Abstract
A hypercoagulable or prothrombotic state of malignancy occurs due to the ability of tumor cells to activate the coagulation system. It has been estimated that hypercoagulation accounts for a significant percentage of mortality and morbidity in cancer patients. Prothrombotic factors in cancer include the ability of tumor cells to produce and secrete procoagulant/fibrinolytic substances and inflammatory cytokines, and the physical interaction between tumor cell and blood (monocytes, platelets, neutrophils) or vascular cells. Other mechanisms of thrombus promotion in malignancy include nonspecific factors such as the generation of acute phase reactants and necrosis (i.e., inflammation), abnormal protein metabolism (i.e., paraproteinemia), and hemodynamic compromise (i.e., stasis). In addition, anticancer therapy (i.e., surgery/chemotherapy/hormone therapy) may significantly increase the risk of thromboembolic events by similar mechanisms, e.g., procoagulant release, endothelial damage, or stimulation of tissue factor production by host cells. However, not all of the mechanisms for the production of a hypercoagulable state of cancer are entirely understood. In this review, we attempt to describe what is currently accepted about the pathophysiology of the hypercoagulable state of cancer. We also discuss whether or not to screen patients with idiopathic deep venous thrombosis for an underlying malignancy, and whether this would be beneficial to patients. It is hoped that a better understanding of these mechanisms will ultimately lead to the development of more targeted treatment to prevent thromboembolic complications in cancer patients. It is also hoped that antithrombotic strategies may also have a positive effect on the process of tumor growth and dissemination.
Keywords: cancer, cancer therapy, hypercoagulation, procoagulants, thrombosis
Introduction
There is considerable evidence that thrombosis is a common complication of malignancy, and represents the second most frequent cause of death in cancer patients [1,2]. Postmortem studies have identified an increased incidence of thromboembolic deaths in cancer, in particular in patients who died of mucinous carcinoma of the pancreas, lung, and gastrointestinal tract [3]. Alternatively, cancer patients represent 20% of all patients in whom deep venous thrombosis (DVT) and pulmonary embolism (PE) are diagnosed.
The close relationship between the coagulation cascade and thrombosis has been suggested by numerous studies [4–12] (Table 1). Clinically detectable venous thromboembolism (VTE) is present in 15% of all cancer patients, and the number is likely to be even higher when subclinical thromboembolism (TE) is taken into account [13,14]. There is evidence that certain cancers are more likely to be prothrombotic, and this is likely to be influenced by disease staging, bedrest, as well as therapeutic intervention. One study found evidence of TE in 5% to 10% of patients with breast cancer undergoing adjuvant chemotherapy and up to 15% of those with metastatic disease [14]. Recurrent TE is also twice as likely in patients with cancer, even when established on oral anticoagulant therapy [15,16]. These patients also tend to require longer hospitalization, respond less well to oral anticoagulant therapy, and have a poorer prognosis after their first episode of VTE.
Table 1.
Examples of Studies Demonstrating a Relationship between Cancer and Thrombosis.
|
However, even in the absence of obvious thrombosis, cancer patients with solid tumors and leukemias commonly present with abnormal laboratory coagulation tests, characterized by varying degrees of clotting activation, indicating a subclinical hypercoagulable condition [17–19].
The purpose of this review is to outline our knowledge about the interactions between the hemostatic system and malignancy, and to review the pathogenetic mechanisms of the increased thrombotic tendency associated with cancer.
Clinical Manifestations and Epidemiology
Thromboembolic disease is often one of the earliest clinical signs of an underlying malignancy. In 1865, Trousseau [20] first noted that “in cancer a special condition of the blood predisposed to spontaneous coagulation even in the absence of inflammatory reactions.” Clinical manifestations can range from abnormal coagulation tests in the absence of symptoms to overt, clinically defined VTE, normally associated with primary solid tumor growth, and disseminated intravascular coagulation (DIC), more common in patients with hematological cancers and metastatic disease [21,22]. Severe DIC with life-threatening hemorrhagic complications is usually caused by the large consumption of clotting factors and platelets, and is thought to be responsible for 10% to 20% of early fatal events in acute leukemia [23].
DVT and PE are the two most common thromboembolic complications in cancer. The risk of lower extremity DVT is about twice that of noncancer patients after abdominal surgery, and the risk of fatal PE postoperatively is even increased four-fold in cancer patients [24–26].
DVT of the upper extremities is associated with specific risk factors: axillary lymphomas, mediastinal tumor masses, central venous catheters, and intravenous chemotherapy. Upper extremity DVT is frequently complicated by PE (8–36%) and chronic venous insufficiency (20–50%). DVT of the upper extremity, if untreated, may lead to central venous thrombosis and clinical superior vena cava syndrome [27].
Trousseau's syndrome is a rare variant of VTE that is characterized by recurrent, migratory thrombosis in superficial veins and in uncommon sites, such as the chest wall and arms. This syndrome is particularly associated with pancreatic and lung cancer [28].
Hepatic vein thrombosis (Budd-Chiari syndrome) with rapid development of ascites and hepatomegaly is specifically seen in patients with myeloproliferative syndromes, or in patients with a hepatocellular carcinoma [29].
Marantic endocarditis is characterized by the presence of sterile, thrombotic vegetations on cardiac valves. This rare syndrome is complicated by arterial emboli, leading to stroke and myocardial infarction [28]. Marantic endocarditis is associated with lung cancer and mucin-producing adenocarcinoma [28,29].
Up to 15% of cancer patients presents with VTE throughout the progression of the disease [28,29]. Interestingly, VTE is not equally common in all types of cancer. The highest incidence is found in mucin-producing adenocarcinomas, pancreas and gastrointestinal tract, lung cancer, and ovarian cancer. TE occurs less often in breast and renal cell carcinoma and rarely in patients with prostate cancer, melanoma, and cancer of unknown primary origin [3,28,29] (Table 2).
Table 2.
Estimated Prevalence of VTE during the Course of Common Types of Cancer.
| Cancer Site | Prevalence (%) |
| All malignancies | 10–15 |
| Pancreas | 28 |
| Lung | 27 |
| Stomach | 13 |
| Colon | 3 |
| Breast premenopausal | 1–2 |
| Breast postmenopausal | 3–8 |
| Prostate | 2 |
| Unknown primary tumor | 1 |
Prothrombotic Mechanisms
Several factors involved in the immune response to neoplasia, such as the development of acute phase reactants, abnormal protein metabolism, necrosis, and hemodynamic rearrangements, can all contribute to the overall activation of blood coagulation in cancer patients. However, a prominent role is attributed to tumor-specific prothrombotic mechanisms, which include a number of tumor cell properties. Malignant cells can interact with the hemostatic system in multiple ways, but the two principal categories of interaction are: 1) the capacity to produce and release procoagulant and fibrinolytic activities, as well as inflammatory cytokines; and 2) direct interaction with other blood cells, i.e., endothelial cells, platelets, and monocytes. The principle modes of interaction are summarized in Table 3. We will now consider each of these mechanisms in more detail.
Table 3.
Prothrombotic Properties of Tumor Cells.
| Property | |
| Procoagulant activity | Production of
|
| Fibrinolytic activity | Expression of
|
| Cytokine release | Release of
|
| Cell-cell interactions | Interaction with
|
Procoagulant Activity (PCA)
Procoagulant properties of tumor cells enable them to promote the formation of fibrin deposits at sites of extravasation and in the tumor microenvironment at an extracellular level [30,31]. The best-characterized procoagulants are tissue factor (TF) and cancer procoagulant (CP).
Tissue Factor TF is a 47-kDa transmembrane glycoprotein that forms a complex with factor VII (FVII)/FVIIa. This TF/FVII complex initiates blood coagulation by proteolytically activating FIX and FX [32,33]. TF is the cellular procoagulant expressed in normal resting cells, including endothelial cells and monocytes-macrophages. However, these cells do not express TF under normal resting conditions, TF is produced in response to proinflammatory stimuli, i.e., the cytokines IL-1β, TNF-α, and bacterial endotoxins [33,34]. However, in contrast to normal cells, malignant cells express TF constitutively and thus have constant PCA.
Cancer Procoagulant CP is a cysteine protease of 68 kDa with an isoelectric point (pI) of 4.8, containing 674 amino acids and no detectable carbohydrate. The only known physiological substrate for CP is coagulation FX [35,36]. CP can activate FX independently of FVII and cleaves the FX heavy chain at a different site compared with other known FX activators [35,36]. CP has been detected in extracts of tumor cells and in amnion-chorion tissues, but not in extracts of normal cells [37–41]. CP antigen, measured by enzymelinked immunosorbent assay (ELISA), has been shown to be elevated in 85% of cancer patient subjects [42]. These findings also correlate with the PCA of CP in cancer patients [43]. The presence of TF and CP has been shown in several human and animal tumor tissues [44].
Fibrinolytic molecules Tumor cells can express everything required for regulation of the fibrinolytic pathway on their cell surface. They possess both the urokinase-type (u-PA) and the tissue-type plasminogen activator (t-PA) and can also produce plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2) [45]. Among activators, u-PA is the most widely expressed within cancerous lesions [46]. Indeed, tumor cells are known to carry the specific PA receptors (u-PAR) on their membranes, which can facilitate the activation of the fibrinolytic system [47]. These receptor-mediated events are presumed to play an important role in the pathogenesis of the bleeding symptoms in some patients with leukemia [23]. In addition to their role in hemostasis, recent data strongly suggest that the delicate balance between plasminogen activators and their inhibitors plays a role in tumor invasion, tumor cell progression, and metastasis. Levels of one or more of these markers have been recognized as predictors of disease-free interval and long-term survival in some patients with malignant disease [45].
Cytokines Tumor cells produce and secrete a number of different proinflammatory cytokines [48,49], some of which can adversely affect the normal anticoagulant system in the vascular endothelium. For example, TNF-α and IL-1β (as well as bacterial endotoxins) can induce the expression of TF by vascular endothelial cells (VECs) [50,51] and downregulate the expression of thrombomodulin (TM), the surface receptor for thrombin [52]. A drop in TM thrombin levels leads to reduced activation of the protein C system, which is one of the main anticoagulant defense systems. In addition to the upregulation of TF, this can cause a conversion of a normal endothelium to a prothrombotic endothelium [53].
The release of vascular endothelial growth factor (VEGF) by tumor cells may account for the increased microvascular permeability found in a wide variety of tumors [54,55], and is considered to play a role in tumor angiogenesis [55]. VEGF induces separation of VEC in the postcapillary venules, is a selective mitogen, and is a chemotactic factor for cultured VECs [56]. In addition to VECs, VEGF is chemotactic for macrophages and induces a number of genes in these cells, including TF [56]. IL-8 is also a potent proangiogenic cytokine elaborated by a number of cells, including VECs. Recent data shows that cross-linked fibrin (XLF), formed on the surface of VECs in tissue culture, can upregulate the IL-8 gene and induce the synthesis and release of increasing concentrations of functional IL-8 in endothelial cells in a dose-dependant manner [57]. This would suggest that blood coagulation reactions can contribute to induction of new vessel formation by more than one pathway. Thus, the regulation of VEGF synthesis by TF in tumor cells and the regulation of IL-8 synthesis by XLF binding to receptors on the surface of VECs could provide a potentially important link in cancer patients among activation of coagulation, the inflammatory cytokine cascade, clinical VTE, angiogenesis, and the growth and metastasis of malignant tumors [58–64].
Angiogenesis Several recent findings suggest a link between tumor angiogenesis and the hypercoagulable state in malignancy [65–68]. For example, the presence of TF expression in the vascular endothelium of breast cancer tissue was shown to strongly correlate with the initiation of angiogenesis [65]. TF expression has also been shown to correlate positively with microvessel density and expression of the angiogenic modulator, VEGF [67]. Animal models suggest that the way in which TF and angiogenesis interact may include the regulation of growth regulatory molecules of the endothelium, a mechanism distinct from TF-mediated activation of coagulation mechanisms [68]. Interestingly, VEGF induces hyperpermeability by a direct action on the endothelium [69] and (unlike basic fibroblast growth factor) promotes platelet activation and adhesion [70] in vitro.
Tumor Cell-Host Cell Interactions
Endothelium Tumor cells can interact with the vascular endothelium by both direct and indirect mechanisms. Indirect mechanisms include those that are induced by inflammatory cytokines synthesized and released by tumor cells (as previously described), which suppress the antithrombotic state and enhance the prothrombotic state of endothelial cells. Direct mechanisms include those that are affected by the direct interaction of tumor cells adhering to the endothelium and/or the extracellular matrix through membrane adhesion molecules [71,72]. Malignant cells attached to the vessel wall may play a major role in promoting localized clotting activation and thrombus formation by the release of cytokines, and the subsequent adhesion of other cells, including leukocytes and platelets. The adhesion of tumor cells to each other or to vascular cells may also facilitate cell migration and extravasation [73]. In addition, the overexpression of EC TF may have major implications in tumor angiogenesis [65].
Platelets Patients with advanced cancer have been shown to exhibit increased platelet activation, also indicated by increased platelet turnover and decreased platelet survival time [74–80]. Laboratory studies have shown that mitogenic cell extracts, cell membrane fragments, and secreted chemicals from various animal and human cancers can directly aggregate platelets, as well as increase platelet turnover and decrease platelet survival time [74,75]. A link has also been proposed among the degree of cell surface sialylation of tumor cells, their ability to aggregate platelets, and the incidence of thrombosis in cancer patients [76]. Indeed, the ability of tumor cells to produce platelet-aggregating ability and plasminogen activator mirrors their metastatic potential in human and experimental models [31]. Intravenous injection of tumor cells into experimental animals leads to platelet aggregation in vivo, whereas many human and animal tumor cells provoke platelet aggregation in vitro [81–83]. Several distinct mechanisms appear to be involved. Tumor cells and tumor vesicles shed from many tumor cells bind to platelets, raising the possibility of platelet aggregation by physical bridging [81,84,85].
Other causes of the increased platelet activation in cancer include cancer-induced thrombin generation, adenosine 5′-diphosphate (ADP), and a cathepsin B-like cysteine proteinase production by tumor cells and raised levels of von Willebrand factor [86–89]. Platelet aggregation is a recognized important mechanism for thrombus formation in many diseases, including cancer. Such platelet microthrombi may afford tumor cells some protection against the host's immune response, thus contributing further to disease progression.
Monocytes-macrophages Tumor cells also have the ability to interact with the monocyte-macrophage system and induce TF expression by these cells [90]. Monocytes-macrophages circulate in the bloodstream or congregate on the vascular surfaces in response to inflammatory stimuli. Mononuclear phagocytes do not express TF under resting conditions, like endothelial cells, but can generate this procoagulant on their surface in response to various stimuli, including bacterial endotoxins, inflammatory molecules, complement, immune complexes, and lymphokines. In vitro data show that tumor cells (and tumor cell products) can induce the expression of monocyte TF [34]. Mononuclear cell activation may also occur in vivo as well. In fact, tumor-associated macrophages from experimental and human tumors have been shown to express significantly increased TF than control cells [34,91]. This mechanism may contribute to the activation of the hemostatic system and the deposition of fibrin within tumor tissue. In addition, circulating monocytes from cancer patients have been shown to express increased TF activity [92]. The generation of procoagulant substances by monocytes-macrophages in vivo could be a mechanism of clotting activation in cancer [34]. Furthermore, there is evidence that tumor-associated macrophages respond to tumor-derived mediators not only by exposing TF, but also by increasing their fibrinolytic enzyme production [93].
Cancer Therapy and Risk of Thrombosis
Treatments for cancer, including surgery, hormonal therapy, cytotoxic chemotherapy, and also the placement of central venous catheters, contribute to the hypercoagulable state and, hence, are independent risk factors for VTE in cancer patients [94–98].
Surgery, usually the first choice for benign solid tumors, can increase the risk of TE due to activation of the hemostatic system [99]. The risk of postoperative thrombosis is raised approximately two-fold in cancer patients compared to noncancer patients, and the risk of fatal PE postoperatively is even increased four-fold in cancer patients [100,101]. One study suggests that a preoperative laboratory evaluation of thrombosis markers, i.e., thrombin-antithrombin levels, may be useful in identifying at-risk patients for postoperative DVT [102].
Chemotherapy can increase the risk of thrombosis in cancer patients. This has been best studied in breast cancer, where tamoxifen and cytotoxic chemotherapy both appear independently to increase the risk of venous thrombosis [103–108]. This increase in risk appears to be greatest in postmenopausal patients. An increased risk for arterial thrombosis has also been observed [105,109]. However, it should be noted that many of the chemotherapy regimens in these studies contained more drugs (up to seven) than are present normally in modern day regimens (up to three).
Thrombotic complications have been shown in association with specific chemotherapeutic agents, including l-asparaginase, mitomycin C, cisplatin, as well as high-dose chemotherapeutic regimens for bone marrow transplantation [110]. Controlled studies have shown that conventional chemotherapy routinely used for treating breast cancer can also increase the risk of TE [108] and that prophylactic treatment with warfarin can reduce this risk [111]. Moreover, hormone therapy with tamoxifen is an additional risk factor for thrombosis in breast cancer. In premenopausal women, the combination of cytotoxic chemotherapy and tamoxifen has shown to have a greater degree of thrombotic complications than chemotherapy alone [105]. Additionally, the use of hematopoietic growth factors [i.e., granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF)] may be implicated in hypercoagulation and clot formation in breast cancer [112,113].
Cancer patients with indwelling long-term central venous catheters are also prone to thrombotic complications [97,114]. Two kinds of catheter-related thrombi may develop: sleeve thrombi developing on the outside of intravenous catheters, and occlusive DVT [114,115].
Screening for Cancer in Idiopathic Thromboembolic Disease
Although venous thrombosis is a well-known complication of cancer, it could also be considered to be a marker of an otherwise occult cancer. If this is the case, it raises the issue of whether otherwise healthy patients presenting with a venous thromboembolic episode should be investigated for an underlying cancer on the grounds that a cancer diagnosed early may be more responsive to medical intervention.
Whether screening for an occult cancer is a good use of resources will depend on the incidence of the particular cancer; the cost, accuracy, and acceptability of the screening tests; and, most importantly, whether early detection of such cancers would improve patient outcome.
Large prospective studies of patients presenting with VTE find an incidence of previously undiagnosed cancer of 4% to 6.5%, giving standardized incidence ratios of 1.3 to 3.2 [116–118]. Smaller retrospective and prospective studies looking particularly at patients with no obvious risk factors for their thrombosis find higher incidences of cancer, of 7.3% to 12%, compared with 1.9% to 2.9% for patients with risk factors [119–121]. In these studies, patients were not specifically investigated for an underlying cancer, the diagnosis being made after routine investigation on admission or after 6 to 12 months follow-up. Two studies in which patients underwent intensive investigations for cancer at the time of presentation found an incidence as high as 19% in patients with no risk factors [122,123].
In patients presenting with VTE, the prevalence of concomitant cancer, defined as cancer not known before VTE, discovered by routine examination [history taking, physical examination, simple laboratory tests like erythrocyte sedimentation rate (ESR), whole blood count, liver and kidney function tests, urinalysis, and chest X-ray] varies considerably between studies (Table 4). This variation might relate to the depth of the routine examinations and to the characteristics of the excluded patients. Another part of the explanation is the variability of definition used for secondary thrombosis and differences in threshold of suspicion. It seems that some of the differences can also be explained by the age of the patients. The studies of Ahmed and Mohyuddin [124] and Subira et al. [125], which both found a zero prevalence, contained almost exclusively patients younger than 40 years. They did not find any concomitant cancer in this age category.
Table 4.
Prevalence of Patients with Concomitant Diagnosis of VTE and Cancer.
| Reference | Study Type | Type of Screening | Prevalence of Occult Cancer in Patients with VTE | ||
| All (%) | Secondary VTE (%) | Idiopathic VTE (%) | |||
| [124] | RET | Unknown | 0/196 (0) | 0/83 (0) | 0/113 (0) |
| [125] | RET | Routine | 0/40 (0) | 0/30 (0) | 0/10 (0) |
| [126] | PRO | Extensive* | 18/232 (8) | 5/154 (3) | 13/78 (17) |
| [123] | PRO | Routine | 13/293 (4.4) | 4/207 (1.9) | 7/86 (8.1) |
| [127] | RET | Routine | 6/104 (5.8) | 1/83 (1.2) | 5/21 (23.8) |
| [122] | PRO | Routine | 8/113 (7.1) | 4/82 (4.9) | 4/31 (12.9) |
| [128] | PRO | Routine | 11/685 (1.6) | 4/573 (0.7) | 7/112 (6.3) |
| [119] | PRO | Routine | 5/260 (1.9) | 0/107 (0) | 5/153 (3.3) |
| [129] | RET | Routine | 26/809 (3.2) | 8/530 (1.5) | 18/279 (6.5) |
| [120] | RET | Routine | - | - | 16/142 (11.3) |
| [130] | PRO | Routine | - | 15/343 (4.4) | |
| [131] | RET | Routine | - | - | 3/21 (14.3) |
RET, retrospective; PRO, prospective.
Extensive = routine + tumor markers, abdominal and pelvic CT scans, mammography >40 years; prostate ultrasonography >60 years; and, in some, thoracic CT scan.
Early detection of cancer would possibly improve patient outcome if the patient has a carcinoma of the breast, ovary, colon, or cervix, but there is no evidence for improved outcomes in carcinomas of the lung, brain, prostate, or pancreas, all of which have been associated with venous thrombosis. Moreover, we cannot assume that these occult cancers are at an early stage of their development because they have already had a major clinical impact. One study recently reported on the survival of patients who were diagnosed with cancer at or around the time of presentation with a thromboembolic event [132]. When these patients were compared with age-matched controls with similar cancers but without an associated thrombosis, 44% was found to have metastases at the time of diagnosis compared with 35% of controls. One-year survival was only 12% compared with 36% in the controls. If the cancer was diagnosed within 12 months of a thromboembolic event, 1-year survival was 38% compared with 47% in the controls. The study concludes that patients with cancer diagnosed at or around the time of a thromboembolic event have a significantly worse prognosis than those patients without such an association.
This raises the question of whether screening for cancer in patients who present with a venous thromboembolic event be an effective use of resources. In the absence of an obvious risk factor for thrombosis, there is a clear increase in the incidence of an underlying carcinoma in these patients. Estimates range from 7.3% to 19% at the time of presentation. Assuming an incidence of perhaps around 10%, screening for cancer becomes a reasonable option. However, on the basis of current evidence, intensive investigation cannot be recommended.
Firstly, cancers associated with venous thrombosis seem to have a relatively poor prognosis, and early diagnosis of many of these cancers has not been shown to improve survival. Secondly, we should not underestimate the potential harm to patients, both psychological and physical, which can be associated with any kind of screening program, as increasingly invasive investigations may be used to follow up abnormal screening tests for what may turn out to be benign or untreatable disease.
Conclusion
Cancer can confer a prothrombotic or hypercoagulable state through an altered balance between the coagulation and fibrinolytic systems, which can be related to long-term prognosis and treatment. The hypercoagulable state reflects the interaction of different mechanisms involving the activation of various hemostatic components, such as the coagulation and fibrinolytic pathways, the vascular endothelium, monocytes, and platelets. Tumor cells interact with all parts of the hemostatic system. They can directly activate the coagulation cascade by producing their own procoagulant factors, or they can stimulate the prothrombotic properties of other blood cell components. Additional mechanisms of clotting activation are initiated by cytotoxic chemotherapy or other cancer therapies. In the last decade, research has greatly improved our understanding of tumor-associated hypercoagulability. At the present time, intensive investigation for cancer in patients presenting with thromboembolic disease is not justified, firstly because there is no evidence of improved survival, and secondly because of the psychological and physical damage a screening program may cause to the patient.
A sound knowledge of the molecular basis of the underlying mechanisms of tumor-associated hypercoagulability may help to identify more targeted strategies to prevent thromboembolic complications in cancer patients, in particular when surgical or chemical therapy is involved.
Acknowledgements
We thank the City Hospital NHS Trust Research and Development Program for support of the Hemostasis, Thrombosis and Vascular Biology Unit.
Footnotes
This work is dedicated to the late Lilian Agnes Caine.
References
- 1.Rickles FR, Edwards RL. Activation of blood coagulation in cancer: Trousseau's syndrome revisited. Blood. 1983;62:14–31. [PubMed] [Google Scholar]
- 2.Donati MB. Cancer and thrombosis: from phlegmasia alba dolens to transgenic mice. Thromb Haemost. 1995;74:278–281. [PubMed] [Google Scholar]
- 3.Dvorak HF. Abnormalities of haemostasis in malignant disease. In: Colman W, Hirsh J, Marder VJ, Salzman EW, editors. Haemostasis and Thrombosis. 3rd edn. Philadelphia, PA: Lippincott; 1994. pp. 1238–1254. [Google Scholar]
- 4.Zacharski LR, Schned AR, Sorensen GD. Occurrence of fibrin and tissue factor antigen in human small cell carcinoma of the lung. Cancer Res. 1983;43:3963–3968. [PubMed] [Google Scholar]
- 5.Zacharski LR, Henderson WG, Rickles FR, Forman WB, Cornell CJ, Jr, Forcier RJ, Edwards R, Headley E, Kim SH, O'Donnell JR, O'Dell R, Tornyos K, Kwaan HC. Effect of warfarin on survival in small cell carcinoma of the lung. VA co-operative study #975. JAMA. 1981;245:831–845. [PubMed] [Google Scholar]
- 6.Chahinian AP, Propert KJ, Ware JH, Zimmer B, Perry MC, Hirsch V, Skarin A, Kopel S, Holland JF, Comis RL. A randomized trial of anticoagulants with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukaemia Group B. J Clin Oncol. 1989;8:993–1002. doi: 10.1200/JCO.1989.7.8.993. [DOI] [PubMed] [Google Scholar]
- 7.International Multicentre Trial, author. Prevention of fatal pulmonary embolism by low dose subcutaneous heparin. Lancet. 1975;12:45–51. [PubMed] [Google Scholar]
- 8.Green D, Hull RD, Brant R, Pineo GF. Lower mortality in cancer patients treated with low molecular weight versus standard heparin. Lancet. 1992;339:1476. doi: 10.1016/0140-6736(92)92064-m. [DOI] [PubMed] [Google Scholar]
- 9.Prandoni P, Lensing AWA, Buller HR, Carta M, Cogo A, Vigo M, Casara D, Ruol A, ten Cate JW. Comparison of LMWH with IV heparin in proximal deep vein thrombosis. Lancet. 1992;339:441–445. doi: 10.1016/0140-6736(92)91054-c. [DOI] [PubMed] [Google Scholar]
- 10.Hull RD, Raskob GL, Pineo GF, Green D, Trowbridge AA, Elliott CG, Lerner RG, Hall J, Sparling T, Brettell HR. Subcutaneous LMWH compared with intravenous heparin in proximal deep vein thrombosis. N Engl J Med. 1992;326:975–982. doi: 10.1056/NEJM199204093261502. [DOI] [PubMed] [Google Scholar]
- 11.Regelson W. Anionic dyes, heparin and heparinoids: the rediscovery of polyanionic tumor inhibitors. J Nat Cancer Inst. 1989;81:1929–1930. doi: 10.1093/jnci/81.24.1929. [DOI] [PubMed] [Google Scholar]
- 12.Folkman J, Langer R, Linhardt RJ, Haudenschild C, Taylor S. Angiogenesis inhibition and tumor regression caused by heparin or a heparin fragment in the presence of cortisone. Science. 1983;221:719–725. doi: 10.1126/science.6192498. [DOI] [PubMed] [Google Scholar]
- 13.Johnson MJ, Sproule MW, Paul J. The prevalence and associated variables of deep venous thrombosis in patients with advanced cancer. Clin Oncol (R Coll Radiol) 1999;11:105–110. doi: 10.1053/clon.1999.9023. [DOI] [PubMed] [Google Scholar]
- 14.Rickles FR, Levine MN. Venous thromboembolism in malignancy and malignancy in thromboembolism. Haemostasis. 1998;28(3):43–49. doi: 10.1159/000022404. [DOI] [PubMed] [Google Scholar]
- 15.Levitan N, Dowlati A, Remick SC, Talsildar HI, Sivinski LD, Beyth R, Rimm AA. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data. Medicine. 1999;78:285–291. doi: 10.1097/00005792-199909000-00001. [DOI] [PubMed] [Google Scholar]
- 16.Bona RD, Hickey AD, Wallace DM. Warfarin is safe as secondary prophylaxis in patients with cancer and a previous episode of venous thrombosis. Am J Clin Oncol. 2000;23:71–73. doi: 10.1097/00000421-200002000-00020. [DOI] [PubMed] [Google Scholar]
- 17.Rickles FR, Levine MN, Edwards RL. Haemostatic alterations in cancer patients. Cancer Metastasis Rev. 1992;11:237–248. doi: 10.1007/BF01307180. [DOI] [PubMed] [Google Scholar]
- 18.Falanga A, Barbui T, Rickles FR, Levine MN. Guidelines for clotting studies in cancer patients. Thromb Haemost. 1993;70:343–350. [PubMed] [Google Scholar]
- 19.Falanga A, Ofosu FA, Delaini F, Oldani E, Dewar L, Lui L, Barbui T. The hypercoagulable state in cancer: evidence for impaired thrombin inhibition. Blood Coagul Fibrinolysis. 1994;1(Suppl):19–23. doi: 10.1097/00001721-199401000-00004. [DOI] [PubMed] [Google Scholar]
- 20.Trousseau A. Clinique Medicale de l'Hotel-Dieu de Paris. 2nd edn. Vol. 3. Paris: Balliere; 1865. Phlegmasia alba dolens; pp. 654–712. [Google Scholar]
- 21.Tallman MS, Kwaan HC, Hakimian D, Rickles FR. New insights into the pathogenesis of coagulation dysfunction in acute promyelocytic leukaemia. Leuk Lymphoma. 1993;11:27–36. doi: 10.3109/10428199309054728. [DOI] [PubMed] [Google Scholar]
- 22.Barbui T, Finazzi G, Falanga A. The management of bleeding and thrombosis in leukaemia. In: Henderson ES, Lister TS, Greaves MF, editors. Leukaemia. Philadelphia, PA: Saunders; 1996. pp. 291–311. [Google Scholar]
- 23.Barbui T, Finazzi G, Falanga A. The impact of all-trans-retinoic acid on the coagulopathy of acute promyelocytic leukaemia. Blood. 1998;91:3093–3102. [PubMed] [Google Scholar]
- 24.Prandoni P. Antithrombotic strategies in patients with cancer. Thromb Haemost. 1997;78:141–144. [PubMed] [Google Scholar]
- 25.Kakkar AK, Williamson RCN. Antithrombotic therapy in cancer. BMJ. 1999;318:1571–1572. doi: 10.1136/bmj.318.7198.1571. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Kakkar AK, Williamson RCN. Prevention of venous thromboembolism in cancer patients. Semin Thromb Haemost. 1999;25:239–243. doi: 10.1055/s-2007-994925. [DOI] [PubMed] [Google Scholar]
- 27.Bona R. Thrombotic complications of central venous catheters in cancer patients. Semin Thromb Haemost. 1999;25:147–155. doi: 10.1055/s-2007-994916. [DOI] [PubMed] [Google Scholar]
- 28.Green KB, Silverstein RL. Hypercoagulability in cancer. Hematol/Oncol Clin North Am. 1996;10:499–530. doi: 10.1016/s0889-8588(05)70349-x. [DOI] [PubMed] [Google Scholar]
- 29.Luzzato G, Schafer AI. The prethrombotic state in cancer. Semin Oncol. 1990;17:147–158. [PubMed] [Google Scholar]
- 30.Gordon SG. Tumor cell procoagulants and their role in malignant disease. Semin Thromb Haemost. 1992;18:424–433. doi: 10.1055/s-2007-1002580. [DOI] [PubMed] [Google Scholar]
- 31.Falanga A, Rickles FR. Pathophysiology of the thrombophilic state in the cancer patient. Semin Thromb Haemost. 1999;25:173–182. doi: 10.1055/s-2007-994919. [DOI] [PubMed] [Google Scholar]
- 32.Andoh D, Kubota T, Takada M, Tanaka H, Kobayashi N, Maekawa T. Tissue factor activity in leukaemia cells: special reference to disseminated intravascular coagulation. Cancer. 1987;59:748–754. doi: 10.1002/1097-0142(19870215)59:4<748::aid-cncr2820590414>3.0.co;2-e. [DOI] [PubMed] [Google Scholar]
- 33.Nemerson Y. The tissue factor pathway of blood coagulation. Semin Haematol. 1992;29:170–176. [PubMed] [Google Scholar]
- 34.Semararo N, Colucci M. Tissue factor in health and disease. Thromb Haemost. 1997;78:759–764. [PubMed] [Google Scholar]
- 35.Gordon SG, Mourad AM. The site of activation of factor X by cancer procoagulant. Blood Coagul Fibrinolysis. 1991;2:735–739. doi: 10.1097/00001721-199112000-00007. [DOI] [PubMed] [Google Scholar]
- 36.Mielicki WP, Gordon SG. Three stage chromogenic assay for the analysis of activation properties of factor X by cancer procoagulant. Blood Coagul Fibrinolysis. 1993;4:441–446. doi: 10.1097/00001721-199306000-00008. [DOI] [PubMed] [Google Scholar]
- 37.Falanga A, Gordon SG. Isolation and characterization of cancer procoagulant: a cysteine protease from malignant tissue. Biochemistry. 1985;24:5558–5567. doi: 10.1021/bi00341a041. [DOI] [PubMed] [Google Scholar]
- 38.Donati MB, Gambacorti Passerini C, Casali B, Falanga A, Vannotti P, Fossati G, Semeraro N, Gordon SG. Cancer procoagulant in human tumor cells: evidence from melanoma patients. Cancer Res. 1986;46:6471–6474. [PubMed] [Google Scholar]
- 39.Gordon SG, Hashiba U, Poole MA, Cross BA, Falanga A. A cysteine protease procoagulant from amnion-chorion. Blood. 1985;66:1261–1265. [PubMed] [Google Scholar]
- 40.Falanga A, Consonni R, Marchetti M, Locatelli G, Garaltini E, Passerini CG, Gordon SG, Barbui T. Cancer procoagulant and tissue factor are differently modulated by all-trans-retinoic acid (ATRA) in acute promyelocytic leukaemia cells. Blood. 1998;92:143–151. [PubMed] [Google Scholar]
- 41.Donati MB, Falanga A, Consonni R, Alessio MS, Bassan R, Buelli M, Borin L, Catani L, Pogliani E, Gugliotti L. Cancer procoagulant in acute non lymphoid leukaemia: relationship of enzyme detection to disease activity. Thromb Haemost. 1990;64:11–16. [PubMed] [Google Scholar]
- 42.Gordon SG, Cross BA. An enzyme-linked immunosorbent assay for cancer procoagulant and its potential as a new tumor marker. Cancer Res. 1990;50:6229–6234. [PubMed] [Google Scholar]
- 43.Gordon SG, Benson B. Analysis of serum cancer procoagulant activity and its possible use as a tumor marker. Thromb Res. 1989;56:431–440. doi: 10.1016/0049-3848(89)90256-9. [DOI] [PubMed] [Google Scholar]
- 44.Edwards RL, Silver J, Rickles FR. Human tumor procoagulants: registry of the Subcommittee on Haemostasis and Malignancy of the Scientific and Standardization Committee, International Society of Thrombosis and Haemostasis. Thromb Haemost. 1993;69:205–213. [PubMed] [Google Scholar]
- 45.Kwaan HC, Keer HN. Fibrinolysis and cancer. Semin Thromb Haemost. 1990;16:230–235. doi: 10.1055/s-2007-1002674. [DOI] [PubMed] [Google Scholar]
- 46.Stephens R, Alitalo R, Tapiovaara H, Vaheri A. Production of an active urokinase by leukaemia cells: a novel distinction from cell lines of solid tumors. Leuk Res. 1988;12:419–422. doi: 10.1016/0145-2126(88)90061-6. [DOI] [PubMed] [Google Scholar]
- 47.Hajjar KA. Cellular receptors in the regulation of plasmin generation. Thromb Haemost. 1995;74:294–301. [PubMed] [Google Scholar]
- 48.Falanga A, Marchetti M, Giovanelli S, Barbui T. All-trans-retinoic acid counteracts endothelial cell procoagulant activity induced by a human promyelocytic leukaemia-derived cell line (NB4) Blood. 1996;87:613–617. [PubMed] [Google Scholar]
- 49.Gianni M, Norio P, Terao M, Falanga A, Marchetti M, Rambaldi A, Garratini E. The effect of dexamethasone on proinflammatory cytokine expression, cell growth and maturation during granulocytic differentiation of acute promyelocytic leukaemic cells. Eur Cytokine Netw. 1995;6:157–165. [PubMed] [Google Scholar]
- 50.Colluci M, Balconi G, Lorenzet R, Pietra A, Locati D, Donati MB, Semeraro N. Cultured human endothelial cells generate tissue factor in response to endotoxin. J Clin Invest. 1983;71:1893–1896. doi: 10.1172/JCI110945. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Bevilacqua MP, Pober JS, Majeau GR, Fiers W, Cotran RS, Gimbrone MA. Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin-1. Proc Natl Acad Sci USA. 1986;83:4533–4537. doi: 10.1073/pnas.83.12.4533. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Dittman WA, Majerus PW. Structure and function of thrombomodulin: a natural anticoagulant. Blood. 1990;75:329–336. [PubMed] [Google Scholar]
- 53.Moore KL, Esmon CT, Esmon NL. Tumor necrosis factor leads to the internalization and degradation of thrombomodulin from the surface of bovine aortic endothelial cells in culture. Blood. 1989;73:159–165. [PubMed] [Google Scholar]
- 54.Dvorak HF, Nagy JA, Berse B, Brown LF, Yeo KT, Yeo TK, Dvorak AM, van De Water L, Sioussat TM, Senger DR. Vascular permeability factor, fibrin, and the pathogenesis of tumor stroma formation. Ann NY Acad Sci. 1992;667:101–111. doi: 10.1111/j.1749-6632.1992.tb51603.x. [DOI] [PubMed] [Google Scholar]
- 55.Brown LF, Detmas M, Claffey K, Nagy JA, Feng D, Dvorak AM, Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a multifunctional angiogenesis factor. In: Goldberg ID, Rosen EM, editors. Regulation of Angiogenesis. Basle: Birkhauser Verlag; 1998. pp. 233–269. [Google Scholar]
- 56.Clauss M, Gerlach M, Gerlach H, Brett F, Wang PC. Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration. J Exp Med. 1990;172:1535–1545. doi: 10.1084/jem.172.6.1535. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.Qi J, Kreutzer DL. Fibrin activation of vascular endothelial cells: induction of IL-8 expression. J Immunol. 1995;155:867–876. [PubMed] [Google Scholar]
- 58.Rickles FR, Levine M, Dvorak HB. Abnormalities of hemostasis in malignancy. In: Colman RW, Hirsch J, Marder VJ, Clowes A, George JN, editors. Haemostasis and Thrombosis. Philadelphia, PA: Lippincott, Williams and Wilkins; 2000. pp. 1132–1152. [Google Scholar]
- 59.Zhang Y, Deng Y, Luther T, Muller M, Ziegler R, Waldher R, Stern DM, Nawroth PP. Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice. J Clin Invest. 1994;94:1320–1327. doi: 10.1172/JCI117451. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60.Abe K, Shoji M, Chen J, Bierhaus A, Danave I, Micko C, Casper K, Dillehay DL, Nawroth PP, Rickles FR. Regulation of vascular endothelial growth factor production and angiogenesis by the cytoplasmic tail of tissue factor. Proc Natl Acad Sci USA. 1999;96:8663–8668. doi: 10.1073/pnas.96.15.8663. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Shoji M, Hancock WW, Abe K, Micko C, Caspar KA, Baine RM, Wilcox JM, Danave I, Dillehay DL, Matthews E, Contrino J, Morrisey JH, Gordon S, Edgington TS, Kudryk B, Kreutzer DL, Rickles FR. Activation of coagulation and angiogenesis in cancer. Immunohistochemical localization in situ of clotting proteins and VEGF in human cancers. Am J Pathol. 1998;152:399–411. [PMC free article] [PubMed] [Google Scholar]
- 62.Contrino J, Hair GA, Kreutzer DL, Rickles FR. In situ detection of the expression of tissue factor in vascular endothelial cells: correlation with the malignant phenotype of human breast disease. Nat Med. 1996;2:209–215. doi: 10.1038/nm0296-209. [DOI] [PubMed] [Google Scholar]
- 63.Shoji M, Abe K, Nawroth PP, Rickles FR. Molecular mechanisms linking thrombosis and angiogenesis in cancer. Trends Cardiovasc Med. 1997;7:52–59. doi: 10.1016/S1050-1738(96)00142-9. [DOI] [PubMed] [Google Scholar]
- 64.Falanga A, Rickles FR. Pathophysiology of the thrombophilic state in the cancer patient. Semin Thromb Haemost. 1999;25:173–182. doi: 10.1055/s-2007-994919. [DOI] [PubMed] [Google Scholar]
- 65.Contrino J, Hair G, Kreutzer DL, Rickles FR. In situ detection of tissue factor in vascular endothelial cells: correlation with the malignant phenotype of breast disease. Nat Med. 1996;2:209–215. doi: 10.1038/nm0296-209. [DOI] [PubMed] [Google Scholar]
- 66.Koomagi R, Volm M. Tissue factor expression in human non-small-cell lung carcinoma measured by immunohistochemistry: correlation between tissue factor and angiogenesis. Int J Cancer. 1998;79:19–22. doi: 10.1002/(sici)1097-0215(19980220)79:1<19::aid-ijc4>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
- 67.Abdulkadir SA, Carvalhal GF, Kaleem Z, Kisiel W, Humphrey PA, Catalona WJ, Milbrandt J. Tissue Factor expression and angiogenesis in human prostate carcinoma. Hum Pathol. 2000;31:443–447. doi: 10.1053/hp.2000.6547. [DOI] [PubMed] [Google Scholar]
- 68.Zhang Y, Deng Y, Luther T, Muller M, Ziegler R, Waldherr R, Stern DM, Nawroth PP. Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice. J Clin Invest. 1994;94:1320–1327. doi: 10.1172/JCI117451. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69.Hippenstiel S, Krull M, Ikemann A, Risau W, Clauss M, Suttorp N. VEGF induces hyperpermeability by a direct action on endothelial cells. Am J Physiol. 1998;274:678–684. doi: 10.1152/ajplung.1998.274.5.L678. [DOI] [PubMed] [Google Scholar]
- 70.Verheul HMW, Jorna AS, Hoekman K, Broxterman HJ, Gebbink MFBG, Pinedo HM. Vascular endothelial growth factor-stimulated endothelial cells promote adhesion and activation of platelets. Blood. 2000;96:4216–4221. [PubMed] [Google Scholar]
- 71.Honn KV, Tang DG, Chen YQ. Platelets and cancer metastasis: more than an epiphenomenon. Semin Thromb Haemost. 1992;18:392–415. doi: 10.1055/s-2007-1002578. [DOI] [PubMed] [Google Scholar]
- 72.Marchetti M, Falanga A, Giovanelli S, Oldani E, Barbui T. All-trans-retinoic acid increases the adhesion to endothelium of the acute promyelocytic leukaemia cell line NB4. Br J Haematol. 1996;93:360–366. doi: 10.1046/j.1365-2141.1996.4911029.x. [DOI] [PubMed] [Google Scholar]
- 73.Rickles FR, Edwards RL. Leukocytes and tumour cells in thrombosis. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, editors. Haemostasis and Thrombosis: Basic Principles and Clinical Practice. Philadelphia, PA, USA: Lippincott; 1994. pp. 1164–1179. [Google Scholar]
- 74.Hara Y, Steiner M, Baldini MG. Characterization of the platelet-aggregating activity of tumour cells. Cancer Res. 1980;40:1217–1222. [PubMed] [Google Scholar]
- 75.Pearlstein EP, Salk PL, Yogeeswaran G, Karpatkin S. Correlation between spontaneous metastatic potential, platelet-aggregating activity of cell extracts, and cell surface sialylation in 10 metastatic-variant derivatives of a rat renal sarcoma line. Proc Natl Acad Sci USA. 1980;77:4336–4339. doi: 10.1073/pnas.77.7.4336. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 76.Scialla SJ, Speckart SF, Haut MJ, Kimball DB. Alterations in platelet surface sialyltransferase activity and platelet aggregation in a group of cancer patients with a high incidence of thrombosis. Cancer Res. 1979;39:2031–2035. [PubMed] [Google Scholar]
- 77.Bidet JM, Ferriere JP, Besse G, Chollet P, Gaillard G, Plagne R. Evaluation of beta thromboglobulin levels in cancer patients: effects of antitumour chemotherapy. Thromb Res. 1980;19:429–433. doi: 10.1016/0049-3848(80)90272-8. [DOI] [PubMed] [Google Scholar]
- 78.Al-Mondhiry H. Beta thromboglobulin and platelet factor 4 in patients with cancer. Am J Haematol. 1983;14:105–111. doi: 10.1002/ajh.2830140202. [DOI] [PubMed] [Google Scholar]
- 79.Van Hulsteijn H, Briet E, Koch C, Hermans J, Bertina R. Diagnostic value of fibrinopeptide A and beta thromboglobulin in acute deep vein thrombosis and pulmonary embolism. Acta Med Scand. 1982;211:323–330. doi: 10.1111/j.0954-6820.1982.tb01956.x. [DOI] [PubMed] [Google Scholar]
- 80.Blann AD, Gurney D, Wadley M, Bareford D, Stonelake P, Lip GYH. Increased soluble P-selectin in patients with haematological and breast cancer: a comparison with fibrinogen, plasminogen activator inhibitor and von Willebrand factor. Blood Coagul Fibrinolysis. 2001;12:9–16. doi: 10.1097/00001721-200101000-00007. [DOI] [PubMed] [Google Scholar]
- 81.Gasic GJ, Gasic TB, Stewart GJ. Mechanisms of platelet aggregation by murine tumor cell shedding. In: Honn KV, Sloane BF, editors. Hemostatic Mechanisms and Metastases. Boston: Martinus Nijhoff; 1984. pp. 127–138. [Google Scholar]
- 82.Karpatkin S, Pearlstein E. Heterogeneous mechanisms of tumor cell-induced platelet aggregation with possible pharmacological strategy toward prevention of metastases. In: Honn KV, Sloane BF, editors. Hemostatic Mechanisms and Metastases. Boston: Martinus Nijhoff; 1984. pp. 139–169. [Google Scholar]
- 83.Gatspar H. Platelet-cancer cell interaction in metastasis formation. J Med. 1977;8:103–114. [PubMed] [Google Scholar]
- 84.Raz A, Lotan R. Endogenous galactoside-binding lectins: a new class of functional tumor cell surface molecules related to metastasis. Cancer Metastasis Rev. 1987;6:433–452. doi: 10.1007/BF00144274. [DOI] [PubMed] [Google Scholar]
- 85.Gasic GJ, Gasic TB. Plasma membrane vesicles as mediators of interactions between tumor cells and components of the hemostatic and immune system. In: Jamieson GA, editor. Interactions of Platelets and Tumor Cells. New York: Alan R. Liss; 1982. pp. 429–439. [PubMed] [Google Scholar]
- 86.Nierodzik ML, Klepfish A, Karpatkin S. Role of platelets, thrombin, integrin IIB-IIIA, fibronectin and von Willebrand factor on tumor adhesion in vitro and metastases in vivo. Thromb Haemost. 1995;74(Suppl):282–290. [PubMed] [Google Scholar]
- 87.Karpatkin S, Nierodzik ML, Klepfish A. Role of platelets and thrombin in cancer. Vessels. 1996;2:17–23. [Google Scholar]
- 88.Grignani G, Jamieson GA. Platelets in tumor metastasis: generation of ADP by tumor cells is specific but unrelated to metastatic potential. Blood. 1988;71:844–849. [PubMed] [Google Scholar]
- 89.Grignani G, Falanga A, Pacchiarini L, Alessio MG, Zuchella M, Fratino P, Donati MB. Human breast and colon carcinomas express cysteine proteinase activities with pro-aggregating and pro-coagulant properties. Int J Cancer. 1988;42:552–557. doi: 10.1002/ijc.2910420414. [DOI] [PubMed] [Google Scholar]
- 90.Rambaldi A, Alessio G, Casali B, Passerini CG, Donati MB, Mantovani A, Semeraro N. Induction of monocyte-macrophage procoagulant activity by transformed cell lines. J Immunol. 1986;136:3848–3855. [PubMed] [Google Scholar]
- 91.Lorenzet R, Peri G, Locati D, Allevana P, Colluci M, Semeraro N, Mantovani A, Donati MB. Generation of procoagulant activity by mononuclear phagocytes: a possible mechanism contributing to blood clotting activation within malignant tissue. Blood. 1983;62:2721–2723. [PubMed] [Google Scholar]
- 92.Semeraro N, Montemurro P, Conese M, Giordano D, Stella M, Restaino A, Cagnazzo G, Colucci M. Procoagulant activity of mononuclear phagocytes from different anatomical sites in patients with gynaecological malignancies. Int J Cancer. 1990;45:251–254. doi: 10.1002/ijc.2910450208. [DOI] [PubMed] [Google Scholar]
- 93.Mussoni L, Donati MB. Expression of plasminogen activator as a marker of stimulation in tumour-associated macrophages. Haemostasis. 1988;18:66–71. doi: 10.1159/000215784. [DOI] [PubMed] [Google Scholar]
- 94.Luzzato G, Schafer AI. The prethrombotic state in cancer. Semin Oncol. 1990;17:147–158. [PubMed] [Google Scholar]
- 95.Levine MN. Prevention of thrombotic disorders in cancer patients undergoing chemotherapy. Thromb Haemost. 1997;78:133–136. [PubMed] [Google Scholar]
- 96.Lee AYY, Levine MN. The thrombophilic state induced by therapeutic agents in cancer patients. Semin Thromb Haemost. 1999;25:137–145. doi: 10.1055/s-2007-994915. [DOI] [PubMed] [Google Scholar]
- 97.Bona R. Thrombotic complications of central venous catheters in cancer patients. Semin Thromb Haemost. 1999;25:147–155. doi: 10.1055/s-2007-994916. [DOI] [PubMed] [Google Scholar]
- 98.Gallus AS. Prevention of post-operative deep leg vein thrombosis in patients with cancer. Thromb Haemost. 1997;78:126–132. [PubMed] [Google Scholar]
- 99.Levine MN, Gent M, Hirsh J, Arnold A, Goodyear MD, Hryniuk W, De Pauw S. The thrombogenic effect of anti-cancer drug therapy in women with stage II breast cancer. N Engl J Med. 1988;318:404–407. doi: 10.1056/NEJM198802183180703. [DOI] [PubMed] [Google Scholar]
- 100.Kakkar VV, Howe CT, Nicholaides AN, Renney JT, Clarke MB. Deep vein thrombosis of the leg. Is there a high risk group? Am J Surg. 1970;120:527–531. doi: 10.1016/s0002-9610(70)80023-x. [DOI] [PubMed] [Google Scholar]
- 101.Clagett GP, Anderson FA, Geerts W, Heit JA, Knudson M, Lieberman JR, Merli GJ, Wheeler HB. Prevention of venous thromboembolism. Chest. 1998;114(Suppl):531–560. doi: 10.1378/chest.114.5_supplement.531s. [DOI] [PubMed] [Google Scholar]
- 102.Falanga A, Ofuso FA, Cortellazo S, Delaini F, Consonni R, Caccia R, Lonpatti S, Maran D, Rodeghiero F, Pogliani E. Preliminary study to identify cancer patients at risk of VTE following major surgery. Br J Haematol. 1993;85:745–750. doi: 10.1111/j.1365-2141.1993.tb03218.x. [DOI] [PubMed] [Google Scholar]
- 103.Fisher B, Constantino J, Redmond C, Poisson R, Bowman D, Couture J, Dimitrov NV, Wolmark N, Wickerham DL, Fisher ER. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node negative breast cancer who have estrogen-receptor positive tumors. N Engl J Med. 1989;320:479–484. doi: 10.1056/NEJM198902233200802. [DOI] [PubMed] [Google Scholar]
- 104.Pritchard KI, Paterson AHG, Paul NA, Zee B, Fine S, Pater J. Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. J Clin Oncol. 1996;14:2731–2737. doi: 10.1200/JCO.1996.14.10.2731. [DOI] [PubMed] [Google Scholar]
- 105.Saphner T, Tormey DC, Gray R. Venous and arterial thrombosis in patients who received adjuvant chemotherapy for breast cancer. J Clin Oncol. 1991;9:286–294. doi: 10.1200/JCO.1991.9.2.286. [DOI] [PubMed] [Google Scholar]
- 106.Goodnough LT, Saito H, Manni A, Jones PK, Pearson OH. Increased incidence of thrombosis in stage IV breast cancer patients treated with a five-drug chemotherapy regimen: a study of 159 patients. Cancer. 1984;54:1264–1268. doi: 10.1002/1097-0142(19841001)54:7<1264::aid-cncr2820540706>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]
- 107.Clahsen PC, Cornelis JH, Julien J-P, Florias TL, Mignolet FY. Thromboembolic complications after perioperative chemotherapy in women with early breast cancer: a EORTC Breast Cancer Cooperative Group study. J Clin Oncol. 1994;12:1266–1271. doi: 10.1200/JCO.1994.12.6.1266. [DOI] [PubMed] [Google Scholar]
- 108.Levine MN, Gent M, Hirsh J, Arnold A, Goodyear MD, Hryniuk W, De Pauw S. The thrombogenic effect of anticancer drug therapy in women with stage II breast cancer. N Engl J Med. 1988;318:404–407. doi: 10.1056/NEJM198802183180703. [DOI] [PubMed] [Google Scholar]
- 109.Wall JG, Weiss RW, Norton L, Perloff M, Rice MA, Korzun AH, Wood WC. Arterial thrombosis associated with adjuvant chemotherapy for breast cancer: a cancer and leukaemia group B study. Am J Med. 1989;87:501–504. doi: 10.1016/s0002-9343(89)80604-7. [DOI] [PubMed] [Google Scholar]
- 110.Falanga A. Mechanisms of hypercoagulation in malignancy and during chemotherapy. Haemostasis. 1998;28(Suppl):50–60. doi: 10.1159/000022405. [DOI] [PubMed] [Google Scholar]
- 111.Levine MN, Gent M, Hirsh J, Arnold A, Warr D, Falanga A, Samosh M, Bramwell V, Pritchard KI, Steward D. Double-blind randomized trial of very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet. 1994;343:886–889. doi: 10.1016/s0140-6736(94)90008-6. [DOI] [PubMed] [Google Scholar]
- 112.Barbui T, Finazzi G, Grassi A, Marchioli M. Thrombosis in cancer patients treated with hematopoietic growth factors — a meta-analysis. Thromb Haemost. 1996;75:368–371. [PubMed] [Google Scholar]
- 113.Falanga A, Marchetti M, Evangelista V, Manarini S, Oldani E, Giovanelli S, Galbusera M, Cerletti C, Barbui T. Neutrophil activation and hemostatic changes in healthy donors given granulocyte-colony stimulating factor. Blood. 1999;93:2506–2514. [PubMed] [Google Scholar]
- 114.Monreal M, Davant E. Thrombotic complications of central venous catheters in cancer patients. Acta Haematol. 2001;106:69–72. doi: 10.1159/000046591. [DOI] [PubMed] [Google Scholar]
- 115.Eastman ME, Khorsand M, Maki DG, Williams EC, Kim K, Sondel PM, Schiller JH, Albertini MR. Central venous device-related infection and thrombosis in patients treated with moderate dose continuous-infusion interleukin-2. Cancer. 2001;91:806–814. [PubMed] [Google Scholar]
- 116.Nordstrom M, Lindblad B, Anderson H, Begquist D, Kjellstrom T. Deep venous thrombosis and occult malignancy: an epidemiological study. BMJ. 1994;308:891–894. doi: 10.1136/bmj.308.6933.891. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 117.Baron JA, Gridley G, Weiderpass E, Nyren O, Linet M. Venous thromboembolism and cancer. Lancet. 1998;351:1077–1080. doi: 10.1016/S0140-6736(97)10018-6. [DOI] [PubMed] [Google Scholar]
- 118.Sorensen HT, Mellemkjaer L, Steffenson FH, Olsen JH, Nielsen GL. The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J Med. 1998;338:1169–1173. doi: 10.1056/NEJM199804233381701. [DOI] [PubMed] [Google Scholar]
- 119.Prandoni P, Lensing AWA, Buller HR, Cogo A, Prins MH, Cattelan AM, Roul A, ten Cate JW. Deep vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med. 1992;327:1128–1133. doi: 10.1056/NEJM199210153271604. [DOI] [PubMed] [Google Scholar]
- 120.Cornuz J, Pearson SD, Creager MA, Cook EF, Goldman L. Importance of findings on the initial evaluation for cancer in patients with symptomatic idiopathic deep venous thrombosis. Ann Intern Med. 1996;125:785–793. doi: 10.7326/0003-4819-125-10-199611150-00001. [DOI] [PubMed] [Google Scholar]
- 121.Hettiarachchi RJK, Lok J, Prins MH, Buller HR, Prandoni P. Undiagnosed malignancy in patients with deep venous thrombosis. Cancer. 1998;83:180–185. doi: 10.1002/(sici)1097-0142(19980701)83:1<180::aid-cncr24>3.0.co;2-s. [DOI] [PubMed] [Google Scholar]
- 122.Monreal M, Lafoz E, Casals A, Inaraja L, Montserrat E, Callejas JM, Martorelli A. Occult cancer in patients with deep venous thrombosis. Cancer. 1991;67:541–545. doi: 10.1002/1097-0142(19910115)67:2<541::aid-cncr2820670237>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
- 123.Bastounis EA, Karayiannakis AJ, Makri GG, Alexiou D, Papalambros EL. The incidence of occult cancer in patients with deep venous thrombosis: a prospective study. J Intern Med. 1996;239:153–156. doi: 10.1046/j.1365-2796.1996.426000.x. [DOI] [PubMed] [Google Scholar]
- 124.Ahmed Z, Mohyuddin Z. Deep-vein thrombosis as a predictor for cancer. Angiology. 1996;47:2615. doi: 10.1177/000331979604700307. [DOI] [PubMed] [Google Scholar]
- 125.Subira M, Mateo J, Souto JC, Altes A, Fontcuberta J. Lack of association between venous thrombosis and subsequent malignancy in a retrospective cohort study in young patients. Am J Hematol. 1999;60:181–184. doi: 10.1002/(sici)1096-8652(199903)60:3<181::aid-ajh2>3.0.co;2-4. [DOI] [PubMed] [Google Scholar]
- 126.Achkar A, Laaban JP, Horellou MH, Rabbat A, Conard J, Nataf J, Samama MM, Rochemaure J. Prospective screening for occult cancer in patients with venous thromboembolism. Thromb Haemost. 1997;1564:383. [Google Scholar]
- 127.Monreal M, Salvador R, Soriano V, Sabria M. Cancer and deep venous thrombosis. Arch Intern Med. 1988;148:485. [PubMed] [Google Scholar]
- 128.Monreal M, Fernandez-Llamazares J, Perandreu J, Urrautia A, Sahuquillo JC, Contel E. Occult cancer in patients with venous thromboembolism: which patients, which cancers. Thromb Haemost. 1997;78:1316–1318. [PubMed] [Google Scholar]
- 129.Rance A, Emmrich J, Guedi C, Fiessinger J-N. Occult cancer in patients with bilateral deep-vein thrombosis. Lancet. 1997;350:1448–1449. doi: 10.1016/S0140-6736(05)64210-9. [DOI] [PubMed] [Google Scholar]
- 130.Girolami A, Prandoni P, Zanon E, Bagatella P, Girolami B. Venous thromboses of upper limbs are more frequently associated with occult cancer as compared with those of lower limbs. Blood Coagul Fibrinolysis. 1999;10:455–457. doi: 10.1097/00001721-199912000-00001. [DOI] [PubMed] [Google Scholar]
- 131.Sanella NA, O'Connor DJ. “Idiopathic” deep venous thrombosis: the value of routine abdominal and pelvic computed tomographic scanning. Ann Vasc Surg. 1991;5:218–222. doi: 10.1007/BF02329376. [DOI] [PubMed] [Google Scholar]
- 132.Sorensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of cancer associated with venous thromboembolism. N Engl J Med. 2000;343:1846–1850. doi: 10.1056/NEJM200012213432504. [DOI] [PubMed] [Google Scholar]