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Cancer associated thrombosis: risk factors and outcomes
S12 Thrombosis Research 140S1 (2016) S12–S17
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Thrombosis Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / t h r o m r e s
Cancer associated thrombosis: risk factors and outcomes Sabine Eichinger* Department of Internal Medicine I, Medical University of Vienna; Karl Landsteiner Institute of Thrombosis Research, Vienna, Austria
k e y w o r d s
a b s t r a c t
Cancer Thrombosis Risk factors Outcome Mortality
Deep vein thrombosis of the leg and pulmonary embolism are frequent diseases and cancer is one of their most important risk factors. Patients with cancer also have a higher prevalence of venous thrombosis located in other parts than in the legs and/or in unusual sites including upper extremity, splanchnic or cerebral veins. Cancer also affects the risk of arterial thrombotic events particularly in patients with myeloproliferative neoplasms and in vascular endothelial growth factor receptor inhibitor recipients. Several risk factors need to interact to trigger thrombosis. In addition to common risk factors such as surgery, hospitalisation, infection and genetic coagulation disorders, the thrombotic risk is also driven and modified by cancer-specific factors including type, histology, and stage of the malignancy, cancer treatment and certain biomarkers. A venous thrombotic event in a cancer patient has serious consequences as the risk of recurrent thrombosis, the risk of bleeding during anticoagulation and hospitalisation rates are all increased. Survival of cancer patients with thrombosis is worse compared to that of cancer patients without thrombosis, and thrombosis is a leading direct cause of death in cancer patients. © 2016 Elsevier Ltd. All rights reserved.
Introduction
Risk of cancer in VTE – risk of VTE in cancer
Venous thromboembolism (VTE), a hypernym of deep-vein thrombosis and pulmonary embolism, is a frequent disease with multiple risk factors. In population studies from Western Europe, North America, Australia and southern Latin America the annual incidence rates of VTE range from 75-269/100.000 individuals [1]. VTE occurs in the absence of an identifiable risk factor in up to 50% of patients, the proportion varying by the exact definition of risk factors [2]. In almost halve of the remaining patients, VTE is seen in the context of a malignant disease. Notably, the incidence of venous thrombosis in cancer patients has increased over recent years. Between 1979 and 1999, the VTE rate increased from 1.5 to 3.5% among hospitalized cancer patients, while rates remained stable in patients without cancer [3]. For the period between 1995 and 2002, a 36% increase in the risk of VTE among cancer patients was reported [4]. Improved survival among cancer patients, more aggressive cancer treatments and a better awareness of cancerassociated VTE are the most likely explanations. The consequences of cancer-associated VTE are serious as morbidity, mortality and health care costs are all increased. In this chapter I will focus on epidemiologic aspects and clinical presentation of cancer-associated VTE, cancer related thrombotic risk factors, and outcomes including mortality.
The increased thrombotic risk associated with cancer has long been established and can be seen from different angles. A malignant disease is found in 15-25% of all patients with VTE [2,5-7]. The prevalence of cancer is higher in patients with an otherwise unprovoked thrombosis than in patients with thrombosis secondary to a transient risk factor [8]. The occurrence of a VTE in a thus far asymptomatic individual may indicate an underlying cancer and may be the first sign of the malignancy. A previously undetected cancer can be found in approximately 4% of patients within one month after the VTE and in approximately 6% of patients within one year [9]. The likelihood for developing cancer was found to be substantially elevated during the first 12 months [10,11] after VTE diagnosis. Data on a persistently increased risk thereafter are conflicting [10,11]. Compared to non-cancer patients, the risk of VTE is 4- to 7-fold higher in cancer patients irrespective of the underlying type [5,12]. In a meta-analysis by Horsted and colleagues the incidence rate of venous thrombosis was 13/1000 person-years in patients classified as average-risk and was 68/1000 person-years in high-risk patients, based on the presence of high-grade or metastatic disease or exposure to thrombogenic treatment regimens [13]. The clinical presentation of deep-vein thrombosis and pulmonary embolism is different in cancer patients compared to that in non-cancer patients and the natural course of VTE tends to be more aggressive. What Armand Trousseau observed and later published in 1865 was indeed the most severe form of venous obstruction in a cancer patient, namely phlegmasia alba dolens [14]. The incidence of bilateral lower limb deep-vein thrombosis was significantly higher in patients
* Corresponding author at: Dept. of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Wien, Austria. Tel.: 43-1-40400-49180; fax: 43-1-40400-40300. E-mail address: [email protected] (S. Eichinger). 0049-3848/© 2016 Elsevier Ltd. All rights reserved.
S. Eichinger / Thrombosis Research 140S1 (2016) S12–S17
with cancer than in patients without cancer (8.5% versus 4.6%), as were the rates of iliocaval thrombosis (22.6% versus 14%) [15], and survival rates of cancer patients with bilateral deep-vein thrombosis were lower than in unilateral deep-vein thrombosis [16]. Also, compared to non-cancer patients, patients with cancer have a higher prevalence of venous thrombosis located in other parts than in the legs and/or in unusual sites with cancer being an independent predictor of incident non-leg deep- vein thrombosis [17]. Upper extremity deep vein thrombosis Deep-vein thrombosis in the upper extremities (UEDVT) only account for a minority (about 4%) of all venous thrombotic events [18]. A third of UEDVT are so called primary events while the majority occurs in relation with a known risk factor. In patients with cancer, UEDVT occurs most often while there is an indwelling central venous catheter as they are frequently used for administration of chemotherapy, antibiotics or nutrition. The frequency of catheter-associated thrombosis decreased over time with improved insertion techniques and catheter material [19]. In a prospective cohort study, patients with cancer were followed while their catheter remained in place. Only 19 of 444 patients (4.3%) had symptomatic catheter-related thrombosis in 19 of 500 catheters (0.3/1000 catheter-days) [20]. The risk of UEDVT in cancer patients is also increased in the absence of central venous catheters. In patients with an active cancer the risk of UEDVT was 18fold increased compared with patients without cancer [21]. Splanchnic vein thrombosis An underlying malignancy is commonly found in splanchnic vein thrombosis including the Budd-Chiari syndrome, extrahepatic portal vein obstruction and mesenteric vein thrombosis [22]. In a prospective cohort study almost 25% of patients with splanchnic vein thrombosis had a solid cancer and 8% a myeloproliferative disorder [23]. Myeloproliferative neoplasms are diagnosed in up to half of the patients with Budd-Chiari syndrome and in one third of those with extrahepatic portal vein obstruction [24]. The diagnosis of a myeloproliferative neoplasm is sometimes preceded by splanchnic vein thrombosis. The JAK2 V617F mutation is present in up to 87% of those with an already diagnosed myeloproliferative neoplasm and in up to 26% of those without other laboratory signs. In the latter, other molecular markers, such as mutations in JAK2 exon 12, CALR and MPL genes, are extremely rare [24]. Among patients with splanchnic vein thrombosis and JAK2 V617F positivity as the sole marker of a hematologic disease at the time of thrombosis, the rate of development of an overt myeloproliferative neoplasm during follow-up is 52% [25]. Cerebral vein thrombosis Cerebral vein thrombosis can be the first symptom of a solid cancer, particularly if the tumour is located in the brain, and of myeloproliferative neoplasms [22]. Ten of 152 patients (6.6%) with cerebral venous thrombosis were carriers of the JAK2 V617F mutation and three of them had no signs of a myeloproliferative neoplasm at the time of diagnosis of the thrombosis but developed the disease during follow-up (median duration 7.8 years) [26]. Thus, as with splanchnic vein thrombosis, positivity for the JAK2 V617F mutation may occur in patients who otherwise do not meet the criteria for a myeloproliferative neoplasm. Superficial vein thrombosis (SVT) Whether cancer is also associated with SVT (or vice versa) is unclear as this has never been systematically evaluated. The occurrence of
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cancer during the first year when compared with the expected number of cancer diagnoses based on national incidence rates (standardised incidence ratios, SIR) was similar for 7.663 patients with SVT (SIR 2.46, 95% CI 2.10–2.86), for 45.252 patients with DVT (SIR 2.75, 95% CI 2.60–2.90), and for 24.332 patients with pulmonary embolism (SIR 3.27, 95% CI 3.03–3.52) [27]. In contrast, in patients with isolated SVT not involving the sapheno-femoral junction and in whom a concomitant deep vein thrombosis was excluded by ultrasonography, occurrence of SVT in the legs did not represent a risk factor for subsequent malignancies [28]. During an average observation period of 26 months cancer was found in 26 (3.5%) of 737 patients with SVT and in 56 (3.9%) of 1438 controls for a hazard ratio of 0.86 (95% CI 0.55%-1.35%). The difference in findings may be explained by the heterogeneity in the diagnosis and definition of SVT. It remains to be shown whether extended SVT or unusual presentations, for example migratory forms, are associated with cancer. Risk factors and biomarkers Venous thromboembolism is a multicausal disease. The relevance of patient-related and circumstantial risk factors, including age, sex, ethnicity, genetic and acquired coagulation disorders and a prior history of thrombosis as regards the risk of a first VTE has been extensively reviewed [29]. Circumstantial factors such as surgery, trauma, immobilization, hospitalization and co-morbidities are also strongly linked to an increased risk of VTE. According to the current pathophysiologic concept several risk factors need to interact to trigger thrombosis. There is nothing to assume that this concept does not hold true also in a cancer patient. Indeed, it has been shown that surgery, immobilisation, and genetic coagulation disorders substantially increase the risk of VTE in cancer patients. Data on the effect of age are controversial [3,6,30,34]. Cancer patients with multiple medical comorbidities or other conditions including infection, pulmonary disease, renal disease, or obesity have about 1.5-fold higher rates of VTE [30]. Cancer patients with a prior history of VTE have a 6to 7-fold increased risk for VTE compared with patients without a history of VTE [31]. The risk of VTE is higher in hospitalized cancer patients than in ambulatory cancer patients [32]. The thrombotic risk is highest during the first months after cancer diagnosis [12,33,34]. An overview on risk factors is provided in Table 1. Cancer-specific risk factors The thrombotic risk is also driven and modified by cancer-specific risk factors including type, histology, and stage of the malignancy, and cancer treatment [13,35]. The incidence of VTE is highest among patients with malignant brain tumours, adenocarcinomas of the lung, ovary, pancreas, colon, stomach, prostate, and kidney and in patients with hematologic malignancies and in those initially diagnosed with metastatic-stage disease [35]. According to a population-based, case-control study from the Netherlands, the risk of VTE was highest in patients with hematologic malignancies (OR 28), lung cancer (OR 22), gastrointestinal cancer (OR 20) or brain cancer (OR 7), and in those with distant metastasis [12]. Compared to cancer patients without distant metastasis, those with metastatic disease had an almost 20-fold increased risk of VTE. The incidence of VTE within 1 and 2 years of cancer diagnosis and the risk factors associated with VTE were determined on the basis of records of more than 235.000 cancer patients [36]. The strongest predictor of VTE was the presence of metastases. The highest incidence of VTE during the first year was found among patients with metastatic-stage pancreatic cancer, cancer of the stomach, bladder, uterus, kidneys or lung [36]. In a population-based cohort study from Denmark, incidence rates for hospitalization for VTE were calculated for more than 57,000 cancer patients and almost 290.000 controls [6]. Strong predictors were cancer site, stage and type of initial cancer treatment. In this study
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Table 1 Risk factors for VTE in cancer patients Risk factor
Approximate risk increase
Reference
Time since cancer diagnosis
Highest during first 6 months
[12,33,34]
Age
Data inconsistent
[3,6,30,34]
Prior history of VTE
6-7 fold
[31]
Hospitalisation/immobilisation
2-4 fold
[32]
Comorbidities
2 fold
[30]
Genetic factors
2-5 fold
[12]
Radiotherapy
2 fold
[41]
Surgery
2-4 fold
Type of cancer
Lowest: breast, prostate Highest: pancreas, brain, ovarian, hematologic, stomach
Histology
2 fold
Stage I-IV
3-17 fold
Distant metastases
20 fold
Grade
2 fold
Chemotherapy
2-6 fold
Angiogenesis inhibitors/immune modulators
1.4-10 fold
[43-46]
Erythropoetin stimulating agents
1.6 fold
[47,48]
the highest incidence of VTE was found in the first year after diagnosis with an 8-fold increase in VTE risk. The adjusted relative risk (aRR) of developing VTE were highest in patients with pancreatic or brain cancer (aRR 16 and 29, respectively) and in patients with multiple myeloma (aRR 46). The risk of VTE was found to be 17-fold increased in patients with metastatic disease [6]. Regarding histology, the risk of VTE is particularly high in patients with adenocarcinomas [37]. In a prospective observational cohort study including patients with newly diagnosed cancer or progression of disease after remission, the cumulative probability of developing VTE after 6 months was higher in patients with high-grade than in those with low-grade tumours (8.2% v 4.0%) [38]. Chemotherapy The most important treatment-related risk factor of VTE besides surgery is systemic anti-cancer therapy [6,37,39,40,42]. In a Danish study the aRR of hospitalization for VTE was 19-fold increased in cancer patients receiving chemotherapy compared to the general population [6]. In a record linkage study, chemotherapy was associated with a 2 fold increased risk of VTE [37]. In a case crossover study from the United States, chemotherapy was identified as an important trigger of hospitalization for VTE and was associated with a 6-fold increased risk [40]. In CATS, surgery and radiotherapy (HRs 2.4 and 2.3 respectively) but not chemotherapy (HR 1.0) were independent predictors of VTE [41]. Various chemotherapeutic agents affect the risk of VTE differently, and certain combination regimens are particularly thrombogenic. Cisplatin-based agents provided an approx. 2-fold higher risk for thrombosis than oxaliplatin in patients with gastro-esophageal cancers [42]. A meta-analysis showed modestly increased risk of VTE in patients treated with the angiogenesis inhibitor bevacizumab (RR 1.3; 95% CI 1.1-1.6) [43]. The risk of VTE is particularly high among multiple myeloma patients treated with chemotherapy or dexamethasone together with thalidomide (VTE rates 12-26%) or lenalidomide (VTE rates 5-75% [44-46]. Supportive therapies, in particular erythropoietin-stimulating agents also increase the risk of VTE [47,48].
[41] [13,35] [37] [6] [6,12,35,36] [38] [6,37,39,40,42]
P-selectin or high in vitro thrombin generation have been related to an increased risk of VTE in patients with cancer. The relevance of these markers with regard to distinguishing patients at high or low risk has been extensively reviewed [49,50]. Ultimately, these markers together with clinical factors have been integrated in risk assessment models for a first and also recurrent VTE in cancer patients [51 for review]. Arterial thrombosis Although almost neglected, patients with cancer are also at an increased risk of arterial thromboembolic events (ATE). The risk is particularly high in those receiving antiangiogenic agents. Vascular endothelial growth factor (VEGF) receptor inhibitor recipients for instance had a 3.5-fold higher risk of myocardial infarction and almost 2-fold higher risk of arterial thrombotic events than controls [52]. Several large clinical trials and meta-analyses showed that the addition of bevacizumab, a humanized monoclonal antibody of the VEGF receptor, to chemotherapy significantly increased the risk of ATE when compared to chemotherapy alone [53-55]. Oral tyrosine kinase inhibitors of VEGF, such as sunitinib and sorafenib, also increase the risk of arterial thrombotic complications by a factor of 3 [56]. In a meta-analysis including more than 9700 patients with VEGF receptor tyrosine kinase inhibitors the incidence of ATEs was 1.5% (95% CI 1.0–2.3%) [57]. The use of VEGF receptor–tyrosin kinase inhibitors significantly increased the risk of developing ATEs when compared with controls (OR 2.26, 95% CI 1.38–3.68). In myeloma patients HRs of arterial thrombotic events at 1, 5 and 10 years after diagnosis were 1.9 (1.8-2.1), 1.5 (1.4-1.6), and 1.5 (1.4-1.5) compared to matched controls [58]. Myeloproliferative neoplasms such as essential thrombocythemia, polycythemia vera, and primary myelofibrosis are also associated with an increased risk of ATE. In these patients, age greater than 60 years, history of prior thrombosis, cardiovascular risk factors (hypertension, diabetes), leukocytosis, and the presence of a JAK2 mutation are associated with higher risk of thrombotic complications [59]. Outcomes of VTE in cancer patients
Biomarkers Leucocytosis or thrombocytosis before chemotherapy, anemia, high levels of D-dimer, prothrombin fragment 1.2, factor VIII, soluble
As soon as VTE is diagnosed immediate and intense anti coagulation is required to reduce the risk of recurrence, emboli zation and thrombus progression. Bleeding complications during
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anticoagulant treatment are higher in cancer than in non-cancer patients [60]. Major bleeding was registered in 4% of cancer patients during the first three months of anticoagulant treatment [61].The 1-year cumulative rate of major bleeding has been reported to be as high as 10-15% in cancer patients receiving anticoagulation [60,62,63]. Cancer is also associated with a several-fold increased risk of recurrent VTE, particularly during chemotherapy, with rates as high as 15-20 % within the first year [60,63,64]. The 6-months cumulative incidence of rehospitalisation for recurrent VTE in patients with DVT was found to be strongly associated with the presence of malignancy [65]. Other adverse effects of VTE in this patient group are interruption of chemotherapy and more frequent and prolonged hospitalizations [62,66]. Cancer-associated thrombosis leads to substantial resource claims and health care costs [62,67], and VTE-related complications occupied 6% of the bed-capacity at an oncology department [68]. Survival Survival of cancer patients with VTE is worse compared to that of cancer patients without thrombosis. Thrombosis is a leading direct cause of death in cancer patients with fatal pulmonary embolism being 3-times more common than in non-cancer patients [69]. Sørensen and colleagues were the first to demonstrate that cancer patients who developed VTE had a two-fold increased risk of death compared to cancer patients without VTE [70]. Several studies have confirmed these findings. Chew and colleagues found that the mortality of cancer-related VTE remained increased after adjustment for age and cancer stage [36]. Colorectal-cancer patients with localized and regional disease but not patients with distant metastasis had an increased mortality after VTE [33]. The authors suggested that the increased mortality among those with nonadvanced cancers and VTE was due to more aggressive cancer in the VTE patients not captured by stage. Mortality estimates from Norway found that VTE patients without cancer had a crude deathrate of 5.1 per 100 person-years as compared to 12.7 per 100 personyears for cancer only and 55 per 100 person-years for those with cancer-related VTE [71]. Autopsy studies have revealed higher rates of pulmonary embolism among cancer patients compared to rates reported for symptomatic VTE. At autopsies performed between 1960 and 1984 pulmonary embolism was found in 10.5% of 6200 subjects with a malignancy, and in 8.4% of the 21,500 non-cancer subjects [72]. A Swedish study from 1970 to 1982 found even higher rates of pulmonary embolism in cancer patients, where 23% of the patients had pulmonary embolism, of which more than 40% were considered fatal [73]. The highest rate of pulmonary embolism was observed in patients with pancreatic cancer where pulmonary embolism was confirmed in more than 40% of the patients. Updated autopsy studies are needed to estimate the true impact of VTE on the mortality among cancer- and non-cancer patients. Summary and conclusions Individuals who are diagnosed with cancer are at an increased risk of venous and arterial thrombosis. The pathophysiology of VTE in general, but especially in cancer patients in whom a multitude of disease-related risk factors exist, is multi-factorial. The clinical presentation of a cancer patient with thrombosis can be different from that of a patient without an underlying malignancy. Certain cancer types including malignancies of the pancreas, brain, stomach, colon, ovaries and the hematopoetic system and an advanced disease stage confer a high thrombotic risk. This risk may change with changing treatment modalities and development of novel anti-tumor compounds. The presence of a thrombotic event affects
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patient outcomes, in particular survival, as mortality rates of cancer patients with VTE are higher than in those without a thrombosis. Venous and arterial thrombotic events can to a large extent be prevented by antithrombotic treatment. Biomarkers including blood cell counts and D-Dimer together with clinical factors are useful to stratify patients according to their venous thrombotic risk. However, a safe strategy for thromboprophylaxis in particular for ambulatory cancer patients has not yet been established. Conflict of interest statement No conflict of interest relevant to the content of this manuscript. References [1] ISTH Steering Committee for World Thrombosis Day. Thrombosis: a major contributor to the global disease burden. J Thromb Haemost 2014;12:1580-90 [2] White RH. The epidemiology of venous thromboembolism. Circulation 2003;107(Supplement 1):I4-8. [3] Stein PD, Beemath A, Meyers FA, Skaf E, Sanchez J, Olson RE. Incidence of venous thromboembolism in patients hospitalized with cancer. Am J Med 2006;119:60-68. [4] Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008;111:4902-07. [5] Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ, 3rd. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case control study. Arch Intern Med 2000;160:809-15. [6] Cronin-Fenton DP, Søndergaard F, Pedersen LA, Fryzek JP, Cetin K, Acquavella J, Baron JA, Sørensen HT. Hospitalisation for venous thromboembolism in cancer patients and the general population: a population-based cohort study in Denmark, 1997-2006. Br J Cancer 2010;103:947-53. [7] Murchison JT, Wylie L, Stockton DL. Excess risk of cancer in patients with primary venous thromboembolism: a national, population-based cohort study. Br J Cancer 2004;91:92-95. [8] Prandoni P, Lensing AW, Büller HR, Cogo A, Prins MH, Cattelan AM, Cuppini S, Noventa F, ten Cate JW. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med 1992;327:1128-33. [9] Carrier M, Le Gal G, Wells PS, Fergusson D, Ramsay T, Rodger MA. Systematic review: the Trousseau syndrome revisited: should we screen extensively for cancer in patients with venous thromboembolism? Ann Intern Med 2008;149:323-33.8. [10] Baron JA, Gridley G, Weiderpass E, Nyre´n O, Linet M. Venous thromboembolism and cancer. Lancet 1998;351:1077-80. [11] Sørensen HT, Mellemkjaer L, Steffensen FH, Olsen JH, Nielsen GL. The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J Med 1998; 338:1169-73. [12] Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005;293:715-22. [13] Horsted F, West J, Grainge MJ. Risk of venous thromboembolism in patients with cancer: a systematic review and meta-analysis. PLoS Med 2012;9:e1001275. [14] Trousseau A. Ulcère chronique simple de l’éstomac. Clinique Medical de l’HôtelDieu de Paris. 1877:105. [15] Imberti D, Agnelli G, Ageno W, Moia M, Palareti G, Pistelli R, Rossi R, Verso M; MASTER Investigators. Clinical characteristics and management of cancer-associated acute venous thromboembolism: findings from the MASTER Registry. Haematologica 2008;93:273-78. [16] Seinturier C, Bosson JL, Colonna M, Imbert B, Carpentier PH. Site and clinical outcome of deep vein thrombosis of the lower limbs: an epidemiological study. J Thromb Haemost 2005;3:1362-67. [17] Lamontagne F, McIntyre L, Dodek P, Heels-Ansdell D, Meade M, Pemberton J, Skrobik Y, Seppelt I, Vlahakis NE, Muscedere J, Reece G, Ostermann M, Padayachee S, Alhashemi J, Walsh M, Lewis B, Schiff D, Moody A, Zytaruk N, Leblanc M, Cook DJ; Prophylaxis for Thromboembolism in Critical Care Trial Investigators; Canadian Critical Care Trials Group; Australian and New Zealand Intensive Care Society Clinical Trials Group. Nonleg venous thrombosis in critically ill adults: a nested prospective cohort study. JAMA Intern Med 2014;174:689-96. [18] Flinterman LE, Van Der Meer FJ, Rosendaal FR, Doggen CJ. Current perspective of venous thrombosis in the upper extremity. J Thromb Haemost 2008;6:1262-66. [19] Murray J, Precious E, Alikhan R. Catheter-related thrombosis in cancer patients. Br J Haematol 2013;162:748-57. [20] Piran S, Ngo V, McDiarmid S, Le Gal G, Petrcich W, Carrier M. Incidence and risk factors of symptomatic venous thromboembolism related to implanted ports in cancer patients. Thromb Res 2014;133:30-3. [21] Blom JW, Doggen CJM, Osanto S, Rosendaal FR. Old and new risk factors for upper extremity deep venous thrombosis. J Thromb Haemost 2005;3:2471–78. [22] Martinelli I, De Stefano V. Rare thromboses of cerebral, splanchnic and upperextremity veins. A narrative review. Thromb Haemost 2010;103:1136-44.
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Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst 2007;99:1232–39. [55] Schutz FA, Je Y, Azzi GR, Nguyen PL, Choueiri TK. Bevacizumab increases the risk of arterial ischemia: a large study in cancer patients with a focus on different subgroup outcomes. Ann Oncol 2011;22:1404–12. [56] Choueiri TK, Schutz FA, Je Y, Rosenberg JE, Bellmunt J. Risk of arterial thromboembolic events with sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. J Clin Oncol 2010;28:2280–85. [57] Qi WX, Shen Z, Tang LN, Yao Y. Risk of arterial thromboembolic events with vascular endothelial growth factor receptor tyrosine kinase inhibitors: an up-to-date meta-analysis. Crit Rev Oncol Hematol 2014;92:71-82. [58] Kristinsson SY, Pfeiffer RM, Björkholm M, Goldin LR, Schulman S, Blimark C, Mellqvist UH, Wahlin A, Turesson I, Landgren O. Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: a population-based study. Blood 2010;115:4991-98. [59] Barbui T, Finazzi G, Carobbio A, Thiele J, Passamonti F, Rumi E, Ruggeri M, Rodeghiero F, Randi ML, Bertozzi I, Gisslinger H, Buxhofer-Ausch V, De Stefano V, Betti S, Rambaldi A, Vannucchi AM, Tefferi A. Development and validation of an International Prognostic Score of thrombosis in World Health Organizationessential thrombocythemia (IPSETthrombosis). Blood 2012;120:5128-33; [60] Prandoni P, Lensing AW, Piccioli A, Bernardi E, Simioni P, Girolami B, Marchiori A, Sabbion P, Prins MH, Noventa F, Girolami A. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002;100:3484-88 [61] Trujillo-Santos J, Nieto JA, Ruiz-Gamietea A, Lopez-Jimenez L, Garcia-Bragado F, Quintavalla R, Monreal M; RIETE Investigators. 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Contents lists available at ScienceDirect
Thrombosis Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / t h r o m r e s
Cancer associated thrombosis: risk factors and outcomes Sabine Eichinger* Department of Internal Medicine I, Medical University of Vienna; Karl Landsteiner Institute of Thrombosis Research, Vienna, Austria
k e y w o r d s
a b s t r a c t
Cancer Thrombosis Risk factors Outcome Mortality
Deep vein thrombosis of the leg and pulmonary embolism are frequent diseases and cancer is one of their most important risk factors. Patients with cancer also have a higher prevalence of venous thrombosis located in other parts than in the legs and/or in unusual sites including upper extremity, splanchnic or cerebral veins. Cancer also affects the risk of arterial thrombotic events particularly in patients with myeloproliferative neoplasms and in vascular endothelial growth factor receptor inhibitor recipients. Several risk factors need to interact to trigger thrombosis. In addition to common risk factors such as surgery, hospitalisation, infection and genetic coagulation disorders, the thrombotic risk is also driven and modified by cancer-specific factors including type, histology, and stage of the malignancy, cancer treatment and certain biomarkers. A venous thrombotic event in a cancer patient has serious consequences as the risk of recurrent thrombosis, the risk of bleeding during anticoagulation and hospitalisation rates are all increased. Survival of cancer patients with thrombosis is worse compared to that of cancer patients without thrombosis, and thrombosis is a leading direct cause of death in cancer patients. © 2016 Elsevier Ltd. All rights reserved.
Introduction
Risk of cancer in VTE – risk of VTE in cancer
Venous thromboembolism (VTE), a hypernym of deep-vein thrombosis and pulmonary embolism, is a frequent disease with multiple risk factors. In population studies from Western Europe, North America, Australia and southern Latin America the annual incidence rates of VTE range from 75-269/100.000 individuals [1]. VTE occurs in the absence of an identifiable risk factor in up to 50% of patients, the proportion varying by the exact definition of risk factors [2]. In almost halve of the remaining patients, VTE is seen in the context of a malignant disease. Notably, the incidence of venous thrombosis in cancer patients has increased over recent years. Between 1979 and 1999, the VTE rate increased from 1.5 to 3.5% among hospitalized cancer patients, while rates remained stable in patients without cancer [3]. For the period between 1995 and 2002, a 36% increase in the risk of VTE among cancer patients was reported [4]. Improved survival among cancer patients, more aggressive cancer treatments and a better awareness of cancerassociated VTE are the most likely explanations. The consequences of cancer-associated VTE are serious as morbidity, mortality and health care costs are all increased. In this chapter I will focus on epidemiologic aspects and clinical presentation of cancer-associated VTE, cancer related thrombotic risk factors, and outcomes including mortality.
The increased thrombotic risk associated with cancer has long been established and can be seen from different angles. A malignant disease is found in 15-25% of all patients with VTE [2,5-7]. The prevalence of cancer is higher in patients with an otherwise unprovoked thrombosis than in patients with thrombosis secondary to a transient risk factor [8]. The occurrence of a VTE in a thus far asymptomatic individual may indicate an underlying cancer and may be the first sign of the malignancy. A previously undetected cancer can be found in approximately 4% of patients within one month after the VTE and in approximately 6% of patients within one year [9]. The likelihood for developing cancer was found to be substantially elevated during the first 12 months [10,11] after VTE diagnosis. Data on a persistently increased risk thereafter are conflicting [10,11]. Compared to non-cancer patients, the risk of VTE is 4- to 7-fold higher in cancer patients irrespective of the underlying type [5,12]. In a meta-analysis by Horsted and colleagues the incidence rate of venous thrombosis was 13/1000 person-years in patients classified as average-risk and was 68/1000 person-years in high-risk patients, based on the presence of high-grade or metastatic disease or exposure to thrombogenic treatment regimens [13]. The clinical presentation of deep-vein thrombosis and pulmonary embolism is different in cancer patients compared to that in non-cancer patients and the natural course of VTE tends to be more aggressive. What Armand Trousseau observed and later published in 1865 was indeed the most severe form of venous obstruction in a cancer patient, namely phlegmasia alba dolens [14]. The incidence of bilateral lower limb deep-vein thrombosis was significantly higher in patients
* Corresponding author at: Dept. of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Wien, Austria. Tel.: 43-1-40400-49180; fax: 43-1-40400-40300. E-mail address: [email protected] (S. Eichinger). 0049-3848/© 2016 Elsevier Ltd. All rights reserved.
S. Eichinger / Thrombosis Research 140S1 (2016) S12–S17
with cancer than in patients without cancer (8.5% versus 4.6%), as were the rates of iliocaval thrombosis (22.6% versus 14%) [15], and survival rates of cancer patients with bilateral deep-vein thrombosis were lower than in unilateral deep-vein thrombosis [16]. Also, compared to non-cancer patients, patients with cancer have a higher prevalence of venous thrombosis located in other parts than in the legs and/or in unusual sites with cancer being an independent predictor of incident non-leg deep- vein thrombosis [17]. Upper extremity deep vein thrombosis Deep-vein thrombosis in the upper extremities (UEDVT) only account for a minority (about 4%) of all venous thrombotic events [18]. A third of UEDVT are so called primary events while the majority occurs in relation with a known risk factor. In patients with cancer, UEDVT occurs most often while there is an indwelling central venous catheter as they are frequently used for administration of chemotherapy, antibiotics or nutrition. The frequency of catheter-associated thrombosis decreased over time with improved insertion techniques and catheter material [19]. In a prospective cohort study, patients with cancer were followed while their catheter remained in place. Only 19 of 444 patients (4.3%) had symptomatic catheter-related thrombosis in 19 of 500 catheters (0.3/1000 catheter-days) [20]. The risk of UEDVT in cancer patients is also increased in the absence of central venous catheters. In patients with an active cancer the risk of UEDVT was 18fold increased compared with patients without cancer [21]. Splanchnic vein thrombosis An underlying malignancy is commonly found in splanchnic vein thrombosis including the Budd-Chiari syndrome, extrahepatic portal vein obstruction and mesenteric vein thrombosis [22]. In a prospective cohort study almost 25% of patients with splanchnic vein thrombosis had a solid cancer and 8% a myeloproliferative disorder [23]. Myeloproliferative neoplasms are diagnosed in up to half of the patients with Budd-Chiari syndrome and in one third of those with extrahepatic portal vein obstruction [24]. The diagnosis of a myeloproliferative neoplasm is sometimes preceded by splanchnic vein thrombosis. The JAK2 V617F mutation is present in up to 87% of those with an already diagnosed myeloproliferative neoplasm and in up to 26% of those without other laboratory signs. In the latter, other molecular markers, such as mutations in JAK2 exon 12, CALR and MPL genes, are extremely rare [24]. Among patients with splanchnic vein thrombosis and JAK2 V617F positivity as the sole marker of a hematologic disease at the time of thrombosis, the rate of development of an overt myeloproliferative neoplasm during follow-up is 52% [25]. Cerebral vein thrombosis Cerebral vein thrombosis can be the first symptom of a solid cancer, particularly if the tumour is located in the brain, and of myeloproliferative neoplasms [22]. Ten of 152 patients (6.6%) with cerebral venous thrombosis were carriers of the JAK2 V617F mutation and three of them had no signs of a myeloproliferative neoplasm at the time of diagnosis of the thrombosis but developed the disease during follow-up (median duration 7.8 years) [26]. Thus, as with splanchnic vein thrombosis, positivity for the JAK2 V617F mutation may occur in patients who otherwise do not meet the criteria for a myeloproliferative neoplasm. Superficial vein thrombosis (SVT) Whether cancer is also associated with SVT (or vice versa) is unclear as this has never been systematically evaluated. The occurrence of
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cancer during the first year when compared with the expected number of cancer diagnoses based on national incidence rates (standardised incidence ratios, SIR) was similar for 7.663 patients with SVT (SIR 2.46, 95% CI 2.10–2.86), for 45.252 patients with DVT (SIR 2.75, 95% CI 2.60–2.90), and for 24.332 patients with pulmonary embolism (SIR 3.27, 95% CI 3.03–3.52) [27]. In contrast, in patients with isolated SVT not involving the sapheno-femoral junction and in whom a concomitant deep vein thrombosis was excluded by ultrasonography, occurrence of SVT in the legs did not represent a risk factor for subsequent malignancies [28]. During an average observation period of 26 months cancer was found in 26 (3.5%) of 737 patients with SVT and in 56 (3.9%) of 1438 controls for a hazard ratio of 0.86 (95% CI 0.55%-1.35%). The difference in findings may be explained by the heterogeneity in the diagnosis and definition of SVT. It remains to be shown whether extended SVT or unusual presentations, for example migratory forms, are associated with cancer. Risk factors and biomarkers Venous thromboembolism is a multicausal disease. The relevance of patient-related and circumstantial risk factors, including age, sex, ethnicity, genetic and acquired coagulation disorders and a prior history of thrombosis as regards the risk of a first VTE has been extensively reviewed [29]. Circumstantial factors such as surgery, trauma, immobilization, hospitalization and co-morbidities are also strongly linked to an increased risk of VTE. According to the current pathophysiologic concept several risk factors need to interact to trigger thrombosis. There is nothing to assume that this concept does not hold true also in a cancer patient. Indeed, it has been shown that surgery, immobilisation, and genetic coagulation disorders substantially increase the risk of VTE in cancer patients. Data on the effect of age are controversial [3,6,30,34]. Cancer patients with multiple medical comorbidities or other conditions including infection, pulmonary disease, renal disease, or obesity have about 1.5-fold higher rates of VTE [30]. Cancer patients with a prior history of VTE have a 6to 7-fold increased risk for VTE compared with patients without a history of VTE [31]. The risk of VTE is higher in hospitalized cancer patients than in ambulatory cancer patients [32]. The thrombotic risk is highest during the first months after cancer diagnosis [12,33,34]. An overview on risk factors is provided in Table 1. Cancer-specific risk factors The thrombotic risk is also driven and modified by cancer-specific risk factors including type, histology, and stage of the malignancy, and cancer treatment [13,35]. The incidence of VTE is highest among patients with malignant brain tumours, adenocarcinomas of the lung, ovary, pancreas, colon, stomach, prostate, and kidney and in patients with hematologic malignancies and in those initially diagnosed with metastatic-stage disease [35]. According to a population-based, case-control study from the Netherlands, the risk of VTE was highest in patients with hematologic malignancies (OR 28), lung cancer (OR 22), gastrointestinal cancer (OR 20) or brain cancer (OR 7), and in those with distant metastasis [12]. Compared to cancer patients without distant metastasis, those with metastatic disease had an almost 20-fold increased risk of VTE. The incidence of VTE within 1 and 2 years of cancer diagnosis and the risk factors associated with VTE were determined on the basis of records of more than 235.000 cancer patients [36]. The strongest predictor of VTE was the presence of metastases. The highest incidence of VTE during the first year was found among patients with metastatic-stage pancreatic cancer, cancer of the stomach, bladder, uterus, kidneys or lung [36]. In a population-based cohort study from Denmark, incidence rates for hospitalization for VTE were calculated for more than 57,000 cancer patients and almost 290.000 controls [6]. Strong predictors were cancer site, stage and type of initial cancer treatment. In this study
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Table 1 Risk factors for VTE in cancer patients Risk factor
Approximate risk increase
Reference
Time since cancer diagnosis
Highest during first 6 months
[12,33,34]
Age
Data inconsistent
[3,6,30,34]
Prior history of VTE
6-7 fold
[31]
Hospitalisation/immobilisation
2-4 fold
[32]
Comorbidities
2 fold
[30]
Genetic factors
2-5 fold
[12]
Radiotherapy
2 fold
[41]
Surgery
2-4 fold
Type of cancer
Lowest: breast, prostate Highest: pancreas, brain, ovarian, hematologic, stomach
Histology
2 fold
Stage I-IV
3-17 fold
Distant metastases
20 fold
Grade
2 fold
Chemotherapy
2-6 fold
Angiogenesis inhibitors/immune modulators
1.4-10 fold
[43-46]
Erythropoetin stimulating agents
1.6 fold
[47,48]
the highest incidence of VTE was found in the first year after diagnosis with an 8-fold increase in VTE risk. The adjusted relative risk (aRR) of developing VTE were highest in patients with pancreatic or brain cancer (aRR 16 and 29, respectively) and in patients with multiple myeloma (aRR 46). The risk of VTE was found to be 17-fold increased in patients with metastatic disease [6]. Regarding histology, the risk of VTE is particularly high in patients with adenocarcinomas [37]. In a prospective observational cohort study including patients with newly diagnosed cancer or progression of disease after remission, the cumulative probability of developing VTE after 6 months was higher in patients with high-grade than in those with low-grade tumours (8.2% v 4.0%) [38]. Chemotherapy The most important treatment-related risk factor of VTE besides surgery is systemic anti-cancer therapy [6,37,39,40,42]. In a Danish study the aRR of hospitalization for VTE was 19-fold increased in cancer patients receiving chemotherapy compared to the general population [6]. In a record linkage study, chemotherapy was associated with a 2 fold increased risk of VTE [37]. In a case crossover study from the United States, chemotherapy was identified as an important trigger of hospitalization for VTE and was associated with a 6-fold increased risk [40]. In CATS, surgery and radiotherapy (HRs 2.4 and 2.3 respectively) but not chemotherapy (HR 1.0) were independent predictors of VTE [41]. Various chemotherapeutic agents affect the risk of VTE differently, and certain combination regimens are particularly thrombogenic. Cisplatin-based agents provided an approx. 2-fold higher risk for thrombosis than oxaliplatin in patients with gastro-esophageal cancers [42]. A meta-analysis showed modestly increased risk of VTE in patients treated with the angiogenesis inhibitor bevacizumab (RR 1.3; 95% CI 1.1-1.6) [43]. The risk of VTE is particularly high among multiple myeloma patients treated with chemotherapy or dexamethasone together with thalidomide (VTE rates 12-26%) or lenalidomide (VTE rates 5-75% [44-46]. Supportive therapies, in particular erythropoietin-stimulating agents also increase the risk of VTE [47,48].
[41] [13,35] [37] [6] [6,12,35,36] [38] [6,37,39,40,42]
P-selectin or high in vitro thrombin generation have been related to an increased risk of VTE in patients with cancer. The relevance of these markers with regard to distinguishing patients at high or low risk has been extensively reviewed [49,50]. Ultimately, these markers together with clinical factors have been integrated in risk assessment models for a first and also recurrent VTE in cancer patients [51 for review]. Arterial thrombosis Although almost neglected, patients with cancer are also at an increased risk of arterial thromboembolic events (ATE). The risk is particularly high in those receiving antiangiogenic agents. Vascular endothelial growth factor (VEGF) receptor inhibitor recipients for instance had a 3.5-fold higher risk of myocardial infarction and almost 2-fold higher risk of arterial thrombotic events than controls [52]. Several large clinical trials and meta-analyses showed that the addition of bevacizumab, a humanized monoclonal antibody of the VEGF receptor, to chemotherapy significantly increased the risk of ATE when compared to chemotherapy alone [53-55]. Oral tyrosine kinase inhibitors of VEGF, such as sunitinib and sorafenib, also increase the risk of arterial thrombotic complications by a factor of 3 [56]. In a meta-analysis including more than 9700 patients with VEGF receptor tyrosine kinase inhibitors the incidence of ATEs was 1.5% (95% CI 1.0–2.3%) [57]. The use of VEGF receptor–tyrosin kinase inhibitors significantly increased the risk of developing ATEs when compared with controls (OR 2.26, 95% CI 1.38–3.68). In myeloma patients HRs of arterial thrombotic events at 1, 5 and 10 years after diagnosis were 1.9 (1.8-2.1), 1.5 (1.4-1.6), and 1.5 (1.4-1.5) compared to matched controls [58]. Myeloproliferative neoplasms such as essential thrombocythemia, polycythemia vera, and primary myelofibrosis are also associated with an increased risk of ATE. In these patients, age greater than 60 years, history of prior thrombosis, cardiovascular risk factors (hypertension, diabetes), leukocytosis, and the presence of a JAK2 mutation are associated with higher risk of thrombotic complications [59]. Outcomes of VTE in cancer patients
Biomarkers Leucocytosis or thrombocytosis before chemotherapy, anemia, high levels of D-dimer, prothrombin fragment 1.2, factor VIII, soluble
As soon as VTE is diagnosed immediate and intense anti coagulation is required to reduce the risk of recurrence, emboli zation and thrombus progression. Bleeding complications during
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anticoagulant treatment are higher in cancer than in non-cancer patients [60]. Major bleeding was registered in 4% of cancer patients during the first three months of anticoagulant treatment [61].The 1-year cumulative rate of major bleeding has been reported to be as high as 10-15% in cancer patients receiving anticoagulation [60,62,63]. Cancer is also associated with a several-fold increased risk of recurrent VTE, particularly during chemotherapy, with rates as high as 15-20 % within the first year [60,63,64]. The 6-months cumulative incidence of rehospitalisation for recurrent VTE in patients with DVT was found to be strongly associated with the presence of malignancy [65]. Other adverse effects of VTE in this patient group are interruption of chemotherapy and more frequent and prolonged hospitalizations [62,66]. Cancer-associated thrombosis leads to substantial resource claims and health care costs [62,67], and VTE-related complications occupied 6% of the bed-capacity at an oncology department [68]. Survival Survival of cancer patients with VTE is worse compared to that of cancer patients without thrombosis. Thrombosis is a leading direct cause of death in cancer patients with fatal pulmonary embolism being 3-times more common than in non-cancer patients [69]. Sørensen and colleagues were the first to demonstrate that cancer patients who developed VTE had a two-fold increased risk of death compared to cancer patients without VTE [70]. Several studies have confirmed these findings. Chew and colleagues found that the mortality of cancer-related VTE remained increased after adjustment for age and cancer stage [36]. Colorectal-cancer patients with localized and regional disease but not patients with distant metastasis had an increased mortality after VTE [33]. The authors suggested that the increased mortality among those with nonadvanced cancers and VTE was due to more aggressive cancer in the VTE patients not captured by stage. Mortality estimates from Norway found that VTE patients without cancer had a crude deathrate of 5.1 per 100 person-years as compared to 12.7 per 100 personyears for cancer only and 55 per 100 person-years for those with cancer-related VTE [71]. Autopsy studies have revealed higher rates of pulmonary embolism among cancer patients compared to rates reported for symptomatic VTE. At autopsies performed between 1960 and 1984 pulmonary embolism was found in 10.5% of 6200 subjects with a malignancy, and in 8.4% of the 21,500 non-cancer subjects [72]. A Swedish study from 1970 to 1982 found even higher rates of pulmonary embolism in cancer patients, where 23% of the patients had pulmonary embolism, of which more than 40% were considered fatal [73]. The highest rate of pulmonary embolism was observed in patients with pancreatic cancer where pulmonary embolism was confirmed in more than 40% of the patients. Updated autopsy studies are needed to estimate the true impact of VTE on the mortality among cancer- and non-cancer patients. Summary and conclusions Individuals who are diagnosed with cancer are at an increased risk of venous and arterial thrombosis. The pathophysiology of VTE in general, but especially in cancer patients in whom a multitude of disease-related risk factors exist, is multi-factorial. The clinical presentation of a cancer patient with thrombosis can be different from that of a patient without an underlying malignancy. Certain cancer types including malignancies of the pancreas, brain, stomach, colon, ovaries and the hematopoetic system and an advanced disease stage confer a high thrombotic risk. This risk may change with changing treatment modalities and development of novel anti-tumor compounds. The presence of a thrombotic event affects
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patient outcomes, in particular survival, as mortality rates of cancer patients with VTE are higher than in those without a thrombosis. Venous and arterial thrombotic events can to a large extent be prevented by antithrombotic treatment. Biomarkers including blood cell counts and D-Dimer together with clinical factors are useful to stratify patients according to their venous thrombotic risk. However, a safe strategy for thromboprophylaxis in particular for ambulatory cancer patients has not yet been established. Conflict of interest statement No conflict of interest relevant to the content of this manuscript. References [1] ISTH Steering Committee for World Thrombosis Day. Thrombosis: a major contributor to the global disease burden. J Thromb Haemost 2014;12:1580-90 [2] White RH. The epidemiology of venous thromboembolism. Circulation 2003;107(Supplement 1):I4-8. [3] Stein PD, Beemath A, Meyers FA, Skaf E, Sanchez J, Olson RE. Incidence of venous thromboembolism in patients hospitalized with cancer. Am J Med 2006;119:60-68. [4] Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008;111:4902-07. [5] Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ, 3rd. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case control study. Arch Intern Med 2000;160:809-15. [6] Cronin-Fenton DP, Søndergaard F, Pedersen LA, Fryzek JP, Cetin K, Acquavella J, Baron JA, Sørensen HT. Hospitalisation for venous thromboembolism in cancer patients and the general population: a population-based cohort study in Denmark, 1997-2006. Br J Cancer 2010;103:947-53. [7] Murchison JT, Wylie L, Stockton DL. Excess risk of cancer in patients with primary venous thromboembolism: a national, population-based cohort study. Br J Cancer 2004;91:92-95. [8] Prandoni P, Lensing AW, Büller HR, Cogo A, Prins MH, Cattelan AM, Cuppini S, Noventa F, ten Cate JW. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med 1992;327:1128-33. [9] Carrier M, Le Gal G, Wells PS, Fergusson D, Ramsay T, Rodger MA. Systematic review: the Trousseau syndrome revisited: should we screen extensively for cancer in patients with venous thromboembolism? Ann Intern Med 2008;149:323-33.8. [10] Baron JA, Gridley G, Weiderpass E, Nyre´n O, Linet M. Venous thromboembolism and cancer. Lancet 1998;351:1077-80. [11] Sørensen HT, Mellemkjaer L, Steffensen FH, Olsen JH, Nielsen GL. The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J Med 1998; 338:1169-73. [12] Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005;293:715-22. [13] Horsted F, West J, Grainge MJ. Risk of venous thromboembolism in patients with cancer: a systematic review and meta-analysis. PLoS Med 2012;9:e1001275. [14] Trousseau A. Ulcère chronique simple de l’éstomac. Clinique Medical de l’HôtelDieu de Paris. 1877:105. [15] Imberti D, Agnelli G, Ageno W, Moia M, Palareti G, Pistelli R, Rossi R, Verso M; MASTER Investigators. Clinical characteristics and management of cancer-associated acute venous thromboembolism: findings from the MASTER Registry. Haematologica 2008;93:273-78. [16] Seinturier C, Bosson JL, Colonna M, Imbert B, Carpentier PH. Site and clinical outcome of deep vein thrombosis of the lower limbs: an epidemiological study. J Thromb Haemost 2005;3:1362-67. [17] Lamontagne F, McIntyre L, Dodek P, Heels-Ansdell D, Meade M, Pemberton J, Skrobik Y, Seppelt I, Vlahakis NE, Muscedere J, Reece G, Ostermann M, Padayachee S, Alhashemi J, Walsh M, Lewis B, Schiff D, Moody A, Zytaruk N, Leblanc M, Cook DJ; Prophylaxis for Thromboembolism in Critical Care Trial Investigators; Canadian Critical Care Trials Group; Australian and New Zealand Intensive Care Society Clinical Trials Group. Nonleg venous thrombosis in critically ill adults: a nested prospective cohort study. JAMA Intern Med 2014;174:689-96. [18] Flinterman LE, Van Der Meer FJ, Rosendaal FR, Doggen CJ. Current perspective of venous thrombosis in the upper extremity. J Thromb Haemost 2008;6:1262-66. [19] Murray J, Precious E, Alikhan R. Catheter-related thrombosis in cancer patients. Br J Haematol 2013;162:748-57. [20] Piran S, Ngo V, McDiarmid S, Le Gal G, Petrcich W, Carrier M. Incidence and risk factors of symptomatic venous thromboembolism related to implanted ports in cancer patients. Thromb Res 2014;133:30-3. [21] Blom JW, Doggen CJM, Osanto S, Rosendaal FR. Old and new risk factors for upper extremity deep venous thrombosis. J Thromb Haemost 2005;3:2471–78. [22] Martinelli I, De Stefano V. Rare thromboses of cerebral, splanchnic and upperextremity veins. A narrative review. Thromb Haemost 2010;103:1136-44.
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