Clin J Gastroenterol (2009) 2:247–251 DOI 10.1007/s12328-009-0092-x
CLINICAL REVIEW
Venous thromboembolism in abdominal cancer surgery Masato Sakon Æ Masataka Ikeda
Received: 11 May 2009 / Accepted: 11 May 2009 / Published online: 19 June 2009 Ó Springer 2009
Abstract Venous thromboembolism (VTE) is recognized as a serious complication in both surgical and non-surgical patients. Cancer, particularly adenocarcinoma developing in the digestive organs, is one of the most potent risk factors for VTE, as first described by Trousseau in 1865. Cell membrane microparticles shedding from cancer cells play a critical role in venous clot formation through tissue factor (TF)-mediated activation of the coagulation system. Since recent prospective studies have demonstrated that VTE risk in Japanese surgical patients is comparable to that in Caucasians, perioperative thromboprophylaxis with anticoagulants is now considered essential in patients undergoing abdominal cancer surgery, in addition to mechanical thromboprophylaxis. Recent multi-center studies have also shown the efficacy and safety of enoxaparin, a low molecular weight heparin (LMWH), and fondaparinux, a synthetic Xa inhibitor, in VTE prevention after abdominal cancer surgery. Anticoagulants like LMWH are expected to exert not only thromboprophylactic but also antineoplastic effects.
Introduction Deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE) are now generically called venous thromboembolism (VTE) because the underlying pathogenesis of these disorders (i.e., venous blood clotting) is identical. VTE has been recognized as one of the most common causes of hospital death in Western countries [1]. It has not been popular until very recently in Japan, but the incidence of VTE has rapidly increased up to the level of Western countries, particularly in patients undergoing orthopedic, gynecological and abdominal surgery [2–4]. Cancer is one of the major risk factors for VTE. Since the significant relationship between gastric cancer and venous thromboembolism was described by Trousseau in 1865 [5], the underlying mechanisms of cancer-mediated venous thrombosis has long been studied [6]. In this article, the current status of VTE in patients undergoing abdominal cancer surgery is reviewed, focusing on the incidence, pathogenesis, prophylaxis and survival impact of anticoagulants.
Keywords Venous thromboembolism Digestive cancer Thromboprophylaxis Current status of VTE in abdominal cancer surgery in Japan
M. Sakon (&) Department of Surgery, Nishinomiya Municipal Central Hospital, 8-24, Hayashida-cho, Nishinomiya, Hyogo 663-8014, Japan e-mail: [email protected] M. Ikeda Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
The incidence of VTE in cancer patients has been considered very low in Japan. The comparative autopsy study in 1964 between Boston and Kyusyu, Japan, demonstrated VTE was extremely rare in the Japanese surgical population compared with that of Boston [7]. Since then, no detailed study on VTE in cancer patients was done in Japan until a bibliographical study revealed that the incidence of symptomatic PTE was 0.3% in patients undergoing abdominal surgery, considerably higher than expected
123
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before [4]. In addition, a prospective multicenter survey by bilateral venography demonstrated that the incidence of VTE in major abdominal surgery (cancer surgery: 87%) has increased up to 24% [8], a level comparable to that of Caucasians, although half of this patient population received mechanical prophylaxis, such as elastic stockings or elastic bandages. Likewise, prospective, multicenter epidemiological studies on VTE in orthopedic surgery like total hip replacement or total knee replacement showed almost the same incidence of VTE as observed in western countries [2], suggesting that the risk of VTE is considerably high at present in Japanese surgical patients. These findings also suggest that pharmacological thromboprophylaxis should be recommended after abdominal cancer surgery in Japan as in Western countries.
Thromboprophylaxis in digestive cancer surgery, recommended by the Japanese guidelines for VTE prevention The Japanese guidelines for VTE prevention were established in 2004. As shown in Table 1, it stratifies VTE risk into four groups (low, moderate, high and highest risk group) with five major risk factors, i.e., age, type of surgery, presence of cancer, thrombotic predisposition and history of VTE [9], and recommends risk-based thromboprophylaxis. Most patients undergoing digestive cancer surgery are classified into the high risk group, and either mechanical or thromboprophylaxis with unfractionated heparin is recommended. Since digestive surgeons are afraid of postoperative bleeding, and are not generally accustomed to prescribing anticoagulants, mechanical prophylaxis with elastic stockings or intermittent pneumatic compression (IPC) has been commonly applied to surgical patients with gastrointestinal malignancies. According to the inquiry survey by the Japanese Society
of Anesthesiologists, the incidence of PTE decreased about by half (from 4.8/104 patients to 2.3/104 patients) within 2 years after its publication, but it has not decreased further in the last 3 years [10]. In addition, the mortality rate of PTE did not change even after publication of the Japanese guidelines, and it still remains around 20%, although about 80% of patients developing postoperative PTE received mechanical prophylaxis. Actually, DVT developed in more than 44% of patients undergoing abdominal surgery who had three or four of the risk factors (more than 60 years old, female, pelvic surgery and operation time of more than 3 h) identified in a multicenter, prospective study [8], as shown in Fig. 1. These high risk patients made up about 30% of the whole study population. Therefore, more extensive prophylaxis with anticoagulants is necessary for Japanese patients undergoing digestive cancer surgery.
Mechanisms of VTE development in digestive cancer patients The pathophysiologic mechanisms of VTE are well known as Virchow’s triad, i.e., endovascular injury, increased coagulability and blood flow stagnation [11]. Among various risk factors related with these mechanisms, cancer has been considered as one of the most potent VTE risk factors. Actually, cancer has been utilized to stratify the VTE risk in most guidelines [9, 12–14]. The risk of VTE in cancer patients is also related with the histology of cancer. Digestive adenocarcinomas like pancreatic cancer or gastric cancer belong to the high VTE risk group, while bladder carcinoma is the lowest, probably depending on tissue factor (TF) expression [15]. TF on microparticles (MP) shedding from cancer cells plays an important role in VTE development, as shown in Fig. 2 [16]. TF on MPs circulating in the peripheral blood
Table 1 Risk levels and thromboprophylaxis methods of the Japanese guidelines for venous thromboembolism prevention in general surgery [9] Risk level
Incidence of PE (%)
Low
0.2
Examples
Prophylaxis
Non-major surgery: \60 year
Aggressive mobilization
major surgery: \40 year Moderate
1–2
Non-major surgery: [60 year or risk factor(?)
ES or IPC
major surgery: [40 year or risk factor(?) High
2–4
Major surgery: [40 year ? cancer
IPC or LDUH (enoxaparina, fondaparinuxa)
Highest
4–10
Major surgery: prior VTE or thrombophilia
IPC/ES ? LDUH/(enoxaparina, fondaparinuxa), ADH, wafarin
PE pulmonary thromboembolism, VTE venous thromboembolism, ES elastic stockings, IPC intermittent pneumatic compression, LDUH lowdose unfractionated heparin, ADH adjusted-dose unfractionated heparin a
Enoxaparin and fondaparinux now being used in Japan were not recommended because they were inapplicable for thromboprophylaxis when the guideline was prepared in 2004
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Clin J Gastroenterol (2009) 2:247–251
249
VTE prophylaxis in patients undergoing cancer surgery
22/50 (44%) 60
Incidence (%)
50 40 30
Risk factor • • • •
Gender: Female Site of surgery: Pelvic Age: ≥60 years old Duration of surgery: ≥3 hours
Mechanical VTE prophylaxis like elastic stockings or intermittent pneumatic compression (IPC) has been widely applied in Japanese patients undergoing cancer surgery for the last 5 years [10]. This tendency was considerably encouraged by the reimbursement of these medical expenses by health insurance. Following the widespread use of mechanical prophylaxis in Japan, the incidence of perioperative PTE decreased by about half, but it has not decreased for the last 3 years [10], as described above. Under these circumstances, abdominal cancer surgery is a major cause of symptomatic PTE following orthopedic surgery, suggesting that the use of more potent thromboprophylaxis like anticoagulants is necessary for further improvement in VTE prevention. Historically, unfractionated heparin has long been used for VTE prevention in high risk patients. However, because of the burden of monitoring coagulation activity and adverse events such as heparin-induced thrombocytopenia (HIT) [22], sophisticated anticoagulants, such as low molecular heparin (LMWH) or fondaparinux, a pentasaccharide molecule exerting its anticoagulant activity through binding to antithrombin-III, were developed and now are widely used for perioperative thromboprophylaxis throughout the world. Enoxaparin (LMWH) and fondaparinux are now available in Japan. Their effectiveness and safety in Japanese patients undergoing abdominal cancer surgery were recently confirmed [23, 24]. In contrast, the clinical importance of VTE prevention in medical cancer patients is not well recognized in Japan. Poor recognition of the importance of VTE prevention is also true in Western countries [25], although the recent study indicated the frequent use of pharmacological prophylaxis [26].
57.1% 41.9%
20 10 0
0 N=4
0
16.7%
16.9%
N=30
N=89
N=43
N=7
1
2
3
4
Number of risk factors Fig. 1 Incidence of venous thromboembolism in major abdominal surgery, stratified by the number of risk factors [8]
continuously stimulates blood coagulation in tumor-bearing patients. Recent studies have demonstrated that the level of D-dimer, a marker of fibrin generation and degradation, increases in tumor-bearing patients and is closely correlated with the clinical stage of cancer [17–19]. In addition, the incidence of VTE is found to be correlated with TF expression in patients with pancreatic cancer [20]. MPs bind directly to endothelial cells or platelets aggregated on the subendothelial tissue through binding between p-selectin and P-selectin glycoprotein ligand (PSGL)-1, and exerts its stimulatory effect on local blood clotting. MPs also induce endothelial contraction, which results in the exposure of subendothelial tissue, leading to the increased thrombogenicity of blood vessels through platelet activation and TF-initiated blood coagulation [21].
Fig. 2 Activation of blood coagulation by tissue factor (TF) located on microparticles (MPs) shedding from cancer cells [16]. MPs adhere to endothelial cells and platelets through P-selectin and P-selectin glycoprotein ligand (PSGL) binding. Tissue factor (TF) on circulating or adhered MPs activates factor X, leading to prothrombin activation and fibrin generation
TF sP PSGL-1
sP
TF
MP
sP
TF
shedding
PSGL-1
Cancer cell
P
sP
sP
TF
P
sF sF
sP P
sP TF
P
fibrin
TF PSGL-1
P
P P
sP
PSGL-1
sP sP
PSGL-1
sP
TF
P
P
P
P P
P
P
P
P
P P
P
P P
P
P
P P
Endothelial Cell P
P
P
MP: Microparticle TF ; Tissue factor on microparticle P; P-selectin sP; soluble P-selectin PSGL(
CLINICAL REVIEW
Venous thromboembolism in abdominal cancer surgery Masato Sakon Æ Masataka Ikeda
Received: 11 May 2009 / Accepted: 11 May 2009 / Published online: 19 June 2009 Ó Springer 2009
Abstract Venous thromboembolism (VTE) is recognized as a serious complication in both surgical and non-surgical patients. Cancer, particularly adenocarcinoma developing in the digestive organs, is one of the most potent risk factors for VTE, as first described by Trousseau in 1865. Cell membrane microparticles shedding from cancer cells play a critical role in venous clot formation through tissue factor (TF)-mediated activation of the coagulation system. Since recent prospective studies have demonstrated that VTE risk in Japanese surgical patients is comparable to that in Caucasians, perioperative thromboprophylaxis with anticoagulants is now considered essential in patients undergoing abdominal cancer surgery, in addition to mechanical thromboprophylaxis. Recent multi-center studies have also shown the efficacy and safety of enoxaparin, a low molecular weight heparin (LMWH), and fondaparinux, a synthetic Xa inhibitor, in VTE prevention after abdominal cancer surgery. Anticoagulants like LMWH are expected to exert not only thromboprophylactic but also antineoplastic effects.
Introduction Deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE) are now generically called venous thromboembolism (VTE) because the underlying pathogenesis of these disorders (i.e., venous blood clotting) is identical. VTE has been recognized as one of the most common causes of hospital death in Western countries [1]. It has not been popular until very recently in Japan, but the incidence of VTE has rapidly increased up to the level of Western countries, particularly in patients undergoing orthopedic, gynecological and abdominal surgery [2–4]. Cancer is one of the major risk factors for VTE. Since the significant relationship between gastric cancer and venous thromboembolism was described by Trousseau in 1865 [5], the underlying mechanisms of cancer-mediated venous thrombosis has long been studied [6]. In this article, the current status of VTE in patients undergoing abdominal cancer surgery is reviewed, focusing on the incidence, pathogenesis, prophylaxis and survival impact of anticoagulants.
Keywords Venous thromboembolism Digestive cancer Thromboprophylaxis Current status of VTE in abdominal cancer surgery in Japan
M. Sakon (&) Department of Surgery, Nishinomiya Municipal Central Hospital, 8-24, Hayashida-cho, Nishinomiya, Hyogo 663-8014, Japan e-mail: [email protected] M. Ikeda Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
The incidence of VTE in cancer patients has been considered very low in Japan. The comparative autopsy study in 1964 between Boston and Kyusyu, Japan, demonstrated VTE was extremely rare in the Japanese surgical population compared with that of Boston [7]. Since then, no detailed study on VTE in cancer patients was done in Japan until a bibliographical study revealed that the incidence of symptomatic PTE was 0.3% in patients undergoing abdominal surgery, considerably higher than expected
123
248
Clin J Gastroenterol (2009) 2:247–251
before [4]. In addition, a prospective multicenter survey by bilateral venography demonstrated that the incidence of VTE in major abdominal surgery (cancer surgery: 87%) has increased up to 24% [8], a level comparable to that of Caucasians, although half of this patient population received mechanical prophylaxis, such as elastic stockings or elastic bandages. Likewise, prospective, multicenter epidemiological studies on VTE in orthopedic surgery like total hip replacement or total knee replacement showed almost the same incidence of VTE as observed in western countries [2], suggesting that the risk of VTE is considerably high at present in Japanese surgical patients. These findings also suggest that pharmacological thromboprophylaxis should be recommended after abdominal cancer surgery in Japan as in Western countries.
Thromboprophylaxis in digestive cancer surgery, recommended by the Japanese guidelines for VTE prevention The Japanese guidelines for VTE prevention were established in 2004. As shown in Table 1, it stratifies VTE risk into four groups (low, moderate, high and highest risk group) with five major risk factors, i.e., age, type of surgery, presence of cancer, thrombotic predisposition and history of VTE [9], and recommends risk-based thromboprophylaxis. Most patients undergoing digestive cancer surgery are classified into the high risk group, and either mechanical or thromboprophylaxis with unfractionated heparin is recommended. Since digestive surgeons are afraid of postoperative bleeding, and are not generally accustomed to prescribing anticoagulants, mechanical prophylaxis with elastic stockings or intermittent pneumatic compression (IPC) has been commonly applied to surgical patients with gastrointestinal malignancies. According to the inquiry survey by the Japanese Society
of Anesthesiologists, the incidence of PTE decreased about by half (from 4.8/104 patients to 2.3/104 patients) within 2 years after its publication, but it has not decreased further in the last 3 years [10]. In addition, the mortality rate of PTE did not change even after publication of the Japanese guidelines, and it still remains around 20%, although about 80% of patients developing postoperative PTE received mechanical prophylaxis. Actually, DVT developed in more than 44% of patients undergoing abdominal surgery who had three or four of the risk factors (more than 60 years old, female, pelvic surgery and operation time of more than 3 h) identified in a multicenter, prospective study [8], as shown in Fig. 1. These high risk patients made up about 30% of the whole study population. Therefore, more extensive prophylaxis with anticoagulants is necessary for Japanese patients undergoing digestive cancer surgery.
Mechanisms of VTE development in digestive cancer patients The pathophysiologic mechanisms of VTE are well known as Virchow’s triad, i.e., endovascular injury, increased coagulability and blood flow stagnation [11]. Among various risk factors related with these mechanisms, cancer has been considered as one of the most potent VTE risk factors. Actually, cancer has been utilized to stratify the VTE risk in most guidelines [9, 12–14]. The risk of VTE in cancer patients is also related with the histology of cancer. Digestive adenocarcinomas like pancreatic cancer or gastric cancer belong to the high VTE risk group, while bladder carcinoma is the lowest, probably depending on tissue factor (TF) expression [15]. TF on microparticles (MP) shedding from cancer cells plays an important role in VTE development, as shown in Fig. 2 [16]. TF on MPs circulating in the peripheral blood
Table 1 Risk levels and thromboprophylaxis methods of the Japanese guidelines for venous thromboembolism prevention in general surgery [9] Risk level
Incidence of PE (%)
Low
0.2
Examples
Prophylaxis
Non-major surgery: \60 year
Aggressive mobilization
major surgery: \40 year Moderate
1–2
Non-major surgery: [60 year or risk factor(?)
ES or IPC
major surgery: [40 year or risk factor(?) High
2–4
Major surgery: [40 year ? cancer
IPC or LDUH (enoxaparina, fondaparinuxa)
Highest
4–10
Major surgery: prior VTE or thrombophilia
IPC/ES ? LDUH/(enoxaparina, fondaparinuxa), ADH, wafarin
PE pulmonary thromboembolism, VTE venous thromboembolism, ES elastic stockings, IPC intermittent pneumatic compression, LDUH lowdose unfractionated heparin, ADH adjusted-dose unfractionated heparin a
Enoxaparin and fondaparinux now being used in Japan were not recommended because they were inapplicable for thromboprophylaxis when the guideline was prepared in 2004
123
Clin J Gastroenterol (2009) 2:247–251
249
VTE prophylaxis in patients undergoing cancer surgery
22/50 (44%) 60
Incidence (%)
50 40 30
Risk factor • • • •
Gender: Female Site of surgery: Pelvic Age: ≥60 years old Duration of surgery: ≥3 hours
Mechanical VTE prophylaxis like elastic stockings or intermittent pneumatic compression (IPC) has been widely applied in Japanese patients undergoing cancer surgery for the last 5 years [10]. This tendency was considerably encouraged by the reimbursement of these medical expenses by health insurance. Following the widespread use of mechanical prophylaxis in Japan, the incidence of perioperative PTE decreased by about half, but it has not decreased for the last 3 years [10], as described above. Under these circumstances, abdominal cancer surgery is a major cause of symptomatic PTE following orthopedic surgery, suggesting that the use of more potent thromboprophylaxis like anticoagulants is necessary for further improvement in VTE prevention. Historically, unfractionated heparin has long been used for VTE prevention in high risk patients. However, because of the burden of monitoring coagulation activity and adverse events such as heparin-induced thrombocytopenia (HIT) [22], sophisticated anticoagulants, such as low molecular heparin (LMWH) or fondaparinux, a pentasaccharide molecule exerting its anticoagulant activity through binding to antithrombin-III, were developed and now are widely used for perioperative thromboprophylaxis throughout the world. Enoxaparin (LMWH) and fondaparinux are now available in Japan. Their effectiveness and safety in Japanese patients undergoing abdominal cancer surgery were recently confirmed [23, 24]. In contrast, the clinical importance of VTE prevention in medical cancer patients is not well recognized in Japan. Poor recognition of the importance of VTE prevention is also true in Western countries [25], although the recent study indicated the frequent use of pharmacological prophylaxis [26].
57.1% 41.9%
20 10 0
0 N=4
0
16.7%
16.9%
N=30
N=89
N=43
N=7
1
2
3
4
Number of risk factors Fig. 1 Incidence of venous thromboembolism in major abdominal surgery, stratified by the number of risk factors [8]
continuously stimulates blood coagulation in tumor-bearing patients. Recent studies have demonstrated that the level of D-dimer, a marker of fibrin generation and degradation, increases in tumor-bearing patients and is closely correlated with the clinical stage of cancer [17–19]. In addition, the incidence of VTE is found to be correlated with TF expression in patients with pancreatic cancer [20]. MPs bind directly to endothelial cells or platelets aggregated on the subendothelial tissue through binding between p-selectin and P-selectin glycoprotein ligand (PSGL)-1, and exerts its stimulatory effect on local blood clotting. MPs also induce endothelial contraction, which results in the exposure of subendothelial tissue, leading to the increased thrombogenicity of blood vessels through platelet activation and TF-initiated blood coagulation [21].
Fig. 2 Activation of blood coagulation by tissue factor (TF) located on microparticles (MPs) shedding from cancer cells [16]. MPs adhere to endothelial cells and platelets through P-selectin and P-selectin glycoprotein ligand (PSGL) binding. Tissue factor (TF) on circulating or adhered MPs activates factor X, leading to prothrombin activation and fibrin generation
TF sP PSGL-1
sP
TF
MP
sP
TF
shedding
PSGL-1
Cancer cell
P
sP
sP
TF
P
sF sF
sP P
sP TF
P
fibrin
TF PSGL-1
P
P P
sP
PSGL-1
sP sP
PSGL-1
sP
TF
P
P
P
P P
P
P
P
P
P P
P
P P
P
P
P P
Endothelial Cell P
P
P
MP: Microparticle TF ; Tissue factor on microparticle P; P-selectin sP; soluble P-selectin PSGL(
