the Management of Bleeding in Pediatric Patients with Isolated Thrombocytopenia

1.1   What are the antenatal diagnostic tests for possible FNAIT?

BSH FNAIT 2019

Fetal HPA typing, preferably using non-invasive methods, if adequately quality assured, should be performed during pregnancy when the father is unknown, unavailable for testing or heterozygous for the implicated antigen.

Balance of harms and benefits: The alternative is amniocentesis, which is associated with risk of fetal demise.

High

Strong

1.2   What are the points in history and examination suggestive of inherited thrombocytopenia?

ITP Consensus

2019

•      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

1.3   What are the tests required to exclude inherited thrombocytopenia?

ITP Consensus

2019

Mean platelet volume may be used to differentiate ITP from inherited thrombocytopenia; increased mean platelet volume can be suspected on smear if there are many large platelets.

Strong

BSH 2011

Flow cytometry should be used in the investigation or confirmation of Bernard Soulier syndrome by moderate to marked reduction in CD42a (GpIX) and CD42b (Gp1bα)

High

Weak (conditional)

BSH 2011

Flowcytometry may also be used to investigate abnormalities in the collagen (GpVI and GpIa/IIa) and thrombin receptors (PAR-1).

High

Strong

1.4   What is the initial evaluation for children and adolescents presenting with bleeding and thrombocytopenia?

ITP consensus 2019

A complete history, physical examination, full blood count, and expert analysis of the peripheral blood smear should be performed and carefully evaluated at initial diagnosis to exclude secondary causes of thrombocytopenia.

Weak (conditional)

1.5   What is a validated general bleeding score?

ISTH SSC – BAT*

International Society of Hemostasis and thrombosis – Bleeding assessment tool (ISTH-SCC BAT)* comprises 14 categories for assessing bleeding symptoms could be used for initial screening of bleeding manifestations

GPS

1.1   What are the diagnostic criteria for immune thrombocytopenia?

ITP Consensus

2019

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

ITP consensus 2019

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

1.2   What are the additional diagnostic tests required in children and adolescents with ITP?

ITP Consensus

2019

Quantitative immunoglobulin (Ig) level testing is indicated to exclude an immune deficiency syndrome or before treatment with IVIg. In children, Ig level testing may be considered at baseline.

Weak (conditional)

ASH 2019

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

High

Strong

1.3   What are the indications of bone marrow examination in patients with ITP?

ASH 2019

Newly diagnosed ITP in children

•      Bone marrow examination is unnecessary in children and adolescents with the typical features of ITP

•      Bone marrow examination is not necessary in children who fail IVIG therapy

•      Bone marrow examination is also not necessary in patients prior to initiation of treatment of corticosteroids.

High

High

Intermediate

Strong

Strong

Weak (conditional)

ITP consensus 2019

•      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

•      This examination should ideally include an aspirate, biopsy, flow cytometry, and cytogenetics

Intermediate

Weak (conditional)

Weak (conditional)

1.4   What are the subsequent investigations in children and adolescents with persistent or chronic ITP?

ITP consensus 2019

Additional evaluation could include

•   A 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)

ITP consensus 2019

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 or morphology

This examination should ideally include an aspirate, biopsy, flow cytometry, and cytogenetics

Intermediate

Weak (conditional)

Weak (conditional)

ASH 2019

Recommendation against routine testing for H pylori in children with persistent or chronic ITP.

High

Strong

CPGL Source

Recommendation

Strength of Recommendation

Quality of Evidence

2.1  What is the initial treatment of bleeding in a neonate with FNAIT?

BSH FNAIT 2019

Platelets should be transfused immediately if life-threatening bleeding is present.

High

Strong

In the presence of life-threatening bleeding such as intracranial or gastrointestinal bleeding, platelets should be transfused to maintain platelet counts initially above 100 x 10⁹ /l and then above 50 x 10⁹ /l for at least 7 days.

High

Weak (conditional)

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)

2.2  What are the indications of platelet transfusion in a neonate with thrombocytopenia?

BSH 2016

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.

•  If Platelet count < (25 x 10⁹/l) transfuse in Neonates with no bleeding

•  If Platelet count < (50× 10⁹/l) transfuse in Neonates with bleeding, current coagulopathy, before surgery, or infants with FNAIT if previously affected sibling with ICH.

•  If Platelet count < (100 x 10⁹/l) transfuse in Neonates with major bleeding or requiring major surgery (e.g., neurosurgery).

Intermediate

Weak (conditional)

2.3  What is the management of a neonate of mother with ITP?

ITP consensus

2019

1) Management of delivery

•  Cordocentesis and fetal scalp blood sampling should be avoided.

Weak (conditional)

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

Weak (conditional)

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

Strong

•  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)

ITP consensus

2019

2) Management after delivery

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

Weak (conditional)

•  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.

Weak (conditional)

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

Weak (conditional)

•  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.

Weak (conditional)

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

Weak (conditional)

•  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)

2.4  What are the indications of hospitalization in pediatric patients with ITP?

ITP consensus

2019

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

Weak (conditional)

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

Weak (conditional)

•   Worsening bleeding or significant comorbidities

Weak (conditional)

•   Risk of ICH (e.g., head trauma or unexplained headaches); patients at higher risk for ICH include those with a history of moderate or severe bleed in the preceding 28 days, recent administration (within 8 hours) of NSAIDs, and another clinically significant coagulopathy (e.g., von Willebrand disease).

Weak (conditional)

•   A change in behavior or mood consistent with significant depression or irritability.

Weak (conditional)

•   Parents are anxious about bleeding and do not believe that they can control (young child) or restrict (older child) their child’s activity.

Weak (conditional)

•   Parents cannot be relied upon to bring the child back readily if there is an emergency (e.g., they live too far away, they cannot afford to return, there are additional social concerns).

Weak (conditional)

•   Child has not spontaneously improved and must be overly restricted in activities.

Weak (conditional)

ASH 2019

•   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.

GPS

•   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).

GPS

2.5  What is the initial treatment of pediatric patients with ITP?

ITP consensus

2019

I.  Watch-and-wait policy based on clinical classification

1.  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

2.  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.

Strong

Weak (conditional)

ASH 2019

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

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

For patients receiving corticosteroids, the treating physician should ensure the patient is adequately monitored for potential side effects regardless of the duration or type of corticosteroid selected (see implementation tool)

GPS

Weak (conditional)

ASH 2019

ITP consensus 2019

-      For patients where corticosteroids are contra-indicated or otherwise not preferred, the intravenous immunoglobulin can be used

-      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.

High

Strong

Weak (conditional)

2.6  What are the indications of platelet transfusion in pediatric patients with thrombocytopenia?

BSH 2016

In non-immune thrombocytopenia

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

§  Platelets < 20 x 10⁹/L transfuse in:

o  Insertion of a non-tunnelled central venous line.

§  Platelets < 50 x 10⁹/L transfuse in:

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

o  Surgery, unless minor (except at critical sites)

§  Platelets < 75-100 x 10⁹/L transfuse in

o  Major hemorrhage or significant post-operative bleeding

o  Surgery at critical sites: central nervous system including eyes

Intermediate

Weak (conditional)

In immune thrombocytopenia

Patients with immune thrombocytopenia should only be transfused with platelets for life-threatening bleeding.

Intermediate

Strong

2.7  What is the treatment of life-threatening bleeding in pediatric patient with thrombocytopenia?

ITP consensus

2019

For children with immune thrombocytopenia

1.      Combination therapy including IV corticosteroids, IVIg, with or without platelet transfusion.

-      Dose: IV methylprednisolone: 30 mg/kg per day, IVIg: 0.8-1.0 g/kg/d.

-      A second dose of IVIg and IV steroids may be required if a platelet response is not seen within 24 hours of the initial dose.

Weak (conditional)

2.      Platelet transfusion.

Weak (conditional)

3.      Antifibrinolytics may be given if bleeding continues despite therapy.

Weak (conditional)

4.      If there is an ICH, emergency splenectomy and/or neurosurgical control of bleeding should be considered in conjunction with emergency platelet-raising therapy.

Weak (conditional)

5.      Thrombopoietin receptor agonist (TPO-Ras) should be considered; they may aid the acute response in patients and prevent a decrease in platelet count if initial response to emergency therapy is lost.

Weak (conditional)

BSH 2016

For children with non-immune thrombocytopenia:

Platelet transfusion is the main line of treatment.

Intermediate

Strong

2.8  What is the adjuvant treatment in pediatric patient with thrombocytopenia?

ITP Consensus 2019

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

-  Dose: 15-20mg/kg every 8 hours orally and e-aminocaproic acid 1-5 g every 4-6 hours [maximum dose, 24 g/d]

Weak (conditional)

2.9  What is the long-term treatment plan in pediatric patients with thrombocytopenia?

ASH 2019

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:

1.      Thrombopoietin receptor agonist (eltrombopag or romiplostim)

2.      Rituximab

3.      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)

2.10  what is the treatment of menorrhagia in adolescent girl with thrombocytopenia

Manage as emergency treatment. Tranexamic acid can be useful and consult gynecologist for hormonal therapy

GPS

CPGL Source

Recommendation

Strength of Recommendation

Quality of Evidence

3.1  How to prevent serious bleeding in a fetus/ neonate with FNAIT?

BSH FNAIT 2019

At time of delivery:

•      If the fetal platelet count is unknown, assisted delivery and invasive procedures on the fetus during delivery should be avoided, including forceps, vacuum-assisted delivery, scalp blood sampling and scalp electrodes

•      A cord blood sample should be sent for platelet count determination immediately after delivery

•      HPA-selected platelets should be available at the time of delivery

High

High

High

Weak (conditional)

BSH FNAIT 2019

After delivery:

•      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 x 10⁹/l.

High

Weak (conditional)

3.2  How to prevent alloimmunization (maternal & transfusion related)?

BSH FNAIT 2019

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.

Intermediate

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.

Intermediate

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)

3.3  What are the drugs to be avoided in a child with history of bleeding?

•        Salicylates

•        NSAID

•        Anticoagulants

GPS

3.4  How to prevent bleeding in a child receiving antiplatelet medications?

BSH 2016

Consider platelet transfusion to prevent bleeding in severe thrombocytopenia (platelet count < 10 x 10⁹/l) caused by abciximab

Intermediate

Weak (conditional)

3.5  How to prevent further bleeding in a child following trauma?

Euro Trauma 2019

Severely injured patients should be transported directly to an appropriate trauma facility.

High

Strong

The time between injury and bleeding control should be minimized.

High

Strong

Local compression is recommended to limit life-threatening bleeding.

High

Strong

Use adjunct tourniquet to stop life-threatening bleeding from open extremity injuries in the pre-surgical setting.

High

Strong

Use adjunct pelvic binder to limit life-threatening bleeding in the presence of a suspected pelvic fracture in the pre-surgical setting.

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

Weak (conditional)

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

High

Weak (conditional)

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

Weak (conditional)

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

High

Weak (conditional)

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

Intermediate

Weak (conditional)

Transfuse at an initial dose of four to eight single platelet units or one aphaeresis pack.

Intermediate

Weak (conditional)

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

High

Weak (conditional)

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

We recommend that protocols for the management of bleeding patients consider administration of the first dose of TXA en route to the hospital.

High

Weak (conditional)

3.6  How to assess the risk of bleeding in children during preoperative evaluation?

ESA 2016

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.

We recommend the use of standardized questionnaires on bleeding and drug history as preferable to the routine use of conventional coagulation screening tests such as activated partial thromboplastin time (aPTT), international normalized ratio (INR) and platelet count 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.

Intermediate

Strong

Bleeding time is not recommended for preoperative bleeding risk stabilization as it is influenced by many variables.

Weak (conditional)