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Venous thromboembolism (VTE) is a common complication in patients with malignant disease. Emerging data have enhanced our understanding of cancer-associated thrombosis, a major cause of morbidity and mortality in patients with cancer. In addition to VTE, arterial occlusion with stroke and anginal symptoms is relatively common among cancer patients, and is possibly related to genetic predisposition. Several risk factors for developing venous thrombosis usually coexist in cancer patients including surgery, hospital admissions and immobilization, the presence of an indwelling central catheter, chemotherapy, use of erythropoiesis-stimulating agents (ESAs) and new molecular-targeted therapies such as antiangiogenic agents. Effective prophylaxis and treatment of VTE reduced morbidity and mortality, and improved quality of life. Low-molecular-weight heparin (LMWH) is preferred as an effective and safe means for prophylaxis and treatment of VTE. It has largely replaced unfractionated heparin (UFH) and vitamin K antagonists (VKAs). Recently, the development of novel oral anticoagulants (NOACs) that directly inhibit factor Xa or thrombin is a milestone achievement in the prevention and treatment of VTE. This review will focus on the epidemiology and pathophysiology of cancer-associated thrombosis, risk factors, and new predictive biomarkers for VTE as well as discuss novel prevention and management regimens of VTE in cancer according to published guidelines.
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PMID:Cancer-associated thrombosis: an overview. 2552 May 67

The target-specific oral anticoagulants are a class of agents that inhibit factor Xa or thrombin. They are effective and safe compared to warfarin for the prevention of stroke and systemic embolism in patients with atrial fibrillation and for the treatment of venous thromboembolism, and they are comparable to low-molecular-weight heparin for thromboprophylaxis after hip or knee arthroplasty. For other indications, however, such as the prevention of stroke in patients with mechanical heart valves, initial studies have been unfavorable for the newer agents, leaving warfarin the anticoagulant of choice. Further studies are needed before the target-specific anticoagulants can be recommended for patients with cancer-associated thrombosis or heparin-induced thrombocytopenia. Concerns also persist about difficulties with the laboratory assessment of anticoagulant effect and the lack of a specific reversal agent. For these reasons, we anticipate that the vitamin K antagonists will continue to be important anticoagulants for years to come.
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PMID:Changing practice of anticoagulation: will target-specific anticoagulants replace warfarin? 2558 51

Venous thromboembolism (VTE) is a common complication of cancer and has a significant impact on morbidity and mortality in patients with malignancies. Low molecular weight heparins (LMWHs) currently represent the drug of choice for both initial and long-term treatment of cancer-associated thrombosis. In recent years, however, a new class of novel oral anticoagulants (NOACs) inhibiting directly thrombin or activated factor X have been proposed as an alternative therapeutic option on the basis the results of subgroup analyses of phase III randomized controlled trials, including few cases of patients with cancer. After analysis of the available literature data, we conclude that although potentially interesting, future research specifically conducted in cancer patients is needed to clarify the role of these newer anticoagulant agents in prevention and treatment of cancer-related VTE.
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PMID:Cancer-associated thrombosis: investigating the role of new oral anticoagulants. 2574 84

Venous limb gangrene (VLG) can occur in cancer patients, but the clinical picture and pathogenesis remain uncertain. We identified 10 patients with metastatic cancer (7 pathologically proven) who developed severe venous limb ischemia (phlegmasia/VLG) after initiating treatment of deep-vein thrombosis (DVT); in 8 patients, cancer was not known or suspected at presentation. The patients exhibited a novel, clinically distinct syndrome: warfarin-associated supratherapeutic international normalized ratio (INR; median, 6.5) at onset of limb ischemia, rising platelet count during heparin anticoagulation, and platelet fall after stopping heparin. Despite supratherapeutic INRs, patient plasma contained markedly elevated thrombin-antithrombin (TAT) complex levels (indicating uncontrolled thrombin generation) and protein C (PC) depletion; this profile resembles the greatly elevated TAT/PC activity ratios reported in patients with warfarin-associated VLG complicating heparin-induced thrombocytopenia. Analyses of vitamin K-dependent factors in 6 cancer patients with available serial plasma samples showed that variations in the INR corresponded most closely with changes in factor VII, with a highly collinear relationship between VII and PC. We conclude that venous limb ischemia/gangrene is explained in some cancer patients by profoundly disturbed procoagulant-anticoagulant balance, whereby warfarin fails to block cancer-associated hypercoagulability while nonetheless contributing to severe PC depletion, manifest as a characteristic supratherapeutic INR caused by parallel severe factor VII depletion.
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PMID:Warfarin-induced venous limb ischemia/gangrene complicating cancer: a novel and clinically distinct syndrome. 2620 43

Venous thromboembolism (VTE) is a preventable disease, yet it is one of the leading causes of death among patients with cancer. Improving risk stratification mechanisms will allow us to personalize thrombo-prophylaxis strategies. We sought to evaluate Collagen and Thrombin Activated Platelets (COAT-platelets) as well as protein C and factor VIII as biomarkers predictive of cancer-associated thrombosis in a prospective cohort of patients with cancer. Protein C was selected as a candidate based on bioinformatics prediction. Blood samples were collected before chemotherapy. All specimen processing was blinded to clinical data. Surveillance and adjudication of the main outcome of VTE was performed for up to 1 year. We used Cox proportional hazard regression to measure the association of biomarkers and incident events using SAS 9.2 for all statistical analysis. Death was modeled as a competing event. Among 241 patients followed for an average of 10.4 months, 15% died and 13% developed a VTE. COAT-platelets were not predictive of VTE. Low levels of pre-chemotherapy protein C (<118%) (HR 2.5; 95% CI 1.1-5.5) and high baseline factor VIII (>261% I) (HR 3.0; 95% CI 1.1-8.0) were predictive of VTE after adjusting for age, Khorana prediction risk, metastatic disease and D dimer. In addition, low protein C was predictive of overall mortality independent of age, metastatic disease and functional status (HR 2.8; 95% CI 1.3-6.0). Addition of these biomarkers to cancer-VTE risk prediction models may add to risk stratification and patient selection to optimize thrombo-prophylaxis.
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PMID:Prospective evaluation of protein C and factor VIII in prediction of cancer-associated thrombosis. 2647 10

Trousseau's syndrome (cancer-associated thrombosis) is the second leading cause of death in cancer patients, after death from cancer itself. The risk of a venous thromboembolism is 4- to 7-fold higher in patients with cancer than in those without cancer. The causes of this impaired coagulation are associated with general patient-related risk factors, and other factors that are specific to the particular cancer or treatment. It is important to assess the risk of thrombotic events in cancer patients and administer effective prophylaxis and treatment. Effective prophylaxis and treatment of venous thromboembolism reduces morbidity and mortality, and improves patients' quality of life. Low molecular weight heparin is the first-line treatment for venous thromboembolism, as an effective and safe means for prophylaxis and treatment, according to guidelines released by international scientific societies. Oral anticoagulation therapy with warfarin is preferable to no therapy. However, warfarin has low efficacy and is associated with high rates of recurrence. If low molecular weight heparin is unavailable, some guidelines recommend the use of vitamin K antagonists that have a target international normalized ratio in the range of 2-3, as acceptable alternatives. Novel oral anticoagulants that directly inhibit factor Xa or thrombin are promising for the prophylaxis of high-risk cancer patients and in the long-term treatment of venous thromboembolism. However, to date, there is insufficient evidence to support the use of these new anticoagulants.
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PMID:Trousseau's syndrome: cancer-associated thrombosis. 2654 90

Cancer-associated venous thromboembolism (VTE) constitutes the second cause of death after cancer. Many risk factors for cancer-associated VTE have been identified, among them soluble tissue factor and microparticles (MPs). Few data are available about the implication of MPs in cancer associated-VTE through animal model of cancer. The objective of the present review was to report the state of the current literature about MPs and cancer-associated VTE in animal model of cancer. Fourteen series have reported the role of MPs in cancer-associated VTE, through three main mouse models: ectopic or orthotopic tumor induction, experimental metastasis by intravenous injection of tumor cells into the lateral tail vein of the mouse. Pancreatic cancer is the most used animal model, due to its high rate of cancer-associated VTE. All the series reported that tumor cell-derived MPs can promote thrombus formation in TF-dependent manner. Some authors reported also the implication of phosphatidylserine and PSGL1 in the generation of thrombin. Moreover, MPs seem to be implicated in cancer progression through a coagulation-dependent mechanism secondary to thrombocytosis, or a mechanism implicating the regulation of the immune response. For these reasons, few authors have reported that antiplatelet and anticoagulant treatments may prevent tumor progression and the formation of metastases in addition of coagulopathy.
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PMID:Microparticles and cancer thrombosis in animal models. 2706 74

Cancer is an established risk factor for venous thromboembolism (VTE) and VTE is the second leading cause of death in patients with cancer. The incidence of cancer-related thrombosis is rising and is associated with worse outcomes. Despite our growing understanding on tumor-driven procoagulant mechanisms including cancer-released procoagulant proteases, expression of tissue factor on cancer cells and derived microvesicles, as well as alterations in the extracellular matrix of the cancer cell milieu, anticoagulation therapy in cancer patients has remained challenging. This review comments on a newly discovered cancer-associated procoagulant pathway. Experimental VTE models in mice and studies on patient cancer material revealed that prostate cancer cells and associated exosomes display the inorganic polymer polyphosphate on their plasma membrane. Polyphosphate activates blood coagulation factor XII and initiates thrombus formation via the intrinsic pathway of coagulation. Pharmacologic inhibition of factor XII activity protects mice from VTE and reduces thrombin coagulant activity in plasma of prostate cancer patients. Factor XII inhibitors provide thrombo-protection without impairing hemostatic mechanisms and thus, unlike currently used anticoagulants, do not increase bleeding risk. Interference with the polyphosphate/factor XII pathway may provide the novel opportunity for safe anticoagulation therapy in patients with malignancies.
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PMID:The polyphosphate/factor XII pathway in cancer-associated thrombosis: novel perspectives for safe anticoagulation in patients with malignancies. 2720 22

Essentials Cancer cachexia and cancer-associated thrombosis have not previously been mechanistically linked. We assessed thrombin generation and coagulation parameters in cachectic C26 tumor-bearing mice. C26 mice are hypercoagulable, partially corrected by blocking tumor derived interleukin-6. Coagulability and anti-inflammatory interventions may be clinically important in cancer cachexia.
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PMID:Increased thrombin generation in a mouse model of cancer cachexia is partially interleukin-6 dependent. 2805 2

Thrombotic diseases caused by cancer progression have been reported as one of the major causes of cancer associated morbidity and mortality along with cancer invasiveness and infectious complications. Moreover, anticoagulant therapy with heparin and heparin-like drugs, or vitamin K antagonists, or the Direct Oral Anticoagulants, is seeing an extended application in cancer patients and offers prolonged life expectancy to oncology patients for whom blood activation and thrombotic events have a variable incidence, depending on cancer type. Laboratory tools are highly useful for identifying patients at thrombotic risk through the measurement of blood activation markers and selecting those appropriate for anticoagulant therapy. Among the pathological markers, DDimer or Extracellular Vesicles have the highest diagnostic value in these pathological conditions. Global assays are useful for dosage adjustment, such as assessing either an induced anticoagulant effect or the measurement of drug activity. Various assays are also developed such as platelet aggregometry techniques for evaluating drug induced- aggregates or methods allowing measurement of the drug activity to its targeted coagulation factors such as: heparin to thrombin or Factor Xa; DOACs to Thrombin or Factor Xa (Dabigatran to thrombin and DiXaIs, Rivaroxaban, Apixaban, and Edoxaban, to Factor Xa). Such explorative techniques help to find the right dosage adjustment to protect patients from developing thrombosis without exposing them bleeding. It also permits exploration of unexpected drug behavior in treated patients, to check the right adherence to therapy in long-term anticoagulant protocols, and prevention of bleeding in patients with impaired renal or hepatic function. Complementary use of blood activation markers brings additional information on the curative effects of the anticoagulant therapy, and allows identification of pro-thrombotic activity in the clinically silent state. These issues are concisely addressed below.
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PMID:Monitoring of anticoagulant therapy in cancer patients with thrombosis and the usefulness of blood activation markers. 2855 90


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