VTE is a highly prevalent and potentially fatal disease, which can develop into the incidence of PE, causing higher mortality. It is estimated that the annual incidence of VTE in patients with cancer is 0.5% compared to 0.1% in the general population. Active cancers account for 20% of the overall incidence of VTE and cancer-associated thrombosis (CAT) has worse survival among VTE patients, which is the second most prevalent cause of death from cancer, second only to cancer itself.In addtion, some therapeutic agents which targets tumor angiogenesis have been reported to be associated with venous and arterial thrombosis or tumor thrombus formation. For example,VEGF Inhibitors like the bevacizumab has been proven that increase the risk of arterial thrombosis. while the risk of VTE is uncertain. EGFR inhibitors like cetuximab and panitumumab have been tied to a signifificant increase in VTE. Further research found that tumor cells can stimulate clotting and thrombosis in multiple approaches, which involves tissue factor (TF), platelets, tumor derived microparticles, CTCs, etc. In metastatic cancer, CTCs are particularly associated with tissue factor, platelets, and tumor derived microparticles in thrombosis. Tissue factor (TF) is a transmembrane glycoprotein and primary initiator of blood coagulation. Circulating TF is mainly present as microparticles that are highly procoagulant, which contribute to venous thrombosis in cancer patients. Phillips et al found that TF-positive CTCs and microparticles from primary tumors may serve as a trigger for cancer-associated thrombosis. And TF can result in enhanced migration and upregulation of VEGF. In addition, TFs are overexpressed on cancer stem cells and on CTCs. It has been demonstrated that EGFR driven EMT in human carcinoma cells results in increased TF expression on these cells with high metastatic phenotype, finally promoting the thrombosis. Platelets can protect tumor cells in circulation from immune response, contributing to metastasis. In addition, platelets can directly interact with tumor and enhance its growth, migration, and colonization through platelet-derived lysophosphatidic acid (LPA) and transforming growth factor β signaling pathway. Mego et al found that CTC-positive patients had a significantly higher level of plasma D-dimer than CTC-negative patients. Plasma D-dimer and CTCs may play a part in coagulation cascade activation in early metastasis.
In this case, preoperative tests indicated elevated platelet and D-dimer levels, which is accord with mechanisms mentioned above. Considering the mechanism of CAT, the pathological examination, and the monism principle, we speculate this patient suffered metastasis after bladder tumor resection. The positive lymph nodes are likely to result from lymphatic metastasis. As for the origin of malignant cells in the thrombus, one scenario was that extranodal extension involving adjacent vascular wall and malignant cells entered circulation. The other scenarios were that the patient had hematogenous metastasis of primary bladder tumor. CTCs expressing TF promoted thrombosis by activating platelets and releasing micro particles, which explains the existence of malignant cells in the embolus.
Given the elevated risk of thrombosis in cancer patients, anticoagulation therapy is essential in preoperative management and anticoagulant therapy remains standard care protocol in patients with acute venous thromboembolism.And clinical guidelines recommend low-molecular-weight heparin (LMWH) as preferred anticoagulant for treatment in the first 6 months in patients with proximal deep venous thrombosis(DVT) or PE and prevention of recurrent VTE in patients with advanced or metastatic cancer. If DVT exists before surgery, anticoagulation therapy might be ineffective or contraindicated or the proximal DVT, then IVCF insertion can be considered. IVCF has been proven effective in preventing DVT and PE, as well as improving prognosis[17, 18]. Nevertheless, filter penetration and fracture as well as the risk of DVT after IVCF insertion has raised concern[18, 19]. As a preventive strategy, IVCF insertion cannot remove the thrombus directly. In this case, the patient missed the time window of thrombolytic therapy. The large emboli containing malignant cells in external iliac vein may not be resolved by conventional anticoagulation. With IVCF inserted to inhibit thrombus dissemination and PE, we performed right external iliac vein thrombectomy after mass resection to relieve the patient’s symptoms in time. Postoperative pathology confirmed a cancer thrombus. External iliac vein incision and thrombectomy is relatively risky, but it can quickly and effectively alleviate symptoms and remove tumor thrombus, reducing the possibility of tumor hematogenous dissemination. In this case, the benefit of thrombectomy outweighed risks. It was reported that thrombectomy was effective to treat acute iliofemoral DVT and had advantages on reducing the length of hospital stay and major bleeding events.
Another characteristic of this case is the cooperation among gynecologists, radiologists, urologists, and pathologists, which highlights the role of MDT and makes it possible to obtain unique and innovative treatments for complex conditions. MDT is viewed as an additive where collaboration with other disciplines provides a new perspective to solving the problem and can create methodological innovations, knowledge, approaches, or paradigms .
In conclusion, Preoperative IVCF insertion and iliac vein thrombectomy combined with MDT in the treatment of this metastatic cancer patient with DVT is effective. Given involvement of CTCs in DVT, when treating DVT patients with malignant tumor history, we should alert to the possibility of tumor metastasis, and the thrombus should be handled appropriately in case of PE. In the future, we should further research the mechanism of thrombosis caused by CTCs, so that we can better prevent the formation of VTE.