PTE, one of the leading causes of sudden death, is common clinically since it lacks specific symptoms and is frequently accompanied by trauma and/or disease. Therefore, PTE not only poses challenges in clinical prevention and treatment but also puts forward higher requirements for forensic pathologists in identifying the causes of death. Here, we analyzed the characteristics of the population, risk factors, latency, source of thrombosis, distribution of thrombi in the pulmonary arteries, and lung-to-heart weight ratio for the forensic pathologist to determine the cause of death and analyze the relationship between risk factors and PTE, in addition to providing a critical window for the prevention of PTE.
PTE is a complex multifactorial disease for which many genetic and acquired risk factors have been identified[1, 2, 6, 8, 9]. Among the main risk factors, surgery and extended hospital admission are considered closely related. Various diseases, including cancer, inflammatory disorders, and infection, are deemed to be responsible for the formation of thrombi. In addition, the use of female hormones, pregnancy, and puerperium increase the risk of thrombogenesis[1, 2, 6]. Traditionally, blood stasis, hypercoagulable state, and vascular endothelial damage are considered the main reasons for thrombosis[3]. In the present study, trauma and fracture caused by traffic accidents or falls were the most frequent types of injuries that induced PTE, among which, fractures of the pelvis, femur, tibia, and fibula were most often observed (72.7%). Fractures in these areas undoubtedly lead to immobilization or being bedridden and possibly require surgical intervention. On one hand, coagulation factors are activated due to bleeding and extensive soft tissue damage, and inflammatory reactions lead to increased blood viscosity [ref]. On the other hand, prolonged immobilization causes blood stasis in the venous system of the lower limbs[6]. Moreover, high-risk factors, such as pregnancy and cesarean section (9.7%), use of antipsychotics (6.2%), and cancer (2.1%), were discovered in our study, in addition to other diseases and electrical injuries also showing a correlation with PTE (Table 2); however, these were not leading causes. Previous studies have provided evidence of a link between PTE, rheumatoid arthritis, and long-term air travel[10, 11]; however, these risk factors were not involved in our study. Taken together, a detailed understanding of the case by forensic pathologists and selection of potential high-risk factors will help to reduce the probability of missing PTE, in addition to analyzing the causal relationship between risk factors and death.
It is estimated that the incidence of PTE is approximately 100–200 cases per 100,000 individuals, and the risk does not differ according to gender; although, it appears to be higher in men than in women when venous thromboembolism related to pregnancy and estrogen therapy are not considered[2, 6]. In the present study, there were slightly more male than female cases (Table 1), which is in accordance with previous reports. However, due to gender-dependent factors such as pregnancy and cesarean section, the number of female cases was higher than that of male cases under the age of 40 (P<0.05) (Table 1), and PTE following cesarean section accounted for 58.3% of female victims in this age group. This age-dependent risk factor appears to be the detrimental factor for individuals in an age group with a relatively low risk of PTE (age <40) (Table 1). Many factors are involved in the pathogenesis of PTE, including an enlarged uterus and shift in global hemostatic valance to a hypercoagulable state during pregnancy, vascular endothelial injury, and postoperative bed rest during or after cesarean section[12, 13]. Moreover, all victims suffered PTE within a critical period of 15 days of cesarean section and, based on the autopsy findings, the thrombi mainly originated from the pelvic and femoral veins. Our results suggest that 15 days after cesarean section is an essential period for PTE. In addition to the lower limb veins, the pelvic vein is an important source of thrombi that requires detailed examination, and it is suggested that the pelvic vein should be inspected during forensic autopsy under the circumstances of cesarean section.
Previous studies have reported a potential link between mental illness, use of antipsychotic drugs, and PTE[10, 11, 14-16]. In the present study, victims with mental illness or antipsychotic drug use appear to form an independent group. As shown in Table 2, we found 9 victims: 7 females and 2 males aged 47.3±7.9 years. All patients had been diagnosed with mental disorders and used antipsychotic drugs, such as clozapine, olanzapine, and chlorpromazine, for a certain period. Dima et al. retrospectively analyzed 23 reported cases of clozapine-related PTE and found that 87% occurred within six months[14]. In our series, as shown in Figure 1, 4 patients had taken antipsychotic drugs for less than six months and the other five for 3 to more than 20 years; however, given the limitation of sample size in our study, the relationship between the length of time taking antipsychotic drugs and PTE may not be accurately reflected. Nevertheless, the relationship between the use of antipsychotic drugs and DVT has been continually revealed, with the possible reasons being attributed to the fact that: (1) the sedative effect of antipsychotic drugs reduces the amount of exercise in patients with mental illness, thereby increasing venous blood siltation[16]; and (2) clozapine and olanzapine can cause obesity, which is associated with both venous stasis and hypercoagulability by decreasing fibrinolytic activity, enhancing platelet activation, and increasing levels of coagulation factors and fibrinogen[10, 14, 17]. In fact, DVT has been reported to be a psychological disease in itself, and it has even been highlighted that the effect of antipsychotic treatment may not be the only factor leading to venous thromboembolism but psychosis itself may play a certain role, which is supported by evidence that higher levels of p-selectin and Factor VIII can be detected in mental patients[15]. It is noteworthy that restriction of patient posture during the onset of mental illness appeared in some of our cases, which is an essential factor leading to venous blood stasis and increasing the incidence of PTE. According to our autopsy findings, the pulmonary arteries and venous system (especially the iliac vein, femoral vein, and posterior tibial vein) should be paid close attention for the presence of thrombi in such cases.
Not all PTE are lethal due to the dual blood supply to the lung. The thrombi that cause fatal PTE are often widely distributed and obstruct at least two or more lobe arteries, which is in accordance with our findings that 87.6% of cases had thrombi distributed in bilateral pulmonary arteries. During autopsy, whitening of the leading edge of the lung, parenchymal ischemia and contraction, enlargement of the right heart auricle, and right heart congestion can be observed[18]. However, our results show no significant difference between the PTE and control groups with respect to the lung-to-heart weight ratio (Figure 2); although the weight of the heart in the PTE group was higher than that in the control group (data not shown), which is consistent with the post-mortem cardiac findings in PTE patients reported by Aysun Yakar et al.[19]. During forensic examination, in addition to checking the venous system of the lower extremities to elucidate the origin of thrombi, the veins adjacent to the injured site are also essential origins of thrombi and should not be overlooked.