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Hypercoagulable disorders associated with malignancy

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Hypercoagulable disorders associated with malignancy
Author
Kenneth A Bauer, MD
Section Editor
Lawrence LK Leung, MD
Deputy Editor
Stephen A Landaw, MD, PhD

Disclosures

Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last updated: Wed Oct 19 00:00:00 GMT 2011 (More)

INTRODUCTION — Patients with cancer are in a hypercoagulable state. The spectrum of hemostatic abnormalities ranges from abnormal coagulation tests in the absence of clinical manifestations to massive, fatal thromboembolism [1,2]. Thrombotic episodes may precede the diagnosis of malignancy by months or years and can present in one of the following ways [3]:

  • Migratory superficial thrombophlebitis (Trousseau’s syndrome)
  • Idiopathic deep venous thrombosis and other venous thrombosis
  • Nonbacterial thrombotic endocarditis (marantic endocarditis)
  • Disseminated intravascular coagulation (DIC)
  • Thrombotic microangiopathy
  • Arterial thrombosis

Clinical thromboembolism occurs in as many as 11 percent of patients with cancer [4] and is the second leading cause of death in patients with overt malignant disease [5]. Autopsy series have described even higher rates of thrombosis for certain tumor types. One study, for example, found evidence of thrombosis in 30 percent of patients who died of pancreatic cancer; the incidence was over 50 percent in those with tumors in the body or tail of the pancreas [6]. Other tumor types commonly associated with thromboembolic complications are carcinomas of the gastrointestinal tract, ovary, prostate, and lung. By virtue of its prevalence, lung cancer accounts for the largest number of thromboembolic events [7].

An estimate of the magnitude of this problem was obtained from a study of the records of more than eight million Medicare patients admitted to a hospital between 1988 and 1990 [8]:

  • The percent of patients with a diagnosis of deep vein thrombosis (DVT) and/or pulmonary embolus (PE) at the initial hospitalization was higher for those with malignancy, compared with those with nonmalignant disease (0.60 versus 0.57 percent).
  • The probability of readmission with recurrent DVT/PE within 183 days of initial hospitalization for patients with or without malignancy was 22 and 6.5 percent, respectively.
  • The probability of death within 183 days of initial hospitalization for DVT/PE among those with or without malignancy was 94 versus 29 percent, respectively. The adverse influence of venous thromboembolism on prognosis in cancer patients (particularly those with pancreatic cancer) has been shown by others [9-12].
  • Those malignancies causing the greatest absolute number of episodes of DVT/PE during this time period were lung, colon, and prostate, while those cancers with the highest rates of DVT/PE (number of episodes per 10,000 patients with a specific malignancy) were ovary, brain, pancreas, and lymphoma.

In addition to hypercoagulability, tumors can also lead to venous thrombosis by external compression of vessels or by vascular invasion. As examples, renal cell carcinoma infiltrates the inferior vena cava in 5 to 9 percent of patients [13], hepatocellular carcinoma can compress or invade the hepatic vein(s), and a large mediastinal tumor or bulky axillary lymphadenopathy can lead to upper extremity venous thrombosis. (See “Clinical manifestations, evaluation, and staging of renal cell carcinoma” and “Clinical features and diagnosis of primary hepatocellular carcinoma” and “Spontaneous upper extremity venous thrombosis (Paget-Schroetter syndrome)”.)

The clinical features of the different hypercoagulable syndromes that can be associated with malignancy will be discussed here. The pathogenesis of these disorders as well as drug-induced thrombosis and vascular disease in patients with malignancy are discussed separately. (See “Pathogenesis of the hypercoagulable state associated with malignancy” and “Drug-induced thrombosis and vascular disease in patients with malignancy”.)

Treatment of VTE in patients with malignancy is discussed separately. (See “Treatment of venous thromboembolism in patients with malignancy”.)

TROUSSEAU’S SYNDROME — An association between venous thrombosis and malignancy was first suggested in 1865 by Trousseau. Of interest, Trousseau subsequently developed unexplained deep venous thrombosis, followed a year later by the development of gastric carcinoma [14].

Trousseau’s syndrome (migratory superficial thrombophlebitis, phlegmasia alba dolens) is a rare variant of venous thrombosis characterized by a recurrent and migratory pattern and involvement of superficial veins, frequently in unusual sites such as the arm or chest. The patient with Trousseau’s syndrome usually has an occult tumor which is not always detectable at the time of presentation. If a tumor is discovered, it is usually an adenocarcinoma. In one review of patients with Trousseau’s syndrome, the following associated tumors were seen [4]:

  • Pancreas — 24 percent
  • Lung — 20 percent
  • Prostate — 13 percent
  • Stomach — 12 percent
  • Acute leukemia — 9 percent
  • Colon — 5 percent

This syndrome occurs in up to 10 percent of patients with pancreatic carcinoma. Treatment is difficult; heparin can relieve some of the manifestations, while coumadin appears to be without effect [15,16].

Mucin — Mucins produced by adenocarcinomas may trigger this syndrome by reacting with leukocyte and platelet selectins, resulting in the production of platelet-rich microthrombi [17-19]. As an example, one study has shown that, while thrombotic risk was increased 20-fold in patients with lung cancer, the relative risk of venous thrombosis was significantly higher in those with (mucin-containing) adenocarcinoma than in the squamous cell variant (hazard ratio 3.1; 95% CI 1.4-6.9) [20]. (See “Pathology of lung malignancies”, section on ‘Adenocarcinoma’.)

Heparin has the property of blocking selectin recognition of ligands, a property not shared by vitamin K antagonists. This may explain the superior efficacy of heparin in this setting [18]. (See “Treatment of venous thromboembolism in patients with malignancy”, section on ‘LMW heparin versus warfarin’.)

VENOUS THROMBOEMBOLISM — The majority of cancers associated with thromboembolic events are clinically evident and have been previously diagnosed at the time of the event. However, some patients with venous thromboembolism (VTE) have an occult malignancy which is not diagnosed until many months following the event.

Known malignancy — The risk factors for VTE in patients with known malignancy have been evaluated in a number of large population-based, case-control studies [21-25]. A number of these are discussed below.

In a Danish cohort study of 57,591 cancer patients and a comparison control of 287,476 general population subjects, the following observations were made [24]:

  • Throughout 9 years of subject accrual and follow-up, the incidence rates of VTE were higher among the cancer patients (IR 8.0; 95% CI 7.6-8.5) than among the general population (IR 4.7; 95% CI 4.3-5.1), especially in the first year after cancer diagnosis (IR 15.0 vs 8.6).
  • Incidence rates were highest in patients with pancreas (IR 41), brain (18), liver (20), multiple myeloma (23), and among those with advanced-stage cancer (28).

Similar results were obtained from a California study that linked cases from its cancer registry to the subsequent diagnosis of VTE from a patient discharge data set. The following results were obtained [22]:

  • Among 235,149 cancer cases, 3775 (1.6 percent) were diagnosed with definite or probable VTE within two years; 12 percent occurred at the time of diagnosis, and the remainder subsequently. The incidence rate of VTE was higher during the first year of follow-up than the second year for virtually all types and stages of cancer.
  • Metastatic disease at the time of diagnosis was the strongest predictor for the development of VTE. The diagnosis of VTE was a significant predictor for decreased survival during the first follow-up year for all cancer types (median overall relative risk 3.7).
  • Expressed as events per 100 patient-years, the highest incidences of VTE occurred during the first year of follow-up among cases with metastatic-stage cancer of the pancreas (20), stomach (10.7), bladder (7.9), uterus (6.4), kidney (6.0), and lung (5.0).

A third study evaluated the incidence and effect on survival of VTE in 68,142 patients with colorectal cancer [23]. The two-year cumulative incidence of VTE was 3.1 percent, with rates of 5.0, 1.4, and 0.6 events/100 patient-years for months zero to 6, months 7 to 12, and during the second year following diagnosis, respectively. Other findings included:

  • Significant predictors of VTE included metastatic stage disease and the presence of three or more comorbid conditions.
  • In risk-adjusted models, VTE was a significant predictor of death within one year of cancer diagnosis among patients with local or regional-stage disease, but not among those with metastatic disease.

In a separate study of FOLFIRI chemotherapy in 266 patients with colorectal cancer and either metastatic disease or locally advanced irresectable disease, VTE was noted in 10 percent overall and 7.6 percent while the patients were receiving FOLFIRI [26]. VTE was the most frequent grade 3/4 toxicity noted in the study.

Additional risk factors — While the presence of a malignancy is associated with an increased risk for VTE, and some malignancies are associated with a higher risk of VTE than others (eg, pancreas, lung, gastrointestinal tract, brain) cancer patients often have multiple co-morbidities which contribute to an increased risk for VTE. In addition to the risks attendant to hospitalization, immobilization, and surgery, these include advanced age, widespread or metastatic disease, presence of circulating tumor cells, presence of a central venous catheter, active chemotherapy and/or radiation therapy, presence of inherited thrombophilia and/or thrombocytosis, as well as transfusion of red cells or platelets [21,26-36]. (See “Overview of the causes of venous thrombosis”, section on ‘Acquired thrombophilia’.)

Occult malignancy — A number of uncontrolled or retrospective studies of patients with venous thromboembolism have indicated a clinically significant incidence of malignancy, diagnosed within the first six months after presentation with thrombosis [37-40]. In one of these studies, investigators reviewed the outcome of 4399 patients who had venography for suspected venous thrombosis. The subsequent incidence of malignancy was higher in the 1383 patients with thrombosis than in the 2412 patients without thrombosis (11 versus 7.5 percent) [37]. The cancers in the group with thrombosis were more likely to have occurred within six months of the study (44 versus 20 percent).

Malignancies developing within the first two years after a diagnosis of VTE are also associated with a significantly poorer prognosis. This was shown in a retrospective study comparing overall survival in 4322 patients diagnosed with a first malignancy occurring within 5 years after a diagnosis of VTE to a group of 299,714 patients with malignancy but without VTE. Hazard ratios for death were 2.48, 1.21, 1.26, and 1.07 for malignancies diagnosed within six months, >6 to 12 months, >1 to 2 years, and >2 to 5 years after the diagnosis of VTE, respectively [12].

A less prominent association was noted in a Danish nationwide study of almost 27,000 patients with DVT or pulmonary embolism; the occurrence of cancer in this cohort was determined by linkage to the Danish Cancer Registry [38]. The standardized incidence ratio for cancer was 1.3 compared with those without DVT or pulmonary embolism. The risk of cancer was substantially elevated only during the first six months of follow-up and declined rapidly thereafter to a constant level slightly above 1.0 one year after the thrombotic event.A study linking over 500,000 cases in the California Cancer Registry with a hospital discharge database for VTE found a SIR for unprovoked VTE of 1.3 (95% CI 1.2-1.5) within one year prior to the diagnosis of cancer [41]. The incidence of preceding VTE was significantly increased over that expected only during the four-month period immediately preceding the date of cancer diagnosis; almost all of these were in patients with an ultimate diagnosis of metastatic disease. Seven cancer types were associated with a significantly increased SIR: acute myeloid leukemia, non-Hodgkin lymphoma, and renal cell, ovarian, pancreatic, stomach, and lung cancer.

A meta-analysis of 40 reports published between 1982 and 2007 found a threefold excess risk of occult cancer in patients with VTE when compared with subjects without VTE (RR 3.2; 95% CI 2.4-4.5) [42]. Risks were highest for occult cancers developing in the ovary (RR 7.0), pancreas (6.1), and liver (5.6).

Several prospective studies have provided further data on this association. In one report, 250 consecutive patients with symptomatic DVT were evaluated [43]. A cause or risk factor for the thrombosis was identified in 105 patients. Malignancy was identified at the time of diagnosis of the thrombotic event in 5 of 153 patients (3.3 percent) with no other identifiable risk factor. During a two-year follow-up, there was an increased incidence of cancer in the patients with idiopathic thrombosis compared with the 105 patients with secondary thrombosis (8 versus 2 percent). The incidence of cancer was considerably higher (17 percent) among the 35 patients with recurrent idiopathic venous thrombosis.

In another series of 400 patients with DVT, 70 (18 percent) already had been diagnosed with malignancy at the time of presentation [44]. Of the remaining 326 patients, 10 new malignancies were diagnosed among 137 patients (7.3 percent) with idiopathic DVT, compared with only three malignancies in 189 patients (1.6 percent) with secondary DVT.

Other studies have reported a higher incidence of occult malignancy (up to 25 percent) among patients with idiopathic DVT or pulmonary embolism [45-48]. This may be explained in part by the use of a more aggressive diagnostic approach for cancer, which included measurement of serum carcinoembryonic antigen and prostate specific antigen, chest radiography, upper gastrointestinal endoscopy, abdominal ultrasound, and computed tomography scanning.

Venous thromboembolism appears more likely to be the presenting sign of pancreatic and prostate cancer, whereas it more frequently occurs late in the course of patients with breast, lung, ovarian, uterine, or brain cancer [49,50].

VTE at least one year after the diagnosis of a malignancy may be indicative of a second malignancy. In a case-control population-based cohort study of 6285 patients with cancer and an episode of VTE, the relative risk of developing a second malignancy was 1.0 if the thrombotic episode occurred within one year following the diagnosis of the first cancer, but rose to 1.4 (95% CI 1.2-1.7) if the episode of VTE occurred more than one year after the diagnosis of the initial cancer [51].

Use of screening — The increased incidence of subsequent malignancy among patients presenting with idiopathic DVT or pulmonary embolism has raised the question of whether extensive screening for cancer would be beneficial. The recommendations are varied [52-54]. The use of extensive screening in two studies [45,47], as discussed above, as well as in a 2008 meta-analysis [55], appears to increase the incidence of detected malignancies. However, the incidence of cancer was also increased in the patients with secondary DVT in these studies, so that the relative risk of diagnosing malignancy among patients with unexplained DVT and secondary thrombosis was comparable to other studies.

Several investigators have attempted to define risk factors to identify the subset of patients likely to benefit from extensive screening for malignancy.

  • In one study, cancer was diagnosed in 16 of 136 patients (12 percent) with idiopathic DVT during the index hospitalization [56]. All 16 had one or more abnormalities suggestive of possible malignancy on at least one of the four components of the initial investigation: history, physical examination, basic laboratory testing, or chest X-ray. During follow-up at a median of 34 months, cancer was diagnosed in 3 of 122 patients (2.5 percent), similar to the age and sex matched United States population.
  • In a second series, 13 new malignancies were diagnosed among 326 patients with DVT during a 6-month follow-up period [44]. Ten of the 13 had some type of clinical abnormality at presentation, and 7 were diagnosed within the first 16 days based upon patient characteristics and clinical findings on initial routine examination and laboratory testing.
  • In an analysis of patients with symptomatic acute VTE enrolled in the RIETE registry, those in whom cancer was diagnosed within the next three months (“hidden cancer”), when compared with those who were not so diagnosed during this period, had an increased incidence of recurrent VTE, major bleeding, and mortality [57]. On multivariate analysis, risk factors for such “hidden cancer” were age 60 to 75 years, presence of anemia, presence of bilateral DVT, and idiopathic (rather than secondary) VTE.
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In the absence of prospective studies demonstrating either cost-effectiveness or improved survival with aggressive diagnostic testing for malignancy [55,58-61], we believe that the evaluation of patients with idiopathic DVT should be limited to a careful history, a complete physical examination (including digital rectal examination and testing for fecal occult blood, pelvic examination in women), and routine laboratory testing (complete blood count, chemistry panel including electrolytes, calcium, creatinine, and liver function tests, urinalysis, chest radiograph, and, in men over the age of 50, prostate-specific antigen). Any abnormality observed on initial testing should then be investigated aggressively. A routine aggressive search for malignancy in all patients does not appear to be warranted [38,54,59,61], except in patients with recurrent idiopathic DVT who represent a high-risk group [43,44,52,57].

Hepatic vein and portal vein thrombosis — Thrombosis of the hepatic vein (the Budd-Chiari syndrome) or portal vein may be associated with myeloproliferative neoplasms (eg, polycythemia vera), the clonal disorder paroxysmal nocturnal hemoglobinuria, as well as renal cell and adrenal carcinomas, hepatomas, and other gastrointestinal malignancies [62].

The most common clinical findings of hepatic vein thrombosis are abdominal pain, hepatomegaly and ascites. Splenomegaly and esophagogastric varices are seen with portal vein thrombosis. Laboratory and in vitro studies (eg, presence of the JAK2 mutation, spontaneous erythroid colony growth in the absence of erythropoietin) suggest that an occult myeloproliferative disorder may be present in as many as 75 percent of patients with apparently idiopathic hepatic or portal vein thrombosis. (See “Etiology of the Budd-Chiari syndrome”.)

PREVENTION OF VTE

Surgical patients — Postoperative deep vein thrombosis is more frequent in patients with known malignant disease than in the general population, occurring in as many as 40 percent of patients in clinical trials employing bilateral venography of the lower extremities. As a result, these patients should be considered as being at high risk for development of postoperative VTE, with 33 to 53 percent of VTE episodes occurring after hospital discharge [63-68].

In one prospective observational study of 44,656 patients undergoing surgery for one of nine different malignancies, significant risk factors for the development of postoperative VTE included the following [68]:

  • Age ≥65
  • Presence of metastatic disease
  • Ascites
  • Presence of congestive failure
  • Body mass index ≥25 kg/m2
  • Platelet count >400,000/microL
  • Serum albumin <3.0 g/dL
  • Operation duration >2 hours

Overall VTE was significantly more likely after gastrointestinal, lung, prostate, and ovarian/uterine operations. In those experiencing an episode of VTE, 30-day mortality increased more than sixfold over those not experiencing VTE (8.0 versus 1.2 percent, respectively). Details on the use and duration of prophylactic anticoagulation were not provided, but the involved hospitals had a high compliance rate (93 percent) for in-hospital prophylactic anticoagulation. A high percentage of the patients developed VTE post-discharge, suggesting that more prolonged prophylactic anticoagulation may be warranted following major cancer surgery [69].

Specific recommendations for the prevention of VTE in cancer patients undergoing surgery, consistent with the 2007 guidelines from the American Society of Clinical Oncology (ASCO) [70-72], are discussed separately. (See “Prevention of venous thromboembolic disease in surgical patients”.)

Hospitalized medical patients — Acutely ill hospitalized medical patients who are confined to bed and have active malignancy are at high risk for development of VTE, both symptomatic as well as asymptomatic [67,73,74]. The 2007 ASCO guidelines recommend that hospitalized patients with cancer should be considered for anticoagulation for prevention of VTE if there is no active bleeding and there are no other contraindications to anticoagulant use (eg, recent surgery, preexisting bleeding diathesis, platelet count <50,000/microL, coagulopathy) [66,70-72].

Recommendations for the prevention of VTE in hospitalized cancer patients, consistent with these ASCO guidelines, are discussed separately. (See “Prevention of venous thromboembolic disease in medical patients”, section on ‘VTE prevention in medical patients’.)

Patients with a central venous catheter — Although the presence of a central venous catheter is a risk factor for VTE in cancer patients, there is no evidence at present to support the routine use of VTE prophylaxis to prevent central venous catheter thrombosis. (See “Catheter-induced upper extremity venous thrombosis”.)

Ambulatory cancer patients — As noted above, the cancer patient has an increased risk for the development of VTE. VTE is a risk factor for reduced survival in these patients, and may also compromise the patient’s ability to receive and respond to definitive treatment [9-11]. This issue was addressed in an analysis of data from the National Cancer Institute of Canada Clinical Trials Group PA3 randomized trial of chemotherapy in ambulatory patients with advanced pancreatic cancer [11]. Patients with VTE either at the time of randomization or during the study had a significantly higher risk of disease progression, a lower chance of achieving a response to treatment, and shorter overall survival than patients without VTE.

Efficacy of anticoagulation — There is not enough information available at this time to recommend for or against the use of anticoagulation to prevent VTE in ambulatory cancer patients receiving, or about to receive, chemotherapy. The 2007 ASCO guidelines, the 2008 ACCP guidelines, a 2009 Consensus Statement of major guidelines panels, and the 2011 Clinical Practice Guidelines in Oncology from the NCCN do not recommend routine VTE prophylaxis in ambulatory patients with cancer, except for those with multiple myeloma receiving thalidomide or lenalidomide plus chemotherapy or dexamethasone [35,66,70,72,75,76]. (See “Thrombotic complications following treatment of multiple myeloma with thalidomide and its analogues”, section on ‘Incidence and risk factors’.)

Randomized studies comparing LMW heparin to placebo in cancer patients receiving chemotherapy are ongoing and will help to determine the risks (eg, bleeding) and benefits (eg, reduction in the incidence of VTE, prolongation of survival) of such anticoagulation. Results from two such studies are presented below. (See ‘Prolongation of survival’ below.)

Results are available from the PROTECHT study, a randomized study of the efficacy and safety of the LMW heparin nadroparin (3800 anti-Xa IU subcutaneously once daily; 769 patients) versus placebo (381 patients) in preventing thromboembolic events in 1150 evaluable patients with metastatic or locally advanced lung, breast, gastrointestinal, ovarian, or head and neck cancer with an ECOG performance status of ≤2 who were receiving active chemotherapy. Study treatment was given for the duration of chemotherapy, up to a maximum of four months. Results included [77]:

  • The incidence of symptomatic venous and arterial thromboembolic events, the primary study outcome, was significantly lower in the nadroparin-treated patients when compared with those receiving placebo (2.0 versus 3.9 percent).
  • The rates of minor bleeding (7.4 versus 7.9 percent, respectively) and major bleeding (0.7 versus zero percent, respectively) were similar in the LMW heparin and placebo-treated groups. The rates of other serious adverse events thought to be related to the investigational drug were also similar (1.2 versus 1.6 percent, respectively).
  • Thromboembolic rates in the placebo-treated patients were highest in those with cancers of the lung (8.8 percent) and pancreas (5.9 percent), suggesting that future studies should concentrate on these high-risk groups. (See ‘Determination of thrombotic risk’ below.)

 

Preliminary results are available from a prospective, randomized study of the efficacy and safety of adding the LMW heparin enoxaparin (1 mg/kg subcutaneously once daily) to chemotherapy in 312 patients with advanced pancreatic cancer (the CONKO 004 trial). Initial results include the following [78]:

  • On an intent-to-treat analysis, there was a 65 percent relative risk reduction of symptomatic VTE following the use of LMW heparin (14.5 percent for the observation group versus 5.0 percent for the enoxaparin-treated group).
  • Major bleeding events were noted in 6.3 and 9.9 percent of those receiving enoxaparin or observation, respectively.
  • Preliminary data showed no differences in time to progression or overall survival.

Early results are also available from the FRAGEM study, in which patients with advanced or metastatic pancreatic cancer were treated with gemcitabine and were randomly assigned to receive or not receive full therapeutic doses of the LMW heparin dalteparin [79]. The overall incidence of VTE was 31 percent in those treated with chemotherapy alone versus 12 percent in those also treated with dalteparin (RR 0.38; 95% CI 0.17-0.84).

Determination of thrombotic risk — It may be possible to determine in advance those patients at an increased risk for VTE [80-85]. As examples:

  • In a study of 123 patients with breast cancer receiving chemotherapy, pretreatment levels of D-dimer, tissue factor, fibrinogen, and plasma vascular endothelial growth factor were all significantly higher in the 9.8 percent of those who did, versus those who did not, develop VTE in the first three months following initiation of chemotherapy [81]. (See “Pathogenesis of the hypercoagulable state associated with malignancy”, section on ‘Pathogenesis’.)
  • In a prospective observational cohort study (the Vienna Cancer and Thrombosis Study) of 821 patients with newly diagnosed malignancy or disease progression who did not recently receive chemotherapy, radiotherapy, or surgical treatment, VTE was objectively confirmed in 62 (7.6 percent) over a median follow-up period of 501 days [82]. On multivariate analysis, the hazard ratios for VTE were significantly increased for elevated D-dimer levels as well as for increased levels of prothrombin fragment 1+2. The cumulative probability of developing VTE after six months was significantly higher in patients with both of these abnormalities when compared with those having neither abnormality (15.2 versus 5.0 percent, hazard ratio 3.6; 95% CI 1.4-9.5).

    In a second report from the same investigators, the cumulative probability of developing VTE after six months was significantly higher in cancer patients demonstrating peak thrombin generation levels >611 nM than in those with lower levels (11 versus 4 percent, respectively; Hazard ratio 2.1; 95% CI 1.3-3.3) [86]. However, there was no significant correlation between peak thrombin generation and D-dimer, prothrombin fragment 1+2, factor VIII, soluble P-selectin, hemoglobin, platelet, or leukocyte count.

  • Using a model for predicting chemotherapy-associated VTE, in which risk factors included site of the malignancy, platelet count >350,000/microL, hemoglobin concentration <10 g/dL, leukocyte count >11,000/microL, and body mass index ≥35 kg/m(2), the risk of developing a VTE over a period of 2.5 months was 0.3, 2.0, and 6.7 percent for those in the low, intermediate, and high risk groups, respectively [80].

    This model was subsequently expanded to include two additional variables: soluble P-selectin and D-dimer levels, with resulting scores varying from zero to eight [87] (table 1). In a retrospective study, the cumulative VTE probability after six months was 35, 20, 10, and 1 percent for those with the highest (≥5), high-intermediate (4), low-intermediate (3), and lowest (zero) scores, respectively. The hazard ratio for development of VTE in patients with the highest score compared with those having the lowest score was 25.9 (95% CI 8.0-85).

    Further details concerning standardization of the assays for these two variables, as well as a demonstration of the utility of this model when tested in a prospective manner, will be required before this model can be fully evaluated.

In addition to thalidomide and lenalidomide, there are a number of drugs employed in cancer patients which have been associated with venous and arterial thrombosis (eg, l-asparaginase, tamoxifen, bevacizumab). This subject is discussed in detail separately. (See “Drug-induced thrombosis and vascular disease in patients with malignancy”.)

Use of statins — A number of studies have suggested that the use of statins decreases the risk of VTE in several groups of medical patients (eg, healthy adults, subjects with atherosclerosis). (See “Prevention of venous thromboembolic disease in medical patients”, section on ‘Statins’.)

The effect of statin use on the risk of VTE in cancer patients was explored in a retrospective, case control study in 740 consecutive patients with a diagnosis of solid organ tumor, who were followed for an average duration of 10.2 months (range: 2 to 41 months). Findings included [88]:

  • Multivariate analysis indicated that statin use was associated with a significant reduction in the risk of VTE (OR 0.33; 95% CI 0.18-0.59).
  • As expected, the same analysis confirmed the presence of known factors that increase the risk of VTE, such as immobilization (OR 2.88), presence of metastatic disease (OR 2.07), and current chemotherapy (OR 1.77).

Prolongation of survival — There is limited information on the use of anticoagulation to prolong survival in cancer patients without VTE. Available results are mixed, as noted below:

 

  • A meta-analysis of 11 randomized controlled studies has concluded that anticoagulation significantly reduced one-year overall mortality in cancer patients WITHOUT VTE by 8 percent for LMW heparin and 3 percent for warfarin, while increasing the risk for bleeding complications [89]. Available trials did not permit subgroup analyses of the influence of cancer type and stage.
  • A 2007 Cochrane review of five randomized controlled trials concluded that therapy with unfractionated or LMW heparin was associated with a clinically significant survival benefit (hazard ratio 0.77; 95% CI 0.65-0.91) in cancer patients without another reason for anticoagulation [90]. In a subgroup analysis, patients with limited small cell lung cancer experienced a clear survival benefit (HR 0.56; 95% CI 0.38-0.83) which was not seen in patients with advanced cancer of any site. The analysis could not rule out an increased risk of bleeding with heparin in these patients (RR 1.8; 95% CI 0.73-4.4).
  • Results from a multicenter randomized study have indicated that use of the LMW heparin nadroparin did not significantly improve median overall survival in 244 patients with advanced cancer (prostate, pancreas, non-small cell lung cancer) when compared with the 259 not receiving this agent (13.1 versus 11.9 months, respectively; adjusted hazard ratio 0.94; 95% CI 0.75-1.18) [91]. In addition, no difference in time to progression was observed between the two study arms. Major bleeding events were comparable between the two groups (4.1 versus 3.5 percent).

In the absence of consistent data indicating a survival benefit, we agree with the 2007 ASCO guidelines and the 2008 ACCP guidelines, which recommended against the use of anticoagulants for the purpose of improving survival in cancer patients without VTE [70,75].

TREATMENT OF VTE — The treatment of VTE in cancer patients is discussed separately. (See “Treatment of venous thromboembolism in patients with malignancy”.)

ARTERIAL THROMBOSIS — Arterial thrombosis is less common than venous thrombosis in cancer patients.

  • In a retrospective cohort study, the incidence of arterial and venous thromboembolism among 66,106 hospitalized adult neutropenic cancer patients was 1.5 and 5.4 percent, respectively [92].
  • In a retrospective cohort study of 504,208 hospitalized cancer patients who did not receive blood transfusions and were admitted between 1995 and 2003 at 60 medical centers, the overall rates of arterial and venous thromboembolism were 3.0 and 3.7 percent, respectively [29]. These rates were as high as 5.2 and 7.2 percent, respectively in those who did receive blood transfusions during their hospitalization.

Such episodes of arterial thromboembolism are most frequently due to nonbacterial thrombotic endocarditis (see below), but some cases of acute ischemic stroke in patients with malignancy may be due to paradoxical brain embolism arising from deep vein thrombosis and a right-to-left shunt [93].

Thrombosis of the arterioles of the central nervous system and extremities may be associated with the myeloproliferative disorders, particularly essential thrombocythemia and polycythemia vera [94]. Digital ischemia may be a paraneoplastic phenomenon in solid tumors [95].

NONBACTERIAL THROMBOTIC ENDOCARDITIS — The term nonbacterial thrombotic endocarditis (NBTE, marantic endocarditis, Libman-Sacks endocarditis, verrucous endocarditis) refers to a spectrum of lesions ranging from microscopic aggregates of platelets to large vegetations on the heart valves (most often aortic and mitral), usually in patients with advanced malignancy. In autopsy series, cancer has been found in as many as 75 percent of cases [96]. The majority are seen in patients with adenocarcinomas (eg, pancreas, lung, colon, prostate); the incidence among patients with lung cancer may be as high as 7 percent [97,98]. (See “Echocardiography in detection of intracardiac sources of embolism”, section on ‘Nonbacterial thrombotic endocarditis’.)

The vegetations consist of degenerating platelets interwoven with strands of fibrin. The masses vary in size from microscopic to large and exuberant with a tendency to cause extensive infarction if embolization occurs.

The initiating factor in the pathogenesis of NBTE is unknown. Endothelial damage caused by circulating cytokines, such as tumor necrosis factor or interleukin-1, might trigger platelet deposition, particularly in the presence of an activated coagulation system. Laboratory evidence for disseminated intravascular coagulation (DIC) is often present.

The major clinical manifestations of NBTE result from systemic emboli rather than valvular dysfunction. The vegetations are easily dislodged since there is little inflammatory reaction at the site of attachment. Common sites of embolization include the spleen, kidney, and extremities, but the most significant morbidity arises from emboli to the central nervous system and coronary arteries [99,100]. Focal or diffuse neurologic abnormalities may be seen.

Diagnosis — The possibility of NBTE should be considered in all cancer patients who develop an acute stroke syndrome as well as in patients presenting with cerebral embolism of unknown etiology [99,101]. The diagnosis of NBTE can be difficult to establish antemortem. Fewer than 50 percent of patients have audible cardiac murmurs, and small lesions (less than 3 mm) may not be identified by echocardiography.

The preferred diagnostic test is transesophageal echocardiography (TEE), which is more sensitive than transthoracic echocardiography for the detection of vegetations. The potential value of TEE in this setting was illustrated in a series of 51 consecutive cancer patients with cerebrovascular events who were referred for TEE [101]. Almost one-half of patients had a definite cardiac source of embolism. Nonbacterial vegetations were detected in nine (18 percent); transthoracic echocardiography was performed in seven of these patients and was negative in four. Other sources of embolism included left atrial thrombus, complex aortic atheroma, and a patent foramen ovale or atrial septal defect in the presence of venous thromboembolism. (See “Echocardiography in detection of intracardiac sources of embolism”, section on ‘Nonbacterial thrombotic endocarditis’.)

Treatment — The 2008 ACCP Guidelines recommend the following anticoagulation in patients with NBTE [102]:

  • Patients with NBTE and systemic or pulmonary emboli should be anticoagulated if there is no contraindication to anticoagulation. They should receive treatment with full-dose intravenous unfractionated heparin or subcutaneous low molecular weight heparin, rather than warfarin.
  • Full-dose intravenous unfractionated heparin or subcutaneous low molecular weight heparin should be used in patients with disseminated cancer or debilitating disease who are found to have aseptic vegetations.

Anticoagulation should be continued indefinitely, since recurrent thromboembolism has occurred in patients following its discontinuation [103]. Treatment of the underlying malignancy, often metastatic at the time of diagnosis of NBTE, is generally unsatisfactory, but should be attempted in appropriate patients.

DISSEMINATED INTRAVASCULAR COAGULATION — Disseminated intravascular coagulation (DIC), resulting from generalized activation of the coagulation system, is the most common coagulopathy associated with malignancy. Malignancy is the third most frequent cause of DIC after infection and trauma, accounting for approximately 7 percent of clinically evident cases. DIC, which may be occult, has been reported in as many as 15 percent of patients with advanced disease and in most patients with acute promyelocytic leukemia (APL).

Acute DIC — Acute, overt DIC is rare in most malignancies, most often occurring with APL and adenocarcinomas [104]. Two tumor cell procoagulants may be of primary importance in APL: tissue factor which forms a complex with factor VII to activate factors X and IX; and cancer procoagulant which activates factor X independent of factor VII [105,106]. (See “Pathogenesis of the hypercoagulable state associated with malignancy”.)

Symptomatic DIC is manifested by bleeding due to utilization of clotting factors by the consumptive process. Affected patients may complain of minor bleeding from mucosal or cutaneous surfaces and/or extensive life-threatening hemorrhage involving visceral sites. Among patients with APL, DIC is often present at the time of diagnosis or soon after the initiation of cytotoxic chemotherapy. It can cause pulmonary or cerebrovascular hemorrhage in up to 40 percent of patients and some studies report a 10 to 20 percent incidence of early hemorrhagic deaths. The induction of tumor cell differentiation with retinoic acid can lead to rapid improvement in the coagulopathy associated with acute promyelocytic leukemia [105]. (See “Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults”.)

Carcinoma of the prostate also may be associated with hemorrhagic symptoms. However, the mechanism is different from DIC, being due to activation of fibrinolysis.

Laboratory evaluation in DIC reveals a typical constellation of findings. These include prolongation of the prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time and reptilase time; thrombocytopenia; and reductions in plasma concentrations of fibrinogen and factors V and VIII. The most useful confirmatory test is the demonstration of increased levels of fibrin degradation products (FDPs).

Chronic DIC — Chronic forms of DIC are more common in patients with cancer, particularly those with solid tumors. Most patients are asymptomatic while laboratory testing reveals low grade activation of coagulation with secondary fibrinolysis. The most common manifestations are modest reductions in plasma fibrinogen and the platelet count, elevated FDPs, and minimal changes in the PT or aPTT. A minority of affected patients have more obvious evidence of platelet, fibrinogen, and coagulation factor consumption. These patients often are hypercoagulable, and can present with deep vein thrombosis, Trousseau’s syndrome, or NBTE.

In one study of 1117 patients with solid tumors, DIC was present in 76 (6.8 percent); 50 patients presented with bleeding, while 31 presented with thrombosis [107]. On multivariate analysis, significant risk factors for development of DIC included:

  • Age >60 years — odds ratio (OR): 5.1
  • Male sex — OR: 4.3
  • Breast cancer — OR: 4.0
  • Tumor necrosis — OR: 3.4
  • Advanced stage disease — OR: 2.6

Median survival for patients with early stage tumors (stages I and II: 16 versus 44 months) as well as advanced stage tumors (stages III and IV: 9 versus 14 months) were significantly reduced in subjects with DIC, as compared with those without DIC, respectively.

THROMBOTIC MICROANGIOPATHY — Thrombotic microangiopathy (TMA) describes a syndrome characterized by a microangiopathic hemolytic anemia (MAHA) (picture 1), thrombocytopenia, microvascular thrombotic lesions, and the involvement of various specific organs. The two major TMA syndromes, which are thought to be pathogenetically similar, are thrombotic thrombocytopenic purpura (TTP) and the hemolytic-uremic syndrome (HUS) [108].

TMA can also be seen as a complication of chemotherapy. This primarily occurs with one of four regimens: mitomycin C; cisplatin with or without bleomycin; gemcitabine; and the use of radiation and high dose chemotherapy prior to hematopoietic cell transplantation (HCT). (See “Causes of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults”, section on ‘Cancer and chemotherapy’ and “Kidney disease following hematopoietic cell transplantation” and “Chemotherapy-related nephrotoxicity and dose modification in patients with renal insufficiency”.)

TMA is thought to reflect direct platelet consumption, due to endothelial injury or primary platelet activation resulting in some cases from accumulation of unusually large von Willebrand factor multimers [108-110]. (See “Causes of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults”, section on ‘Pathogenesis’.)

This is different from the direct activation of the coagulation pathway in DIC. As a result, TMA is characterized by thrombocytopenia, increased turnover of platelets but not fibrin, and usually normal levels of the coagulation components and little or no prolongation of the prothrombin time or activated partial thromboplastin time [108].

Disseminated malignancy — Cases of TMA with thrombocytopenia mimicking TTP have been reported in association with disseminated, often occult, mucin-producing adenocarcinoma of the breast, gastrointestinal tract, pancreas, lung, or prostate [109,111-114]. Neurologic abnormalities, such as headache, confusion, or paresis, can be seen, but renal failure is uncommon in carcinoma-associated TMA. This complication can occur in as many as 6 percent of patients with metastatic carcinoma. There are two main differences between these patients and those with TTP:

  • Levels of the von Willebrand factor cleaving protease (ADAMTS13) are normal [115], which is in contrast to the marked reduction seen in TTP. (See “Diagnosis of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults”.)
  • Patients respond poorly, if at all, to plasma exchange [112], which is the standard of care in TTP. (See “Treatment of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults”.)

A search for systemic malignancy, including a bone marrow biopsy, is appropriate when patients with apparent TTP have atypical clinical features or fail to respond to plasma exchange. (See “Causes of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults”, section on ‘Disseminated malignancy’.)

Patients presenting with this complication usually die within days to weeks of diagnosis unless the underlying malignancy can be controlled [112-119].

ACTIVATION OF COAGULATION PRIOR TO THE CLINICAL DIAGNOSIS OF MALIGNANCY — A number of studies have documented an increased incidence of malignancy subsequent to the diagnosis of idiopathic VTE. (See ‘Venous thromboembolism’ above.)

In addition, increased thrombin generation may be associated with an increase in cancer mortality even in the absence of symptomatic thrombosis [120,121]. This issue was addressed in the Second Northwick Park Study, which evaluated 3053 middle-aged men clinically free of malignancy to determine whether activation of coagulation had an impact on subsequent mortality [120]. Subjects with persistent activation of coagulation (ie, prothrombin fragment 1+2 and fibrinopeptide A concentrations in the upper quartile of the population distribution in two consecutive annual examinations) had an increased total mortality due to a higher mortality from all cancers, especially those of the gastrointestinal tract.

Two explanations for these observations are that the underlying malignancy produced a hypercoagulable state or that increased thrombin generation and activity might predispose to enhanced growth of malignant cells through promotion of angiogenesis and tumor cell proliferation.

SUMMARY — Clinical thromboembolism occurs in as many as 11 percent of patients with cancer and is the second leading cause of death in patients with overt malignant disease. Thrombotic episodes may precede the diagnosis of malignancy by months or years and can present in one or more of the following ways:

  • Migratory superficial thrombophlebitis (Trousseau’s syndrome). (See ‘Trousseau’s syndrome’ above.)
  • Idiopathic deep venous thrombosis and other venous thrombosis. (See ‘Venous thromboembolism’ above.)
  • Nonbacterial thrombotic endocarditis (marantic endocarditis). (See ‘Nonbacterial thrombotic endocarditis’ above.)
  • Disseminated intravascular coagulation (DIC). (See ‘Disseminated intravascular coagulation’ above.)
  • Thrombotic microangiopathy. (See ‘Thrombotic microangiopathy’ above.)
  • Arterial thrombosis. (See ‘Arterial thrombosis’ above.)

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