Thrombophilia and VTE — Clinical Case

DCE Long Case

Patient profile

Mrs K is a 38-year-old marketing executive who presents to the emergency department with a three-day history of left calf pain and progressive swelling. [1]

Presenting concern: For three days she has noticed progressive left calf pain and swelling, initially after a long day at her desk, and worsening despite elevation. There is no history of trauma, recent surgery, prolonged travel, or immobilisation. She has no chest pain, shortness of breath, or haemoptysis. [1]

Past medical history:

• Metastatic breast cancer (invasive ductal carcinoma, ER/PR positive, HER2 negative) diagnosed 18 months ago. Initially treated with wide local excision, sentinel node biopsy, adjuvant radiotherapy and chemotherapy (docetaxel and cyclophosphamide). Now on palliative palbociclib 125 mg daily (3 weeks on, 1 week off) and letrozole 2.5 mg daily. Recent staging showed stable bone metastases and a new liver metastasis.
• Right proximal DVT 8 months ago, treated with apixaban 5 mg twice daily for 6 months then stopped by her oncologist 2 months ago.
• One fetal loss at 20 weeks gestation two years ago, attributed at the time to severe pre-eclampsia and placental insufficiency.
• No other medical history. No known thrombophilia. [1]

Medications: palbociclib 125 mg days 1 to 21 of 28-day cycle, letrozole 2.5 mg daily, paracetamol as needed for bone pain. No over-the-counter medications or supplements. [1]

Family history: Mother with breast cancer (diagnosed age 55, alive). Father with type 2 diabetes (alive, age 65). No known family history of VTE or thrombophilia. One sibling, well. One son, age 5, well. [1]

Social: Lives with her husband (an accountant) and 5-year-old son in their own home. Works full-time as a marketing executive. Non-smoker. Alcohol 2 to 3 standard drinks per week. No illicit drugs. [1]

Examination:

• Alert, comfortable at rest. Temperature 36.8. Pulse 88 regular. Blood pressure 128/76. Respiratory rate 16. SpO2 98 per cent room air.
• Left calf: swollen, 3 cm asymmetry measured 10 cm below the tibial tuberosity. Tender along the deep venous system. Mild warmth. Pitting oedema to mid-thigh.
• Right leg: no acute swelling. Mild ankle oedema. No hyperpigmentation or ulceration.
• Livedo reticularis noted on both thighs and forearms — a persistent mottled net-like discolouration.
• Chest clear. Heart sounds normal, no murmur. JVP not elevated.
• Abdomen: soft, non-tender. Liver edge palpable 2 cm below the costal margin (consistent with known liver metastasis).
• No focal neurological signs. [1]

Investigations:

• Haemoglobin 112 g/L; platelets 180; white cell count 6.2; INR 1.0; aPTT 48 seconds (prolonged).
• Mixing study: aPTT does not correct with normal plasma (48 seconds), but corrects to 32 seconds with excess phospholipid — consistent with a lupus anticoagulant.
• Compression ultrasound: extensive left proximal DVT from the popliteal to the common femoral vein.
• Anticardiolipin IgG 52 GPL (positive, above 40 GPL threshold). Anti-beta-2 glycoprotein I IgG positive (above 99th percentile).
• Lupus anticoagulant positive (confirmed on dRVVT).
• Renal function normal. Liver function tests mildly abnormal (ALP 180, GGT 95) consistent with known liver metastasis. [1]

Candidate's opening statement (SASPOP)

"This is Mrs K, a 38-year-old marketing executive presenting with a second unprovoked proximal DVT, in the context of metastatic breast cancer on palliative therapy and newly diagnosed triple-positive antiphospholipid syndrome. The APS is confirmed by lupus anticoagulant, high-titre anticardiolipin and positive anti-beta-2 glycoprotein I, with both clinical criteria — vascular thrombosis (two DVTs) and pregnancy morbidity (a fetal loss at 20 weeks with pre-eclampsia). Her main problems are the acute DVT requiring immediate therapeutic anticoagulation; the triple-positive APS, which means warfarin is preferred over a DOAC based on the TRAPS trial showing excess thrombosis with rivaroxaban in this subgroup; the metastatic breast cancer, which independently makes this a cancer-associated VTE requiring indefinite anticoagulation; the history of fetal loss at 20 weeks, which is part of the APS syndrome and has implications for any future pregnancy; and the psychosocial impact of recurrent thrombosis in a young woman with metastatic cancer. My priorities are to establish immediate therapeutic anticoagulation with LMWH, transition to warfarin for long-term therapy, engage the haematology and oncology multidisciplinary team, and plan a shared decision on duration and the approach to future pregnancy." [1]

Structured problem list (numbered, prioritised)

1. Acute left proximal DVT — extensive, from popliteal to common femoral; requires immediate therapeutic anticoagulation.
2. Triple-positive antiphospholipid syndrome (APS) — newly diagnosed; confirmed by lupus anticoagulant, high-titre anticardiolipin and positive anti-beta-2 glycoprotein I, with both clinical criteria (vascular thrombosis and pregnancy morbidity).
3. Metastatic breast cancer on palliative therapy — a second independent prothrombotic state; makes this a cancer-associated VTE requiring indefinite anticoagulation.
4. History of fetal loss at 20 weeks with pre-eclampsia — the obstetric APS component; has implications for future pregnancy planning.
5. Psychosocial impact — recurrent thrombosis in the setting of metastatic cancer in a young mother; needs honest communication and support. [1]

Integrated management plan

Step 1 — Immediate anticoagulation: [1]

I would commence therapeutic low molecular weight heparin (enoxaparin 1 mg/kg subcutaneously twice daily). The reasons for choosing LMWH rather than a DOAC are twofold. First, this patient has triple-positive APS, and the TRAPS trial demonstrated excess thrombotic events with rivaroxaban compared with warfarin in this subgroup [1]. By extrapolation, DOACs as a class are avoided in triple-positive APS until further evidence is available. Second, she has active cancer, and LMWH is well-established for cancer-associated VTE, especially in patients where a DOAC is contraindicated. LMWH is safe, effective, and does not require an INR — it is the ideal bridging agent while we establish the long-term warfarin.

Step 2 — Transition to warfarin for long-term therapy: [1]

After 5 to 10 days of LMWH, I would transition to warfarin with a target INR of 2.0 to 3.0, overlapping LMWH with warfarin for at least 5 days and until the INR is therapeutic for 2 consecutive days. Warfarin is the standard of care for APS-associated VTE [1]. I would avoid a loading dose because APS patients may have concurrent protein C or S deficiency, and rapid warfarin-induced depletion of these natural anticoagulants can precipitate skin necrosis.

Step 3 — Duration of anticoagulation: indefinite. [1]

This patient has three independent indications for indefinite anticoagulation: (1) APS-associated VTE (recurrence rate 20 to 30 per cent per year after stopping), (2) a documented recurrence after a previous 6-month course — she is now on her second DVT, and (3) active metastatic cancer (cancer-associated VTE requires indefinite anticoagulation while the cancer is active). If she has a further recurrence despite a therapeutic INR, the escalation is to increase the target INR to 3.0 to 4.0 and to consider adding low-dose aspirin. [1]

Step 4 — Cancer management coordination: [1]

I would coordinate with her oncologist. The palbociclib is a CYP3A4 inhibitor and can potentiate warfarin, requiring closer INR monitoring during co-administration. The cancer is metastatic and palliative — the goal is disease control and symptom management. I would review her cancer prognosis with the oncologist to ensure the anticoagulation plan is aligned with her overall goals of care. The liver metastasis is relevant — deteriorating liver function will affect warfarin metabolism and may necessitate a return to LMWH. [1]

Step 5 — Thrombophilia testing: [1]

She already has confirmed triple-positive APS. I would NOT repeat the APS panel now (she is on LMWH, which interferes with the lupus anticoagulant assay). I would arrange to repeat the APS panel at 12 weeks to confirm persistence, as required by the Sydney criteria [2]. For the inherited thrombophilias (Factor V Leiden, prothrombin G20210A, antithrombin, protein C, protein S), I would send the genetic tests (Factor V Leiden and prothrombin G20210A) now since they are unaffected by anticoagulation, and defer the functional assays (antithrombin, protein C, protein S) until she is off anticoagulation for 4 to 6 weeks — which is impractical given she needs indefinite therapy. In practice, the inherited thrombophilia screen is less important in this patient because the APS and cancer are sufficient to explain her thrombosis and to mandate lifelong anticoagulation.

Step 6 — Supportive care and safety netting: [1]

• I would assess for PE — her oxygen saturation is normal and she has no chest symptoms, but I would maintain a low threshold for CTPA if she develops dyspnoea or chest pain.
• I would not place an IVC filter — these are reserved for patients with absolute contraindications to anticoagulation or recurrent emboli despite adequate anticoagulation, and they do not prevent long-term recurrence.
• I would monitor her platelet count every 2 to 3 days for the first 2 weeks to screen for HIT (the 4T score), even though LMWH is less likely to cause HIT than unfractionated heparin. [1]

Step 7 — Communication, follow-up and safety: [1]

I would sit with Mrs K and her husband in a quiet room, with the haematologist and a clinical nurse specialist. I would explain the APS diagnosis in plain language and the shift from the DOAC she took for her first DVT to warfarin, citing the TRAPS trial. I would explain the lifelong nature of the anticoagulation, the practicalities of warfarin (regular INR, dietary consistency, drug interactions), and the approach to any future pregnancy (LMWH plus aspirin, switch from warfarin before conception). I would acknowledge the emotional burden of recurrent illness in the setting of metastatic cancer, offer social work and palliative care support, and document the shared decisions. [1]

Probing questions the examiner would ask

Q: On day 7 of her admission, her platelet count falls from 180 to 75 (a 58 per cent fall). The 4T score is 6. How do you respond? [1]

A: "This is a high-probability 4T score for heparin-induced thrombocytopenia (HIT). I would stop ALL heparin products immediately — LMWH and unfractionated heparin, and even heparin flushes and heparin-coated lines. I would switch to argatroban, a direct thrombin inhibitor given intravenously and cleared hepatically (preferred because she has cancer and potential renal impairment), and send a PF4 ELISA and a serotonin release assay to confirm. I would NOT transfuse platelets unless she is actively bleeding. The transition to warfarin would be delayed until the platelet count has recovered to at least 150, with slow overlap. The practical issue is that warfarin is still the long-term agent of choice for her APS, but the bridging would be from argatroban, not from heparin. I would also screen for new thrombosis — about 30 to 50 per cent of HIT patients develop a thrombosis, and I would perform a lower limb ultrasound." [1]

Q: How would your management differ if she did NOT have APS — pure cancer-associated VTE? [1]

A: "Without APS, this would be a straightforward cancer-associated VTE. The Caravaggio trial (Agnelli et al, NEJM 2020) showed that apixaban was non-inferior to dalteparin for cancer-associated VTE, with no significant increase in major bleeding [3]. Unlike the Hokusai-CANVAS (edoxaban) and SELECT-D (rivaroxaban) trials, which showed a GI bleeding signal, Caravaggio with apixaban did not. So for most cancer-associated VTE without APS, apixaban would be first-line — a simpler oral regimen with no INR monitoring, no dietary restrictions, and fewer drug interactions than warfarin. The APS is the specific reason this patient needs warfarin rather than a DOAC."

Q: She develops a headache, visual disturbance and right-sided weakness three months later. CT shows a haemorrhagic infarct and CT venography shows a superior sagittal sinus thrombosis. How do you manage this? [1]

A: "This is a cerebral venous sinus thrombosis (CVST) — a manifestation of her APS, complicated by haemorrhagic infarction. The key principle is that I would anticoagulate DESPITE the haemorrhagic infarct. The rationale is that the bleeding is from venous congestion — the sinus is blocked, the venous pressure rises, and the congested venules rupture. The treatment is to clear the clot, which is done with anticoagulation. Withholding anticoagulation because of the bleed is the classic and dangerous error. I would continue her warfarin (or switch to LMWH if she is acutely unwell and unable to take oral medications), manage her intracranial pressure if raised, give anticonvulsants for seizure prophylaxis, and involve neurology and neurosurgery. The ISCVT study showed a generally favourable prognosis with anticoagulation — mortality about 8 per cent and full recovery in about 80 per cent [5]."

Q: She asks whether her 5-year-old son should be tested for thrombophilia. How do you answer? [1]

A: "For APS specifically — no. APS is an acquired condition caused by antibodies, not inherited genes, so her son is not at risk of inheriting it. For the inherited thrombophilias — I would first determine whether she carries any of these (Factor V Leiden, prothrombin G20210A, antithrombin, protein C, protein S deficiency) by testing her when she is off anticoagulation. However, even if she is positive, routine testing of asymptomatic children is not recommended by the ASH or BSH guidelines — the absolute risk is too low, and the result does not change childhood management. Testing may be considered when the child is older, especially before high-risk situations (surgery, oestrogen use in a female relative, contact sports in antithrombin deficiency). For now, I would reassure her that APS is not inherited and that her son's risk of thrombosis is not elevated by her diagnosis." [1]

Q: How would you counsel her about warfarin and her cancer therapy? [1]

A: "The main interaction is between palbociclib (a CYP3A4 inhibitor) and warfarin. Palbociclib can potentiate warfarin by inhibiting its metabolism, leading to a higher INR and bleeding risk. I would monitor the INR more frequently — every 2 to 3 days initially and after any palbociclib dose change — and expect that the warfarin dose may need to be lower than usual. Letrozole does not significantly interact with warfarin. I would also counsel her on the signs of bleeding (bruising, gum bleeding, blood in urine or stool), the importance of consistent vitamin K intake, and the need to inform any doctor or dentist about her warfarin before procedures. I would give her a warfarin card and arrange anticoagulation clinic follow-up." [1]

Communication and shared decision-making

"I would sit with Mrs K and her husband in a quiet room, with the haematologist and a clinical nurse specialist. I would explain the APS diagnosis in plain language — an acquired condition in which the immune system makes antibodies that increase the tendency to clot, affecting both veins and the placenta. I would explain that the combination of APS and metastatic cancer means she needs lifelong anticoagulation, and that the specific antibody profile (triple-positive) means warfarin is the preferred agent over the newer blood thinners, based on a clinical trial called TRAPS. I would acknowledge the shift from the apixaban she took for her first DVT — and explain that the new APS diagnosis is the reason for the change. I would set out the practicalities of warfarin — regular blood tests, dietary consistency, drug interactions — and arrange anticoagulation clinic support. I would address the emotional burden of recurrent illness in the setting of metastatic cancer, and offer the social work and palliative care team. I would discuss the approach to any future pregnancy — a planned switch to LMWH plus aspirin before conception, with close obstetric and haematology collaboration. I would document the shared decisions and review them as her clinical picture evolves." [1]

DCE Short Case — Lower Limb and General Systems Examination in VTE and APS

Instruction

"Examine this patient's lower limbs and general systems." [1]

Systematic examination routine

1. End of bed — observe for swelling, asymmetry, erythema, discolouration, varicose veins, body habitus. Note any walking aids, compression stockings, or wounds.
2. Both legs fully exposed — compare side to side. Measure calf circumference 10 cm below the tibial tuberosity and thigh circumference 15 cm above the patella. Note asymmetry of 3 cm or more.
3. Inspection — look for erythema, dilated superficial veins, pitting oedema, discolouration (hyperpigmentation, haemosiderin, venous eczema), and ulceration (especially in the gaiter area above the medial malleolus).
4. Palpation — assess temperature (warmth in DVT or cellulitis), tenderness along the deep venous system (posterior calf, popliteal fossa, medial thigh), pitting oedema, and the peripheral pulses (femoral, popliteal, posterior tibial, dorsalis pedis — exclude arterial insufficiency).
5. Look for APS stigmata — livedo reticularis (mottled net-like discolouration on thighs and arms), skin necrosis scars, digital ischaemia, splinter haemorrhages.
6. Examine for PE signs — tachypnoea, tachycardia, raised JVP, right ventricular heave, loud pulmonary component of the second heart sound, pleural rub.
7. Abdomen — exclude a pelvic mass (compressing the iliac veins), check for hepatosplenomegaly (cancer, myeloproliferative neoplasm).
8. General — check for stigmata of SLE (if secondary APS suspected): malar rash, oral ulcers, alopecia, joint swelling. [1]

Key physical signs the patient demonstrates (for this case)

• Left calf swelling, 3 cm asymmetry, with tenderness along the deep venous system
• Pitting oedema to the mid-thigh on the left
• Mild warmth in the left calf
• Livedo reticularis on the thighs and forearms (cutaneous manifestation of APS)
• Mild pallor (anaemia of chronic disease from metastatic cancer)
• Palpable liver edge (known liver metastasis)
• No venous ulceration or post-thrombotic skin changes in the right leg [1]

Presentation template

"I examined Mrs K, a 38-year-old woman who appears comfortable at rest. The left leg is visibly swollen compared with the right, with a 3 cm calf asymmetry measured 10 cm below the tibial tuberosity. The left calf is tender along the deep venous system with pitting oedema to the mid-thigh and mild warmth. The peripheral pulses are intact and symmetrical. There is no venous ulceration or hyperpigmentation in either leg. I also note a mottled, net-like discolouration over both thighs and forearms consistent with livedo reticularis. The abdomen reveals a palpable liver edge 2 cm below the costal margin. These findings are consistent with an acute left proximal DVT and a cutaneous manifestation of a systemic prothrombotic condition — antiphospholipid syndrome — in a patient with known metastatic breast cancer. I would examine for signs of PE (tachypnoea, tachycardia, raised JVP, right ventricular heave), confirm the DVT with compression ultrasound, and send a coagulation screen including aPTT with mixing study and the full antiphospholipid antibody panel." [1]

Discussion questions

Q: What is the significance of the prolonged aPTT that does not correct on mixing? [1]

A: "A prolonged aPTT that does not correct on mixing study indicates the presence of an inhibitor — either a specific factor inhibitor (e.g. Factor VIII inhibitor in acquired haemophilia, which presents with bleeding) or a lupus anticoagulant (which presents with thrombosis). The next step is to test with excess phospholipid — if the aPTT corrects, it is a lupus anticoagulant (the antibody is phospholipid-dependent). In Mrs K, the lupus anticoagulant is confirmed by the correction with excess phospholipid, and the high-titre anticardiolipin and positive anti-beta-2 glycoprotein I complete the triple-positive APS picture. The paradox is that a test that looks anticoagulant in the laboratory (prolonged aPTT) is actually prothrombotic in the body — this is a favourite exam question." [1]

Q: What is the mechanism of Factor V Leiden? [1]

A: "Factor V Leiden is a point mutation (G1691A) in the Factor V gene that substitutes glutamine for arginine at position 506. This residue is one of the sites where activated protein C normally cleaves and inactivates Factor Va. The mutation makes Factor V resistant to activated protein C — hence the original name 'APC resistance' — so the procoagulant Factor Va persists longer in the coagulation cascade, generating more thrombin and increasing the thrombotic tendency [5]. Factor V Leiden is the most common inherited thrombophilia in Caucasian populations, with a prevalence of about 5 per cent. Heterozygotes have a 3- to 8-fold increased relative risk of VTE, but the absolute annual risk is low (about 1 per cent). Most heterozygous carriers never thrombose. The original discovery was by Bertina and colleagues in Nature in 1994."

Q: How would your management change if this was her first VTE, provoked by a long-haul flight? [1]

A: "If this was a first VTE provoked by a major transient risk factor (long-haul travel over 4 hours), and she had no APS and no active cancer, the duration of anticoagulation would be 3 months, not indefinite. The agent would be a DOAC (apixaban or rivaroxaban) first-line, not warfarin. The recurrence risk after stopping would be low (under 5 per cent per year). Thrombophilia testing would not be indicated because the result would not change management — she gets 3 months regardless. The clinical context (provoked vs unprovoked, with or without APS, with or without cancer) is the key determinant of both the agent and the duration." [1]

Q: What is the role of compression stockings in this patient? [1]

A: "Graduated compression stockings serve two roles. First, for symptom relief in the acute DVT — they reduce pain and swelling, which is their main practical value. Second, for the prevention of post-thrombotic syndrome (PTS) — the SOX trial challenged the traditional recommendation that stockings prevent PTS after a proximal DVT, showing no significant reduction in PTS with active versus placebo stockings. Current practice is to offer stockings for symptom control rather than routine PTS prevention. In Mrs K, I would offer knee-high graduated compression stockings (30 to 40 mmHg at the ankle) for the left leg symptomatically, but I would not present them as a guaranteed prevention of PTS. The focus should be on weight management, regular exercise, and limb elevation." [1]

Q: How do you decide between DOACs and warfarin in a patient with VTE? [1]

A: "The decision rests on three questions. First, does the patient have triple-positive APS? If yes, warfarin (TRAPS trial). Second, is the patient pregnant or planning pregnancy? If yes, LMWH during pregnancy, warfarin postpartum. Third, does the patient have a mechanical heart valve? If yes, warfarin (RE-ALIGN showed harm with dabigatran). If none of these apply, a DOAC is first-line for most VTE — simpler, safer (lower intracranial haemorrhage), and equally effective. Within the DOAC class, apixaban and rivaroxaban can be started immediately (single-drug approach), while dabigatran and edoxaban require a 5 to 10 day lead-in of heparin. For cancer-associated VTE, apixaban or edoxaban is first-line for most, with LMWH preferred in GI or GU cancers at high bleeding risk and in thrombocytopenia. The EINSTEIN-CHOICE trial supports low-dose rivaroxaban (10 mg daily) as the preferred extended-therapy option after the initial 6 to 12 months [1]."