Pediatric Annals

HEMOSTATIC DISORDERS IN CHILDREN 

Idiopathic Thrombocytopenic Purpura in Childhood

R Buchanan, MD

Abstract

Idiopathic or immune thrombocytopenic purpura (ITP) is one of the most common bleeding disorders in children. The usual clinical scenario is straightforward: a previously well child has recovered from a recent viral infection and then suddenly is noted to have unexplained bruises and pinpoint red spots (petechiae) on the skin, sometimes accompanied by epistaxis and bleeding from the mouth. The child otherwise feels well. The physical examination shows a healthy-appearing child with petechiae, purpura, and, in some cases, mucous membrane hemorrhage. There is no lymphadenopathy, hepatosplenomegaly, or other evidence of an underlying disorder. Results of a complete blood cell count are normal except for thrombocytopenia. In fact, the platelet count is often less than 10,000 /mm3. Now some decisions need to be made: what other diagnoses should be entertained, what treatment should be given, and what is the child's prognosis?

The purpose of this article is to answer these questions, with the proviso that there is much controversy (and many differences of opinion) among alleged "experts" in the field and that virtually no recommendations regarding ITP are based on sound scientific data. Some of the key controversies are summarized in Table 1. This article attempts. to put some of these uncertainties into perspective for pediatricians who encounter this interesting disorder.

DIAGNOSIS AND PATHOGENESIS

There are few diagnostic dilemmas related to childhood ITP. Although the peak age of incidence ranges from 18 months to 6 years, ITP can be seen in infants as young as 2 or 3 months and adolescents. In fact, it is sometimes encountered in middle-aged and elderly adults. However, classic ITP is not seen in neonates. Instead, an infant 2 months or younger with severe symptomatic thrombocytopenia is likely to have acquired an anti-platelet antibody from his or her mother, who had ITP or was sensitized to an antigen on the infant's and the father's platelets (socalled neonatal alloimmune thrombocytopenia).

Approximately 1 in 1,500 individuals has ITP during childhood, and this translates to 4 to 5 cases per 100,000 children annually.1 Males and females are affected equally, except during adolescence when girls predominate. ITP is rarely due to drug exposure. Thus, most drugs being taken by a child in whom ITP develops can be continued safely. This is different from the situation in adults, where immune-mediated thrombocytopenia due to pharmacologic agents is more common.

Table

Chronic ITP is managed similarly to the acute form of this disease (ie, emphasis is placed on the extent of bleeding and the impact of the disease and its treatment on the quality of life rather than on the actual platelet count). Most patients with chronic ITP require no therapy, although those with continued hemorrhage may be negatively affected because of the need to restrict activities, the constant fear of more serious hemorrhage, or both. It is these children who may benefit from therapy.

Long-term daily corticosteroids are contraindicated. Intermittent pulses of dexamethasone were explored a decade ago and reported as effective,13 but the treatment is toxic and infrequently results in sustained responses.14 Regular infusions of IVIG or anti-D immunoglobulin have been recommended. This approach is costly and associated with side effects, but it is sometimes preferred in very young patients for whom splenectomy is undesirable. A variety of immunosuppressive agents have been studied, including cyclophosphamide, azathioprine, cyclosporine, dapsone, interferon, danazol (a weak synthetic androgen), and anti-CD20 monoclonal antibody, but convincing data regarding their utility for children (or even adults) are lacking. Therefore, the only effective "curative" options for children with ITP are "watchful waiting" for the disease to enter a spontaneous remission (which it often will if one can wait long…

Idiopathic or immune thrombocytopenic purpura (ITP) is one of the most common bleeding disorders in children. The usual clinical scenario is straightforward: a previously well child has recovered from a recent viral infection and then suddenly is noted to have unexplained bruises and pinpoint red spots (petechiae) on the skin, sometimes accompanied by epistaxis and bleeding from the mouth. The child otherwise feels well. The physical examination shows a healthy-appearing child with petechiae, purpura, and, in some cases, mucous membrane hemorrhage. There is no lymphadenopathy, hepatosplenomegaly, or other evidence of an underlying disorder. Results of a complete blood cell count are normal except for thrombocytopenia. In fact, the platelet count is often less than 10,000 /mm3. Now some decisions need to be made: what other diagnoses should be entertained, what treatment should be given, and what is the child's prognosis?

The purpose of this article is to answer these questions, with the proviso that there is much controversy (and many differences of opinion) among alleged "experts" in the field and that virtually no recommendations regarding ITP are based on sound scientific data. Some of the key controversies are summarized in Table 1. This article attempts. to put some of these uncertainties into perspective for pediatricians who encounter this interesting disorder.

DIAGNOSIS AND PATHOGENESIS

There are few diagnostic dilemmas related to childhood ITP. Although the peak age of incidence ranges from 18 months to 6 years, ITP can be seen in infants as young as 2 or 3 months and adolescents. In fact, it is sometimes encountered in middle-aged and elderly adults. However, classic ITP is not seen in neonates. Instead, an infant 2 months or younger with severe symptomatic thrombocytopenia is likely to have acquired an anti-platelet antibody from his or her mother, who had ITP or was sensitized to an antigen on the infant's and the father's platelets (socalled neonatal alloimmune thrombocytopenia).

Approximately 1 in 1,500 individuals has ITP during childhood, and this translates to 4 to 5 cases per 100,000 children annually.1 Males and females are affected equally, except during adolescence when girls predominate. ITP is rarely due to drug exposure. Thus, most drugs being taken by a child in whom ITP develops can be continued safely. This is different from the situation in adults, where immune-mediated thrombocytopenia due to pharmacologic agents is more common.

Table

TABLE 1Some of the Key Controversies in Childhood Idiopathic Thrombocytopenic Purpura (ITP)

TABLE 1

Some of the Key Controversies in Childhood Idiopathic Thrombocytopenic Purpura (ITP)

Although ITP is said to be triggered by a prior viral infection, the evidence to support this is slim. Children, regardless of whether they are newly diagnosed as having ITP, have frequently had an infectious illness during the preceding several weeks. ITP results from rapid destruction of platelets by macrophages in the spleen and the liver. It is attractive to hypothesize that the antiplatelet antibody or immune complex that causes this platelet destruction is the consequence of an immunologic response to a recent infection. Although ITP is not thought of as a hereditary disorder, the seemingly frequent occurrence of ITP in children with a positive family history of rheumatic or immunologic disease is of interest.

A key to the clinical diagnosis of ITP is that the thrombocytopenia is isolated (ie, associated with a normal hemoglobin and white blood cell [WBC] count). The differential diagnosis of such isolated severe thrombocytopenia is then limited. Hemolytic uremic syndrome and disseminated intravascular coagulation are not likely to be confused with ITP because these make patients ill. Acute leukemia and aplastic anemia should always be given serious consideration. However, nearly all children with leukemia present with abnormal WBC counts (both quantitative and qualitative), anemia, lymphadenopathy and hepatosplenomegaly, or all of these. Aplastic anemia may present with thrombocytopenia, and at first glance this may appear to be an isolated abnormality. Yet, this disorder is usually associated with other (sometimes subtle) alterations in the blood cell count (eg, elevated erythrocyte mean corpuscular volume or mild neutropenia).

A bone marrow aspiration to rule out these diagnostic possibilities is not routinely required, but should be performed (thus necessitating an immediate referral to a pediatric hematologistoncologist) if there is even the slightest evidence for one of them, such as thrombocytopenia and an abnormality in the blood cell count that is not readily explained (eg, anemia not accompanying external bleeding). Other laboratory testing is not required. An anti-platelet antibody measurement, a bleeding time test, blood coagulation screening (prothrombin time [PT] and partial thromboplastin time [PTT]), liver chemistries, electrolytes, and evaluation for connective tissue disease have no role in the diagnosis of acute childhood ITP.

Some patients present with an insidious history of bruising during many months and have a milder thrombocytopenia (platelet counts between 20,000 and 80,000 /mm3). Here again, leukemia and aplastic anemia need to be considered as alternative diagnoses, as should hereditary thrombocytopenia, thrombocytopenia accompanying splenomegaly and portal hypertension, and immune thrombocytopenia due to a connective tissue disease. However, many of these patients will have chronic ITP. Many patients with chronic GG? who are mildly affected are diagnosed "accidentally" when a blood cell count is performed for another purpose and are sometimes described as having "incidental thrombocytopenia."

WHO SHOULD MANAGE ITP?

Should the pediatrician be able to diagnose ITP or is a specialist necessary? In most cases, the pediatrician can diagnose and manage ITP. However, it is advisable to obtain a telephone consultation with a pediatric hematology-oncology specialist before making the diagnosis and starting treatment. For those children with atypical presentations, especially when they are bleeding profusely, a hematologist-oncologist should definitely be involved.

Although the prominent bruises and petechiae that characterize most children with ITP are alarming, these hemorrhagic manifestations are not actually dangerous. Approximately 15% to 20% of children with ITP have mucous membrane hemorrhages (so-called "wet purpura"), but only a small proportion of them have profuse bleeding, continuous bleeding, or both that results in a declining hemoglobin concentration.1 Some of these children require a red blood cell transfusion and should be referred to a specialist.

It is critical that pediatricians not panic when they encounter children with newly diagnosed ITP. The platelets of these children are newly made by the bone marrow and exhibit excellent function. However, due to their large size, their numbers are often underestimated by the electronic cell counter because they have been enumerated as leukocytes. Thus, therapeutic decision making should be based on clinical manifestations of bleeding rather than platelet count per se. Only 2% to 3% of children with ITP have a "major" hemorrhage that results in continued external bleeding or internal hemorrhage. The most serious is intracranial hemorrhage, and this occurs in only 0.1% to 0.5% (1 in 200 to 1 in 1,000) of patients with ITP.2

TREATMENT

Treatment of any medical condition first requires an understanding of what the outcome will be without any active intervention (ie, with supportive care alone). Fortunately, ITP is generally self-limited.3,4 Most children exhibit a decrease in bleeding within a week or so of diagnosis, and the platelet count typically begins to rise after several weeks. It returns to normal in 80% of these children within 6 months. Those with persistent thrombocytopenia (documented for more than 6 months) are arbitrarily designated as having chronic ITP. Many such children are mildly affected (eg, they have incidental and asymptomatic thrombocytopenia), exhibit resolution of their disease within 1 to 2 years, or both.

It is generally agreed that standard supportive care following the diagnosis of acute ITP includes avoidance of aspirin, drugs containing aspirin, and Ibuprofen (although the latter agent's antiplatelet effects are weak and do not permanently injure the platelet). If possible, the child's activities should be limited as long as the platelet count is less than 20,000 /mm3, there is excessive bruising and new petechiae are still appearing, or both. However, it should be possible for the child to return to school or day care as long as supervisory personnel are aware of the need to avoid head injury. Contact sports should be avoided while the platelet count is less than 50,000 /mm3.

A special dilemma exists when dealing with toddlers and other active young children with ITP and marked thrombocytopenia. Limiting their activities is not feasible. Protective headgear may be helpful, along with a heavy dose of hand holding and reassurance. Parents are nervous about the risk of bleeding following head trauma, an event that is rare. Hospitalization is not generally indicated for thrombocytopenia without complications.

Because bleeding tendency is inversely proportional to the platelet count, it seems intuitive to administer drug therapy to raise the platelet count. Several different treatments have been employed for ITP, all of which block the ability of macrophages in the spleen and the liver to ingest antibody-coated platelets. The three primary drug treatments used to raise the platelet count are corticosteroids, intravenous immunoglobulin (IVIG), and anti-D immunoglobulin (Table 2).

Each of these medications has its staunch advocates and detractors as a result of the advantages and disadvantages associated with administering it (Table 3). Following treatment with one or more of these agents, the platelet count will likely rise more rapidly than if no drug treatment is given. Whether the child benefits from this increased platelet count is unproved. Each medication has side effects, costs, and inconveniences that conceivably might interfere with the child's and the family's quality of life more than the bleeding manifestations of the ITP. The relatively uncommon patient with ITP who already had a major bleed at presentation should receive drug therapy (Table 2). Yet, no study has shown that therapy with corticosteroids, IVIG, or anti-D immunoglobulin prevents intracranial or other life-threatening hemorrhage. In fact, approximately half of the children with ITP in the literature who had intracranial hemorrhage had previously received at least one of these agents.2

Table

TABLE 2Drug Treatments for Childhood Idiopathic Thrombocytopenic Purpura

TABLE 2

Drug Treatments for Childhood Idiopathic Thrombocytopenic Purpura

Table

TABLE 3The Advantages and Disadvantages of Routine Drug Treatment for Children With Idiopathic Thrombocytopenic Purpura

TABLE 3

The Advantages and Disadvantages of Routine Drug Treatment for Children With Idiopathic Thrombocytopenic Purpura

Although some pediatric hematologists (myself included) do not believe that most children with acute GG? require drug therapy, many others prescribe these treatments (Table 3). They believe that all efforts should be made to raise the platelet count as quickly as possible with the aim of preventing serious bleeding. This strategy is based on the results of several randomized trials showing that corticosteroids, IVIG, and anti-D immunoglobulin raise platelet counts more rapidly than if no drug therapy is given.5,6 Prednisone is the easiest to administer and the least costly. A short course of therapy has few serious side effects. PvTG raises the platelet count more rapidly - platelets exceed 50,000 /mm3 within 3 days in more than 85% of patients. However, the administration of IVIG is time-consuming and requires intravenous access. Moreover, Pv7IG often causes severe headaches,7 nausea and vomiting, and chills. Plus, IVIG is costly at $2,000 to $10,000 per dose, depending on the weight of the patient. Anti-D immunoglobulin is easier to administer than IVIG. However, it is expensive and its side effects include hemolytic anemia and, rarely, renal failure.8 It raises the platelet count nearly as promptly as IVIG.

The problem is that none of these agents have been shown to prevent serious bleeding,3,4 and there are several arguments against using them for uncomplicated TTP. For example, children who already exhibit major hemorrhage at diagnosis often do not respond to them.9 Also, the "artificial" and temporary rise in platelet count, sometimes lasting just a week or two, provides a false sense of security, and parents and pediatricians are often discouraged on recurrence of the thrombocytopenia. The temptation then exists to again treat the platelet count rather than the child, in whom the likelihood of serious bleeding remains extremely low. Although the platelet count is widely viewed as a surrogate measure of hemorrhagic risk in ITP, there are no data to support this notion.

It is my practice to administer drug treatment to only those children with acute ITP who exhibit clinically significant mucous membrane hemorrhage or when parents insist that something be given to raise their child's platelet count, despite my counseling and reassurance. A recent report from Germany of 55 consecutive children with acute ITP managed successfully without drug therapy10 supports this "wait and see" strategy, which incidentally was well accepted by the parents. Some physicians argue that drug therapy should be offered to every symptomatic child with ITP for medicolegal reasons. However, treatment does not spare the physician from being sued if there is an adverse outcome. I am aware of at least a half-dozen cases in recent years where physicians of children with intracranial hemorrhage complicating ITP have been sued despite the fact that they had administered one or more pharmacologic agents before the event.

So, what is the "bottom line" regarding therapy? Currently, the question of whether drug therapy should be given to patients with uncomplicated ITP simply remains unanswered. Randomized studies to examine outcome measures, such as bleeding severity, cost, side effects of treatment, and health-related quality of life, are badly needed.11 Some advantages and disadvantages of drug therapy are summarized in Table 3, and some practical "dos" and "don'ts" regarding the management of ITP are listed in Table 4.

Regarding intracranial hemorrhage, existing (and incomplete) data indicate that this complication occurs in between 1 in 200 and 1 in 1,000 cases and cannot be predicted, except for the fact that the platelet count is usually less than 10,000/ mm3 at the time.1'2 Of course, when this event is suspected or documented, aggressive pharmacologic therapy is required. In addition to high doses of corticosteroids and IVIG, platelet transfusions and other emergent medical and surgical support (including splenectomy, craniotomy, or both if necessary) should be initiated. As a result, more than 50% of children with intracerebral hemorrhage survive, most of them neurologically intact.1

Table

TABLE 4Some Dos and Don'ts of the Management of Idiopathic Thrombocytopenic Purpura

TABLE 4

Some Dos and Don'ts of the Management of Idiopathic Thrombocytopenic Purpura

CHRONIC ITP

Approximately 20% of children with ITP have chronic disease (ie, they continue to have a platelet count of less than 150,000 /mm3 for at least 6 months following diagnosis).1 These children fall into two categories. One includes patients who presented suddenly with severe thrombocytopenia and were considered to have acute disease, but failed to recover. The other consists of children with milder thrombocytopenia and minimal bleeding symptoms who presented nonspecifically with a history of bleeding manifestations during many months or even years. This category also includes patients with incidental thrombocytopenia who are totally asymptomatic.

Similar to patients with acute ITP, children with chronic disease are usually otherwise normal. However, a greater percentage have a positive family history of an immunologic disorder and a personal history (often nonspecific or subtle) of allergic or immunologic disease. Approximately 20% of patients with chronic ITP have positive results on an antinuclear antibody test, although only a few have antibody against native DNA and are thus destined to have systemic lupus erythematosus or another welldefined rheumatologic condition.1 Occasionally an ITP-like illness is accompanied by a positive result on a Coombs' test, indicating autoimmune hemolytic anemia (so-called Evans syndrome). When this is associated with lymphadenopathy and a positive family history, the diagnosis of autoimmune lymphoproliferative syndrome should be suspected. This disorder is characterized by a mutation in the fas gene or its ligand, resulting in an inhibition of programmed cell death. Thus, lymphoid cells continue to proliferate in an unrestrained fashion, with disregulated autoantibody formation.12

Table

TABLE 5Web Sites on Idiopathic Thrombocytopenic Purpura (ITP)

TABLE 5

Web Sites on Idiopathic Thrombocytopenic Purpura (ITP)

Chronic ITP is managed similarly to the acute form of this disease (ie, emphasis is placed on the extent of bleeding and the impact of the disease and its treatment on the quality of life rather than on the actual platelet count). Most patients with chronic ITP require no therapy, although those with continued hemorrhage may be negatively affected because of the need to restrict activities, the constant fear of more serious hemorrhage, or both. It is these children who may benefit from therapy.

Long-term daily corticosteroids are contraindicated. Intermittent pulses of dexamethasone were explored a decade ago and reported as effective,13 but the treatment is toxic and infrequently results in sustained responses.14 Regular infusions of IVIG or anti-D immunoglobulin have been recommended. This approach is costly and associated with side effects, but it is sometimes preferred in very young patients for whom splenectomy is undesirable. A variety of immunosuppressive agents have been studied, including cyclophosphamide, azathioprine, cyclosporine, dapsone, interferon, danazol (a weak synthetic androgen), and anti-CD20 monoclonal antibody, but convincing data regarding their utility for children (or even adults) are lacking. Therefore, the only effective "curative" options for children with ITP are "watchful waiting" for the disease to enter a spontaneous remission (which it often will if one can wait long enough11) or a splenectomy.

The spleen is the primary site of both platelet destruction and synthesis of anti-platelet antibody. Therefore, in at least 80% of cases, splenectomy is successful (ie, it is followed by a rise in the platelet count to normal or to a level where bleeding manifestations are reduced and a more normal lifestyle can be resumed).15 Laparoscopic splenectomy is preferred to the open procedure.16 Precautions must be taken to prevent severe hemorrhage from this procedure and post-splenectomy septicemia. Prevention of the latter includes using prophylactic penicillin, vaccines against encapsulated bacteria, and aggressive management of febrile illnesses.

CONCLUSION

ITP causes much anxiety among pediatricians who are unfamiliar with diagnosing and treating patients with severe thrombocytopenia. However, the excellent platelet function, normal hematologic findings other than thrombocytopenia, otherwise good health of these patients, and self-limited nature of the illness make for a disease with an outcome that is nearly always excellent. As I often tell my patients and their parents, "If you have to have a blood disease, this is the one to have." As with so many conditions during childhood, some reassuring hand holding by the pediatrician and "tincture of time" usually bring success. Table 5 lists some useful web sites regarding ITP.

REFERENCES

1. Medeiros D, Buchanan GR. Current controversies in the management of idiopathic thrombocytopenic purpura during childhood. Pediatr Clin North Am. 1996;43:757-772.

2. Lilleyman JS. Intracranial hemorrhage in idiopathic thrombocytopenic purpura. Arch Dis Child. 1994;71:251253.

3. Lilleyman JS. Management of childhood idiopathic thrombocytopenic purpura. Br J Haematol. 1999;105:871875.

4. Bolton-Maggs PH. Idiopathic thrombocytopenic purpura. Arch Dis Child. 2000;83:220-222.

5. Blanchette VS, Luke B, Andrew M, et al. A prospective, randomized trial of high-dose intravenous immune globulin G therapy, oral prednisone therapy, and no therapy in childhood acute immune thrombocytopenic purpura. / Pediatr. 1993;123:989-995.

6. Blanchette VS, Imbach P, Andrew M, et al. Randomised trial of intravenous immunoglobulin G, intravenous antiD, and oral prednisone in childhood acute immune thrombocytopenic purpura. Lancet. 1994;344:703-707.

7. Kattamis AC, Shankar S, Cohen AR. Neurologic complications of treatment of childhood acute immune thrombocytopenic purpura with intravenously administered immunoglobulin G. J Pediatr. 1997,130:281-283.

8. Gaines AR. Acute onset hemoglobinemia and /or hemoglobinuria and sequelae following Rh(o)(D) immune globulin intravenous administration in immune thrombocytopenic purpura patients. Blood. 2000;95:2523-2529.

9. Medeiros D, Buchanan GR. Idiopathic thrombocytopenic purpura: beyond consensus. Curr Opin Pediatr. 2000;12:49.

10. Dickerhoff R, von Ruecker A. The clinical course of immune thrombocytopenic purpura in children who did not receive intravenous immunoglobulins or sustained prednisone treatment. / Pediatr. 2000;137:629-632.

11. Buchanan GR, Adix L. Outcome measures and treatment endpoints other than platelet count in childhood idiopathic thrombocytopenic purpura. Semin Thromb Hemost. 2001;27:277-285.

12. Infante AJ, Brirton HA, DeNapoli T, et al. The clinical spectrum in a large kindred with autoimmune lymphoproliferative syndrome caused by a Fas mutation that impairs lymphocyte apoptosis. / Pediatr. 1998;133:629-633.

13. Andersen JC. Response of resistant idiopathic thrombocytopenic purpura to pulsed high-dose dexamethasone therapy. N Engl J Med. 1994;330:1560-1564.

14. Kühne T, Freedman J, Semple JW, Doyle J, Butchart S, Blanchette VS. Platelet and immune responses to oral cyclic dexamethasone therapy in childhood chronic immune thrombocytopenic purpura. / Pediatr. 1997;130: 17-24.

15. Mantadakis E, Buchanan GR. Elective splenectomy in children with idiopathic thrombocytopenic purpura. J Pediatr Hematoi Oncol. 2000;22:148-153.

16. Farah RA, Rogers ZR, Thompson WR, Hicks BA, Guzzetta PC, Buchanan GR. Comparison of laparoscopic and open splenectomy in children with hematologic disorders. J Pediatr. 1997;131:41-46.

TABLE 1

Some of the Key Controversies in Childhood Idiopathic Thrombocytopenic Purpura (ITP)

TABLE 2

Drug Treatments for Childhood Idiopathic Thrombocytopenic Purpura

TABLE 3

The Advantages and Disadvantages of Routine Drug Treatment for Children With Idiopathic Thrombocytopenic Purpura

TABLE 4

Some Dos and Don'ts of the Management of Idiopathic Thrombocytopenic Purpura

TABLE 5

Web Sites on Idiopathic Thrombocytopenic Purpura (ITP)

10.3928/0090-4481-20010901-07

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