Adverse Drug Reactions — DCE Clinical Case

DCE Long Case — Heparin-Induced Thrombocytopenia in a Complex Elderly Man

The patient

A 78-year-old man with atrial fibrillation (on apixaban), heart failure with reduced ejection fraction, type 2 diabetes, chronic kidney disease (eGFR 35) and osteoarthritis was admitted eight days ago with a proximal left leg deep vein thrombosis and a submassive pulmonary embolism. His apixaban was withheld on admission and he was started on therapeutic subcutaneous enoxaparin. Today, day 8, his platelet count has fallen from 260 to 120 times ten to the ninth per litre (a fall of 54 per cent). He has new swelling and pain in the right leg. A Doppler ultrasound confirms a new right iliofemoral deep vein thrombosis. He is afebrile, his other bloods are stable, and he has no bleeding. His medications are enoxaparin, metoprolol, frusemide, spironolactone, empagliflozin (held on admission), pantoprazole, and paracetamol. [1]

Candidate's opening statement (SASPOP format)

"A 78-year-old man with an acute, evolving and dangerous haematological complication of anticoagulation (symptoms and presentation), aged 78 (age), male (sex), presenting on day 8 of an admission for pulmonary embolism (presentation), who is a retired teacher (occupation), with the following problems: (1) heparin-induced thrombocytopenia — HIT — a severe Type B adverse drug reaction to enoxaparin, complicated by a new contralateral iliofemoral deep vein thrombosis; (2) the original submassive pulmonary embolism and left proximal DVT; (3) atrial fibrillation with an indication for long-term anticoagulation; (4) heart failure with reduced ejection fraction; (5) chronic kidney disease stage 3b with an eGFR of 35; (6) type 2 diabetes; and (7) osteoarthritis. The immediate threat is the prothrombotic state of HIT, which can produce limb-threatening or life-threatening thrombosis. My immediate plan is to stop all heparin, start an alternative non-heparin anticoagulant at a therapeutic dose, send a PF4 antibody, and arrange ongoing anticoagulation strategy with haematology." [1]

Structured problem list

1. Heparin-induced thrombocytopenia (Type B ADR) — confirmed by the 50 per cent platelet fall, the 5 to 14 day timing, the new thrombosis, and the high pre-test probability on the 4T score.
2. New right iliofemoral DVT — a thrombotic complication of HIT.
3. Submassive pulmonary embolism and left proximal DVT (the original presentation).
4. Atrial fibrillation with a long-term oral anticoagulation indication.
5. Heart failure with reduced ejection fraction on guideline therapy.
6. Chronic kidney disease stage 3b (eGFR 35), which influences the choice of alternative anticoagulant.
7. Type 2 diabetes and osteoarthritis. [1]

Integrated management plan

Problem 1 and 2 — HIT and the new DVT: [1]

I calculate the 4T score: Thrombocytopenia (fall of 54 per cent, nadir above 100 — score 1), Timing (day 8 of first heparin exposure, consistent with 5 to 14 days — score 2), Thrombosis (new iliofemoral DVT — score 1), and oTher cause (none — score 1). The total is 5, a high pre-test probability. This effectively confirms HIT clinically, though I will send a PF4 enzyme immunoassay and consider a serotonin release assay for confirmation. [1]

The immediate management is:

• Stop all heparin immediately — including the enoxaparin, any heparin flushes, and heparin-coated lines. I do not switch to unfractionated heparin because the antibody cross-reacts with all heparins.
• Start an alternative non-heparin anticoagulant at a therapeutic dose. Given his chronic kidney disease (eGFR 35), I would use argatroban (hepatically cleared, preferred in renal impairment) or fondaparinux (partially renal, dose-adjusted) or a direct oral anticoagulant such as rivaroxaban or apixaban (which are increasingly used and supported by recent guidance). Apixaban is reasonable here because he was already on it for atrial fibrillation and it covers both the HIT and the long-term indication.
• I do not give a platelet transfusion unless there is life-threatening bleeding, because platelets can fuel thrombosis in HIT.
• I monitor the platelet count daily and expect recovery over 5 to 7 days.
• Warfarin transition is delayed until the platelet count has recovered to at least 150, and is overlapped with the alternative anticoagulant because warfarin alone can cause skin necrosis in acute HIT from early protein C depletion. In this patient I would favour continuing apixaban rather than transitioning to warfarin. [1]

Problem 3 — the original PE and DVT: managed by the alternative anticoagulant above; the duration will be extended (lifelong) because of the HIT and the atrial fibrillation indication. [1]

Problem 4 — atrial fibrillation: the long-term anticoagulation will be apixaban (resuming his pre-admission therapy), which covers both the AF and the venous thromboembolism. [1]

Problem 5 — heart failure: continue the guideline therapy (metoprolol, frusemide, spironolactone), resume empagliflozin once the acute phase has settled, and avoid fluid overload during the alternative anticoagulation. [1]

Problem 6 — chronic kidney disease: the dose of fondaparinux, argatroban or DOAC must be adjusted to the eGFR; argatroban is preferred if the renal function deteriorates further. [1]

Problem 7 — diabetes and osteoarthritis: routine; resume the empagliflozin when stable. [1]

Probing questions the examiner would ask

Examiner: Why is HIT thrombotic rather than haemorrhagic? [1]

"HIT is caused by IgG antibodies against the complex of platelet factor 4 and heparin. The antibody binds to platelets and activates them, producing both thrombocytopenia (from platelet clearance) and a striking prothrombotic state, because the activated platelets generate thrombin. The patient is therefore at risk of venous and arterial thrombosis — including limb gangrene, stroke, myocardial infarction and pulmonary embolism — rather than of bleeding. This is why we give a therapeutic dose of an alternative anticoagulant even before the platelet count has recovered, and why we do not give prophylactic platelets." [1]

Examiner: What is the difference between typical-onset and rapid-onset HIT? [1]

"Typical-onset HIT occurs 5 to 14 days after first heparin exposure — the antibody is being formed de novo. Rapid-onset HIT occurs within 24 hours of heparin re-exposure in a patient who has circulating antibody from a heparin exposure within the previous 30 to 100 days. A delayed-onset form also exists, in which the thrombocytopenia and thrombosis continue or worsen after the heparin has been stopped, driven by the antibody alone." [1]

Examiner: How would you classify HIT in the ABCDEF system, and why does that matter? [1]

"HIT is a Type B — bizarre — adverse drug reaction: it is idiosyncratic, dose-independent, rare, and not predictable from heparin's known pharmacology (which is anticoagulation, not thrombosis). The management implication is that heparin must be stopped permanently and never re-challenged, and the patient must carry an alert. The irony — a drug used to prevent thrombosis causing thrombosis — is the hallmark of a Type B reaction." [1]

Examiner: How would you communicate this to the patient and family? [1]

"I would explain in plain language that the blood-thinning injection he has been receiving has, paradoxically, caused a reaction that made his blood more likely to clot, that his platelet count has fallen, that he has developed a new clot in the opposite leg as a result, and that I have stopped that injection and started a different blood thinner. I would tell him he must never receive heparin again, that this has been recorded in his chart, and that he should carry an alert card or medical identification. I would report the reaction to the Therapeutic Goods Administration via the Blue Card and tell him I have done so. I would set out the plan for the next days — daily blood counts, monitoring of the leg, and the transition to long-term apixaban — and I would invite questions." [1]

Communication and shared decision-making

The shared decision here is about the long-term anticoagulation strategy: apixaban (resuming his pre-admission therapy, covering both the AF and the VTE, with no INR monitoring and a lower bleeding risk than warfarin) versus warfarin (the traditional choice post-HIT, with INR monitoring and the need for a prolonged overlap with a parenteral alternative). For most patients, including this one, apixaban is the preferred and more convenient option; I would discuss the bleeding risk, the irreversibility (no specific antidote at the time of the consultation, though andexanet is increasingly available), and the importance of adherence. I would also discuss the lifelong heparin avoidance and its implications for future surgery, dialysis, or line placement. [1]

DCE Short Case — Skin Examination of a Patient with a Severe Cutaneous Adverse Drug Reaction

Examination instruction

"Examine this patient's skin. The patient was started on a new medication six weeks ago and has developed a rash. The instruction is: examine the skin and report your findings to the examiner." [1]

Systematic examination routine

1. Introduce, consent, position and expose. Position the patient at 45 degrees with good lighting and full exposure of the skin, including the back. Ask about pain before touching.
2. General inspection. Note the patient's overall appearance — is the patient unwell, distressed, febrile? Is there obvious facial swelling or oedema?
3. Skin — distribution and morphology. Examine from head to toe. Describe the distribution (generalised, acral, flexural, sun-exposed), the morphology (macular, papular, morbilliform, vesicular, bullous, target, purpuric), and the colour. Look for desquamation or scaling.
4. Mucous membranes. Inspect the lips, oral mucosa, conjunctivae, and the urogenital area for erosion, blistering or injection.
5. Palpation. Palpate the lesions for induration and tenderness. Palpate for lymphadenopathy in the cervical, axillary and inguinal regions.
6. Nikolsky sign. Apply gentle lateral pressure to apparently normal-appearing skin adjacent to an erosion or blister. A positive sign is sloughing of the epidermis.
7. Body surface area estimation. Use the rule of nines (or the patient's palm, which is approximately 1 per cent of body surface area) to estimate the percentage of epidermal detachment.
8. Systemic examination. Auscultate the chest (for pneumonitis), examine the abdomen (for hepatomegaly), and check the vital signs (for fever, tachycardia, hypotension).
9. Complete the examination. Offer to examine the eyes with fluorescein for corneal erosion, and to review the drug chart and the blood tests (eosinophils, liver function, renal function). [1]

Key physical signs the patient demonstrates

"The patient has a confluent, morbilliform rash over the trunk and face with marked facial oedema, generalised lymphadenopathy, and no blistering, no mucosal involvement, and a negative Nikolsky sign. There is no epidermal detachment. The patient is febrile at 38.8 degrees. There is no jaundice, no pallor, and no cyanosis. The chest is clear. These findings, in the context of a new drug six weeks ago, are those of Drug Reaction with Eosinophilia and Systemic Symptoms — DRESS." [1]

Presentation to the examiner

"Sir, this patient has a confluent morbilliform rash over the trunk and face with marked facial oedema, generalised lymphadenopathy, fever, and no blistering, no mucosal involvement and a negative Nikolsky sign. There is no epidermal detachment. My findings are those of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), a severe Type B adverse drug reaction. I would like to confirm the diagnosis with the eosinophil count and the liver function tests, to identify the culprit drug from the medication chart — most likely one of the aromatic anticonvulsants, allopurinol, minocycline, a sulfonamide or dapsone — and to manage the patient by stopping the drug and starting systemic corticosteroids for the visceral involvement." [1]

Discussion

Examiner: How would you distinguish DRESS from SJS/TEN? [1]

"DRESS presents with a morbilliform rash, facial oedema, eosinophilia, lymphadenopathy and visceral organ involvement, with a latency of 2 to 8 weeks, no blistering, and a negative Nikolsky sign. SJS and TEN present with painful blistering, target lesions, flaccid bullae, sheet-like epidermal detachment with a positive Nikolsky sign, and mucosal involvement of at least two sites, with a latency of 1 to 8 weeks. The two share some triggers — allopurinol and the aromatic anticonvulsants can cause either — but the clinical signatures are distinct, and the management differs: DRESS is managed with corticosteroids, while SJS/TEN is managed in a burns unit with supportive care and, controversially, IVIG." [1]

Examiner: Calculate a SCORTEN for a patient with SJS/TEN. [1]

"The seven components, each scoring one point, are: age above 40 years, malignancy, heart rate above 120 beats per minute, initial detached body surface area above 10 per cent, serum urea above 10 mmol per litre, serum glucose above 14 mmol per litre, and serum bicarbonate below 20 mmol per litre. A score of 0 to 1 predicts a mortality of about 3 per cent; 2 about 12 per cent; 3 about 35 per cent; 4 about 58 per cent; and 5 or more above 90 per cent. The score guides the level of care — a high score mandates transfer to an ICU or specialist burns unit." [1]

Examiner: What is Hy's Law, and when does it apply? [1]

"Hy's Law is present when ALT or AST is more than three times the upper limit of normal, serum bilirubin is more than two times the upper limit of normal, there is no significant cholestasis (ALP less than two times the upper limit of normal), and there is no alternative cause. It predicts a case fatality of around 10 per cent from acute liver failure, and it is a stopping rule in drug development and post-marketing surveillance. Any drug that produces a Hy's Law case must be presumed capable of fatal hepatotoxicity until proven otherwise." [1]

Examiner: Give me the ABCDEF classification with an example each. [1]

"Augmented — Type A — beta-blocker bradycardia. Bizarre — Type B — DRESS, SJS/TEN, anaphylaxis, HIT, agranulocytosis. Chronic — Type C — bisphosphonate osteonecrosis of the jaw, methotrexate hepatic fibrosis. Delayed — Type D — thalidomide teratogenesis, diethylstilboestrol and clear-cell vaginal carcinoma. End-of-use — Type E — adrenal suppression after long-term steroids, opiate withdrawal. Failure — Type F — oral contraceptive failure with rifampicin." [1]

Examiner: How would you report a severe ADR? [1]

"I would report every severe or previously unrecognised adverse drug reaction to the Therapeutic Goods Administration via the Blue Card in Australia, or to the MHRA Yellow Card scheme in the United Kingdom. I would report all suspected reactions to new (black triangle) drugs and all serious reactions regardless of how long the drug has been marketed. A reaction is serious if it is fatal, life-threatening, requires or prolongs hospitalisation, causes persistent or significant disability, or is a congenital anomaly. Reporting is voluntary — a suspicion is enough; causality is assessed centrally using the Naranjo scale." [1]