Microangiopathic haemolytic anaemia: a rare first presentation of lung cancer

Clinical record

A 76‐year‐old woman with no significant medical history presented to hospital after 3days of vomiting. There were no concerning features to her vomiting, no diarrhoea, no abdominal pain or distension, no fevers, and no recent weight loss. She was an ex‐smoker, took no regular medications, and was the full‐time carer for her husband. Her physical examination was unremarkable.

Initial blood tests showed a creatinine concentration of 693μmol/L (reference interval [RI], 63–97μmol/L), a platelet count of 46×10⁹/L (RI, 150–400×10⁹/L) and a haemoglobin level of 104g/L (RI, 115–165g/L). An urgent diagnostic workup was commenced to determine the cause of her renal failure, thrombocytopenia and anaemia (Box 1).

A coagulopathy screen showed a fibrinogen level of 4.5g/L (RI, 2–4g/L), a D‐dimer level>20mg/L (RI, <0.5mg/L), and a normal international normalised ratio. This ruled out a coagulopathic cause but was suspicious for venous thromboembolism. Her haemolytic screen was consistent with haemolysis, showing a lactate dehydrogenase level of 2407U/L (RI, 129–250U/L), a haptoglobin level<0.1g/L (range, 0.5–2.2), a reticulocyte count of 71×10⁹/L (RI, 10–100×10⁹/L), and a peripheral blood film with schistocytes and spherocytes (Box 2). Her direct antiglobulin test result was negative, ruling out immune haemolysis and confirming microangiopathic haemolytic anaemia (MAHA).

Key differentials included thrombotic thrombocytopenic purpura (TTP), haemolytic uraemic syndrome (HUS) and complement‐mediated (atypical) HUS. She was admitted to the intensive care unit and treated provisionally for TTP with plasmapheresis, steroids and haemodialysis. Her ADAMTS‐13 level was 59% (RI, 60–130%), ruling out TTP. Her stool sample was negative for Shiga toxin and she had normal complement C3/C4 levels.

A computed tomography pulmonary angiogram was ordered to investigate her raised D‐dimer level and the possibility of underlying malignancy. It showed multiple pulmonary emboli, which were treated with a heparin infusion owing to her renal failure, and a right upper lobe mass suspicious for malignancy (Box 3, A). A follow‐up positron emission tomography scan confirmed fluorodeoxyglucose‐avid lesions in the right lung, bilateral iliac bones, and rectum (Box 3, B). Tissue biopsy samples of her lung and iliac lesions were taken. The microscopic appearance, molecular testing and immunohistochemistry results in both samples were consistent with a diagnosis of primary lung adenocarcinoma (Box 4). A colonoscopy showed rectal polyps with benign appearance (biopsy was not performed because of her bleeding risk).

Acutely, she responded well to plasmapheresis and haemodialysis. Once stabilised, she began rapid treatment with combination chemotherapy and immunotherapy of carboplatin, pemetrexed and pembrolizumab, to which she responded extremely well. She recently completed palliative radiotherapy and at the time of writing was functioning fully independently at home while receiving maintenance palliative chemotherapy.

Discussion

Thrombotic microangiopathies (TMAs) are a group of conditions that cause endothelial damage and microthrombi deposition in arterioles and capillaries. This causes physical shearing of red blood cells and increases platelet activation, resulting in a MAHA characterised by schistocytes on peripheral blood film, consumptive thrombocytopenia, and end‐organ damage such as renal failure or neurological dysfunction.1,2 The underlying cause of the TMA needs to be urgently differentiated to guide treatment, with primary causes first being considered:

1. ▪ TTP: a deficiency in ADAMTS‐13 leads to abnormal von Willebrand factor clearance, ultimately leading to aggregation of platelet von Willebrand factor complexes in microvasculature.2
2. ▪ HUS: infection with Shiga toxin‐producing bacteria causes endothelial damage and platelet aggregation in microvasculature.2
3. ▪ Complement‐mediated TMA: uncontrolled complement activation in microvasculature causes platelet aggregation and endothelial damage.2

However, as this case demonstrates, TMAs can also be secondary to systemic conditions such as malignant hypertension, infection or malignancy, and these must also be excluded.3,4 Malignancy‐associated TMA is well described in the literature, almost always in patients with a known active or past malignancy.3,4 It is extremely rare for a patient with no history of malignancy to present with a malignancy‐associated TMA, with only a handful of documented cases of lung adenocarcinoma presenting in this way.5,6

All TMAs require supportive care, often including haemodialysis. In addition, TTP requires emergency plasmapheresis and immunosuppression to correct abnormal von Willebrand factor and ADAMTS‐13 profiles, while complement‐mediated TMA also requires specific anti‐complement agents.2 While it is reasonable to start plasmapheresis on suspicion of TTP (particularly with severe end‐organ injury present), investigation for an underlying malignancy should be a priority. Malignancy‐associated TMA has a poor prognosis, but rapid identification does provide the opportunity for specific antineoplastic treatment which may reverse advanced neoplastic disease if started quickly.3,6

TMAs are life‐threatening and have a dismal prognosis if emergency therapy is not instituted rapidly. Alongside emergency supportive management, determining the underlying cause is critically important to guide correct treatment. While malignancy presenting as MAHA is rare, it should be part of the initial diagnostic workup to enable potentially life‐saving chemotherapy to commence as quickly as possible.