Venous thromboembolism, pulmonary embolism and thrombophilia in children — formative SAQs

SAQ 1 (10 marks)

A six-year-old boy with acute lymphoblastic leukaemia, three months into induction chemotherapy, presents with a swollen, warm and tender right leg over 48 hours. He has a tunnelled central venous catheter in situ. His observations are stable, his platelet count is 85 times 10 to the ninth per litre and his renal function is normal. A compression ultrasound confirms a non-occlusive right femoral deep vein thrombosis. [3] [6]

1. Give the most likely provoking factors and explain the pathophysiology of this child's thrombosis. (3) [1] [11]
2. Outline the initial and definitive anticoagulant management, including the drug, dose, monitoring and duration. (4) [7] [1]
3. Discuss whether and when you would test this child for hereditary thrombophilia, and how you would interpret the results. (3) [8]

Model answer — SAQ 1

(1) Provoking factors and pathophysiology (3). This child's thrombosis is provoked and secondary, as are over 90 percent of paediatric events. The dominant provoking factors here are the central venous catheter (the single largest paediatric provoking factor, accounting for around half of cases), the malignancy itself producing a hypercoagulable state, and the chemotherapy — particularly asparaginase, which lowers antithrombin and is a well-recognised prothrombotic agent in acute lymphoblastic leukaemia. The pathophysiology follows Virchow's triad. The catheter disturbs venous flow and injures the endothelium at its tip (stasis and endothelial injury), while the leukaemia and asparaginase-induced antithrombin depletion create a hypercoagulable state. The three arms converge around the catheter tip to form the femoral thrombus. [1] [11]

(2) Anticoagulant management (4). The initial and definitive agent is low molecular weight heparin, recommended by both the CHEST and ASH guidelines. For a child over two months, enoxaparin is given at 1 mg per kg subcutaneously every 12 hours. The anti-factor Xa level is checked after the third or fourth dose, drawn around four hours after a subcutaneous injection, and titrated to a target of 0.5 to 1.0 IU per mL for twice-daily dosing, adjusting in increments of about 25 percent until steady and therapeutic. The platelet count of 85 is adequate for anticoagulation. The duration for a provoked catheter-related thrombosis is 6 weeks to 3 months, with removal of the central line once it is no longer needed and the clot has stabilised, typically after three to five days of anticoagulation. Bodyweight-adjusted oral rivaroxaban, established by the EINSTEIN-Jr CVC-VTE subgroup, is an alternative that avoids injections, and should be discussed with the paediatric haematology team. Supportive care includes analgesia, elevation of the leg, mobilisation as tolerated, and avoidance of intramuscular injections. [7] [1] [6]

(3) Thrombophilia testing (3). Thrombophilia testing is selective and is not routinely 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 a child already burdened with malignancy adds anxiety without changing management. Testing becomes reasonable if the thrombosis is unprovoked, recurrent, in an unusual site, or if there is a strong family history. When testing is performed, it is deferred until the acute phase and chemotherapy effects have passed, because active thrombosis, inflammation and asparaginase transiently lower antithrombin, protein C and protein S and can produce false results. The panel would include factor V Leiden and prothrombin gene mutation (genetic, 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 rather than hereditary and should be confirmed by repeat testing when the child is in remission and off chemotherapy. [8]

SAQ 2 (10 marks)

A fifteen-year-old girl who takes the combined oral contraceptive pill presents to the emergency department with sudden onset of right-sided pleuritic chest pain and breathlessness. Her oxygen saturations are 93 percent in air, her heart rate is 110 beats per minute, and she is haemodynamically stable. A CT pulmonary angiogram confirms a segmental pulmonary embolism. Her mother states she had a deep vein thrombosis at age 40. [3] [11]

1. Give the immediate and definitive management of this adolescent's pulmonary embolism. (4) [1] [2]
2. Explain how you would investigate the family history and the role of hereditary thrombophilia testing in this case. (3) [8]
3. Discuss the contraceptive counselling and long-term follow-up for this girl. (3) [8] [2]

Model answer — SAQ 2

(1) Immediate and definitive management (4). The immediate management is oxygen to correct her hypoxia, analgesia for the pleuritic pain, and therapeutic anticoagulation. As she is haemodynamically stable, low molecular weight heparin is the agent of choice: enoxaparin 1 mg per kg subcutaneously every 12 hours, with the anti-factor Xa level checked after the third or fourth dose and titrated to a target of 0.5 to 1.0 IU per mL for twice-daily dosing. For a teenager who can swallow tablets and whose renal function is normal, bodyweight-adjusted oral rivaroxaban, established by the EINSTEIN-Jr phase 3 trial, is an excellent licensed alternative that avoids injections and routine monitoring and is preferred by many families. Systemic thrombolysis is reserved for a life-threatening massive pulmonary embolism with shock, which this stable girl does not have. The definitive duration for an unprovoked or oestrogen-related pulmonary embolism is 3 to 6 months, with the combined oral contraceptive pill stopped immediately and permanently. She should be admitted for observation, anticoagulation education, and involvement of the paediatric haematology team. [1] [2] [4]

(2) Family history and thrombophilia testing (3). The strong family history — a first-degree relative with a deep vein thrombosis at age 40 — combined with an unprovoked-equivalent event (oestrogen-provoked but with a clear genetic suspicion) makes this a setting where hereditary thrombophilia testing is indicated. Testing is performed outside the acute phase, because active thrombosis and inflammation transiently alter the anticoagulant proteins. The panel includes factor V Leiden and prothrombin gene mutation (genetic tests unaffected by the acute phase, so they can be sent at any time), antithrombin, protein C and protein S activity, and antiphospholipid antibodies (lupus anticoagulant, anticardiolipin and beta-2 glycoprotein I). The antiphospholipid antibodies are confirmed on repeat testing at 12 weeks. A positive result — most commonly heterozygous factor V Leiden — informs counselling about the magnitude of risk and the lifelong avoidance of oestrogen, but it rarely extends the anticoagulation beyond the standard 3 to 6 months for a single event. The mother should also be offered testing given her own history. [8]

(3) Contraceptive counselling and follow-up (3). The combined oral contraceptive pill must be stopped immediately and permanently, because oestrogen-containing contraception substantially raises the risk of recurrent thrombosis, and this risk is magnified in a carrier of a thrombophilia. Future contraception should be progestogen-only (the progestogen-only pill, the depot injection, or the levonorgestrel intrauterine system) or non-hormonal. Long-term follow-up is through the paediatric haematology service with coordination of the anticoagulation regimen, monitoring, and structured transition to adult care. She should carry a medic alert device and a written action plan, understand the warning signs of recurrence and bleeding, and be counselled about the implications for future pregnancy, where she will need an individualised thromboprophylaxis plan. The post-thrombotic syndrome is a longer-term consideration, and she should be advised to report persistent leg swelling or pain. [8] [2]