Pediatrics in Review 2000 Chu 95 104

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DOI: 10.1542/pir.21-3-952000;21;95Pediatrics in Review

Yu-Waye Chu, James Korb and Kathleen M. SakamotoIdiopathic Thrombocytopenic Purpura

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Idiopathic Thrombocytopenic Purpura Yu-Waye Chu, MD,* James Korb, MD,† and Kathleen M. Sakamoto, MD*

OBJECTIVES

After completing this article, readers should be able to:

1. Describe the clinical and laboratory features of idiopathic thrombocy-topenic purpura (ITP) and explain how they differ in acute andchronic ITP.

2. List the features of ITP that distinguish it from other causes of thrombocytopenia.

3. Explain the role of bone marrow examination in the diagnosis of ITP.4. Describe the advantages and disadvantages of the primary therapies

for ITP.5. Delineate the differences in therapeutic strategies for ITP and neona-

tal alloimmune thrombocytopenia.6. Describe the role of splenectomy in the treatment of ITP.

Epidemiology and

Pathophysiology Idiopathic thrombocytopenic purpura(ITP) is an acquired hemorrhagicdisorder characterized by: 1) throm-bocytopenia that is defined as aplatelet count less than 150 x 109 /L(150,000/mcL), 2) a purpuric rash,3) normal bone marrow, and 4) theabsence of signs of other identifiablecauses of thrombocytopenia. ITP isclassified as acute or chronic, withthe latter defined as the persistenceof thrombocytopenia for more than

6 months from the initial presenta-tion of signs and symptoms.

ITP is estimated to be one of themost common acquired bleedingdisorders encountered by pediatri-cians, with the incidence of symp-tomatic disease being approximately3 to 8 per 100,000 children per year.Acute ITP is more prevalent amongchildren younger than 10 years of age, affects males and femalesequally, and is more prevalent dur-ing the late winter and spring.

Chronic ITP affects adolescentsmore often than younger children,with females being affected morefrequently than males. Unlike acute

ITP, it does not show a seasonal

predilection. Patients who havechronic ITP are more likely toexhibit an underlying autoimmunedisorder, with up to one third havingclinical and laboratory manifesta-tions of collagen-vascular disease.

Although the focus of this articleis on the clinical presentation, diag-nosis, and management of ITP, thepathophysiology of this conditiondeserves mention because the mech-anisms contributing to thrombocyto-penia are more complex than origi-

nally thought. It is widely believedthat the destruction of platelets inITP involves autoantibodies to gly-coproteins normally expressed onplatelet membranes. The spleen andother organs of the reticuloendothe-lial system subsequently destroythese antibody-coated platelets in amanner analogous to what isobserved in autoimmune hemolyticanemia. In addition to increasedimmune-mediated destruction of platelets, there is evidence that

platelet production in ITP is altered,especially in chronic ITP. Althoughthe number of megakaryocytes inthe bone marrow are normal orincreased in ITP, plasma thrombo-poietin levels, which are a measureof proliferation and maturation of megakaryocytic progenitors, are sig-nificantly decreased. In chronic ITP,platelet turnover is markedly lowerdespite decreased platelet survival,and megakaryocytes isolated fromaffected patients demonstrate sup-

pressed growth in vitro.

The clinical and epidemiologicaldifferences between acute andchronic ITP suggest that the result-ing thrombocytopenia may have dif-

ferent pathophysiologic mechanisms.In acute ITP, it has been postulatedthat platelet destruction arises fromantibodies generated during theimmune response to a viral or bacte-rial infection that cross-react withplatelet antigens. Other mediators of the immune response arising frominfection may play an additional rolein suppressing platelet production.Chronic ITP, on the other hand, maybe a consequence of an inherentdefect in immune regulation, as is

seen in other autoimmune disorders,resulting in the generation of platelet-specific antibodies. To date,a number of platelet surface glyco-proteins (GPs) have been identifiedas specific targets for autoantibodiesin ITP, including GP IIb-IIIa, GP Ib,and GP V. How these antiplateletantibodies arise in ITP, their signifi-cance in distinguishing the patho-physiology of acute versus chronicITP, and the cellular and biochemi-cal components that are involved intheir regulation remain unknown.Current therapeutic regimens used inthe management of ITP, therefore,are limited in their efficacy becausethey fail to target specific immuno-logic pathways responsible for alter-ation of platelet production anddestruction.

Clinical and Laboratory Features

CLINICAL FINDINGS

ITP is diagnosed largely on clinicalfindings. Familiarity with the fea-tures of acute ITP plays an impor-tant role in determining the extent of

* Division of Hematology-Oncology,

Department of Pediatrics.† Division of General Pediatrics, Department of Pediatrics, UCLA School of Medicine,

Los Angeles, CA.

This work was supported by a Resident

Research Grant from the American Academy of Pediatrics (Y-WC). KMS is a

Scholar of the Leukemia Society of America.

ABBREVIATIONS

CBC: complete blood count

GP: glycoprotein

ICH: intracranial hemorrhage

ITP: idiopathic thrombocytopenicpurpura

IVIG: intravenous immunoglobulins

ARTICLE

Pediatrics in Review Vol. 21 No. 3 March 2000 95








the diagnostic evaluation. The typi-cal clinical presentation is that of anotherwise healthy child who devel-ops easy bruising and a purpuricrash. Bleeding from mucous mem-branes, such as nosebleeds or gingi-val bleeding, is seen in about onethird of cases. Other sites of bleed-

ing include the gastrointestinal tract,vaginal mucosa, the urinary tract,the retina, and conjunctivae. In acuteITP, the onset of signs and symp-toms often is preceded by a viralillness. Except for the manifestationsof bleeding, findings on the physicalexamination are otherwise com-pletely normal. Pertinent negativesof the examination include theabsence of lymphadenopathy andhepatosplenomegaly. The presenceof either should raise the consider-

ation of other diseases, particularlyleukemia. Similarly, the presence of pallor, hyperbilirubinemia, andsplenomegaly are features of a con-comitant hemolytic anemia, whichcan be seen in conjunction withthrombocytopenia in Evans syn-drome and other autoimmune dis-eases. In chronic ITP, the presenta-tion may be more insidious, andoften the patient may beasymptomatic.

The distribution of the patient’sbruises and bleeding sites providesadditional clues to the etiology. Indisorders of primary hemostasissuch as ITP and other platelet disor-ders, bruises are generalized andoccur in areas not exposed totrauma. Bruises found in these areasare distinctly abnormal and warrantfurther investigation. In contrast,bruising in a healthy, active childoccurs in exposed areas, especiallyover hard bony surfaces. Bruisingalso can be a feature of child abuse,which should be considered in a

child who has generalized bruisingand a normal platelet count.

LABORATORY FINDINGS

The laboratory features of ITP helpto distinguish it from other causes of thrombocytopenia. Key to the labo-ratory diagnosis of acute ITP is thepresence of a low platelet count(usually 20 to 30 x 109 /L[20,000 to 30,000/mcL]), generallywith normal values for age in all

other cell lines. In about 15% of

patients, mild anemia due to bleed-ing is present, but red blood cellindices are normal. If results of thecomplete blood count (CBC) areconsistent with ITP, coagulationstudies are not warranted. The pro-thrombin time and partial thrombo-plastin time are invariably normal,

but the bleeding time, which is adirect test of platelet function,almost always is prolonged. Abnor-mal leukocyte or red blood cellcounts should prompt further diag-nostic investigation to exclude thepossibility of an underlying leuke-mia or aplastic anemia.

In addition to the CBC, it isessential to examine a peripheralblood smear under light microscopyfor several reasons. First, it serves torule out “pseudothrombocytopenia,”

an in vitro artifact caused by theclumping of platelets in tubes con-taining the anticoagulant ethylene-diamine-tetraacetic acid, whichresults in low platelet counts whenmeasured on an automated cellcounter. Second, characterization of red blood cell morphology enablesthe examiner to detect the presenceof a concomitant hemolytic process(eg, hemolytic-uremic syndrome,disseminated intravascular coagula-tion, or Evans syndrome) orhypoproliferative anemia (eg, ane-mia due to nutritional deficiencies).Third, abnormal white blood cellcounts or the presence of immaturenucleated forms may indicate anunderlying primary or secondarybone marrow neoplasm. Fourth,examination of individual plateletsaids in the diagnosis of ITP. Plateletsize is increased noticeably in acuteITP, reflecting increased plateletturnover and the release of younger,larger platelets from the bone mar-row, while it may be reduced in

other thromboctyopenic entities (seeDifferential Diagnosis).

An examination of the bone mar-row is indicated in certain situations(see following section). Megakaryo-cytes usually are present in normalor increased numbers in acute ITP.Bone marrow examination also isuseful in confirming normal mor-phologies in other cell types and inascertaining the presence of blastcells suggestive of leukemia or otherlymphoproliferative disorders.

Finally, it can help to determine the

presence of metastatic disease, suchas neuroblastoma.

In chronic ITP, the platelet countat presentation is generally between20 and 70 x 109 /L (20,000 and70,000/mcL). Additional tests shouldbe performed before making thediagnosis of chronic ITP, including

a evaluation for autoimmune dis-ease, infection, and immunodefi-ciency (Table 1). Thyroid studies areobtained to rule out autoimmunethyroid disease, which has beenassociated with chronic ITP.A Coombs test and measurement of the reticulocyte count are employedto exclude Evans syndrome(immune thrombocytopenia withautoimmune hemolytic anemia).Numerous viral infections have beenimplicated in causing thrombocyto-

penia. Isolated thrombocytopeniacan be the presenting symptom of human immunodeficiency virusinfection and may be seen afterimmunization with measle-mumps-rubella vaccine.

TABLE 1. Laboratory Testsin the Evaluation of

Chronic ImmuneThrombocytopenic Purpura

Autoimmune Disease●

Antinuclear antibody● Anti-DNA antibody● Antiphospholipid antibody● Sedimentation rate● Coombs test/reticulocyte

count● Thyroid studies (if thyroid

disease is suspected)

Infection● Human immunodeficiency

virus (HIV)● Cytomegalovirus titers● Epstein-Barr virus titers●

Consider other viraletiologies (less common):—Rubella—Measles—Varicella—Mumps—Hepatitis

Immunodeficiency● HIV titer● Quantitative

immunoglobulins● Quantitation of T and B cell

subsets

HEMATOLOGY Idiopathic Thrombocytopenic Purpura

96 Pediatrics in Review Vol. 21 No. 3 March 2000








The Role of Bone Marrow Aspirations in Diagnosis

Whether bone marrow should beexamined routinely in patients whohave suspected ITP is controversial.Historically, such examinations werecommon to rule out diseases such asleukemia and aplastic anemia ascauses of the thrombocytopenia.However, there is increasing argu-ment against performing bone mar-row aspirations to diagnose acuteITP. As stated previously, acute ITPis largely a clinical diagnosis that isconfirmed relatively easily by rou-tine blood tests. A growing numberof studies have demonstrated thatthe likelihood of a newly diagnosedleukemia presenting as an isolatedthrombocytopenia is extremely low.

Among 2,239 patients newly diag-nosed with acute lymphoblastic leu-kemia in a recent Pediatric Oncol-ogy Group study population, forexample, none exhibited isolatedthrombocytopenia in the presence of an otherwise normal CBC and cellmorphologies on peripheral smear.In a retrospective review of 127cases of children who had an initialdiagnosis of acute ITP and in whomconfirmatory bone marrow aspira-tions were performed, only fivecases were identified where exami-nation of the bone marrow led to adifferent diagnosis from ITP. Ineach of these five cases, features oninitial clinical presentation wereatypical for acute ITP. A morerecent review of 322 cases of chil-dren who had provisional diagnosesof acute ITP confirmed by bonemarrow aspiration also failed toreveal a single case of leukemia.

Furthermore, the decision to per-form a bone marrow aspiration canbe deferred if a patient is to be

treated initially with intravenousimmunoglobulins (IVIG) pendingthe response to treatment. Thisapproach avoids the concern of interfering with the diagnosis of leu-kemia by partially treating a patientwho presumably has ITP withsteroids.

Even though bone marrow exami-nations have apparent limited valuein the diagnosis of acute ITP, theymust be performed in situationswhere the diagnosis does not abso-

lutely correlate with the expected

clinical and laboratory findings (seeDifferential Diagnosis). Theseinclude: 1) unusual findings on his-tory and physical examination (eg,history of fevers, weight loss,fatigue, bone pain, and presence of lymphadenopathy or splenomegalyon physical examination); 2) the

presence of abnormal white or redblood cell counts and indices on theCBC; and 3) cases in which steroidsare to be used for treatment, eitheras a first-line drug or as a secondoption when IVIG fails to resolvethe thrombocytopenia. Bone marrowexamination is also important inevaluating chronic ITP and in casesof thrombocytopenia that are refrac-tory to multiple treatment modali-ties. The importance of performingbone marrow aspirations in these

circumstances is highlighted by casereports in which the diagnosis of leukemia or aplastic anemia not onlywas delayed, but it was masked bythe partial treatment with steroids of patients initially diagnosed as havingITP.

Although examination of thebone marrow is the “gold standard”in diagnosing acute ITP, noninvasivetests to distinguish acute ITP fromother thrombocytopenic disorderscontinue to be developed and maydecrease further the need to performbone marrow aspirations. None is ingeneral clinical use to date, but theyshow promise as useful adjuncts toother laboratory tests for diagnosingITP. One such method involvesmeasurement of the reticulatedplatelet count. As mentioned previ-ously, platelets on the peripheralblood smear from patients who haveacute ITP are larger, indicatingincreased platelet turnover and ahigher percentage of young plateletsin the circulation. These platelets

contain a higher RNA content thando more mature platelets, as doimmature red blood cells (ie, reticu-locytes). These platelets have beentermed “reticulated platelets.” Byemploying fluorescent dyes that bindnucleic acid and measuring dye flu-orescence by flow cytometry, it ispossible to quantitate reticulatedplatelets and distinguish between ahyperproliferative (eg, acute ITP)and a hypoproliferative (eg, leuke-mia, aplastic anemia) process. Com-

parison of the reticulated platelet

count in 15 patients who had acuteITP, 20 patients who had acute lym-phoblastic leukemia, 10 patients whohad aplastic anemia, and 27 healthychildren revealed a significantlyhigher count among those who hadacute ITP compared with the othergroups. Importantly, the degree of

elevation in the reticulated plateletcount in acute ITP is such that therewas no overlap with the hypoprolif-erative groups, providing a positivepredictive value, sensitivity, andspecificity approaching 100% whenthe reticulated platelet countexceeded 13.7% and the total plate-let count was less than 50 x 109 /L(50,000/mcL). Tests such as thispotentially can assist in the diagno-sis of ITP without the need to per-form more invasive procedures. Its

utility in distinguishing acute ITPfrom other non-neoplastic causes of thrombocytopenia and its role in thediagnosis of chronic ITP, however,warrant further investigation.

Differential Diagnosis

The differential diagnosis for throm-bocytopenia is very broad. A lowplatelet count can result from immu-nologic and nonimmunologic enti-ties. Table 2 lists selected causes of thrombocytopenia and the clinicaland laboratory associations that dis-tinguish them from ITP. It is worthstressing again that the diagnosis of ITP is based on the presence of anisolated thrombocytopenia in theabsence of clinical and laboratoryfeatures suggestive of other disor-ders. The distinction of these dis-eases from ITP is based almostentirely on findings from the historyand physical examination and inter-pretation of the CBC. As stated pre-viously, ordering additional tests or

examining the bone marrow usuallyis not necessary to establish thediagnosis of ITP.

Management of Acute ITP

Acute ITP generally can be diagnosedand managed in an outpatient settingby the primary care pediatrician.Referral to a hematologist-oncologistis warranted if there is evidence of concurrent disease, such as malig-nancy, bone marrow failure, autoim-

mune disease, or immunodeficiency.










TABLE 2. Differential Diagnosis of Thrombocytopenia

DISORDER ASSOCIATED CLINICALFEATURES

LABORATORY FEATURES

Decreased Platelet ProductionCongenital

● Thrombocytopenia-Absent

Radius (TAR) syndrome

● Absence of radii at birth●

Other skeletal anomalies may bepresent

● Platelet count usually 15 to 30

109

/L (15,000 to 30,000/mcL)

● Congenital heart disease associatedin one third of cases

● Fanconi anemia ● Short stature ● Pancytopenia due to aplasticanemia● Skin hyperpigmentation

● Hypoplasia of thumb and radii● Renal abnormalities may be present● Microcephaly● Microphthalmia

● Amegakaryocyticthrombocytopenia

● Absence of skeletal abnormalitiesseen in TAR syndrome

● Thrombocytopenia present in theneonatal period

Acquired ● Leukemia ● History of chronic fatigue, fevers,

weight loss, pallor, bone pain● Lymphadenopathy● Splenomegaly● Hepatomegaly may be present

● Elevated white blood cell count● Anemia● Blast cells on peripheral smear

(ie, leukoerythroblastosis)

● Aplastic anemia ● History of fatigue, bleeding, orrecurrent infection

● Physical examination findingsnonspecific

● Absence of splenomegaly

● Pancytopenia● Severe neutropenia● Low reticulocyte count

● Neuroblastoma ● Abdominal mass in majority of

cases

● Thrombocytopenia due to bone

marrow metastasis● Presence of paraneoplastic

syndromes● Neurologic manifestations from

spinal cord involvement

● Nutritional deficiency ● History of poor nutrition orspecialized diets

● Pallor, weakness, and fatigue dueto anemia

● Neurologic deficits in vitamin B12

deficiency

● Megaloblastic anemia present● Hypersegmented neutrophils on

peripheral smear● Low reticulocyte count● Low vitamin B12 or folate levels

● Drugs (see Table 3) ● History of drug use or recent

change in dose

Increased Platelet Destruction Immune

● Neonatal allommunethrombocytopenia

● Generalized petechiae within firstseveral hours of birth

● Platelet count in mother is normal

● Drugs (see Table 3) ● History of drug use or recentchange in dose

● Human immunodeficiencyvirus (HIV) infection

● Systemic signs and symptoms of HIV infection

● Abnormalities in any or all celllineages

● HIV serologies confirm thediagnosis










SUPPORTIVE MEASURES

Supportive measures are importantin the management of acute ITP.These include restricting physicalactivity, wearing protective head-gear, lining the crib with protec-

tive padding, avoiding medications

that suppress platelet production oralter their function (Table 3), andmaintaining a low threshold forprompt evaluation of the childwho has thrombocytopenia andsustains blunt head or abdominal

trauma.

PHARMACOLOGIC

MANAGEMENT

The pharmacologic management of acute ITP continues to be the sub-

ject of much controversy becausemost cases of ITP are self-limited;

80% to 90% of patients will make a

TABLE 2. Continued

DISORDER ASSOCIATED CLINICALFEATURES

LABORATORY FEATURES

● Posttransfusion purpura ● History of platelet transfusion a fewhours prior to thrombocytopenia

● Acute marked thrombocytopenia

● Collagen-vascular disease/ autoimmune disease

● Systemic manifestations, including joint pain/swelling, dermatologicfindings

● Anemia of chronic disease usuallypresent

● White blood cell countsoccasionally abnormal

Nonimmune● Hemolytic-uremic syndrome ● History of bloody diarrhea (from

Escherichia coli O157:H7, Shigella sp)

● Microangiopathic microcyticanemia on peripheral smear

● Renal failure

● Disseminated intravascularcoagulation

● Signs and symptoms of sepsis(eg, fever, tachycardia, hypotension)

● Prothrombin time and partialthromboplastin time are elevated

● Microangiopathic microcyticanemia on peripheral smear

● Fibrinogen level decreased● D-dimers present

● Cyanotic heart disease ● Cyanosis ● Compensatory polycythemia● Congestive heart failure

Qualitative Platelet Disorders● Wiskott-Aldrich syndrome ● X-linked inheritency pattern

● Eczema

● Platelet count 20 to 100 109 /L(20,000 to 100,000/mcL)

● Recurrent infections due toimmunodeficiency

● Platelets very small on peripheralsmear

● Bernard-Soulier syndrome ● Autosomal dominant inheritancepattern

● Ecchymoses and gingival and

gastrointestinal bleeding common

● Large platelets on peripheral smear,occasionally larger thanlymphocytes

● May-Hegglin anomaly ● Autosomal dominant inheritancepattern

● Most patients asymptomatic

● Giant platelets on peripheral smear● Inclusion bodies present in

leukocytes (Dohle bodies)

● Gray platelet syndrome ● Bleeding, usually mild ● Platelets on peripheral smearappear pale and oval

Sequestration● Kasabach-Merritt syndrome ● Rapid increase in size of a

hemangioendothelioma occurring inthe neonatal period

● Hypersplenism ● History of liver disease/portal

hypertension● Splenomegaly on physical

examination

● Concomitant anemia and abnormal

leukocyte count, depending on thedisease

● Associated with leukemia and otherinfiltrative disease










full and sustained recovery within6 months without any treatment.However, at present there are nodefinitive diagnostic predictors toenable the physician to identify the10% to 20% of patients who willprogress to chronic ITP. Moreover,patients who have extremely lowplatelet counts (ie, 10 to 20 x109 /L [10,000 to 20,000/mcL]) areat increased risk for significantbleeding, the most devastating of which is intracranial hemorrhage(ICH). ICH always should be con-sidered in the patient who hasthrombocytopenia and presents witha persistent headache. Although theincidence of ICH is extremely low(only 56 documented cases identi-fied from 1975 to 1996), the mortal-ity rate is significant (46%), andvirtually all episodes have beenassociated with platelet counts of less than 2 x 109 /L (20,000/mcL).

Thus, the rationale for aggressivetreatment of severe ITP at the timeof diagnosis is to raise the plateletcount to a level that decreases therisk of significant bleeding events.

IVIG and Steroids

Currently, the mainstays of pharma-cologic management for acute ITPare IVIG and corticosteroids. Theability of both of these agents toraise platelet counts has been docu-

mented in multiple studies, with

mean time to raise platelet counts20 x 109 /L (20,000/mcL) rangingfrom 24 to 72 hours after initiationof therapy. There currently are noclear criteria for selecting IVIG orsteroids as a first-line agent. IVIGhas several advantages over steroids.First, it appears to induce a morerapid increase in platelet count. Sec-ond, the adverse effects of steroiduse, including weight gain, hyper-tension, hyperglycemia, Cushingsyndrome, osteoporosis, and psycho-logical disorders, are avoided withIVIG. Third, the physician can begina therapeutic trial with IVIG withoutbone marrow aspiration to rule outleukemia.

The disadvantages of IVIG as afirst-line agent include its highercost and difficulty with administra-tion. It requires intravenous access,and the infusion requires severalhours of observation. Moreover,

IVIG is associated with a number of adverse effects. An aseptic meningi-tis effect will produce symptomssimilar to that of an acute ICH,leading to additional costly tests todifferentiate these two diagnoses. Ina recent study examining 38 chil-dren who had acute ITP treated withIVIG, 34% had neurologic compli-cations, and virtually all of thoseaffected required hospitalizations fora period longer than what wasrequired for the ITP alone. Twenty-

four percent of these patients

required emergent computed tomog-raphy to rule out ICH. The combina-tion of prolonged hospitalization andadditional diagnostic studies resultedin an increased cost of approxi-mately $1,700 for each patient whoexperienced neurologic side effectsfrom IVIG.

ANTI-Rh(D)

Another agent under investigation inthe treatment of acute ITP is anti-Rh(D). It is less expensive thanIVIG and has been shown to raiseplatelet counts effectively. However,it is useful only in patients who areRh-positive, and hemolytic anemiacan occur as a side effect. In somepublished reports, treatment withanti-Rh(D) resulted in a slower risein platelet count than with steroids

or IVIG, which theoretically couldprolong the interval in which apatient is at risk for ICH. However,other studies have shown that anincreased dose of anti-Rh(D) raisedplatelet counts as quickly as didIVIG; the length of hospital staywas identical for patients receivinganti-Rh(D) and IVIG.

DOSING

Dosing schedules for IVIG and ste-roids are highly variable (Table 4).IVIG in a dose of 0.25 to 1 g/kg perday for two consecutive days or as asingle dose of 0.8 g/kg has beenshown to increase platelet counts.Dosage recommendations for oralprednisone vary even more, rangingfrom 4 mg/kg per day for 4 dayswith or without a subsequent taperto 2 mg/kg per day for 2 to3 weeks. Some investigators alsohave demonstrated a role for high-dose intravenous methylprednisone(30 mg/kg per day for 2 to 3 days)

in raising platelet counts. Anti-Rh(D), in the comparison trials withIVIG and prednisone, was adminis-tered intramuscularly in doses of 25 to 50 mcg/kg per day for twoconsecutive days. It is important tonote that the schedules listed inTable 4 are based on studies involv-ing relatively few patients. Theresults of large, randomized, andcontrolled studies to establish theoptimal doses of IVIG, steroids, andanti-Rh(D) have yet to be published.

Although IVIG, steroids, and

TABLE 3. Common Drugs and Thrombocytopenia

Drugs Associated With Decreased Platelet Production● Chemotherapeutic agents● Thiazide diuretics● Alcohol● Estrogen● Chloramphenicol● Ionizing radiation

Drugs Associated With Increased Platelet Destruction● Sulfonamides● Quinidine● Quinine● Carbamazepine● Valproic acid● Heparin● Digoxin

Drugs Associated With Altered Platelet Function● Aspirin● Dipyridamole










anti-Rh(D) have been shown toshorten the duration of thrombocyto-penia, it is essential to realize thatthey are not cures for ITP. Theyonly have the potential to shortenthe period of thrombocytopenia andminimize the risk of life-threateningbleeding events. As stated previ-ously, ITP is a self-limited diseasein most pediatric patients. All of thestudies performed to date on thetreatment of acute ITP have focusedon a rise in platelet counts as theendpoint; no studies have docu-mented decreases in morbidity ormortality. Accordingly, despite theexistence of agents that can raise theplatelet count, a number of impor-tant questions remain: 1) Are therefactors other than platelet countsless than 20 x 109 /L (20,000/mcL)that contribute to an increased risk of intracranial hemorrhage? 2) Whatis the cost-effectiveness of treatingpatients who have acute ITP withIVIG versus steroids versus anti-

Rh(D), given each agent’s advan-tages and disadvantages? 3) Howeffective are these agents in the pre-vention of chronic ITP?

Neonatal Thrombocytopenia

Immune thrombocytopenia can bemanifested during the neonatalperiod in infants born to motherswho have ITP and, much morerarely, in neonatal alloimmunethrombocytopenia. In the latter,

which occurs in approximately 1 in

5,000 newborns, the platelets of theaffected infant contain different anti-gens from those of the mother, andthe subsequent formation of mater-nal alloantibodies that cross the pla-centa result in platelet destruction.Both diseases are self-limiting; inmost cases, the thrombocytopeniaresolves within 6 weeks of birth.However, there are significant dif-ferences between the two diseasesthat deserve mentioning. First, deter-mining the maternal history is essen-tial in distinguishing between thetwo diagnoses. In maternal ITP, themother’s platelet count is generallybelow normal, and in most casesthere is a well-documented historyof chronic ITP. In neonatal alloim-mune thrombocytopenia, the motherhas a normal platelet count and hasno history of immune thrombocyto-penia. However, a history of a sib-ling who has neonatal thrombocyto-penia is strongly suggestive of neonatal alloimmune thrombocyto-

penia because subsequent affectedsiblings are affected more severelythan the first. Second, neonatal allo-immune thrombocytopenia is a farmore serious disorder. Not only isthe platelet count lower comparedwith that of the infant born to amother who has ITP, but the inci-dence of ICH is significantly higher(10% to 30% versus 1% in infantsborn to mothers who have ITP).

The management of the infantwho has autoimmune or alloimmune

thrombocytopenia is similar. IVIG,

steroids, platelet transfusions, andexchange transfusions all have beeninvestigated. The important distinc-tion in treatment is that in neonatalalloimmune thrombocytopenia, plas-mapheresed or washed plateletsfrom the mother should be used fortransfusion because they lack the

alloantigen responsible for the for-mation of antiplatelet antibodies. Ininfants born to mothers who haveITP, transfusion with maternal plate-lets is avoided because they containthe antigens responsible for the for-mation of platelet autoantibodies.Furthermore, because most cases of neonatal thrombocytopenia due tomaternal ITP are mild and self-limiting, aggressive therapy usuallyis not required.

Management of Chronic ITP

In the minority of cases in whichthrombocytopenia persists for morethan 6 months (ie, chronic ITP),management is highly individualizedand depends primarily on the degreeof thrombocytopenia and the need topreserve the patient’s quality of life.Studies examining the natural courseof chronic ITP suggest that mostpatients maintain platelet countsabove 30 x 109 /L (30,000/mcL). Ina significant percentage of patients(40% to 79%), complete remission(defined as a platelet count 100 x109 /L [100,000/mcL]) is achievedover the course of 3 months to15 years. As in acute ITP, the goalof management is to minimize therisk of significant bleeding. Patientsshould be directed to avoid activitiesthat increase the risk of trauma andto avoid all medications that sup-press platelet production and func-tion (Table 3). Platelet counts must

be monitored regularly because thismay determine the aggressiveness of further treatment. Finally, patientsshould be evaluated for autoimmunedisease as previously describedbecause a greater percentage of patients who have features of chronic ITP have an underlyingautoimmune disorder. It is importantto re-evaluate these patients overtime if the initial evaluation fails toestablish a diagnosis. In some cases,the diagnosis may not be apparent

for years.

TABLE 4. Selected Dosing Schedules for Therapy of Acute ITP

DRUG DOSE SCHEDULES

Oral prednisone 2 mg/kg per day for 14 to 21 days60 mg/m2 per day for 21 days4 mg/kg per day for 7 days, followed by

14-day taper

Intravenous methylprednisolone 10 to 30 mg/kg per day for 3 to 5 days

IVIG 0.8 g/kg per dose for 1 dose1 g/kg per day for 2 days250 mg/kg per day for 2 days400 mg/kg per day for 2 days500 mg/kg per day for 2 days0.4 g/kg per day for 5 days

Anti-Rh(D) 25 mcg/kg per day for 2 days45 to 50 mcg/kg per day for 2 days










PHARMACOLOGIC OPTIONS

Pharmacologic approaches to themanagement of chronic ITP thathave been studied to date includesteroids, IVIG, androgens, anti-Rh(D), recombinant humaninterferon-alpha-2b, and immunosup-pressive agents used alone or incombination. Although all of thesehave been shown to induce a tran-sient rise in platelet counts, none hasdemonstrated an ability to sustain adesirable platelet count; therefore,repeated treatments may be required.This not only potentiates chronicdrug toxicity, but it greatly increasesthe cost of therapy. Whether any of these agents alters the natural courseof chronic ITP, affects long-termmorbidity or mortality, or increasesthe rate of long-term remissionremains unclear. Because the major-ity of cases of chronic ITP remiteither spontaneously or with treat-ment and because the associatedmortality and morbidity are low, anumber of authors advocate inter-ventions only when the plateletcount is dangerously low or if thepatient is symptomatic.

SPLENECTOMY

Splenectomy has been shown toinduce long-term remission inchronic steroid/IVIG-resistant ITP.The benefits of splenectomy overlong-term drug therapy include theavoidance of chronic drug toxicityand potentially greater cost-effectiveness. However, splenectomyentails inherent risks of morbidityand mortality. Postsurgical hemor-rhage and postsplenectomy sepsisare two of the life-threatening com-plications. Although the risk of post-operative bleeding is surprisingly

low, the risk of postsplenectomysepsis is significant, with the inci-dence of septic mortality rangingfrom 3% to 11%. Furthermore, theincidence of postsplenectomy sepsisis highest among patients youngerthan 5 years of age. Causativeorganisms include pneumococcus,

Haemophilus influenzae, and menin-gococcus. Immunization with pneu-mococcal, Haemophilus, and menin-gococcal vaccines before splenec-tomy, administration of prophylactic

antibiotic therapy, and delay of sple-

nectomy for as long as possible forpatients in the high-risk age groupare recommended to minimize therisk of postsplenectomy sepsis.

Splenectomy does not ensurelong-term remission in all patients;only 60% to 90% of those who havechronic ITP respond to splenectomy.The need to identify patients whoare likely to respond to splenectomyis abundantly clear. Results of sev-eral retrospective studies haveshown that those who demonstrateda significant, although transient, risein platelet count after treatment witheither steroids or IVIG had a goodresponse to splenectomy (ie, theydid not require any subsequent med-ical therapy for their thrombocyto-penia). In contrast, those who did

not respond well initially to medicaltherapy had relatively poorresponses to splenectomy andrequired continuing medicalmanagement.

Splenectomy is reserved for thosepatients who have extremely lowplatelet counts (and, therefore, are atincreased risk of bleeding) and whoare refractory to pharmacologicmanagement. In cases of life-threatening hemorrhage due to ITP,emergent splenectomy may be

required to increase the plateletcount rapidly. It is important toremember that platelet transfusionsalone prior to splenectomy, althoughhelpful, will not raise the plateletcount. IVIG and steroids also arerequired to disrupt the autoimmunedestruction of platelets and maintainthe platelet count at a level desirablefor surgery. A noninvasive alterna-tive to splenectomy in the treatmentof chronic ITP is the use of a shortcourse of radiation therapy, which

resulted in a sustained increase inplatelet counts in a small group of older adult patients who were con-sidered too unstable for surgery. Useof this therapeutic approach in thepediatric population remains to beevaluated.

Acknowledgments

The authors thank Dr Stephen Feigfor helpful suggestions and WendyAft for preparation of the

manuscript.

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PIR QUIZ

Quiz also available online at

www.pedsinreview.org.

14. Neonatal alloimmune thrombocyto-penia and neonatal autoimmunethrombocytopenia are similar in thatboth:

A. Are associated with previoussiblings being affected by thedisease.

B. Are self-limiting.C. Have maternal platelet counts in

the same range.D. Occur primarily in infants born

to mothers who have immunethrombocytopenia purpura.

E. Resolve within 7 to 10 days afterbirth.

15. Which endocrine disorder has beenassociated with chronic immunethrombocytopenia purpura (ITP)?

A. Addison disease.

B. Autoimmune thyroid disease.C. Congenital adrenal hyperplasia.D. Hyperparathyroidism.E. Hypopituitarism.

16. A 32-year-old woman has just deliv-ered her third child. Both of herprevious children were diagnosed ashaving neonatal alloimmune throm-bocytopenia that required treatment.Findings on the physical examina-tion of the newborn are unremark-able except for a few petechiae onhis arms and legs. A complete bloodcount is unremarkable except for aplatelet count of 30 x 109 /L (30,000/ mcL). The best treatment for this

child’s ITP is:A. Anti-Rh(D).B. Corticosteroids.C. Intravenous immunoglobulin.D. None.E. Plasmapheresed maternal platelets.

17. A 4-year-old girl presents with a1-week history of extensive bruisingof the arms and legs and intermittent

episodes of epistaxis. Physical exam-ination reveals large palpable bruiseson both arms and legs and crustedblood in the nares. A complete

blood count reveals a white bloodcell count of 10.5 x 109 /L (10.5 x103 /mcL), hemoglobin of 6.51 mmol/L (10.5 g/dL), hematocritof 0.32 (32%), and platelet count of

20 x 109 /L (20,000/mcL). Thedifferential count includes 80%segmented forms, 8% bands, 12%lymphs, and a blood smear with

normal red blood cell morphologyand decreased platelets. The plateletsthat are visualized are large. Youdecide to initiate treatment for

suspected acute ITP with intrave-nous immunoglobulin (IVIG). The

primary advantage of using IVIGover corticosteroids to treat this

child’s acute ITP is:

A. Cost of administration.B. Ease of administration.

C. Lack of complications.D. More rapid increase in the

platelet count.E. Ready availability for administra-

tion.

18. You hospitalized a 4-year-old childwith a diagnosis of acute ITP. Onadmission, the child had a platelet

count of 20 x 109 /L (20,000/mcL).Initial treatment is an infusion of IVIG. A repeat platelet count 4 dayslater shows a platelet count of 22 x

109 /L (22,000/mcL). However, thefollowing day the patient suddenlydevelops confusion and somnolence.Physical examination revealsincreased numbers of petechiae on

the trunk and ecchymoses at thevenipuncture sites. Your next stepshould include all of the following

except :

A. Consulting neurology for furtherevaluation.

B. Initiating a transfusion of plate-lets.

C. Obtaining a STAT completeblood count with platelets.

D. Obtaining immediate computedtomography of the head.

E. Starting antibiotics at the appro-priate doses to treat possiblemeningococcemia.










DOI: 10.1542/pir.21-3-952000;21;95Pediatrics in Review

Yu-Waye Chu, James Korb and Kathleen M. SakamotoIdiopathic Thrombocytopenic Purpura

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