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Use of vena cava filters in cancer patients in California
Abstracts / Thrombosis Research 129, Supplement 1 (2012) S155–S194
Trousseau, the association between thrombosis and cancer has been extensively documented. This disease constitutes one of the main cause of death during the evolution of the cancer and represents a major therapeutic problem. During the evolution of a tumor a procoagulant/thrombotic phenotype takes place conferring numerous advantages to the cancer cells. In mice, depletion of platelets form the bloodstream strongly affect the kinetics of tumor growth and the formation of experimental metastasis, suggesting that platelet activation is playing a key role in the development of a tumor. However to date, treatment using antiplatelet drugs in cancer was never examined. Aim: The goal of this study was to compare in a mouse model, development of the tumors and phenotypes of coagulation in absence or presence of an antiplatelet (Clopidogrel) or anticoagulant (Low Molecular Weight Heparin, LMWH) treatment. Materials and methods: A syngeneic ectopic model of cancer was induced in wild-type mice using the mouse pancreatic cancer cell line Panc02. Kinetics of thrombus formation and fibrin generation as a marker of the activation of the coagulation cascade were determined in real time by digital real time intravital microscopy in wild-type mice, mice bearing a tumor treated or not. The growth of the tumor was measured and compared in the different groups of mice. Results: A diminution of kinetics of tumor growth was observed in mice treated by the 2 drugs in comparison with non-treated mice. Twenty days following injection of cancer cells, the volume of the tumor was reduced by 85% and 87% when LMHW or Clopidogrel were used, respectively, indicating that both anticoagulant and anti-platelets drugs affect the kinetics of tumor growth. Following a laser-induced injury, platelets accumulate more rapidly at the site of injury and the thrombus reaches a more important size in mice developing a tumor in comparison with wild-type mice. This thrombotic phenotype disappears when mice were treated by Clopidogrel. Kinetics of thrombus formation was comparable in mice developing a tumor and treated by Clopidogrel versus wild type mice. Interestingly, whereas dosage used for LMWH and Clopidogrel were both calculated to decrease the size of the thrombus by 50% in wild type mice, treatment with LMWH significantly reduced kinetics of thrombus formation in mice bearing a tumor in comparison with wild-type mice. Also, we observed that cancer-cell derived microparticles interaction with a growing thrombus was prevented exclusively when mice were treated by Clopidogrel. The use of anti-platelets drug may thus constitute an alternative to treat cancer and thrombosis associated with cancer.
S161
CD227 (MUC-1) and 19% (0.62-41) with CD24, both markers of cancer cells (Fig. 1). Furthermore, 28% (11-63) of the TF-exposing MP stained for CD61, platelet glycoprotein IIIa, 3.9% (0.39-55) for the monocyte LPS-receptor (CD14), while 3.0% (1.4-3.5) of TF-MP stained for the erythrocyte marker CD235, and 0.97% (0.53-4.5) for the granulocyte marker CD66b.
Figure 1
Discussion: Levels of TF-exposing MP in cancer patients are higher than in healthy subjects. Strikingly, but not unexpectedly, we could not demonstrate a relationship between levels of TF-exposing MP and coagulant activity. Therefore, at least part of the TF exposed on circulating MP may be involved in other TF-dependent functions, such as angiogenesis or signal transduction. Most TF-exposing MP seem to originate from cancer cells, as they stained double positive with typical tumour cell markers such as CD227 and CD24. However, most TF-exposing MP also labelled positive for typical blood cell CD antigens, therefore these microparticles might be of mixed cellular origin, being shed after a tumour cell has incorporated blood cell characteristics. This phenomenon is specific rather than an artefact, since no double-labelling was observed with some markers such as CD235.
Plenary Session 8: Prevention and treatment of thrombosis OC-14 Cellular origin and procoagulant activity of tissue factor-exposing microparticles in cancer patients A. Kleinjan 1 , R.J. Berckmans 2 , A.N. Böing 2 , A. Sturk 2 , H.R. Büller 1 , P.W. Kamphuisen 1 , R. Nieuwland 2 Departments of 1 Vascular Medicine and 2 Clinical Chemistry, Academic Medical Center, Amsterdam, the Netherlands Background: In patients with cancer, tissue factor-exposing microparticles (TF-exposing MP) have been associated with disease progression and thrombosis. The cellular origin and coagulant activity of TF-exposing MP, however, remain disputed. Therefore, we investigated the cellular origin of the TF-exposing MP and the procoagulant activity in cancer patients. Methods: The cellular origin of TF-exposing MP was investigated by flow cytometry in a cohort of 209 cancer patients (59 pancreatic, 97 gastrointestinal, 23 breast, 15 lung, 5 prostate cancer and 10 other types), and 22 healthy controls. We first determined the numbers of TF-exposing MP in plasma from all patients and measured TF-exposing MP coagulant activity in a fibrin generation test. Based on previous results, a prolongation of the clotting time in the presence of an inhibitory antibody against factor VIIa above 13% was considered abnormal. Second, we selected those patients with numbers of TF-exposing MP above the 95th percentile, and determined the cellular origin of TF-exposing MP in these patients. Results: The numbers of TF-exposing MP were increased in the cancer patients compared to the healthy subjects (median: 2.0 vs 0.40×105 /mL; p=0.01). 30% of the cancer patients had an abnormal FGT test, indicating TF-exposing MP coagulant activity. There was no correlation between the number and coagulant activity of TF-exposing MP (r=0.029, p=0.685). 13 patients had TF-exposing MP above the 95th percentile. Of these TF-exposing MP, 5.9% (median; interquartile range (IQR) 0.69-54) double stained with
OC-15 Use of vena cava filters in cancer patients in California R.H. White, A. Brunson, S. Murin, D.J. Tancredi, T. Wun University of California, Davis, CA, USA Background: There are few studies that have reported how frequently inferior vena cava filters (IVCFs) are inserted in cancer patients together with information about the clinical indication(s) that led to IVCF placement. Methods: State of California Hospital discharge data was used to identify all cases discharged between Jan 1. 1996-Dec 31, 2009 that had both a cancer diagnosis (ICD-9-CM = 140-208.9 – except non melanoma skin cancer) and a first-time insertion of a IVCF (38.7). Cases were categorized based on presence of: 1) prior VTE, back to 1990; 2) definite-acute VTE, defined as either a principal diagnosis of acute VTE, or acute VTE first diagnosed during the hospital stay (present-on-admission flag = No), 3) probable-acute VTE, based on a secondary diagnose of VTE flagged as present-on-admission, 4) undergoing major surgery, and 5) timing of VCF insertion (before or after surgery). Cancer type was classified as low-VTE risk (head and neck, thyroid, etc.), high-VTE risk (pancreatic, gastric, leukemias, and metastatic cancers), and moderate VTE risk (all other non-metastatic cancers). Results: During the 14 year time period, 80,326 IVCFs were placed in patients hospitalized in California hospitals; 21,944 (27%) of these had cancer an: 55% of the cancer cases had high-VTE risk/metastatic cancer. Overall, IVCF use in cancer patients increased 3.1 fold from 748 in 1996 to 2342 in 2009. However, relative to total IVCF use, there was a modest but significant downward trend in the relative frequency of IVCF use in cancer patients, from ∼28-30% in 1997-2000 down to 25-26% in 2008-2009 (P<0.001). Among cases discharged between Jan 1, 2006 – Dec 31, 2008, 6117 IVCFs were placed in cases with cancer: 68% had high-VTE risk, 23%
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Abstracts / Thrombosis Research 129, Supplement 1 (2012) S155–S194
had moderate-VTE risk, and 9% had low-VTE risk cancers. The average age was 67 years; 52.3% were classified as having definite-acute VTE, 43.4% had probable-acute VTE, and the remainder had trauma or other indication. Twenty-four percent (1390/5852) of IVCF cases with definite or probable –acute VTE had a hemorrhage diagnosis. Thirty-one percent of these IVCF cases underwent major surgery during the admission, and among these, 67% had the filter inserted before surgery or on the day of surgery (55% of these had hospital-acquired acute VTE before the surgery), and 33% had the filter placed after surgery (37% of these had hospital-acquired acute-VTE). Overall, 60% of the patients died < 180 days after filter placement compared to 20% among the non-cancer cases that received a IVCF. Conclusions: The absolute number of IVCFs placed in cancer patients increased dramatically. In 2006-2009, 66% had high-VTE risk cancers, 95% had acute (or prior) VTE, 24% had bleeding and 60% died within 6 months. Clinical trials in cancer patients are needed to determine if use of IVCFs is more effective than standard care in improving survival and/or improving the morbidity associated with VTE.
OC-16 Incidence of venous thromboembolism in patients undergoing laparoscopic surgery for colorectal cancer M.C. Vedovati 1 , C. Becattini 1 , F. Rondelli 2 , M. Boncompagni 3 , G. Camporese 4 , R. Balzarotti 5 , E. Mariani 6 , O. Flamini 7 , G. Natalini 3 , G. Agnelli 1 1 Internal and Cardiovascular Medicine and Stroke Unit, University of Perugia; 2 Oncologic Surgery, University of Perugia; 3 General Surgery, S. Maria della Misericordia Hospital, Perugia; 4 Unit of Angiology, University Hospital of Padua; 5 General Surgery, Niguarda Hospital, Milan; 6 General Surgery, S. Giovanni Battista Hospital, Foligno; 7 Angiology, S. Giovanni Battista Hospital, Foligno, Italy Background: The incidence of venous thromboembolism (VTE) after laparoscopic surgery for cancer is unknown.
Methods: We performed a prospective multicenter study aimed at assessing the incidence of VTE in patients with colorectal cancer undergoing elective laparoscopic surgery. No restriction was given regarding measures for antithrombotic prophylaxis. Complete compression ultrasonography of the lower limbs was performed at 6 to 10 days after surgery. The primary outcome of the study was the incidence of any VTE at day 6 to 10 after surgery. Results: Overall, 237 consecutive patients were evaluated for inclusion in the study as for December 22nd, 2011. Four patients were excluded as surgery was converted to laparotomy. Thus, 233 patients were included in the study. Overall, 58% of the patients were males, the mean age was 65±11 years. Obesity was found in 8% (mean BMI 25±4), bed rest in 1% and previous venous thrombosis in 1%. Mean surgery duration was 180±78 minutes (range 60-540) and mean duration of post-surgical immobilization 33±22 hours. The most common type of cancer was adenocarcinoma (84% of the patients). All the included patients had prophylaxis with low molecular weight heparin from 12 hours after surgery to ultrasound assessment. After 6.4±2.3 days, 39 VTE were observed (16.7%), all deep vein thrombosis of the lower limbs. Thrombosis was symptomatic in 1 patient (0.5%) and proximal in 2 other patient (0.8%), for an overall incidence of major VTE of 1.3%. The remaining thrombosis were peroneal in 8 (3.4%), tibial in 7 (3.0%) and muscular in 21 (9.0%). A bilateral VTE was found in 9 patients (4.3%). After surgery, 1 patient had a major bleeding and one patient had a clinically relevant non-major bleeding. No correlation was observed between VTE and type of cancer, site of disease, age, gender, risk factors and comorbidities. Conclusion: Patients who had laparoscopic surgery for colorectal cancer have a substantial risk of developing VTE despite antithrombotic prophylaxis.
Trousseau, the association between thrombosis and cancer has been extensively documented. This disease constitutes one of the main cause of death during the evolution of the cancer and represents a major therapeutic problem. During the evolution of a tumor a procoagulant/thrombotic phenotype takes place conferring numerous advantages to the cancer cells. In mice, depletion of platelets form the bloodstream strongly affect the kinetics of tumor growth and the formation of experimental metastasis, suggesting that platelet activation is playing a key role in the development of a tumor. However to date, treatment using antiplatelet drugs in cancer was never examined. Aim: The goal of this study was to compare in a mouse model, development of the tumors and phenotypes of coagulation in absence or presence of an antiplatelet (Clopidogrel) or anticoagulant (Low Molecular Weight Heparin, LMWH) treatment. Materials and methods: A syngeneic ectopic model of cancer was induced in wild-type mice using the mouse pancreatic cancer cell line Panc02. Kinetics of thrombus formation and fibrin generation as a marker of the activation of the coagulation cascade were determined in real time by digital real time intravital microscopy in wild-type mice, mice bearing a tumor treated or not. The growth of the tumor was measured and compared in the different groups of mice. Results: A diminution of kinetics of tumor growth was observed in mice treated by the 2 drugs in comparison with non-treated mice. Twenty days following injection of cancer cells, the volume of the tumor was reduced by 85% and 87% when LMHW or Clopidogrel were used, respectively, indicating that both anticoagulant and anti-platelets drugs affect the kinetics of tumor growth. Following a laser-induced injury, platelets accumulate more rapidly at the site of injury and the thrombus reaches a more important size in mice developing a tumor in comparison with wild-type mice. This thrombotic phenotype disappears when mice were treated by Clopidogrel. Kinetics of thrombus formation was comparable in mice developing a tumor and treated by Clopidogrel versus wild type mice. Interestingly, whereas dosage used for LMWH and Clopidogrel were both calculated to decrease the size of the thrombus by 50% in wild type mice, treatment with LMWH significantly reduced kinetics of thrombus formation in mice bearing a tumor in comparison with wild-type mice. Also, we observed that cancer-cell derived microparticles interaction with a growing thrombus was prevented exclusively when mice were treated by Clopidogrel. The use of anti-platelets drug may thus constitute an alternative to treat cancer and thrombosis associated with cancer.
S161
CD227 (MUC-1) and 19% (0.62-41) with CD24, both markers of cancer cells (Fig. 1). Furthermore, 28% (11-63) of the TF-exposing MP stained for CD61, platelet glycoprotein IIIa, 3.9% (0.39-55) for the monocyte LPS-receptor (CD14), while 3.0% (1.4-3.5) of TF-MP stained for the erythrocyte marker CD235, and 0.97% (0.53-4.5) for the granulocyte marker CD66b.
Figure 1
Discussion: Levels of TF-exposing MP in cancer patients are higher than in healthy subjects. Strikingly, but not unexpectedly, we could not demonstrate a relationship between levels of TF-exposing MP and coagulant activity. Therefore, at least part of the TF exposed on circulating MP may be involved in other TF-dependent functions, such as angiogenesis or signal transduction. Most TF-exposing MP seem to originate from cancer cells, as they stained double positive with typical tumour cell markers such as CD227 and CD24. However, most TF-exposing MP also labelled positive for typical blood cell CD antigens, therefore these microparticles might be of mixed cellular origin, being shed after a tumour cell has incorporated blood cell characteristics. This phenomenon is specific rather than an artefact, since no double-labelling was observed with some markers such as CD235.
Plenary Session 8: Prevention and treatment of thrombosis OC-14 Cellular origin and procoagulant activity of tissue factor-exposing microparticles in cancer patients A. Kleinjan 1 , R.J. Berckmans 2 , A.N. Böing 2 , A. Sturk 2 , H.R. Büller 1 , P.W. Kamphuisen 1 , R. Nieuwland 2 Departments of 1 Vascular Medicine and 2 Clinical Chemistry, Academic Medical Center, Amsterdam, the Netherlands Background: In patients with cancer, tissue factor-exposing microparticles (TF-exposing MP) have been associated with disease progression and thrombosis. The cellular origin and coagulant activity of TF-exposing MP, however, remain disputed. Therefore, we investigated the cellular origin of the TF-exposing MP and the procoagulant activity in cancer patients. Methods: The cellular origin of TF-exposing MP was investigated by flow cytometry in a cohort of 209 cancer patients (59 pancreatic, 97 gastrointestinal, 23 breast, 15 lung, 5 prostate cancer and 10 other types), and 22 healthy controls. We first determined the numbers of TF-exposing MP in plasma from all patients and measured TF-exposing MP coagulant activity in a fibrin generation test. Based on previous results, a prolongation of the clotting time in the presence of an inhibitory antibody against factor VIIa above 13% was considered abnormal. Second, we selected those patients with numbers of TF-exposing MP above the 95th percentile, and determined the cellular origin of TF-exposing MP in these patients. Results: The numbers of TF-exposing MP were increased in the cancer patients compared to the healthy subjects (median: 2.0 vs 0.40×105 /mL; p=0.01). 30% of the cancer patients had an abnormal FGT test, indicating TF-exposing MP coagulant activity. There was no correlation between the number and coagulant activity of TF-exposing MP (r=0.029, p=0.685). 13 patients had TF-exposing MP above the 95th percentile. Of these TF-exposing MP, 5.9% (median; interquartile range (IQR) 0.69-54) double stained with
OC-15 Use of vena cava filters in cancer patients in California R.H. White, A. Brunson, S. Murin, D.J. Tancredi, T. Wun University of California, Davis, CA, USA Background: There are few studies that have reported how frequently inferior vena cava filters (IVCFs) are inserted in cancer patients together with information about the clinical indication(s) that led to IVCF placement. Methods: State of California Hospital discharge data was used to identify all cases discharged between Jan 1. 1996-Dec 31, 2009 that had both a cancer diagnosis (ICD-9-CM = 140-208.9 – except non melanoma skin cancer) and a first-time insertion of a IVCF (38.7). Cases were categorized based on presence of: 1) prior VTE, back to 1990; 2) definite-acute VTE, defined as either a principal diagnosis of acute VTE, or acute VTE first diagnosed during the hospital stay (present-on-admission flag = No), 3) probable-acute VTE, based on a secondary diagnose of VTE flagged as present-on-admission, 4) undergoing major surgery, and 5) timing of VCF insertion (before or after surgery). Cancer type was classified as low-VTE risk (head and neck, thyroid, etc.), high-VTE risk (pancreatic, gastric, leukemias, and metastatic cancers), and moderate VTE risk (all other non-metastatic cancers). Results: During the 14 year time period, 80,326 IVCFs were placed in patients hospitalized in California hospitals; 21,944 (27%) of these had cancer an: 55% of the cancer cases had high-VTE risk/metastatic cancer. Overall, IVCF use in cancer patients increased 3.1 fold from 748 in 1996 to 2342 in 2009. However, relative to total IVCF use, there was a modest but significant downward trend in the relative frequency of IVCF use in cancer patients, from ∼28-30% in 1997-2000 down to 25-26% in 2008-2009 (P<0.001). Among cases discharged between Jan 1, 2006 – Dec 31, 2008, 6117 IVCFs were placed in cases with cancer: 68% had high-VTE risk, 23%
S162
Abstracts / Thrombosis Research 129, Supplement 1 (2012) S155–S194
had moderate-VTE risk, and 9% had low-VTE risk cancers. The average age was 67 years; 52.3% were classified as having definite-acute VTE, 43.4% had probable-acute VTE, and the remainder had trauma or other indication. Twenty-four percent (1390/5852) of IVCF cases with definite or probable –acute VTE had a hemorrhage diagnosis. Thirty-one percent of these IVCF cases underwent major surgery during the admission, and among these, 67% had the filter inserted before surgery or on the day of surgery (55% of these had hospital-acquired acute VTE before the surgery), and 33% had the filter placed after surgery (37% of these had hospital-acquired acute-VTE). Overall, 60% of the patients died < 180 days after filter placement compared to 20% among the non-cancer cases that received a IVCF. Conclusions: The absolute number of IVCFs placed in cancer patients increased dramatically. In 2006-2009, 66% had high-VTE risk cancers, 95% had acute (or prior) VTE, 24% had bleeding and 60% died within 6 months. Clinical trials in cancer patients are needed to determine if use of IVCFs is more effective than standard care in improving survival and/or improving the morbidity associated with VTE.
OC-16 Incidence of venous thromboembolism in patients undergoing laparoscopic surgery for colorectal cancer M.C. Vedovati 1 , C. Becattini 1 , F. Rondelli 2 , M. Boncompagni 3 , G. Camporese 4 , R. Balzarotti 5 , E. Mariani 6 , O. Flamini 7 , G. Natalini 3 , G. Agnelli 1 1 Internal and Cardiovascular Medicine and Stroke Unit, University of Perugia; 2 Oncologic Surgery, University of Perugia; 3 General Surgery, S. Maria della Misericordia Hospital, Perugia; 4 Unit of Angiology, University Hospital of Padua; 5 General Surgery, Niguarda Hospital, Milan; 6 General Surgery, S. Giovanni Battista Hospital, Foligno; 7 Angiology, S. Giovanni Battista Hospital, Foligno, Italy Background: The incidence of venous thromboembolism (VTE) after laparoscopic surgery for cancer is unknown.
Methods: We performed a prospective multicenter study aimed at assessing the incidence of VTE in patients with colorectal cancer undergoing elective laparoscopic surgery. No restriction was given regarding measures for antithrombotic prophylaxis. Complete compression ultrasonography of the lower limbs was performed at 6 to 10 days after surgery. The primary outcome of the study was the incidence of any VTE at day 6 to 10 after surgery. Results: Overall, 237 consecutive patients were evaluated for inclusion in the study as for December 22nd, 2011. Four patients were excluded as surgery was converted to laparotomy. Thus, 233 patients were included in the study. Overall, 58% of the patients were males, the mean age was 65±11 years. Obesity was found in 8% (mean BMI 25±4), bed rest in 1% and previous venous thrombosis in 1%. Mean surgery duration was 180±78 minutes (range 60-540) and mean duration of post-surgical immobilization 33±22 hours. The most common type of cancer was adenocarcinoma (84% of the patients). All the included patients had prophylaxis with low molecular weight heparin from 12 hours after surgery to ultrasound assessment. After 6.4±2.3 days, 39 VTE were observed (16.7%), all deep vein thrombosis of the lower limbs. Thrombosis was symptomatic in 1 patient (0.5%) and proximal in 2 other patient (0.8%), for an overall incidence of major VTE of 1.3%. The remaining thrombosis were peroneal in 8 (3.4%), tibial in 7 (3.0%) and muscular in 21 (9.0%). A bilateral VTE was found in 9 patients (4.3%). After surgery, 1 patient had a major bleeding and one patient had a clinically relevant non-major bleeding. No correlation was observed between VTE and type of cancer, site of disease, age, gender, risk factors and comorbidities. Conclusion: Patients who had laparoscopic surgery for colorectal cancer have a substantial risk of developing VTE despite antithrombotic prophylaxis.