg, but maintenance IVlg therapy has become necessary in two of six patients with acute ITP, three of four patients with intermittent ITP, and three of seven patients with chronic ITP. In the three cases of severe chronic ITP, the disease could not be adequately controlled over long periods of time with IVIg. In general, IVlg for the treatment of ITP is efficacious, but its effects are not long lasting. The use of IVlg for adult ITP has been less successful than for childhood ITP, 4~'~'~' possibly from differences in the disease itself, since acute ITP in adulthood is rare. The long-term efficacy of IVIg is not yet known. B. Mechanisms of Action Despite the well-documented efficacy of IVlg for the treatment of childhood ITP) the mechanisms of its action arc not fully understood. Current research suggests that IVIg acts upon the immune system in several ways. The studies leading to the current proposed mechanisms of action will be reviewed. In their initial reports, Imbach and co-workers(3'4. postulated that the mode of action of IVlg was an overloading and blocking of the RES by lgG catabolism. In addition, they hypothesized that immediate effects could result from interaction of IVlg with PAIgG, either on the platelet surface or in the plasma, while late effects could result from activation of T cells and suppression of B cells. They noted that a single patient with acute ITP who received a pepsin-treated gammaglobulin F(ab)2 fragment] had no rise in platelet count, and suggested a role for the Fc portion of the immunoglobulin. Fehr and co-workers'~ tested the hypothesis of transient blockade of the RES using clearance studies of autologous erythrocytes. In each of four Rh-positive adults with ITP, autologous erythrocytes were first labeled with ~'Tc, next coated with IgG-anti Rh(D), and finally injected intravenously back into the donor patients. Serial blood samples were obtained, and clearance curves were generated. Treatment with IVIg
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caused a consistent transient prolongation in the circulation of the immune particles (labeled sensitized erythrocytes). They also noted that the platelet-count response was closely correlated with the erythrocyte-clearance rate. A poor platelet-count response to IVIg was associated with a less pronounced prolongation of the erythrocyte-clearance time. Because these artificial immune markers are known to be cleared by Fr receptors in ~_heRES, ss the authors postulated that the IVIg competes with the Pcreceptor binding of the RES macrophages. Bussel et al. s~ used SJCr-labeled lgG-sensitized autologous erythrocytes to measure immune clearance and P,ES blockade in 11 children and adults with ITP. They found maximal blockade by day 8 after administration, with a return to baseline by 4 weeks. In some patients, however, there was a persistence elevation in the platelet count, leading the authors to postulate that decreased autoantibody synthesis also occurs. From the previous studies and other research, it appears that there are at least four mechanisms of action for IVIg in the treatments of childhood ITP.
I. Blockade of the RES In addition to the previously mentioned evidence for competitive inhibition of macrophage Fc receptors by IVIg, s7 there is also evidence that Wig decreases the number of Fc receptors and perhaps the affinity of Fc receptors for lgG. ss It is not clear which portions of the IVIg preparation, i.e., monomeric vs. oligomerie forms, certain subclasses, or purity are responsible for its activity. Despite one report to the contrary, the Fc portion of the lgG seems necessary for a good effect, s9 2. Interference with IgU or Immune Complex (IC) Binding to Platelets There is evidence that monomeric IgG inhibits IC binding to platelets, 6~possibly by forming a protective coat on the platelet surface. Winiarski et al. 6' used an enzymelinked immunosorbant assay (ELISA) technique on three patients with ITP both before and after therapy with lVlg. They found a decrease in the direct PAIgG and an increase in indirect PAIgG upon infusion of the IVfg. These findings suggest that IVIg interferes with antibody binding to the platelet surface, and perhaps displaces antibody already bound. 3. Elimination of Circulating Immune Complexes There are few data to support this idea. The theory proposes the following:6~the immune complexes are formed in a state of relative antigen excess. The Wig can create a state of antibody excess, which leads to clearance of the immune complexes. This clearance of the circulating immune complexes allows the platelet count to rise. 4. Decrease in Antoantlbody Synthesis This mechanism also has few data to support it. The theory arises from the observed long-term remissions that occasionally result from IVlg administration. To our knowledge, IgG synthesis studies before and after IVlg therapy have not been done. C. Description The various immanoglobulin preparations are obtained by fractionated alcohol cryoprecipitation of plasma pooled from many blood donors. The important features of the immunoglobulir, concentrates for the treatment of ITP include: I.
2. 3.
Elimination of lgG aggregates, which can activate complement and cause anaphylactoid reactions. Preservation of specific and nonspecific antibody and effector functions. Retention of the Fc portion of the IgG molecule.
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There are many trade names available on the market today, but most of the published reports used IgG-SRK (identical with Sandoglobulin). In IgG-SRK, the immunoglobulin fraction contains 85% monomeric (7S) IgG, a few percent dimeric, polymeric or fragmented IgG, and traces of IgA and IgM. ~ The polyvalent immunoglobulin concentrate has normal lgG subclass distribution, and preserved eflector and antibody functions. There are no studies which compare different IVlg preparations. D, Dose Uchino and associates 5~ used three dosing regimens in their large cooperative trial, varying the amount from 200 to 400 mg/kg/day and the duration from 3 to 5 days. Their optimal regimen was 400 mg/kg/day for 5 consecutive days. Most investigators use the following approach when administering IV lgG preparations for childhood lTP: 1. 2.
IgG preparation 400 to 1000 mg/kg/day x 5 consecutive days. Subsequent booster infusions of 400 mg/kg as a single dose, given at 2- to 8-week intervals, depending upon the platelet count and hemorrhagic symptoms.
E. Side Effects In the original reports by Imbach et aI.' ~ ' ' there were no untoward effects during or after immunotherapy. Subsequent articles have anecdotally reported a variety of symptoms, including headache, malaise, pallor, chills, rash, and fever. '~'~3'5~The large cooperative study by Uchino et al?' reported side effects in 11 of 177 patients, including fever, headache, nausea, dermal pruritis, and local edema. All symptoms spontaneously resolved within hours. In general, the infusion of IVlg is tolerated well, and any mild side effects are brief and do not require cessation of therapy. There are no reports to date of hepatitis or acquired immunodeficiency syndrome (AIDS) following IVlg infusion. V. AI~TERNATIVE TREATMENTS Over the years, a variety of other therapeutic modalities have been used for the treatment of ITP. Although not all of these agents have been used on children with ITP, they will be briefly mentioned. The main category of alternative therapeutic agents contains chemotherapeutic agents, which act to decrease antibody production and interfere with macrophage function. Azathioprine, 6-mercaptopurine, and cyclophosphamide have been used most commonly?a,62The occasional response in children is only slight, may take months to become evident, and is usually unsustained. The side effects of immunosuppression, bone marrow depression, and possible carcinogenesis make these modalities double edged. The vinca alkaloids, however, are more notable because their effect is more immediate, they stimulate thrombopoiesis, and are not known to be carcinogenic? 3 In addition, vinca alkaloids bind to tubulin, a structural protein of platelets. This binding property allows treatment with "vinca-loaded" platelets. In this method of treatment, allogeneic platelets are loaded in vitro with the vinca alkaloids, then are transfused into the patient. The platelets act as vehicles to deliver the drug to the macrophage. In a recent report, slow intravenous infusions of vinca alkaloids were used to achieve in vivo loading of platdets." Results using vinea alkaloids, particularly the slow-infusion method, are somewhat better than with the other immunosuppressants.
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Plasmapheresis has been used in the treatment of ITP, in an attempt to remove antibodies and immune complexes from the plasma. A preliminary report suggest that this method yields mild responses. "~ Because transient blockade of the RES has been successful in the treatment of ITP, an alternative method to IVIg infusion was recently described. ' ' Ten Rh-positive patients with ITP were given intravenous anti-gho(D) igG, which causes in vivo coating of erythrocytes. The RES recognizes these sensitized erythrocytes and removes them from the circulation. The authors found a transient rise in platelet count with this therapy, presumably secondary to competitive inhibition for the macrophage and the resulting mild RES blockade. There was evidence of hemolysis in seven of ten patients, however, and no clear advantages over 1Vlg was noted. It is possible, however, that alternative methods of RES blockade more economical than IVlg will become available. Other agents with even less clinical experience and usefulness include Colchicine, Danazol, Tamoxifen, and testosterone. 62 For each of the above alternative therapeutic modallties, it should be noted that there is very little experience with childhood ITP. VI. G U I D E L I N E S FOR M A N A G E M E N T O F C H I L D H O O D I T P The following paragraphs outline an approach to the diagnosis and management of ITP in children based upon the current understanding of the pathophysiology, published results of various treatment regimens, and the authors' own experience with the management of children with both acute and chronic ITP. The therapeutic suggestions are proposed as guidelines. The therapy for the individual patient must be tailored to the individual patient's specific clinical circumstance. The clinician must also be guided by the fact that the majority of patients will resolve their illness with time and without serious adverse effects. As previously mentioned, ITP is a diagnosis of exclusion. The clinical history and physical examination are useful to exclude infections, collagen vascular diseases, drug reactions, stem ceil failure, or malignancy as an etiology for the thrombocytopeaia. There is no laboratory test which is diagnostic of ITP. There are however several tests which can establish the diagnosis with reasonable certainty. These include the complete blood count (CBC) with piaielet count, inspection of the peripheral smear, a bone marrow aspirate, and measurement of both direct and indirect PAIgG levels. It has been argued that only the CBC, platelet count, and inspection of the peripheral smear need be performed routinely for those children with typical histories compatible with ITP. 6' We feel, however, that all of the previously mentioned tests are extremely useful to confirm the diagnosis. The bone marrow examination excludes both leukemia and aplastic anemia, while the PAIgG levels at diagnosis and prior to treatment may assist in predicting the clinical course. In general, those patients with higher direct PAIgG levels have been shown to have an acute course while those with lower levels of direct PAIgG will have a chronic course. Several other laboratory tests may be indicated based upon the findings from the clinical history or physical examination. These tests include a prothrombin time, par. tiai thrombopiastin time, urinalysis, blood culture, serum creatinine, antinuclear or anti-DNA antibodies, and both direct and indirect Coombs' tests. Once the diagnosis of iTP has been established with a reasonable degree of certainty, we begin P~ednisone 2 mg/kg/day in three divided doses (maximum dose of 60 mg daily) if the platelet count is less than 20 x 10*/l or if there are significant hemorrhagic symptoms including evidence of mucous membrane bleeding. Parents and patients are told that the patient must avoid aspirin because of its adverse effect on platelet rune-
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tion. Hospitalization is reserved for those patients with severe thrombocytopenia, those with serious hemorrhagic manifestations, and those in which the home situation is deemed less than adequate. Prednisone is maintained at the initial dose for 3 weeks and then is discontinued gradually over an additional week. Platdet transfusions are not routinely utilized because of the immune-mediated nature of platelet destruction. In life threatening situations, however, piateiet transfusions may be employed in conjunction with emergency splenectomy. The majority of children will have an increase in the platelet count during the course of steroids, usually by 7 to 10 days, although this rise may be spontaneous. Prednisone is not continued at the 2 m g / k g daily dose for longer than 3 weeks even if the patient fails to obtain a significant increase in the count. Similarly, if the patient has a recurrence of the thromboeytopenia when Prednisone is discontinued, steroids are not resumed unless there is significant clinical bleeding or the platelet count is below 20 x 10'/L If Prednisone is restarted, it is resumed at the original dose until thrombocytopenia improves and then is changed to an every-other-day schedule at the lowest possible dose to maintain a platelet count above 50 x 109/1. iVlg therapy is recommended for several groups of patients: (I) those presenting with serious hemorrhagic symptoms; (2) those with severe thromboeytopenia (less than 20 • 10"/1) refractory to Prednisone; (3) those with severe thromoboeytopenia recurring after Prednlsone therapy; or (4) those requiring chronic Prednisone administration to minimize severe thrombocytopenia. Presently we employ an initial dose of 1000 m s / kg daily for 2 days. If thromboeytopenia improves, subequent IVlg doses of 1000 m g / kg are administered at 2 to 8 week intervals to control severe thromboeytopenia. In general, splenectomy is reserved for patients whose thrombocytopenia is refractory to therapy with either steroids or IVIg, or in those very rare instances when intracranial hemorrhage occurs. Also, spleneetomy is used for those patients requiring prolonged steroid therapy or IVlg therapy to reduce hemorrhagic symptoms. It is our practice to attempt to delay spienectomy for at least I year from the date of initial diagnosis when possible, as spontaneous remission during this period of time is common. We also try to avoid the procedure ~f at all possible for those children under the age of 5 years because of the increased risk of sepsis from encapsulated organisms following this procedure. Prior to splenectomy, polyvalent pneumococcal vaccine is administered and following the procedure prophylactic penicillin is recommended for life.
REFERENCES I. Matoth, u Zaizov, R., and Frankel, J., Minimal cerebral dysfunction in children with chronic thrornboeytopenia, Pediatrics, 47,698, 1971. 2. Lushcr, J. and Ivery, R., Idiopathic thrombocytopenie purpura in children, Semin. Thromb. Hemostas., 3, 175, 1977. 3. McWillJams, N. and Maurer, H., Acute idiopathic thromhocytopenlc purpura in children, Am. J. Hematol., 7, 87, 1979. 4. Wocrner, S., Abildgaard, C., and French, B., Intracranial hemorrhage in children with idiopathic thrombocytopenie purpura, Pediatrics, 67,453, 1981. 5. Krlvit, W., "Fate, D., White, J., et al., Idiopathic thrombocytopenic purpura and intraeranial hemorrhage, Pediatrics,67, 570, 1981. d. Ware, R. and Kinney, T. R., The immunopatbo[ogy of childhood idiopathic thrombocytopcnic purpura, Crit. Rev. HcmatoL O•col., 7,139, 1987. 7. McWilliams, N. and Maurer, H,, Controlled clinical trial of prednisone in childhood idiopathic thromboeytopenir ptlrpura (I.T.P.), Pediatr. Res.~ I I(Abstr.), 476, 1977. 8. Sartorius, J., Steroid treatment o[ idiopathic thrombocytopenir purpura in children, Am. 7. Pediltr. Hematot. Oncol,, 6, 165, 1984.
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9. Lusher, J., Emami, A., Ravindranath, Y,, et ai., Idiopathic thromhocytopenle parpora in chi]drcn. The case for management without corticosteroids, Am, J, Ped~atr. Hematol. Oncol.,6, 149, 1984. 10. Buchanan, G. and Holtkamp, C., Prednisone therapy for children with newly diagnosed idiopathic thrombocytopenic purpura, Am. J. Pedialr. HematoL Oncol., 6) 355, 1984. 11. Weinblatt, M. and Ortega, J., Steroid responsiveness, Am, 3". Dis. Child., 136, 1064, 1982. 12. Branehog, I. and Weinfdd, A., Platelet survival and platdet production in idiopathic thrombocytopanic purpura ~ITP) before nnd during treatment with eortieosteroids, Scrod. ]. HacmatoL, 12, 69, 1974, 13. Jail, R., Firnzvi, T., arid Spurling, C,, Chronic idiopathic thromboeytopenie purpura, Arch. lnter. Mad., I32, 380, 1973. 14. Dixon, R., Rosse, W., and Ebbert, L,, Quantltative determination of antibody in idiopathic thromboeytopenic purpara, N. Engl. I. Mad., 292,230, ] 975. 15. Ware, R., Kinney, T., Friedman, H,, et al., Prognostic implications for direct pJatelel associated IgG in childhood idiopathlc thrQmbocytopenic purpura, Am. J. Pediatr. HematoL Oncot.,8(I), 32, I986, 15a, Harrington, W., Mianieh, V., Hollingsworth, J,, et al., Demonstration of a thrombocytopenle factor in the blood of patients with thromboeytopenic purpura, J. Lab. Clio. Mad., 38, I, 1951. 16. Shuiman, N,, Weinraeh, R., Libre, E., et at., The role of the retJculoendothelial system in the pathogenesis of idiopathic thromhocytopenic purptJra, Trans. Assoc. Am. Phys., 78, 374, J 965. 17. McMillaa, R.. Longmire, R., Tavassoli, M., et aL, In vitro p]atelet phagoeytosis by splenic leukocytes in idiopathic thrombocytopenie purpura. N. Enal. J. Mad., 290, 249. 1974. 18. Handin, R. and Stossr T., Effect of corticosteroid therapy on the phagocytosis of antibody-coated platelcts by human leukocytes, Blood, 51,771, 1978. 19. van Horn, D. and Johnson, S., The mechanism of thromhoeytopenie bleeding, Am. J. Clio, b'athol., 46,204, 1966. 20. Kitchens, C. and Weiss, L., Ultrastructural changes of andothelium associated with thrombocytopenia, Blood, 46, 567, 1975. 21. Kitchens, C,, Amdi~raslon of endothelial abnormalities by prednisone in experimental thrombocytopenia in the rabbit, J. Clln, Invest., 60, 1129, 1977. 22. Senyl, A., Blajchman, M., and Harsh, J,, The experimental corrective effect of hydrocortisone on the bleeding time in thrombocytopenie rabbits, Blood,46(Abstr.), 1034. 1975. 23. Butler, W., Corticosteroids and immunoglobulin synthesis, Transplant P~oc,, 7, 49. 1974. 24. Butler, W. and Rossea, R., Effects of corlieosteroid~ on immunity in man, J. Clio. Invest., 52, 2629, 1973. 25. McMiilan, R., Longmire, R., and Yeienosky. R., The effect of eorlicosteroids on human lgG synthesis, I, lmrannol., 116, 1592, 1976. 26. Goodman, L. and Gilman, A., Eds., The Pharmacological Basis of Therapeutics, 4th ed., MacMillan, New York. 1970, 1636. 27. Karpatkin, M. and Karpatkin, S., Immune thrombocytopenia in children, Am. J. Pediatr. Hamatol. OncoL, 3,213, 1981, 28. Russell E. and Maurer, H., Alternatives to splenectomy in the management of chronic idiopathic thrombocytopenir purpura in chitdhood, Am. J. Pediatr. Hematol. Oncol., 6. 175, 1984. 29. Thompson, R.. Moore, R., Hess, C., et al., Idiopathic thrombocytopenic purpura. Long-term results of treatment and the prognostic significance of response to cortlcosteroids, Arch. Intern. Mad.. 130, 730, 1972. 30. Bxennan, M., Rappeport, J., Moloney, W., et al., Correlation between response to corticostero!ds and splenectomy for adult idiopathic thromhocytopenic purpura, Am. J. Surg., 129, 490, 1975. 31. Gugliotta. L., lsacchi. G.. Guarani, A., et ~I) Chronic idiopathic thrombocytopenic purpura (ITP): site of platelet sequestration and results of splenectomy, Stand..L Haematoh, 26,407, 1981. 32. Pawelski, S., Konopka, L., and Zdziechowska, H., Recurrence of thrombocytopenla in patients splenectomized for idiopathic thrombocytopenie purpura, Blut, 43, 355, 1981. 33. Eraklis, A. and Filler. R., Splenectomy in childhood: a review of 1413 cases, ,I. Pediatr. Sur~., 7, 382, 1972. 34. Lightsey, A. arid McMillau, R., The role of the spleen in "~tutoimmune" blood disorders, Am. J, Pedlatr, HematoL OncoL, 1, 33I, 1979. 35, Heyns, A., Lotter, M., Badenhorst, P., et al,, Kinetics and sites of destruction of [nd[um-oxinelabeled platelets in idiopathic thrombocytopenic purpura: a quantitative study. Am. J. Hematol., 12, 167, 1982. 36. Dickerman, J., Spleneetomy and sepsis: a warning. Pediatrics, 63,935, 1979. 37. Amsbangh, D., Prescott, B., and Baker, P., Effect of spleneetomy on the expression of regulatory T cell activity, J, lmmunol., 121, 1483,1978. 38. $chumacher, M., Serum ilnmuanglobulin and transferrin levels after childhood splenectomy, Arch. Dis, Child..45. 114. 1970.
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39. Andersen, V., Cohn, J., and $orcnsen, S , Immunological studies in children before and after spleneclomy, Acta Paedialr. Stand., 65,409,1976 40. Sullivan, J., Schlfg'man, G., Miner, J., et al., lmmone response after sp/enoctomy. La~zcct, I, 178, 1978, 41. Carlisle, H. and Saw S., Properdln levels in spleneetomized persons, Pron. Sor F.xp, 8iol. &led,, 102, 150, 1959. 42. Polhi11, g. and Johnston, R,, Diminished alternative complement pathway (ACP)activity after splenectomy, Pediatr. Bes., 9(Ahstr,L JJh, ~975. 43, Imbach, P.. Barandnn. S., Baamgartner, C., et ~1.. High-dose ir~travenous gemmagIob~lirt therapy of refractory, in particular idiopalhic thromhocylop~nia in childhood~ Holy. Paedlatr. Aeta, 46, g I, 198t. 44. Imhach, P,, d'Apuzzo, V., Hirt, A., et aL, High-dose intravenous gammaglobulln for idiopathic thromboeytopenie purpma in childhood, Lancet, 1,1228, 1981. 45. Fehr, J., Hofmann, V., and Kappeler, O., Transient reversal of thromboeytopenia in idiopathic thromboeytopenie purpara by high-dose intravenous gamma g',obulln, N. E~gh J. M~d., 306, 1254, 1982, 46. Bussd, J., Schulman, 1., Hilgartner, M., at aL, Intravenous use of gammaglobulin in the treatment of chronic immune thrombocytopeaic putputa as a mr to d~fer spleneelomy, ], Pediatr,, 103, 651, 1983. 47. Beck, R., Gammaglobolln therapy for neonatal ITP (tetter~, L Pediatr., ~04, 638, I984. 4ft. Chirir162G., Dose, M., Ugazlo, A,, et aL, High-doze. intravenous gammaglohulin therapy for passive immune thromhocytopenia in the neonate, J. Pcdiatr., ]03,654, 1983~ 49. Morg~nstern, G., Mc~day, B., and Hedge, U., Autoimtouae thrombocytopenia in pregnancy. New approach to manor.carom, Be. &led, J., 287,584, 1983. 50. Wenske, C., Gaedick~, G., Kuenzlen, E., et hi., Treatmem of idiopathic thrombocytic pmpura in pregnancy b.'; high-dose intravenous immunoglobulin, Blur,,16, 347, 1'~3. 51. Uchino. H., Yasnnaga, K., and Akatsuka~ J., A cooperatNe clinical trial of high-dose immunoglobolin therapy in 177 cases ol idiopathic thrombocylopenie purpura, Thromh. Haemost~s~, 51, 182, I984. 52. lmbach, P., Barandan, S.. Hirt, A., r aI, Intravenous hnma~oglobu[in for idiopathic thrombocytopenic purpura (ITP)in childhood, Am. J. Ped~alr. HematoL OneoL, 6, 171, 1984, Sh. Lung, L, paradji, A., Oiron, C., r aL, High-do~e intravenous IgG for chr
139
T H E R A P E U T I C CONSIDERATIONS IN C H I L D H O O D IDIOPATHIC THROMBOCYTOPENIC PURPURA Authors:
Russell Ware Thomas R. Kinney Division of Hematology/Ontology Department of Pediatrics Duke University Medical Center Durham, North Carolina
Referee:
Campbell W, McMillan Department of Pedlatr[cs Univershyof North Carolina School of Medicine;and North Carolln~,Memorial Hospital Chapel Hill, North Carolina
I. INTRODUCTION Idiopathic thrombocytopenic purpura (ITP) in childhood is characterized by isolated thrombocytopenia, normal to increased numbers of megakaryocytes on bone marrow aspirate, and absence of other etiologies such as connective-tissue disease, sepsis, disseminated intravascular coagulation, drug reaction, and malignancy. In ITP, the thrombocytopenia is immune-medlated; platelets are sensitized by antibody, complement, and/or immune complexes and are destroyed by the reticuloendothelial system (RES). In children, 1TP generally follows one of three clinical courses: acute, chronic, or acute recurrent. Morbidity from ITP arises from the tendency to bleed. Bleeding into the gastrointestinal tract occurs in 2 to 8% of patients, hematuria in
2. 3.
Reducethe incidence and/or mortality of ICH. This goal is difficult to assess in a clinical trial, because of the low incidence of ICH. Assuming an incidence of 1% for ICH in childhood ITP, approximately 14,000 patients would have to enter a randomized trial in order to detect a 50% reduction in the incidence of ICH. ~ Shorten the disease course of acute 1TP. This is a self-limited illness, but therapy could minimize the duration of thrombocytopenia and hemorrhagic symptoms. Induce remission in chronic ITP. There are several therapeutic choices for chronic ITP, with varying efficacy and side effects. The risk/benefit ratio for any therapy must be assessed for each patient.
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In a previous monograph, the clinical course and pathophysiology of childhood ITP have been discussed.' In this monograph, current therapy for acute and chronic ITP is described. Efficacy, mechanisms of action, and side effects of corticosteroids, splcnectomy, and intravenous immunoglobulin (1Ylg) will be presented. Next, alternative therapeutic modalities will be mentioned. Finally, guidelines for the management of a child with ITP will be presented. II. C O R T I C O S T E R O I D S A. Efficacy The use of corticosteroids in acute childhood ITP is an area of intense controversy. Until recently, all clinical studies were flawed because they were retrospective, involved small patient numbers, and/or had nonrandom treatment regimens. The first well designed study was by MeWilliams and Maurer,' in which 13 children were randomized to receive either Preduisone 2 mg/kg/day orally for 3 weeks or no corticosteroid therapy. They showed that the median time to normalization of platelet count was significantly shorter in the treated group. In a recently published larger trial from Europe,' 73 children were randomized to receive either Prednisolone 60 mg/m2/day orally for 3 weeks or placebo. The treated group had significantly shorter duration of platelet counts less than 30 x 10"/1 and platelet counts less than I00 x 109/1 as well as a shorter duration of a prolonged bleeding time. These data suggest that corticosteroids accelerated the rise in platelet count and improved the capillary resistance. Both of these effects would decrease hemorrhagic symptoms. The opposite viewpoint is championed by Lusher and co-workers. ~'9 They reported that in 465 consecutive cases of childhood ITP, no child less than 13 years old has ever had an ICH. In addition, their study of corticosteroid usage suggests that r,orticosteroids slightly prolonged the duration of thrombocytopenia and could cause rebound or withdrawal thrombocytopenia. A recent controlled prospective study by Buchanan et al.'~ failed to show a significant benefit from Prednisone therapy. The efficacy of corticosteroid therapy in chronic ITP is well accepted. T M The response rate of chronic ITP to corticosteroids has been estimated to be 50% .'~ Despite an initial response with normalization of platelet count, rarely can this remission be sustained off therapy. Low-dose therapy, even alternate-day therapy, however, may be adequate to maintain hemostasis. Only if the hemorrhagic symptoms continue or the side effects of corticosteroids become intolerable, should other therapies be considered. B. Mechanisms of Action Even though there is an abundance of literature on the Use of corticosteroids in childhood ITP, the precise mechanisms of action are not fully understood. The data show that corticosteroids have many effects upon the immune system, several of which may be important in ITP. At present, there appears to be at least four possible mechanisms by which corticosteroids act in the treatment of ITP. I. Decreased Binding of Antibody to Platelets Thi~ effect can be shown best if platdet-associated l e g (PAIgG) levels are measured before and during corticosteroid therapy. Data supporting this mechanism of action first appeared in the paper of Dixon, Rosse, and Ebbed," in which the first quantitative antiglobulin consumption (QAC) assay for PAIgG was described. They showed that response to corticosteroids was associated with a decrease in direct PAIgG, but correlation with indirect or serum PAIgG was poor. This effect was not immediate,
Volume 7, Issue 2 (1987) eft*~to~ - -
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FIGURE 1. Seria]platelet counts and PAlgG levelsin a patient with acute ITP. for both the rise in platelet count and fall in direct PAIgG took several weeks. A change in antibody production could explain these findings as well. The same laboratory carefully studied a 15-year-old male with acute ITP, using serial blood samples during treatment with corticosteroids. 's The data on this patient are shown in Figure I. The direct PAIgG, representing IgG on the platelet surface, returned to normal by 2 weeks. The indirect or serum PAIgG level transiently rose before returning to normal. The platelet count rose to 50 x 109/1 by 2 weeks, and was normal by 4 weeks. This anecdotal report suggests that the effect of corticosteroids on autoantibody binding is fairly rapid. It is tempting to postulate that the costicosteroids release the IgG from the platelet surface, causing the temporary rise in the indirect (serum) PAIgG level. Serial measurement of direct and indirect PAIgG, using an accurate direct-labeled assay, needs to be done on a group of patients before, during, and aft~,'r therapy with eorticosteroids. Only then can the effect of corticosteroids on antibody binding to the platelet surface be elucidated. 2. Decreased Platelet Phagocytosis by the R E S
The recognition and ingestion of sensitized platelets by phagocytosis is a major aspect of clearance in childhood [TP. The theory that cnrticosternid therapy interferes with RES clearance is supported by several studies. Over 30 years ago, Harrington and co-workers demonstrated that infusion of plasma from patients with ITP will cause thromboeytopenia in normal recipients. 's" Over a decade later, Shulman verified this finding, '~ but then modified the experiment. When the volunteers were given corticosteroids prior to the infusion, the resulting thrombocytopenia was partially inhibited. This protective effect of corticosteroids was the same if given 3 days or 3 hr before infusion the ITP plasma, but continued administration was necessary to assure effectiveness. If corticosteroids were stopped 1 or 2 days after the infusion of ITP plasma, thrombocytopenia would occur. Because splenectomized
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individuals did not develop thromboeytopenia from transfusion of plasma from patients with ITP, the protection afforded by eotticosteroids seen in normal volunteers was attributed to interference with RES clearance. In 1974, Branehog and Weinfeld .2 used platelet-labeling techniques to show that the piatelet life span in patients with ITP is prolonged after corticosteroids are instituted. The proposed mechanism is a change in RES clearance, specifically by altering the spleen/liver clearance ratio. That same year, MeMillan et al.*l described an in vitro assay using splenic leukocytes to phagoeytose normal platelets. They found that splenic leukocytes from patients with resistant ITP were more phagocytic than those from patients with ITP sensitive to corticosteroids or from normal controls. They postulated that the corticosteroids affect the ability of the splenic leukocytes to phagocytose platelets. Handin and Stossel" used another in vitro test to study the effects of cortleosteroids. Their assay measured phagocytosis of antibody coated platelets by peripheral lenkocytes. High-dose corticostcroids decreased the ability of peripheral blood monoeytes and granulocytes to phagocytose sensitized platelets, either by affecting the number or the affinity of leukocyte Fc receptors.
3. Altered Vascular Permeability and Improved Capillary Integrity Without platelets to repair microvaseular injury, thrombocytopenic patients have easy bruisability and spontaneous petechiae and purpura. In addition to vascular repair, however, platelets somehow support the integrity of the vascular endothelium. '~ Thrombocytopenia from irradiation, immune destruction, or chemotherapy results in well documented changes in the vascular endothelium, z~with fenestrations and microvascular thinning. Using a rabbit model, Kitchens2. has shown that corticosteroids reverse the endothelial lesions which accompany thrombocytopenia. The capillary integrity and therefore hemostasis may therefore be improved. Similarly, Senyi and co-workers22 have reported that corticosteroids improve the bleeding times of thrombocytopcnlc rabbits. It is unclear at this time whether or not these findings are applicable to childhood ITP or human thromboeytopeqia in general. g. Decreased Autoantlbody Production This mechanism of action could account for the long-term remissions that are observed with chronic eorticosteroid use. There are several reports which support this proposed effect. In 1973, Butler and Rossen2'." used normal human volunteers to show that a brief course of methylprednisolone caused a signficaat decrease in serum igG. In their study, the nadir occurred in the 3rd week following therapy. Clearance of radiolabeled IgG suggested that this decrease was largely attributable to decreased synthesis of leG, and not increased catabolism. They found that corticosteroids had no affect upon the ability to mount a primary or secondary antibody response to antigens given during the drug-treatment period, but did seem to inhibit ongoing antibody synthesis. These findings support the idea that cortieosteroids can change specific antibody production. Soon after, MeMillan r al) g studied the effects of eorticosteroids on IgG synthesis in patients with lTD. Using bone marrow and splenic tissue from these patients, they showed that splenic production of IgG was not affected by corticosteroids, but the larger mari-ow production was greatly decreased. Marrow IgG production began to decrease 3 weeks after starting corticosteroid therapy and reached 25~ of pretreatment production rates after 6 weeks. They hypothesized that the corticosteroids affect a lymphocyticeffector ceil important for the normal marrow humoral immune response.
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Table 1 SIDE EFFECTS RESULTING FROM CORTiCOSTEROID USE Fluid and electrolytes Sodium retention/waterretention Hypokalcmicalkalosis Hyperglycemia G~strointestinal Pancreatitis Felatic ulceration Masculoskeletal Osteoporosis Myo0athy Growthsuppression Skin Cutaneous thinning Ecehymoses Ache Hirsutism
Cushing's Habitus "Moon face" "Buffaio hump" Supraclar fat pads Trunca] obesity Striae CiqS Psychosis Psychiatricdisturbances Hematological
Hypercoagulabillty Miscellaneous Increasedrisk of infection Hypertension Cataracts
C. Dose A typical initial corticosteroid preparation and dose prescribed for childhood ITP is Prednisone,'2,mg/kg/day (maximum 60 mg daily) orally for 3 weeks. The Prednisone is gradually discontinued over I to 2 additional weeks. There are no data to justify longer therapy for treatment of acute ITP. If the thrombocytopenia recurs and is accompanied by significant bleeding, Prednisone may be reinstituted at the lowest possible dose to minimize bleeding if the thrombocytopenia is responsive to steroids. If prolonged steroid therapy is required, attempts should be made to utilize an alternateday schedule to reduce side effects. D. Side Effects The iist of side effects from corsticosteroids is long, and includes mineraio- and glucocorticoid effects. Most of the side effects are related to the dose, frequency, and duration of therapy. The principal complications resulting from corticosteroid use are listed in Table 1.26 Ili. S P L E N E C T O M Y A. Introduction The majority of children diagnosed with ITP will achieve normal platelet count within a few months of diagnosis. In the small percentage of children who remain thrombocytopenic, become corticosteroid dependent, or have life-threatening hemorrhagic symptoms, splenectomy is usually recommended. The spleen is a significant source of antibody production as well as the potential site of platelet destruction in ITP. There a~'~ .~zveral reports on the use of splenectomy in childhood ITP.
B. Efficacy The actual percentage of children who willachieve normal plateletcount aftersplenectomy varies,but is usually reported to be from 55 to 88%. 2,,.',~BAnother I0 to 20070 more will have less bleeding despite persistent thrombocytopenia. The typical response to splenectomy is an immediate rise in platelet count, often within hours after surgerY~ The plg,teiet count may rise to 1000 to 2000 • 10".1"1after splenectomy. Thrombotic complications from this thrombocytosis have not been reported. Most children
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will have a relatively high platelet count (500 to 1000 x iON/I) for several weeks, which will usually return to normal values by 6 months. 2 It is difficult to predict which children will respond to splenectomy. Some authors have associated a previous response to corticosteroids with a subsequent response to splenectomy, t0,~9'3~while others do not find such a correlation. 2'z7 The precise predictive value of a response to corticosteroids is not known, but a lack of response does not contraindicate splenectomy. Theoretically, patients who have massive platelet destruction in the spleen should respond well to splenectomy. In a recent study of platelet kinetics and splenectomy in ITP, the authors used S~Cr-labeled platelets to determine the pattern of platelet sequestration. ~j They found that children and adult patients with a splenic or splenohepatic sequestration (75~ were much more likely to have a good response to splenectomy than those patients with hepatic or diffuse patterns of platelet sequestration. Studies of platelet kinetics and sequestration may be useful in predicting response to splenectomy, but at this time their efficacy has not been established. In some patients with ITP who achieve remission after splenectomy, there is recurrence of thrombocytopenia. ~2 In a retrospective study involving 177 patients (59 children) with chronic ITP who underwent splenectomy, 145 (82070)had immediate remission after surgery and 14 (8%) more achieved remission later. Of the patients in remission, 32 (200/o) had recurrence of thrombocytopenia, most frequently between 6 and 48 months postsplenectomy. Of the 32 patients with relapse, 13 had transient thrombocytopenia associated with a viral illness, and 12 had recurrence from accessory spleens found at repeat surgery. The prevalence of one or more accessory spleen is reported to be 16~ in children undergoing splenectomy) ~ These data point to the importance of searching vigorously for accessory spleens at the time of original splenectomy. C. Mechanisms of Action As previously noted, the spleen is an important site of antibody production in 1TP. Its removal is usually associated with normalization of the PAIgG level, as well as normalization of the platelet count. '~ The spleen is also an important site of platelet destruction in ITP. Its active RES, high antibody concentration, abundant platelet pool, and slow circulation provide a unique environment for platelet destruction. As the platelets slowly traverse the splenic cords, they are in prolonged contact with platelet antibody and phagocytic cells. The value of spleneetomy is therefore more than simple removal of a large RE cell population; rather it is the removal of the entire milieu conducive to platelet destruction. The small percentage of children who undergo splenectomy for ITP and do not achieve remission probably have other mechanisms or sites of platelet destruction. As noted in an earlier section, the liver, bone marrow, and other lymphoid tissue may be a site of destruction for platelets in ITP. ~.~(.a~Alternatively, as detailed in our previous monograph, platelet destruction may be mediated by complement, immune complexes, or cellular immune mechanisms? D, Side Effects The most significant danger after splenectomy results from the loss of a major part of the immune system. Beyond the morbidity and mortality of surgery, there is now awareness of an increased chance of postsplenectomy infection and sepsis. In a review of splenectomy and postsplenectomy sepsis, Dickerman ~' noted the importance of the spleen for a competent immune system. After splenectomy) patients have an increased susceptibility to sepsis from encapsulatedorganismssuch as Streptococcus pneumoniae and Haemophilus influenzae. In ~addition, splenectomy c a n
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cause impaired clearance of bacteria in the bloodstream; decreased amplified T cell function; ~' low serum lgM levels;~'~ decreased immunologic response to some antigens, including perhaps the switch from lgM to lgG synthesis;4~ and altered complement function. '~.'2 The use of the pneumococcal polysaccharide vaccine and prophylactic penicillin may reduce the risk of postsplenectomy sepsis. In an attempt to quantitate the riks of splenectomy, a nationwide survey was conducted by the surgical section of the American Academy of Pediatrics. a3 Of 1413 children who had undergone splenectomy, 765 (54%) had a hematologic disease (e.g., ITP, autoimmuue hemolytic anemia, hereditary spherocytosis) in which the spleen was the primary site of cell destruction, and 265 (18%) of the children had 1TP. The overall hospital mortality was 47 patients (3.3%), but only 4 (0.3%) died from overwhelming infection. There were three hospital deaths in the 265 children with ITP, all due to intracranial bleeding. In two, the intracranial bleeding was related to thrombocytopenia persisting after spleneetomy. Of the patients available for follow-up (541), 34 (6%) died of infection. Of these 34 deaths from sepsis, 16 were in children less than 2 years of age at splenectomy. The authors state that for patients with ITP, overalI mortality from elective sptenectomy should be < 1%. In summary, splenectomy is a very effective treatment for childhood ITP, although not invariably successful. Splenectomy should be considered successful if the platelet count achieved allows normal activity and symptomatic control, regardless of the actual number. Splenectom!, should never be considered early in the course of the disease, unless there are life-threatening hemorrhagic symptoms. Splenectomy carries the risk of postoperative infection and sepsis. This risk may be reduced by the pneumococcal vaccine, prophylactic penicillin, and heightened clinical suspicion of sepsis when the asplenic patient presents with fever. 1V. IVIg In the past few years, the use of intravenous immunoglobulin (IVIg) has become popular in the treatment of ITP. Although its true potential is not yet clear, IVig promises to be both a tool for the study of the immune system, plus a useful therapeutic modality fur autoimmune diseases including ITP. A. Efficacy In 1965, Shulman and co-workers t6 published their landmark article on the role of the RES in ITP. They studied the effects of corticosteroids on RES clearance, but also noted another form of RES inhibition, in patients with "autoerythrocyte sensitization" prior infusion of red cell stroma partially inhibited the thrombocytopenia resulting from infusion of ITP plasma. This was probably the first demonstration of RES blockade, and the authors anticipated the efficacy st RES blockade in lTP. Many years passed, however, before their foresight was realized. In 1981 ]mbach et al. '3~4 published two reports on the use of intravenous immunnglobulin (IVIg) in childhood ITP. They had been using the IVIg preparation in a group of patients with congenital or acquired agammag[obullnemia and hypogammaglobullnemia, in two such patients with severe thrombocytopc'nia, they noted a resolution of the thrombocytopenia after IVlg administration. These observations prompted the use of IVIg on a patient with refractory ITP, and the results were very impressive. In their first report on four of four children with refractory ITP, the platelet count rose to 300 to 650 x I&/! within 5 to 10 days of IVIg infusion. In two of two children with idiopathic aplastic anemia, however, there was no response. Their second report provided data on seven children with chronic or intermi:tent ITP and six with acute ITP. In all pa-
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tients the platelet count rose sharply within 5 days, but the initial resonse and subsequent course varied. Additional reports on the efficacy of IVlg in ITP quickly followed. In 1982, Fehr et al. (~ reported the use of high-dose IVIg in four adults with ITP, none of whom had undergone splenectomy. All patients had a transient rise in the platelet count within 4 to 5 days of administration, but the duration of response was much shorter than that reported in children. Bussel and co-workers4~ used IVIg on 12 consecutive children with chronic 1TP, and reported that nine had responses which postponed splenectomy. Of these nine with good responses, four required booster doses of [VIg every 4 to 10 weeks, while five required no further therapy. In 1983, literature appeared on the use of IVlg for "neonatal I T P " , 47-~~which is congenital thrombocytopenia in an infant born to a mother with ITP, secondary to transplacental passage of platelet antibodies. The benefits of ante- and postnatal IVIg were reported. In the largest series reported to date, Uchino eta[. ~j reported the use of high-dose IVlg in 177 cases of ITP with 102 children and 75 adults. Overall, 87% of the patients had a rise in platelet count during the first week of therapy, but in the majority of cases the platelet count was back to the pretreatment level within 1 month. A shorter duration of ITP at the time of evaluation was associated with better results, but previous response so corticosteroids or presence of spleen did not affect the results of IVlg administration. Because IVlg is a relatively new therapeutic modality for the treatment of ITP, few follow-up data are available. Imbach52 recently reported on 17 children with ITP, all followed from 18 to 27 months. All had initial responses to IVlg, but maintenance IVlg therapy has become necessary in two of six patients with acute ITP, three of four patients with intermittent ITP, and three of seven patients with chronic ITP. In the three cases of severe chronic ITP, the disease could not be adequately controlled over long periods of time with IVIg. In general, IVlg for the treatment of ITP is efficacious, but its effects are not long lasting. The use of IVlg for adult ITP has been less successful than for childhood ITP, 4~'~'~' possibly from differences in the disease itself, since acute ITP in adulthood is rare. The long-term efficacy of IVIg is not yet known. B. Mechanisms of Action Despite the well-documented efficacy of IVlg for the treatment of childhood ITP) the mechanisms of its action arc not fully understood. Current research suggests that IVIg acts upon the immune system in several ways. The studies leading to the current proposed mechanisms of action will be reviewed. In their initial reports, Imbach and co-workers(3'4. postulated that the mode of action of IVlg was an overloading and blocking of the RES by lgG catabolism. In addition, they hypothesized that immediate effects could result from interaction of IVlg with PAIgG, either on the platelet surface or in the plasma, while late effects could result from activation of T cells and suppression of B cells. They noted that a single patient with acute ITP who received a pepsin-treated gammaglobulin F(ab)2 fragment] had no rise in platelet count, and suggested a role for the Fc portion of the immunoglobulin. Fehr and co-workers'~ tested the hypothesis of transient blockade of the RES using clearance studies of autologous erythrocytes. In each of four Rh-positive adults with ITP, autologous erythrocytes were first labeled with ~'Tc, next coated with IgG-anti Rh(D), and finally injected intravenously back into the donor patients. Serial blood samples were obtained, and clearance curves were generated. Treatment with IVIg
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caused a consistent transient prolongation in the circulation of the immune particles (labeled sensitized erythrocytes). They also noted that the platelet-count response was closely correlated with the erythrocyte-clearance rate. A poor platelet-count response to IVIg was associated with a less pronounced prolongation of the erythrocyte-clearance time. Because these artificial immune markers are known to be cleared by Fr receptors in ~_heRES, ss the authors postulated that the IVIg competes with the Pcreceptor binding of the RES macrophages. Bussel et al. s~ used SJCr-labeled lgG-sensitized autologous erythrocytes to measure immune clearance and P,ES blockade in 11 children and adults with ITP. They found maximal blockade by day 8 after administration, with a return to baseline by 4 weeks. In some patients, however, there was a persistence elevation in the platelet count, leading the authors to postulate that decreased autoantibody synthesis also occurs. From the previous studies and other research, it appears that there are at least four mechanisms of action for IVIg in the treatments of childhood ITP.
I. Blockade of the RES In addition to the previously mentioned evidence for competitive inhibition of macrophage Fc receptors by IVIg, s7 there is also evidence that Wig decreases the number of Fc receptors and perhaps the affinity of Fc receptors for lgG. ss It is not clear which portions of the IVIg preparation, i.e., monomeric vs. oligomerie forms, certain subclasses, or purity are responsible for its activity. Despite one report to the contrary, the Fc portion of the lgG seems necessary for a good effect, s9 2. Interference with IgU or Immune Complex (IC) Binding to Platelets There is evidence that monomeric IgG inhibits IC binding to platelets, 6~possibly by forming a protective coat on the platelet surface. Winiarski et al. 6' used an enzymelinked immunosorbant assay (ELISA) technique on three patients with ITP both before and after therapy with lVlg. They found a decrease in the direct PAIgG and an increase in indirect PAIgG upon infusion of the IVfg. These findings suggest that IVIg interferes with antibody binding to the platelet surface, and perhaps displaces antibody already bound. 3. Elimination of Circulating Immune Complexes There are few data to support this idea. The theory proposes the following:6~the immune complexes are formed in a state of relative antigen excess. The Wig can create a state of antibody excess, which leads to clearance of the immune complexes. This clearance of the circulating immune complexes allows the platelet count to rise. 4. Decrease in Antoantlbody Synthesis This mechanism also has few data to support it. The theory arises from the observed long-term remissions that occasionally result from IVlg administration. To our knowledge, IgG synthesis studies before and after IVlg therapy have not been done. C. Description The various immanoglobulin preparations are obtained by fractionated alcohol cryoprecipitation of plasma pooled from many blood donors. The important features of the immunoglobulir, concentrates for the treatment of ITP include: I.
2. 3.
Elimination of lgG aggregates, which can activate complement and cause anaphylactoid reactions. Preservation of specific and nonspecific antibody and effector functions. Retention of the Fc portion of the IgG molecule.
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There are many trade names available on the market today, but most of the published reports used IgG-SRK (identical with Sandoglobulin). In IgG-SRK, the immunoglobulin fraction contains 85% monomeric (7S) IgG, a few percent dimeric, polymeric or fragmented IgG, and traces of IgA and IgM. ~ The polyvalent immunoglobulin concentrate has normal lgG subclass distribution, and preserved eflector and antibody functions. There are no studies which compare different IVlg preparations. D, Dose Uchino and associates 5~ used three dosing regimens in their large cooperative trial, varying the amount from 200 to 400 mg/kg/day and the duration from 3 to 5 days. Their optimal regimen was 400 mg/kg/day for 5 consecutive days. Most investigators use the following approach when administering IV lgG preparations for childhood lTP: 1. 2.
IgG preparation 400 to 1000 mg/kg/day x 5 consecutive days. Subsequent booster infusions of 400 mg/kg as a single dose, given at 2- to 8-week intervals, depending upon the platelet count and hemorrhagic symptoms.
E. Side Effects In the original reports by Imbach et aI.' ~ ' ' there were no untoward effects during or after immunotherapy. Subsequent articles have anecdotally reported a variety of symptoms, including headache, malaise, pallor, chills, rash, and fever. '~'~3'5~The large cooperative study by Uchino et al?' reported side effects in 11 of 177 patients, including fever, headache, nausea, dermal pruritis, and local edema. All symptoms spontaneously resolved within hours. In general, the infusion of IVlg is tolerated well, and any mild side effects are brief and do not require cessation of therapy. There are no reports to date of hepatitis or acquired immunodeficiency syndrome (AIDS) following IVlg infusion. V. AI~TERNATIVE TREATMENTS Over the years, a variety of other therapeutic modalities have been used for the treatment of ITP. Although not all of these agents have been used on children with ITP, they will be briefly mentioned. The main category of alternative therapeutic agents contains chemotherapeutic agents, which act to decrease antibody production and interfere with macrophage function. Azathioprine, 6-mercaptopurine, and cyclophosphamide have been used most commonly?a,62The occasional response in children is only slight, may take months to become evident, and is usually unsustained. The side effects of immunosuppression, bone marrow depression, and possible carcinogenesis make these modalities double edged. The vinca alkaloids, however, are more notable because their effect is more immediate, they stimulate thrombopoiesis, and are not known to be carcinogenic? 3 In addition, vinca alkaloids bind to tubulin, a structural protein of platelets. This binding property allows treatment with "vinca-loaded" platelets. In this method of treatment, allogeneic platelets are loaded in vitro with the vinca alkaloids, then are transfused into the patient. The platelets act as vehicles to deliver the drug to the macrophage. In a recent report, slow intravenous infusions of vinca alkaloids were used to achieve in vivo loading of platdets." Results using vinea alkaloids, particularly the slow-infusion method, are somewhat better than with the other immunosuppressants.
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Plasmapheresis has been used in the treatment of ITP, in an attempt to remove antibodies and immune complexes from the plasma. A preliminary report suggest that this method yields mild responses. "~ Because transient blockade of the RES has been successful in the treatment of ITP, an alternative method to IVIg infusion was recently described. ' ' Ten Rh-positive patients with ITP were given intravenous anti-gho(D) igG, which causes in vivo coating of erythrocytes. The RES recognizes these sensitized erythrocytes and removes them from the circulation. The authors found a transient rise in platelet count with this therapy, presumably secondary to competitive inhibition for the macrophage and the resulting mild RES blockade. There was evidence of hemolysis in seven of ten patients, however, and no clear advantages over 1Vlg was noted. It is possible, however, that alternative methods of RES blockade more economical than IVlg will become available. Other agents with even less clinical experience and usefulness include Colchicine, Danazol, Tamoxifen, and testosterone. 62 For each of the above alternative therapeutic modallties, it should be noted that there is very little experience with childhood ITP. VI. G U I D E L I N E S FOR M A N A G E M E N T O F C H I L D H O O D I T P The following paragraphs outline an approach to the diagnosis and management of ITP in children based upon the current understanding of the pathophysiology, published results of various treatment regimens, and the authors' own experience with the management of children with both acute and chronic ITP. The therapeutic suggestions are proposed as guidelines. The therapy for the individual patient must be tailored to the individual patient's specific clinical circumstance. The clinician must also be guided by the fact that the majority of patients will resolve their illness with time and without serious adverse effects. As previously mentioned, ITP is a diagnosis of exclusion. The clinical history and physical examination are useful to exclude infections, collagen vascular diseases, drug reactions, stem ceil failure, or malignancy as an etiology for the thrombocytopeaia. There is no laboratory test which is diagnostic of ITP. There are however several tests which can establish the diagnosis with reasonable certainty. These include the complete blood count (CBC) with piaielet count, inspection of the peripheral smear, a bone marrow aspirate, and measurement of both direct and indirect PAIgG levels. It has been argued that only the CBC, platelet count, and inspection of the peripheral smear need be performed routinely for those children with typical histories compatible with ITP. 6' We feel, however, that all of the previously mentioned tests are extremely useful to confirm the diagnosis. The bone marrow examination excludes both leukemia and aplastic anemia, while the PAIgG levels at diagnosis and prior to treatment may assist in predicting the clinical course. In general, those patients with higher direct PAIgG levels have been shown to have an acute course while those with lower levels of direct PAIgG will have a chronic course. Several other laboratory tests may be indicated based upon the findings from the clinical history or physical examination. These tests include a prothrombin time, par. tiai thrombopiastin time, urinalysis, blood culture, serum creatinine, antinuclear or anti-DNA antibodies, and both direct and indirect Coombs' tests. Once the diagnosis of iTP has been established with a reasonable degree of certainty, we begin P~ednisone 2 mg/kg/day in three divided doses (maximum dose of 60 mg daily) if the platelet count is less than 20 x 10*/l or if there are significant hemorrhagic symptoms including evidence of mucous membrane bleeding. Parents and patients are told that the patient must avoid aspirin because of its adverse effect on platelet rune-
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tion. Hospitalization is reserved for those patients with severe thrombocytopenia, those with serious hemorrhagic manifestations, and those in which the home situation is deemed less than adequate. Prednisone is maintained at the initial dose for 3 weeks and then is discontinued gradually over an additional week. Platdet transfusions are not routinely utilized because of the immune-mediated nature of platelet destruction. In life threatening situations, however, piateiet transfusions may be employed in conjunction with emergency splenectomy. The majority of children will have an increase in the platelet count during the course of steroids, usually by 7 to 10 days, although this rise may be spontaneous. Prednisone is not continued at the 2 m g / k g daily dose for longer than 3 weeks even if the patient fails to obtain a significant increase in the count. Similarly, if the patient has a recurrence of the thromboeytopenia when Prednisone is discontinued, steroids are not resumed unless there is significant clinical bleeding or the platelet count is below 20 x 10'/L If Prednisone is restarted, it is resumed at the original dose until thrombocytopenia improves and then is changed to an every-other-day schedule at the lowest possible dose to maintain a platelet count above 50 x 109/1. iVlg therapy is recommended for several groups of patients: (I) those presenting with serious hemorrhagic symptoms; (2) those with severe thromboeytopenia (less than 20 • 10"/1) refractory to Prednisone; (3) those with severe thromoboeytopenia recurring after Prednlsone therapy; or (4) those requiring chronic Prednisone administration to minimize severe thrombocytopenia. Presently we employ an initial dose of 1000 m s / kg daily for 2 days. If thromboeytopenia improves, subequent IVlg doses of 1000 m g / kg are administered at 2 to 8 week intervals to control severe thromboeytopenia. In general, splenectomy is reserved for patients whose thrombocytopenia is refractory to therapy with either steroids or IVIg, or in those very rare instances when intracranial hemorrhage occurs. Also, spleneetomy is used for those patients requiring prolonged steroid therapy or IVlg therapy to reduce hemorrhagic symptoms. It is our practice to attempt to delay spienectomy for at least I year from the date of initial diagnosis when possible, as spontaneous remission during this period of time is common. We also try to avoid the procedure ~f at all possible for those children under the age of 5 years because of the increased risk of sepsis from encapsulated organisms following this procedure. Prior to splenectomy, polyvalent pneumococcal vaccine is administered and following the procedure prophylactic penicillin is recommended for life.
REFERENCES I. Matoth, u Zaizov, R., and Frankel, J., Minimal cerebral dysfunction in children with chronic thrornboeytopenia, Pediatrics, 47,698, 1971. 2. Lushcr, J. and Ivery, R., Idiopathic thrombocytopenie purpura in children, Semin. Thromb. Hemostas., 3, 175, 1977. 3. McWillJams, N. and Maurer, H., Acute idiopathic thromhocytopenlc purpura in children, Am. J. Hematol., 7, 87, 1979. 4. Wocrner, S., Abildgaard, C., and French, B., Intracranial hemorrhage in children with idiopathic thrombocytopenie purpura, Pediatrics, 67,453, 1981. 5. Krlvit, W., "Fate, D., White, J., et al., Idiopathic thrombocytopenic purpura and intraeranial hemorrhage, Pediatrics,67, 570, 1981. d. Ware, R. and Kinney, T. R., The immunopatbo[ogy of childhood idiopathic thrombocytopcnic purpura, Crit. Rev. HcmatoL O•col., 7,139, 1987. 7. McWilliams, N. and Maurer, H,, Controlled clinical trial of prednisone in childhood idiopathic thromboeytopenir ptlrpura (I.T.P.), Pediatr. Res.~ I I(Abstr.), 476, 1977. 8. Sartorius, J., Steroid treatment o[ idiopathic thrombocytopenir purpura in children, Am. 7. Pediltr. Hematot. Oncol,, 6, 165, 1984.
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9. Lusher, J., Emami, A., Ravindranath, Y,, et ai., Idiopathic thromhocytopenle parpora in chi]drcn. The case for management without corticosteroids, Am, J, Ped~atr. Hematol. Oncol.,6, 149, 1984. 10. Buchanan, G. and Holtkamp, C., Prednisone therapy for children with newly diagnosed idiopathic thrombocytopenic purpura, Am. J. Pedialr. HematoL Oncol., 6) 355, 1984. 11. Weinblatt, M. and Ortega, J., Steroid responsiveness, Am, 3". Dis. Child., 136, 1064, 1982. 12. Branehog, I. and Weinfdd, A., Platelet survival and platdet production in idiopathic thrombocytopanic purpura ~ITP) before nnd during treatment with eortieosteroids, Scrod. ]. HacmatoL, 12, 69, 1974, 13. Jail, R., Firnzvi, T., arid Spurling, C,, Chronic idiopathic thromboeytopenie purpura, Arch. lnter. Mad., I32, 380, 1973. 14. Dixon, R., Rosse, W., and Ebbert, L,, Quantltative determination of antibody in idiopathic thromboeytopenic purpara, N. Engl. I. Mad., 292,230, ] 975. 15. Ware, R., Kinney, T., Friedman, H,, et al., Prognostic implications for direct pJatelel associated IgG in childhood idiopathlc thrQmbocytopenic purpura, Am. J. Pediatr. HematoL Oncot.,8(I), 32, I986, 15a, Harrington, W., Mianieh, V., Hollingsworth, J,, et al., Demonstration of a thrombocytopenle factor in the blood of patients with thromboeytopenic purpura, J. Lab. Clio. Mad., 38, I, 1951. 16. Shuiman, N,, Weinraeh, R., Libre, E., et at., The role of the retJculoendothelial system in the pathogenesis of idiopathic thromhocytopenic purptJra, Trans. Assoc. Am. Phys., 78, 374, J 965. 17. McMillaa, R.. Longmire, R., Tavassoli, M., et aL, In vitro p]atelet phagoeytosis by splenic leukocytes in idiopathic thrombocytopenie purpura. N. Enal. J. Mad., 290, 249. 1974. 18. Handin, R. and Stossr T., Effect of corticosteroid therapy on the phagocytosis of antibody-coated platelcts by human leukocytes, Blood, 51,771, 1978. 19. van Horn, D. and Johnson, S., The mechanism of thromhoeytopenie bleeding, Am. J. Clio, b'athol., 46,204, 1966. 20. Kitchens, C. and Weiss, L., Ultrastructural changes of andothelium associated with thrombocytopenia, Blood, 46, 567, 1975. 21. Kitchens, C,, Amdi~raslon of endothelial abnormalities by prednisone in experimental thrombocytopenia in the rabbit, J. Clln, Invest., 60, 1129, 1977. 22. Senyl, A., Blajchman, M., and Harsh, J,, The experimental corrective effect of hydrocortisone on the bleeding time in thrombocytopenie rabbits, Blood,46(Abstr.), 1034. 1975. 23. Butler, W., Corticosteroids and immunoglobulin synthesis, Transplant P~oc,, 7, 49. 1974. 24. Butler, W. and Rossea, R., Effects of corlieosteroid~ on immunity in man, J. Clio. Invest., 52, 2629, 1973. 25. McMiilan, R., Longmire, R., and Yeienosky. R., The effect of eorlicosteroids on human lgG synthesis, I, lmrannol., 116, 1592, 1976. 26. Goodman, L. and Gilman, A., Eds., The Pharmacological Basis of Therapeutics, 4th ed., MacMillan, New York. 1970, 1636. 27. Karpatkin, M. and Karpatkin, S., Immune thrombocytopenia in children, Am. J. Pediatr. Hamatol. OncoL, 3,213, 1981, 28. Russell E. and Maurer, H., Alternatives to splenectomy in the management of chronic idiopathic thrombocytopenir purpura in chitdhood, Am. J. Pediatr. Hematol. Oncol., 6. 175, 1984. 29. Thompson, R.. Moore, R., Hess, C., et al., Idiopathic thrombocytopenic purpura. Long-term results of treatment and the prognostic significance of response to cortlcosteroids, Arch. Intern. Mad.. 130, 730, 1972. 30. Bxennan, M., Rappeport, J., Moloney, W., et al., Correlation between response to corticostero!ds and splenectomy for adult idiopathic thromhocytopenic purpura, Am. J. Surg., 129, 490, 1975. 31. Gugliotta. L., lsacchi. G.. Guarani, A., et ~I) Chronic idiopathic thrombocytopenic purpura (ITP): site of platelet sequestration and results of splenectomy, Stand..L Haematoh, 26,407, 1981. 32. Pawelski, S., Konopka, L., and Zdziechowska, H., Recurrence of thrombocytopenla in patients splenectomized for idiopathic thrombocytopenie purpura, Blut, 43, 355, 1981. 33. Eraklis, A. and Filler. R., Splenectomy in childhood: a review of 1413 cases, ,I. Pediatr. Sur~., 7, 382, 1972. 34. Lightsey, A. arid McMillau, R., The role of the spleen in "~tutoimmune" blood disorders, Am. J, Pedlatr, HematoL OncoL, 1, 33I, 1979. 35, Heyns, A., Lotter, M., Badenhorst, P., et al,, Kinetics and sites of destruction of [nd[um-oxinelabeled platelets in idiopathic thrombocytopenic purpura: a quantitative study. Am. J. Hematol., 12, 167, 1982. 36. Dickerman, J., Spleneetomy and sepsis: a warning. Pediatrics, 63,935, 1979. 37. Amsbangh, D., Prescott, B., and Baker, P., Effect of spleneetomy on the expression of regulatory T cell activity, J, lmmunol., 121, 1483,1978. 38. $chumacher, M., Serum ilnmuanglobulin and transferrin levels after childhood splenectomy, Arch. Dis, Child..45. 114. 1970.
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39. Andersen, V., Cohn, J., and $orcnsen, S , Immunological studies in children before and after spleneclomy, Acta Paedialr. Stand., 65,409,1976 40. Sullivan, J., Schlfg'man, G., Miner, J., et al., lmmone response after sp/enoctomy. La~zcct, I, 178, 1978, 41. Carlisle, H. and Saw S., Properdln levels in spleneetomized persons, Pron. Sor F.xp, 8iol. &led,, 102, 150, 1959. 42. Polhi11, g. and Johnston, R,, Diminished alternative complement pathway (ACP)activity after splenectomy, Pediatr. Bes., 9(Ahstr,L JJh, ~975. 43, Imbach, P.. Barandnn. S., Baamgartner, C., et ~1.. High-dose ir~travenous gemmagIob~lirt therapy of refractory, in particular idiopalhic thromhocylop~nia in childhood~ Holy. Paedlatr. Aeta, 46, g I, 198t. 44. Imhach, P,, d'Apuzzo, V., Hirt, A., et aL, High-dose intravenous gammaglobulln for idiopathic thromboeytopenie purpma in childhood, Lancet, 1,1228, 1981. 45. Fehr, J., Hofmann, V., and Kappeler, O., Transient reversal of thromboeytopenia in idiopathic thromboeytopenie purpara by high-dose intravenous gamma g',obulln, N. E~gh J. M~d., 306, 1254, 1982, 46. Bussd, J., Schulman, 1., Hilgartner, M., at aL, Intravenous use of gammaglobulin in the treatment of chronic immune thrombocytopeaic putputa as a mr to d~fer spleneelomy, ], Pediatr,, 103, 651, 1983. 47. Beck, R., Gammaglobolln therapy for neonatal ITP (tetter~, L Pediatr., ~04, 638, I984. 4ft. Chirir162G., Dose, M., Ugazlo, A,, et aL, High-doze. intravenous gammaglohulin therapy for passive immune thromhocytopenia in the neonate, J. Pcdiatr., ]03,654, 1983~ 49. Morg~nstern, G., Mc~day, B., and Hedge, U., Autoimtouae thrombocytopenia in pregnancy. New approach to manor.carom, Be. &led, J., 287,584, 1983. 50. Wenske, C., Gaedick~, G., Kuenzlen, E., et hi., Treatmem of idiopathic thrombocytic pmpura in pregnancy b.'; high-dose intravenous immunoglobulin, Blur,,16, 347, 1'~3. 51. Uchino. H., Yasnnaga, K., and Akatsuka~ J., A cooperatNe clinical trial of high-dose immunoglobolin therapy in 177 cases ol idiopathic thrombocylopenie purpura, Thromh. Haemost~s~, 51, 182, I984. 52. lmbach, P., Barandan, S.. Hirt, A., r aI, Intravenous hnma~oglobu[in for idiopathic thrombocytopenic purpura (ITP)in childhood, Am. J. Ped~alr. HematoL OneoL, 6, 171, 1984, Sh. Lung, L, paradji, A., Oiron, C., r aL, High-do~e intravenous IgG for chr