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Potential Mechanisms of Cancer-Related Hypercoagulability
The association between cancer and thrombosis has been known for over a century and a half. However, the mechanisms that underlie this correlation are not fully characterized. Hypercoagulability in cancer patients can be classified into two main categories: Type I and Type II. Type I occurs when the balance of endogenous heparin production and degradation is disturbed, with increased degradation of endogenous heparin by tumor-secreted heparanase. Type II hypercoagulability includes all the other etiologies, with factors related to the patient, the tumor, and/or the treatment. Patients with poor performance status are at higher risk of venous thromboembolism (VTE). Tumors can result in VTE through direct pressure on blood vessels, resulting in stasis. Several medications for cancer are correlated with a high risk of thrombosis. These include hormonal therapy (e.g., tamoxifen), chemotherapy (e.g., cisplatin, thalidomide and asparaginase), molecular targeted therapy (e.g., lenvatinib, osimertinib), and anti-angiogenesis monoclonal antibodies (e.g., bevacizumab and ramucirumab).
3. Anti-Neoplastic Medications Associated with Increased Risk of Thrombosis
Cisplatin. Cisplatin is associated with an increased risk of VTE and arterial thrombosis. A retrospective analysis from the Memorial Sloan Kettering Cancer Center found that 18.1% of cancer patients developed thrombosis during cisplatin treatment. Most of these cases (88%) occurred during the first 100 days from the initiation of cisplatin . A meta-analysis of randomized controlled trials evaluating the incidence and risk of VTE associated with cisplatin-based chemotherapy showed a significantly increased risk of VTE with a relative risk of 1.67 . VTE rates were 1.92% versus 0.79% in patients treated with cisplatin-based and non-cisplatin-based chemotherapy regimens, respectively . A report from the UK National Cancer Research Institute of a randomized trial of patients with advanced gastroesophageal cancer randomized to epirubicin/(fluorouracil or capecitabine) and cisplatin or oxaliplatin found fewer thrombotic events in the oxaliplatin compared with the cisplatin groups, 7.6% vs. 15.1%, respectively; p = 0.0003 .
Thalidomide. Thalidomide inhibits the production of interleukin (IL)-6, while suppressing proliferation and activating apoptosis of myeloma cells . A study that treated patients with multiple myeloma using thalidomide and dexamethasone in preparation for autologous stem cell transplantation found VTE in 13% and 26% of patients treated with or without low-dose prophylactic warfarin, respectively . A phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma showed that VTE occurred in 19.6% and 2.9% of patients treated with and without thalidomide, respectively .
Asparaginase. Asparaginase is an enzyme that degrades L-asparagine, resulting in inhibition of protein synthesis in tumor cells . A retrospective study reported thrombotic complications in adult patients with acute lymphoblastic leukemia receiving L-asparaginase during induction therapy in 4.2% of the patients . A meta-analysis of 1752 patients from 17 prospective trials involving treatment with asparaginase demonstrated a rate of symptomatic thrombosis of 5.2% . The UK ALL 2003 study reported asparaginase-related venous thrombosis in 3.2% of 1824 treated patients . The use of prednisone and asparaginase concomitantly administered in a leukemic patient suffering from a prothrombotic risk factor (such as protein C deficiency, protein S deficiency, antithrombin deficiency, or factor V Leiden) was responsible for the onset of venous thrombosis in the majority of cases .
3.3. Molecular Targeted Therapies
Lenvatinib is an oral medication that inhibits multiple receptor tyrosine kinases, including vascular endothelial growth factor receptors, fibroblast growth factor receptors, and platelet-derived growth factor receptor alpha . A phase 2 trial treating patients with advanced, radioiodine-refractory thyroid cancer with lenvatinib, reported pulmonary embolism in 3% of the patients and DVT in 3% of the patients .
Osimertinib is an epidermal growth factor receptor inhibitor that is implicated with an enhanced risk of thrombosis. The dose escalation study showed that pulmonary embolism occurred in 2.4% of the treated patients . Osimertinib-induced VTE after initiation of osimertinib treatment was reported recently by Shiroyama et al. .
3.4. Anti-angiogenesis Monoclonal Antibodies
Bevacizumab. Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGF) in the circulation. The addition of bevacizumab to irinotecan, fluorouracil, and leucovorin resulted in improvement in survival among patients with metastatic colorectal cancer; however, thrombotic events were higher in patients treated with bevacizumab compared to patients treated with chemotherapy alone (19.4% versus 16.2%, respectively, p = 0.26) . Analysis of data pooled from five randomized controlled trials found that the combination of bevacizumab and chemotherapy, compared with chemotherapy alone, was associated with an increased risk of arterial thromboembolism with a hazard ratio of 2.0 . A meta-analysis of 20 randomized controlled trials found that the incidence of arterial thrombotic events in patients receiving bevacizumab was 3.3% . This meta-analysis showed the varying risk for arterial thrombotic events with different malignancies treated with bevacizumab, with the highest relative risk of 3.72 for patients with renal cell cancer, and with the relative risk being 1.89 in patients with colorectal cancer treated .
Ramucirumab. Ramucirumab is a monoclonal antibody that targets the extracellular domain of VEGF receptor 2, and thus prevents its activation by VEGF . A phase I pharmacologic and biologic study of ramucirumab reported DVT in 5.4% of the patients . A study comparing ramucirumab versus placebo in combination with second-line chemotherapy in patients with metastatic colorectal carcinoma reported a nonsignificant difference in VTE of 8.2% and 6.3% with ramucirumab and placebo, respectively .
4. Heparin and Heparan Sulphate
The entry is from 10.3390/cancers12030566
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