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Hematology 2006
=A9 2006 T= he=20 American Society of Hematology

Immune Thrombocytopenic Purpura of Childhood =

Diane=20 J. Nugent

Correspondence: Diane Nugent, MD, Children=92s = Hospital of Orange=20 County, 455 S Main St., Orange CA 92868-3835; Phone 714-532-8744; Fax=20 714-532-8771; Email djn0{at}choc.org

Abstract

Immune mediated thrombocytopenia (ITP) is a common manifestation = of autoimmune disease in children. Although patients often = present=20 with bruises, petechiae, and some mucosal bleeding, the = incidence=20 of life-threatening hemorrhage is rare (0.2=960.9%) but = can be=20 fatal when presenting in vital organs. A wide range of = therapeutic=20 regimens are currently in use, including observation alone, = as the=20 majority of children recover within 4=966 months regardless = of=20 treatment. A growing understanding of the pathophysiology of = acute=20 ITP in children has not impacted the controversy surrounding=20 treatment, but has clarified the mechanism of action of the = most=20 frequently used agents in chronic ITP. Newer monoclonal = antibodies=20 such as Rituxan have proved very useful in chronic or = refractory ITP=20 and studies are ongoing to determine the best regimens using = this=20 form of immune modulation. Splenectomy and newer agents to = boost=20 platelet production are also under study in chronic ITP. = Neonates may=20 also have a form of immune thrombocytopenia with extensive = bruising=20 and thrombocytopenia called neonatal alloimmune = thrombocytopenic=20 purpura (NATP). Rather than autoantibodies, the platelet = destruction=20 is secondary to transplacental maternal IgG alloantibodies. = During=20 pregnancy mothers may become sensitized to platelet membrane=20 antigens present on fetal platelets. These antibodies may = result in=20 serious bleeding, including intracranial hemorrhage in the=20 perinatal period. Once identified, these mothers may require=20 treatment during future pregnancies to minimize serious = bleeding in=20 the fetus and neonate. Treatment in utero and = immediately=20 following delivery is focused on restoring neonatal platelets = to a=20 safe level and preventing life-threatening bleeding. =

Recent advances in our understanding of the role of individual=20 genetic risk factors and immune dysregulation in immune=20 thrombocytopenic purpura (ITP) have opened the door to new = avenues of=20 research in the most common form of hematological autoimmune=20 disease in adults and children. The childhood form of ITP is = seen=20 most frequently in patients 1=967 years of age. For this = reason,=20 most pediatricians will be confronted at some point by a = patient=20 with bruises, petechiae, mucosal bleeding and very anxious = parents.=20 Rapid diagnosis, reasonable care plan and education on the = etiology=20 and course of this syndrome, will allay the fears of the = patient=20 and family members. Much work has been done in the past = decade=20 in the pathophysiology and treatment of ITP in adults, but = there=20 have been significant advances in the management of childhood = ITP as well.

Clarification of the major pathways that lead to childhood ITP=20 have influenced our approach to therapy and may ultimately = aid=20 in the early identification of individuals who may need more=20 aggressive intervention versus no treatment at all. By = decreasing=20 the risk of hemorrhage and minimizing the long-term side = effects=20 of treatment, these insights have greatly improved the care = of=20 patients with ITP. This review will briefly discuss current = practice=20 in the diagnosis and management of acute and chronic ITP of=20 childhood, as basics of this disease are well known to = practicing=20 hematologists and several comprehensive reviews of current = practice=20 have recently been published.1=963=20 The remainder of this article will examine new insights into=20 pathophysiology of immune thrombocytopenia in children, = including=20 neonatal alloimmunization, as well as novel therapeutic = approaches=20 currently in use and those emerging on the horizon. =

Diagnosis

In reviewing the current literature, it is clear that the = pattern=20 of presentation in acute ITP of childhood has changed very = little=20 over the years.1=963=20 For decades, physicians and researchers have commented on the = rapid=20 onset of bruising and mucosal bleeding in a severely = thrombocytopenic=20 child with minimal or no trauma.4=20 The remainder of the complete blood count and physical exam=20 should be normal. Although generally healthy at the time of=20 presentation, parents often report a preceding illness or = other=20 immune stimulant such as allergic reaction, insect bite, or=20 immunizations, especially the MMR as noted in a large = Canadian=20 prospective study.5=20 Another common observation supporting an environmental immune = trigger=20 in childhood ITP is its seasonal nature: it occurs most in = winter and=20 fall, least in summer.

Even in uncomplicated ITP, there is considerable variation in=20 presentation and prognosis. Based on the duration of=20 thrombocytopenia, a distinction is made between "acute" = versus=20 "chronic" ITP. Thrombocytopenia lasting less than 6 months is = termed=20 acute, and greater than 6 months is termed chronic. Children = are=20 more likely to have the acute form of ITP and in 60=9675% = of=20 the patients, the thrombocytopenia resolves within 2=964 = months=20 of diagnosis regardless of therapy.1=963=20 There is an equal incidence of ITP in both males and females = in the=20 1- to 7-year-old age group in acute ITP of childhood. These=20 features are distinctly different from the adult form of the=20 disease, which is more likely to be chronic, with a much = greater=20 incidence in females and no seasonal predilection. =

Laboratory studies at presentation (Table 1) and history are the mainstay of = diagnosis in=20 childhood ITP. Although many parents are anxious to rule out = leukemia=20 when referred to a hematologist, it is usually not necessary = to=20 perform a bone marrow aspirate with isolated thrombocytopenia = if a=20 thorough physical examination and review of the blood smear = is=20 performed. However, if more than one cell lineage is = decreased and=20 the patient has splenomegaly or adenopathy, the bone marrow = must be=20 evaluated prior to administration of medications such as = steroids,=20 which might confound the diagnosis of leukemia, delay = therapy, or=20 trigger an unrecognized tumor lysis syndrome. Other syndromes = that=20 might be misdiagnosed as ITP are listed in Table 2. Antiplatelet autoantibody testing has = flourished=20 over the past 20 years, but it is rarely used to make the = diagnosis=20 of acute ITP in children as the other forms of = thrombocytopenia=20 listed in Table 2, can generally be readily distinguished = without=20 this assay. Assays used to identify target antigens on the = platelet=20 surface have been used to in clinical research along with = measurement=20 of platelet bound autoantibody isotype using flow cytometry = to=20 determine whether certain antibodies are more likely to = predict a=20 more severe or chronic form of ITP.


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  		Table 1. Common = laboratory tests=20 obtained in the thrombocytopenic patient at = presentation.=20 =
 

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  		Table 2. History and = physical=20 findings not consistent with immune thrombocytopenic purpura = (ITP)=20 of childhood.=20
 
Pathophysiology

The majority of children with ITP have a strikingly negative = past=20 medical history, with puzzled parents often describing the = patient as=20 the "healthiest" one in the family. In a sense, these = children are=20 victims of their own exuberant defense system which, in = responding to=20 an immune trigger in the previous weeks, has created a = permissive=20 state where antiplatelet autoantibodies may emerge. These may = be=20 promiscuous antibodies that bind to viral or bacterial = antigens and=20 crossreact with platelets, or a previously suppressed = autoreactive=20 antibody that has escaped peripheral tolerance as described=20 below.

Recent articles have revealed the dominance of a = pro-inflammatory=20 state in ITP following a relatively benign viral or = environmental=20 trigger.6,7=20 Both the pro-inflammatory cytokines and T cell repertoire = seem to=20 persist in some children creating a permissive environment = for the=20 emergence of previously suppressed autoantibodies that bind = to=20 platelet membrane antigens. A most interesting approach to = assess the=20 immune status of ITP at presentation has recently been = published by=20 Zehnder et al. Using a whole blood gene expression microarray = with=20 24,473 unique genes per run, they demonstrated the increased=20 expression of gamma interferon dependent genes in the early = stage of=20 ITP, supporting a pro-inflammatory or TH1 dominant state.8=20 In addition, several articles have documented the persistence = of=20 inflammatory cytokines7,9=20 and disturbed T cell apoptosis in childhood ITP.10=9612=20

Given the diversity of immunoglobulin specificity, every child = and=20 adult has the potential to form autoantibodies to platelets. = For=20 unclear reasons, these self-reactive antiplatelet clones are = not=20 deleted during fetal development and persist in the antibody=20 repertoire of the mature individual.13=20 In vivo, some antiplatelet antibodies are "naturally=20 occurring" antibodies that are kept under tight control by a = form of=20 natural immune suppression called peripheral tolerance. =

In childhood ITP, the key pathologic event may be failure to=20 suppress these previously sequestered autoantibodies.14=20 Specifically, it has been proposed that the T lymphocyte = pathways=20 characterized by the CD25+ T regulatory cells may = not be=20 fully mature in children 2=965 years of age, thus permitting = autoimmune=20 antibody production and antigen presentation by B lymphocytes = that=20 had escaped thymic deletion due to their crossreactivity with = viral antigens. The T cell profile and cytokines in these=20 patients, at presentation, are most consistent with a = protracted T=20 cell helper 1 (TH1) response with elevated interleukin = (IL)-1 or IL-1=DF and decreased IL-4 as has been = described in=20 juvenile rheumatoid arthritis (JRA) and early onset diabetes.6,7,9=20 In general, it is a polyclonal response with many children = producing=20 both IgG and IgM autoantibodies to a variety of platelet = epitopes=20 including the more common glycoproteins 3D{alpha}=202 =DF3 and GPIb complex. = Certain Fc=20 gamma receptor IIa and IIIa polymorphisms have an increased=20 association with childhood ITP. This observation may point = toward=20 individual differences in the clearance of autoantibody-bound = platelets in the onset and duration of ITP. Early studies = suggest=20 that these Fc gamma receptor polymorphisms may play a role in = predicting response to therapy as well.7,15=20

Recent articles suggest that the generation of a critical=20 CD4+CD25+ regulatory T cell = (TR) in=20 the thymus during a pro-inflammatory response may be = essential in the=20 prevention of auto-reactive effector cells and antibodies.14=20 Indeed, children who have thymic hypoplasia as a result of a=20 heterozygous deletion of chromosome 22q11.2 also have a=20 predisposition to autoimmune disease. Absolute numbers of=20 CD4+ CD25+ T cells were markedly higher in = healthy=20 infants than in infants with chromosome 22q11.2 deletion = syndrome14=20 where the incidence of autoimmune disease is 10%.

With or without treatment, the ultimate resolution of = thrombocytopenia=20 during the first 6 months or "acute" phase of ITP may rest on = the patient=92s ability to reestablish this network of = peripheral=20 tolerance and autoantibody suppression. Current therapy is = primarily=20 directed toward decreasing platelet consumption until these=20 regulatory pathways are reestablished.

Megakaryopoiesis in ITP

Increased megakaryocyte number in the bone marrow has been a=20 hallmark of immune-mediated platelet destruction in patients=20 with ITP. Over 20 years ago, researchers demonstrated that = more=20 than one third of all adults with ITP had inadequate platelet = production despite increased megakaryocyte numbers in the = bone=20 marrow.16=9618=20 It was assumed that autoantibody interfered with platelet = formation=20 or egress from the marrow space. A number of studies = ultimately=20 confirmed this hypothesis with both in vitro and in = vivo platelet production studies.19=9622=20

Like adults, certain pediatric patients also demonstrate = decreased=20 megakaryocytopoiesis in the presence of ITP plasma containing = anti-GPIb-IX autoantibodies alone or in combination with 3D{alpha}=20IIb-=DFIIIa (GPIIb-IIIa) = autoantibodies,=20 in vitro compared to control normal AB plasma = (Figure=20 1; see Color Figures, page = 516).21,22=20 However, those children with ITP mediated by platelet=20 autoantibodies directed against other epitopes (unknown = antibody=20 group in Figure 1; see Color Figures, page = 516),=20 demonstrated little or no suppression. Furthermore, those = pediatric=20 patients with 3D{alpha}=20IIb-=DFIIIa (GPIIb-IIIa) = autoantibodies=20 alone demonstrated a mixed response, with certain plasmas = being=20 highly suppressive, while others actually appeared to = stimulate=20 growth.

McMillan et al recently demonstrated that autoantibody = suppression=20 of megakaryocytes by autoantibody may be associated with = increased=20 apoptosis.22=20 This was not observed in the pediatric ITP megakaryocytopoiesis=20 studies, despite similar autoantibody specificities.23=20 It is possible that lymphocyte signaling, receptor occupancy = and=20 clustering may also play a more critical role in triggering=20 megakaryocyte apoptosis in the adults. Alternatively, = antiplatelet=20 autoantibodies in childhood ITP may not recognize the same = epitopes=20 on target molecules, nor have the same affinity and = complement=20 binding capacity due to a less mature immune system. = Adolescent=20 ITP patients are much more likely to have anti-GPIb=20 autoantibodies and have a clinical course similar to that of = the=20 adult with ITP.

The disparities in suppression of megakaryocytopoiesis observed=20 between adult and pediatric ITP patients reinforces the = growing=20 evidence that the immunologic trigger, course and outcome for = children with immune mediated thrombocytopenia is quite = different=20 than that of adults.

Treatment Options in Childhood = ITP

Pediatric hematologists must consider a number of factors when=20 considering the management of a child with ITP.4,24=9630=20 In the absence of hemorrhage, the child with scattered = petechiae=20 and superficial bruising may only warrant close observation, = as=20 long as the parents are informed of the risks associated with = severe=20 thrombocytopenia and can rapidly return to the hospital = should=20 bleeding occur. If the family is geographically isolated or = unable to=20 closely observe their child, treatment to increase the = platelet count=20 above 20,000 and shorten the duration of thrombocytopenia = should be=20 considered.31=20 Most common treatment options are listed in Table 3.


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  		Table 3. Comparison of = acute=20 immune thrombocytopenic purpura (ITP) treatment regimens in=20 children.=20
 
If= the=20 decision is made to treat a child with ITP, the most common = approach=20 would include either IVIG, anti-D immunoglobulin in the=20 Rh+ patient, or steroids once one is confident there = is no=20 risk of leukemia. Many opt for IVIG in the first few hours, = as it may=20 take some time to obtain the red cell antibody studies or Rh = status=20 needed prior to giving anti-D immunoglobulin. In addition, if = the=20 patient has significant bleeding prior to presentation, = hematologists=20 may wish to avoid agents that might lower the hemoglobin even = further. Immunoglobulin preparations should be given slowly = initially=20 as the large protein load is more commonly associated with = headache=20 and vomiting in the 24=9648 hours following infusion. Besides = the=20 discomfort for the patient, these symptoms are also = associated with=20 increased intracranial pressure and may result in an urgent = CT scan=20 to rule out central nervous system (CNS) bleeding. Running = the IVIG=20 at 1 g/kg over 18=9624 hours with hydration can minimize this = complication and avert the need for costly studies to rule = out=20 intracranial hemorrhage. Mild to moderate neutropenia = following IVIG=20 is another common observation, usually resolves after 48 = hours and=20 should not prompt the need for a bone marrow aspiration. = Either=20 anti-D immunoglobulin or IVIG has roughly the same timeframe = for=20 platelet increases to > 20,000 and 50,000/mm3 = and the=20 same durability in the child with acute ITP. Usually children = are=20 admitted and observed for 24=9648 hours with initial = treatment, so=20 there is no benefit to one treatment over another, but with=20 subsequent treatment anti-D immunoglobulin may be given in = clinic or=20 infusion centers with observation. The acute massive = hemolysis seen=20 with anti-D use has discouraged its use in many centers. = Ongoing=20 studies in Europe with subcutaneous anti-D immunoglobulin = suggest=20 that these side effects are much decreased if not eliminated=20 all together.

Regardless of which regimen is implemented, it is important = to=20 remember that it takes several weeks for the antiplatelet=20 immunoglobulin to go through one half-life even if = autoantibody=20 production were to halt at presentation, which would be = highly=20 unlikely. Treatment with agents that impact platelet = clearance=20 by the spleen and reticuloendothelial (RE) system, lose their = effectiveness over 3=964 weeks at which point the platelet = count=20 may once again drop below 20,000/mm3. However, unlike=20 presentation, there will be little to no bleeding and = strikingly=20 fewer bruises or petechiae. Many parents are puzzled by this=20 lack of consistency between platelet count and physical = findings.=20 The reason for this improved hemostasis lies in the bone = marrow,=20 where platelet production has increased 5- to 10-fold over = the=20 first 3=964 weeks, resulting in younger more functional=20 thrombocytes. Investigational agents to stimulate platelet = production=20 are currently in clinical trials and may prove useful for = chronic=20 ITP patients with immune-mediated suppression at the level of = the megakaryocyte.16,32=20

Chronic ITP

When the patient remains thrombocytopenic for greater than 6=20 months, despite therapy, it is both discouraging and = frustrating=20 for the patient, family and healthcare team.33=20 If the platelet count remains in a hemostatically "safe" = range (>=20 20,000/mm3), patients are often observed without=20 intervention, as these patients continue to show spontaneous=20 remission rates of ~50%/year.1,11=20 Treatment is reserved for clear signs of bleeding: increased=20 bruising, menorrhagia, or prolonged epistaxis.33,34=20

However, older children wishing to participate in sports = requiring=20 a higher platelet count may opt for treatment based on = quality=20 of life issues and a desire to enter fully into school = activities.=20 For many years, the gold standard therapies used in acute ITP30,33=9636=20 (IVIG, anti-D immunoglobulin, and corticosteroids) were = administered=20 as needed to chronic ITP patients, in combination with = vincristine=20 or danazol, or on a monthly basis to maintain platelet counts = > 50,000/mm3. Alternatively, splenectomy is = successful=20 in resolution of life threatening thrombocytopenia in = 75=9685%=20 of pediatric patients,36=20 but the irreversible nature of this procedure and the = increased risk=20 of sepsis, albeit slight, has decreased the frequency of this = procedure except in the frankly hemorrhagic patient. =

Over the last 5 years, newer agents designed to interrupt the=20 immune dysregulation driving the production of autoantibody=20 have been used in clinical trials involving adults and = children=20 with chronic ITP (Figure 2; see Color Figures, page = 516).=20 These therapies are most commonly humanized monoclonal=20 antibodies that bind to immune receptors on the early B = lymphocyte=20 anti-CD20 (Rituxan), anti-CD40, or bind to the T cell such as = anti-154 (CD40L/or its soluble form), anti-tumor necrosis = factor=20 (TNF) or its receptor (Enbrel, Remicade).

The success of Rituxan in adult ITP patients has prompted many=20 pediatric hematologists to use this agent in children with = chronic=20 ITP in order to improve platelet counts and to avoid = splenectomy.12,37,38=20 Using a standard dose of 375 mg/m2 in 4 weekly doses, = Wang=20 et al demonstrated a complete response (plt count >=20 150,000/mm3), lasting for an average of 13 months, = in just=20 over 50% of pediatric patients with chronic ITP.37=20 A single annual dose of Rituxan would certainly lessen = hospital time=20 and optimize quality of life in these patients.38=9640=20 Concerns regarding possible infection have proved to be = unwarranted,=20 with the exception of those patients who receive Rituxan = following or=20 in combination with other immune suppression such as = high-dose=20 steroids, azathioprine, or cyclosporin. Other centers are = beginning=20 to assess whether the standard dose of 375 mg/m2 = for 4=20 consecutive weeks is necessary, as this dose was initiated = for the=20 treatment of CLL patients with a much larger number of=20 CD20+ cells. Many have suggested that much less = Rituxan=20 would be necessary for ITP where there are far fewer = CD20+=20 cells than in CLL. Indeed, a single infusion is usually = adequate to=20 clear circulating CD20+ pre-B cells in ITP, but = only=20 clinical trials can assess whether a single large dose or = serial=20 infusions of 1=964 doses is optimal to treat the pool of=20 CD20+ cells in the spleen and elsewhere.38,39=20 It is important to realize that the CD20+ pre-B = cells do=20 not produce the antiplatelet antibody, which is the job of = the plasma=20 cells; rather, it is highly effective at presenting antigen = to T=20 cells, which in turn are driving the autoimmune response.=20 Disruption of this interaction ultimately results in = decreased=20 antiplatelet autoantibody with very little to no decrease in = normal=20 immunoglobulin production.

Final Thoughts on Childhood = ITP

The future of safe and effective management of childhood ITP = will=20 be greatly expanded by the optimal application of such = therapies that=20 target the selected areas of immune dysfunction, rather than = using=20 agents which result in either profound immune suppression or = result=20 in serious toxicities. Although we are not yet at a point = where=20 molecular markers, cytokine and lymphocyte panels can match = ITP=20 patients with personalized treatment regimens, the = coordinated=20 efforts of the medical, research, and patient community have = brought=20 that goal much closer to reality.

Neonatal Alloimmune Thrombocytopenia=20 (NATP)

Neonatal alloimmune thrombocytopenia is caused by maternal = sensitization=20 to paternal alloantigens on fetal platelets (Table 4). A correct diagnosis of NATP must first = eliminate=20 other cause of thrombocytopenia that may occur during = pregnancy. When=20 severe, NATP may result in intracranial hemorrhage leading to = hydrocephalus and fetal death. Fetal hydrocephalus, = unexplained fetal=20 thrombocytopenia with or without anemia, or recurrent = miscarriages=20 should be considered as indicators of possible NATP. = Multiparous=20 women with a history of at least one incident of NATP should = be=20 monitored carefully for subsequent episodes. Postnatal = management=20 involves transfusion of compatible platelets, and washed = maternal=20 platelets are often used. Antenatal management is = controversial but=20 can include a combination of maternal intravenous gamma = globulin=20 (IVIG) administration, intrauterine platelet transfusions and = corticosteroid therapy, while monitoring fetal platelet = counts=20 closely throughout the pregnancy.


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  		Table 4. Neonatal = alloimmune=20 thrombocytopenic purpura: key points.=20 =
 
Th= e=20 biological diagnosis is normally made by genotyping of maternal = and=20 paternal platelet alloantigens and a serological search for=20 antibodies in maternal plasma or serum that reacts with = paternal=20 platelets.

It is intriguing that only a fraction of those mothers negative=20 for the platelet antigen in question deliver infants affected = with NATP. For example, in the western world, responsiveness = to=20 HPA-1a is most commonly the cause of NATP, yet the frequency = of=20 homozygous HPA-1b mothers in the general Caucasian population = is 2%,=20 and estimates of the incidence of NATP are no greater than = 0.05%. A=20 key to understanding this discrepancy lies in the finding = that=20 responsiveness to HPA-1a shows an HLA restriction. = Individuals who=20 are homozygous for Pro33 (homozygous HPA-1b) and=20 responsive to the predominant HPA-1a antigen are almost = exclusively=20 HLA DRB3*0101 or DQB1*02. In the case of DRB3*0101, the = calculated=20 risk factor is 141, a risk level equivalent to that of the = hallmark=20 of HLA-restriction in autoimmune disease, ankylosing = spondylitis and=20 HLA B27. In contrast, responsiveness of homozygous HPA-1a = individuals=20 to the HPA-1b allele is not linked to HLA. T cells are the = likely=20 candidates for providing HLA-restriction in this case, and = Maslanka=20 et al provided elegant evidence that in one case of NATP, T = cells=20 that share CDR3 motifs are stimulated by peptides that = contain the=20 same Leu33 polymorphism that is recognized by = anti-HPA-1a=20 al-loantibodies.41=20 Responsiveness to HPA-1a is not the sole cause of NATP. The=20 association of NATP with other alloantigens, such as HPA-3a, = HPA-3b,=20 HPA-1b or HPA-2b, has been noted, but is rare. Obviously,=20 differences in allelic gene frequencies between different = racial or=20 ethnic populations will have an important impact on the = frequency=20 of responsiveness to a particular alloantigen.

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Opera = requires=0A= the Sun Java Runtime Environment .=0A= =0A= by Andrew Gregory=0A= http://www.scss.com.au/family/andrew/webdesign/xmlhttprequest/=0A= =0A= This work is licensed under the Creative Commons Attribution License. To = view a=0A= copy of this license, visit = http://creativecommons.org/licenses/by-sa/2.5/ or=0A= send a letter to Creative Commons, 559 Nathan Abbott Way, Stanford, = California=0A= 94305, USA.=0A= =0A= Attribution: Leave my name and web address in this script intact.=0A= =0A= Not Supported in Opera=0A= ----------------------=0A= * user/password authentication=0A= * responseXML data member=0A= =0A= Not Fully Supported in Opera=0A= ----------------------------=0A= * async requests=0A= * abort()=0A= * getAllResponseHeaders(), getAllResponseHeader(header)=0A= =0A= */=0A= // IE support=0A= if (window.ActiveXObject && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= var msxmls =3D new Array(=0A= 'Msxml2.XMLHTTP.5.0',=0A= 'Msxml2.XMLHTTP.4.0',=0A= 'Msxml2.XMLHTTP.3.0',=0A= 'Msxml2.XMLHTTP',=0A= 'Microsoft.XMLHTTP');=0A= for (var i =3D 0; i < msxmls.length; i++) {=0A= try {=0A= return new ActiveXObject(msxmls[i]);=0A= } catch (e) {=0A= }=0A= }=0A= return null;=0A= };=0A= }=0A= // Gecko support=0A= /* ;-) */=0A= // Opera support=0A= if (window.opera && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= this.readyState =3D 0; // = 0=3Duninitialized,1=3Dloading,2=3Dloaded,3=3Dinteractive,4=3Dcomplete=0A= this.status =3D 0; // HTTP status codes=0A= this.statusText =3D '';=0A= this._headers =3D [];=0A= this._aborted =3D false;=0A= this._async =3D true;=0A= this._defaultCharset =3D 'ISO-8859-1';=0A= this._getCharset =3D function() {=0A= var charset =3D _defaultCharset;=0A= var contentType =3D = this.getResponseHeader('Content-type').toUpperCase();=0A= val =3D contentType.indexOf('CHARSET=3D');=0A= if (val !=3D -1) {=0A= charset =3D contentType.substring(val);=0A= }=0A= val =3D charset.indexOf(';');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= val =3D charset.indexOf(',');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= return charset;=0A= };=0A= this.abort =3D function() {=0A= this._aborted =3D true;=0A= };=0A= this.getAllResponseHeaders =3D function() {=0A= return this.getAllResponseHeader('*');=0A= };=0A= this.getAllResponseHeader =3D function(header) {=0A= var ret =3D '';=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= if (header =3D=3D '*' || this._headers[i].h =3D=3D header) {=0A= ret +=3D this._headers[i].h + ': ' + this._headers[i].v + '\n';=0A= }=0A= }=0A= return ret;=0A= };=0A= this.getResponseHeader =3D function(header) {=0A= var ret =3D getAllResponseHeader(header);=0A= var i =3D ret.indexOf('\n');=0A= if (i !=3D -1) {=0A= ret =3D ret.substring(0, i);=0A= }=0A= return ret;=0A= };=0A= this.setRequestHeader =3D function(header, value) {=0A= this._headers[this._headers.length] =3D {h:header, v:value};=0A= };=0A= this.open =3D function(method, url, async, user, password) {=0A= this.method =3D method;=0A= this.url =3D url;=0A= this._async =3D true;=0A= this._aborted =3D false;=0A= this._headers =3D [];=0A= if (arguments.length >=3D 3) {=0A= this._async =3D async;=0A= }=0A= if (arguments.length > 3) {=0A= opera.postError('XMLHttpRequest.open() - user/password not = supported');=0A= }=0A= this.readyState =3D 1;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= };=0A= this.send =3D function(data) {=0A= if (!navigator.javaEnabled()) {=0A= alert("XMLHttpRequest.send() - Java must be installed and = enabled.");=0A= return;=0A= }=0A= if (this._async) {=0A= setTimeout(this._sendasync, 0, this, data);=0A= // this is not really asynchronous and won't execute until the = current=0A= // execution context ends=0A= } else {=0A= this._sendsync(data);=0A= }=0A= }=0A= this._sendasync =3D function(req, data) {=0A= if (!req._aborted) {=0A= req._sendsync(data);=0A= }=0A= };=0A= this._sendsync =3D function(data) {=0A= this.readyState =3D 2;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= // open connection=0A= var url =3D new java.net.URL(new = java.net.URL(window.location.href), this.url);=0A= var conn =3D url.openConnection();=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= conn.setRequestProperty(this._headers[i].h, this._headers[i].v);=0A= }=0A= this._headers =3D [];=0A= if (this.method =3D=3D 'POST') {=0A= // POST data=0A= conn.setDoOutput(true);=0A= var wr =3D new = java.io.OutputStreamWriter(conn.getOutputStream(), this._getCharset());=0A= wr.write(data);=0A= wr.flush();=0A= wr.close();=0A= }=0A= // read response headers=0A= // NOTE: the getHeaderField() methods always return nulls for me :(=0A= var gotContentEncoding =3D false;=0A= var gotContentLength =3D false;=0A= var gotContentType =3D false;=0A= var gotDate =3D false;=0A= var gotExpiration =3D false;=0A= var gotLastModified =3D false;=0A= for (var i =3D 0; ; i++) {=0A= var hdrName =3D conn.getHeaderFieldKey(i);=0A= var hdrValue =3D conn.getHeaderField(i);=0A= if (hdrName =3D=3D null && hdrValue =3D=3D null) {=0A= break;=0A= }=0A= if (hdrName !=3D null) {=0A= this._headers[this._headers.length] =3D {h:hdrName, = v:hdrValue};=0A= switch (hdrName.toLowerCase()) {=0A= case 'content-encoding': gotContentEncoding =3D true; break;=0A= case 'content-length' : gotContentLength =3D true; break;=0A= case 'content-type' : gotContentType =3D true; break;=0A= case 'date' : gotDate =3D true; break;=0A= case 'expires' : gotExpiration =3D true; break;=0A= case 'last-modified' : gotLastModified =3D true; break;=0A= }=0A= }=0A= }=0A= // try to fill in any missing header information=0A= var val;=0A= val =3D conn.getContentEncoding();=0A= if (val !=3D null && !gotContentEncoding) = this._headers[this._headers.length] =3D {h:'Content-encoding', v:val};=0A= val =3D conn.getContentLength();=0A= if (val !=3D -1 && !gotContentLength) = this._headers[this._headers.length] =3D {h:'Content-length', v:val};=0A= val =3D conn.getContentType();=0A= if (val !=3D null && !gotContentType) = this._headers[this._headers.length] =3D {h:'Content-type', v:val};=0A= val =3D conn.getDate();=0A= if (val !=3D 0 && !gotDate) this._headers[this._headers.length] = =3D {h:'Date', v:(new Date(val)).toUTCString()};=0A= val =3D conn.getExpiration();=0A= if (val !=3D 0 && !gotExpiration) = this._headers[this._headers.length] =3D {h:'Expires', v:(new = Date(val)).toUTCString()};=0A= val =3D conn.getLastModified();=0A= if (val !=3D 0 && !gotLastModified) = this._headers[this._headers.length] =3D {h:'Last-modified', v:(new = Date(val)).toUTCString()};=0A= // read response data=0A= var reqdata =3D '';=0A= var stream =3D conn.getInputStream();=0A= if (stream) {=0A= var reader =3D new java.io.BufferedReader(new = java.io.InputStreamReader(stream, this._getCharset()));=0A= var line;=0A= while ((line =3D reader.readLine()) !=3D null) {=0A= if (this.readyState =3D=3D 2) {=0A= this.readyState =3D 3;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= }=0A= reqdata +=3D line + '\n';=0A= }=0A= reader.close();=0A= this.status =3D 200;=0A= this.statusText =3D 'OK';=0A= this.responseText =3D reqdata;=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onload) {=0A= this.onload();=0A= }=0A= } else {=0A= // error=0A= this.status =3D 404;=0A= this.statusText =3D 'Not Found';=0A= this.responseText =3D '';=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onerror) {=0A= this.onerror();=0A= }=0A= }=0A= };=0A= };=0A= }=0A= // ActiveXObject emulation=0A= if (!window.ActiveXObject && window.XMLHttpRequest) {=0A= window.ActiveXObject =3D function(type) {=0A= switch (type.toLowerCase()) {=0A= case 'microsoft.xmlhttp':=0A= case 'msxml2.xmlhttp':=0A= case 'msxml2.xmlhttp.3.0':=0A= case 'msxml2.xmlhttp.4.0':=0A= case 'msxml2.xmlhttp.5.0':=0A= return new XMLHttpRequest();=0A= }=0A= return null;=0A= };=0A= }=0A= ------=_NextPart_000_0037_01C917F2.2812E060 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://asheducationbook.hematologylibrary.org/javascript/ajax/utility.js /************************************************************************= *****=0A= * javascript/ajax/utility.js=0A= *=0A= * Utility functions for working with XMLHttpRequest data.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Copy XML nodes into an HTMLElement. This effectively=0A= * clones XML markup which uses XHTML naming conventions=0A= * into an HTML DOM.=0A= */=0A= function copy_xml_to_html(src, dst) {=0A= if (src.nodeType =3D=3D 1) { /* Node.ELEMENT_NODE */=0A= var e =3D document.createElement(src.nodeName);=0A= for (var i =3D 0; i < src.childNodes.length; i++) {=0A= copy_xml_to_html(src.childNodes[i], e);=0A= }=0A= for (var i =3D 0; i < src.attributes.length; i++) {=0A= var n =3D src.attributes[i].name;=0A= var v =3D unescape_xml_string(src.attributes[i].value); =0A= e.setAttribute(n, v);=0A= if (n =3D=3D "class") {=0A= e.className =3D v;=0A= }=0A= else if (n =3D=3D "style") {=0A= set_css_style(v, e, "");=0A= }=0A= }=0A= dst.appendChild(e);=0A= }=0A= else if (src.nodeType =3D=3D 3) { /* Node.TEXT_NODE */=0A= dst.appendChild(document.createTextNode(src.nodeValue));=0A= }=0A= }=0A= =0A= /* =0A= * It is unclear that this is the right thing to be calling=0A= * from copy_xml_to_html, but it appears that Safari decides=0A= * to convert & to the NCR #, and then encodes that=0A= * NCR to &%26%2338;. So, I'm going to treat the DOM Attr=0A= * value as a plain string, and run our XML string input=0A= * through the decoding routine below.=0A= */=0A= function unescape_xml_string(s) {=0A= return s.replace(/'/g, "'")=0A= .replace(/'/g, "'")=0A= .replace(/"/g, "\"")=0A= .replace(/"/g, "\"")=0A= .replace(/>/g, ">")=0A= .replace(/>/g, ">")=0A= .replace(/</g, "<")=0A= .replace(/</g, "<")=0A= .replace(/&/g, "&")=0A= .replace(/&/g, "&");=0A= }=0A= =0A= /*=0A= * Parse set of CSS rules and apply them to an element.=0A= * This is quite horrifying, but I'm unable to determine=0A= * how else to handle this with IE 6. FireFox and other=0A= * sane browsers let you simply set the style attribute=0A= * or use e.style.setProperty(rule, value, priority),=0A= * IE 6 appears to have neither of these capabilities..=0A= */=0A= function set_css_style(css, e, priority) {=0A= var rules =3D css.split(";");=0A= for (var i =3D 0; i < rules.length; i++) {=0A= var nvpair =3D rules[i].split(":");=0A= if (nvpair.length =3D=3D 2) {=0A= try {=0A= var name =3D nvpair[0]; /* style attribute */=0A= var value =3D nvpair[1]; /* attribute value */=0A= =0A= /*=0A= * For each possible style attribute, set the=0A= * appropriate style property in the element.=0A= */=0A= if (name =3D=3D "background") {=0A= e.style.background =3D value;=0A= }=0A= else if (name =3D=3D "background-attachment") {=0A= e.style.backgroundAttachment =3D value;=0A= }=0A= else if (name =3D=3D "background-color") {=0A= e.style.backgroundColor =3D value;=0A= }=0A= else if (name =3D=3D "background-image") {=0A= e.style.backgroundImage =3D value;=0A= }=0A= else if (name =3D=3D "background-position") {=0A= e.style.backgroundPosition =3D value;=0A= }=0A= else if (name =3D=3D "background-position-x") {=0A= e.style.backgroundPositionX =3D value;=0A= }=0A= else if (name =3D=3D "background-position-y") {=0A= e.style.backgroundPositionY =3D value;=0A= }=0A= else if (name =3D=3D "background-repeat") {=0A= e.style.backgroundRepeat =3D value;=0A= }=0A= else if (name =3D=3D "behavior") {=0A= e.style.behavior =3D value;=0A= }=0A= else if (name =3D=3D "border") {=0A= e.style.border =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom") {=0A= e.style.borderBottom =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-color") {=0A= e.style.borderBottomColor =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-style") {=0A= e.style.borderBottomStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-width") {=0A= e.style.borderBottomWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-collapse") {=0A= e.style.borderCollapse =3D value;=0A= }=0A= else if (name =3D=3D "border-color") {=0A= e.style.borderColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left") {=0A= e.style.borderLeft =3D value;=0A= }=0A= else if (name =3D=3D "border-left-color") {=0A= e.style.borderLeftColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left-style") {=0A= e.style.borderLeftStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-left-width") {=0A= e.style.borderLeftWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-right") {=0A= e.style.borderRight =3D value;=0A= }=0A= else if (name =3D=3D "border-right-color") {=0A= e.style.borderRightColor =3D value;=0A= }=0A= else if (name =3D=3D "border-right-style") {=0A= e.style.borderRightStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-right-width") {=0A= e.style.borderRightWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-style") {=0A= e.style.borderStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top") {=0A= e.style.borderTop =3D value;=0A= }=0A= else if (name =3D=3D "border-top-color") {=0A= e.style.borderTopColor =3D value;=0A= }=0A= else if (name =3D=3D "border-top-style") {=0A= e.style.borderTopStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top-width") {=0A= e.style.borderTopWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-width") {=0A= e.style.borderWidth =3D value;=0A= }=0A= else if (name =3D=3D "bottom") {=0A= e.style.bottom =3D value;=0A= }=0A= else if (name =3D=3D "clear") {=0A= e.style.clear =3D value;=0A= }=0A= else if (name =3D=3D "clip") {=0A= e.style.clip =3D value;=0A= }=0A= else if (name =3D=3D "color") {=0A= e.style.color =3D value;=0A= }=0A= else if (name =3D=3D "cssText") {=0A= e.style.Sets =3D value;=0A= }=0A= else if (name =3D=3D "cursor") {=0A= e.style.cursor =3D value;=0A= }=0A= else if (name =3D=3D "direction") {=0A= e.style.direction =3D value;=0A= }=0A= else if (name =3D=3D "display") {=0A= e.style.display =3D value;=0A= }=0A= else if (name =3D=3D "font") {=0A= e.style.font =3D value;=0A= }=0A= else if (name =3D=3D "font-family") {=0A= e.style.fontFamily =3D value;=0A= }=0A= else if (name =3D=3D "font-size") {=0A= e.style.fontSize =3D value;=0A= }=0A= else if (name =3D=3D "font-style") {=0A= e.style.fontStyle =3D value;=0A= }=0A= else if (name =3D=3D "font-variant") {=0A= e.style.fontVariant =3D value;=0A= }=0A= else if (name =3D=3D "font-weight") {=0A= e.style.fontWeight =3D value;=0A= }=0A= else if (name =3D=3D "height") {=0A= e.style.height =3D value;=0A= }=0A= else if (name =3D=3D "ime-mode") {=0A= e.style.imeMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-flow") {=0A= e.style.layoutFlow =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid") {=0A= e.style.layoutGrid =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-char") {=0A= e.style.layoutGridChar =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-line") {=0A= e.style.layoutGridLine =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-mode") {=0A= e.style.layoutGridMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-type") {=0A= e.style.layoutGridType =3D value;=0A= }=0A= else if (name =3D=3D "left") {=0A= e.style.left =3D value;=0A= }=0A= else if (name =3D=3D "letter-spacing") {=0A= e.style.letterSpacing =3D value;=0A= }=0A= else if (name =3D=3D "line-break") {=0A= e.style.lineBreak =3D value;=0A= }=0A= else if (name =3D=3D "line-height") {=0A= e.style.lineHeight =3D value;=0A= }=0A= else if (name =3D=3D "list-style") {=0A= e.style.listStyle =3D value;=0A= }=0A= else if (name =3D=3D "list-style-image") {=0A= e.style.listStyleImage =3D value;=0A= }=0A= else if (name =3D=3D "list-style-position") {=0A= e.style.listStylePosition =3D value;=0A= }=0A= else if (name =3D=3D "list-style-type") {=0A= e.style.listStyleType =3D value;=0A= }=0A= else if (name =3D=3D "margin") {=0A= e.style.margin =3D value;=0A= }=0A= else if (name =3D=3D "margin-bottom") {=0A= e.style.marginBottom =3D value;=0A= }=0A= else if (name =3D=3D "margin-left") {=0A= e.style.marginLeft =3D value;=0A= }=0A= else 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quoted-printable Content-Location: http://asheducationbook.hematologylibrary.org/javascript/entrez/callback.js /************************************************************************= *****=0A= * javascript/entrez/callback.js=0A= *=0A= * Entrez Linking callback to populate content box.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Execute callback to fill content box with Entrez Linking information.=0A= */=0A= function entrez_callback(pmid, callback_url) {=0A= /*=0A= * MSIE 5.5 and below have issues with the JavaScript=0A= * used for Entrez Linking. 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