The Bidirectional Relationship Between Cancer and VTE

The relationship between cancer and VTE is bidirectional; VTE, especially idiopathic VTE, can be a harbinger of an occult malignancy.² Population-based observational studies have documented an increased risk of malignancy after a first episode of idiopathic VTE.^33,34 In an analysis of the Swedish Cancer Registry,³³ Baron et al.³³ found that at the time of VTE diagnosis or during the first year of follow-up, there was a large increase in the risk for virtually all cancers (standardized incidence ratio of 4.4; 95% CI, 4.2-4.6) The increased risk of future cancer diagnosis in patients with VTE compared with those without VTE persisted for 2 through 25 years after admission to hospital with the index VTE.³³ In a large analysis of the Danish Cancer Registry, an increased standardized incidence ratio of 1.3 (95% CI, 1.21-1.33) for cancer diagnosis was found for patients with a VTE episode.³⁴ The risk was substantially elevated only during the first 6 months of follow-up and declined rapidly thereafter to a constant level slightly above 1.0 one year after the VTE episode.³⁴ The risk of cancer was twofold higher for patients diagnosed with idiopathic versus triggered VTE.³⁴ The association was most pronounced for cancers of the pancreas, ovary, liver, and brain.³⁴ Unfortunately, extensive cancer screening at the time of VTE diagnosis is not associated with improved outcome because most cancers associated with VTE are metastatic at the time of VTE diagnosis.^35,36 Consequently, the possibility of an underlying cancer among patients presenting with an idiopathic VTE always should be taken into consideration, but cancer screening should be limited to age-appropriate screening procedures in the absence of obvious signs of an underlying malignancy.³⁴

VTE is Associated with Worse Outcomes in Patients with Cancer

Studies have shown that diagnosis of VTE in patients with malignancy is associated with worse outcomes and shortened survival.24,25,28–30,36–39 VTE is the second most common cause of mortality after cancer itself among patients with malignancy.^25,40 In fact, 15% of deaths occurring in hospitalized patients with cancer are attributable to PE.^15,41 Chew et al.²¹ analyzed approximately 235,000 patients with cancer in the California Cancer Registry who were linked to the California Patient Discharge Data Set and found in a multivariate analysis that diagnosis of VTE during the first year of follow-up was a significant predictor of death and decreased survival for most cancer types and stages. The 1-year survival of patients with cancer who were diagnosed with VTE is one third (12% versus 36%) that of patients with cancer who do not have VTE.³⁶ Levitan et al.²³ noted a threefold increase in 6-month mortality among patients with cancer who had VTE compared with those without VTE.

In addition to symptomatic VTE, unsuspected asymptomatic PE found on routine cancer staging computed tomography (CT) imaging was found to adversely affect survival in patients with cancer.37,39,42 In a retrospective matched cohort study, the hazard ratio (HR) for death among patients who had cancer with unsuspected PE detected on staging CT was 1.51 (95% CI, 1.01-2.27), with the risk attributable to proximal rather than subsegmental unsuspected PE.³⁷ Another retrospective study showed that patients with cancer who were diagnosed with and treated for incidental PE have similar rates of recurrent VTE, bleeding, and mortality compared with patients with cancer who had symptomatic PE.³⁸ Moreover, several studies in patients with cancer have correlated increases in biomarkers of thrombin generation, even in absence of documented VTE, with more aggressive cancer biology and worse outcomes.^42–45 Despite ongoing anticoagulation therapy, patients with cancer have a 3.2-fold increased risk of recurrent VTE compared with patients without cancer (12-month cumulative VTE incidence 20.7% vs. 6.8%).⁴⁶ Additionally, the incidence of major bleeding is 2.2-fold higher in patients with cancer compared with patients without cancer (12.4% vs. 4.9%).⁴⁶ The risks of recurrent VTE and bleeding appear to correlate with the extent of the malignancy.⁴⁶ As expected, the development of VTE in patients with cancer is associated with a significant increase in the consumption of health care resources.⁴⁷

Tumor-Specific Factors

Malignancy is characterized by a bidirectional interrelationship connecting cancer growth, progression, and metastasis with activation of the coagulation cascade and subsequent thrombin generation and inflammation.7,48–50 As discussed earlier, tumor-associated factors such as site, histology, and stage all influence the risk of thrombosis. Cancer cells can disrupt the hemostatic balance via several different pathways, including production of procoagulant, profibrinolytic, proproteolytic, and proaggregating activities, expression of adhesion molecules that mediate direct interactions with host vascular and blood cells, and secretion of proinflammatory and proangiogenic cytokines.^{7,27,40,50,51} Figure 35-2 depicts some of the tumor-specific factors that contribute to the hypercoagulable state of cancer. Cancer procoagulant is a cysteine protease expressed only by malignant cells that can directly activate factor X independent of factor VII.^54–54 In addition, cancer procoagulant has been demonstrated to activate platelets, further adding to its prothrombotic potential.⁵⁵ Cancer procoagulant has been identified in a wide variety of cancer types and has been noted to have increased activity at disease onset with a subsequent slow decline.^7,52–56

Tissue factor (TF) is the principal initiator of the coagulation protease cascade and is normally expressed as a transmembrane glycoprotein on vascular subendothelial cells.3,7,48,49 Therefore TF is not normally in contact with blood unless vascular endothelial integrity is compromised or if its expression is induced on endothelial cells by inflammatory stimuli.^3,7,48,49 Many types of cancer cells such as pancreatic adenocarcinoma and malignant glioma express high levels of TF, which can subsequently lead to activation of both factor X and factor IX, thrombin formation, and ultimately, fibrin clot formation.^7,57 TF, which can also be produced by cells in the cancer microenvironment depending on cancer type and context, has been associated with cancer initiation, metastasis, progression, and angiogenesis, in addition to activation of coagulation.^49,58–63 Laboratory studies have demonstrated a correlation between increasing TF expression in glioma cells and histologic grade, progression, and the risk of intravascular thrombosis.^64,65 In pancreatic adenocarcinoma, it has been shown that fibrinogen and plasminogen activator inhibitors (PAIs) 1, 2, and 3 exist throughout the tumor stroma and that tumor cells stain for TF, PAI, prothrombin, and several other coagulation factors.⁶⁶ In another study, expression of TF was found to correlate strongly with the degree of histologic differentiation in pancreatic adenocarcinoma. Tumors with stronger immunoreactivity for TF were more poorly differentiated.⁶⁰ Based on these observations, it has been theorized that local coagulation activation may regulate growth and progression of pancreatic adenocarcinoma.^65,66 TF can drive cancer progression by coagulation-dependent and coagulation-independent mechanisms.^49,67 The circulating form of TF has been proposed to contribute more significantly to the pathogenesis of cancer-associated VTE than TF expressed on primary cancer cells.⁴⁹ In a retrospective study, patients with cancer who had circulating TF-expressing microparticles had a 1-year cumulative incidence of VTE of 34.8% versus 0% in those without detectable TF-bearing microparticles.⁶⁸ This and other similar observations suggest that cancer-derived TF-bearing microparticles are thrombogenic in vivo and are likely to play a central role in the pathogenesis of cancer-associated VTE.⁴⁹ The clinical utility of this assay has not been demonstrated yet, and it remains an investigational tool at the current time.

Most patients with cancer have been found to exhibit increased levels of coagulation factors V, VIII, IX, XI, and biomarkers of thrombin generation such as prothrombin fragment 1+2 and D dimer.48,59 As mentioned previously, elevated biomarkers of thrombin generation have been associated with aggressive cancer biology and worse clinical outcomes.^42–45 The fibrinolytic system can also be significantly dysregulated in patients with cancer.⁶⁹ Malignant cells can express different proteins in the fibrinolytic system, including urokinase-type and tissue-type plasminogen activators (UPA and TPA, respectively) and PAIs.^7,69,70 For example, acute promyelocytic leukemia is often associated at onset with a life-threatening coagulopathy associated with hypofibrinogenemia, increased thrombin generation and fibrin degradation, and prolonged prothrombin and thrombin times.²⁷ The leukemic cells in acute promyelocytic leukemia can express the UPA receptor on their surface, which activates UPA and TPA, contributing to the fibrinolytic state characteristic of the disease.⁷¹ Other leukemic cells are also capable of expressing various fibrinolytic and proteolytic enzymes that can mediate the bleeding complications seen in some patients with acute leukemia.^27,51,69 Similarly, plasminogen activators, PAIs, and other proteins that regulate the fibrinolytic system are also expressed by solid tumor cells, and the resulting imbalance in fibrinolysis may contribute to the hypofibrinolytic and procoagulant state seen in some affected patients.^7,69,70 Additionally, cancers can be associated with deficiencies in the natural anticoagulants, antithrombin, protein C, and protein S, further promoting the cancer-associated thrombogenic state.^72,73 The degree of activation of the coagulation cascade and fibrinolysis differs between various tumor types. As noted earlier, some patients with cancer will exhibit clinically evident manifestations of activated coagulation such as DIC and/or venous or arterial thromboembolism, whereas many other patients with cancer will only have laboratory markers of a procoagulant state such as elevated D dimer.^74,75

Cancer cells can also modulate the hemostatic balance in an indirect fashion through their interaction with host immune cells such as monocytes and macrophages, leading to activation of platelets and factors X and XII.² Tumor cells can directly produce inflammatory cytokines or indirectly stimulate their production by host cells (leukocytes and endothelial cells), promoting a hypercoagulable state.^2,3 These inflammatory cytokines, such as tumor necrosis factor–alpha (TNF-α), interleukin-1 (IL-1), and vascular endothelial growth factor (VEGF) can induce TF production by endothelial cells and monocytes, stimulate PAI-1 production, and downregulate expression of the natural anticoagulant protein, thrombomodulin, on endothelial cells.^3,4A,76,77 In addition, these cytokines can lead to vascular endothelial cell damage and conversion of vascular lining into a thrombogenic surface.² In addition to activation of TF production by endothelial cells and monocytes, the effects of VEGF include induction of angiogenesis and increased local vascular permeability, therefore increasing the exposure of TF and promoting cancer-associated thrombogenesis.⁷⁸ The acute phase reactants induced by inflammatory cytokines in patients with cancer include procoagulants such as von Willebrand factor (vWF), factor VIII, and fibrinogen, therefore favoring a thrombogenic hemostatic milieu. Tumor cells can also promote nonenzymatic activation of factor X through the sialic acid moieties of mucin produced by adenocarcinomas.² Although increased levels of factor VIII, vWF, fibrinogen, PAI, and markers of thrombin generation and fibrin degradation have been associated with more advanced cancers and worse outcomes, these biomarkers have not shown any benefit to date in selecting patients with cancer who might benefit from primary anticoagulant VTE prophylaxis.^{14,42–45,79}

Tumor cells can also directly aggregate platelets and secrete important platelet aggregation agonists such as thrombin and adenosine diphosphate.⁸⁰ In addition to these biochemical procoagulant mechanisms, direct cell-cell interactions and the local mass effect of tumors contribute to VTE pathogenesis in patients with cancer. Vascular invasion and physical compression by the tumor can mechanically obstruct venous blood flow, leading to venous stagnation, endothelial lining damage, and local activation of the coagulation cascade, all of which predispose to VTE.^14,81,82 In patients with myeloma, increased plasma viscosity, elevated levels of circulating immunoglobulins, autoantibodies targeting natural anticoagulants, and secretion of inflammatory mediators with procoagulant activity have all been proposed to contribute to the pathogenesis of VTE.^31,32,83

Host-Specific Factors

Studies have shown that some host-specific factors can also modify the risk of VTE. Older age (≥65 years) has been modestly associated with cancer-associated VTE in hospitalized patients.⁸⁴ Poor performance status in patients with lung cancer who are receiving chemotherapy, which might be a surrogate for limited mobility, has been prospectively associated with increased VTE risk.⁸⁵ Patient race (African Americans have a higher risk, whereas Asians have a lower risk) and comorbidities such obesity and renal disease have also been associated with increased risk of cancer-associated VTE, whereas gender does not significantly influence risk.^5,8,84,86 ABO blood group status, which was found to affect the risk of VTE in the general population, has also been found to modify the risk of VTE in patients with malignant glioma.^87,88 Although the pathophysiology of the ABO blood group’s association with VTE is not fully clarified, ABO blood group status does influence factor VIII and vWF levels, which might mediate this effect.^89,90

The presence of prothrombotic genetic alterations has been also shown to influence the risk of VTE in patients with cancer. In a large population-based, case-control study of 3220 consecutive patients aged 18 to 70 years in the Netherlands, patients with cancer who were carriers of factor V Leiden or the prothrombin gene 20210A mutation had a fourfold increased risk of VTE compared with patients with cancer who did not have these mutations.⁵ In contrast, a smaller study from Brazil found no significant difference in the prevalence of four thrombophilic genetic mutations/polymorphisms (factor V Leiden, prothrombin gene 20210A mutation, FXIII Val34Leu polymorphism, and methylenetetrahydrofolate reductase [MTHFR] C677T polymorphism) in patients with cancer who did and did not have VTE.⁹¹ A third study in patients with gastrointestinal adenocarcinoma found a significant association between VTE and factor V Leiden mutation but not with prothrombin gene 20210A mutation or the MTHFR C677T polymorphism.⁹² A matched nested, case-control study of breast cancer prevention using tamoxifen found no significant association between the factor V Leiden mutation or the prothrombin gene 20210A mutation and VTE risk.⁹³

Environmental Factors

Environmental factors significantly modulate VTE risk in patients with cancer. As expected, many modifiable VTE risk factors increase VTE risk in patients with and without cancer.

Prevention of VTE in Ambulatory Medical Patients with Cancer

Because most episodes of VTE in patients with cancer occur in the outpatient setting, prevention of VTE in ambulatory medical oncology patients has been the focus of extensive investigation. In 1994, Levine and coworkers¹⁷³ reported a double-blind, randomized study of very low dose warfarin thromboprophylaxis in patients with stage IV breast cancer. In this study, 152 patients received very low dose warfarin (1 mg adjusted to achieve an INR of 1.3-1.9), whereas 159 patients received placebo. Seven cases of VTE (six DVT and one PE) occurred in the placebo group and one PE occurred in the warfarin group (P = .031), representing an 85% risk reduction. Major bleeding occurred in two placebo recipients and one patient treated with warfarin.¹⁷³ In the Prophylaxis of Thromboembolism During Chemotherapy Trial (PROTECHT), Agnelli et al.¹⁷⁴ randomly assigned 1166 patients in a double-blind fashion to evaluate the clinical benefit of prophylactic-dose nadroparin for thromboprophylaxis in ambulatory patients with cancer who were actively receiving chemotherapy for metastatic or locally advanced solid tumors. Participants with lung, gastrointestinal, pancreatic, breast, ovarian, or head and neck cancers were randomly assigned in a 2 : 1 schema to receive either nadroparin (3800 IU subcutaneously daily, n = 779) or placebo (n = 387) for the duration of chemotherapy up to a maximum of 4 months. The primary end point was a composite of independently adjudicated symptomatic VTE or arterial thromboembolism. In total, 1150 patients (769 patients in the nadroparin arm and 381 patients in the placebo arm) were evaluated for the primary efficacy and safety analyses using a modified intention-to-treat approach. In the nadroparin arm, the primary outcome developed in 15 patients (2%), compared with 15 patients (3.9%) in the placebo group (single-sided P = .02). There was no statistically significant difference in the rates of major bleeding events (0.7% for the nadroparin group vs. 0% in the placebo group, two-sided P = .18) or minor bleeding (7.4% in the nadroparin group compared with 7.9% in placebo arm). In total, 15.7% serious adverse events occurred in the nadroparin group versus 17.6% in the placebo group. The authors concluded that nadroparin reduces the incidence of thromboembolic events in ambulatory patients with metastatic or locally advanced malignancies who are receiving chemotherapy.¹⁷⁴ It is worth noting that breast and head and neck cancers are not usually considered high risk for VTE development, and the inclusion of these patients in this study may have accounted for the observed low thromboembolic event rates.⁸⁶

In another prospective study, the UK-FRAGEM trial, 123 patients with advanced pancreatic carcinoma were randomly assigned to receive either gemcitabine or gemcitabine plus a weight-adjusted therapeutic dose of dalteparin for 12 weeks (200 IU/kg daily × 1 month and then 150 IU/kg daily for months 2 and 3).¹⁷⁵ The primary end point was the reduction of all-type VTE during the study period. The incidence of the primary outcome was decreased from 23% to 3.4% (P = .002) in favor of the dalteparin group, with a risk ratio of 0.15 (95% CI, 0.035-0.61), corresponding to an 85% risk reduction. At the end of follow-up, all instances of VTE were also reduced significantly from 28% to 12% (P = .039), with a risk ratio of 0.42 (95% CI, 0.19-0.94), a 58% risk reduction. Lethal VTE occurring earlier than 100 days was seen only in the control arm (8.3% compared with 0%, P = .057, with a risk ratio of 0.092, 95% CI, 0.005-1.635). No difference in overall survival was found. The authors concluded that weight-adjusted dalteparin used as primary VTE prophylaxis for 12 weeks in patients with advanced pancreatic carcinoma who receive gemcitabine is safe and is associated with a significant reduction of all VTEs during the prophylaxis period.¹⁷⁵ It should be noted the PROTECHT study used prophylactic-dose nadroparin, whereas the UK-FRAGEM trial used therapeutic-dose dalteparin.⁸⁶

In the SAVE-ONCO trial, a recently published, double-blind, multicenter randomized study, investigators evaluated the efficacy and safety of the new ultra low molecular weight heparin, semuloparin, for VTE prophylaxis in patients with cancer who were undergoing chemotherapy.¹⁷⁶ In this study, 3212 patients with metastatic or locally advanced solid tumors who were starting chemotherapy were randomly assigned to receive subcutaneous semuloparin, 20 mg once daily, or placebo until there was a change of chemotherapy regimen. The primary efficacy outcome of the study was a composite of any symptomatic DVT, any nonfatal PE, and death related to VTE, whereas the primary safety outcome was the incidence of clinically relevant bleeding. The median duration of therapy was 3.5 months. In the semuloparin arm, VTE occurred in 1.2% in comparison with 3.4% in the placebo arm (HR, 0.36; 95% CI, 0.21-0.60; P < .001), with consistent efficacy among subgroups defined based on origin and stage of cancer and the baseline risk of VTE. There was no significant difference in clinically relevant bleeding between the two groups (2.8% vs. 2% in the semuloparin and placebo groups, respectively; HR, 1.40; 95% CI, 0.89-2.21). The authors concluded that semuloparin reduces the incidence of VTE in patients with cancer receiving chemotherapy without a significant increase in major bleeding episodes.¹⁷⁶

As discussed earlier, thalidomide and lenalidomide therapy in patients with MM has been associated with an increased incidence of VTE, especially in combination with chemotherapy or high-dose corticosteroids. The 2008 International Myeloma Working Group issued a consensus statement on the prevention of VTE associated with thalidomide and lenalidomide with specific recommendations based on type of therapy and individual VTE and bleeding risks.¹⁷⁷ The group developed a risk assessment model based on patient-related (e.g., obesity), myeloma-related (e.g., hyperviscosity) and therapy-related (e.g., high-dose dexamethasone) risk factors for VTE. The panel recommended aspirin for patients with ≤1 VTE risk factor and low molecular weight heparin (LMWH, equivalent to enoxaparin, 40 mg daily) for patients with ≥2 individual or myeloma-related risk factors (Table 35-1).¹⁷⁷ LMWH has been recommended for all patients receiving concurrent high-dose dexamethasone or doxorubicin. Full-dose warfarin (INR goal of 2 to 3) has been listed as an alternative to LMWH. The panel acknowledged the limited high-quality data in the literature.¹⁷⁷ Subsequent to this consensus statement, two large randomized studies of VTE prophylaxis in patients with MM who were treated with lenalidomide- or thalidomide-based combination regimens have been published.^178,179 The first study was a prospective, open-label, randomized study comparing the efficacy and safety of VTE prophylaxis with low-dose aspirin or LMWH in patients with newly diagnosed MM who were treated with lenalidomide and low-dose dexamethasone induction and melphalan-prednisone-lenalidomide consolidation.¹⁷⁸ A total of 342 patients without clinical indications or contraindications to antiplatelet or anticoagulant therapy were randomly assigned to receive aspirin, 100 mg daily (n = 176), or enoxaparin, 40 mg daily (n = 166). There was no statistically significant difference in the incidence of VTE between the two groups (2.27% in the aspirin group vs. 1.2% in the LMWH group, corresponding to an absolute risk difference of 1.07%; 95% CI, −1.69-3.83; P = .452). Although PE was observed in 1.7% of patients in the aspirin arm compared with none in the LMWH group, no arterial thrombosis, acute cardiovascular events, major bleeding complications, or sudden deaths were reported. The authors concluded that in newly diagnosed patients with MM who are receiving lenalidomide in conjunction with low-dose dexamethasone, aspirin can offer an effective and less-expensive alternative to LMWH for VTE prophylaxis.¹⁷⁸