Charles Schlappi, MD, Varsha Kulkarni, MBBS, Prasannalaxmi Palabindela, MBBS, OutcomesChristina Bemrich-Stolz, MD, MSPH, in Thomas Mild Howard, MD, to Lee Hilliard, Moderate MD, IsolatedJeffrey Lebensburger, DO, ThrombocytopeniaMSPH OBJECTIVES: abstract

Incidental isolated mild to moderate is a frequent laboratory finding prompting a referral to pediatric -oncology. We tested the hypothesis – that patients with isolated asymptomatic mild thrombocytopenia would not progress to METHODS: require an intervention from a pediatric hematologist oncologist. – This is a 5-year retrospective review of 113 patients referred to pediatric hematology oncology for isolated thrombocytopenia. Initial, lowest, and current – × μ counts along with clinical course and need for interventions were recorded. – × μ – × μ 3 Thrombocytopenia was categorized as mild (platelet count: 101 140 10 / L), moderate ≤ × μ3 3 (platelet count: 51 100 10 / L), severe (platelet count: 21 50 10 / L), and very severe RESULTS: 3 (platelet count: 20 10 / L). Eight of 48 patients (17%) referred for initial mild isolated thrombocytopenia progressed to moderate thrombocytopenia at 1 visit. At present, 2 of these patients have moderate thrombocytopenia, 17 remain with mild thrombocytopenia, and 29 patients have resolved thrombocytopenia. Nine of 65 patients (14%) referred for moderate thrombocytopenia progressed to severe or very severe thrombocytopenia on 1 occasion. At present, no patients have severe thrombocytopenia, 18 remain with moderate thrombocytopenia, 14 improved to mild thrombocytopenia, and 33 have resolved thrombocytopenia. Only 3 patients required interventions from a hematologist, whereas CONCLUSIONS: 10 patients required therapy from other subspecialties. We only identified 3 patients (3%) with mild to moderate thrombocytopenia who required an intervention from a hematologist to improve platelet counts. Patients with isolated mild thrombocytopenia with a normal history and physical examination NIH findings frequently have normalized their platelet counts within 1 month.

Division of Pediatric Hematology Oncology. University of Alabama at Birmingham, Birmingham, Alabama WHAT’S KNOWN ON THIS SUBJECT: Isolated thrombocytopenia is a common pediatric laboratory Dr Lebensburger conceptualized and designed the study and drafted the initial manuscript; finding among patients with a bleeding or bruising Drs Schlappi, Kulkarni, and Palabindela designed and coordinated data collection, conducted history as well as being an incidental laboratory the initial analyses, and reviewed and revised the manuscript; Drs Bemrich-Stolz, Howard, and finding. The outcomes and need for referral to pediatric Hilliard participated in the design of the study, reviewed the analyses, and critically reviewed hematology oncology have not been established. the manuscript; and all authors approved the final manuscript as submitted. – DOI: https://​doi.​org/​10.​1542/​peds.​2017-​3804 WHAT THIS STUDY ADDS: The majority of patients with mild or moderate thrombocytopenia normalized Accepted for publication Apr 19, 2018 platelet counts within 3 months. Mild isolated Address correspondence to Jeffrey Lebensburger, DO, MSPH, University of Alabama at thrombocytopenia without a bleeding history Birmingham, 1600 7th Ave South, Lowder 512, Birmingham, AL 35223. E-mail: jlebensburger@peds. or abnormal physical findings did not require uab.edu interventions from pediatric hematology–oncology; PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). moderate isolated thrombocytopenia cases rarely required interventions. Copyright © 2018 by the American Academy of Pediatrics

To cite: Schlappi C, Kulkarni V, Palabindela P, et al. Outcomes in Mild to Moderate Isolated Thrombocytopenia. Pediatrics. 2018;142(1):e20173804

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 142, number 1, July 2018:e20173804 ARTICLE – × µ A broad differential diagnosis exists outcomes for patients with mild categorized patients as having mild –3 × for pediatric patients diagnosed with or moderate thrombocytopenia (platelet count: 101 140 10 / L), – × μ µ isolated thrombocytopenia, defined as and identified only 1 adult study moderate (platelet count: 51 100 3 – 1,×2​ –3 × µ a platelet count <140 150 10 / L. ‍ of patients with mild persistent 10 / L), severe (platelet count: μ 3 ≤ × µ When3 platelet counts drop to <30 50 thrombocytopenia. Among the 191 21 50 10 / L), and very3 severe 10 / L, patients may develop adult patients with mild persistent (platelet count: 20 10 / L) petechiae, bruising, and epistaxis, thrombocytopenia, 60% remained thrombocytopenia at the time of prompting primary care providers3,4​ to with mild thrombocytopenia, 7% referral on the basis of the lowest obtain a . ‍ normalized their platelet counts, platelet count and current platelet Isolated thrombocytopenia may 7% developed an autoimmune count. We included 1 patient as mild also be incidentally identified by a disorder, and 6% were diagnosed at the time of referral despite being × µ primary care provider who performs with immune thrombocytopenia referred for thrombocytopenia3 with a complete blood count for other (ITP); 6 patients developed adult- a platelet count of 143 10 / L; indications, including concerns specific malignancies (including this patient had a previous clinic for , and/or breast, lung, and colorectal cancers history of mild thrombocytopenia 7 × µ , or as part of a routine and myelodysplasia). To better and an initial3 in-clinic platelet count health screening with5 understand the outcomes for of 123 10 / L. History of bruising and/or hematocrit. Once isolated pediatric patients with isolated mild at the time of referral, age, sex, and thrombocytopenia is identified, a to moderate thrombocytopenia, referring provider were recorded primary care provider may further we conducted a retrospective chart from clinic and referral notes. – evaluate or refer that patient to a review to assess the incidence, Therapeutic interventions and reason – pediatric hematologist oncologist outcomes, and need for intervention for intervention were recorded from ’ on the basis of either the primary from a pediatric hematologist pediatric hematology clinic notes. care provider6 s concern or parental oncologist among all patients Finally, antineutrophil antibody, desire. Parents and patients referred referred for thrombocytopenia antinuclear antibody, platelet for isolated mild to moderate over a 5-year period. We tested the antibody, and immunoglobulin G thrombocytopenia may experience hypothesis that patients with isolated levels were recorded. Descriptive emotional distress either during mild thrombocytopenia without statistics and univariate analysis the wait for their referral visit and/ bruising and/or bleeding symptoms were conducted by using JMP Pro 12 – or the time spent in a waiting room would not progress to require (SAS Institute, Inc, Cary, NC). – at a pediatric hematology oncology an intervention from a pediatric RESULTS clinic. Often, this distress is due hematologist oncologist. to concern by the patient and/or METHODS parent that the child has cancer. In addition, current health economics Among 2820 patients referred to the necessitates improved use of health outpatient UAB Pediatric Hematology – care specialists. Therefore, having We conducted an institutional review Oncology Clinic over a 5-year period, a clear understanding of which board approved retrospective study 2256 patients were referred for patients with mild to moderate of all outpatient referrals to the evaluation of a hematologic disease. thrombocytopenia require evaluation – University of Alabama at Birmingham The most commonn hematologic or intervention from a pediatric (UAB) Pediatric Hematology referral to our clinic was for sickle hematologist oncologist would help Oncology Clinic from June 2012 to cell disease ( = 296; 13%) and nthe primary care providers make the June 2017. We excluded patients second most common referral was ’ most beneficial referrals. initially admitted to the hematology to evaluate thrombocytopenia ( = oncology service at Children s of 204; 9%). Among the 204 patients Although we hypothesize that Alabama for thrombocytopenia who with an outpatient referral for pediatric patients with mild to required additional follow-up in our thrombocytopenia, 113 of these moderate thrombocytopenia, no outpatient clinic. The diagnosis and referrals were for isolated moderate or clinical symptoms, or any abnormal demographics were recorded for mild thrombocytopenia. The incidence physical findings may not warrant every patient. We recorded the date of referrals for mild to moderate – an immediate referral to a pediatric and platelet count at the time of the isolated thrombocytopenia was 23 hematologist oncologist, there is first episode of thrombocytopenia patients per year. The mean age at minimal literature that can support and the referral visit, lowest platelet referral was 10.6 years, and younger this hypothesis. We could not count, and the most recent platelet age was associated with a lower identify any pediatric reports of count (as of January 2018). We platelet count at the time of referral Downloaded from www.aappublications.org/news by guest on September 29, 2021 2 SCHLAPPI et al TABLE 1 Referral Platelet Counts Variables n Mean Platelet Count at Range Referral thrombocytopenia, 23 resolved within 1 month and 3 additional Categorical platelet count at time of referral 3 patients resolved between 1 and 2 Mild (101–140 × 10 /μL) 48 120 103–143 Moderate (51–100 × 103/μL) 65 75 52–100 months. Two patients remain with Sex moderate thrombocytopenia, 1 patient Male 63 98 54–143 continues to be monitored by pediatric Female 50 89 52–139 hematology for a RUNX1 mutation Referral (familial platelet disorder with Pediatrician 91 96 52–143 Family medicine 12 88 54–139 predisposition to acute myelogenous Subspecialist (orthopedics, rheumatology, 5 81 58–106 ), and the other patient is infectious disease) being treated in rheumatology for Internal medicine 4 89 77–100 juvenile idiopathic arthritis. Hematology–oncology 1 122 Bruising Positive 29 89 53–140 Sixty-five patients were referred with Negative 84 96 52–143 isolated moderate thrombocytopenia. Eight patients (12%) progressed to P the severe thrombocytopenic range, and 1 patient (2%) progressed to ( = .02). More patients were of male pediatric hematology clinic, 48 (42%) very severe thrombocytopenia sex, and the majority of practitioners had isolated mild thrombocytopenia at on at least 1 occasion (Table 2). making referrals were pediatricians the time of referral. Among the patients For these patients with moderate (Table 1). There were no statistical with isolated mild thrombocytopenia, thrombocytopenia at the time of differences in the mean referral platelet 8 (17%) progressed to the moderate referral, 33 (51%) currently have count among 29 patients (26%) range during at least 1 point of a normal platelet count, 14 (22%) referred with a parent or referral follow-up, but no patients progressed are in the mild range, 18 (28%) report of increased bruising and/or to the severe or very severe ranges have moderate thrombocytopenia, bleeding as compared withP 84 patients (Table 2). Twenty-nine (60%) of these and no patients have severe without a reported history of bruising patients currently have normal platelet thrombocytopenia on the basis of and/or bleeding history ( = .2). counts, 17 (35%) have persistent mild their most recent blood count. thrombocytopenia, and 2 (4%) have Among the 113 patients with isolated moderate thrombocytopenia. Among To determine the role of monitoring thrombocytopenia evaluated in our those patients who had resolved of complete blood counts before TABLE 2 Outcomes for Patients With Isolated Mild to Moderate Thrombocytopenia That Progressed to a Lower Platelet Category Change in Category Referral Lowest Platelet Current Therapeutic Intervention Outcomes Platelet Counta Counta Platelet Counta Mild thrombocytopenia that 111 74 78 No intervention RUNX-1 mutation; monitoring for progression progressed to moderate to AML (FPD AML) thrombocytopenia (n = 8) 106 89 89 Methotrexate, etanercept Juvenile idiopathic arthritis 125 78 106 Steroids Immunology managing for likely CVID 125 53 107 Infliximab Crohn disease 109 88 112 No intervention Resolved 106 86 146 No intervention Resolved 127 93 147 No intervention Viral illness, resolved 129 74 150 No intervention Resolved Moderate thrombocytopenia 77 35 58 No intervention Concern for ALPS that progressed to severe 80 38 58 IVIG for sports ITP; immunology managing for low thrombocytopenia (n = 9) participation immunoglobulin 71 5 64 IVIG, steroids ITP 81 44 70 No intervention Thrombocytopenia 56 47 89 No intervention Thrombocytopenia ANA-positive 61 41 93 No intervention Thrombocytopenia 60 44 158 IVIG, steroids for sports ITP 68 41 191 No intervention Resolved 70 46 241 No intervention Resolved ALPS, autoimmune lymphoproliferative syndrome; AML, acute myelogenous leukemia; ANA, antinuclear antibody; CVID, chronic variable immunodeficiency disease; FPD, familial platelet disorder; IVIG, intravenous immunoglobulin. a Platelet count units ×103/μL.

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 142, number 1, July 2018 3 TABLE 3 Current Diagnoses for Referred Patients Current Diagnosis N Mean Referral Range referral, we analyzed the time to Platelet Counta normalization for platelet counts. Thrombocytopenia, unspecified 61 100 53–140 Among 62 patients who had ITP 14 77 54–121 normalized platelet counts, 43 (69%) – Drug-induced thrombocytopenia 12 84 52–124 normalized at their initial referral Viral-induced thrombocytopenia 5 93 59–111 visit to pediatric hematology Systemic erythematosus 3 101 70–143 oncology. In total, 50 (81%) patients Inflammatory bowel disease 2 102 78–125 Juvenile idiopathic arthritis 2 123 106–139 had a normalized platelet count Neonatal alloimmune thrombocytopenia 2 59 58–59 within 1 month of their referral visit, Concern for immunodeficiency 1 84 75–92 and 55 (89%) normalized within 2 RUNX1 mutation 1 111 — months. Next, to evaluate outcomes Henoch-Schonlein 1 132 — on the basis of the length of time End-stage renal disease 1 100 — DiGeorge syndrome 1 82 — patients had thrombocytopenia ADP receptor deficiency 1 63 — before the primary care provider Common variable immune deficiency 1 125 — referral, we reviewed the 2 most Autoimmune lymphoproliferative 1 77 — syndrome common clinic visitsn resulting in a diagnosis of thrombocytopenia: Hypothyroidism 1 59 — n X-linked thrombocytopenia 1 122 — (1) acute illness ( = 32) and (2) NICU, premature 1 97 — well-child evaluations ( = 18). ADP, adenosine diphosphate; —, not applicable. Thirty-one of these patients were a Platelet count units ×103/μL. evaluated within 2 months of their first episode of thrombocytopenia. Twenty-three (74%) currently have normal platelet counts, including 14 whose counts had normalized thrombocytopenia (4 for valproic and 2 for sports participation). at the time of the referral and 19 acid, 2 for methylphenidate, 2 The remaining 10 patients who who resolved within 2 months for dexmethylphenidate, 2 for required an intervention for after referral. In contrast, of the 19 risperidone, 1 for valganciclovir, thrombocytopenia received patients with thrombocytopenia and 1 for sertraline). Five patients those interventions from another identified during an acute illness were diagnosed with rheumatologic subspecialist (Supplemental Table 4). or well-child evaluation who had diseases (3 for systemic lupus thrombocytopenia for at least 3 erythematous [SLE] and 2 for DISCUSSION months before the referral visit, juvenile idiopathic arthritis). Two only 10 (53%) have normal platelet of these 5 patients presented with counts. joint pain and thrombocytopenia; Few patients with newly diagnosed 1 patient developed joint pain 1 isolated mild to moderate The majority of patients were month after the thrombocytopenia thrombocytopenia progressed to not identified with a specific referral; 1 patient developed fever, very severe thrombocytopenia in this diagnosis for their mild to moderate rash, and joint pain 20 months after thrombocytopenia. Several of cohort, and only 3 patients required the thrombocytopenia referral; and these patients presented with viral interventions prescribed by a 1 patient with a history of lupus symptoms at or around the time of pediatric hematologist for moderate developed thrombocytopenia 6 years referral, and the symptoms either chronic ITP. One patient with a after the lupus diagnosis. Finally, we resolved before the clinic visit history of bruising and moderate identified 1 patient with a clinical or soon thereafter. Specific viral isolated thrombocytopenia was etiologies were not commonly tested history of bruising and moderate diagnosed with a rare, qualitative for, and only 2 patients were formally isolated thrombocytopenia who was platelet defect. No patients with an diagnosed with Epstein-Barr virus diagnosed with a rare, qualitative initial outpatient referral for isolated infection during their evaluation platelet defect (Table 3). mild to moderate thrombocytopenia for thrombocytopenia. Fourteen Among the 115 cases of mild and progressed to leukemia. patients referred with moderate moderate isolated thrombocytopenia, Many patients referred for mild to thrombocytopenia were diagnosed we identified 13 patients (11%) moderate isolated thrombocytopenia with ITP, but only 3 patients required who required an intervention. Only had a recent history of virallike interventions. Twelve patients were 3 patients required therapy from a symptoms. The majority of these diagnosed with a drug-induced hematologist for ITP (1 for bruising patients had a normalization of their Downloaded from www.aappublications.org/news by guest on September 29, 2021 4 SCHLAPPI et al platelet counts within 1 to 2 months. SLE by clinical history and physical patients with mild to moderate Pediatric patients with congenital examination, and in patients with thrombocytopenia, assessing or acquired viral infections may high clinical suspicion, further bleeding history in a more develop thrombocytopenia testing with antinuclear antibody is comprehensive and standardized because of alterations in platelet warranted. A second nonhematologic manner is helpful. There are several production or platelet destruction. diagnosis to consider in patients pediatric bleeding questionnaires Prevalent viruses linked to with thrombocytopenia is Crohn designed to help distinguish– thrombocytopenia include HIV, disease or ulcerative colitis as between children with and17 20 without hepatitis C, cytomegalovirus, an extraintestinal manifestation . ‍ ‍ varicella virus, Epstein-Barr of these diseases. Similar to SLE, A second limitation exists because virus, and others. In patients anemia is the more common patients could develop progressive presenting with viral symptoms, hematologic manifestation of thrombocytopenia that was not isolated thrombocytopenia, and Crohn disease or ulcerative colitis, identified. Because patients may normal physical examination yet our group and others have not experience clinical signs of results (including lack of identified thrombocytopenia as thrombocytopenia until a platelet ), the isolated a rare presenting hematologic count is very low, we may have 14,15​ × µ thrombocytopenia may continue manifestation. ‍ Finally, we missed patients 3with platelet over the course of the viral illness. identified 1 referral for a patient counts <50 10 / L between clinic Although there is concern that who was diagnosed with a rare, visits. Third, we continue to follow thrombocytopenia and fever might inherited functional platelet defect. some patients with persistent mild be a presentation of leukemia, our These patients often present to moderate thrombocytopenia results mirror those in other large with manifestations of bruising, without clinical signs or symptoms reviews of children with leukemia epistaxis, and/or menorrhagia in who lack a defined diagnosis. demonstrating that isolated the setting of mild to moderate These patients may have a mild thrombocytopenia with a normal thrombocytopenia and a family autoimmune thrombocytopenia hemoglobin, white blood cell count, history of mucocutaneous bleeding or platelet antibodies not yet and physical examination– results and or menorrhagia. identified, but because they are no symptoms of is unlikely not progressive in their current 8 11 The most common diagnosis to be leukemia. ‍‍ disease course, more expensive and for all referred patients with invasive testing has been deferred. thrombocytopenia was ITP. Drug-induced thrombocytopenia was Thus, an ultimate diagnosis may However, these patients frequently the second most common diagnosis not have been made. Fourth, we presented with severe or very for patients in this cohort with mild diagnosed several patients referred severe thrombocytopenia rather to moderate thrombocytopenia. with 2 cell line abnormalities with than mild or moderate isolated An established database for a bone marrow failure syndrome or thrombocytopenia. In addition, medications with a high incidence . We acknowledge several case patients with ITP for drug-induced thrombocytopenia that some patients with bone presented to the emergency is available at http://​www.​ouhsc.​ marrow failure syndromes may department rather than in edu/​/​ditp.​html. We also initially present with isolated mild referral to our outpatient clinic. identified several potential additional to moderate thrombocytopenia Patients with mild to moderate diagnoses, such as SLE. Juvenile and require continued serial blood thrombocytopenia that progress idiopathic arthritis and Crohn disease count monitoring for progression to very severe thrombocytopenia and/or ulcerative colitis should to additional cytopenias. Finally, during ITP typically present be considered by a primary care we do not have a systematic with acute onset of bleeding or provider when patients present with 16 referral system in place in which significant bruising. all thrombocytopenia cases in mild to moderate thrombocytopenia. – Although anemia is the most common As a retrospective study, some Alabama are referred to a pediatric hematologic manifestation of SLE, limitations are worth noting. One hematologist oncologist at UAB. identified in up to 90% of cases, 40% limitation is that we analyzed Therefore, we would expect that × µ of case patients with SLE present 3 history of a bleeding disorder from several case patients with isolated with a platelet count of <150 10 / L the referral clinic notes rather than mild to moderate thrombocytopenia × µ and 27% present with3 a 12,platelet13​ using a validated bleeding score. were not referred to us by their count of <100 10 / L. ‍ Our Therefore, to fully assess the risk primary care providers. However, data is used to support screening for disease-specific progression we expect that the majority of those patients with thrombocytopenia for of thrombocytopenia among missing cases would have resolved Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 142, number 1, July 2018 5 rather than progressed without with mild isolated thrombocytopenia assess for any clinical manifestations referral. Therefore, this missing and 50% of patients with moderate ACKNOWLEDGMENTSof thrombocytopenia. data are unlikely to change our thrombocytopenia resolved. Among ∼ findings. those patients with resolved CONCLUSIONS thrombocytopenia, 90% resolved We acknowledge Lisa Allred, RN, for within 2 months. We also identified her amazing job leading our referral autoimmune disorders or drug- service and keeping excellent referral The study shows that few patients induced thrombocytopenia as records. with isolated mild to moderate potential diagnoses in patients thrombocytopenia require with persistent mild to moderate ABBREVIATIONS interventions from a pediatric thrombocytopenia. Repeat serial hematologist. Interestingly, the histories, physicals, and complete majority of patients who needed an blood counts can be used to ITP: immune thrombocytopenia intervention after referral for mild differentiate an acute versus chronic SLE: systemic lupus to moderate thrombocytopenia course of thrombocytopenia. These erythematous received treatment from measures are needed to rule out UAB: University of Alabama at subspecialties other than progressive cytopenias, macrocytosis, Birmingham hematology. Sixty percent of patients and organomegaly as well as to

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: Dr Lebensburger is funded by the National Institutes of Health (5K23HL127100) and an American Society of Hematology Scholar Award for research in sickle cell nephropathy that is not relevant to this article. Funded by the National Institutes of Health (NIH). POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 142, number 1, July 2018 7 Outcomes in Mild to Moderate Isolated Thrombocytopenia Charles Schlappi, Varsha Kulkarni, Prasannalaxmi Palabindela, Christina Bemrich-Stolz, Thomas Howard, Lee Hilliard and Jeffrey Lebensburger Pediatrics 2018;142; DOI: 10.1542/peds.2017-3804 originally published online June 11, 2018;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/142/1/e20173804 References This article cites 19 articles, 2 of which you can access for free at: http://pediatrics.aappublications.org/content/142/1/e20173804#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Community Pediatrics http://www.aappublications.org/cgi/collection/community_pediatrics _sub Hematology/Oncology http://www.aappublications.org/cgi/collection/hematology:oncology_ sub Blood Disorders http://www.aappublications.org/cgi/collection/blood_disorders_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 29, 2021 Outcomes in Mild to Moderate Isolated Thrombocytopenia Charles Schlappi, Varsha Kulkarni, Prasannalaxmi Palabindela, Christina Bemrich-Stolz, Thomas Howard, Lee Hilliard and Jeffrey Lebensburger Pediatrics 2018;142; DOI: 10.1542/peds.2017-3804 originally published online June 11, 2018;

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