the Management of Bleeding in Pediatric Patients with Isolated Thrombocytopenia

- Executive Summary

➡️Introduction

Pediatric thrombocytopenia is a complex area of medicine covering a wide age range of different patho etiologies. Establishing the cause of thrombocytopenia has obvious clinical repercussions but is sometimes quite challenging.

Compared to adult practice, there is a relative lack of high-quality research to inform evidence-based guidelines for the diagnosis and management of thrombocytopenia in pediatrics.

The aim of this adapted clinical practice guideline (CPG) is to provide evidence-based recommendations for the diagnosis and management of thrombocytopenia in the pediatric age group.

➡️Scope

This guideline focuses on any disease or condition causing bleeding in neonates, infants, children, and adolescents (with focus on thrombocytopenia). It Provides an evidence-based document for the appropriate clues for diagnosis, and management of different causes of thrombocytopenia in pediatrics.

It also identifies neonates, infants, children, and adolescents at high risk of bleeding and methods of prevention of further bleeding episodes in the target population.

 ➡️Guideline development process and methods

After reviewing all the inclusion and exclusion criteria and quality appraisal results, the GDG/ GAG recommended using the following source original clinical practice guidelines (CPGs):

1. American Society of Hematology 2019 guidelines for immune thrombocytopenia. (ASH 2019)¹
2. The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition. (European 2019)²
3. Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology. (ESA 2016)³
4. Fetal and neonatal alloimmune thrombocytopenia: recommendations for evidence-based practice, an international approach. (BSH, 2019)⁴
5. Guidelines on transfusion for fetuses, neonates and older children. (BSH 2016)⁵
6. Guidelines for the Laboratory Investigations of heritable disorders of platelet function. (BSH 2011)⁶
7. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. (ASH ITP consensus 2019).⁷

We conducted Adolopment for these guidelines: (Adoption, Adaptation, and Development)

         -  Adoption for most of the guideline recommendations.

         -    Development of Good Practice Statements

➡️Recommendations and Good Practice Statements (GPS)

This version of the CPG includes recommendations and good practice statements on the following four sub-sections:

A. Diagnosis of pediatric isolated thrombocytopenia:

The guideline covers recommendations for diagnosis of isolated thrombocytopenia in neonates as well as in infants and children.

This guideline emphasis on clinical manifestations and investigations for different cases of thrombocytopenia.

B. Management of pediatric isolated thrombocytopenia:

This section includes recommendations and good practice statements on how to manage pediatric thrombocytopenia according to different clinical situations and diagnoses.

C. Prevention of pediatric isolated thrombocytopenia:

This section handles the prevention of thrombocytopenia in pediatrics.

We can summarize the guidelines’ recommendations for management of isolated thrombocytopenia in Pediatric Age Groups in the following:

Diagnosis of pediatric isolated thrombocytopenia:

▪️The NeoBAT is a modified WHO bleeding assessment tool to record neonatal bleeding episodes to standardise the clinical recording of bleeding in premature and term neonates in an intensive care setting. GPS.      

▪️ A cranial ultrasound should be performed to screen for intracranial hemorrhage (ICH) in all neonates suspected of fetal/neonatal alloimmune thrombocytopenia (FNAIT) within 24 h of delivery. High, Weak (conditional)           .

▪️  A neonate with FNAIT should have platelet counts monitored until the platelets are normal in the absence of treatment. High, Weak (conditional). 

▪️ Clues for inherited thrombocytopenia diagnosis:

-      Thrombocytopenia has been present since early life.

-      A positive family history for a similar disorder.

-      Characteristic physical features are present.

-      Failure to respond to first-line treatment. GPS.    

·     Mean platelet volume may be used to differentiate ITP from inherited thrombocytopenia. Strong.          

▪️  Flow cytometry should be used in the investigation or confirmation of Bernard Soulier syndrome and abnormalities in the collagen (GpVI and GpIa/IIa) and thrombin receptors (PAR-1). High, Weak (conditional).

▪️ The International Society of Hemostasis and thrombosis – Bleeding assessment tool (ISTH-SCC BAT), a validated general bleeding assessment score, could be used for initial screening of bleeding manifestations. GPS.

▪️  The diagnosis of ITP is based principally on the exclusion of other causes of isolated thrombocytopenia using patient history, physical examination, blood count, and evaluation of the peripheral blood film (to exclude other hematological conditions). Strong.      

In isolated thrombocytopenia with no abnormal physical findings and no abnormal blood smear, a bone marrow examination is not required in the initial diagnosis, whether or not treatment is recommended.   Strong.

▪️ Testing for antinuclear antibodies is not necessary in the evaluation of children and adolescents with newly diagnosed ITP. High, Strong.      

▪️  Bone marrow examination is unnecessary in children and adolescents with the typical features of ITP. Strong.

▪️  Bone marrow examination could be appropriate in those relapsing after remission, in patients not responding to initial treatment options, where splenectomy is considered, or if other abnormalities are detected in the blood count (bicytopenia or pancytopenia) or morphology . Weak (conditional).

▪️  Additional evaluation could include: 

-  DAT is recommended to exclude coexistent autoimmune hemolytic anemia, especially prior to therapy.

-  Immunoglobulin levels.

-  Lupus and other markers of autoimmune diseases that might require specific treatment (e.g., test for APLAs, ANAs, anti-cardiolipin antibody, lupus anticoagulant, and serum Igs)

-  Chronic infections (hepatitis, cytomegalovirus and/or HIV in at-risk populations or when there is no other explanation)

-  Complex immunodeficiency diseases

Genetic screening for inherited thrombocytopenia and bone marrow failure syndromes. Weak (conditional).

➡️Treatment of thrombocytopenia:

▪️  In a neonate with FNAIT, platelets should be transfused immediately if life-threatening bleeding is present to maintain platelet counts initially above 100 x 109 /l and then above 50 x 109 /l for at least 7 days. High, Strong.   

▪️ If an ICH is suspected clinically, do not delay platelet transfusion while awaiting confirmation by imaging studies. High, Weak (conditional).       

▪️   In the absence of life-threatening bleeding in a neonate, such as intracranial or gastrointestinal bleeding, platelets should be transfused to maintain a platelet count above 30 × 109 /l.  High, Weak (conditional)                                  

▪️  In the rare circumstance where either HPA unselected or HPA selected platelets are not available; infuse the neonate with IVIG 1 g/kg. High, Weak (conditional).

▪️  For preterm neonates with very severe thrombocytopenia (platelet count below 25 x 109/l) platelet transfusions should be administered in addition to treating the underlying cause of the thrombocytopenia. Intermediate, Weak (conditional).

▪️  In case of maternal ITP:

1- Management of delivery:  

-  FNAIT should be excluded by parental testing if the neonate presents with severe thrombocytopenia.          

- The mode of delivery should be determined by obstetric indications, not by anticipation of the neonatal platelet count.        

-  Procedures during labor that may be associated with increased hemorrhagic risk to the fetus should be avoided, specifically the use of fetal scalp electrodes, fetal blood sampling, ventouse delivery, and rotational forceps. Weak (conditional).

2) Management after delivery

-  Umbilical cord platelet count should be obtained at the time of delivery or as soon as possible.           

-  Repeat the platelet count as needed depending on platelet levels, trends in the count, and response to treatment (if any). If cord platelet count is <100 x 109/L, repeat the platelet count daily until stable.         

-  If platelet count is <50 x 109/L at birth, perform a cranial ultrasound.  

-  In the case of ICH, give IVIg and limited steroids to maintain platelet count > 100 x 109/L for 1 week if possible and > 50 x 109/L for another week.            

-   If there is symptomatic bleeding or if platelet count is < 30 x 109/L, with or without platelet transfusion, give IVIg.                

-  If severe thrombocytopenia continues for > 1 week in a breast-fed infant, consider pausing breastfeeding for a few days to see whether platelet count increases. Weak (conditional).

▪️ Indications for hospitalization in ITP:

-  Any severe (grade 4) bleeding requires immediate hospital admission and treatment to increase platelet levels until bleeding has decreased.                   

-  Any moderate (grade 3) bleeding requires hospital review and consideration for admission and therapy.

- Patient with ITP with uncertainty about the diagnosis, those with social concerns, those who live far from the hospital, or those for whom follow up cannot be guaranteed, admission to the hospital may be preferable. Weak (conditional).

▪️ Patients not admitted to the hospital should receive education and expedited follow-up with a hematologist (within 24 to 72 hours of the diagnosis or disease relapse). Weak (conditional).       

▪️  At diagnosis, children and adolescents with ITP and mild or even moderate bleeding on a pediatric bleeding assessment tool (grade 1-3) may be managed expectantly with supportive advice and a 24-hour contact point, irrespective of platelet count. Weak (conditional).

▪️ In patients with persistent and chronic ITP, observation or watch and wait is less validated because it is based on the expectation of spontaneous future improvement.        Weak (conditional).

▪️  In children with newly diagnosed ITP who have non–life-threatening mucosal bleeding and/or diminished HRQoL can start with any of the 1st line therapy:

-  Prednisone (2 - 4 mg/kg/day; maximum, 120 mg daily, for 5-7 days) (Time to initial response 4-14 days).

- IVIG in single dose of 0.8 to 1.0 g/kg. (Time to initial response 1-3 days).

-  A second dose of IVIg may be administered if there is a suboptimal initial response and/or ongoing bleeding.  Weak (conditional).

▪️ Indications of platelets transfusion in thrombocytopenia:

➡️In non-immune thrombocytopenia

-  Platelets < 10 x 109/L transfuse Irrespective of signs of hemorrhage.

-  Platelets < 20 x 109/L transfuse in:

-  Insertion of a non-tunnelled central venous line.

-  Platelets < 50 x 109/L transfuse in:

-  Moderate hemorrhage (e.g., gastrointestinal bleeding).

-   Surgery, unless minor (except at critical sites). Strong.

▪️ Tranexamic acid (TXA) may be useful in certain dental or surgical procedures or a substantial risk for bleeding. GPS.

▪️  In children with ITP lasting ≥3 months who have non-life-threatening mucosal bleeding and/or diminished health-related quality of life and do not respond to first-line treatment, refer to hematologist for second-line therapies presented in the order they should be pursued:

- Thrombopoietin receptor agonist (eltrombopag or romiplostim)

-   Rituximab

-  Splenectomy (if possible, splenectomy should be delayed as long as possible after diagnosis because of the potential for spontaneous remission in the first year). Weak (conditional).

▪️ For menorrhagia in adolescent girl with thrombocytopenia manage as emergency treatment. Tranexamic acid can be useful and consult gynecologist for hormonal therapy. GPS.

➡️Prevention of thrombocytopenia:

▪️ In patients identified by screening or sisters of patients with FNAIT, the presence and/or concentration of HPA antibodies in subsequent pregnancies may be useful to determine the risk of FNAIT. High, Weak (conditional).

▪️ Consecutive assessments of levels of anti-HPA-1a antibody in HPA-1a-immunised women may be useful in identifying the risk of FNAIT. High, Weak (conditional).    

▪️ Antenatal IVIG administration to the mother, commencing 1 g/kg/week at 12–16 weeks gestation, increase to 2 g/kg/week at 20 weeks or IVIG 1 g/kg/week at 12–16 weeks with the addition of corticosteroids at 1 mg/kg/day at 20 weeks or IVIG 0.5 g/kg/week at 12–16 weeks for the entire pregnancy or IVIG 2 g/kg/week at 12–16 or IVIG 2 g/kg/week at 12–16 weeks, add corticosteroids 1 mg/kg/day at 20 weeks should be suggested to all women in a subsequent pregnancy with maternal fetal incompatibility who have had a previous fetus or neonate with FNAIT-related ICH. High, Weak (conditional).   

▪️ If corticosteroids are used with IVIG, dexamethasone should not be used because of the associated risk of oligohydramnios. High, Weak (conditional).

▪️  In a child with history of bleeding, avoid the following drugs:

-   Salicylates.

-  NSAID.

-   Anticoagulants. GPS.        

▪️Consider platelet transfusion to prevent bleeding in severe thrombocytopenia (platelet count < 10 x 109/l) caused by abciximab . Intermediate, Weak (conditional).        

▪️Following trauma, severely injured patients should be transported directly to an appropriate trauma facility. The time between injury and bleeding control should be minimized.        Local compression is recommended to limit life-threatening bleeding. High, Strong.

▪️ Patients with an obvious bleeding source and those presenting with hemorrhagic shock in extremis and a suspected source of bleeding should undergo an immediate bleeding control procedure. High, Strong.

▪️Use focused assessment with sonography in trauma (FAST) ultrasound for the detection of free fluid in patients with torso trauma. High, Strong.                   

▪️  Early imaging using contrast-enhanced whole-body CT (WBCT) for the detection and identification of type of injury and potential source of bleeding is recommended. High, Strong.                   

▪️  Laboratory screening of patients treated or suspected of being treated with anticoagulant agents should be done.      High, Strong.  

▪️  Platelets should be administered to maintain a platelet count above 50 x 109/L. High, Strong.         

▪️   Maintain a platelet count above 100 x 109/L in patients with ongoing bleeding and/or traumatic brain injury. High, Strong.                    

▪️  Maintain a hemoglobin level of 70 to 90 g/L in patients with ongoing bleeding and/or traumatic brain injury.       High, Strong.  

▪️ We recommend that TXA be administered to the trauma patient who is bleeding or at risk of significant hemorrhage as soon as possible and within 3 h after injury at a loading dose of 1 g infused over 10 min, followed by IV. infusion of 1 g over 8 h. High, Strong.         

▪️ Before surgery or invasive procedures, use a structured patient interview or standardized questionnaire which considers clinical and family bleeding history and detailed information on the patient's medication.          High, Weak (conditional).

▪️ Routine use of conventional coagulation screening tests such as activated partial thromboplastin time (aPTT), international normalized ratio (INR) and platelet count is not recommended in elective surgery. High, Weak (conditional).      

▪️ In patients with normal platelet counts, preoperative platelet function testing is suggested only in association with a positive bleeding history, decreased platelet function caused by medical conditions or antiplatelet medication. High, Weak (conditional).        

▪️Bleeding time is not recommended for preoperative bleeding risk stabilization as it is influenced by many variables. Weak (conditional).                 

➡️Guideline Registration

- Recommendations

Part I: Diagnosis of thrombocytopenia:

* Added to implementation tools

- Acknowledgements

▪️ The GDG/ GAG acknowledge EPG for its help in completing this project.

▪️  We acknowledge the British Society of Haematology (BSH), the American Society of Hematology (ASH), and the European Society of Anaesthesiology (ESA) for their cooperation in providing the permission for adapting our guidelines.

▪️   Finally, we wish the best for all our patients and their families who inspired us. It is for them this work is being finalized.

Funding

▪️This work is not related to any pharmaceutical or industrial company. The members of the GDG/ GAG and their institutes and universities volunteered their participation and contributions.

- Abbreviations

- Introduction

Thrombocytopenia was defined as a platelet count of less than 150 000 per microliter and can be acquired or inherited.⁸ However, platelet counts between 100 and 150 × 109/L do not necessarily indicate disease if they have been stable,⁹ and a cutoff value of 100 ×109/L may be more appropriate to identify a pathologic condition.¹⁰ Isolated thrombocytopenia is defined as a low platelet count in the absence of abnormalities of RBC and WBC lineages and no signs or symptoms of systemic illness. The most prevalent etiologies are ITP and drug-induced ITP (DITP).¹¹

Establishing the cause of thrombocytopenia has obvious clinical repercussions but is sometimes quite challenging. We aimed to describe the different etiologies, clinical presentation, clues for diagnosis and management of primary immune thrombocytopenic purpura (ITP) and non-immune thrombocytopenia (non-IT).

An individual with newly diagnosed thrombocytopenia is more likely to have an acquired disorder rather than an inherited genetic mutation. The myriad causes of acquired thrombocytopenia include autoimmune diseases, increased platelet consumption, splenomegaly, marrow suppression, and bone marrow failure. Two important clinical characteristics for recognizing inherited thrombocytopenia syndromes are the age of presentation and the chronicity/duration of symptoms. In the event of severe thrombocytopenia or profound platelet dysfunction, thrombocytopenia is usually recognized during the perinatal period. Milder disorders are noted sporadically at times of hemostatic stress (onset of menses).¹²

Depending on the patient’s age of onset, the causes of thrombocytopenia will vary. In newborn, a prevalence of thrombocytopenia reaching 22–35% of all admissions neonatal intensive care units has been reported, ^{13, 14} particularly in very low birth weight preterm neonates in which a prevalence of 70–80% has been reported. ^{15, 16} A recent meta-analysis reported a prevalence of 24 % across 21 studies.

In preterm neonates, early-onset thrombocytopenia (<72 h) is usually secondary to antenatal causes, has a characteristic pattern and resolves without complications or the need for treatment. By contrast, late-onset thrombocytopenia in preterm neonates (>72 h) is nearly always due to post-natal acquired bacterial infection and/or necrotizing enterocolitis, which rapidly leads to severe thrombocytopenia (platelet count < 50 x 109/l). Thrombocytopenia is much less common in term neonates and the most important cause is neonatal alloimmune thrombocytopenia (NAIT).¹⁷

Immune thrombocytopenia (ITP) is relatively common in childhood, with an annual incidence of 1.9–6.4 per 100,000 children.¹⁸ Diagnosis is made when isolated thrombocytopenia occurs in the absence of identifiable and specific precipitants.¹⁹ Guidelines have recommended a minimum evaluative process to look for secondary causes of thrombocytopenia before the diagnosis of ITP.²⁰ Differential diagnosis includes infectious, immune, hematologic, endocrine, and neoplastic causes of thrombocytopenia. ^21-25

Diagnosis of ITP in children is essentially one of exclusion. To differentiate it from other conditions, medical history should include type and severity of bleeding, systemic symptoms, history of respiratory infections, recent live viral vaccine, medications, presence of bone pain, and family history of bleeding disorders. Clinical examination should include observation for any dysmorphic features, especially skeletal anomalies, and the presence or absence of hepatosplenomegaly and/ or lymphadenopathy.²⁶

Khalifa et al. reported in a large Egyptian study a 30% rate of chronic ITP, matching the international reports.²⁷ There was no gender preference in most acute ITP studies; however, chronic ITP was more frequent in females in Egypt.²⁸ A retrospective report from Lebanon indicated a much lower chronicity rate of 10%.²⁹

Secondary ITP and non-IT are rare and sometimes difficult to recognize. Moreover, other manifestations of the underlying disease may emerge only during the follow-up period.³⁰ Red flags that raise the suspicion of secondary ITP and other non-immune causes of thrombocytopenia include positive family history, older age (adolescence), chronic course, platelet size either above or below the normal range, moderate (instead of severe) thrombocytopenia at first presentation, nonresponse to first-line treatments, and new symptoms or laboratory abnormalities during the disease course.³¹

Patients with thrombocytopenia typically experience mucocutaneous bleeding. The presence of joint or extensive soft tissue bleeding suggests coagulation abnormalities. Ischemic limb of skin necrosis should raise suspicion of heparin-induced thrombocytopenia.³²

There is no single hematologic or biochemical test that is conclusive for a given mechanism of thrombocytopenia.³³ If a decision is made to observe the child, even in typical cases, a CBC and blood smear should be repeated periodically to exclude the evolution of a serious bone marrow or other hematologic disorder until the diagnosis is clear or recovery has occurred.⁷

From registry data, 0% to 4% of children with newly diagnosed ITP have severe bleeding requiring immediate intervention³⁴ with incidence of ICH from; 0% to 1%.³⁵ Risk factors for ICH include low platelet count, non-steroidal anti-inflammatory drugs (NSAIDs) and arteriovenous malformation. Consensus favors consideration of multiple factors when deciding to treat or not, including bleeding symptoms, platelet count, recent trauma, existence of headache, recent medication use, psychosocial and lifestyle issues.⁷

In children, the symptoms of ITP are of greater impact in treatment decisions than platelet count. The ITP IWG recommends a treatment goal of a safe platelet count in the absence of bleeding, not a normal platelet count.¹⁰ Most children do not require therapy “Expectant watch-and-wait policy”.⁷

 The most recent updated consensus report on the investigations and management of primary ITP stated the following: 1) Treatment goals should be individualized to the patient and the phase of the disease, 2) Treatment should prevent severe bleeding episodes, 3) treatment should maintain a target platelet level of 20-30 x 109 at least for symptomatic patients (because risk of major bleeding increases below this level), 4) treatment should be with minimal toxicity, 4) treatment should optimize health related quality of life (HRQoL).⁷

Although there are numerous publications on the diagnosis and treatment of ITP, knowledge gaps remain, and up-to-date expert opinion and experience are key elements for management of cases.   

The aim of this adapted clinical practice guideline (CPG) is to provide evidence-based recommendations for the diagnosis and managment of thrombocytopenia in the paediatric age group. These recommendations were adapted from the relevant CPGs using a formal methodology for CPG adaptation: the Adapted-ADAPTE.

➡️Purpose and Scope

These guidelines have been developed to standardize the delivery of services and to implement the guidance on the prevention, diagnosis and management of bleeding in pediatric patients with isolated thrombocytopenia.

It provides guidance to primary health care physicians at Ministry of Health (MOH), general practitioners, family medicine specialists and pediatricians.

This guideline focuses on the diagnosis, treatment and prevention of thrombocytopenia in pediatrics. It provides an evidence-based document for how to prevent mortality and morbidity from bleeding, prevent sequelae and disabilities, and prevent further episodes.

This version of the guideline includes recommendations and good practice statements for the diagnosis, management and prevention of bleeding in the pediatric age group with special focus on thrombocytopenia.

- Methods

➡️Methods of search:

A comprehensive search for guidelines was undertaken to identify the most relevant guidelines to consider for adaptation. Keywords used for search were: childhood thrombocytopenia, pediatric thrombocytopenia, immune thrombocytopenic purpura, idiopathic thrombocytopenic purpura, autoimmune thrombocytopenic purpura, isolated thrombocytopenia, neonatal thrombocytopenia, and Inherited thrombocytopenia.

 Inclusion / exclusion criteria followed in the search and retrieval of guidelines to be adapted:

• Selecting only evidence-based guidelines (guideline must include a report on methodology of development including the systematic literature searches and explicit links between individual recommendations and their supporting evidence)

• Selecting national and/or international guidelines

• Specific range of dates for publication (using Guidelines published or updated 2011 and later or the last 10 years)

• Selecting peer-reviewed publications only

• Selecting guidelines written in English language

• Excluding guidelines written by a single author

The following three categories of databases and websites were searched:

1. CPG databases and libraries (e.g., GIN, ECRI, SIGN, DynaMed, BIGG-REC PAHO)

2. Bibliographic databases (e.g., PubMed, Google Scholar)

3. Specialized professional societies (related to the pediatric subspecialty)

All retrieved Guidelines were screened and appraised using AGREE II instrument (www.agreetrust.org) ^36-39 by at least two members. The panel decided a cut-off point or rank the guidelines (any guideline scoring above 60% on the rigor dimension was retained)

After reviewing all the previous criteria the GDG/ GAG recommended using 7 guidelines:

1. 1. American Society of Hematology 2019 guidelines for immune thrombocytopenia. (ASH 2019)¹
2. The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition. (European 2019)²
3. Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology. (ESA 2016)³
4. Fetal and neonatal alloimmune thrombocytopenia: recommendations for evidence-based practice, an international approach. (BSH, 2019)⁴
5. Guidelines on transfusion for fetuses, neonates and older children. (BSH 2016)⁵
6. Guidelines for the Laboratory Investigations of heritable disorders of platelet function. (BSH 2011)⁶
7. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. (ASH ITP consensus 2019).⁷

We did Adolopment for these guidelines: (Adoption, Adaptation, and Development)^40-43

         -  Adoption for most of the guideline recommendations.

         -  Development of Good Practice Statement

Contributors to the guideline development process:

Guideline Development Group (GDG)/ Guideline Adaptation Group (GAG):

The GDG/ GAG included two subgroups; the clinicians/ healthcare providers subgroup and the guideline methodologists’ subgroup.

➡️Clinicians Subgroups

The clinicians’ subgroup or clinical panel for this guideline included experts with a range of knowledge, technical skills and diverse perspectives in the field of pediatric hematology.

The main functions of the clinical panel were adolopment of thrombocytopenia in pediatrics Guidelines, determining the scope of the guideline and guideline, reviewing the evidence, and formulating evidence-informed recommendations in case of changing strength of recommendations.

➡️Guideline Methodologists Subgroup

There were two guideline methodologists with expertise in guidelines development, adaptation, GRADE and translation of evidence into recommendations. Methodologists provided orientation and overview of evidence-informed guideline development processes using the GRADE approach, guideline adaptation using the Adapted ADAPTE, provided AGREE II assessment of the source guidelines in collaboration with the clinicians subgroup, generation of the EtD frameworks whenever applicable.

➡️External Review Group:

The External Review Group for this guideline comprises 3 clinical national experts who have interest and expertise in as well as eminent international reviewers.

They were identified by Egyptian Pediatric Clinical Practice Guidelines Committee (EPG) as people who can provide valuable insights during the guideline development process.

The External Review Group was asked to comment on (peer review) the final guideline to identify any criticism on the content and to comment on clarity and applicability as well as issues relating to implementation, dissemination, ethics, regulations, or monitoring, but not to change the recommendations formulated by the GDG/ GAG. The members of the External Review Group were required to submit declarations of interest before the peer review process.

➡️Guideline Development/ Adaptation Group meetings:

GDG/ GAG meetings were organized virtually (weekly/bimonthly). Due to the extensive scope of

the guideline, EPG was responsible for overseeing the adolopment process. the timetable and objectives of each meeting. GDG/ GAG meetings were also attended by members of the methodologists. Working rules for each contributor type were outlined by the chair at the start of each meeting, covering aspects such as vocal rights, voting, and evidence to decision and recommendation formulating processes.

➡️Declarations of interests:

Prospective members of the GDG/ GAG were asked to fill in and sign the standard WHO declaration of interest and confidentiality undertaking forms. All guideline members and methodologists were also asked to fill in and sign the standard WHO declaration-of-interests.

Members of the external review group will be asked to fill in and sign the standard WHO declaration-of-interests form before the peer review process.

➡️Evidence for the guideline:

We used the GRADE system (Grading of Recommendations, Assessment, Development and Evaluation) for assigning the quality of evidence and strength of recommendations that includes the following definitions. ^36-39  

Description of the interpretation of the GRADE four levels of certainty of evidence:

Table 1. Classification of the Quality of Evidence

Table 2. Classification of the Strengths of Recommendations

➡️Developing good practice statements:

The GDG/ GAG also developed good practice statements for this guideline, which are actionable messages relevant to the guideline questions. The justification for each good practice statement was carefully considered by the GDG/ GAG with an emphasis that they are clearly needed. Good practice statements were developed, guided by the following GRADE criteria:

1- Message is necessary with regard to actual healthcare practice

2- Have large net positive consequence (relevant outcomes and downstream consequences) (GRADE EtD domains)

3- Collecting and summarizing the evidence is a poor use of time and resources

4- Include awell-documented, clear rationale connecting indirect evidence

5- Are clear and actionable statements.

The GDG/ GAG collectively drafted and finalized good practice statements with relevant justifications and remarks to help with their interpretation, with close support and input from the consultant and guideline methodologists.

We have used the Reporting Items for Practice Guidelines in Healthcare (RIGHT) extension for adapted guidelines (RIGHT-Ad@pt Tool) as a reporting checklist for this guideline adaptation process as recommended by the EQUATOR network.

- Evidence to recommendations: Considerations

The GDG/ GAG was guided by the results of the AGREE II appraisals of the eligible CPGs and thoroughly reviewed the recommendations of the original source WHO CPGs in consideration of local contextual factors related to the national Egyptian health system like burden of the disease, equity, acceptability, feasibility, and other relevant factors. The GDG decided through an informal consensus process to adopt most recommendations. Also, GDG/ GAG develops group of good practice statements to improve acceptability and feasibility.

- Implementation Tools and Considerations

To improve healthcare provision, quality, safety, and patient outcome, evidence-based recommendations must not only be developed, but also disseminated and implemented at national and local levels and integrated into clinical practice.

Dissemination involves educating related healthcare providers to improve their awareness, knowledge and understanding of the guideline’s recommendations. It is one part of implementation, which involved translation of evidence-based guidelines into real life practice with improvement of health outcomes for the patients.

Implementation requires an evidence-based strategy involving professional groups and stakeholders and should consider the local cultural and socioeconomic conditions. Cost-effectiveness of implementation programs should be assessed.

Specific steps need to be followed before clinical practice recommendations can be integrated into local clinical practice, particularly in low resource settings.

Steps of implementing strategies for the diagnosis, prevention and management of thrombocytopenia in pediatric age group into the Egyptian health system:

1. Develop a multidisciplinary working group.

2. Assess the status of nutritional care delivery, care gaps and current needs.

3. Select the material to be implemented, agree on the main goals, identify the key recommendations for diagnosis, treatment and prevention and adapt them to the local context or environment.

4. Identify barriers to, and facilitators of implementation.

5. Select an implementation framework and its component strategies.

6.  Develop a step-by-step implementation plan:

▪️  Select the target populations and evaluate the outcome.

▪️  Identify the local resources to support the implementation.

▪️   Set timelines.

▪️  Distribute the tasks to the members.

▪️     Evaluate the outcomes.

7.  Continuously review the progress and results to determine if the strategy requires modification.

Guideline implementation strategies will focus on the following: -

1. For Practitioners

▪️  Educational meetings: conferences, lectures, workshops, grand rounds, seminars, and symposia.

▪️  Educational materials: printed or electronic information (software).

▪️   Web-based education: computer-based educational activities.

▪️   A trained person meets with providers in their practice setting to provide information with the intention of changing the provider’s practice. The information may include feedback on the performance of the provider(s).

▪️   Reminders: the provision of information verbally, on papers or on a computer screen to prompt a health professional to recall information or to perform or avoid a particular action related to patient care.

▪️  Optimize professional-patient interactions, through mass media campaigns, reminders, and education materials.

▪️   Practice tools: tools designed to facilitate behavioral/practice changes, e.g., flow charts.

2. For Patients and care givers

▪️  Patient education materials (Arabic booklet): Printed/electronic information aimed at the patient/consumer, family, caregivers, etc.

▪️   Reminders: the provision of information verbally, on papers or electronically to remind a patient/consumer to perform a particular health-related behaviors.

▪️   Mass media campaigns.

3.  For Nurses

▪️ Educational meetings: lectures, workshops or traineeships, seminars, and symposia.

▪️  Educational materials: printed.

▪️   A trained person meets with nurses in their practice setting to provide information with the intention of changing the provider’s practice.

▪️ Reminders: the provision of information verbally, on paper or on a computer screen to prompt them to recall information or to perform or avoid a particular action related to patient care.

▪️  Practice tools: tools designed to facilitate behavioral/practice changes.

4. For Stakeholders

Plans have been made to contact with all the health sectors in Egypt including all sectors of the Ministry of Health and Population, National Nutrition Institute, University Hospitals, Ministry of Interior, Ministry of Defense, Non-Governmental Organizations, Private sector, and all Health Care Facilities.

▪️ Information and communication technology: Electronic decision support, order sets, care maps, electronic health records, office-based personal digital assistants, etc.

▪️  Any summary of clinical provision of health care over a specified period may include recommendations for clinical action. The information is obtained from medical records, databases, or observations by patients. Summary may be targeted at the individual practitioner or the organization.

▪️  Administrative policies and procedures.

▪️   Formularies: Drug safety programs, electronic medication administration records.

5.  Other activities to assist the implementation of the adapted guideline’s recommendations include:

▪️   International initiative: Dissemination of the presented adapted CPG internationally via sending the final adapted CPG to the Guidelines International Network (GIN) Adaptation Working Group and contacting the CPG developers.

▪️   Gantt chart has been designed to manage the dissemination and implementation stages for the adapted CPG over an accurate time frame (Appendix).

➡️Guideline Implementation Tools

Educational materials based on this Adapted CPG for treatment of CAP in children have been made available in several forms including: algorithms, pathways, tables, and parents’ educational health guide (in Arabic).

Table S1: Modified WHO Bleeding assessment score

Table S2. Causes of neonatal thrombocytopenia ⁴⁵

Sillers L, Van Slambrouck C, Lapping-Carr G. Neonatal Thrombocytopenia: Etiology and Diagnosis. Pediatr Ann. 2015 Jul;44(7):e175-80. doi: 10.3928/00904481-20150710-11. PubMed PMID: 26171707; PubMed Central PMCID: PMCPMC6107300.

Table S3. Suggested thresholds of platelet count for neonatal platelet transfusion ⁴⁶

NAIT, neonatal alloimmune thrombocytopenia; ICH, intracranial hemorrhage.

New HV, Berryman J, Bolton-Maggs PH, Cantwell C, Chalmers EA, Davies T, Gottstein R, Kelleher A, Kumar S, Morley SL, Stanworth SJ; British Committee for Standards in Haematology. Guidelines on transfusion for fetuses, neonates and older children. Br J Haematol. 2016 Dec;175(5):784-828. doi: 10.1111/bjh.14233. Epub 2016 Nov 11. PMID: 27861734.

Figure S1: (A) Postnatal Algorithm for FNAIT. (B) Antenatal Algorithm for FNAIT ⁴⁷

FNAIT, fetal and neonatal alloimmune thrombocytopenia; HLA, human leucocyte antigen; ICH, intracranial hemorrhage; NIPT, non-invasive prenatal testing.

Lieberman L, Greinacher A, Murphy MF, Bussel J, Bakchoul T, Corke S, Kjaer M, Kjeldsen-Kragh J, Bertrand G, Oepkes D, Baker JM, Hume H, Massey E, Kaplan C, Arnold DM, Baidya S, Ryan G, Savoia H, Landry D, Shehata N; International Collaboration for Transfusion Medicine Guidelines (ICTMG). Fetal and neonatal alloimmune thrombocytopenia: recommendations for evidence-based practice, an international approach. Br J Haematol. 2019 May;185(3):549-562. doi: 10.1111/bjh.15813. Epub 2019 Mar 3. PMID: 30828796.

Table S5. Differential diagnosis of thrombocytopenia ⁴⁹

APS, antiphospholipid syndrome; CVID, common variable immunodeficiency; DIC, disseminated intravascular coagulation; HUS, hemolytic-uremic syndrome; MYH9, myosin heavy chain 9; PD-1, programmed cell death protein 1; TAR, thrombocytopenia-absent radius; TTP, thrombotic thrombocytopenic purpura; VWD, von Willebrand disease.

Provan D, Arnold DM, Bussel JB, Chong BH, Cooper N, Gernsheimer T, Ghanima W, Godeau B, González-López TJ, Grainger J, Hou M, Kruse C, McDonald V, Michel M, Newland AC, Pavord S, Rodeghiero F, Scully M, Tomiyama Y, Wong RS, Zaja F, Kuter DJ. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019 Nov 26;3(22):3780-3817. doi: 10.1182/bloodadvances.2019000812. PMID: 31770441; PMCID: PMC6880896.

Table S6 Bleeding assessment tool in pediatric patient with primary immune thrombocytopenia ⁴⁹

This bleeding scale is based on the one used in the previous consensus report,¹  updated based on the authors’ opinion. Hb, hemoglobin.

Provan D, Arnold DM, Bussel JB, Chong BH, Cooper N, Gernsheimer T, Ghanima W, Godeau B, González-López TJ, Grainger J, Hou M, Kruse C, McDonald V, Michel M, Newland AC, Pavord S, Rodeghiero F, Scully M, Tomiyama Y, Wong RS, Zaja F, Kuter DJ. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019 Nov 26;3(22):3780-3817. doi: 10.1182/bloodadvances.2019000812. PMID: 31770441; PMCID: PMC6880896

Table S7 Recommendations for the diagnosis of ITP in children and adults ⁴⁹

CMV, cytomegalovirus; EBV, Epstein-Barr virus; PCR, polymerase chain reaction; PTT, partial thromboplastin time; Rh, rhesus; TPO, thrombopoietin.

*These tests have no proven role in the differential diagnosis of ITP from other thrombocytopenias and do not guide patient management.

†Quantitative Ig level measurement should be considered in children with ITP and is recommended in children with persistent or chronic ITP as part of the reassessment evaluation.

‡Recommended by the majority of the panel for adult patients in the appropriate geographic setting.

Provan D, Arnold DM, Bussel JB, Chong BH, Cooper N, Gernsheimer T, Ghanima W, Godeau B, González-López TJ, Grainger J, Hou M, Kruse C, McDonald V, Michel M, Newland AC, Pavord S, Rodeghiero F, Scully M, Tomiyama Y, Wong RS, Zaja F, Kuter DJ. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019 Nov 26;3(22):3780-3817. doi: 10.1182/bloodadvances.2019000812. PMID: 31770441; PMCID: PMC6880896.

Table S8: Therapies for the treatment of ITP ⁴⁹

Treatment options for ITP are listed in alphabetical order and do not imply a preferred treatment option.

HSCT, hematopoietic stem cell transplantation; TPO-RA, TPO receptor agonist.

Provan D, Arnold DM, Bussel JB, Chong BH, Cooper N, Gernsheimer T, Ghanima W, Godeau B, González-López TJ, Grainger J, Hou M, Kruse C, McDonald V, Michel M, Newland AC, Pavord S, Rodeghiero F, Scully M, Tomiyama Y, Wong RS, Zaja F, Kuter DJ. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019 Nov 26;3(22):3780-3817. doi: 10.1182/bloodadvances.2019000812. PMID: 31770441; PMCID: PMC6880896

Table S9. Suggested thresholds of platelet count for platelet transfusion in children with non-immune thrombocytopenia ⁵⁰

·        ALL, acute lymphoblastic leukemia; DIC, disseminated intravascular coagulation; HIT, heparin-induced thrombocytopenia; HUS, hemolytic uremic syndrome; ITP, immune thrombocytopenia; LP, lumbar puncture; TTP, thrombotic thrombocytopenic purpura.

·        ^a Note: routine screening by standard coagulation tests not advocated without clinical indication; for laboratory evidence of DIC see Section 5.6.4.

·        ^b It is accepted that prior to lumbar puncture some clinicians will transfuse platelets at higher counts (e.g., 50 × 10⁹/l) in clinically unstable children, non-ALL patients, or for the first LP in newly-diagnosed ALL patients to avoid hemorrhage and cerebrospinal fluid contamination with blasts, or at lower counts (≤20 × 10⁹/l) in stable patients with ALL, depending on the clinical situation. These practices emphasize the importance of considering the clinical setting and patient factors.

New HV, Berryman J, Bolton-Maggs PH, Cantwell C, Chalmers EA, Davies T, Gottstein R, Kelleher A, Kumar S, Morley SL, Stanworth SJ; British Committee for Standards in Haematology. Guidelines on transfusion for fetuses, neonates and older children. Br J Haematol. 2016 Dec;175(5):784-828. doi: 10.1111/bjh.14233. Epub 2016 Nov 11. PMID: 27861734.

- Limitations and suggestions for further research needs

Future research recommendations for the diagnosis, prevention and management of thrombocytopenia in pediatric age groups in the Egyptian context could include:

▪️ Implementation of hemovigilance system at different institutional levels.

▪️ Screening programs for specific populations.

These recommendations aim to address specific challenges and characteristics of the Egyptian context, potentially leading to more effective prevention, diagnosis and management strategies for Thrombocytopenia and Bleeding in children.

Challenges

▪️ Implementation of international guidelines in resource limited settings.

▪️ The optimum use of the available resources to fulfill the requirements of Egyptian population.

Strengthen the evidence base of the next update of this guideline by generating GRADE summary of finding tables, evidence profiles, and EtD frameworks.

- Monitoring and evaluating the impact of the guideline.

The following are two performance measures or indicators for implementing this adapted CPG for Management of isolated thrombocytopenia in pediatrics: 

Adherence to Management of isolated thrombocytopenia Guidelines

▪️ Numerator: Number of children with isolated thrombocytopenia who received management as per guideline recommendations.

▪️Denominator: Total number of children who had isolated thrombocytopenia.

▪️  Data Source: Hospital or clinic patient records.

These key performance indicators are designed to measure the effectiveness and adherence to the guidelines.

- Updating of the guideline

The EPG Haematology GAG has decided to conduct the next review of this adapted CPG for updates after five years. This should be carried out in 2027 after checking for updates in the source CPGs, consultation of expert opinion on the changes needed for updating according to the newest evidence and recommendations published in this area and the clinical audit and feedback from implementation efforts in the aforementioned local healthcare settings except if any breakthrough evidence- based recommendations are published before that date. The process will be guided by the Checklist for the Reporting of Updated Guidelines (CheckUp) Tool that is freely provided by the AGREE Enterprise and by the Reporting Items for Practice Guidelines in Healthcare (RIGHT) extension for adapted guidelines RIGHT-Ad@pt Checklist.

- References

1.  Neunert C, Terrell DR, Arnold DM, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019 Dec 10;3(23):3829-3866. doi: 10.1182/bloodadvances.2019000966. PubMed PMID: 31794604; PubMed Central PMCID: PMCPMC6963252.
2.  Spahn DR, Bouillon B, Cerny V, et al. The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition. Crit Care. 2019 Mar 27;23(1):98. doi: 10.1186/s13054-019-2347-3. PubMed PMID: 30917843; PubMed Central PMCID: PMCPMC6436241.
3.  Kozek-Langenecker SA, Ahmed AB, Afshari A, et al. Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology: First update 2016. Eur J Anaesthesiol. 2017 Jun;34(6):332-395. doi: 10.1097/EJA.0000000000000630. PubMed PMID: 28459785.
4.  Lieberman L, Greinacher A, Murphy MF, et al. Fetal and neonatal alloimmune thrombocytopenia: recommendations for evidence-based practice, an international approach. Br J Haematol. 2019 May;185(3):549-562. doi: 10.1111/bjh.15813. PubMed PMID: 30828796.
5.  New HV, Berryman J, Bolton-Maggs PH, et al. Guidelines on transfusion for fetuses, neonates and older children. Br J Haematol. 2016 Dec;175(5):784-828. doi: 10.1111/bjh.14233. PubMed PMID: 27861734.
6.  Harrison P, Mackie I, Mumford A, et al. Guidelines for the laboratory investigation of heritable disorders of platelet function. Br J Haematol. 2011 Oct;155(1):30-44. doi: 10.1111/j.1365-2141.2011.08793.x. PubMed PMID: 21790527.
7.   Provan D, Arnold DM, Bussel JB, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019 Nov 26;3(22):3780-3817. doi: 10.1182/bloodadvances.2019000812. PubMed PMID: 31770441; PubMed Central PMCID: PMCPMC6880896.
8.  Johnson B, Fletcher SJ, Morgan NV. Inherited thrombocytopenia: novel insights into megakaryocyte maturation, proplatelet formation and platelet lifespan. Platelets. 2016 Sep;27(6):519-25. doi: 10.3109/09537104.2016.1148806. PubMed PMID: 27025194; PubMed Central PMCID: PMCPMC5000870.
9.  Stasi R, Amadori S, Osborn J, et al. Long-term outcome of otherwise healthy individuals with incidentally discovered borderline thrombocytopenia. PLoS Med. 2006 Mar;3(3):e24. doi: 10.1371/journal.pmed.0030024. PubMed PMID: 16401142; PubMed Central PMCID: PMCPMC1326262.
10.  Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009 Mar 12;113(11):2386-93. doi: 10.1182/blood-2008-07-162503. PubMed PMID: 19005182.
11. Stasi R. How to approach thrombocytopenia. Hematology Am Soc Hematol Educ Program. 2012;2012:191-7. doi: 10.1182/asheducation-2012.1.191. PubMed PMID: 23233580.
12.  Drachman JG. Inherited thrombocytopenia: when a low platelet count does not mean ITP. Blood. 2004 Jan 15;103(2):390-8. doi: 10.1182/blood-2003-05-1742. PubMed PMID: 14504084.
13.  Roberts I, Stanworth S, Murray NA. Thrombocytopenia in the neonate. Blood Rev. 2008 Jul;22(4):173-86. doi: 10.1016/j.blre.2008.03.004. PubMed PMID: 18433954.
14.  Sola-Visner M, Saxonhouse MA, Brown RE. Neonatal thrombocytopenia: what we do and don't know. Early Hum Dev. 2008 Aug;84(8):499-506. doi: 10.1016/j.earlhumdev.2008.06.004. PubMed PMID: 18684573.
15.  Ferrer-Marin F, Chavda C, Lampa M, et al. Effects of in vitro adult platelet transfusions on neonatal hemostasis. Journal of thrombosis and haemostasis : JTH. 2011;9(5):1020-1028. doi: 10.1111/j.1538-7836.2011.04233.x. PubMed PMID: 21320282; eng.
16.  Mehta P, Vasa R, Neumann L, et al. Thrombocytopenia in the high-risk infant. J Pediatr. 1980 Nov;97(5):791-4. doi: 10.1016/s0022-3476(80)80272-1. PubMed PMID: 7431175.
17.  Chakravorty S, Roberts I. How I manage neonatal thrombocytopenia. Br J Haematol. 2012 Jan;156(2):155-62. doi: 10.1111/j.1365-2141.2011.08892.x. PubMed PMID: 21950766; eng.
18. Terrell DR, Beebe LA, Vesely SK, et al. The incidence of immune thrombocytopenic purpura in children and adults: A critical review of published reports. Am J Hematol. 2010 Mar;85(3):174-80. doi: 10.1002/ajh.21616. PubMed PMID: 20131303.
19. Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011 Apr 21;117(16):4190-207. doi: 10.1182/blood-2010-08-302984. PubMed PMID: 21325604.
20.  Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010 Jan 14;115(2):168-86. doi: 10.1182/blood-2009-06-225565. PubMed PMID: 19846889.
21. Elmas Dal S, Ersoy Y, Ali Erkurt M, et al. An uncommon case of acute brucellosis presenting with severe thrombocytopenia. Intern Med. 2012;51(23):3291-3. doi: 10.2169/internalmedicine.51.7365. PubMed PMID: 23207127.
22. Kumar S, Nair S, Rajam L. Case series of pediatric systemic lupus erythematosus from Kerala: comparison with other Indian series. Int J Rheum Dis. 2010 Oct;13(4):391-5. doi: 10.1111/j.1756-185X.2010.01536.x. PubMed PMID: 21199476.
23. Hatta K, Kunishima S, Suganuma H, et al. A family having type 2B von Willebrand disease with a novel VWF p.R1308S mutation: Detection of characteristic platelet aggregates on peripheral blood smears as the key aspect of diagnosis. Thrombosis research. 2015 Oct;136(4):813-7. doi: 10.1016/j.thromres.2015.08.004. PubMed PMID: 26278967; eng.
24.  Lee AC, Li CH, Wong LM. Childhood thrombocytopenia associated with Graves disease is distinct from idiopathic thrombocytopenic purpura. Pediatr Hematol Oncol. 2003 Jan-Feb;20(1):39-42. PubMed PMID: 12687752.
25. Olaniyi JA. An Acute Leukaemia Masquerading as Immune Thrombocytopaenic Purpura (ITP)? A Case Report. Clin Med Case Rep. 2009;2:31-34. doi: 10.4137/ccrep.s2394. PubMed PMID: 24179370; eng.
26.  British Committee for Standards in Haematology General Haematology Task F. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol. 2003 Feb;120(4):574-96. doi: 10.1046/j.1365-2141.2003.04131.x. PubMed PMID: 12588344.
27. Khalifa AS, Tolba KA, el-Alfy MS, et al. Idiopathic thrombocytopenic purpura in Egyptian children. Acta Haematol. 1993;90(3):125-9. doi: 10.1159/000204392. PubMed PMID: 8291370.
28. ElAlfy M, Farid S, Abdel Maksoud A. Predictors of chronic idiopathic thrombocytopenic purpura. Pediatr Blood Cancer. 2010 Jul 1;54(7):959-62. doi: 10.1002/pbc.22481. PubMed PMID: 20405514.
29.  Bryant N, Watts R. Thrombocytopenic syndromes masquerading as childhood immune thrombocytopenic purpura. Clin Pediatr (Phila). 2011 Mar;50(3):225-30. doi: 10.1177/0009922810385676. PubMed PMID: 21098529.
30.  Aboud N, Depré F, Salama A. Is Autoimmune Thrombocytopenia Itself the Primary Disease in the Presence of Second Diseases Data from a Long-Term Observation. Transfusion Medicine and Hemotherapy. 2017;44(1):23-28. doi: 10.1159/000449038.
31.  Rotz SJ, Ware RE, Kumar A. Diagnosis and management of chronic and refractory immune cytopenias in children, adolescents, and young adults. Pediatr Blood Cancer. 2018 Oct;65(10):e27260. doi: 10.1002/pbc.27260. PubMed PMID: 29856527.
32.  Pons I, Monteagudo M, Lucchetti G, et al. Correlation between immature platelet fraction and reticulated platelets. Usefulness in the etiology diagnosis of thrombocytopenia. European journal of haematology. 2010 Aug;85(2):158-63. doi: 10.1111/j.1600-0609.2010.01468.x. PubMed PMID: 20477866; eng.
33. Monteagudo M, Amengual MJ, Munoz L, et al. Reticulated platelets as a screening test to identify thrombocytopenia aetiology. QJM. 2008 Jul;101(7):549-55. doi: 10.1093/qjmed/hcn047. PubMed PMID: 18400777.
34. Grimaldi-Bensouda L, Nordon C, Leblanc T, et al. Childhood immune thrombocytopenia: A nationwide cohort study on condition management and outcomes. Pediatr Blood Cancer. 2017 Jul;64(7). doi: 10.1002/pbc.26389. PubMed PMID: 27905681.
35. Heitink-Polle KMJ, Uiterwaal C, Porcelijn L, et al. Intravenous immunoglobulin vs observation in childhood immune thrombocytopenia: a randomized controlled trial. Blood. 2018 Aug 30;132(9):883-891. doi: 10.1182/blood-2018-02-830844. PubMed PMID: 29945954.
36. Venkatesh V, Curley A, Khan R, et al. A novel approach to standardised recording of bleeding in a high risk neonatal population. 2013;98(3):F260-F263. doi: 10.1136/archdischild-2012-302443 %J Archives of Disease in Childhood - Fetal and Neonatal Edition.
37.  Sillers L, Van Slambrouck C, Lapping-Carr G. Neonatal Thrombocytopenia: Etiology and Diagnosis. Pediatr Ann. 2015 Jul;44(7):e175-80. doi: 10.3928/00904481-20150710-11. PubMed PMID: 26171707; PubMed Central PMCID: PMCPMC6107300.
38.  Rodeghiero F, Tosetto A, Abshire T, et al. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost. 2010 Sep;8(9):2063-5. doi: 10.1111/j.1538-7836.2010.03975.x. PubMed PMID: 20626619.
 
References of materials used in creating this EBCPG
1-  ADAPTE Resource Toolkit versions 2.0 (2009) Available from: 
www.g-i-n.net/document-store/adapte-resource-toolkit-guideline-adaptation-version-2 (Version 2.0 downloaded free without registration).
2- Amer YS, Elzalabany MM, Omar TI, Ibrahim AG and Dowidar NL. The ‘Adapted ADAPTE’: an approach to improve utilization of the ADAPTE guideline adaptation resource toolkit in the Alexandria Center for Evidence-Based Clinical Practice Guidelines. Journal of Evaluation in Clinical Practice 2015; 21: 1095 – 106.
3- AGREE (II) Instrument (if used) available from thewww.agreecollaboration.org/instrument/ (downloaded free).

- Annexes

Annex Table 2. Results of the AGREE II assessment of the seven source guidelines for bleeding and thrombocytopenia in pediatric age groups

Practice guideline REgistration for transPAREncy (PREPARE) Guideline Protocol Registration Receipt