Acute drug toxicity as a risk factor for lethal deep venous thrombosis

Introduction

Thrombosis of the deep veins of the legs is a relatively common occurrence in clinical practice that may predispose to pulmonary thromboembolism with its attendant risk of acute pulmonary outflow obstruction with lethal right ventricular decompensation. ¹

Thrombosis occurs when there is venous stasis (from extrinsic compression, venous obstruction, heart failure or shock), endothelial damage (from trauma, surgery, central lines and inflammation) or alterations in the composition of the blood (from hypercoagulable states due to thrombophilias, malignancy, inflammatory bowel disease and pregnancy). This is known as Virchow's triad after the great nineteenth century Prussian pathologist Rudolph Virchow. ² It is not uncommon, however, at autopsy to find no potential risk factors for thrombosis.

Deep venous thrombosis with pulmonary thromboembolism is more common in older adults but may also occur in infancy and childhood associated with similar risk factors.^3,4 Immobility is also a well-known predisposing factor for deep venous thrombosis and has been reported after knee surgery, strokes and lengthy air flights. The following case is reported to demonstrate yet another rare cause of lethal pulmonary thromboembolism arising from a deep venous thrombosis due to drug-induced immobility.

Case report

A 50-year-old male was found in his car that was parked off the highway in a rural area 2 days after being reported as a missing person. His medical history included type II diabetes mellitus and hypertension but not depression. He had been reported as missing by his estranged wife who also noted that amitriptyline and oxycodone had been taken from her house.

At the scene the decedent was sitting in the driver's seat slumped forward. A note was present, although there was no obvious means for committing suicide.

At autopsy the body weighed 89 kg with a length of 172 cm (body mass index, BMI – 30.1; obese). There were early putrefactive changes with venous marbling and greenish discolouration of the skin. Both calves had a circumference of 41.5 cm. Finely granular tablet residue was present in the stomach. Dissection of both calves revealed thrombi within the intramuscular veins and the proximal posterior tibial veins bilaterally. Within the chest cavity long coiled thromboemboli ranging from 5 to 7 mm in diameter were present in both pulmonary arteries and major branches. Histological examination of the deep vein thromboses and pulmonary thromboemboli confirmed the presence of typical laminated thrombi (Figures 1(a) and (b)). There were no other underlying organic diseases present that could have caused or contributed to death and there was no evidence of trauma.

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Figure 1.

(a) Microscopic section of one of the deep venous thrombi from the calf of the decedent showing characteristic lines of Zahn from laminated platelets, fibrin and erythrocytes. A portion of skeletal muscle is present in the bottom left hand corner (haematoxylin and eosin, H&E ×150). (b) Microscopy of one of many thromboemboli within pulmonary arterioles again showing characteristic lines of Zahn. Putrefaction had resulted in loss of histologic detail of the surrounding alveoli (H&E ×150).

Toxicological examination of blood showed no alcohol and a normal carboxyhaemoglobin level (2%). Potentially toxic levels of amitriptyline (0.92 mg/L), nortriptyline (0.41 mg/L) and oxycodone (0.17 mg/L) were found. No other common prescription or non-prescription medications were identified. Biochemical analysis of vitreous humour showed a glucose level of 0.6 mmol/L and a non-elevated level of β-hydroxybutyrate (1.23 mmol/L). Death was due to pulmonary thromboembolism arising from bilateral deep venous thromboses complicating mixed drug toxicity and obesity.

Discussion

Globally, pulmonary thromboembolism ranks third behind myocardial infarction and cerebrovascular accidents as a major cause of cardiovascular deaths^5,6 with approximately 10 million cases occurring worldwide annually. ⁷ In Australia the yearly incidence of pulmonary thromboembolism is estimated to be 17,000 cases, or 0.83 per 1000 population, with a lifetime risk of 8%.^8,9 Thus it represents a significant health burden.

As noted above there are a variety of both endogenous and exogenous factors that increase the risk of venous thomboembolism. In the reported case there was no evidence on clinical history review or at autopsy of trauma, recent surgery, malignancy or inflammatory bowel disease.^10,11 There was also no history of recent long distance flights^12,13 or autopsy findings of space-occupying pelvic lesions such as an enlarged prostate with urinary retention.^14,15

There is known a relationship between taking drugs and thromboembolism with intravenous drug users having an increased incidence of deep venous thrombosis (although not of pulmonary thromboembolism). ¹⁶ This has been attributed to reduced blood flow from tourniquets, endothelial damage from injections, and altered coagulation factors from infection introduced via injections. The current case however demonstrates a rare alternative mechanism with venous thrombosis occurring after prolonged immobility due to loss of consciousness from mixed drug toxicity administered orally. The taking of medications, the isolated position of the vehicle and the note were all supportive of suicidal intent. It is quite possible that the initial drug levels were higher than those measured at the time of autopsy given that metabolism and breakdown would have occurred during the period of prolonged loss of consciousness and the prolonged post mortem interval.

Protracted sitting was certainly reported in the literature decades ago as a cause of venous thrombosis by causing proximal venous compression. ¹⁷ An additional factor which may have contributed to thrombosis in the current cases was the presence of obesity (BMI 30.1). ¹⁸ Obesity has a direct relationship with thrombosis associated with metabolic dysregulation ¹⁹ resulting in alterations in inflammatory responses, the coagulation cascade and overall thrombotic potential.^20–22 In addition, less physical activity may be a further factor in causing thrombosis in obese individuals. ¹⁹ A weakness in the present report is the lack of information on possible underlying thrombophilias, as disorders of coagulation may certainly predispose to thrombosis, ²³ however, there was no history of previous thromboembolic events.

It is recognised that the diagnosis of pulmonary thromboembolism may be overlooked in clinical settings due to the non-specificity of presenting symptoms and signs and the presence of numerous comorbidities. ²⁴ This means that monitoring of the incidence relies heavily on autopsy examinations. With the decline in hospital autopsies and the reliance on external examinations with computed tomography (CT) and toxicology in suspected deaths due to drug toxicity the detection rate of rare entities such as the one reported (i.e. drug-induced deep venous thrombosis) will unfortunately decline. It is also possible that once pulmonary embolism has been identified in other cases at autopsy, that toxicology would not be considered. Given that prolonged immobility may be a possible mechanism for venous thrombosis in drug takers, toxicological evaluations should perhaps be considered more often in cases of ‘straightforward’ pulmonary thromboembolism without obvious risk factors.