Cancer and the prothrombotic state

Gregory YH Lip , Bernard SP Chin , and Andrew D Blann

Article outline:: Summary; Clinical manifestations of thrombosis; Pathogenesis of the prothrombotic state in cancer; Cancer and ‘abnormal blood constituents’; Tissue factor and cancer procoagulant; Cancer and ‘abnormalities of vessel walls’; Cancer and ‘abnormalities of blood flow’; Other factors contributing to thrombosis; Cancer, thrombosis, and the prothrombotic state; Prevention and treatment of thromboembolism in cancer; Conclusions; Search strategy and selection criteria; Acknowledgments; References; Vitae

Summary
Thrombosis is a frequent complication of cancer, so it follows that the presence of a tumour confers a prothrombotic state. Indeed, in patients with cancer, each of the three components of Virchow's triad that predispose for thrombus formation have abnormalities, thus fulfilling the requirement for a prothrombotic or hypercoagulable state. The many signs and symptoms of the prothrombotic state in cancer range from asymptomatic basic abnormal coagulation tests to massive clinical thromboembolism, when the patient may be gravely ill. Many procoagulant factors, such as tissue factor and cancer procoagulant, are secreted by or are expressed at the cell surface of many tumours. Platelet turnover and activity are also increased. Damaged endothelium and abnormalities of blood flow in cancer also seem to play a part, as does abnormal tumour angiogenesis. Some studies have even suggested that these abnormalities may be related to long-term prognosis and treatment. We briefly describe the various clinical manifestations of thrombosis in cancer and discuss the evidence for the existence of a prothrombotic or hypercoagulable state associated with this disease. Further work is needed to examine the mechanisms leading to the prothrombotic state in cancer, the potential prognostic and treatment implications, and the possible value of quantifying indices of hypercoagulability in clinical practice.

The association between cancer and thromboembolism was first described by Trousseau in 1865, who noted an association between venous thrombosis and malignant disease. Despite modern interventions, venous and, rarely, arterial thromboembolic disorders are still among the most common complications of cancer, and are a cause of substantial morbidity and mortality in these patients. The severity, number of complications, and recurrence rates of thromboembolic disease are also greater.

Clinically detectable venous thromboembolism is found in 15% of all cancer patients, and the proportion is likely to be even higher when subclinical thromboembolism is taken into account. ^1,2 Some cancers are more likely to be prothrombotic than others, but this feature is also influenced by disease staging, immobility, and being in hospital, as well as by interventions such as chemotherapy or surgery. One survey found evidence of thromboembolism in 5–10% of patients with breast cancer undergoing adjuvant chemotherapy, and up to 15% of those with metastatic disease. ² Recurrent thromboembolism is twice as likely to occur in patients with cancer as in healthy individuals, even when established on oral anticoagulant therapy. ^3,4 These patients also tend to need longer stays in hospital, respond less well to oral anticoagulant therapy, and have a poorer prognosis after their first episode of venous thromboembolism.

Clinical manifestations of thrombosis

The signs and symptoms of the prothrombotic state in cancer range from asymptomatic abnormal coagulation tests to massive thromboembolism and disseminated intravascular coagulation (DIC), when the patient may be gravely ill ( Figure 1 ). In general, thromboembolic disease in patients with cancer does not differ clinically from that in other types of patients. Indeed, deep-venous thrombosis (DVT) of the leg is the most common clinical manifestation of thromboembolic disease in cancer patients, although arm DVT, pulmonary embolism, cerebral sinus thrombosis, migratory superficial thrombophlebitis, DIC, and thrombotic microangiopathy have all been described in cancer. ^5–8 Indeed, clinical thromboembolism may appear even before the detection of cancer, raising the issue of whether intensive screening and investigation for occult malignant disease is justified in all patients who present with thromboembolism. ^9–11

Figure 1.Massive pulmonary thromboembolism, seen at pulmonary angiography in a patient with recent resection of colonic cancer, undergoing chemotherapy, who had suddenly collapsed in the ward.

Idiopathic venous thrombosis
Cohort studies ^9–11 of patients presenting with primary idiopathic DVT have a three to four times greater risk of developing cancer within the next 6 months. In the study by Pradoni and colleagues, ⁹ routine examination at the time of diagnosis of the venous thrombosis revealed underlying malignant disease in 3.3% of patients, but not in any of the patients with secondary venous thrombosis. During follow-up, a further 7.6% of patients with idiopathic venous thromboses were diagnosed with cancer, compared with 1.9% in those with secondary thromboses (odds ratio: 2.3; 95% CI, 1.0–5.2). The frequency of cancer in patients with recurrent idiopathic venous thrombosis was also higher. Indeed, idiopathic venous thrombosis is commonly the presenting feature of several cancers, such as pancreatic and prostate cancer, although it is a late complication in patients with breast, lung, or uterine cancer. ¹¹

Migratory superficial thrombophlebitis
Migratory superficial thrombophlebitis (Trousseau's syndrome) is characterised by a recurrent and migratory pattern of superficial thrombophlebitis, in most cases with involvement of superficial veins of the arm or chest. An occult cancer is commonly present, affecting mainly the pancreas (in up to 24% of cases), lung (20%), prostate (13%), stomach (12%), and colon (5%). ⁵ This case series also reported the presence of haematological abnormalities, including intravascular coagulation, with hypofibrinogenaemia and thrombocytopenia. Other abnormalities included prolonged prothrombin time, increased fibrinogen degradation products, cryofibrinogenaemia, and microangiopathic haemolytic anaemia.

Non-bacterial thrombotic endocarditis (marantic endocarditis)
Autopsy studies have shown that cancer is present in up to 75% of cases of nonbacterial thrombotic endocarditis, ⁶ although the condition per se is rare. It can range from microscopic aggregates of platelets to large platelet–fibrin vegetations on the heart valves, generally in patients with advanced malignant disease (most commonly adenocarcinomas). Many patients have other manifestations of thrombosis. Non-bacterial thrombotic endocarditis presents in most cases with systemic emboli, rather than valvular dysfunction, because the vegetations are easily dislodged. ⁶

DIC and thrombotic microangiopathy
Some of the manifestations of DIC are very common, and may involve extreme disturbances of coagulation associated with cancer, caused by a general activation of the coagulation system. ⁷ Overt clinical DIC, however, is rare, and may result in severe bleeding. Advanced cancer, especially acute promyelocytic leukemia, is one of the most frequent causes of DIC, after infection and trauma, accounting for about 7% of clinical cases. ⁷

Thrombotic microangiopathy is common with haematological malignant diseases, but it is also occasionally seen in solid cancers, including gastric, pancreatic, breast, and lung carcinomas, and may also be associated with use of chemotherapy. ^8,12,13 The condition is characterised by renal insufficiency, microangiopathic haemolytic anaemia, thrombocytopenia, microvascular thrombotic lesions, and the involvement of various specific organs. Histological examination of renal tissue shows evidence of intravascular coagulation, primarily affecting the small arteries, arterioles, and glomeruli. Two other major syndromes often seen in cancer, considered to be pathogenetically similar, are thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome. ^8,12

Arterial thrombosis
For reasons that are currently unclear, arterial thromboembolism is much less common than venous thrombosis in cancer, although it can be secondary to non-bacterial thrombotic endocarditis. ⁶ However, there is evidence of an association between arterial disease and the disturbances in haemostasis, thrombosis, and vascular function, ¹⁴ that are also present in cancer. This association may help to provide clues to the pathogenesis of abnormal coagulation in patients with cancer.

Pathogenesis of the prothrombotic state in cancer

Much attention has focused on the mechanisms involved in the pathogenesis of cancer, but the study of the prothrombotic or hypercoagulable state is relatively undeveloped, despite the fact that thromboembolism is a major problem in many of these patients.

Over 150 years ago, Virchow postulated that three features predispose to thrombus formation, namely abnormalities in blood constituents, the vessel wall, and blood flow. Although Virchow was referring to venous thrombosis, the concepts can equally be applied to arterial thrombosis. An update of Virchow's triad for thrombogenesis can be considered by reference to abnormalities in platelets as well as to the coagulation and fibrinolytic pathways, abnormalities in the endothelium, and of haemorheology and turbulence in abnormal blood vessels, respectively ( Table 1 ).


Abnormal blood flow	Abnormal blood constituents	Abnormal blood vessel wall


Increased viscosity	Increased platelet activation and aggregation	Damaged or dysfunctional endothelium


Increased stasis from immobility	Increased procoagulant factors	Loss of anticoagulant nature


	Decreased anticoagulant and fibrinolytic factors	? Angiogenesis

Table 1. Virchow's triad in cancer

Recent improvements in laboratory techniques have enabled us to quantify different components of these processes. ¹⁴ Indeed, patients with various cancers commonly show abnormalities in each component of Virchow's triad, leading to a prothrombotic or hypercoagulable state ( Table 2 ). There are likely to be several, probably synergistic, mechanisms. For example, tumour cells may be directly prothrombotic, inducing thrombin generation, whereas normal host tissues may stimulate (or be stimulated to) prothrombotic activity as a secondary response to the cancer. Accompanying causes of morbidity, such as bed rest, infection, surgery, and drugs, are probably contributory and will determine whether an asymptomatic increase in the prothrombotic or hypercoagulable state becomes manifest clinically.


Study	Ref	Cancer type	Study details	Factor(s) altered


Clotting factors


Tissue factor	15	Solid tumours	106 patients versus 72 controls	TF 67% higher in cancer patients


	17	Ductal adeno-carcinoma of pancreas	55 patients versus 18 controls	Increased TF expression in poorly differentiated cancer cells


	18	Colorectal cancer	17 patients with liver metastases and 79 without	TF expression higher in metastatic cancers


Cancer procoagulant	24	Melanoma	Cell extracts from 32 patients	Cancer procoagulant activity present in extracts and cell suspensions from all patients and in extracts with metastases


Fibrinogen, FDP, and D-dimers	27	Breast cancer	73 patients versus controls	Significantly raised D-dimer concentrations and strong correlation with presence of CA15-3 and CEA


t-PA	25	Gastrointestinal cancer	20 patients versus 84 controls	Reduced activity of thrombolytic tPA in cancer patients


Antithrombin III + other thrombin inhibitor complexes	28	Solid tumours	39 patients versus 38 controls	Increased prothrombin activation without corresponding increase in thrombin inhibitor complexes


APC resistance	25	Gastrointestinal cancer	20 patients versus 84 controls


High prevalence of


acquired APC resistance


PAI-1 and other inhibitors of fibrinolysis	26	Solid tumours	67 patients versus 50 controls	PAI-1 and plasmin-a 2 antiplasmin complex substantially higher in all cancer patients





Platelets


Platelet activation	34	Gynaecological cancers	21 endometrial cancer patients and 10 cervical cancer patients	Increased platelet activation and reduced sensitivity to prostacyclin in both groups compared with controls


Soluble P selectin	38	Breast cancer and haematological cancers	41 cases versus 41 controls	Increased soluble P selectin in breast cancer and haematological cancers





Endothelial damage or dysfunction


vWF	26	Solid tumours	36 with metastasis and 31 without	vWF, marker of endothelial dysfunction is substantially higher in patients with metastases


	38	Breast cancer and haematological cancers	41 cases versus 41 controls	Raised vWF in both groups: no relation with breast tumour stage, type, or vascularity


	68	Breast cancer	101 women with newly diagnosed breast cancer, 64 women with normal breasts	Raised vWF in cases, but no difference between early and advanced cancer

APC, activated protein C; CEA, carcinoembryonic antigen: FDP, fibrinogen degradation products; PAI-1, plasminogen activator inhibitor; TF, tissue factor; vWF, von Willebrand factor.

Table 2. Examples of abnormal haemostasis and cancer

Cancer and ‘abnormal blood constituents’

Most cancer patients have some degree of altered coagulation, leading to a prothrombotic state ( Table 2). The normal clotting–fibrinolytic system involves a fine balance between activation and inhibition of platelets, procoagulant factors, anticoagulant factors, and fibrinolytic factors ( Figure 2 ). In cancer, tumour cells can activate the coagulation system directly, through interactions with platelets, clotting, and fibrinolytic systems to generate thrombin. The delicate balance between the coagulation and fibrinolytic systems can easily shift to induce a prothrombotic state, perhaps via an excess of procoagulant proteins such as tissue factor, fibrinogen, and plasminogen activator inhibitor, or deficiencies in other molecules, such as antithrombin III, proteins C and S, and tissue plasminogen activator.

Figure 2.The clotting–fibrinolytic system and the influence of cancer procoagulant (CP) and tissue factor (TF).

Tissue factor and cancer procoagulant

These prothrombotic factors may be of primary importance in the pathogenesis of thromboembolism in cancer. Tissue factor, which forms a complex with factor VII to activate factors IX and X, is normally produced by monocytes and by the endothelium. In cancer, monocytes may also be activated by immune complexes or cytokines such as tumour necrosis factor ^15,16 and certain malignant cells, ^17,18 whereas other cells, including those of sarcoma, melanoma, neuroblastoma, lymphoma, and acute promyelocytic leukaemia, can express tissue factor per se. ¹⁹ In vivo expression of tissue factor, by either tumour or ‘normal’ cells, or both, has been implicated in intratumoral and systemic activation of blood coagulation via the extrinsic pathway, ²⁰ as well as in tumour growth and dissemination. ^15,18,19 Certainly, upregulation of endothelial tissue factor, due to high circulating concentrations of vascular endothelial growth factor, may contribute, ²⁰ raising the possibility that tissue factor is a marker for a ‘switch’ to an angiogenic and prothrombotic phenotype in, for instance, breast cancer.

Cancer procoagulant is a cysteine proteinase growth factor, consisting of a calcium-dependent, manganese stimulated enzyme. Unlike tissue factor, cancer procoagulant is a direct activator of factor X, without the need for factor VII, and is found in malignant and foetal tissue, but not in normally differentiated tissue. ²² In the presence of factor V, cancer procoagulant may increase thrombin generation by up to three times the amount found in normal tissue. Increased cancer procoagulant concentrations have been reported in patients with acute promyelocytic leukaemia, malignant melanoma, and cancers of the colon, breast, lung, and kidney. ^23,24 Antibodies to cancer procoagulant also block the metastatic seeding of lung-cancer colonies in vivo and diminish the viability of tumour cells in vitro. ²³

Other clotting factors
Concentrations of several other proteins within the coagulation cascade are abnormally raised in cancer, and this is often associated with a fall in the activity of ‘anticoagulant’ factors. For example, reduced amounts of tissue plasminogen activator have been described in patients with gastrointestinal cancer, ²⁵ whereas the concentrations of plasminogen activator inhibitor-1 and other inhibitory factors of the fibrinolytic pathway may be raised, ²⁶ leading to a prothrombotic or hypercoagulable state. Decreases in other anticoagulant factors have also been observed, including antithrombin III and resistance to activated protein C. ^25–28 The evidence of this continuing underlying state of heightened coagulation in cancer is clear from the many studies that have looked at concentrations of fibrinogen and other indices of fibrin turnover, including fibrinogen degradation products, fibrinopeptides A and B, fibrin D-dimer and prothrombin fragment 1+2 (F1 + 2) ^25–31 ( Table 2 and Table 3 ).


Cancer Type	Refs	Findings


Pancreas	17	TF expression present in pancreatic adenocarcinomas and correlated with tissue differentiation


Prostate	29	High fibrinopeptide A and D-dimer concentrations with strong relations with positive bone scans


Lung	60	Thrombosis-inducing activity increases with stage of lung cancer (all cell types) and associated with shorter survival time in inoperable non-small-cell lung cancer


Breast	30	Increased plasma concentrations D-dimer and thrombin-antithrombin III complexes


	38	Increased soluble P selectin, vWF and fibrinogen


	68	Increased vWF, but not between early or advanced cancer


Stomach	25	High concentrations of fibrinogen, D-dimers, prothrombin F1+2 with corresponding fall in tPA and increase in APC resistance


Colorectal	18	TF present in 58% of all cancer patients and 80% of patients with metastasis

APC, activated protien C; TF, tissue factor; tPA, tissue plasminogen activator; vWF, von Willebrand factor.

Table 3. Examples of some cancers that are associated with a prothrombotic state

Platelets
Patients with metastatic cancers also have increased platelet aggregation and activation. ^32–38 Laboratory studies have shown that mitogenic cell extracts, cell membrane fragments, and secreted chemicals from various animal and human cancers can directly cause aggregation of platelets. ^32,33 Furthermore, platelet numbers and turnover are increased and survival time is decreased in many tumours. Scialla and colleagues ³⁴ suggested a possible link between the degree of cell-surface sialylation of tumour cells, their ability to aggregate platelets, and the frequency of thrombosis in cancer patients. Furthermore, the ability of tumour cells to produce platelet-aggregating activity and plasminogen activator can be related to their metastatic potential in animal and experimental systems. ³³

Cancer cells also activate platelets in vitro by contact, releasing adenosine 5′-diphosphate (ADP) and thromboxane A₂ and generating thrombin through the activity of the tumour-associated procoagulants. Increased von Willebrand factor, risocetin cofactor, and enhanced ADP-induced platelet aggregation have all been demonstrated in vivo, as has reduced sensitivity of platelets to prostacyclin. ^32,34

Two plasma markers of platelet function are worthy of mention. High concentrations of the a granule matrix constituent b-thromboglobulin have been described in various malignant diseases, ^35–37 with the highest concentrations found in active disease ³⁶ and a fall observed after chemotherapy. ³⁷ We have recently described raised soluble P selectin (normally a component of the a granule membrane) in breast and leucocyte malignancies, although in the former there was no relation to tumour burden or staging. ³⁸ These studies lend support to the concept of increased platelet activity in cancer.

Cancer and ‘abnormalities of vessel walls’

Vascular function and coagulopathy
The role of endothelium in mediating the prothrombotic or hypercoagulable state is well known, and disturbances in vascular function may be assessed by changes in plasma concentrations of certain molecules such as von Willebrand factor, soluble thrombomodulin, and soluble E selectin. Increased amounts of von Willebrand factor not only indicate endothelial damage, but also probably contribute to thrombosis by promoting platelet–platelet and platelet–subendothelium adhesion. ³⁹ Similarly, increased soluble (ie plasma) thrombomodulin may imply loss of anticoagulant membrane thrombomodulin at the endothelial surface. ⁴⁰ Both these mechanisms promote coagulopathy, thereby providing a basic theory for thrombosis in cancer.

Endothelial cells may become prothrombotic under the influence of inflammatory cytokines such as tumour necrosis factor (TNF) and interleukin-1. Such cytokines suppress endothelial fibrinolytic activity, increase endothelial-cell production of interleukin-1 and von Willebrand factor, and downregulate thrombomodulin expression; activation of the anticoagulant protein C is decreased. ⁴¹ TNF and interleukin-1 also raise the endothelial expression of E selectin, platelet activating factors, and tissue factor. ⁴⁰ Thus, hypoxia or cytokine-mediated endothelial-cell damage or dysfunction, or both, further contribute to the hypercoagulable state in malignant disease. A damaged endothelium may also present less of a challenge to a metastatic tumour cell seeking to penetrate the vessel wall. Solid tumours growing outside the blood vasculature may also make the microvasculature hyperpermeable, allowing fibrinogen and other plasma clotting proteins to leak into the extravascular space, where procoagulants associated with tumour cells or with benign stromal cells can initiate clotting and subsequent fibrin deposition. ⁴²

Angiogenesis
There is considerable evidence to suggest a link between angiogenesis and thrombosis. Investigators have localised tissue-factor expression in the vascular endothelium of breast-cancer tissue, and this feature is strongly related to the initiation of angiogenesis, therefore suggesting a possible link between the prothrombotic states and angiogenesis in these patients. ^20,42–45 Tissue-factor expression is also positively correlated with microvessel density and the expression of the angiogenic modulator, vascular endothelial growth factor. ⁴⁴

The results of work in animals have suggested that the interaction between tissue factor and angiogenesis may involve the regulation of endothelial growth factors, a mechanism which is distinct from tissue-factor-mediated activation of coagulation mechanisms. ⁴⁵ Interestingly, in vitro, vascular endothelial growth factor induces hyperpermeability by acting directly on the endothelium, ⁴⁶ and (unlike basic fibroblast growth factor) promotes platelet activation and adhesion. ⁴⁷

Cancer and ‘abnormalities of blood flow’

Work in animal xenograft models has provided evidence of specific flow abnormalities in tumour vasculature, which could generate thrombotic events. Conditions such as flow reversals, stagnation points, abnormal vessel branching patterns, and capillary diameter distribution, inclusion of tumour cells in vessel walls, and flow transition states have been documented in these experimental models. ^48–50 Although there is currently little evidence that these ‘abnormal flow’ conditions exist in the clinical setting, the similarity in vascular architecture between these models and human tumours suggests that such conditions could be present in human tumours. ⁵¹

There are limited clinical data linking changes in blood flow with thrombosis in cancer. What might be a likely mechanism in cardiovascular disease may not be the same in neoplasia. Nevertheless, blood viscosity at both high and low rates of shear, measured preoperatively in cancer patients, have been correlated with frequency of postoperative DVT. ⁵² Abnormal blood vessel formation (perhaps related to cancer angiogenesis and factors promoting this) may cause flow disturbance, but additional clinical data are required to support this hypothesis.

Other factors contributing to thrombosis

Chemotherapy and surgery
Surgery and postoperative immobility are risk factors for thromboembolism, an important consideration, since 60% of all cancer patients undergo surgery of some sort. Some chemotherapeutic agents and drug combinations used for cancer are well known to induce thrombosis. ^53,54 For example, the frequency of thrombosis was 17.6% higher in patients with stage IV breast cancer treated with a five-drug chemotherapeutic regimen than in control patients. ⁵⁴ Other chemotherapeutic agents, including cisplastin and etoposide, as well as hormonal therapies used in cancer, such as medroxyprogesterone acetate and tamoxifen, have all been implicated as risk factors for thromboembolism. ⁵⁵ Placement of central venous catheters, sepsis, and venous stasis as a result of immobility also contribute to the risk of thromboembolism, ⁵⁶ although some of this extra risk may be due to local inflammation, infection, or both.

Association with staging, prognosis, and intervention
Activation of coagulation and fibrinolysis within tumour tissue is thought to be associated with tumour growth, angiogenesis, and metastasis. Concentrations of plasma markers of thrombin and plasmin generation have therefore been related to staging, prognosis, and intervention in patients with various cancers, including those of the cervix, lung, ovary, prostate, and breast. ^57–61 Although some results have suggested that they are indicators of tumour progression, remission, or treatment response, some of these studies were of weak design, involved small sample sizes, or were observational in nature.

In the study by Gadducci and co-workers, ⁵⁷ prothrombotic indices were substantially increased in patients with cervical cancer; this state was related to surgical–pathological stage and tumour size, but not to histological type. Similarly, several studies have shown an association between activation of blood coagulation and fibrinolysis with distant metastasis, histological tumour type, and response to chemotherapy; indeed, gross abnormalities of prothrombotic indices might even be a sign of unfavourable prognosis in patients with lung cancer. ^31,58,60

This association is by no means universal. In one study of patients with breast cancer, ⁶¹ there was no relation between early recurrent disease and either preoperative or sequential measurements up to 9 months postoperatively of fibrinopeptide A, fibrin fragment B, ^15–42 fibrinogen, serum fibrinogen degradation products, or the fibrin plate lysis assay. More work and larger trials are needed before we can confidently associate an altered coagulation test with prognosis or with response to treatment of a particular cancer.

Cancer, thrombosis, and the prothrombotic state

Raised plasma markers of a prothrombotic state are consistently associated with various cancers, but this may be explained by a reactive or secondary rise in the plasma haemostatic factors, either as an acute-phase response, ³⁹ or as a cancer-related ‘haematological stress syndrome’, similar to that seen in atherosclerosis. ^41,62 Since thrombogenesis has certain similarities to inflammatory disease, the increases in concentrations of various molecules may reflect the severity of vascular disorders as a secondary phenomenon, rather than being a real prognostic factor.

There is some evidence that certain prothrombotic indices may be increased by glucocorticoids and cytokines (such as interleukin-1 and TNF), produced by monocytes and macrophages. ⁴¹ Furthermore, since some clotting factors are also acute-phase proteins, increased concentrations may simply reflect clotting activation or stimulation, and not dysfunction of the coagulation–fibrinolytic system. The precise mechanisms that lead to increased concentrations of various prothrombotic markers in cancer therefore remain uncertain.

Prevention and treatment of thromboembolism in cancer

Despite the apparently close association between thrombosis and cancer, ^2,5–7 Fennerty has suggested that extensive screening for underlying malignant disease in patients with, for example, idiopathic DVT, is probably not yet justified. ⁶³ Indeed, cancers associated with venous thromboembolism have a relatively poor prognosis, and early diagnosis has not been shown to improve survival. There is also the potential for psychological and even physical harm to patients from a screening programme, because increasingly invasive investigations may be used to follow up abnormal screening tests, for what may turn out to be benign or untreatable disease. ⁶³ Nevertheless, intensive screening may be appropriate in cases of recurrent thromboses, and abnormal clinical and laboratory findings during the initial clinical assessment should raise suspicion of underlying malignant disease. More information from large prospective studies is needed, to assess whether incorporation of investigations such as tumour markers, faecal occult blood, and computed tomography into a screening protocol will lead to improved outcomes for those patients who are found to have cancer. ⁶³

A detailed discussion of the prevention and treatment of thromboembolism in cancer is beyond the scope of this review. However, primary prevention of venous thrombosis, possibly by oral anticoagulants, should be considered for ‘high-risk’ cancer patients during and immediately after chemotherapy, when long-term indwelling central venous catheters are placed, during long spells of immobilisation from any cause, and after surgical interventions. ⁵⁶ For example, in cancer patients going for general surgery without prophylaxis, the frequency of DVT is about 29%, compared with 19% in patients who do not have cancer. ⁶⁴ Simple, non-pharmacological, prophylactic measures such as compression stockings may be helpful. Low-molecular-weight heparin once a day is as effective as low-dose, unfractionated heparin three times a day, when used prophylactically in the perioperative period. Patients at very high risk (those aged over 40 years, those with a previous history of thromboembolism, and those undergoing major surgery) will require higher daily doses of low-molecular-weight heparin, or perioperative warfarin, as prophylaxis.

Another possibility for the prevention of venous thromboembolism in high-risk patients undergoing surgery or adjuvant chemotherapy may be the use of long-term, low-intensity anticoagulation. ^4,65 One trial of low-dose warfarin (1 mg daily for 6 weeks, then adjusted to maintain an international normalised ratio of 1.3–1.9) resulted in a relative thromboembolic risk reduction of 85%, with a low bleeding rate. ⁶⁵

The initial treatment of acute venous thromboembolism in cancer patients does not differ from that used for other patients. ⁶⁶ Initial hospital treatment includes unfractionated heparin or low-molecular-weight heparin, to be continued for at least 5 days. Warfarin is started at the same time and should overlap heparin therapy for at least 4–5 days. Heparin can be stopped once the international normalised ratio has been above 2 for 2 consecutive days. Warfarin should be continued for at least 6 months in patients with a first episode of idiopathic DVT, but patients with cancer and with recurrent thromboembolism require long-term anticoagulation therapy. ⁶⁴ The rates of recurrent thrombosis (suggesting some ‘warfarin resistance’) in patients with malignant disease who have been treated with oral anticoagulants are greater than would be expected. ⁶⁶ In recurrent pulmonary thromboembolism, despite warfarin, other measures such as placement of a filter on the inferior vena cava should be considered.

Conclusions

Cancer appears to cause a prothrombotic or hypercoagulable state, through an altered balance between the coagulation and fibrinolytic systems; this can be related to long-term prognosis and treatment. Procoagulants such as tissue factor are expressed by many tumours, although platelet turnover and activity are also increased. Damaged endothelium and blood-flow abnormalities may also play a part in cancer, as may abnormal tumour angiogenesis. Nevertheless, much of the evidence is inconsistent and, in many instances, its clinical relevance is unknown, possibly because of our tendency to pool patients with, and markers from, different diseases with varying pathophysiologies.

Further work is needed to elucidate the mechanisms leading to the prothrombotic state in cancer, the potential prognostic and treatment implications, and the possible value of quantifying indices of hypercoagulability in routine clinical practice. Carefully designed studies with the appropriate methodology, ⁶⁷ will be required to establish the predictive value of various abnormalities of the prothrombotic or hypercoagulable state.

Search strategy and selection criteria

Published and unpublished data for this review were identified by searches of MEDLINE, EMBASE, CancerLit, and reference lists from relevant articles. Searches were concentrated on the prevalence of thromboembolic disease in cancer and indices of the prothrombotic state and, in particular, cancer procoagulants. Representative studies for various components of the clotting cascade that provide evidence for the existence of a prothrombotic or hypercoagulable state in cancer patients were also included. No date or language restrictions were applied.

Acknowledgments

We acknowledge the support of the City Hospital Research and Development programme for the Haemostasis Thrombosis and Vascular Biology Unit.

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Vitae:
GYHL is a Reader in Medicine, BSPC is a Research Fellow, and ADB is a Senior Lecturer in Medicine, all at the Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK.

Correspondence: Dr GYH Lip, Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham B18 7QH, UK. Tel: +44 121 507 5080. Fax: +44 121 554 4083.

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