Arterial Thrombosis and Cancer: Implications for Screening and Risk Modification

Abstract

The association between cancer and venous thromboembolism (VTE) has been well established by thorough community-based epidemiology studies, mechanistic basic research, and randomized controlled trials for primary prevention, acute treatment, and secondary prevention. Societal guidelines inform best practices for cancer screening in the context of unprovoked VTE, prophylaxis for ambulatory, hospitalized, and postsurgical cancer patients and anticoagulant recommendations for managing acute VTE. The relative risk of developing VTE has been established for specific cancers, and several scoring tools which combine these estimates with other clinical and laboratory variables have been derived and validated. By comparison, there is much less information available regarding the interface between cancer and arterial thrombosis.In this issue of Mayo Clinic Proceedings, Wang et al1Wang J. Kim Y. Kim C. Incidence and Risk of Various Types of Arterial Thromboembolism in Patients with Cancer.Mayo Clin Proc. 2021; 96: 592-600Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar assessed the incidence of arterial thromboembolic events in patients with cancer. By exploring a large electronic health record database of nearly 2.7 million cancer patients, 63,520 (2.4%) were identified with an acute arterial thrombotic event. To establish a temporal relationship, the authors limited the analysis to arterial thrombosis occurring within 720 days before and after the new cancer diagnosis. An impressive increase in the incidence ratio of arterial and venous thrombotic events began 30 days before the cancer diagnosis, peaked at 30 days after the cancer diagnosis, and did not return to basal values for 8 months thereafter. Brain, colorectal, pancreas, and lung cancers were among the most common cancers. Surprisingly, the 30-day incidence ratio for arterial thrombosis was only modestly lower than for VTE, and a prior history of VTE increased the likelihood of an arterial thrombotic event. Patients suffering an arterial thrombotic event were more likely to have traditional cardiovascular risk factors for atherosclerosis including obesity, diabetes mellitus, hypertension, active smoking, and dyslipidemia. Finally, there was a striking anatomic relationship between cancer type and arterial thrombus location.This work builds on several previously reported epidemiology studies by others. To aid interpretation of such studies, it may be helpful to parse the literature into two categories: the risk of arterial thrombosis in patients with established cancer; and the likelihood of finding a new cancer in patients who have suffered an arterial thrombotic event. Both are important yet tell a slightly different story and have unique implications. First, does established cancer increase the risk of future arterial thrombosis? Navi et al2Navi B.B. Reiner A.S. Kamel H. et al.Risk of Arterial Thromboembolism in Patients With Cancer.J Am Coll Cardiol. 2017; 70: 926-938Crossref PubMed Scopus (298) Google Scholar assessed the 6-month cumulative risk of myocardial infarction (MI) and stroke among nearly 280,000 cancer patients from the Surveillance, Epidemiology, and End Results (SEER) Medicare database. They reported an incidence rate of 4.7% which was two-fold greater than age- and sex-matched controls. The risk of arterial thrombosis was greatest during the first month following the cancer diagnosis. Lung, gastric, pancreas, and colorectal cancers carried the greatest risk. The incidence and relative hazard of arterial thrombosis increased directly with cancer stage and negatively impacted survival rates. The excess risk for MI persisted for several months following the cancer diagnosis. Similarly, others have found a two-fold increased risk of both ischemic and hemorrhagic stroke and a 1.7- fold increased risk for MI during the first 6 months following cancer diagnosis.3Zöller B. Ji J. Sundquist J. Sundquist K. Risk of haemorrhagic and ischaemic stroke in patients with cancer: a nationwide follow-up study from Sweden.Eur J Cancer. 2012; 48: 1875-1883Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar,4Zöller B. Ji J. Sundquist J. Sundquist K. Risk of coronary heart disease in patients with cancer: a nationwide follow-up study from Sweden.Eur J Cancer. 2012; 48: 121-128Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar In sum, there appears to be a strong relationship between cancer and arterial thrombosis, an association that is similar to what is observed with venous thrombosis.There are several potential mechanisms to explain the temporal relationship between newly diagnosed cancer, cancer treatment, and arterial thrombosis (Table). Wang et al1Wang J. Kim Y. Kim C. Incidence and Risk of Various Types of Arterial Thromboembolism in Patients with Cancer.Mayo Clin Proc. 2021; 96: 592-600Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar showed a strong risk relationship between traditional atherosclerosis risk factors and arterial thrombosis among cancer patients in the current series. The implications of these findings are that modifiable atherosclerosis risk factors should not be left unattended simply due to the newly diagnosed cancer. Whether current guideline-directed risk modification for non-cancer patients is sufficient to impact outcomes in cancer patients is not clear. Beyond impacting survival, preventing the morbidity associated with stroke, MI, acute limb ischemia, or organ infarction remain meaningful goals.TableMechanisms of Cancer-Associated Arterial ThrombosisaICAM, intercellular adhesion molecule; IL, interleukin; G-CSF, granulocyte colony-stimulating factor; PAI-1, plasminogen activator inhibitor 1; TNFα, tumor necrosis factor alpha; VCAM, vascular cell adhesion molecule; VEGF, vascular endothelial growth factor.Cancer related (pre-cancer diagnosis) Marantic endocarditis Secondary antiphospholipid syndrome Tumor embolization Tumor arterial invasion Tumor arterial compression Tumor specific coagulation activationTissue factor expressionHeparanase expression and releaseCancer procoagulant – factor X activatorMicroparticle releaseCell adhesion molecule expression (VCAM, ICAM) Tumor specific host fibrinolysis inhibition (PAI-1, Annexin II) Cancer Associated Soluble Mediators (TNFα, IL-1, VEGF, G-CSF)Cancer- and cancer therapy–related (post diagnosis) ChemotherapyPlatinum-based agentsImmunomodulatorsVEGF and VEGF receptor inhibitorsTyrosine kinase inhibitorsTaxanes Tumor resection with arterial ligation Catheter-directed tumor infarction Cardiotoxicity — cardiac source of embolism Anticoagulant interruption for an invasive procedurea ICAM, intercellular adhesion molecule; IL, interleukin; G-CSF, granulocyte colony-stimulating factor; PAI-1, plasminogen activator inhibitor 1; TNFα, tumor necrosis factor alpha; VCAM, vascular cell adhesion molecule; VEGF, vascular endothelial growth factor. Open table in a new tab Second, does an arterial thrombosis have implications for a search for occult malignancy? Exploring the SEER-Medicare database, the temporal relationship between arterial thrombosis and occult cancer was explored among more than 374,000 case-control pairs.5Navi B.B. Reiner A.S. Kamel H. et al.Arterial thromboembolic events preceding the diagnosis of cancer in older persons.Blood. 2019; 133: 781-789Crossref PubMed Scopus (85) Google Scholar The rate of arterial thrombotic events started to increase 5 months before the cancer diagnosis and peaked 30 days before diagnosis. During this 30-day interval pre-cancer diagnosis, the odds ratio for developing arterial thrombosis increased nearly six-fold. Lung and colorectal cancer carried the greatest risk and nearly 40% of patients had either stage III or IV cancer at the time. Similarly, the Tromsø study followed 28,763 subjects forward in time to assess the association between MI and future risk of incident cancer.6Rinde L.B. Småbrekke B. Hald E.M. et al.Myocardial infarction and future risk of cancer in the general population-the Tromsø Study.Eur J Epidemiol. 2017; 32: 193-201Crossref PubMed Scopus (34) Google Scholar Of the 1747 subjects with incident MI, the hazard ratio for developing a future cancer was 46% higher than subjects without MI. The increased cancer rate was highest during the initial 6 months post-MI. Colorectal, prostate, and lung cancer were the three most common cancer locations. Nearly 43% of patients with MI had a smoking history as a “shared” risk factor. A Danish study using a nationwide population-based medical registry sample examined the risk of developing cancer in 6600 patients with lower limb arterial thrombosis.7Sundbøll J. Veres K. Horváth-Puhó E. Adelborg K. Sørensen H.T. Risk and prognosis of cancer after lower limb arterial thrombosis.Circulation. 2018; 138: 669-677Crossref PubMed Scopus (29) Google Scholar During the first 6 months after the thrombotic event, the incidence ratio of developing cancer was more than three-fold increased. Lung and other smoking-related cancers carried the strongest association. In summary, it appears that the clinical presentation of an occult malignancy may include an arterial thrombotic event similar to an unprovoked VTE. The mechanism for these arterial events may stem from shared risk factors including smoking, obesity, and increased age. Thrombogenesis may also reflect mechanical or biochemical propensities unique to the tumor (Table). The implications of these studies is that an acute arterial thrombotic event, particularly if otherwise unexpected, should prompt a thorough general medical evaluation including guideline-endorsed age-appropriate cancer screening similar to that of a VTE event.For patients who have suffered an arterial thrombotic event, the prompt return of organ perfusion through an open artery should be an urgent priority. Antithrombotic strategies for secondary prevention have not been established. For patients with other comorbidities such as atrial fibrillation, heart valve mechanical prosthesis, antiphospholipid antibody syndrome, or co-existing VTE, strategies including an anticoagulant should be used. For the many cancer patients without these comorbidities, choosing between an anticoagulant, antiplatelet, or combination therapy is not well established by randomized trial data or by guideline best-practice consensus statements. Balancing the risk for recurrent thrombosis and major bleeding can be complicated and require careful deliberation given the increased risk of both.In conclusion, the work of Wang et al1Wang J. Kim Y. Kim C. Incidence and Risk of Various Types of Arterial Thromboembolism in Patients with Cancer.Mayo Clin Proc. 2021; 96: 592-600Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar calls attention to the relationship between arterial thrombosis and cancer: First, arterial thrombosis may serve as a harbinger of a cancer that is subsequently diagnosed; and second, arterial thrombosis may occur in the wake of the diagnosis of a given cancer. As such, these important findings alert us to the existence of an association that is insufficiently appreciated, and one that has significant implications for our clinical practice. The association between cancer and venous thromboembolism (VTE) has been well established by thorough community-based epidemiology studies, mechanistic basic research, and randomized controlled trials for primary prevention, acute treatment, and secondary prevention. Societal guidelines inform best practices for cancer screening in the context of unprovoked VTE, prophylaxis for ambulatory, hospitalized, and postsurgical cancer patients and anticoagulant recommendations for managing acute VTE. The relative risk of developing VTE has been established for specific cancers, and several scoring tools which combine these estimates with other clinical and laboratory variables have been derived and validated. By comparison, there is much less information available regarding the interface between cancer and arterial thrombosis. In this issue of Mayo Clinic Proceedings, Wang et al1Wang J. Kim Y. Kim C. Incidence and Risk of Various Types of Arterial Thromboembolism in Patients with Cancer.Mayo Clin Proc. 2021; 96: 592-600Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar assessed the incidence of arterial thromboembolic events in patients with cancer. By exploring a large electronic health record database of nearly 2.7 million cancer patients, 63,520 (2.4%) were identified with an acute arterial thrombotic event. To establish a temporal relationship, the authors limited the analysis to arterial thrombosis occurring within 720 days before and after the new cancer diagnosis. An impressive increase in the incidence ratio of arterial and venous thrombotic events began 30 days before the cancer diagnosis, peaked at 30 days after the cancer diagnosis, and did not return to basal values for 8 months thereafter. Brain, colorectal, pancreas, and lung cancers were among the most common cancers. Surprisingly, the 30-day incidence ratio for arterial thrombosis was only modestly lower than for VTE, and a prior history of VTE increased the likelihood of an arterial thrombotic event. Patients suffering an arterial thrombotic event were more likely to have traditional cardiovascular risk factors for atherosclerosis including obesity, diabetes mellitus, hypertension, active smoking, and dyslipidemia. Finally, there was a striking anatomic relationship between cancer type and arterial thrombus location. This work builds on several previously reported epidemiology studies by others. To aid interpretation of such studies, it may be helpful to parse the literature into two categories: the risk of arterial thrombosis in patients with established cancer; and the likelihood of finding a new cancer in patients who have suffered an arterial thrombotic event. Both are important yet tell a slightly different story and have unique implications. First, does established cancer increase the risk of future arterial thrombosis? Navi et al2Navi B.B. Reiner A.S. Kamel H. et al.Risk of Arterial Thromboembolism in Patients With Cancer.J Am Coll Cardiol. 2017; 70: 926-938Crossref PubMed Scopus (298) Google Scholar assessed the 6-month cumulative risk of myocardial infarction (MI) and stroke among nearly 280,000 cancer patients from the Surveillance, Epidemiology, and End Results (SEER) Medicare database. They reported an incidence rate of 4.7% which was two-fold greater than age- and sex-matched controls. The risk of arterial thrombosis was greatest during the first month following the cancer diagnosis. Lung, gastric, pancreas, and colorectal cancers carried the greatest risk. The incidence and relative hazard of arterial thrombosis increased directly with cancer stage and negatively impacted survival rates. The excess risk for MI persisted for several months following the cancer diagnosis. Similarly, others have found a two-fold increased risk of both ischemic and hemorrhagic stroke and a 1.7- fold increased risk for MI during the first 6 months following cancer diagnosis.3Zöller B. Ji J. Sundquist J. Sundquist K. Risk of haemorrhagic and ischaemic stroke in patients with cancer: a nationwide follow-up study from Sweden.Eur J Cancer. 2012; 48: 1875-1883Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar,4Zöller B. Ji J. Sundquist J. Sundquist K. Risk of coronary heart disease in patients with cancer: a nationwide follow-up study from Sweden.Eur J Cancer. 2012; 48: 121-128Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar In sum, there appears to be a strong relationship between cancer and arterial thrombosis, an association that is similar to what is observed with venous thrombosis. There are several potential mechanisms to explain the temporal relationship between newly diagnosed cancer, cancer treatment, and arterial thrombosis (Table). Wang et al1Wang J. Kim Y. Kim C. Incidence and Risk of Various Types of Arterial Thromboembolism in Patients with Cancer.Mayo Clin Proc. 2021; 96: 592-600Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar showed a strong risk relationship between traditional atherosclerosis risk factors and arterial thrombosis among cancer patients in the current series. The implications of these findings are that modifiable atherosclerosis risk factors should not be left unattended simply due to the newly diagnosed cancer. Whether current guideline-directed risk modification for non-cancer patients is sufficient to impact outcomes in cancer patients is not clear. Beyond impacting survival, preventing the morbidity associated with stroke, MI, acute limb ischemia, or organ infarction remain meaningful goals. Second, does an arterial thrombosis have implications for a search for occult malignancy? Exploring the SEER-Medicare database, the temporal relationship between arterial thrombosis and occult cancer was explored among more than 374,000 case-control pairs.5Navi B.B. Reiner A.S. Kamel H. et al.Arterial thromboembolic events preceding the diagnosis of cancer in older persons.Blood. 2019; 133: 781-789Crossref PubMed Scopus (85) Google Scholar The rate of arterial thrombotic events started to increase 5 months before the cancer diagnosis and peaked 30 days before diagnosis. During this 30-day interval pre-cancer diagnosis, the odds ratio for developing arterial thrombosis increased nearly six-fold. Lung and colorectal cancer carried the greatest risk and nearly 40% of patients had either stage III or IV cancer at the time. Similarly, the Tromsø study followed 28,763 subjects forward in time to assess the association between MI and future risk of incident cancer.6Rinde L.B. Småbrekke B. Hald E.M. et al.Myocardial infarction and future risk of cancer in the general population-the Tromsø Study.Eur J Epidemiol. 2017; 32: 193-201Crossref PubMed Scopus (34) Google Scholar Of the 1747 subjects with incident MI, the hazard ratio for developing a future cancer was 46% higher than subjects without MI. The increased cancer rate was highest during the initial 6 months post-MI. Colorectal, prostate, and lung cancer were the three most common cancer locations. Nearly 43% of patients with MI had a smoking history as a “shared” risk factor. A Danish study using a nationwide population-based medical registry sample examined the risk of developing cancer in 6600 patients with lower limb arterial thrombosis.7Sundbøll J. Veres K. Horváth-Puhó E. Adelborg K. Sørensen H.T. Risk and prognosis of cancer after lower limb arterial thrombosis.Circulation. 2018; 138: 669-677Crossref PubMed Scopus (29) Google Scholar During the first 6 months after the thrombotic event, the incidence ratio of developing cancer was more than three-fold increased. Lung and other smoking-related cancers carried the strongest association. In summary, it appears that the clinical presentation of an occult malignancy may include an arterial thrombotic event similar to an unprovoked VTE. The mechanism for these arterial events may stem from shared risk factors including smoking, obesity, and increased age. Thrombogenesis may also reflect mechanical or biochemical propensities unique to the tumor (Table). The implications of these studies is that an acute arterial thrombotic event, particularly if otherwise unexpected, should prompt a thorough general medical evaluation including guideline-endorsed age-appropriate cancer screening similar to that of a VTE event. For patients who have suffered an arterial thrombotic event, the prompt return of organ perfusion through an open artery should be an urgent priority. Antithrombotic strategies for secondary prevention have not been established. For patients with other comorbidities such as atrial fibrillation, heart valve mechanical prosthesis, antiphospholipid antibody syndrome, or co-existing VTE, strategies including an anticoagulant should be used. For the many cancer patients without these comorbidities, choosing between an anticoagulant, antiplatelet, or combination therapy is not well established by randomized trial data or by guideline best-practice consensus statements. Balancing the risk for recurrent thrombosis and major bleeding can be complicated and require careful deliberation given the increased risk of both. In conclusion, the work of Wang et al1Wang J. Kim Y. Kim C. Incidence and Risk of Various Types of Arterial Thromboembolism in Patients with Cancer.Mayo Clin Proc. 2021; 96: 592-600Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar calls attention to the relationship between arterial thrombosis and cancer: First, arterial thrombosis may serve as a harbinger of a cancer that is subsequently diagnosed; and second, arterial thrombosis may occur in the wake of the diagnosis of a given cancer. As such, these important findings alert us to the existence of an association that is insufficiently appreciated, and one that has significant implications for our clinical practice. Incidence and Risk of Various Types of Arterial Thromboembolism in Patients With CancerMayo Clinic ProceedingsVol. 96Issue 3PreviewTo describe the temporal association and identify risk factors between cancer diagnosis and various types of arterial thromboembolism (ATE). Full-Text PDF