Cancer and thrombosis: from molecular mechanisms to clinical presentations
2007; Elsevier BV; Volume: 5; Linguagem: Inglês
10.1111/j.1538-7836.2007.02497.x
ISSN1538-7933
AutoresHarry R. Büller, Frederiek F van Doormaal, Geerte L. Van Sluis, Pieter W. Kamphuisen,
Tópico(s)Atrial Fibrillation Management and Outcomes
ResumoSummaryAlthough the bidirectional association between cancer and venous thromboembolism (VTE) has been known for almost two centuries, recent advances in our understanding of the clinical, laboratory, and epidemiologic aspects of this association have created a renewed interest in this topic. This review consists of two parts. The first part discusses the occurrence, determinants and significance of VTE in those with cancer, as well as the risk of developing and the possible need to detect cancer in those presenting with VTE. The second part reviews the role of hemostatic constituents (coagulation and fibrinolytic proteins and platelets) in promoting growth and progression of cancer, as well as the effects and possible mechanisms of the low molecular weight heparins (LMWH) in this process. Although the bidirectional association between cancer and venous thromboembolism (VTE) has been known for almost two centuries, recent advances in our understanding of the clinical, laboratory, and epidemiologic aspects of this association have created a renewed interest in this topic. This review consists of two parts. The first part discusses the occurrence, determinants and significance of VTE in those with cancer, as well as the risk of developing and the possible need to detect cancer in those presenting with VTE. The second part reviews the role of hemostatic constituents (coagulation and fibrinolytic proteins and platelets) in promoting growth and progression of cancer, as well as the effects and possible mechanisms of the low molecular weight heparins (LMWH) in this process. Historically, Armand Trousseau, the French physician (1801–1867), is often considered to have been the first scientist to describe the association between cancer and venous thrombosis. This is incorrect for both the relationship of cancer with subsequent complicating VTE as well as for occult cancer in thrombosis patients. A careful literature analysis revealed that already in 1823 Bouillaud described three cancer patients with deep venous thrombosis [1Bouillaud S. De l'Obliteration des veines et de son influence sur la formation des hydropisies partielles: consideration sur la hydropisies passive et general.Arch Gen Med. 1823; 1: 188-204Google Scholar, 2Otten HM. Thrombosis and cancer, Thesis, Academic Medical Center, University of Amsterdam, 2002.Google Scholar]. He speculated in his monogram that the peripheral edema in the legs of these cancer patients was the result of obstruction of the veins by 'caillot fibrineux' (fibrin clots) induced by the cancer process. Trousseau was 22 years old at that time. In the frequently quoted book by Trousseau, published in 1865, he indeed described in detail the relationship between cancer and VTE, but that was 42 years after Bouillaud [3Trousseau A. Trousseau A. Phlegmasia alba dolens.Clinique medicinale de l'Hotel-Dieu de Paris. Bailliere J.-B. et fils, 1865: 645-712Google Scholar]. Trousseau is also often quoted for the link between venous thrombosis and occult cancer. Close reading of his papers reveal that all his patients described with VTE already had extensive evidence of cancer at the time of the diagnosis of thrombosis [4Trousseau A. Ulcere chronique simple de l'estomac.in: Peter M Clinique Medicinale de l'Hotel-Dieu de Paris. Bailliere J.-B. et fils, 1877: 80-107Google Scholar, 5Trousseau A. Phlegmasia alba dolens.in: Peter M Clinique Medicinale de l'Hotel-Dieu de Paris. Bailliere J.-B. et fils, 1877: 695-739Google Scholar]. The honor of the first description of a patient with deep venous thrombosis and the manifestation of a gastric cancer several months later goes to Illtyd James and Matheson [6Illtyd James T. Matheson N. Thromboplebitis in cancer.Practitioner. 1935; 134: 683-4Google Scholar]. They published their paper in 1935. Interestingly, the first proper cohort study in patients with VTE to assess the incidence of occult cancer was only published in 1982 [7Gore J.M. Appelbaum J.S. Greene H.L. Dexter L. Dalen J.E. Occult cancer in patients with acute pulmonary embolism.Ann Intern Med. 1982; 96: 556-60Crossref PubMed Scopus (145) Google Scholar]. These authors coined the question of whether an extensive search for cancer at the time of VTE diagnosis was indicated. The focus in this part of the review will be on deep vein thrombosis of the leg (DVT) or pulmonary embolism (PE) and the two-way association with cancer, with special emphasis on the epidemiologic aspects, the magnitude and consequences. Other manifestations of venous thrombosis, such as superficial flebitis, arm vein thrombosis, and catheter-related thrombosis, as well as the prevention and treatment of DVT and PE are outside the scope of this contribution. In cancer patients VTE complications are common and the second leading cause of death [8Haddad T.C. Greeno E.W. Chemotherapy-induced thrombosis.Thromb Res. 2006; 118: 555-68Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar, 9Prandoni P. Falanga A. Piccioli A. Cancer and venous thromboembolism.Lancet Oncol. 2005; 6: 401-10Abstract Full Text Full Text PDF PubMed Scopus (493) Google Scholar, 10Rickles F.R. Edwards R.L. Activation of blood coagulation in cancer: Trousseau's syndrome revisited.Blood. 1983; 62: 14-31Crossref PubMed Google Scholar]. Of every seven patients with cancer who die in hospital, one dies of pulmonary embolism [11Shen V.S. Pollak E.W. Fatal pulmonary embolism in cancer patients: is heparin prophylaxis justified?.South Med J. 1980; 73: 841-3Crossref PubMed Scopus (134) Google Scholar]. Compared with non-cancer patients the risk of developing symptomatic VTE is six to seven times higher in cancer patients, with similar risks for the components of VTE (i.e. DVT and PE) [12Heit J.A. Mohr D.N. Silverstein M.D. Petterson T.M. O'Fallon W.M. Melton III, L.J. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study.Arch Intern Med. 2000; 160: 761-8Crossref PubMed Scopus (773) Google Scholar, 13Blom J.W. Doggen C.J. Osanto S. Rosendaal F.R. Malignancies, prothrombotic mutations, and the risk of venous thrombosis.JAMA. 2005; 293: 715-22Crossref PubMed Scopus (1504) Google Scholar]. The precise incidence and time course of VTE complications among cancer patients have until recently largely been unknown [14Chew H.K. Wun T. Harvey D. Zhou H. White R.H. Incidence of venous thromboembolism and its effect on survival among patients with common cancers.Arch Intern Med. 2006; 166: 458-64Crossref PubMed Scopus (1018) Google Scholar]. Initially, small cohort studies estimated the incidence among patients with various types and stages of cancer to be approximately 4% [14Chew H.K. Wun T. Harvey D. Zhou H. White R.H. Incidence of venous thromboembolism and its effect on survival among patients with common cancers.Arch Intern Med. 2006; 166: 458-64Crossref PubMed Scopus (1018) Google Scholar]. Subsequent larger epidemiologic studies found incidences of clinically manifest VTE of 110–120 events per 10 000 patients [15Levitan N. Dowlati A. Remick S.C. Tahsildar H.I. Sivinski L.D. Beyth R. Rimm A.A. Rates of initial and recurrent thromboembolic disease among patients with malignancy vs. those without malignancy. Risk analysis using Medicare claims data.Medicine (Baltimore). 1999; 78: 285-91Crossref PubMed Scopus (791) Google Scholar, 16Thodiyil P.A. Kakkar A.K. Variation in relative risk of venous thromboembolism in different cancers.Thromb Haemost. 2002; 87: 1076-7Crossref PubMed Scopus (124) Google Scholar]. Recently, a large population-based study determined the incidence of VTE among patients diagnosed with specific types and stages of cancer [14Chew H.K. Wun T. Harvey D. Zhou H. White R.H. Incidence of venous thromboembolism and its effect on survival among patients with common cancers.Arch Intern Med. 2006; 166: 458-64Crossref PubMed Scopus (1018) Google Scholar]. Among 235 149 cancer cases, confirmed symptomatic VTE events were diagnosed within 2 years in 1.6%. Twelve percentage of these events occurred at the time cancer was diagnosed and the remaining 88% were observed subsequently. In another recent large population-based study the duration between the diagnosis of cancer and the occurrence of VTE was determined [13Blom J.W. Doggen C.J. Osanto S. Rosendaal F.R. Malignancies, prothrombotic mutations, and the risk of venous thrombosis.JAMA. 2005; 293: 715-22Crossref PubMed Scopus (1504) Google Scholar]. In the first 3 months the risk of VTE was the highest, with an odds ratio of 54, whereas in the period between 3 and 12 months following the cancer diagnosis, the odds ratio of VTE was 14, and between 1 and 3 years this figure was 4 [13Blom J.W. Doggen C.J. Osanto S. Rosendaal F.R. Malignancies, prothrombotic mutations, and the risk of venous thrombosis.JAMA. 2005; 293: 715-22Crossref PubMed Scopus (1504) Google Scholar]. Table 1 details the determinants for the risk of symptomatic episodes of VTE in patients with cancer. In risk-adjusted models Chew and colleagues found metastatic disease at the time of cancer diagnosis the strongest predictor of VTE [14Chew H.K. Wun T. Harvey D. Zhou H. White R.H. Incidence of venous thromboembolism and its effect on survival among patients with common cancers.Arch Intern Med. 2006; 166: 458-64Crossref PubMed Scopus (1018) Google Scholar]. The risk was four to 13 times higher as compared with cases with localized disease. In patients with metastatic-stage disease the highest incidences (expressed as VTE events per 100 patient-years) were observed for pancreatic (20.0), stomach (10.7), bladder (7.9), uterine (6.4), renal (6.0), and lung (5.0) cancer. Most of the VTE complications occurred in the first year of follow-up [14Chew H.K. Wun T. Harvey D. Zhou H. White R.H. Incidence of venous thromboembolism and its effect on survival among patients with common cancers.Arch Intern Med. 2006; 166: 458-64Crossref PubMed Scopus (1018) Google Scholar]. Blom and colleagues also determined the significance of distant metastases for the risk of VTE and found an odds ratio of 20 as compared with patients without distant metastases [13Blom J.W. Doggen C.J. Osanto S. Rosendaal F.R. Malignancies, prothrombotic mutations, and the risk of venous thrombosis.JAMA. 2005; 293: 715-22Crossref PubMed Scopus (1504) Google Scholar].Table 1Determinants for the risk of venous thromboembolism in cancer patientsTumor stageTumor typeAnticancer therapyChemotherapyHormonal therapyAngiogenesis inhibitorsSupportive therapySurgeryProthrombotic abnormalities Open table in a new tab All hematologic and solid tumor types have been associated with VTE. However, conflicting data exist about the relative risk of VTE according to tumor histology and site of primary location [8Haddad T.C. Greeno E.W. Chemotherapy-induced thrombosis.Thromb Res. 2006; 118: 555-68Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar]. It is, however, clear that the VTE risk is not equal among the various types of cancer. Adjusted for age and sex, Blom et al. observed, in a population-based study, the highest risk of VTE among patients with hematological malignancies (odds ratio 28), followed by lung cancer (odds ratio 22) and gastrointestinal cancer (odds ratio 20) [13Blom J.W. Doggen C.J. Osanto S. Rosendaal F.R. Malignancies, prothrombotic mutations, and the risk of venous thrombosis.JAMA. 2005; 293: 715-22Crossref PubMed Scopus (1504) Google Scholar]. In another population-based study, Heit and colleagues noted that pancreatic cancer, lymphoma, and brain cancer have relative risks of VTE >25, followed by liver cancer, leukemia, and other gastrointestinal (esophagus, gallbladder) and gynecological cancer, with a relative risk above 17 [17Heit J.A. Cancer and venous thromboembolism: scope of the problem.Cancer Control. 2005; 12: 5-10Crossref PubMed Google Scholar]. In a study of hospitalized patients the highest incidence of VTE occurred among women with ovarian cancer, followed by brain and pancreas cancer and lymphoma [15Levitan N. Dowlati A. Remick S.C. Tahsildar H.I. Sivinski L.D. Beyth R. Rimm A.A. Rates of initial and recurrent thromboembolic disease among patients with malignancy vs. those without malignancy. Risk analysis using Medicare claims data.Medicine (Baltimore). 1999; 78: 285-91Crossref PubMed Scopus (791) Google Scholar, 16Thodiyil P.A. Kakkar A.K. Variation in relative risk of venous thromboembolism in different cancers.Thromb Haemost. 2002; 87: 1076-7Crossref PubMed Scopus (124) Google Scholar]. The third and probably at present the most changing determinant for the risk of VTE is anticancer therapy (Table 1). Chemotherapy is a well-recognized independent risk factor for VTE and the annual incidence has been estimated to be 10%–20% depending on the type of drugs given [8Haddad T.C. Greeno E.W. Chemotherapy-induced thrombosis.Thromb Res. 2006; 118: 555-68Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar, 18Otten H.M. Mathijssen J. Ten Cate H. Soesan M. Inghels M. Richel D.J. Prins M.H. Symptomatic venous thromboembolism in cancer patients treated with chemotherapy: an underestimated phenomenon.Arch Intern Med. 2004; 164: 190-4Crossref PubMed Scopus (225) Google Scholar]. However, one of the most prominent reasons for the increasing importance of anticancer therapy as a determinant for the thrombosis risk is that in addition to chemotherapy, other frequently combined therapies to treat the cancer, such as hormonal therapy, angiogenesis inhibitors, and supportive therapy, carry their own risk to induce a hypercoagulable state [8Haddad T.C. Greeno E.W. Chemotherapy-induced thrombosis.Thromb Res. 2006; 118: 555-68Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar]. Probably the best-studied influence of chemotherapy on the risk of thrombosis is in patients with breast cancer. In early stage breast cancer the risk of VTE is similar to that in the general population (approximately 0.2%). With chemotherapy or hormonal treatment this increases to 1%–2%. When in stages I–II chemotherapy and hormonal therapy are combined the incidence rises to 5%–7% [8Haddad T.C. Greeno E.W. Chemotherapy-induced thrombosis.Thromb Res. 2006; 118: 555-68Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar, 19Otten H.M. Prins M.H. Smorenburg S.M. Hutten B.A. Risk assessment and prophylaxis of venous thromboembolism in non-surgical patients: cancer as a risk factor.Haemostasis. 2000; 30: 72-6PubMed Google Scholar, 20Levine M.N. Prevention of thrombotic disorders in cancer patients undergoing chemotherapy.Thromb Haemost. 1997; 78: 133-6Crossref PubMed Scopus (123) Google Scholar]. For patients with stage IV breast cancer these rates may be as high as 18% with the combined treatments [8Haddad T.C. Greeno E.W. Chemotherapy-induced thrombosis.Thromb Res. 2006; 118: 555-68Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar]. Other chemotherapeutic agents, such as cisplatin (reported VTE rates of 8%–18%), l-asparaginase (reported VTE rates in adults of 4%–14%) and fluorouracil (reported VTE rates of 15%–17%), often in combination with other forms of chemotherapy, have been clearly associated in retro and prospective studies with an increased risk of VTE [8Haddad T.C. Greeno E.W. Chemotherapy-induced thrombosis.Thromb Res. 2006; 118: 555-68Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar]. Thalidomide, particularly in combination with dexamethasone or doxorubicin, may induce VTE rates as high as 20%–40% [8Haddad T.C. Greeno E.W. Chemotherapy-induced thrombosis.Thromb Res. 2006; 118: 555-68Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar, 21Zangari M. Barlogie B. Anaissie E. Saghafifar F. Eddlemon P. Jacobson J. Lee C.K. Thertulien R. Talamo G. Thomas T. Van R.F. Fassas A. Fink L. Tricot G. Deep vein thrombosis in patients with multiple myeloma treated with thalidomide and chemotherapy: effects of prophylactic and therapeutic anticoagulation.Br J Haematol. 2004; 126: 715-21Crossref PubMed Scopus (210) Google Scholar]. Whether the newer thalidomide analogs (IMiDs) really have lower VTE complication rates remains to be demonstrated, in particular when combined with other forms of chemotherapy. Initially, angiogenesis inhibitors (such as bevacizumab), again in combination with chemotherapy, were reported to induce higher rates of VTE, but more recent comparisons (with and without bevacizumab) suggest that the contribution of angiogenesis inhibitors may be marginal [8Haddad T.C. Greeno E.W. Chemotherapy-induced thrombosis.Thromb Res. 2006; 118: 555-68Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar, 22Hurwitz H. Fehrenbacher L. Novotny W. Cartwright T. Hainsworth J. Heim W. Berlin J. Baron A. Griffing S. Holmgren E. Ferrara N. Fyfe G. Rogers B. Ross R. Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.N Engl J Med. 2004; 350: 2335-42Crossref PubMed Scopus (9201) Google Scholar]. Finally, supportive therapies associated with an increased risk of VTE include erythropoietin, hemotopoietic colony-stimulating factors, and high-dose corticosteroids. Cancer patients undergoing surgical procedures have an approximately 2-fold higher risk of developing VTE as compared with non-cancer patients [12Heit J.A. Mohr D.N. Silverstein M.D. Petterson T.M. O'Fallon W.M. Melton III, L.J. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study.Arch Intern Med. 2000; 160: 761-8Crossref PubMed Scopus (773) Google Scholar, 23White R.H. Zhou H. Romano P.S. Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures.Thromb Haemost. 2003; 90: 446-55Crossref PubMed Google Scholar]. Incidences of symptomatic VTE within 91 days after the procedure in cancer patients were as high as 3%–4% for radical cystectomy, nephrostomy, brain surgery, and total hip replacement [23White R.H. Zhou H. Romano P.S. Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures.Thromb Haemost. 2003; 90: 446-55Crossref PubMed Google Scholar]. Other determinants of the VTE risk in cancer patients include the classical risk factors such as immobility, age, and also prothrombotic abnormalities. Carriers of the factor (F) V Leiden mutation who also had cancer had a 12-fold increased risk of developing VTE as compared with individuals with the mutation but no cancer [13Blom J.W. Doggen C.J. Osanto S. Rosendaal F.R. Malignancies, prothrombotic mutations, and the risk of venous thrombosis.JAMA. 2005; 293: 715-22Crossref PubMed Scopus (1504) Google Scholar]. This is in agreement with earlier observation and also applies to other genetic thrombophilias, such as the prothrombin mutation [13Blom J.W. Doggen C.J. Osanto S. Rosendaal F.R. Malignancies, prothrombotic mutations, and the risk of venous thrombosis.JAMA. 2005; 293: 715-22Crossref PubMed Scopus (1504) Google Scholar, 24Otterson G.A. Monahan B.P. Harold N. Steinberg S.M. Frame J.N. Kaye F.J. Clinical significance of the FV:Q506 mutation in unselected oncology patients.Am J Med. 1996; 101: 406-12Abstract Full Text PDF PubMed Scopus (47) Google Scholar, 25Pihusch R. Danzl G. Scholz M. Harich D. Pihusch M. Lohse P. Hiller E. Impact of thrombophilic gene mutations on thrombosis risk in patients with gastrointestinal carcinoma.Cancer. 2002; 94: 3120-6Crossref PubMed Scopus (57) Google Scholar]. Cancer patients who have developed VTE have an approximately 3-fold higher risk of experiencing a recurrent thrombosis in the first 12 months as compared with VTE patients without cancer [12Heit J.A. Mohr D.N. Silverstein M.D. Petterson T.M. O'Fallon W.M. Melton III, L.J. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study.Arch Intern Med. 2000; 160: 761-8Crossref PubMed Scopus (773) Google Scholar, 15Levitan N. Dowlati A. Remick S.C. Tahsildar H.I. Sivinski L.D. Beyth R. Rimm A.A. Rates of initial and recurrent thromboembolic disease among patients with malignancy vs. those without malignancy. Risk analysis using Medicare claims data.Medicine (Baltimore). 1999; 78: 285-91Crossref PubMed Scopus (791) Google Scholar, 26Prandoni P. Lensing A.W. Piccioli A. Bernardi E. Simioni P. Girolami B. Marchiori A. Sabbion P. Prins M.H. Noventa F. Girolami A. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis.Blood. 2002; 100: 3484-8Crossref PubMed Scopus (1483) Google Scholar]. Prandoni and colleagues observed recurrent VTE in 6.8% of patients without cancer, whereas in those with cancer the incidence was 20.7% [26Prandoni P. Lensing A.W. Piccioli A. Bernardi E. Simioni P. Girolami B. Marchiori A. Sabbion P. Prins M.H. Noventa F. Girolami A. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis.Blood. 2002; 100: 3484-8Crossref PubMed Scopus (1483) Google Scholar]. Developing VTE predicts a worse prognosis in cancer patients [15Levitan N. Dowlati A. Remick S.C. Tahsildar H.I. Sivinski L.D. Beyth R. Rimm A.A. Rates of initial and recurrent thromboembolic disease among patients with malignancy vs. those without malignancy. Risk analysis using Medicare claims data.Medicine (Baltimore). 1999; 78: 285-91Crossref PubMed Scopus (791) Google Scholar, 27Sorensen H.T. Mellemkjaer L. Olsen J.H. Baron J.A. Prognosis of cancers associated with venous thromboembolism.N Engl J Med. 2000; 343: 1846-50Crossref PubMed Scopus (1333) Google Scholar]. The 1-year survival was 12% in patients diagnosed with cancer and VTE at the same time, compared with 36% in cancer patients without VTE in a population-based study [27Sorensen H.T. Mellemkjaer L. Olsen J.H. Baron J.A. Prognosis of cancers associated with venous thromboembolism.N Engl J Med. 2000; 343: 1846-50Crossref PubMed Scopus (1333) Google Scholar]. Figure 1 shows the mortality rates in the first 180 days in patients with cancer and VTE, which are more than 2-fold higher than those in cancer patients without VTE [27Sorensen H.T. Mellemkjaer L. Olsen J.H. Baron J.A. Prognosis of cancers associated with venous thromboembolism.N Engl J Med. 2000; 343: 1846-50Crossref PubMed Scopus (1333) Google Scholar]. In patients with symptomatic VTE, the incidence of concomitant cancer (i.e. cancer not known before the diagnosis of VTE and discovered by routine investigation) at the time of VTE diagnosis, varies in the larger studies between 4% and 12% [28Otten H.M. Prins M.H. Venous thromboembolism and occult malignancy.Thromb Res. 2001; 102: V187-94Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar]. The cancer stage in patients with concurrently diagnosed VTE is often advanced [27Sorensen H.T. Mellemkjaer L. Olsen J.H. Baron J.A. Prognosis of cancers associated with venous thromboembolism.N Engl J Med. 2000; 343: 1846-50Crossref PubMed Scopus (1333) Google Scholar, 29White R.H. Chew H.K. Zhou H. Parikh-Patel A. Harris D. Harvey D. Wun T. Incidence of venous thromboembolism in the year before the diagnosis of cancer in 528,693 adults.Arch Intern Med. 2005; 165: 1782-7Crossref PubMed Scopus (204) Google Scholar]. Furthermore, the risk of concomitant cancer is 3- to 4-fold increased in patients with idiopathic VTE compared with secondary VTE [28Otten H.M. Prins M.H. Venous thromboembolism and occult malignancy.Thromb Res. 2001; 102: V187-94Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar]. The risk of occult cancer (i.e. cancer that becomes clinically apparent during follow-up) is also increased in patients with VTE. Summarizing 17 cohort and two population-based studies, Otten and Prins calculated an incidence of new cancer in patients with idiopathic VTE of 4%–10%, diagnosed within 3 years after the thrombotic event [28Otten H.M. Prins M.H. Venous thromboembolism and occult malignancy.Thromb Res. 2001; 102: V187-94Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar]. Again, this incidence was higher in idiopathic VTE than in patients with secondary VTE. The incidence of cancer is the highest shortly after VTE has been diagnosed. During the first year, the standardized incidence ratio for cancer in patients with VTE is 2.1–4.6, while after this period the risk gradually decreases [30Lee A.Y. Thrombosis and cancer: the role of screening for occult cancer and recognizing the underlying biological mechanisms.Hematol Am Soc Hematol Educ Program. 2006; : 438-43Crossref PubMed Scopus (43) Google Scholar]. In the large Californian registry, White et al. showed that the incidence of cancer was the highest during the first 60 days after an unprovoked episode of VTE (Fig. 2), with a gradual decline afterwards [29White R.H. Chew H.K. Zhou H. Parikh-Patel A. Harris D. Harvey D. Wun T. Incidence of venous thromboembolism in the year before the diagnosis of cancer in 528,693 adults.Arch Intern Med. 2005; 165: 1782-7Crossref PubMed Scopus (204) Google Scholar]. In the first 4 months after VTE diagnosis, the standardized incidence ratio was 2-fold higher than the expected incidence, whereas the observed and expected incidences of cancer 4–12 months after VTE were virtually the same. Also the occurrence of metastasized disease was the highest in the first 4 months after an unprovoked VTE. This indicates that the risk of cancer is only increased in the first months to a year after a VTE, while many patients already have metastases. The risk of developing overt cancer after VTE also depends on the type of cancer. In the large Danish registry, Sørensen and colleagues showed that around 15% of the patients with VTE and cancer within 1 year had lung cancer, followed by prostate (11.4%), pancreas (7.9%), colon (7%), and breast (4.3%) cancer [27Sorensen H.T. Mellemkjaer L. Olsen J.H. Baron J.A. Prognosis of cancers associated with venous thromboembolism.N Engl J Med. 2000; 343: 1846-50Crossref PubMed Scopus (1333) Google Scholar]. Leukemia and non-Hodgkin lymphoma were found in 2.5% of the patients [27Sorensen H.T. Mellemkjaer L. Olsen J.H. Baron J.A. Prognosis of cancers associated with venous thromboembolism.N Engl J Med. 2000; 343: 1846-50Crossref PubMed Scopus (1333) Google Scholar]. In the Californian cancer registry, White et al. revealed the highest standardized incidence ratios for acute myelogenous leukemia (4.2), followed by ovarian cancer (2.8), non-Hodgkin lymphoma (2.7), pancreatic (2.6), renal cell (2.5), stomach and lung cancer (1.8) [29White R.H. Chew H.K. Zhou H. Parikh-Patel A. Harris D. Harvey D. Wun T. Incidence of venous thromboembolism in the year before the diagnosis of cancer in 528,693 adults.Arch Intern Med. 2005; 165: 1782-7Crossref PubMed Scopus (204) Google Scholar]. Considering the high incidence of cancer in the first months after VTE, screening for an underlying malignancy may be clinically relevant. The literature is, however, not concordant on whether extensive screening for occult malignancy is indicated. Retrospective studies indicated that a careful medical history, physical examination, and laboratory testing detected most occult cancers in patients with VTE [31Cornuz J. Pearson S.D. Creager M.A. Cook E.F. Goldman L. Importance of findings on the initial evaluation for cancer in patients with symptomatic idiopathic deep venous thrombosis.Ann Intern Med. 1996; 125: 785-93Crossref PubMed Scopus (146) Google Scholar, 32Nordstrom M. Lindblad B. Anderson H. Bergqvist D. Kjellstrom T. Deep venous thrombosis and occult malignancy: an epidemiological study.BMJ. 1994; 308: 891-4Crossref PubMed Scopus (246) Google Scholar, 33Hettiarachchi R.J. Lok J. Prins M.H. Buller H.R. Prandoni P. 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