- Email: [email protected]
Coagulation, angiogenesis, and venous thromboembolism in cancer
CORRESPONDENCE
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are Americans being sold? Lancet 2001; 358: 1141–46. Dal-Pizzol F, Silva T, Schenkel EP. Adequacy of drug advertisements distributed to prescribers in Southern Brazil. Cad Saude Publica 1998; 14: 85–91. Criterios eticos para la promoción de medicamentos. Geneva: WHO, 1988. Dal-Pizzol F, Silva T, Schenkel EP. Quality of drug advertisements in medical journals. Acta Farm Bonaerense 1999; 18: 69–74. Heineck I, Gallina S, Silva T, Dal-Pizzol F, Schenkel EP. Analysis of non-prescription drug radio advertisement in Rio Grande do Sul State, Brazil. Cad Saude Publica 1998; 14: 193–98.
Doctors and torture after Sept 11 Sir—We agree with your Nov 24 editorial,1 in which you ask whether the developed world still takes human rights seriously. You draw attention to Newsweek columnist, Jonathan Alter, who has suggested it is time to think about torture. Short of physical torture, terrorists should be subjected to psychological torture, and the Federal Bureau of Investigation be allowed to use sodium pentothal (the so-called truth serum).2 We point to another worrying feature of this discussion that you do not mention: medical involvement in torture. In the shameful history of torture, doctors have had a mainly passive role. Alter now actually advocates a new and active role of doctors, psychologists, and medical methods. Irrespective of ethical issues, there is no evidence for a rationale in torture. On the contrary, torture was abolished in Austria in 1776, after the physician Ferdinand Leber had proven the unreliability of testimony made under torture.3 From an ethical point of view, the 1975 Declaration of Tokyo of the World Medical Association is very clear: no medical participation in torture. Medical involvement in criminal prosecution and law enforcement is in danger of loosening ethical limits. First, medical equipment replaced the electric chair, and now it is suggested that proscribed methods of torture should be replaced by injections and psychology. Times are definitely difficult, but thinking about torture and medical involvement in torture will only make things worse. It is time for all doctors to firmly say no. *Georg Röggla, Hannelore Röggla *Municipal Hospital of Neunkirchen, 2620 Neunkirchen, Austria; and Department of Medical Psychology, University of Vienna, Vienna, Austria (e-mail: [email protected])
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The Lancet. Does the western world still take human rights seriously? Lancet 2001; 358: 1741. Alter J. Time to think about torture. Newsweek 2001; 139: 45. Maio G. History of medical involvement in torture. Lancet 2001; 357: 1609–11.
Coagulation, angiogenesis, and venous thromboembolism in cancer Sir—Angiogenesis holds a prominent position in the evolution and natural history of neoplastic diseases, and plays an important part in nutritional support and metastatic spread of tumour cells. The angiogenic process is tightly regulated with the balanced action of tens of different growth factors and other molecules, including various factors of the coagulation system. Many cancer patients have hypercoagulability disorders that cause substantial morbidity and mortality. We wonder whether the mechanisms underlying tumour angiogenesis and venous thromboembolism in cancer are distinct or just two sides of the same coin? What are the exact causes of hypercoagulability in cancer? Although the role of the clotting system (including platelets) in formation of new blood vessels has been elucidated,1 little is known about the exact connection between angiogenesis and venous thromboembolism in cancer and the factors precipitating the clinical presentation of hypercoagulability disorders in cancer patients. One possible link lies in the biochemical pathway of angiostatin synthesis from plasminogen. Prostatecancer cells, for example, produce urokinase type-plasminogen activator and prostate-specific antigen that drive the proteolysis of plasminogen to plasmin, which is subsequently converted to angiostatin resulting in inadequate plasmin-mediated fibrinolytic activity.2 Similarly, antithrombin acts as an inhibitor of angiogenesis only after its carboxyl-terminal loop, necessary for its anticoagulant activity, has been cleaved,3 and this mechanism might result in impaired inactivation of thrombin. However, these mechanisms provide just a piece of the puzzle; for instance, angiostatin is not produced by all tumours. Moreover, various angiogenic factors regulate the synthesis of clotting factors (eg, vascular endothelial growth factor induces tissue-factor expression),
which might exacerbate the hypercoagulable state. From the other side, clotting factors promote the angiogenic process, for example via thrombinmediated transcriptional activation of hypoxia-inducible factor-1-␣ which drives the synthesis of VEGF and a second recently-described vascularspecific growth factor, EG-VEGF (endocrine gland-VEGF).1,4 Is hypercoagulability in cancer patients the result of excessive activation of angiogenic factors (eg, when VEGF turns on tissue factor gene)? Or does it reflect an effort to limit tumour development, through the production of angiogenic inhibitors, by cleaving plasminogen and antithrombin? Perhaps the truth lies at the interface between these two possible mechanisms. Nevertheless, whatever the role of the clotting system in tumour angiogenesis or in venous thromboembolism in cancer may be, anticoagulant administration might be efficient to treat hypercoagulability disorders and down-regulate angiogenesis. The risk of developing new cancer in the first 2 years of anticoagulant use is low.5 Maybe anticoagulants could be tested in combination with chemotherapy. *Eleftherios I Agorogiannis, George I Agorogiannis University of Thessaly Medical School, 41222 Larissa, Greece (e-mail: [email protected]) 1 2
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Carmeliet P. Clotting factors build blood vessels. Science 2001; 293: 1602–04. Gately S, Twardowski P, Stack MS, et al. The mechanism of cancer-mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin. Proc Natl Acad Sci USA 1997; 94: 10868–72. O’Reilly MS, Pirie-Shepherd S, Lane WS, Folkman J. Antiangiogenic activity of the cleaved conformation of the serpin antithrombin. Science 1999; 285: 1926–28. LeCouter J, Kowalski J, Foster J, et al. Identification of an angiogenic mitogen selective for endocrine gland endothelium. Nature 2001; 412: 877–84. Schulman S, Lindmarker P. Incidence of cancer after prophylaxis with warfarin against recurrent venous thromboembolism. N Engl J Med 2000; 342: 1953–58.
Read, write, and rewrite Sir—Ruth Charon’s advice to a newly qualified doctor—read, write, read, write—in her Feb 16 Lifeline, will encourage verbosity. Doctors, young and old, should be advised instead to read, write, and rewrite. Jeremy Hugh Baron Gastroenterology Division, Mount Sinai School of Medicine, Box 1069, New York, NY 10029, USA (e-mail: [email protected])
THE LANCET • Vol 359 • April 20, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
2
3 4
5
are Americans being sold? Lancet 2001; 358: 1141–46. Dal-Pizzol F, Silva T, Schenkel EP. Adequacy of drug advertisements distributed to prescribers in Southern Brazil. Cad Saude Publica 1998; 14: 85–91. Criterios eticos para la promoción de medicamentos. Geneva: WHO, 1988. Dal-Pizzol F, Silva T, Schenkel EP. Quality of drug advertisements in medical journals. Acta Farm Bonaerense 1999; 18: 69–74. Heineck I, Gallina S, Silva T, Dal-Pizzol F, Schenkel EP. Analysis of non-prescription drug radio advertisement in Rio Grande do Sul State, Brazil. Cad Saude Publica 1998; 14: 193–98.
Doctors and torture after Sept 11 Sir—We agree with your Nov 24 editorial,1 in which you ask whether the developed world still takes human rights seriously. You draw attention to Newsweek columnist, Jonathan Alter, who has suggested it is time to think about torture. Short of physical torture, terrorists should be subjected to psychological torture, and the Federal Bureau of Investigation be allowed to use sodium pentothal (the so-called truth serum).2 We point to another worrying feature of this discussion that you do not mention: medical involvement in torture. In the shameful history of torture, doctors have had a mainly passive role. Alter now actually advocates a new and active role of doctors, psychologists, and medical methods. Irrespective of ethical issues, there is no evidence for a rationale in torture. On the contrary, torture was abolished in Austria in 1776, after the physician Ferdinand Leber had proven the unreliability of testimony made under torture.3 From an ethical point of view, the 1975 Declaration of Tokyo of the World Medical Association is very clear: no medical participation in torture. Medical involvement in criminal prosecution and law enforcement is in danger of loosening ethical limits. First, medical equipment replaced the electric chair, and now it is suggested that proscribed methods of torture should be replaced by injections and psychology. Times are definitely difficult, but thinking about torture and medical involvement in torture will only make things worse. It is time for all doctors to firmly say no. *Georg Röggla, Hannelore Röggla *Municipal Hospital of Neunkirchen, 2620 Neunkirchen, Austria; and Department of Medical Psychology, University of Vienna, Vienna, Austria (e-mail: [email protected])
1440
1
2 3
The Lancet. Does the western world still take human rights seriously? Lancet 2001; 358: 1741. Alter J. Time to think about torture. Newsweek 2001; 139: 45. Maio G. History of medical involvement in torture. Lancet 2001; 357: 1609–11.
Coagulation, angiogenesis, and venous thromboembolism in cancer Sir—Angiogenesis holds a prominent position in the evolution and natural history of neoplastic diseases, and plays an important part in nutritional support and metastatic spread of tumour cells. The angiogenic process is tightly regulated with the balanced action of tens of different growth factors and other molecules, including various factors of the coagulation system. Many cancer patients have hypercoagulability disorders that cause substantial morbidity and mortality. We wonder whether the mechanisms underlying tumour angiogenesis and venous thromboembolism in cancer are distinct or just two sides of the same coin? What are the exact causes of hypercoagulability in cancer? Although the role of the clotting system (including platelets) in formation of new blood vessels has been elucidated,1 little is known about the exact connection between angiogenesis and venous thromboembolism in cancer and the factors precipitating the clinical presentation of hypercoagulability disorders in cancer patients. One possible link lies in the biochemical pathway of angiostatin synthesis from plasminogen. Prostatecancer cells, for example, produce urokinase type-plasminogen activator and prostate-specific antigen that drive the proteolysis of plasminogen to plasmin, which is subsequently converted to angiostatin resulting in inadequate plasmin-mediated fibrinolytic activity.2 Similarly, antithrombin acts as an inhibitor of angiogenesis only after its carboxyl-terminal loop, necessary for its anticoagulant activity, has been cleaved,3 and this mechanism might result in impaired inactivation of thrombin. However, these mechanisms provide just a piece of the puzzle; for instance, angiostatin is not produced by all tumours. Moreover, various angiogenic factors regulate the synthesis of clotting factors (eg, vascular endothelial growth factor induces tissue-factor expression),
which might exacerbate the hypercoagulable state. From the other side, clotting factors promote the angiogenic process, for example via thrombinmediated transcriptional activation of hypoxia-inducible factor-1-␣ which drives the synthesis of VEGF and a second recently-described vascularspecific growth factor, EG-VEGF (endocrine gland-VEGF).1,4 Is hypercoagulability in cancer patients the result of excessive activation of angiogenic factors (eg, when VEGF turns on tissue factor gene)? Or does it reflect an effort to limit tumour development, through the production of angiogenic inhibitors, by cleaving plasminogen and antithrombin? Perhaps the truth lies at the interface between these two possible mechanisms. Nevertheless, whatever the role of the clotting system in tumour angiogenesis or in venous thromboembolism in cancer may be, anticoagulant administration might be efficient to treat hypercoagulability disorders and down-regulate angiogenesis. The risk of developing new cancer in the first 2 years of anticoagulant use is low.5 Maybe anticoagulants could be tested in combination with chemotherapy. *Eleftherios I Agorogiannis, George I Agorogiannis University of Thessaly Medical School, 41222 Larissa, Greece (e-mail: [email protected]) 1 2
3
4
5
Carmeliet P. Clotting factors build blood vessels. Science 2001; 293: 1602–04. Gately S, Twardowski P, Stack MS, et al. The mechanism of cancer-mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin. Proc Natl Acad Sci USA 1997; 94: 10868–72. O’Reilly MS, Pirie-Shepherd S, Lane WS, Folkman J. Antiangiogenic activity of the cleaved conformation of the serpin antithrombin. Science 1999; 285: 1926–28. LeCouter J, Kowalski J, Foster J, et al. Identification of an angiogenic mitogen selective for endocrine gland endothelium. Nature 2001; 412: 877–84. Schulman S, Lindmarker P. Incidence of cancer after prophylaxis with warfarin against recurrent venous thromboembolism. N Engl J Med 2000; 342: 1953–58.
Read, write, and rewrite Sir—Ruth Charon’s advice to a newly qualified doctor—read, write, read, write—in her Feb 16 Lifeline, will encourage verbosity. Doctors, young and old, should be advised instead to read, write, and rewrite. Jeremy Hugh Baron Gastroenterology Division, Mount Sinai School of Medicine, Box 1069, New York, NY 10029, USA (e-mail: [email protected])
THE LANCET • Vol 359 • April 20, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.