Cancer-associated Venous Thrombosis Research Articles

Polymorphisms of the coagulation system and risk of cancer

Hypercoagulability is a frequently finding in patients with cancer, and is associated with an increased risk of venous thrombosis (VT). Cancer-associated VT is associated with poor prognosis and represents the leading non-cancer cause of death among these patients. Conversely, patients experiencing VT are at increased risk of subsequent cancer, suggesting an epidemiological bidirectional link between cancer and hemostasis, and indicating a role of the hemostatic system in cancer development. How the coagulation system relates to cancer etiology at the genetic level is largely unexplored. Data on the association of polymorphisms in genes involved in coagulation with cancer development is important to clarify the role of the coagulation system in cancer pathogenesis. Effects of coagulation-related gene polymorphisms on cancer risk may possibly be translated into novel treatment- and prevention strategies of cancer-associated thrombosis and the cancer itself. This article reviews the current knowledge of the relation between polymorphisms in genes involved in coagulation and cancer risk in solid tumors.

Increased Levels of NF-kB-Dependent Markers in Cancer-Associated Deep Venous Thrombosis.

Several studies highlight the role of inflammatory markers in thrombosis as well as in cancer. However, their combined role in cancer-associated deep vein thrombosis (DVT) and the molecular mechanisms, involved in its pathophysiology, needs further investigations. In the present study, C-reactive protein, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1β), matrix metalloproteases-9 (MMP-9), vascular endothelial growth factor (VEGF), tissue factor (TF), fibrinogen and soluble P-selectin, were analyzed in plasma and in monocyte samples from 385 cancer patients, of whom 64 were concomitantly affected by DVT (+). All these markers were higher in cancer patients DVT+ than in those DVT-. Accordingly, significantly higher NF-kB activity was observed in cancer patients DVT+ than DVT-. Significant correlation between data obtained in plasma and monocyte samples was observed. NF-kB inhibition was associated with decreased levels of all molecules in both cancer DVT+ and DVT-. To further demonstrate the involvement of NF-kB activation by the above mentioned molecules, we treated monocyte derived from healthy donors with a pool of sera from cancer patients with and without DVT. These set of experiments further suggest the significant role played by some molecules, regulated by NF-kB, and detected in cancer patients with DVT. Our data support the notion that NF-kB may be considered as a therapeutic target for cancer patients, especially those complicated by DVT. Treatment with NF-kB inhibitors may represent a possible strategy to prevent or reduce the risk of DVT in cancer patients.

Tissue factor expressed by circulating cancer cell‐derived microparticles drastically increases the incidence of deep vein thrombosis in mice

The risk of thrombotic complications such as deep vein thrombosis (DVT) during tumor development is well known. Tumors release into the circulation procoagulant microparticles (MPs) that can participate in thrombus formation following vessel injury. The importance of this MP tissue factor (TF) in the initiation of cancer-associated DVT remains uncertain. To investigate how pancreatic cancer MPs promote DVT in vivo. We combined a DVT mouse model in which thrombosis is induced by flow restriction in the inferior vena cava with one of subcutaneous pancreatic cancer in C57BL/6J mice. We infused high-TF and low-TF tumor MPs to determine the importance of TF in experimental cancer-associated DVT. Both tumor-bearing mice and mice infused with tumor MPs subjected to 3 h of partial flow restriction developed an occlusive thrombus; fewer than one-third of the control mice did. We observed that MPs adhered to neutrophil extracellular traps (NETs), which are functionally important players during DVT, whereas neither P-selectin nor glycoprotein Ib were required for MP recruitment in DVT. The thrombotic phenotype induced by MP infusion was suppressed by hirudin, suggesting the importance of thrombin generation. TF carried by tumor MPs was essential to promote DVT, as mice infused with low-TF tumor MPs had less thrombosis than mice infused with high-TF tumor MPs. TF expressed on tumor MPs contributes to the increased incidence of cancer-associated venous thrombosis in mice in vivo. These MPs may adhere to NETs formed at the site of thrombosis.

Cancer-Associated Thrombosis: Cancer Cell-Derived Microparticles As a Trigger of Venous Thrombosis in a Mouse Model of Flow Restriction

Abstract 34Thrombotic complications are common side effects in cancer patients and up to 20% of all symptomatic cases of deep vein thrombosis (DVT) are thought to be cancer-related. Since Armand Trousseau established a direct correlation between thrombophlebitis and cancer in 1865, cancer-associated thrombosis has been the focus of several studies. All tumor types are associated with thrombosis but the incidence is particularly high (up to 57%) in patients suffering from pancreatic cancer (Sack et al Medicine 1977; Blom et al Eur J Cancer 2006; Cronin-Fenton et al Br J Cancer 2010). Cancer cells shed procoagulant microparticles (MPs) that can reach the bloodstream of pancreatic tumor-bearing mice and of patients with pancreatic cancer (Thomas et al J Exp Med 2009, Zwicker et al Thromb Res 2009). At their surface, these vesicles express a higher density of active tissue factor (TF) when compared to their parental cell (> 100-fold), and were shown to contribute to vessel injury-induced thrombosis (Thomas et al J Exp Med 2009). Furthermore, the concentration of circulating TF-bearing tumor-derived MPs has been correlated with cancer-associated venous thromboembolic events in patients (Del Conde et al J Thromb Haem 2007; Hron et al Thromb Haemost 2007; Langer et al Ann Hematol 2008; Zwicker et al Thromb Res 2009). In this study, we addressed experimentally whether circulating tumor microparticles play a role in DVT associated with cancer. We used a mouse model of DVT where thrombosis is induced by flow restriction (90% reduction in the lumen size) of the inferior vena cava (IVC) (Brill et al Blood 2010). In contrast to most DVT models, this model maintains blood flow in the IVC and it does not induce injury or endothelial denudation and thus is suitable for comparisons to human patients. The DVT model was used in combination with a model of murine pancreatic cancer (Thomas et al J Exp Med 2009). We observed that all the mice implanted subcutaneously with pancreatic cancer cells (Panc02 cell line) and submitted 35 days later to partial flow restriction of the IVC (n=8) developed an occlusive thrombus after 3 hours of flow restriction, while only 2 out of 7 control mice did (P < 0.05). We observed in this DVT model that mice infused with cancer cell-derived MPs have the same phenotype as the tumor-bearing mice since 100% of them developed a thrombus (P < 0.05 when compared to control mice), indicating that circulating tumoral microparticles play an important part in the triggering of cancer-associated DVT. A pro-thrombotic effect could be observed as early as 1 hour after stenosis in cancer cell-derived MPs-injected mice (P < 0.05 when compared to control mice). Moreover, thrombus formation after 1 hour of stenosis could be abolished when mice were pretreated with hirudin, suggesting the importance of the MP-generated thrombin likely by MP-derived TF activity.In conclusion, our results support the hypothesis that tumoral microparticles trigger cancer-associated venous thrombosis. Thus targeting their recruitment or activity could help to prevent cancer-associated DVT and its complication, pulmonary embolism. Disclosures:No relevant conflicts of interest to declare.

The role of fibrinogen plasma levels, the –455G&gt;A fibrinogen and the factor XIII A subunit (FXIII-A) Val34Leu polymorphism in cancer-associated venous thrombosis

Venous thromboembolism (VTE) is a life-threatening complication in cancer patients. Identification of risk factors has been in focus in the past years. Functional single nucleotide polymorphisms (SNP) of coagulation factors known to influence the concentration or function may be considered to influence the risk of VTE in cancer patients. We evaluated the influence of fibrinogen plasma levels, the -455G>A SNP in the fibrinogen beta gene and the Val34Leu (163G>T) SNP in the factor XIII A-subunit (FXIII-A) gene on the risk of VTE. In 1,079 tumour patients recruited for the prospective Vienna Cancer and Thrombosis Study (CATS) fibrinogen levels were determined by the Clauss method. The FXIII-A Val34Leu and the fibrinogen -455G>A SNPs were tested by allele-specific PCR. The median follow-up time was 604 days, 83 thrombotic events occurred. The median fibrinogen level was 381 mg/dl (25th-75th percentile: 312 to 467). In a multivariable Cox model adjusted to chemotherapy, surgery, radiotherapy, age and sex, neither the fibrinogen concentration (hazard ratio [HR] =1.05, confidence interval [CI] 0.839-1.310 p=0.68), nor the -455G>A SNP (HR=0.77, 95%CI 0.491-1.197; p=0.24), nor the Val34Leu SNP (HR=0.99, 95%CI 0.646-1.542 p=0.99) were associated with occurrence of VTE. The fibrinogen concentration was not significantly different among the fibrinogen -455G or A genotype carriers (p = 0.33). Disseminated intravascular coagulation was observed in only five patients, none of these developed VTE. In conclusion, fibrinogen plasma levels, the fibrinogen -455G>A and the FXIII-A Val34Leu polymorphisms were not associated with VTE in our study.

Cancer-Associated Venous Thrombosis in the Surgical Setting

Cancer patients are at a relatively high risk of venous thromboembolism (VTE), and this has implications for surgical outcome. English literature search including the keywords cancer, surgery and VTE was undertaken to review the risk, etiology, prevention and treatment of VTE in surgical oncology patients. Malignant disease is highlighted as an important risk factor for VTE with an odds ratio of 6.5. The risk factors include higher age, previous VTE, advanced cancer, length of operation and immobility. Use of in-hospital thromboprophylaxis with low-molecular-weight heparin (LMWH) or low dose unfractionated heparin with graded stockings has been validated both in terms of safety and efficacy and should be considered for all patients. Subcutaneous LMWH has replaced unfractionated heparin for the initial treatment of VTE. The use of long-term LMWH instead of oral anticoagulants can substantially reduce the risk of recurrent VTE without increased bleeding. Recently, results of few trials have shown that LMWH may improve patient survival.

Treatment of Cancer-Associated Venous Thrombosis

Venous thromboembolism (VTE) is an important complication in cancer patients, which is associated with bad outcome. Increased recurrence rates and bleeding complications as compared to non-cancer patients during the treatment of VTE, require special attention. This review aims to summarize the available evidence on both the anticoagulant and non-anticoagulant treatment of symptomatic VTE in patients with active malignancy.

Management of cancer-associated venous thrombosis

The association between malignancy and venous thromboembolic disease has been recognized for over a century and a half. During this time, a substantial body of literature has developed showing that malignancy is not only a hypercoagulable state characterized by an increased risk of thrombosis but also that components of blood coagulation reactions are capable of supporting tumor growth and dissemination. In recent years a succession of meticulously performed clinical trials has clarified optimal therapy intended to both prevent and treat thromboembolism that occurs in the setting of cancer. However, much remains to be accomplished in terms of practitioner education on the merits of optimal therapy. Of perhaps greater interest is the possibility that drugs capable of controlling cancer-associated hypercoagulability may provide a means for improving cancer survival while avoiding the toxicities characteristic of conventional anti-tumor therapy. Clearly, ample incentive exists for collaboration between basic and clinical scientists interested in improving the management of malignancy and its thromboembolic complications.

Venous Limb Gangrene during Warfarin Treatment of Cancer-Associated Deep Venous Thrombosis

The cause of cancer-associated venous limb gangrene is unknown but could paradoxically be due to warfarin. To determine the pathogenesis of venous gangrene in a patient with cancer. Case report. University hospital in Ontario, Canada. 66-year-old woman with metastatic lung cancer and deep venous thrombosis. Levels of vitamin K-dependent factors, additional coagulation factors, and thrombin-antithrombin complexes (marker of thrombin generation). During warfarin use, venous limb gangrene developed when the international normalized ratio (INR) reached 6.0 (therapeutic range, 2.0 to 3.0); at this time, the level of protein C (a vitamin K-dependent natural anticoagulant) was severely reduced, but thrombin-antithrombin complexes remained markedly elevated. The supratherapeutic INR was explained by the greatly reduced levels of factor VII, which correlated closely with protein C levels; therefore, the high INR was a surrogate marker for severely reduced protein C activity. Warfarin may contribute to the pathogenesis of cancer-associated venous limb gangrene by leading to severe depletion of protein C while at the same time failing to reduce thrombin generation.