Venous thromboembolism, pulmonary embolism and thrombophilia in children — branching viva

Examiner opening (Examiner)

You are the general paediatric registrar on the ward. A six-year-old boy with acute lymphoblastic leukaemia, three months into induction chemotherapy with a tunnelled central venous catheter, presents with a swollen warm right leg over 48 hours. A compression ultrasound confirms a right femoral deep vein thrombosis. Talk me through your assessment and management plan. [3]

Exemplar opening (Candidate)

This boy has a provoked deep vein thrombosis. The central venous catheter is the dominant provoking factor in paediatric thrombosis, accounting for around half of all events, and the leukaemia itself and the induction chemotherapy — particularly asparaginase, which depletes antithrombin — create a hypercoagulable state. The combination is classic. My management is to start therapeutic anticoagulation with low molecular weight heparin, enoxaparin 1 mg per kg subcutaneously every 12 hours, check the anti-factor Xa level after the third or fourth dose with a target of 0.5 to 1.0 IU per mL for twice-daily dosing, treat for 6 weeks to 3 months, and remove the central line once it is no longer needed and the clot has stabilised. I will involve the paediatric haematology team early. [1] [7]

Branch 1 — epidemiology and provoking factors (Examiner)

How common is venous thromboembolism in children, and what are the main risk factors? [3]

Exemplar (Candidate)

Paediatric venous thromboembolism is far rarer than the adult disease but has risen dramatically. Raffini and colleagues showed the rate in United States children's hospitals rose from 34 to 58 cases per 10,000 admissions between 2001 and 2007, a 70 percent increase, driven by better survival of critically ill children, more central lines, and improved imaging. Over 90 percent of paediatric events are provoked and secondary. The incidence is bimodal, peaking in neonates (developmental haemostasis and central lines) and in adolescents (oestrogen and adult-style risk factors). The risk factors cluster into Virchow's triad: stasis (immobility, critical illness, central line), endothelial injury (catheter tip, surgery, infection), and hypercoagulability (malignancy, sepsis, congenital heart disease, nephrotic syndrome, oestrogen, hereditary thrombophilia). A central venous access device is the single largest provoking factor. [3] [11]

Branch 2 — pathophysiology and developmental haemostasis (Examiner)

Explain the pathophysiology, and tell me why a neonate needs a different heparin dose from an older child. [7]

Exemplar (Candidate)

Thrombus formation follows Virchow's triad. Venous stasis from immobility or disturbed flow around a catheter tip, endothelial injury from the catheter or surgery, and hypercoagulability from malignancy, sepsis or hereditary thrombophilia converge to form a clot. The central venous catheter is special because it combines all three arms. In children, the third arm is modified by developmental haemostasis. The neonatal haemostatic system has physiologically low levels of the vitamin K dependent factors and the anticoagulant proteins antithrombin, protein C and protein S, which rise toward adult values over the first six months. Neonates also clear heparin faster, with a larger volume of distribution and higher renal clearance, so they need a higher weight-based dose — enoxaparin 1.5 mg per kg twice daily in a neonate compared with 1 mg per kg twice daily in a child over two months. The neonatal dose is 50 percent higher for this reason. [7] [1]

Branch 3 — investigations and monitoring (Examiner)

How do you confirm the diagnosis, and how do you monitor the anticoagulation? [11]

Exemplar (Candidate)

The first-line test for a limb deep vein thrombosis is compression ultrasonography, and the diagnostic criterion is a non-compressible vein under probe pressure. A Doppler flow assessment alone is not sufficient. A negative ultrasound with a high clinical suspicion is repeated within a week. For pulmonary embolism, CT pulmonary angiography directly visualises the clot. The D-dimer is an adjunct that helps exclude in low-probability settings but is often raised in hospitalised children from the underlying illness and cannot rule out thrombosis alone. I monitor low molecular weight heparin with the anti-factor Xa level, drawn around four hours after a subcutaneous dose, with a therapeutic target of 0.5 to 1.0 IU per mL for twice-daily dosing, adjusting the dose in increments of about 25 percent until steady and therapeutic. [11] [7]

Branch 4 — definitive management and rivaroxaban (Examiner)

What are the definitive treatment options, and what did the EINSTEIN-Jr trials show? [4]

Exemplar (Candidate)

The definitive management is therapeutic anticoagulation for a defined duration. Low molecular weight heparin remains the workhorse and is recommended by the CHEST and ASH guidelines. The modern alternative is rivaroxaban, a direct factor Xa inhibitor now licensed for children based on the EINSTEIN-Jr programme. The phase 2 studies established the bodyweight-adjusted dosing that achieves adult-equivalent drug exposure, and the phase 3 randomised trial showed that rivaroxaban compared favourably with standard anticoagulants for recurrent thrombosis and bleeding. The catheter-related subgroup, the EINSTEIN-Jr CVC-VTE study, confirmed efficacy and safety in central venous catheter thrombosis specifically, which is the dominant paediatric category. Rivaroxaban is given as a tablet or oral suspension and avoids the need for injections and routine monitoring, which is a major quality-of-life advantage. Warfarin is now a third-line option because of its monitoring burden and interactions, but it remains useful for mechanical heart valves and antiphospholipid syndrome. The duration follows the provoked status: 6 weeks to 3 months for a provoked catheter-related clot, 3 to 6 months for an unprovoked event. [4] [6] [2]

Branch 5 — thrombophilia testing (Examiner)

Would you test this boy for hereditary thrombophilia, and what would the panel include? [8]

Exemplar (Candidate)

Not routinely. Thrombophilia testing is selective and is not indicated for a clearly provoked catheter-related thrombosis in a child with leukaemia, because the common abnormalities such as factor V Leiden have a low positive predictive value and over-labelling adds anxiety without changing management. I would test if the thrombosis were unprovoked, recurrent, in an unusual site, or with a strong family history. When testing is performed, it is deferred until the acute phase and chemotherapy effects have passed, because active thrombosis and asparaginase transiently lower antithrombin, protein C and protein S. The panel includes factor V Leiden and prothrombin gene mutation, which are genetic and unaffected by the acute phase; antithrombin, protein C and protein S activity; and antiphospholipid antibodies. An isolated low antithrombin during induction is likely treatment-related and should be confirmed by repeat testing in remission. [8]

Branch 6 — pulmonary embolism and the red flag (Examiner)

If this boy suddenly becomes breathless and hypoxic, what are you worried about and what do you do? [11]

Exemplar (Candidate)

A child with a known or suspected deep vein thrombosis who becomes breathless, tachycardic or hypoxic has a pulmonary embolism until proven otherwise. Paediatric pulmonary embolism is increasingly recognised and frequently missed because the symptoms overlap with commoner conditions. My immediate steps are high-flow oxygen and circulatory support, escalation to the paediatric intensive care team, and urgent CT pulmonary angiography if he is stable enough, or a bedside echocardiogram for right ventricular strain if he is unstable. I continue and ensure therapeutic anticoagulation, and for a life-threatening massive pulmonary embolism with shock I involve haematology and critical care to consider systemic thrombolysis with alteplase or catheter-directed thrombolysis. The key is to think of pulmonary embolism early in any child with a clot who deteriorates. [11] [3]

Examiner wrap-up (Examiner)

Thank you. Summarise the three points you most want the examiner to remember. [1]

Exemplar (Candidate)

First, paediatric venous thromboembolism is provoked and secondary in over 90 percent of cases, and the central venous access device is the single largest provoking factor, so think of thrombosis in any child with a central line, critical illness or malignancy. Second, the treatment backbone is low molecular weight heparin — enoxaparin 1.5 mg per kg twice daily in a neonate and 1 mg per kg twice daily in a child over two months, monitored by the anti-factor Xa level with a target of 0.5 to 1.0 IU per mL — and bodyweight-adjusted oral rivaroxaban is now licensed after the EINSTEIN-Jr trials and avoids injections. Third, thrombophilia testing is selective, never universal, reserved for an unprovoked, recurrent or unusual-site thrombosis or a strong family history, and a girl who carries factor V Leiden should avoid the combined oral contraceptive pill. [1] [4] [8]