CPGL Source

Recommendation

SoR

The clinical presentation of VTE in children depends on several factors, including the patient's age, anatomic location of the thrombosis, affected organ system(s), characteristics of the thrombus (occlusive vs. nonocclusive), and chronicity.

₋  Common symptoms of an acute extremity deep venous thrombosis (DVT) include unilateral limb pain, swelling, and redness of the involved extremity.

₋  In the upper extremity, in specific, DVT extension and occlusion of the superior vena cava (SVC) can result in SVC syndrome characterized by swelling of the neck and face; dilatation of the superficial collateral venous circulation of the arms, neck, and chest; bilateral periorbital edema; and headaches.

₋  In the case of CVC-associated DVTs, the initial presenting symptom is often dysfunction of the CVC.

₋  Chronic DVTs, as in the case of adults, can presents with signs of chronic venous obstruction or post-thrombotic syndrome (PTS) including edema, venous stasis dermatitis, limb pain, and skin ulceration.

₋  In neonates, acute DVT may present with new-onset thrombocytopenia.

₋  Renal vein thrombosis classically presents with thrombocytopenia and hematuria and, if bilateral, can lead to renal insufficiency. In the neonatal period, it can also manifest with a palpable flank mass on examination, while in older children it is often associated with nephrotic syndrome and presents with peripheral and periorbital edema.

₋  Thrombocytopenia can also be one of the presenting symptoms in intracardiac thrombosis and portal vein thrombosis with the latter also resulting in upper gastrointestinal bleeding in children.

GPS

I-  Laboratory investigations

BSH 2011 ad 2021

Acute venous thrombosis

·   Laboratory investigations are required to aid the exclusion of systemic disorders in children presenting with a suspected VTE.

Strong

·   Haematology investigations (full blood count, clotting screen) and renal function should be undertaken to confirm safe baselines prior to anticoagulation.

Strong

·   D-Dimers should not be used to exclude VTE in children.

Conditional

BSH 2011 ad 2021

Heritable and acquired thrombophilia

·   Routine testing for heritable thrombophilia with a first episode of VTE is not indicated.

Strong

·   Children presenting with an unprovoked VTE should be tested for the presence of anti-phospholipid antibodies and those with persistently positive results should remain on long-term anticoagulation.

Strong

BSH 2011 ad 2021

Purpura fulminant (PF)

·   Neonates and children with PF should be tested urgently for protein C and S deficiency.

Strong

·   Children with early onset spontaneous thrombotic events should be screened for antithrombin (AT) deficiency.

Strong

II- Radiological

BSH 2011 ad 2021

CVL and non-CVL related VTE in the upper limb (UL)

·   Ultrasound (US) is recommended for the initial assessment of the peripheral upper limb, axillary, subclavian and internal jugular veins but may be relatively insensitive for the detection of central intra-thoracic VTE.

Strong

·   Contrast MRV is recommended for assessing the central veins for VTE.

Strong

·   Multi-detector computerized tomography (CT) venography (MDCT venography) may be considered for the assessment of the central veins if MRV is unavailable. Magnetic resonance imaging (MRI) should always be preferred to CT due to radiation dose considerations in children.

Conditional

BSH 2011 ad 2021

CVL and non-CVL related VTE in the lower limb (LL)

·   Doppler US is recommended to assess the LL venous system for VTE.

Strong

·   If the US is normal and the clinical suspicion of VTE remains high this should be repeated after a week to assess for proximal progression of any calf vein thrombus.

Strong

·   MRV should be considered in children with suspected proximal extension of femoral VTE.

Conditional

·   Patients presenting with bilateral lower limb DVT should have their inferior vena cava (IVC) imaged to exclude IVC thrombosis.

Strong

BSH 2011 ad 2021

For blocked central venous lines

·   A chest X-Ray is recommended to visualize the CVL position.

Conditional

·   Doppler US, conventional venography or contrast enhanced MRV may be required to exclude large vessel thrombosis.

Conditional

BSH 2011 ad 2021

For Diagnosis of cerebral sino-venous thrombosis

·   Urgent brain MRI including T2* imaging and MRV to detect both intraparenchymal haemorrhage and sinus thrombosis.

Strong

·   If urgent MRI is unavailable, a pre- and post-contrast CT scan with CT venography (CTV) should be performed.

Strong

·   Children in whome CSVT is suspected on CT could have confirmatory MRI replaced by CTV if MRI/MRV is not available.

Strong

BSH 2022

₋   We suggest testing for PNH in patients with thrombosis at unusual sites and abnormal haematological parameters (i.e., cytopenia and abnormal red cell indices) or evidence of haemolysis (i.e., raised lactate dehydrogenase, bilirubin and reticulocyte count).

Conditional

₋   We recommend testing for myeloproliferative neoplasms (MPN) panel (including JAK2 V617F, JAK2 exon 12, CALR, MPL mutation analysis) in patients with thrombosis at unusual sites and with full blood count abnormalities suggestive of a myeloproliferative neoplasm.

Strong

₋   Screening for antiphospholipid antibodies is recommended following unprovoked VTE because this may alter management including choice of antithrombotic therapy.

Strong

₋   Screening for antiphospholipid antibodies is suggested in patients with VTE provoked by a minor risk factor as this may alter management including choice of antithrombotic therapy.

Conditional

₋   Patients with acute multiple thrombotic events and evidence of organ failure suggestive of CAPS should be tested for antiphospholipid antibodies.

Strong

₋   As antiphospholipid syndrome (APS) is an acquired thrombophilia, screening for antiphospholipid antibodies is not recommended in family members of patients with thrombosis.

Strong

Pediatric patients may present with nonspecific (i.e., cough, crackles/ rales, tachycardia, and persistent tachypnea) or mild symptoms in the setting of a PE, especially when the PE is limited to the segmental branches of the pulmonary arteries.

Adolescents most frequently present with pleuritic chest pain, dyspnea, cough, and hemoptysis.

GPS

BSH 2011
ad 2021

If available, isotope lung scanning may be considered as the initial imaging investigation, providing the chest X-ray is normal and there is no significant concurrent cardiopulmonary disease. Otherwise, CT pulmonary angiography (CTPA) is recommended as the initial imaging modality for suspected PE.

Strong

Non-diagnostic isotope lung scanning should be followed by further imaging.

Strong

Patients with a good quality negative CTPA do not require further investigation or treatment.

Strong

Pulmonary magnetic resonance angiography (MRA) should be considered as an alternative to CTPA when iodinated contrast injection or radiation is a significant consideration.

Conditonal

We suggest to assess clues from history and physical examination

History clues:

Assess for:

•  Interventional catheterization especially balloon dilatation, valvotomy procedure.

•  Larger central line catheter size.

•  Repeated central catheter manipulations.

•  Longer duration of cannulation.

Physical examination:

Evaluation of the limb for signs and symptoms of acute peripheral arterial occlusion in the form of:

•  Non-Palpable pulses.

•  Difference in blood pressure > 10 mmHg between right and left legs.

•  Decrease in skin temperature.

•  Skin discoloration (pallor or cyanosis).

•  Prolonged capillary refill time.

GPS

Children presenting with sudden onset of the following symptoms are at high risk of stroke and should undergo immediate neurological assessment and consideration of urgent neuroimaging: (i) focal weakness, (ii) visual or speech disturbances, (iii) limb incoordination or ataxia, (iv) altered mental status, (v) headache, (vi) signs of raised intracranial pressure, or (vii) seizures with additional neurological symptoms.

GPS

In children presenting with neurological symptoms or signs relevant for stroke, the use of adult stroke recognition tools to differentiate childhood stroke from its mimics are not recommended in their current form.

GPS

BSH 2022

In patients with stroke, an abnormal full blood count should prompt consideration for testing with an MPN panel and for PNH.

Conditional

BSH 2022

Testing for heritable thrombophilia is not recommended in patients with stroke, regardless of age.

Strong

BSH 2022

Testing for antiphospholipid antibodies should be considered in young patients in the absence of identifiable risk factors of cardiovascular disease because this may alter management including choice of antithrombotic therapy.

Strong

•        Unprovoked thrombosis at an early age

•        Recurrent episodes of thrombosis or thrombophlebitis

•        Strong family history of thrombosis or thrombotic events especially at an early age (< 45 years)

•        Thrombosis at multiple or unusual locations including in cerebral and jugular

•        Migratory episodes or diffuse form of thrombotic events

•        Severity out of proportion to any recognized known stimulus for thrombosis

•        Unexplained neonatal thrombosis or fetal loss

•        Skin necrosis particularly if on coumarins or warfarin

•        Unexplained, prolonged, activated partial thromboplastin time

•        Patients with idiopathic thrombocytopenia, SLE or recurrent thrombosis including deep venous thrombosis, pulmonary embolus or superficial venous thrombosis

Thrombosis in arteries with the absence of arterial disease

GPS

BSH 2011 ad 2021

Children with early onset spontaneous thrombotic events should be screened for AT deficiency.

Strong

BSH 2022

Neonates and children with purpura fulminans should be tested urgently for protein C and S deficiency.

Strong

BSH 2022

In neonates with multiple unexplained thrombosis, especially with clinical evidence suggestive of catastrophic antiphospholipid syndrome (CAPS), testing for antiphospholipid antibodies and heritable thrombophilia should be considered

Conditional

BSH 2022

Thrombophilia screening is not routinely recommended for neonatal stroke.

Conditional

BSH 2011
ad 2021

Routine testing for heritable thrombophilia in unselected children presenting with a first episode of VTE is not indicated.

Strong

BSH 2011
ad 2021

Testing for heritable thrombophilia after a first episode of VTE has uncertain predictive value for recurrence.

Strong

BSH 2011
ad 2021

We do not recommend offering routine thrombophilia testing to first-degree relatives of people with a history of VTE.

Conditional

BSH 2022

Genetic testing for variants in genes (e.g., MTHFR, SERPINE1  variants (PAI-1plasma level)) without a clinically significant link to thrombosis is not recommended.

Conditional

BSH2022

Routine testing of coagulation factors to assess the risk of  thrombosis is not currently recommended.

Conditional

BSH 2022

The presence of a patent foramen ovale (PFO ) in patients with a stroke is not an indication for thrombophilia testing.

Conditional

BSH 2022

We suggest selective testing of asymptomatic first-degree relatives of probands with protein C, protein S and antithrombin deficiency where this may influence the management and life choices depending on personal circumstances.

Conditional

BSH 2011
ad 2021

Children presenting with an unprovoked VTE should be tested for the presence of anti-phospholipid antibodies and those with persistently positive results should remain on long-term anticoagulation.

Strong

BSH 2018

Assessment of an individual’s VTE risk, based on the factors listed, should be made at diagnosis and at appropriate times during the course of their illness (e.g. re-admission to hospital), particularly in adolescent patients, given their higher baseline risk of thrombosis.

Conditional

Patient-related factors

Age >10 years (particularly adolescents)

Inherited thrombophilia

Personal or family history of VTE

Obesity

Immobilisation

Concurrent infection

Disease-related factors

Presence of pulmonary/intrathoracic/ pelvic disease

Sarcomas (rhabdomyosarcoma, Ewing sarcoma, osteosarcoma)

Acute promyelocytic leukaemia

Acute lymphoblastic leukaemia

Lymphomas

Treatment-related factors

Major surgery

Use of CVLs

Induction chemotherapy for ALL: concurrent administration of corticosteroids and asparaginase

BSH 2018

Routine thrombophilia screening is not recommended outside the context of large, well-conducted prospective studies intended to assess the impact of prothrombotic defects in modern treatment protocols

Strong

BSH 2022

Testing for deficiencies of physiological anticoagulants should be performed only after 3 months of anticoagulation for acute thrombosis.

Conditional

CPGL Source

Recommendation

SoR

ASH 2018

•  We recommend using anticoagulation rather than no anticoagulation in pediatric patients with symptomatic DVT or PE

Strong

ASH 2018

•  We suggest either using anticoagulation or no anticoagulation in pediatric patients with asymptomatic DVT or PE 

Conditional

ASH 2018

•  We suggest against using thrombolysis followed by anticoagulation; rather, anticoagulation alone should be used in pediatric patients with DVT

Conditional

ASH 2018

•  We suggest using either low-molecular-weight heparin or vitamin K antagonists in pediatric patients with symptomatic DVT or PE

Conditional

BSH 2011
ad 2021

•  The use of thrombolytic therapy is not indicated for the majority of children with VTE but should be considered in the presence of extensive thrombosis, particularly those involving the pelvic veins, SVC, IVC or intracardiac sites

Strong

ASH 2018

•  We suggest against using thrombolysis followed by anticoagulation; rather, anticoagulation alone should be used in pediatric patients with submassive PE

Conditional

ASH 2018

•  We suggest using thrombolysis followed by anticoagulation, rather than anticoagulation alone, in pediatric patients with PE with hemodynamic compromise

Conditional

ASH 2018

•  We suggest using anticoagulation for <3 months rather than anticoagulation for > 3 months in pediatric patients with provoked DVT or PE

Conditional

ASH 2018

•  We suggest using anticoagulation for 6 to 12 months rather than anticoagulation for > 6 to 12 months in pediatric patients with unprovoked DVT or PE

Conditional

BSH 2011
ad 2021

•  In recurrent idiopathic VTE and children with antiphospholipid syndrome: duration should be life-long.

Strong

BSH 2011
ad 2021

•  Anticoagulation should be initiated with low molecular weight heparin (LWMH) followed by warfarin (INR 2.5) or continuingLMWH.

Strong

BSH 2011
ad 2021

•  Unfractionated heparin (UFH) may be used for initial therapy where rapid reversal of anticoagulation may be required.

Conditional

BSH 2011
ad 2021

•  Ongoing therapy with LMWH may be preferable in infants under 1 year of Age.

Conditional

ACCP 2012

•  We recommend initial treatment with UFH or LMWH for at least 5 days

•  For ongoing therapy, we recommend LMWH or UFH. For patients in whom clinicians will subsequently prescribe VKAs, we recommend beginning oral therapy as early as day 1 and discontinuing UFH/LMWH on day 6 or later than day 6 if the INR has not exceeded 2.0 compared with no therapy.

Strong

Considerations for initiating DOACs for treatment of pediatric VTE

•     Stable patient (unlikely to need an urgent procedure)

•     Tolerating good oral intake or on full nasogastric feeds

•     Adequate renal and hepatic function

•     Unlikely to have antiphospholipid antibody syndrome

•     ≥5 days of parenteral anticoagulation

•     No drug interactions (consult clinical pharmacy)

•     Gestational age > 37 weeks and weight > 2.6 kg

GPS

ASH 2018

We suggest against using thrombectomy followed by anticoagulation; rather, anticoagulation alone should be used in pediatric patients with symptomatic DVT or PE.

Conditional

ASH 2018

We suggest against using inferior vena cava (IVC) filter; rather anticoagulation alone should be used in pediatric patients with symptomatic DVT or PE.

Conditional

ACCP 2012

We suggest that therapeutic UFH in children is titrated to achieve a target range of anti-Xa activity of 0.35 to 0.7 units/mL or an activated partial thromboplastin time (aPTT) range that correlates to this anti-Xa range or to a protamine titration range of 0.2 to 0.4 units/mL.

Conditional

ACCP 2012

We suggest, for neonates and children receiving either once- or twice-daily therapeutic LMW that the drug be monitored to a target anti-Xa activity range of 0.5 to 1.0 units/mL in a sample taken 4 to 6 h after subcutaneous injection or 0.5 to 0.8 units/mL in a sample taken 2 to 6 h after subcutaneous injection.

Conditional

ACCP 2012

We suggest, for children receiving vitamin K antagonists (VKAs), that the drug be monitored to a target international normalized ratio (INR) of 2.5 (range, 2.0-3.0), except in the setting of prosthetic cardiac valves where we suggest adherence to the adult recommendations.

Conditional

ASH 2018

We suggest using anticoagulation, rather than no anticoagulation, in pediatric patients with right atrial thrombosis.

Conditional

ASH 2018

We suggest against using thrombolysis or surgical thrombectomy followed by standard anticoagulation; rather, anticoagulation alone should be used in pediatric patients with right atrial thrombosis

Conditional

ASH 2018

We suggest no removal, rather than removal, of a functioning CVAD in pediatric patients with symptomatic CVAD-related thrombosis who continue to require venous access.

Conditional

ASH 2018

We suggest either removal or no removal of a functioning CVAD in pediatric patients who have symptomatic CVAD-related thrombosis with worsening signs or symptoms, despite anticoagulation, and who continue to require venous access.

Conditional

ASH 2018

We recommend removal rather than no removal of a non-functioning or unneeded CVAD in pediatric patients with symptomatic CVAD-related thrombosis.

Strong

ASH 2018

We suggest delayed removal of a CVAD until after initiation of anticoagulation (days), rather than immediate removal in pediatric patients with symptomatic CVAD–related thrombosis who no longer require venous access or in whom the CVAD is nonfunctioning

Conditional

ASH 2018

We recommend using anticoagulation rather than no anticoagulation in pediatric patients with CSVT without hemorrhage.

Strong

ASH 2018

We suggest using anticoagulation rather than no anticoagulation in pediatric patients with CSVT with hemorrhage

Conditional

ASH 2018

We suggest against using thrombolysis followed by standard anticoagulation; rather, anticoagulation alone should be used in pediatric patients with CSVT.

Conditional

BSH 2011 ad 2021

₋   Anticoagulation should be continued for

·  Three months if there was a clear and treated precipitating factor e.g. infection.

Strong

·  Six months if there is no identified precipitant.

Strong

·  Anticoagulation may need to be continued for longer in patients where there is an ongoing risk factor (e.g. continuing treatment with asparaginase), in those with recurrent idiopathic CVT and in those with ongoing symptoms or signs attributable to venous hypertension) - duration should be considered on an individual basis.

Conditional

₋   Re-imaging should be undertaken prior to stopping anticoagulation in patients with ongoing symptoms attributable to venous hypertension (e.g. headache, vomiting, papilloedema, visual obscurations, visual field deficit) or with progressive neurological signs.

₋   Re-imaging is not required in patients with stable neurological signs, unless consideration is being given to extending anticoagulant therapy, in which case it may be helpful to establish whether or not recanalization has occurred.

Conditional

ASH 2018

•  We suggest using anticoagulation rather than no anticoagulation in neonates with RVT.

Conditional

ASH 2018

•  We recommend against using thrombolysis, followed by standard anticoagulation; rather, anticoagulation alone should be used in neonates with nonlife-threatening RVT.

Conditional

ASH 2018

•  We suggest using thrombolysis followed by standard anticoagulation rather than anticoagulation alone in neonates with life-threatening RVT.

Conditional

ACCP 2012

•  For unilateral renal vein thrombosis (RVT) in the absence of renal impairment or extension into the inferior vena cava (IVC), ACCP suggest either (1) supportive care with radiologic monitoring for extension of thrombosis (if extension occurs we suggest anticoagulation) or (2) anticoagulation with UFH/LMWH or LMWH in therapeutic doses rather than no therapy.

Conditional

ACCP 2012

•  For unilateral RVT that extends into the IVC, ACCP suggest anticoagulation with UFH/LMWH or LMWH

Conditional

ACCP 2012

•  For bilateral RVT with evidence of renal impairment, ACCP suggest anticoagulation with UFH/LMWH or initial thrombolytic therapywith tissue plasminogen activator (tPA) followed by anticoagulation with UFH/LMWH

Conditional

ACCP 2012

•  For unilateral renal vein thrombosis (RVT) in the absence of renal impairment or extension into the inferior vena cava, ACCP suggest a total duration of between 6 weeks and 3 months rather than shorter or longer durations of therapy

Conditional

ACCP 2012

•  For unilateral RVT that extends into the IVC, ACCP suggest anticoagulation with UFH/LMWH or LMWH for a total duration of between 6 weeks and 3 months

Conditional

ASH 2018

We suggest using anticoagulation rather than no anticoagulation in pediatric patients with PVT with occlusive thrombus, post liver transplant, and idiopathic PVT.

Conditional

ASH 2018

We suggest using no anticoagulation rather than anticoagulation in pediatric patients with PVT with nonocclusive thrombus or portal hypertension

Conditional

ASH 2018

In children who will not be anticoagulated, follow-up monitoring is important, because extension of thrombus or organ dysfunction may require reconsideration of treatment options.

Conditional

BSH 2018

Children with VTE unrelated to CVLs should receive anticoagulation for an initial period of 3 months.

Strong

BSH 2018

Continuation of treatment beyond 3 months should be considered in patients with active cancer or other ongoing risk factors.

Conditional

BSH 2018

Children with cancer who are found to have incidental VTE should be considered for systemic anticoagulation as per protocols for symptomatic disease. However, if the thrombosis is solely CVL-related, then it is reasonable to withhold anticoagulation initially and monitor the patient.

Conditional

BSH 2018

LMWH is the anticoagulant of choice for VTE in children with malignancy

Conditional

BSH 2018

Unfractionated heparin can be also used for the initial treatment of established VTE for patients with cancer when LMWH or direct oral anticoagulants are contraindicated, or not available.

Conditional

BSH 2018

Routine antithrombin supplementation is not recommended during LMWH or unfractionated heparin (UFH) anticoagulation.

Conditional

BSH 2018

Routine measurement of peak anti-Xa activity, with a target range of 0.5–1.0 units/mL, is recommended for children receiving LMWH.

Conditional

BSH 2018

Coagulopathies should be corrected and fibrinogen levels maintained above 1 g/l in children on anticoagulant therapy.

Conditional

At least 3 months or as long as active cancer or cancer therapy.

•  For non–catheter-associated DVT or PE recommend indefinite anticoagulation while cancer is active, under treatment, or if risk factors for recurrence persist.

•  For symptomatic catheter-associated DVT, consider anticoagulation treatment for at least 3 months or as long as the catheter is in place.

GPS

BSH 2018

Therapeutic anticoagulation may be continued while theplatelet count is >50 x 10⁹/l.

Strong

BSH 2018

Outside of these scenarios, an alternative approach of reducing the anticoagulation dose to 50% when the platelet count is between 25 and 50 x109/l and temporarily interrupting anticoagulation when <25 x 109/l could be considered.

Conditional

BSH 2018

For children with normal renal function on LMWH, the last therapeutic dose should be given at least 24 h prior to an invasive procedure and the last prophylactic dose at least 12 h prior to an invasive procedure. LMWH should be restarted no sooner than 4–6 h after a procedure

Strong

BSH 2018

For children on warfarin, the last dose should be given 4– 5 days prior to an invasive procedure. Bridging anticoagulation with LMWH when the International Normalised Ratio (INR) becomes sub-therapeutic will be required for individuals within 1 month of a VTE. This should also be considered for up to 3 months after a VTE in those judged to be at particularly high risk of recurrence

Conditional

BSH 2018

Removal of the CVL is not necessary if it is still required for venous access, in a good position and functioning well

Conditional

BSH 2018

Symptomatic CVL-related VTE should be treated with anticoagulation for a minimum of 3 months

Strong

BSH 2018

Further doses of asparaginase may be administered following an asparaginase-related VTE provided they are covered by prophylactic or therapeutic anticoagulation

Strong

BSH 2018

Such anticoagulation should be continued for at least 3 weeks following each dose of pegylated asparaginase

Strong

BSH 2018

We suggest that that re-exposure to asparaginase is delayed until symptoms of the initial VTE have improved and, in the case of CVT, repeat imaging demonstrates stabilisation or improvement of the thrombosis

Conditional

In the event of VTE recurrence, three options can be considered:

(1)    increase LMWH by 20–25% or switch to direct oral anticoagulants;

(2)    for direct oral anticoagulants, switch to LMWH; and

(3)    for vitamin K antagonist, switch to LMWH or direct oral anticoagulants

(guidance, based on evidence of very low quality and an unknown balance between desirable and undesirable effects).

GPS

ACCP

2012

GPS

UW Health 2023

All hospitalized patients 6 months of age or older should be evaluated for both bleeding and VTE risk within 24 hours of admission, upon transferring level of care, and periodically during hospital stay (every 48-72 hours)

Strong

VTE Risk factors:

Acute conditions

₋ Reduced mobility longer than 48 hrs

₋ Central venous access device

₋  Activee infection

₋  Major trauma or burn

₋  Major surgery

₋  Critically ill

₋  Hypoalbuminemia

₋  Blood transfusion withing the previous 48 hours

Chronic medical condition

₋  Post-pubertal and/or age 12 years or older

₋  Autoimmune disorders associated with thrombosis

₋  Thrombophilic condition

₋   Active malignancy

₋  Obesity

Historical factors

₋   Asparaginase therapy within the previous 30 days

₋   Recentt surgery within the past 30 days

₋  History of thrombosis

₋  Family history of VTE in a 1st degree relative < 40 year old at time of clot.

GPS

Risk Factor Stratification definitions:

Low VTE risk: No altered mobility and 0-2 risk factors

Moderate VTE risk:

₋  No altered mobility and 3-4 risk factors

₋  Altered mobility and 0-2 other risk factors

High VTE risk:

₋ No altered mobility and ≥ 5 risk factors

₋  Altered mobility and ≥ 3 other risk factors

GPS

Risk assessment

UW Health 2023

₋  If a patient meets at least one of the criteria of the “Chemical Prophylaxis NOT Recommended” list, avoid chemical prophylaxis as risk outweighs benefit.

₋  If patient meets at least one of the following criteria in the “Consider Avoiding Chemical Prophylaxis” list, consider avoiding chemical prophylaxis.

-  Consider consulting hematology for recommendations if patient is considered at high risk for VTE, but also with high bleeding risk.

-  Uncontrolled hypertension is defined as systolic or diastolic blood pressure greater than 95^thpercentile for age, height, and gender.

Strong

Conditional

GPS

GPS

UW Health 2023

Recommendations for specific factors associated with increased bleeding risk:

Strong

Non-pharmacological (Physical) methods for thromboprophylaxis

-   Children should be encouraged to reduce their risk of VTE by maintenance of good hydration, early mobilisation whenever possible. 

GPS

BSH 2011 ad 2021

-   The use of physical methods for VTE risk reduction should be considered in older children and adolescents who are at increased risk of VTE.

Strong

BSH 2011 ad 2021

-   In suitable patients, physical methods may be helpful when there is a high risk of bleeding or to complement anticoagulant-based prophylaxis when there is a particularly high risk of VTE.

Strong

-   Mechanical prophylaxis methods may include sequential compression device (SCD), graduated compression stockings (GCS), or consulting physical therapy and/or occupational therapy to assist with movement of the patient .

GPS

UW Health 2023

-   Contraindications to mechanical prophylaxis:

· Extremity has acute fracture,

· Extremity has peripheral IV access,

· Skin condition affecting extremity (i.e., dermatitis, burn, etc.),

· Unable to achieve correct fit due to patient size,

· Lower extremity peripheral arterial insufficiency.

Strong

Pharmacological thromboprophylaxis (LMWH, VKA)

BSH 2011 ad 2021

-   There is no evidence for the use of aspirin for VTE prophylaxis in children.

Conditional

BSH 2011 ad 2021

-   Children, particularly adolescents, with multiple risk factors for VTE should be considered for thromboprophylaxis with LMWH.

Conditional

1. Low molecular weigh heparin (LMWH)

UW Health 2023

·  Enoxaparin is the preferred pharmacologic prophylaxis agent for pediatric patient.

Strong

· Use of subcutaneous (SQ) injections is preferred due to lack of evidence of intravenous administration in the prophylactic setting.

GPS

UW Health 2023

· Avoid enoxaparin or heparin if patient has hypersensitivity to enoxaparin, heparin, pork products, or any component of the formulation. 

Strong

·  Recommended ‘prophylaxis’ doses are usually half the following treatment doses:

₋  Dalteparin: 100 u/kg twice per day or 200 u/kg once per day s.c.

₋ Enoxaparin: 1 mg/kg twice per day or 2 mg/kg once per day s.c.

₋ Tinzaparin: 175 u/kg once per day s.c.

· Infants <8 weeks of age and/or <5 kg require 50% larger doses e.gDalteparin 150 u/kg twice per day and Enoxaparin 1.5 mg/ kg twice per day, possibly due to a larger volume of distribution and/or reduced anti thrombin levels.

· Target anti-Xa activity taken 4 h following subcutaneous injection. Prophylactic 0.1–0.4 u/ml.

GPS

2. Warfarin

₋ Initial loading dose of 0.2 mg/kg p.o. for 2 d.

GPS

₋ Subsequent dose adjustments should be based on the INR result.

₋ Reversal of warfarin with Vitamin K: Vitamin K can be given p.o. or i.v., dosing regimens vary but doses of 30 µg/kg or 0.3–5 mg have been reported to be effective (Bolton-Maggs& Brook, 2002). 

GPS

3. Rivaroxaban

UW Health 2023

· Rivaroxaban, an oral anticoagulant with FDA approval in the pediatric population, may be considered for prophylaxis in patients with high VTE risk if appropriate based on patient characteristics

Conditional

UW Health 2023

· Rivaroxaban may be used based on individual considerations.

-  Only use rivaroxaban in infants weighing at least 2.6 kg whose serum creatinine is less than the 97.5^thpercentile and children or adolescents with eGFR > 50 mL/min/1.73 m².

-  Patients should receive at least five days of parenteral anticoagulation and at least ten days of enteral feeding prior to starting rivaroxaban for VTE prophylaxis.

Strong

Strong

Strong

Recommendations for patients with special risk factors

ASH 2018

Patients with congenital purpura fulminant due to homozygous protein C deficiency

The ASH guideline panel suggests using either liver transplantation or no liver transplantation (anticoagulation or protein C replacement) in pediatric patients with congenital purpura fulminans due to homozygous protein C deficiency.

Conditional

BSH 2011 ad 2021

Patients with CVL

- Thromboprophylaxis for primary prevention of CVL related thrombosis is not recommended.

-   Consideration may be given to the use of heparin-bonded CVLs, if available, for short-term use.

Conditional

Conditional

BSH 2018

Children with cancer

-  Simple measures should be encouraged: early mobilisation, good hydration and prompt removal of central venous lines (CVLs) when no longer required.

-  Routine thromboprophylaxis in children with cancer is not recommended, but should be considered in adolescents with multiple risk factors.

Patient-related factors

Age >10 years(particularly adolescents)

Inherited thrombophilia

Personal or family history of VTE

Obesity

Immobilisation

Concurrent infection

Disease-related factors

Presence of pulmonary/intrathoracic/pelvic disease

Sarcomas (rhabdomyosarcoma,Ewing sarcoma, osteosarcoma)

Acute promyelocytic leukaemia

Acute lymphoblastic leukaemia

Lymphomas

Treatment-related factors

Major surgery

Use of CVLs

Induction chemotherapyfor ALL: concurrentadministration of corticosteroidsand asparaginase

Conditional

Conditional

BSH 2018

Children with cancer and CVL

-  Removal of the CVL is not necessary if it is still required for venous access, in a good position and functioning well

Conditional

BSH 2018

-   For children requiring a CVL and at high risk of VTE, an internal device (port) should be used in preference to an external tunnelled device (Hickman or Broviac catheter) 

Conditional

BSH 2018

-   Until further paediatric data are available, we suggest using tunnelled  lines  in  preference  to  peripherally inserted central catheter (PICC) lines in children with cancer, where practicable

Conditional

BSH 2018

-   There are insufficient data to support a preference for jugular or subclavian vein access for CVL insertion. Femoral vein access in children is associated with a higher risk of thrombosis and should be avoided if possible

Strong

BSH 2018

-   There is no definitive evidence that deferring CVL placement until the end of acute lymphoblastic leukaemia (ALL) induction therapy reduces the risk of line-associated thrombosis. The decision regarding timing of CVL placement should take into account the physical and psychological consequences of delaying CVL placement in individuals with poor venous access

Conditional

BSH 2018

-   Symptomatic CVL-related VTE should be treated with anticoagulation for a minimum of 3 months

Strong

BSH 2018

-   Anticoagulation according to standard VTE protocols is recommended for cerebral venous thrombosis (CVT) in children with cancer and should be given for a minimum of 3 months

Strong

A positive thrombophilia evaluation is not a sufficient basis to offer extended anticoagulation following an episode of provoked VTE.

GPS

A negative thrombophilia evaluation is not a sufficient basis to stop anticoagulants following an episode of unprovoked VTE in a patient with low bleeding risk and willingness to continue therapy.

GPS

Heterozygosity for FVL or PGM does not increase the predicted risk of recurrence after unprovoked VTE to a clinically significant degree.

GPS

As a family history of VTE confers an excess risk of

thrombosis, relatives should be counseled regarding use of

prophylaxis in high risk situations.

GPS

Especially in high-risk group for VTE, physicians should be cautious when using some drugs that may alter the balance between different coagulation factors, and some drugs that can increase blood viscosity as hormonal therapy, steroids, intravenous immunoglobulin.

GPS

UW Health 2023

1. Complete blood count (CBC): Obtain baseline CBC within 48 hours of initiation of enoxaparin or heparin.

Strong

2. International normalized ratio (INR): a target INR of 2.5 is generally accepted as being appropriate for the management of childhood VTE.

GPS

UW Health 2023

3. Anti-Xa:

-   May consider checking anti-Xa level if the patient experiences active bleeding or has evidence of renal dysfunction while receiving enoxaparin.

Conditional

-   Routine anti-Xa levels are not recommended with the use of enoxaparin, heparin, or rivaroxaban at prophylactic doses.

GPS

Good hydration maintains the blood volume and improves viscosity.

GPS

Obesity is a risk factor for many diseases including heart diseases and thrombosis, therefore maintaining optimal growth and preventing obesity is recommended. 

GPS

A well-balanced diet containing a variety nutrient is a way to keep our children healthy.  Some food that improves the cholesterol levels, act as antioxidants, and decrease inflammation can prevent blood clot as:

₋  Fruits (grapes, cherries, apples, prunes, pears, citrus)

₋ Whole grains

₋ black or green tea

₋ Nuts

₋ Leeks, onions, and garlic reduce cholesterol production

₋ Legumes and soy products

GPS

Full Name

Affiliation(s)

Role/ Clinical specialty

Prof. Galila Mohamed Mokhtar

Paediatrics Department, PaediatricHaematology/ Oncology & BMT UnitFaculty of Medicine, Ain Shams University, Cairo, Egypt

Editor, Clinical expert, GAG member

Prof. Amira Adly

Professor of Paediatrics, PaediatricHaematology/ Oncology & BMT Unit, Ain Shams University, Cairo, Egypt

Clinical expert

GAG member

Prof. Gehan Lotfy

Professor of Paediatrics, Minia University, Egypt

Clinical expert

GAG member

Prof. Hanafy Hafez

Professor of Pediatric Oncology, National Cancer Institute, Cairo University, Egypt

Prof. Hanafy Hafez

Prof. Hoda Hassab

Professor of Paediatrics and PaediatricsHaematology, Alexandria University, Egypt

Clinical expert

GAG member

Prof. Ilham Youssry

Professor of Paediatrics and Head of the PaediatricHaematology& BMT unit, Cairo University, Cairo, Egypt

Clinical expert

GAG member

Prof. Iman Ragab

Professor of Paediatrics, PaediatricHaematology/ Oncology & BMT Unit, Ain Shams University, Cairo, Egypt

Clinical expert

GAG member

Prof. Laila Sherief

Professor of Paediatrics and PaediatricsHaematology& Oncology, Zagazig University, Egypt

Clinical expert

GAG member

Prof. Marwa Zakaria

Associate Professor of Paediatricsand Pediatric Hematology & Oncology, Zagazig University, Egypt

Clinical expert

GAG member

Prof. Mervat Hesham

Professor of Pediatrics and Pediatric Hematology & Oncology, Zagazig University, Egypt

Clinical expert

GAG member

Prof. Mervat Mansour

Professor of Pediatrics and, Pediatric ICU, Ain Shams Universiy, Egypt

Prof. Mervat Mansour

Dr. Naglaa Shaheen

Consultant of Pediatric Hematology, Health Insurance Organization

Clinical expert

GAG member

Dr. Nouran Yousef

Lecturer of Paediatrics, Paediatric Diabetes, Endocrinology & Metabolism unit, Ain Shams University, AFCM, Cairo, Egypt

Clinical expert

GAG member

Prof. Rasha Abdel-Raouf Afifi

Professor of Paediatrics and PaediatricHaematology, Cairo University, Cairo, Egypt

Clinical expert

GAG member

Dr. Sara Makkeyah

Associate Professor of Paediatrics, PaediatricHaematology / Oncology Unit & BMT, Ain Shams University, Cairo, Egypt

Clinical expert

GAG member

Prof. Sonia Adolf

Professor of Paediatrics and PaediatricHaematology, National Research Center, Cairo, Egypt

Clinical expert

GAG member

Full Name

Affiliation(s)

Role/ Clinical specialty

Prof. Ashraf Abdel Baky

Chairman of EPG

Professor of Paediatrics and Pediatric Allergy and Immunology, Ain Shams University, Cairo, Egypt

Guideline Methodology expert

GAG member

Prof. Tarek Omar

Vice Chair of EPG

Professor of Pediatrics and Pediatric Neurology, Alexandria University, Egypt

Guideline Methodology expert

GAG member

Dr. Yasser S. Amer

Pediatrician & Guideline Methodologist

Research Chair for Evidence-Based Health Care & Knowledge Translation, King Saud University, Riyadh, Saudi Arabia

Alexandria Center for Evidence-Based CPG

Consultancy Board Member, EPG, Egypt

Guideline Methodology expert

GAG member

Dr. Heba Hussein

Associate Professor of Oral Medicine, Oral Diagnosis, and Periodontology Department, Faculty of Dentistry, Cairo University, Cairo, Egypt

Dr. Heba Hussein

Health / Clinical Question (PIPOH)

P: Patient (Target Population):

•Gender: Both genders.

• Age group: Neonates, Infants, children & adolescents less than 18 years.

•  Disease/ Condition: thrombosis (arterial/venous,  site, disease categories).

•  Exclusion criteria: thrombotic microangiopathy,  disseminated intravascular coagulopathy, thrombosis due to stasis and/ or blood vessel injury.

I: Interventions and Practices Considered / CPG Category:

Diagnosis:

• Venous thrombosis

•  Arterial thrombosis

Treatment

•  Venous thrombosis

• Arterial thrombosis

Prevention

P: Professionals (Intended / Target Users or Stakeholders)   :

Primary health care physicians at the Ministry of Health, general practitioners, family medicine specialists, pediatricians, hematologists, oncologists, neonatologists, intensive care specialists, surgeons, neurologists, nurses, and medical students.

O: Major Outcomes Considered:

•  Primary outcome:

-  Prevent mortality and morbidity from thrombosis.

- Prevent sequelae and disabilities

•  Secondary outcome:

-  Family counseling

-  Prevention of recurrence

H: Healthcare Settings:

Primary, secondary, and tertiary healthcare services mainly outpatient clinics and emergency rooms in governmental, non-governmental and private sectors in Egypt.

High

Further research is very unlikely to change our confidence in the estimate of effect

Moderate

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Low

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low

Any estimate of effect is very uncertain.

Strong

the panel is confident that the desirable effects of adherence to a recommendation outweigh the unesirable effects

conditional

the panel concludes that the desirable effects of adherence to a recommendation probably outweigh the undesirable effects, but is not confident.

CPGs

AGREE II DOMAINS

CPG1

CPG2

CPG3

CPG4

CPG5

CPG6

D1: Scope & Purpose

94.44

77.78

72.2

61

91.65

83.33

D2: Stakeholder Involvement

50

77.78

83.3

72.2

91.65

72.22

D3:Rigour of Development

68.75

87.75

93.75

68.8

86.45

85.42

D4: Clarity & Presentation

94.44

83.33

100

77.8

88.9

88.88

D5: Applicability

50

62.5

83.3

58.3

83.35

83.33

D6: Editorial Independence

60

91.67

100

883.3

91.65

83.33

OA 1

68.12

80.12

89.1

71.7

88.1

84.06

OA 2 (Recommend for use)

Yes

Yes

Yes

Yes

Yes

Yes

This table uses the AGREE II Domain Score Color codes (< 40% red; > 41 – 70% yellow; > 71 % green)

1.     Are you aware of any new evidence relevant to this CPG statement? Yes/ No

2.     Is there any new evidence to invalidate any of the recommendations comprising the CPG? Yes/ No

3.     Are there any plans to update the CPG in the near future? Yes/ No

4.     When the CPG was last updated?

5.     What is the citation for the latest version? See Reference www.epg.edu.eg

PHASE

MODULE

STEP

TOOL

DECISION

REASON (if not utilized)

Utilized

Not utilized

ONE: SET-UP

1.1.       Preparation

1

1

√

2

√

2

√

3

√

4

√

5

3

√

4

√

1

√

6

5

√

TWO: ADAPTATION

2.1. Scope and Purpose

7

6

√

2.2. Search and Screen

8

2

√

7

√

9

8

√

10

9

√

Decided to rely on inclusion/ exclusion criteria (filters) & PIPOH compatibility

10

√

2.3. Assessment

11

9

√

10

√

12

11

√

13

12

√

Decided to select NICU (Amer et al,2015) of the CPG

14

13

√

Decided to rely on D3 Scores of AGREE II

14

√

15

15

√

Decided to rely on D5, D2 Scores of AGREE II

2.4. Decision and Selection

16

Table

√

17

Decision making and selection

√

2.5. Customization

18

16

√

THREE: FINALIZATION

3.1. External Review and Acknowledgment Module

19

17

√

20

√

21

√

22

√

3.2. Aftercare Planning

23

18

√

3.3. Final Production

24

√