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

PREPARE (Practice guideline REgistration for transPAREncy) platform, WHO Collaborating Center for Guideline Implementation and Knowledge Translation, EBM Center, University of Lanzhou, Lanzhou, China. Registration Number: (PREPARE-2022CN791). Link: http://www.guidelines-registry.org/