Abstract
Malignancy often results in clotting abnormalities. The aetiology of haemostasis problems in cancer is complex, and is still not completely understood. We describe a case of a patient with malignant mesothelioma, who was found to have elevated activated partial thromboplastin time, due to lupus anticoagulant. We suggest that patients with malignancy should have their coagulation checked prior to any invasive procedures.
Keywords
Case report
A 77-year-old male, retired company director, presented with a history of several months’ duration of increasing breathlessness, dry cough and hoarseness. There was associated loss of appetite, weight loss and dyspepsia.
His past medical history was remarkable for a myocardial infarction in 2008, abdominal aortic aneurysm (4 cm in diameter) and urothelial tumour (resected in 1999). His regular medications consisted of aspirin, simvastatin, levothyroxine, omeprazole, bisoprolol, didasteride and perindopril.
He smoked pipes for 50 years, finally quitting smoking in 2006. He was exposed to asbestos as a trainee working in power stations in the 1950s. He lived with his wife, and had previously good exercise tolerance.
On general examination, he was noted to be pale. There were no signs of jaundice, clubbing or oedema. The heart sounds were normal. Chest examination revealed a left-sided pleural effusion. Abdominal examination was unremarkable.
Blood tests revealed a raised platelet count of 611 × 109 per litre. A chest radiograph confirmed the presence of a large effusion at the left base. A computerized tomography scan of the thorax and abdomen, with contrast, revealed a left hydropneumothorax and enhancing pleural tissue in the left hemithorax (including the mediastinal pleura). Calcified pleural plaques suggesting previous asbestos exposure were also identified. There was no evidence of a pulmonary mass, mediastinal lymphadenopathy or abdominal metastases. A 4-cm infrarenal aortic aneurysm was detected incidentally.
On the basis of the history, examination and investigation results, the working diagnosis of mesothelioma was made. Aspirin was discontinued and a pleural tap was performed. Cytology from the pleural fluid confirmed the diagnosis.
About a month after diagnosis, he was urgently admitted to the District General Hospital with a cutaneous abscess on the left side of his back. This was incised, drained and packed with a primary wound dressing, based on sodium carboxymethyl cellulose. He was subsequently readmitted to the District General Hospital a few days later, with increasing breathlessness secondary to reaccumulation of pleural fluid, as well as four episodes of epistaxis. During this admission, it was noted that the abscess site was still bleeding continuously. At this point, a coagulation screen was taken. This revealed a prothrombin time (PT) of 16 seconds (normal range 9-12 seconds) and an elevated activated partial thromboplastin time (APTT) of 79 seconds (normal range 25-37 seconds). The coagulation screen was entirely normal in 2008. He was not on anticoagulant or antiplatelet medications.
The APTT was not corrected with administration of four units of fresh frozen plasma. In vitro coagulation tests revealed normal levels of factor II, V and X, and low levels of factors VII and VIII. The level of factor VII was 43 (normal range 67-153 IU/dL) and that of factor VIII was 10 (58-152 IU/dL). Lupus anticoagulant (LA) was found to be positive.
Discussion
There is evidence that thrombosis is a common complication of malignancy, and represents the second most frequent cause of death in cancer patients.1,2 Patients with malignancy are at higher risk of thromboembolic complications than healthy people for many reasons. First, there is a complex relationship between tumour and host cells, which troubles the balance between coagulation and fibrinolysis. 3 Tumour cells secrete proangiogenic factors which stimulate new blood vessel formation, but these factors, such as vascular endothelial growth factor, can also promote a thrombophilic state by causing the secretion of procoagulant substances from vascular endothelial cells. The same tumour cells can secrete procoagulant substances 4 and inhibit anticoagulant properties of endothelial cells; the tumour can induce stasis also by local vascular invasion. 5 Cancer takes advantage of a thrombophilic state because essential factors of haemostasis such as tissue factor, thrombin and urokinase plasminogen activators can promote its growth and progression. 6 Finally, general responses of the host to the tumour, 7 prolonged immobilization, use of central venous catheters and cyto-toxic therapy promote a thrombophilic state. 5
The APTT is the time for plasma to clot after the addition of an intrinsic pathway activator, e.g. silica or ellagic acid, phospholipid and calcium. It measures the integrity of the intrinsic and common pathways of the coagulation cascade. It is used in conjunction with the PT, which measures the extrinsic pathway. Prolongation of the APTT can be attributed to a number of causes. These include anticoagulant medications (heparin, hirudin analogues and argatroban); inherited coagulation factor deficiencies associated with significant haemorrhage (most commonly factors VIII, IX and XI); acquired coagulation factor deficiencies in patients with liver disease or consumption coagulopathy; deficiencies of coagulation factors involved in contact activation (factor XII, prekallikrein and high-molecular-weight kininogen) with no associated bleeding tendency; and autoantibodies which bind to phospholipids in plasma. When autoantibodies such as LA, anticardiolipin and factor VIII antibodies are present in plasma, the prolonged APTT fails to correct when normal plasma is added.
Disseminated venous thrombosis and antiphospholipid syndrome (APS) secondary to malignant mesothelioma, which is treatment-resistant autoimmune paraneoplastic syndrome, has been previously reported in the literature. 8 To the best of our knowledge, the association of malignant peritoneal mesothelioma, epistaxis and persistent bleeding from an abscess site with LA positivity, has not been reported previously. LA was positive; no other reason was detected to cause a raised APTT in this patient. No symptoms or signs leading us to suspect arterial or venous thrombosis were detected in this patient; therefore, the diagnosis of APS was never conclusively made.
Regarding the cause for the bleeding tendency, we postulated that the excessive bleeding was related to some other reason and that the raised APTT was not directly linked to his symptoms. Interestingly, the coagulation screen revealed low levels of factor VII – the reason for this is unknown, but it is possible that the low factor VII levels were related to excessive bleeding. Unfortunately it was not possible to investigate further, as the patient died a few weeks later.
There is a definite association between LA and malignancy. Antiphospholipid antibodies (APA) can be primary or associated with autoimmune disorders. Raised APA titres have been observed in some neoplastic disorders and APS has also been considered as a paraneoplastic rheumatic disorder.9–11 Estimates of APS in malignant disease vary. These include carcinomas of lung, kidney, colon, prostate gland, liver, ovary, trachea and thymoma.12,13 In 1988, Jude and colleagues found that among a series of patients with positive LA, 17 patients had a history of neoplasia including haematological malignancies, and a variety of solid tumours including carcinoma of the breast, uterus, ovary, tongue and lip. 14
In neoplastic patients, APA can be associated with a higher risk of thromboembolic events. APA healthy carriers can be at higher risk to develop a malignancy. In case of serious ischaemic APA-associated event, catastrophic APS or primary APS, especially in elderly patients, a malignancy should be excluded. 15
It should be standard practice to check coagulation prior to any procedures in patients with malignancy, particularly due to the increased likelihood of detecting coagulation abnormalities in this category of patients.
We declare that we have no financial interest.