Cancer-associated thrombosis: an update

Drug Discovery Today: Disease Mechanisms

DRUG DISCOVERY

TODAY

Vol. 8, No. 1-2 2011

Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Charles Lowenstein – University of Rochester Medical Center, Rochester, NY.

DISEASE Haematology MECHANISMS

Cancer-associated thrombosis: an update Abhay R. Shelke, Alok A. Khorana* Division of Hematology/Oncology, James P. Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

Cancer-associated thrombosis is a common complication seen in oncology patients, and its incidence is rising. Thromboembolism is the second most common

Section editor: Craig Morrell – University of Rochester School of Medicine, New York, USA.

cause of death in cancer patients. Cancer-associated venous thromboembolism (VTE) is associated with high rate of recurrence, increased risk of bleeding, and a requirement for long-term anticoagulation.

mechanisms of thrombosis in cancer, discusses novel therapeutic targets for development of new anticoagulants, and describes the published guidelines for prevention and treatment of cancer-associated thrombosis.

The hypercoagulable state in cancer involves several complex interdependent mechanisms including emerging roles for tumor-derived tissue factor and platelets. Identifying patients at risk for VTE and utilizing available anticoagulant agents for primary or secondary prophylaxis is crucial to reduce morbidity, enhance quality of life, and improve survival. Introduction Venous thromboembolism (VTE), which includes both deepvein thrombosis (DVT) and pulmonary embolism (PE), together with arterial events, including stroke and myocardial infarction, are the second-leading causes of death in hospitalized and ambulatory cancer patients [1]. Cancer patients are at substantially higher risk for development of new and recurrent VTE. The risk of VTE in cancer patients is increased three- to fivefold for those who are undergoing surgery and 6.5-fold for those who are receiving chemotherapy [2]. VTE has a significant impact on health-related outcomes, as it adversely affects quality of life, morbidity and mortality [3], and adds considerably to healthcare resource use [4]. This article reviews emerging data regarding the *Corresponding author.: A.A. Khorana ([email protected]) 1740-6765/$ ß 2012 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.ddmec.2012.02.001

Mechanisms of cancer-associated thrombosis The pathophysiology of cancer-associated thrombosis is not entirely understood. The hypercoagulable state in cancer involves several complex interdependent mechanisms (Fig. 1). Key roles in pathophysiology are played by tissue factor (TF), inflammatory cytokines and platelets. TF, a transmembrane glycoprotein, is the key physiologic initiator of coagulation and is expressed by malignant cells across a variety of cancers, including many solid tumors as well as by leukemia blast cells, tumor-associated macrophages, and endothelial cells. TF expression in variety of human cancers is induced by activation of oncogenes or inactivation of tumor suppressor genes [5]. TF may also be induced by various mediators including tumor necrosis factor-a (TNF-a), interleukin-1b, or CD40 ligand, thrombin, oxidized LDL and vascular endothelial growth factor (VEGF) [6]. TF can be detected in the bloodstream of cancer patients. This circulating or blood-borne TF is associated with microparticles (MPs) originating from endothelial cells, vascular smooth muscle cells, leukocytes, or platelets. MPs are released from these cells upon activation through a cytosolic calcium dependent mechanism involving formation of cytoplasmic protrusions [7]. Over-expression of TF in tumor cells or elevated TF levels may contribute to the procoagulant state e39

Drug Discovery Today: Disease Mechanisms | Haematology

Vol. 8, No. 1-2 2011

Inflammatory Cytokines (TNF-α, IL-1) and VEGF

Extrinsic Factors

• Chemotherapy • Anti-angiogenic therapy Thrombosis

Tumor Cells

• Hormonal Therapy

Procoagulant Molecules (Tissue Factor and Others)

Central Venous Catheters Platelets Drug Discovery Today: Mechanisms

Figure 1. Potential mechanism of cancer-associated thrombosis.

[6]. In addition to hemostasis, TF also plays a role in angiogenesis, tumor growth, and the metastatic potential of some cancers [8]. Owing to the wide expression of TF across various malignancies, recent investigations have focused on utilizing it as a biomarker predictive of clinical thrombotic events (reviewed by Khorana [9]). Assays to evaluate TF include immunohistochemical grading of TF expression on tumor cells, measurement of circulating antigen using ELISA, TF MP procoagulant activity or impedance-based flow cytometry. Unfortunately, there is no consensus ‘standard’ TF assay. Initial reports suggested a significant association of elevated TF with subsequent VTE. However, the majority of these data were derived from patients with pancreatic cancers. In a recent large study with a heterogeneous cancer population, elevated procoagulant MPs (albeit not TF-specific) were not found to be predictive of VTE. Further, in a prospective analysis of subgroups of the Vienna CATS registry, TF was predictive of VTE in pancreatic but not brain or colorectal cancers. For now, TF is still considered an investigational biomarker [9]. Tumor cells also release inflammatory cytokines and chemokines, such as tumor necrosis factor alpha (TNF-a), interleukin-1, and VEGF, which in turn act on leukocytes and endothelial cells to synthesize and express TF as well as a number of other cell adhesion molecules that might predispose or promote venous thrombosis [10]. There is also growing evidence to suggest that platelets play a role in the hypercoagulable state of cancer, and may particularly be involved in cancer progression and metastasis [11]. Experimental blockade of key platelet receptors, such as GP1b/IX/V, GPIIb/IIIa and GPVI, has been shown to decrease lung colonization of cancer cells, suggesting attenuation of e40

www.drugdiscoverytoday.com

the metastatic process [12]. Recent data suggest that aspirin use in combination with the surgical treatment of non-smallcell lung cancer and colorectal cancer is associated with increased survival [13,14]. Cancer procoagulant (CP) is a cysteine protease found only on malignant cells and in amniotic tissue. Although the protein sequence and cDNA encoding CP is not clear, it is found to directly activate factor X in the absence of factor VIIa [10]. CP has been shown to stimulate blood platelet adhesion in a mechanism similar to thrombin, and inducing dosedependent platelet activation [10]. However, due to the lack of definitive evidence, the precise role of CP in cancer-associated thrombosis remains speculative. Additionally, extrinsic factors such as chemotherapy administration can result in activation of hemostasis via a variety of mechanisms, including induction of TF in tumor cells and monocytes, down regulation of anticoagulant proteins such as protein C and S, damage to vascular endothelium and platelet activation [15]. Newer targeted therapy agents such as bevacizumab, thalidomide and lenalidomide and multi-targeted tyrosine kinase inhibitors such as sunitinib and sorafenib do not cause the typical toxicities associated with chemotherapy, but are associated with thrombotic events. The mechanisms underlying this association are unknown, but may include endothelial cell and platelet activation [16].

Risk factors and biomarkers for cancer-associated thrombosis Potential risk factors for VTE in oncology patients can be categorized into patient-, cancer-, and treatment-related factors (Table 1) [17]. Advanced age, female gender,

Vol. 8, No. 1-2 2011

Drug Discovery Today: Disease Mechanisms | Haematology

African-American race, and prothrombotic mutations are associated with risk of VTE. Comorbidities such as infection, obesity, anemia, pulmonary and renal disease demonstrably increase the risk of VTE [17]. The primary site of cancer is one of the strongest risk factors for VTE, with highest rates observed in patients with brain, pancreas, gastric, kidney, ovary and lung cancers and lymphoma [17]. A populationbased study reported highest risk of VTE during the first three months after the diagnosis of cancer (OR 53.5, 95% CI 8.6– 334.3) [18]. Specific antineoplastic agents enhance risk of VTE. Thalidomide and lenalidomide, when combined with steroids, doxorubicin, or other chemotherapeutic regimens for treatment of myeloma are associated with increased risk of cancer-associated VTE [19]. Bevacizumab, a monoclonal antibody directed against the pro-angiogenic molecule VEGF (used in the treatment of several solid tumors) has been linked with increased risk of arterial thromboembolism [20]. The association between bevacizumab and VTE is unclear with conflicting results from meta-analyses [21,22]. Sunitinib and sorafenib, agents targeting the angiogenesis pathway, are associated with elevated risk for arterial events [RR 3.03 (95% CI 1.25–7.37)] suggesting this may be a class effect for anti-angiogenic agents [23]. Erythropoiesisstimulating agents (ESAs) and red blood cell transfusions have also been found to increase the risk of VTE. Recent research has identified novel candidate biomarkers that may be predictive of cancer-associated VTE. Observational studies have shown that, pre-chemotherapy platelet count 350,000/mm3 and elevated pre-chemotherapy leukocyte count of >11,000/mm3 were independently associated with an increased risk of VTE [24]. Several other

biomarkers including high grades of TF expression in tumor cells and elevated levels of circulating biomarkers such as TF, soluble P-selectin, D-dimer and C-reactive protein have been associated with the risk of VTE in cancer [25]. A risk model for chemotherapy-associated VTE has been recently developed and validated [24]. Rates of VTE according to the risk categories are depicted in Table 2. Rates of VTE in this high-risk subgroup are comparable to hospitalized patients for whom prophylaxis is safe and effective. This risk score was recently validated in an independent population of the Vienna CATS study [26]. The National Heart, Lung and Blood Institute has recently funded a research to study VTE prophylaxis at the outpatient setting in cancer patients who were identified as high-risk based on this model.

Prevention of VTE Prophylactic anticoagulation therapy is considered in three clinical settings–hospitalized, surgical and ambulatory cancer patients. All cancer patients admitted to the hospital must receive primary anticoagulant prophylaxis based on data from three major studies carried out in this setting: the prophylaxis of Medical Patients with Enoxaparin (MEDENOX) study [27], the Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients Trial (PREVENT) study [28] and the Arixtra for Thromboembolism Prevention in Medical Indications Study (ARTEMIS) [29]. The MEDENOX trial, which included 1102 hospitalized patients showed significant reduction in VTE risk with 40 mg of enoxaparin (relative risk 0.37, P < 0.001). In the PREVENT study, the incidence of VTE was significantly lower in the dalteparin group as compared to the placebo group (2.77%

Table 1. Risk factors for cancer thrombosis Patient-related factors

Cancer-related factors

Treatment-related factors

Biomarkers

 Older age

 Primary site of cancer

 Major surgery

 Pre-chemotherapy platelet count 350,000/mm3

 Female gender

 Race  Higher in African American  Lower in Asian-Pacific Islander

 Brain, pancreas, kidney, stomach, lung, gynecologic, lymphoma, myeloma  Advanced stage of cancer  Initial period after diagnosis of cancer

 Hospitalization

 Cancer therapy

 Pre-chemotherapy leukocyte count >11,000/mm3

 Chemotherapy

 Tissue factor (TF)

 Hormonal therapy

 High TF expression by tumor cells

 Comorbidities

 Anti-angiogenic agents

 High TF plasma levels

 Infection, renal disease, pulmonary disease, obesity

 Thalidomide, lenalidomide, bevacizumab

 Soluble P-selectin

 Inherited prothrombotic mutations

 Erythropoiesis-stimulating agents

 D-dimer

 Prior history of VTE

 Transfusions

 C-reactive protein

 Central venous catheters www.drugdiscoverytoday.com

e41

Drug Discovery Today: Disease Mechanisms | Haematology

Vol. 8, No. 1-2 2011

Table 2. Predictive model for chemotherapy-associated VTE Patient characteristic

Risk score

 Site of cancer - Very high risk (stomach, pancreas)

2

- High risk (lung, lymphoma, gynecologic, bladder, testicular)

1

 Pre-chemotherapy platelet count 350,000/mm3

1

 Hemoglobin <10 g/dL or use of red cell growth factors

1

2

 Body mass index 35 kg/m

1

 Pre-chemotherapy leukocyte count >11,000/mm3

1

Score

Risk category

Incidence of VTE over 2.5 months

0

Low

0.3–08%

1 or 2

Intermediate

1.8–2%

3 or higher

High

6.7–7.1%

versus 4.96% respectively; P = 0.0015; 45% RRR and 2.19 ARR). The ARTEMIS study showed significantly low rates of VTE (5.6%) in the fondaparinux group (odds reduction 49.5%, P = 0.029) compared to the placebo group (10.5%). Fondaparinux also reduced fatal PE (P = 0.029) in these patients. Unfortunately, in most of these studies cancer patients represented only a 5–15% of study patients. Despite the lack of cancer-specific data, both the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines support the use of pharmacologic VTE prophylaxis in hospitalized cancer patients in the absence of bleeding or other contraindications to anticoagulation [30,31]. Three major studies have evaluated extended prophylaxis with LMWH in surgical cancer patients and shown benefit from a longer duration of prophylaxis for up to 1 month after surgery – the ENOXACAN II, the Cancer, Bemiparin and Surgery Evaluation (CANBESURE), and the Fragmin After Major Abdominal Surgery (FAME) study. The ENOXACAN II trial, showed that patients who received enoxaparin for a month after abdominal or pelvic surgery had a 60% greater risk reduction in VTE compared to those who received the standard duration of 6–10 days (4.8% versus 12.0%; P = 0.02) [32]. The CANBESURE study reported low rates of major VTE after a four-week thromboprophylaxis with bemiparin compared to the group receiving only one-week Bemiparin prophylaxis (0.4% versus 3.3%, respectively; P = 0.016), without any increase in hemorrhagic complications (major bleeding: 0.6% versus 0.3%, respectively) [33]. However, the primary efficacy outcome in this study was not reached. FAME study demonstrated additional benefit for risk reduction in VTE with four-week administration of dalteparin after major abdominal surgery, compared with one week of thromboprophylaxis, without increasing the risk of bleeding [34]. e42

www.drugdiscoverytoday.com

According to the ASCO guidelines, relative contraindications to anticoagulation include active, uncontrollable bleeding; active cerebrovascular hemorrhage; dissecting or cerebral aneurysm; bacterial endocarditis; pericarditis, active peptic or other gastrointestinal ulceration; severe, uncontrolled, or malignant hypertension; severe head trauma; pregnancy (for warfarin); heparin-induced thrombocytopenia; and epidural catheter placement [30]. The safety and efficacy of thromboprophylaxis during the perioperative period for cancer patients undergoing major surgeries has been established in multiple clinical trials. Both the ASCO and the NCCN guidelines support either UFH, LMWH or fondaparinux in the surgical cancer patient for VTE prophylaxis and suggest using prolonged prophylaxis in high-risk patients [30,31]. Subgroups of cancer patients treated at ambulatory setting may have rates of VTE as high as those in hospitalized medical or surgical patients. In recent years there has been a shift in the care of cancer patients from the hospital setting to the ambulatory setting, so the rates of VTE events reported in the outpatient setting are on the rise. Thromboprophylaxis may therefore be beneficial in such groups. Variable results have been reported in several clinical trials conducted to evaluate the benefit of thromboprophylaxis in cancer outpatients. Data from a recent, large study found that nadroparin reduced the incidence of thromboembolic events in ambulatory patients with metastatic or locally advanced cancer who are receiving chemotherapy. Fewer (2.0% versus 3.9% P = 0.033) thromboembolic events (venous and arterial combined) were reported in the nadroparin arm (n = 769) than in the placebo arm (n = 381) [35]. Most recently, SAVE-ONCO, a large prospective, randomized, double-blind, multicenter study of 3200 patients with locally advanced or metastatic solid tumors evaluated the role of semuloparin in thromboprophylaxis for patients

Vol. 8, No. 1-2 2011

Drug Discovery Today: Disease Mechanisms | Haematology

Table 3. Novel anti-coagulants, targets of mechanism, and current status Target

Mechanism

Drug

Status

Ref.

Thrombin (IIa)

Oral DTIs

Ximelagatran

Withdrawn from market in 2006 due to hepatotoxicity

[41]

Dabigatran

Approved for A. Fib

[42]

Lepirudin

HIT

[43]

Argatroban

Approved for HIT

[43]

Bivalirudin

Approved for HIT and PCI adjunct

[43]

Direct Xa inhibitors

DX9065a

Phase II trial

[43]

Indirect Xa inhibitors

Fondaparinux

VTE

Idraparinux

Phase III trial

[19]

Apixaban

Phase III trial

[34]

Parenteral DTIs

Xa

Oral Xa inhibitor

TF pathway inhibitor

Tissue factor/VIIa inhibitor

Edoxaban

Phase III trial

[44]

Rivaraxaban

Approved for VTE prophylaxis before hip/knee surgery

[45]

Betrixaban

Phase II trial

[46]

Tifacogin

Phase III trial

[47]

initiating chemotherapy for cancer [36]. Patients receiving prophylactic semuloparin had 64% relative risk reduction for a thromboembolic event (hazard ratio: 0.36; 95% CI [0.21, 0.60]; P < 0.0001) (1.2% versus 3.4%) compared to placebo. Current guidelines do not recommend prophylaxis for cancer outpatients; however, these newer studies have not yet been taken into account. ASCO and NCCN recommend that myeloma patients receiving chemotherapy with thalidomide/lenalidomide-based regimens should receive prophylaxis with either LMWH or warfarin based on data from non-randomized studies [30,31].

Treatment of VTE in cancer patients Although, warfarin has previously been the standard for longterm anticoagulation, clinical trials data suggest that LMWHs are superior to warfarin in the oncology setting. The CLOT (Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer) trial is the largest randomized trial of VTE treatment in patients with cancer (n = 672), comparing dalteparin with vitamin K antagonist (VKA) therapy. This study reported a 52% RRR in the incidence of recurrent VTE in favor of dalteparin: during the 6-month study period, the probability of recurrent thromboembolism was 17% in the dalteparin group and 9% in the VKA group (P = 0.002). No significant differences in the rates of major bleeding or any bleeding were observed between the two groups [37]. These results are consistent with data from several other smaller studies and a recent Cochrane systematic review [38]. On the basis of the available evidence, ASCO and NCCN guidelines recommend LMWH for at least six months as the standard of care for treatment of VTE in cancer [30,31]. The issue of optimal duration of

anticoagulation in cancer patients with VTE remains undefined, as these patients remain at risk for VTE as long as they have active cancer. Guidelines recommend that patients with active cancer be considered for indefinite anticoagulation, but the decision should be based on careful evaluation of risk and benefit ratio. Treatment data for the newer oral direct thrombin inhibitors (DTIs) and direct Xa inhibitors, including dabigatran and rivaroxaban, show that they are comparable to warfarin in efficacy and safety, but very few patients with cancer were enrolled in these studies [39]. The results from an extension trial investigating the effectiveness of rivaroxaban in the setting of secondary prevention showed rivaroxaban is associated with a significant reduction (1.3% versus 7.1%) in the risk of recurrent VTE events in patients who completed a course of anticoagulant therapy [40]. These new agents are appealing because of oral administration and minimal laboratory monitoring, but their efficacy and safety in oncology patients need to be explored fully.

Conclusions Cancer-associated thrombosis remains a challenging clinical problem. Currently available anticoagulants are effective and relatively safe for the prevention and treatment of cancerassociated thrombosis, but are inconvenient for patients. Novel agents such as DTIs, and oral direct Xa inhibitors (rivaroxaban, apixaban, and others) appear promising; however, more data is needed in the oncology population (Table 3). Selective inhibitors of specific factors such as FIXa, FVIIa and the TF pathway are at an early stage of development. Preclinical studies suggest that some of these anticoagulants may alter cancer pathogenesis by affecting angiogenesis and cell adhesion. Future research may identify the elusive www.drugdiscoverytoday.com

e43

Drug Discovery Today: Disease Mechanisms | Haematology

common target that triggers both the progression of cancer and the pro-coagulant state in these patients. Understanding the pathophysiology of cancer-associated thrombosis and its impact on tumor biology is crucial to identifying high-risk patients who would benefit most from primary prophylaxis, and also to discover more efficacious and safer therapies that are simple to administer and monitor. The pace of ongoing research certainly holds the realistic possibility of identifying such an ideal anticoagulant agent, with the overarching goal of improving quality of life and survival in cancer patients.

Acknowledgements Dr. Khorana’s research work is supported by grants from the National Cancer Institute K23 CA120587, the National Heart, Lung and Blood Institute 1R01HL095109-01 and the V Foundation.

Vol. 8, No. 1-2 2011

19

20

21

22

23

24 25 26 27

References 1 Khorana, A.A. et al. (2007) Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J. Thromb. Hemost. 5, 632–634 2 Heit, J.A. et al. (2000) Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case–control study. Arch. Intern. Med. 160, 809–815 3 Kahn, S.R. et al. (2005) Prospective evaluation of health-related quality of life in patients with deep venous thrombosis. Arch. Intern. Med. 165, 1173–1178 4 Elting, L.S. et al. (2004) Outcomes and cost of deep venous thrombosis among patients with cancer. Arch. Intern. Med. 164, 1653–1661 5 Yu, J.L. et al. (2005) Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications for tumor progression and angiogenesis. Blood 105, 1734–1741 6 Mackman, N. (2004) Role of tissue factor in hemostasis, thrombosis, and vascular development. Arterioscler. Thromb. Vasc. Biol. 24, 1015–1022 7 Piccin, A. et al. (2007) Circulating microparticles: pathophysiology and clinical implications. Blood Rev. 21, 157–171 8 Khorana, A.A. et al. (2007) Tissue factor expression, angiogenesis, and thrombosis in pancreatic cancer. Clin. Cancer Res. 13, 2870–2875 9 Khorana, A.A. (2011) Risk assessment and prophylaxis for VTE in cancer patients. J. Natl. Compr. Canc. Netw. 9, 789–797 10 Andrea, N. et al. (2003) Management of thrombosis in the cancer patient. J. Support. Oncol. 1, 235–238 11 Bambace, N.M. et al. (2011) The platelet contribution to cancer progression. J. Thromb. Haemost. 9, 237–249 12 Nierodzik, M.L. et al. (1995) Role of platelets, thrombin, integrin IIb–IIIa, fibronectin and von Willebrand factor on tumor adhesion in vitro and metastasis in vivo. Thromb. Haemost. 74, 282–290 13 Fontaine, E. et al. (2010) Aspirin and non-small cell lung cancer resections: effect on long-term survival. Eur. J. Cardiothorac. Surg. 38, 21–26 14 Rothwell, P.M. et al. (2010) Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomized trials. Lancet 376, 1741–1750 15 Sousou, T. et al. (2009) New insights into cancer-associated thrombosis. Arterioscler. Thromb. Vasc. Biol. 29, 316–320 16 Zwicker, J.I. et al. (2007) Cancer-associated thrombosis. Crit. Rev. Oncol. Hematol. 62, 126–136 17 Khorana, A.A. et al. (2007) Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer 110, 2339–2346 18 Blom, J.W. et al. (2005) Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 293, 715–722

e44

www.drugdiscoverytoday.com

28

29

30

31

32

33

34

35

36

37

38

39 40 41

van Doormaal, F.F. et al. (2010) Idraparinux versus standard therapy in the treatment of deep venous thrombosis in cancer patients: a subgroup analysis of the Van Gogh DVT trial. Thromb. Haemost. 104, 86–91 Scappaticci, F.A. et al. (2007) Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J. Natl. Cancer Inst. 99, 1232–1239 Hurwitz, H.I. et al. (2011) Venous thromboembolic events with chemotherapy plus bevacizumab: a pooled analysis of patients in randomized phase II and III studies. J. Clin. Oncol. 29, 1757–1764 Nalluri, S.R. et al. (2008) Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA 300, 2277–2285 Choueiri, T.K. et al. (2010) Risk of arterial thromboembolic events with sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. J. Clin. Oncol. 28, 2280–2285 Khorana, A.A. et al. (2008) Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 111, 4902–4907 Gale, A.J. et al. (2001) Update on tumor cell procoagulant factors. Acta Haematol. 106, 25–32 Ay, C. et al. (2010) Prediction of venous thromboembolism in cancer patients. Blood 116, 5377–5382 Samama, M.M. et al. (1999) A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N. Engl. J. Med. 341, 793–800 Leizorovicz, A. et al. (2004) Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation 110, 874–879 Cohen, A.T. et al. (2006) Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 332, 325–329 Lyman, G.H. et al. (2007) American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J. Clin. Oncol. 25, 5490–5505 Wagman, L.D. et al. (2008) Venous thromboembolic disease. NCCN. Clinical practice guidelines in oncology. J. Natl. Compr. Canc. Netw. 6, 716–753 Lassen, M.R. et al. (2010) Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N. Engl. J. Med. 363, 2487– 2498 Kakkar, V.V. et al. (2010) Extended prophylaxis with bemiparin for the prevention of venous thromboembolism after abdominal or pelvic surgery for cancer: the CANBESURE randomized study. J. Thromb. Haemost. 8, 1223–1229 Rasmussen, M.S. et al. (2006) Prolonged prophylaxis with dalteparin to prevent late thromboembolic complications in patients undergoing major abdominal surgery: a multicenter randomized open-label study. J. Thromb. Haemost. 4, 2384–2390 Lassen, M.R. et al. (2007) The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement. J. Thromb. Haemost. 5, 2368–2375 Agnelli, G. et al. (2011) The ultra-low molecular weight heparin (ULMWH) semuloparin for prevention of venous thromboembolism (VTE) in patients with cancer receiving chemotherapy: SAVE ONCO study. American Society of Clinical Oncology Annual Meeting, Chicago, IL, USA, 4–8 June 2011 (abstract no.: LBA9014) Lee, A.Y.Y. et al. (2003) Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N. Engl. J. Med. 349, 146–153 Akl, E.A. et al. (2011) Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst. Rev. 4, CD006649 Schulman, S. et al. (2009) Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N. Engl. J. Med. 361, 2342–2352 Bauersachs, R. et al. (2010) Oral rivaroxaban for symptomatic venous thromboembolism. N. Engl. J. Med. 23, 2499–2510 Mousa, S.A. (2010) Novel anticoagulant therapy: principle and practice. Methods Mol. Biol. 663, 157–179

Vol. 8, No. 1-2 2011

42 43 44

Poller, L. et al. (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 361, 2673–2674 Gomez-Outes, A. et al. (2011) New parenteral anticoagulants in development. Therap. Adv. Cardiovasc. Dis. 5, 33–59 Ruff, C.T. et al. (2010) Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective azNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48). Am. Heart J. 160, 635–641

Drug Discovery Today: Disease Mechanisms | Haematology

45

46

47

Turpie, A.G.G. et al. (2009) Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 373, 1673–1680 Turpie, A.G.G. et al. (2009) A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT). Thromb. Haemost. 101, 68–76 Abraham, E. et al. (2003) Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 290, 238–247

www.drugdiscoverytoday.com

e45