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Intrahepatic Cholangiocarcinoma Associated Paradoxical Peripheral Embolism and a Submassive Pulmonary Embolism
Case Report Intrahepatic Cholangiocarcinoma Associated Paradoxical Peripheral Embolism and a Submassive Pulmonary Embolism Song-Lin Zhang,1 Yu-Shun Zhang,1 Feng Wei,1 and Lucas DeYoung,2 Xi’an, China and Little Rock, Arkansas
Paradoxical peripheral embolism and submassive pulmonary embolism (PE), secondary to cancer-associated thrombosis, are yet to be reported in the literature. Here we describe a case presenting with an acute peripheral arterial embolism. Subsequent testing revealed a PE and an intrahepatic cholangiocarcinoma as the likely risk factors for thrombus, with arterial spread likely achieved through a patent foramen ovale. The patient’s symptoms almost relieved upon catheter-directed thrombus fragmentation and aspiration, catheter-directed thrombolysis, and combined anticoagulation. Embolism and major bleeding did not occur during 6 months of follow-up under systemic anticoagulation with rivaroxaban. This case documents that catheter-directed thrombolysis and anticoagulation could be likely effective and safe in the treatment and prevention of recurrence of paradoxical embolism and PE secondary to cancerassociated thrombosis.
Paradoxical peripheral embolism is a rare clinical event, accounting for less than 2% of all arterial embolisms.1 Although paradoxical embolism (PDE) is known to risk serious complications, the diagnosis is often not considered and remains under-reported.2 Early diagnosis and prompt treatment of PDE are critical to avoid morbidity and mortality. Unfortunately, accurate and early diagnosis of PDE is often difficult, as multisystem involvement can obscure a single cause of disease. Formulaic approaches to acute PDE treatment are complicated by innumerable combinations of
1 Department of Structural Heart Disease, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China. 2 Department of Biochemistry, University of Arkansas for Medical Science, Little Rock, AR.
Correspondence to: Feng Wei, Department of Structural Heart Disease, The First Affiliated Hospital of Xi’an Jiaotong University, 277 West Yanta Road, Xi’an 710061, China; E-mail: [email protected] Ann Vasc Surg 2019; -: 1.e1–1.e4 https://doi.org/10.1016/j.avsg.2019.05.038 Ó 2019 Elsevier Inc. All rights reserved. Manuscript received: June 29, 2018; manuscript accepted: May 22, 2019; published online: - - -
emboli locations and compromised organ systems. Subsequently, there is no clear consensus on the treatment of acute PDE.
CASE REPORT A 59-year-old woman suffered a sudden dysfunction of her left upper limb with symptoms of pain and paralysis 8 hr before admission. The patient recalled a bout of severe dyspnea after a hard exercise 6 days ago, but otherwise noted no remarkable medical or family history. Physical examination revealed a heart rate of 78 beats/min. Oxygen saturation (SO2) was 89% while receiving low flow oxygen therapy. Blood pressure of her right upper limb was 140/90 mm Hg but was undetectable in her left upper limb. The patient’s left arm was cool to the touch and absent of brachial and radial pulse. Patient D-dimers and amino-terminal pro-brain natriuretic peptide (NTproBNP) were elevated to 15.42 mg/L (normal range <1 mg/L) and 2,637 ng/L (normal range <125 ng/L), respectively. Arterial oxygen pressure (PaO2) was 63.5 mm Hg. Color Doppler ultrasound investigated blood circulation in the patient’s left upper limb, revealing an obstruction in the left brachial artery. Electrocardiography (ECG) showed a normal sinus rhythm with inverted T waves in the inferior and anterior leads, as well as a 1.e1
1.e2 Case report
Annals of Vascular Surgery
Fig. 1. (A) Electrocardiogram showed inverted T waves in inferior and anterior leads and a deep S wave in lead I; (B) TTE revealed that the right atrium and ventricle were significantly dilated and also revealed an atrial septal aneurysm (white arrowhead ); (C) assessment of pulmonary arterial hypertension by TTE; (D) TTE detected a PFO shunt from right to left; (E) pulmonary
angiography demonstrated the embolism of the left lower lobe and the right middle and lower lobes (white arrowheads); (F) angiography showed the total occlusion of the left brachial artery (black arrowhead ); and (G) contrast-enhanced computed tomography revealed an intrahepatic cholangiocarcinoma (black arrowhead ).
deep S wave in lead I (Fig. 1A). Transthoracic echocardiography (TTE) revealed a patent foramen ovale (PFO) associated with an atrial septal aneurysm (ASA) and a complete right to left shunting. The right atrium and ventricle were significantly dilated. Tricuspid regurgitation and pulmonary arterial hypertension (79 mm Hg) were also detected (Fig. 1BeD). At the same time, vascular ultrasound detected a muscular calf vein thrombosis (MCVT) in her left lower limb. Pulmonary angiography showed vascular obstruction of the left lower lobe, right middle lobe, and right lower lobe (Fig. 1E). Pulmonary
arterial pressure was measured at 61/31/17 mm Hg. Restoration of pulmonary arterial circulation was prioritized. Fragmentation of pulmonary thrombus was achieved using a rotating pigtail catheter followed by catheter-directed administration of 250,000 IU of urokinase. The treatment was successful. Pulmonary arterial pressure decreased to 51/22/2 mm Hg and SO2 improved to 92%. We next moved to address the patient’s left brachial artery occlusion (Fig. 1F). Left subclavian and axillary arteries were notably free from occlusion. Manual
Volume
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catheter-directed aspiration of thrombus was implemented and catheter-directed thrombolysis combined anticoagulation was carried out by continuing alternative infusion of urokinase (40,000 IU/hr, totaling 500,000 IU) and argatroban (1 mg/hr, totaling 20 mg). After catheterdirect treatment, symptoms of ischemia on upper extremity were completely relieved. Systemic anticoagulation was maintained by rivaroxaban (15 mg/day, twice a day) during the patient’s remaining hospital stay. Before discharge, 24-hr Holter ECG had not detected any evidence of atrial fibrillation. Ultrasound cardiography showed that pulmonary arterial pressure was decreased to 46 mm Hg. Right atrium and ventricle were back to normal size. NT-proBNP decreased to 183 pg/mL and PaO2 increased to 74 mm Hg. Symptoms of pulmonary embolism (PE) were almost relieved leaving a mild shortness of breath after a hard exercise. Occlusion of PFO by interventional procedure was suggested to prevent the recurrence of PDE. The intervention was complicated when blood tests returned positive for cancer biomarkers of CA199 (121.9 U/mL, normal range <35 U/mL) and CA125 (1,747 U/ mL, normal range <39 U/mL). The patient also tested positive for hepatitis B virus core antigen (anti-HBc). Contrastenhanced computed tomography revealed an intrahepatic cholangiocarcinoma (Fig. 1G). To prevent recurrent PDE, both surgical treatment of the discovered cholangiocarcinoma and closure of PFO were recommended, but the patient declined to undergo further surgery. The patient did agree to the continuation of systemic anticoagulation by rivaroxaban, and no recurrence of PDE or major bleeding was observed in 6-months of follow-up.
DISCUSSION According to diagnosis criteria,3 this case presenting with peripheral arterial embolism (without common cardiogenic or arterial risk factors), venous thromboembolism (VTE), and a PFO with ASA could be diagnosed with PDE. It is easy to quickly diagnose the acute arterial embolism at admission. But the cause of arterial embolism seemed uncommon since the patient had no common risk factors (atrial fibrillation, severe atherosclerosis, etc.) for arterial embolism. Based on physical examination, blood testing (D-Dimer, PaO2, NT-proBNP), and ECG, we hypothesized that PE might cause shortness of breath and finally resulted in a paradoxical arterial embolism by increasing right heart chambers’ pressure, allowing a right to left shunting through a PFO or other abnormal passages between 2 sides of heart chambers. Subsequently, PE and PFO associated ASA were revealed. It seemed likely that VTE pass through PFO, resulting in a paradoxical arterial embolism, although the possibility of thrombus from ASA could not be completely ruled out. It is widely accepted that ASA is a risk factor
Case report 1.e3
for cryptogenic stroke, but the high proportion (90%) of ASA patients with interatrial shunting (PFO, etc.) suggests paradoxical embolization as a potential cause.4 Furthermore, Mangiafico reported that except for interatrial shunting, isolated ASA could not be considered as an independent risk factor for cryptogenic stroke.5 As the patient neared discharge from the hospital, her diagnosis seemed incomplete. There was no obvious cause of the precipitating VTE. The patient possessed no common risk factors associated with VTE, such as recent trauma, surgery, immobility, previous VTE, and oral contraceptive use. The risk factors of the VTE were clarified upon testing the patient’s blood for biomarkers for common cancers. Elevated levels of CA199 and CA125 were discovered along with testing positive for hepatitis B virus core antigen (anti-HBc). Intrahepatic cholangiocarcinoma was diagnosed, which is a well-documented high-risk factor for VTE,6 thus offering a more complete explanation for our patient’s development of PDE. Furthermore, as a major risk factor, chronic hepatitis B infection may be an explanation for patient’s susceptibility to intrahepatic cholangiocarcinoma.7 There is no clear consensus on the treatment of PDE. Presenting symptoms largely depend upon the location of the embolus, necessitating a different approach for each patient. Our patient suffered from acute arterial embolism, PE, pulmonary hypertension, MCVT, PFO associated with ASA, and intrahepatic cholangiocarcinoma. Among these diseases, acute arterial embolism and PE were most severe and emergent, with a high risk of disability and death, respectively. We arranged an emergency intervention procedure to treat acute arterial embolism. Simultaneously, we applied thrombus fragmentation and catheter-directed thrombolysis instead of systemic thrombolysis to treat submassive PE because of our assessment of a high bleeding risk (systemic thrombolysis could significantly increase risk of bleeding when catheter-directed continuing thrombolysis combined anticoagulation undergo during treatment of peripheral arterial embolism) and a recommendation of catheter-directed thrombolysis combined mechanical thrombectomy in the acute submassive PE.8 In recent years, more evidences showed that catheter-based reperfusion therapy was as efficient as systemic thrombolysis, but with a more safety profile.9 To prevent PDE from recurring, patients should receive PFO closure or antithrombotic medication. Because the interventional procedure was rejected, long-term anticoagulation was considered. For convenience, the patient accepted rivaroxaban instead of
1.e4 Case report
low-molecular-weight heparin (LMWH) for anticoagulation. Over the course of a 6-month follow up, rivaroxaban has proven safe and effective in prevention of PDE in spite of our patient’s elevated risk of cancer-associated VTE. Other studies have demonstrated rivaroxaban’s efficacy in treating cancerassociated VTE, compared with LMWH10; however, we report rivaroxaban’s efficacy in a patient with PFO and PDE risk. For paradoxical peripheral embolism, pathological diagnosis-based clinical thinking and practice is helpful for finding out multisystemic involved hidden diseases and quickly getting an entire and accurate diagnosis. Prompt treatment and appropriate prevention of recurrence should be personalized. In intrahepatic cholangiocarcinoma associated paradoxical peripheral embolism and PE, it seems safe and effective, at least in this case, in treatment by catheter-directed thrombolysis combined anticoagulation, as well as prevention of recurrence by systemic anticoagulation with rivaroxaban.
This study was supported by National Natural Science Foundation of China (81000063).
Annals of Vascular Surgery
REFERENCES 1. d’Audiffret A, Shenoy S, Ricotta J, et al. The role of thrombolytic therapy in the management of paradoxical embolism. Cardiovasc Surg 1998;6:302e6. 2. Windecker S, Stortecky S, Meier B. Paradoxical embolism. J Am Coll Cardiol 2014;64:403e15. 3. Meister SG, Grossman W, Dexter L, et al. Paradoxical embolism: diagnosis during life. Am J Med 1972;53:292e8. 4. Belkin RN, Hurwitz BJ, Kisslo J. Atrial septal aneurysm: association with cerebrovascular and peripheral embolic events. Stroke 1987;18:856e62. 5. Mangiafico S. Atrial septal aneurysm is always linked to right-left shunt and cardio embolic risk. Clin Med Res 2013;2:48e52. 6. Khalil J, Bensaid B, Elkacemi H, et al. Venous thromboembolism in cancer patients: an underestimated major health problem. World J Surg Oncol 2015;13:1e17. 7. Palmer WC, Patel T. Are common factors involved in the pathogenesis of primary liver cancers? A meta- analysis of risk factors for intrahepatic cholangiocarcinoma. J Hepatol 2012;57:69e76. 8. Streiff MB, Agnelli G, Connors JM, et al. Guidance for the treatment of deep vein thrombosis and pulmonary embolism. J Thromb Thrombolysis 2016;41:32e67. 9. Engelberger RP, Kucher N. Reperfusion treatment for acute pulmonary embolism. Hamostaseologie 2018;38:98e105. 10. Mantha S, Laube E, Miao Y, et al. Safe and effective use of rivaroxaban for treatment of cancer-associated venous thromboembolic disease: a prospective cohort study. J Thromb Thrombolysis 2017;43:166e71.
Paradoxical peripheral embolism and submassive pulmonary embolism (PE), secondary to cancer-associated thrombosis, are yet to be reported in the literature. Here we describe a case presenting with an acute peripheral arterial embolism. Subsequent testing revealed a PE and an intrahepatic cholangiocarcinoma as the likely risk factors for thrombus, with arterial spread likely achieved through a patent foramen ovale. The patient’s symptoms almost relieved upon catheter-directed thrombus fragmentation and aspiration, catheter-directed thrombolysis, and combined anticoagulation. Embolism and major bleeding did not occur during 6 months of follow-up under systemic anticoagulation with rivaroxaban. This case documents that catheter-directed thrombolysis and anticoagulation could be likely effective and safe in the treatment and prevention of recurrence of paradoxical embolism and PE secondary to cancerassociated thrombosis.
Paradoxical peripheral embolism is a rare clinical event, accounting for less than 2% of all arterial embolisms.1 Although paradoxical embolism (PDE) is known to risk serious complications, the diagnosis is often not considered and remains under-reported.2 Early diagnosis and prompt treatment of PDE are critical to avoid morbidity and mortality. Unfortunately, accurate and early diagnosis of PDE is often difficult, as multisystem involvement can obscure a single cause of disease. Formulaic approaches to acute PDE treatment are complicated by innumerable combinations of
1 Department of Structural Heart Disease, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China. 2 Department of Biochemistry, University of Arkansas for Medical Science, Little Rock, AR.
Correspondence to: Feng Wei, Department of Structural Heart Disease, The First Affiliated Hospital of Xi’an Jiaotong University, 277 West Yanta Road, Xi’an 710061, China; E-mail: [email protected] Ann Vasc Surg 2019; -: 1.e1–1.e4 https://doi.org/10.1016/j.avsg.2019.05.038 Ó 2019 Elsevier Inc. All rights reserved. Manuscript received: June 29, 2018; manuscript accepted: May 22, 2019; published online: - - -
emboli locations and compromised organ systems. Subsequently, there is no clear consensus on the treatment of acute PDE.
CASE REPORT A 59-year-old woman suffered a sudden dysfunction of her left upper limb with symptoms of pain and paralysis 8 hr before admission. The patient recalled a bout of severe dyspnea after a hard exercise 6 days ago, but otherwise noted no remarkable medical or family history. Physical examination revealed a heart rate of 78 beats/min. Oxygen saturation (SO2) was 89% while receiving low flow oxygen therapy. Blood pressure of her right upper limb was 140/90 mm Hg but was undetectable in her left upper limb. The patient’s left arm was cool to the touch and absent of brachial and radial pulse. Patient D-dimers and amino-terminal pro-brain natriuretic peptide (NTproBNP) were elevated to 15.42 mg/L (normal range <1 mg/L) and 2,637 ng/L (normal range <125 ng/L), respectively. Arterial oxygen pressure (PaO2) was 63.5 mm Hg. Color Doppler ultrasound investigated blood circulation in the patient’s left upper limb, revealing an obstruction in the left brachial artery. Electrocardiography (ECG) showed a normal sinus rhythm with inverted T waves in the inferior and anterior leads, as well as a 1.e1
1.e2 Case report
Annals of Vascular Surgery
Fig. 1. (A) Electrocardiogram showed inverted T waves in inferior and anterior leads and a deep S wave in lead I; (B) TTE revealed that the right atrium and ventricle were significantly dilated and also revealed an atrial septal aneurysm (white arrowhead ); (C) assessment of pulmonary arterial hypertension by TTE; (D) TTE detected a PFO shunt from right to left; (E) pulmonary
angiography demonstrated the embolism of the left lower lobe and the right middle and lower lobes (white arrowheads); (F) angiography showed the total occlusion of the left brachial artery (black arrowhead ); and (G) contrast-enhanced computed tomography revealed an intrahepatic cholangiocarcinoma (black arrowhead ).
deep S wave in lead I (Fig. 1A). Transthoracic echocardiography (TTE) revealed a patent foramen ovale (PFO) associated with an atrial septal aneurysm (ASA) and a complete right to left shunting. The right atrium and ventricle were significantly dilated. Tricuspid regurgitation and pulmonary arterial hypertension (79 mm Hg) were also detected (Fig. 1BeD). At the same time, vascular ultrasound detected a muscular calf vein thrombosis (MCVT) in her left lower limb. Pulmonary angiography showed vascular obstruction of the left lower lobe, right middle lobe, and right lower lobe (Fig. 1E). Pulmonary
arterial pressure was measured at 61/31/17 mm Hg. Restoration of pulmonary arterial circulation was prioritized. Fragmentation of pulmonary thrombus was achieved using a rotating pigtail catheter followed by catheter-directed administration of 250,000 IU of urokinase. The treatment was successful. Pulmonary arterial pressure decreased to 51/22/2 mm Hg and SO2 improved to 92%. We next moved to address the patient’s left brachial artery occlusion (Fig. 1F). Left subclavian and axillary arteries were notably free from occlusion. Manual
Volume
-, -
2019
catheter-directed aspiration of thrombus was implemented and catheter-directed thrombolysis combined anticoagulation was carried out by continuing alternative infusion of urokinase (40,000 IU/hr, totaling 500,000 IU) and argatroban (1 mg/hr, totaling 20 mg). After catheterdirect treatment, symptoms of ischemia on upper extremity were completely relieved. Systemic anticoagulation was maintained by rivaroxaban (15 mg/day, twice a day) during the patient’s remaining hospital stay. Before discharge, 24-hr Holter ECG had not detected any evidence of atrial fibrillation. Ultrasound cardiography showed that pulmonary arterial pressure was decreased to 46 mm Hg. Right atrium and ventricle were back to normal size. NT-proBNP decreased to 183 pg/mL and PaO2 increased to 74 mm Hg. Symptoms of pulmonary embolism (PE) were almost relieved leaving a mild shortness of breath after a hard exercise. Occlusion of PFO by interventional procedure was suggested to prevent the recurrence of PDE. The intervention was complicated when blood tests returned positive for cancer biomarkers of CA199 (121.9 U/mL, normal range <35 U/mL) and CA125 (1,747 U/ mL, normal range <39 U/mL). The patient also tested positive for hepatitis B virus core antigen (anti-HBc). Contrastenhanced computed tomography revealed an intrahepatic cholangiocarcinoma (Fig. 1G). To prevent recurrent PDE, both surgical treatment of the discovered cholangiocarcinoma and closure of PFO were recommended, but the patient declined to undergo further surgery. The patient did agree to the continuation of systemic anticoagulation by rivaroxaban, and no recurrence of PDE or major bleeding was observed in 6-months of follow-up.
DISCUSSION According to diagnosis criteria,3 this case presenting with peripheral arterial embolism (without common cardiogenic or arterial risk factors), venous thromboembolism (VTE), and a PFO with ASA could be diagnosed with PDE. It is easy to quickly diagnose the acute arterial embolism at admission. But the cause of arterial embolism seemed uncommon since the patient had no common risk factors (atrial fibrillation, severe atherosclerosis, etc.) for arterial embolism. Based on physical examination, blood testing (D-Dimer, PaO2, NT-proBNP), and ECG, we hypothesized that PE might cause shortness of breath and finally resulted in a paradoxical arterial embolism by increasing right heart chambers’ pressure, allowing a right to left shunting through a PFO or other abnormal passages between 2 sides of heart chambers. Subsequently, PE and PFO associated ASA were revealed. It seemed likely that VTE pass through PFO, resulting in a paradoxical arterial embolism, although the possibility of thrombus from ASA could not be completely ruled out. It is widely accepted that ASA is a risk factor
Case report 1.e3
for cryptogenic stroke, but the high proportion (90%) of ASA patients with interatrial shunting (PFO, etc.) suggests paradoxical embolization as a potential cause.4 Furthermore, Mangiafico reported that except for interatrial shunting, isolated ASA could not be considered as an independent risk factor for cryptogenic stroke.5 As the patient neared discharge from the hospital, her diagnosis seemed incomplete. There was no obvious cause of the precipitating VTE. The patient possessed no common risk factors associated with VTE, such as recent trauma, surgery, immobility, previous VTE, and oral contraceptive use. The risk factors of the VTE were clarified upon testing the patient’s blood for biomarkers for common cancers. Elevated levels of CA199 and CA125 were discovered along with testing positive for hepatitis B virus core antigen (anti-HBc). Intrahepatic cholangiocarcinoma was diagnosed, which is a well-documented high-risk factor for VTE,6 thus offering a more complete explanation for our patient’s development of PDE. Furthermore, as a major risk factor, chronic hepatitis B infection may be an explanation for patient’s susceptibility to intrahepatic cholangiocarcinoma.7 There is no clear consensus on the treatment of PDE. Presenting symptoms largely depend upon the location of the embolus, necessitating a different approach for each patient. Our patient suffered from acute arterial embolism, PE, pulmonary hypertension, MCVT, PFO associated with ASA, and intrahepatic cholangiocarcinoma. Among these diseases, acute arterial embolism and PE were most severe and emergent, with a high risk of disability and death, respectively. We arranged an emergency intervention procedure to treat acute arterial embolism. Simultaneously, we applied thrombus fragmentation and catheter-directed thrombolysis instead of systemic thrombolysis to treat submassive PE because of our assessment of a high bleeding risk (systemic thrombolysis could significantly increase risk of bleeding when catheter-directed continuing thrombolysis combined anticoagulation undergo during treatment of peripheral arterial embolism) and a recommendation of catheter-directed thrombolysis combined mechanical thrombectomy in the acute submassive PE.8 In recent years, more evidences showed that catheter-based reperfusion therapy was as efficient as systemic thrombolysis, but with a more safety profile.9 To prevent PDE from recurring, patients should receive PFO closure or antithrombotic medication. Because the interventional procedure was rejected, long-term anticoagulation was considered. For convenience, the patient accepted rivaroxaban instead of
1.e4 Case report
low-molecular-weight heparin (LMWH) for anticoagulation. Over the course of a 6-month follow up, rivaroxaban has proven safe and effective in prevention of PDE in spite of our patient’s elevated risk of cancer-associated VTE. Other studies have demonstrated rivaroxaban’s efficacy in treating cancerassociated VTE, compared with LMWH10; however, we report rivaroxaban’s efficacy in a patient with PFO and PDE risk. For paradoxical peripheral embolism, pathological diagnosis-based clinical thinking and practice is helpful for finding out multisystemic involved hidden diseases and quickly getting an entire and accurate diagnosis. Prompt treatment and appropriate prevention of recurrence should be personalized. In intrahepatic cholangiocarcinoma associated paradoxical peripheral embolism and PE, it seems safe and effective, at least in this case, in treatment by catheter-directed thrombolysis combined anticoagulation, as well as prevention of recurrence by systemic anticoagulation with rivaroxaban.
This study was supported by National Natural Science Foundation of China (81000063).
Annals of Vascular Surgery
REFERENCES 1. d’Audiffret A, Shenoy S, Ricotta J, et al. The role of thrombolytic therapy in the management of paradoxical embolism. Cardiovasc Surg 1998;6:302e6. 2. Windecker S, Stortecky S, Meier B. Paradoxical embolism. J Am Coll Cardiol 2014;64:403e15. 3. Meister SG, Grossman W, Dexter L, et al. Paradoxical embolism: diagnosis during life. Am J Med 1972;53:292e8. 4. Belkin RN, Hurwitz BJ, Kisslo J. Atrial septal aneurysm: association with cerebrovascular and peripheral embolic events. Stroke 1987;18:856e62. 5. Mangiafico S. Atrial septal aneurysm is always linked to right-left shunt and cardio embolic risk. Clin Med Res 2013;2:48e52. 6. Khalil J, Bensaid B, Elkacemi H, et al. Venous thromboembolism in cancer patients: an underestimated major health problem. World J Surg Oncol 2015;13:1e17. 7. Palmer WC, Patel T. Are common factors involved in the pathogenesis of primary liver cancers? A meta- analysis of risk factors for intrahepatic cholangiocarcinoma. J Hepatol 2012;57:69e76. 8. Streiff MB, Agnelli G, Connors JM, et al. Guidance for the treatment of deep vein thrombosis and pulmonary embolism. J Thromb Thrombolysis 2016;41:32e67. 9. Engelberger RP, Kucher N. Reperfusion treatment for acute pulmonary embolism. Hamostaseologie 2018;38:98e105. 10. Mantha S, Laube E, Miao Y, et al. Safe and effective use of rivaroxaban for treatment of cancer-associated venous thromboembolic disease: a prospective cohort study. J Thromb Thrombolysis 2017;43:166e71.