Background: Cancer-associated venous thromboembolism (VTE) is a critical complication in patients with cancer. However, the pathological findings of VTE are limited. Here, we investigated the histopathological features of cancer-associated VTE in human autopsy cases. Methods: We clinically examined the autopsy cases of VTE with (n=114) and without cancer (n=66) and immunohistochemically analyzed the expression of prothrombotic factors in intrathrombus cancer cells, the thrombus contents of erythrocytes, fibrin, platelets, citrullinated histone H3, and degree of organization. Results: Vascular wall invasion or small cell clusters of cancer cells was observed in thrombi in 27.5% of deep vein thrombosis and 25.9% of pulmonary embolism cases. The majority of the cancer cells in deep vein thrombi appeared to be invading the vessel wall, whereas the majority of pulmonary thrombi had cancer cell clusters, consistent with embolization via blood flow. These cancer cells were immunohistochemically positive for TF (tissue factors) or podoplanin in up to 88% of VTE cases. The frequency of TF-positive monocyte/macrophages in thrombi was higher in cancer-associated VTE than that in VTE without cancer. Citrullinated histone H3 was predominantly observed in the early stages of organizing thrombi. There was no significant difference in thrombus components between VTE with cancer and without cancer groups. Conclusions: Vascular wall invasion or cancer cell clusters in thrombi might influence thrombogenesis of cancer-associated VTE. TF and podoplanin in cancer cells and in monocyte/macrophages may induce coagulation reactions and platelet aggregation. Neutrophil extracellular traps may play a role in the early stages of VTE, regardless of cancer status.

Patients with peripheral artery disease (PAD) have a high prevalence of cardiovascular morbidity and mortality; however, majority of patients with PAD are asymptomatic. This study aimed to histologically evaluate whether asymptomatic, lower extremity artery plaques are associated with systemic atherosclerosis and the onset of cardiovascular disease (CVD) events using autopsy cases. We histologically investigated the atherosclerotic plaques of the common iliac, common carotid, coronary, and renal arteries from 121 autopsy cases without symptoms of PAD (mean age:67.6 years; 63% men; 83% non-CVD death). We evaluated the relationship between the degree of iliac artery atherosclerosis and that of other arteries, and also the presence of any CVD, myocardial infarction, stroke, and renal failure. Advanced atherosclerotic plaques (American Heart Association ≥4) were present in 86 (72%) common iliac arteries in these cases. These arteries also showed high frequencies of calcification (66%), intraplaque hemorrhage (42%), and plaque disruption (24%). These advanced lesions were associated with age (≥60 years), sex (male), hypertension, diabetes, and smoking habit (all P＜0.05). Additionally, it was significantly associated with CVD (odds ratio, 95% confidence interval; 6.2, 2.2-22), myocardial infarction (6.4, 1.2-19), stroke (8.7, 1.7-16), and renal failure/hemodialysis (5.8, 1.1-11). Cases with advanced iliac artery plaques had advanced coronary and carotid atherosclerosis. These results indicate that asymptomatic advanced plaques are frequently observed in common iliac arteries, and are associated with generalized atherosclerosis and CVD events.

Thrombolytic therapy is effective in selected patients with deep vein thrombosis (DVT). Therefore, identification of a marker that reflects the age of thrombus is of particular concern. This pilot study aimed to identify a marker that reflects the time after onset in human aspirated DVT. We histologically and immunohistochemically analyzed 16 aspirated thrombi. The times from onset to aspiration ranged from 5 to 60 days (median of 13 days). Paraffin sections were stained with hematoxylin and eosin and antibodies for fibrin, glycophorin A, integrin α2bβ3, macrophage markers (CD68, CD163, and CD206), CD34, and smooth muscle actin (SMA). All thrombi were immunopositive for glycophorin A, fibrin, integrin α2bβ3, CD68, CD163, and CD206, and contained granulocytes. Almost all of the thrombi had small foci of CD34- or SMA-immunopositive areas. CD68- and CD163-immunopositive cell numbers were positively correlated with the time after onset, while the glycophorin A-immunopositive area was negatively correlated with the time after onset. In double immunohistochemistry, CD163-positive cells existed predominantly among the CD68-immunopositive macrophage population. CD163-positive macrophages were closely localized with glycophorin A, CD34, or SMA-positive cell-rich areas. These findings indicate that CD163 macrophage and erythrocyte contents could be markers for evaluation of the age of thrombus in DVT. Additionally, CD163 macrophages might play a role in organization of the process of venous thrombus.