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SHOULD WE STAND ALL DAY?
81
with the Wiskott-Aldrich syndrome.28 The fact that leucocyte extracts can activate cellular immunity in patients who are congenitally deficient in T-lymphocytes suggests not only that the material is capable of supplying lymphocytes with certain receptor specificities but also that it may somehow promote differentiation of Tlymphocyte precursors. Alternatively, the leucocyte extracts could have an adjuvant activity8 capable of enhancing whatever underdeveloped cellularimmunity mechanisms such patients may possess. Thus it is not clear how far the clinical benefits of treatment with leucocyte extract depend on transfer of specific cellular immunity and how far they are due to non-specific activity of such extracts. It is indeed possible that both types of activity may be required for a clinical response. While leucocyte dialysates do not seem to have any serious side-effects,25 general use of T.F. in medical treatment is premature and clinical trials are urgently needed to define its place in the management of chronic infections and immunity-deficiency syndromes. One such trial in leprosy patients is now being conducted in collaboration with W.H.O., and in this trial T.F. from both lepromin-negative and lepromin-positive donors is used. More such trials, together with attempts at purification and basic research on the nature and mechanism of action of T.F., will be required before practical guidelines can be laid down for its clinical application. But if its early promise is fulfilled, the discovery of transfer factor could prove to have been a medical milestone. in
some
patients
SHOULD WE STAND ALL DAY?
JUST how much do venous stasis and blood hypercoagulability contribute to thrombosis ? And what of ’the third member of the triad-changes in the vessel wall ? Venous stasis is widely regarded as a major factor in deep venous thrombosis in hospital patients, international congress in Vienna last month Wright 29 pointed out that children and adults nowadays may be sitting for as much as ten hours a day. Thrombophlebitis is certainly underdiagnosed: in one series," 72% of 261 unselected necropsies revealed peripheral venous thrombosis. Certain postures-notably, sitting-can slow the circulation in the legs, 31and there is some evidence that prolonged stasis may activate the coagulation system. 3The main evidence that reduced blood-flow has a role is indirect
and
at an
I. S.
27. Mogerman, S. N., Levin, A. S., Spitler, L. E., Stites, D. P., Fudenberg, H. H., Shinefield, H. R. ibid. p. 310. 28. Spitler, L. E., Levin, A. S., Stites, D. P., Fudenberg, H. H., Pirofsky, B., August, C. S., Stiehm, E. R., Hitzig, W. H., Gatti, R. A. J. clin. Invest. 1972, 51, 3216. 29. Wright, I. S. Abst.IV int. Congr. Thromb. Hœmostasis, Vienna, 1973,
p.273. 30. 31. 32.
Havig, Ø. ibid. p. 274. Boyd, A. M., Catchpole, B. N., Jepson, R. P., Rose, S. S. J. Bone Jt Surg. 1952, 34B, 599. Marin, H. M., Lemieux, J., Mueller, L. Surgery Gynec. Obstet. 1961, 113, 293.
-the reduction of thrombosis achieved by early mobilisation and active physiotherapy after operation. Lately, intermittent pneumatic compression of the calf muscles during and after surgery has also been shown to reduce postoperative thrombosis, as assessed by the
1-nbrinogen test.33,34 Nevertheless, none of these precautions offers complete protection, and calf compression is valueless in patients with malignant disease. 33 Thus, venous stasis cannot be the whole answer.
Hypercoagulability of blood is a sequel to surgery, and several drugs prevent some of the coagulation changes. Slow-release heparin reduces deep venous thrombosis (as detected by125I-fibrinogen) both in general surgical patients 35 and in patients with acute myocardial infarction. 36 There is, however, an increased risk of wound haemorrhage, and one series of patients having operations for hip fracture seemed not to benefit at all.35 Acetylsalicylic acid, which in a dose of 1-5 g. daily inhibits platelet aggregation, reduces venous thrombosis but increases bleeding from a surgical wound. 371 Dextran 70 both inhibits platelet aggregation and improves peripheral blood-flow, and when given perioperatively it reduces the risk of venous thrombosis even in patients with malignant disease .31 But hsematoma and excessive oedema of the wound are more common than with other agents, and there may be allergic reactions. The large volumes of dextran recommended by some workers are contraindicated in patients with cardiac or renal failure.39 Changes in the vessel wall have received least attention. Vascular endothelium is known to release plasminogen activator’40,4and one suggestion is that damage to the vessel wall interferes with release of this fibrinolytic agent, thus allowing thrombosis to start. However, the sharp decrease in fibrinolytic activity immediately after operation does not correlate with subsequent venous thrombosis, 4 2 and stimulation of fibrinolytic activity with phenformin and ethylaestrenol, before and after operation, does not prevent thrombosis.433 None of the prophylactic measures for venous thrombosis provides complete protection without complications, and none seems suitable for routine use in all hospital patients. Furthermore, there is still no evidence that they reduce fatal pulmonary embolism. Thus, at present there is no complete explanation of the pathogenesis of venous thrombosis. Is Virchow’s triad still valid, after 120 years ? It has proved an invaluable concept, but perhaps we should now be looking harder at the normal vessel wall and at the biochemical responses of the body to trauma. 33.
34. 35. 36. 37. 38. 39. 40. 41. 42.
43.
Hills, N. H., Pflug, J. J., Jeyasingh, K., Boardman, L., Calnan, J. S. Br. med. J. 1972, i, 131. Ruckley, C. V., Clark, W. B., McGregor, A. B. M., Prescott, R. J. Abst. IV int. Congr. Thromb. Hœmostasis, Vienna, 1973, p. 282. Gallus, A. S., Hirsh, J., Turpie, A. G. G., Tuttle, R. ibid. p. 276. Warlow, C., Beattie, A. G., McIntosh, R., Terry, G., Ogston, D., Douglas, A. S. ibid. p. 275. Zekert, F., Kohn, P., Vormittag, E. ibid. p. 281. Bonnar, J., Walsh, J. J., Haddon, M. ibid. p. 278. Evarts, C. M. ibid. p. 279. Todd, A. S. J. Path. Bact. 1959, 78, 281. Warren, B. A. Br. J. exp. Path. 1963, 44, 365. Allan, N. C., Webber, R. G., Macintyre, I. M. C., Crispin, J. R., Ruckley, C. V. Abst. IV int. Congr. Thromb. Hœmostasis, Vienna, 1973, p. 163. Fossard, D. P., Corrigan, T. P., Field, E. S., Friend, J., Kakkar, V. V., Flute, P. T. ibid. p. 283.
with the Wiskott-Aldrich syndrome.28 The fact that leucocyte extracts can activate cellular immunity in patients who are congenitally deficient in T-lymphocytes suggests not only that the material is capable of supplying lymphocytes with certain receptor specificities but also that it may somehow promote differentiation of Tlymphocyte precursors. Alternatively, the leucocyte extracts could have an adjuvant activity8 capable of enhancing whatever underdeveloped cellularimmunity mechanisms such patients may possess. Thus it is not clear how far the clinical benefits of treatment with leucocyte extract depend on transfer of specific cellular immunity and how far they are due to non-specific activity of such extracts. It is indeed possible that both types of activity may be required for a clinical response. While leucocyte dialysates do not seem to have any serious side-effects,25 general use of T.F. in medical treatment is premature and clinical trials are urgently needed to define its place in the management of chronic infections and immunity-deficiency syndromes. One such trial in leprosy patients is now being conducted in collaboration with W.H.O., and in this trial T.F. from both lepromin-negative and lepromin-positive donors is used. More such trials, together with attempts at purification and basic research on the nature and mechanism of action of T.F., will be required before practical guidelines can be laid down for its clinical application. But if its early promise is fulfilled, the discovery of transfer factor could prove to have been a medical milestone. in
some
patients
SHOULD WE STAND ALL DAY?
JUST how much do venous stasis and blood hypercoagulability contribute to thrombosis ? And what of ’the third member of the triad-changes in the vessel wall ? Venous stasis is widely regarded as a major factor in deep venous thrombosis in hospital patients, international congress in Vienna last month Wright 29 pointed out that children and adults nowadays may be sitting for as much as ten hours a day. Thrombophlebitis is certainly underdiagnosed: in one series," 72% of 261 unselected necropsies revealed peripheral venous thrombosis. Certain postures-notably, sitting-can slow the circulation in the legs, 31and there is some evidence that prolonged stasis may activate the coagulation system. 3The main evidence that reduced blood-flow has a role is indirect
and
at an
I. S.
27. Mogerman, S. N., Levin, A. S., Spitler, L. E., Stites, D. P., Fudenberg, H. H., Shinefield, H. R. ibid. p. 310. 28. Spitler, L. E., Levin, A. S., Stites, D. P., Fudenberg, H. H., Pirofsky, B., August, C. S., Stiehm, E. R., Hitzig, W. H., Gatti, R. A. J. clin. Invest. 1972, 51, 3216. 29. Wright, I. S. Abst.IV int. Congr. Thromb. Hœmostasis, Vienna, 1973,
p.273. 30. 31. 32.
Havig, Ø. ibid. p. 274. Boyd, A. M., Catchpole, B. N., Jepson, R. P., Rose, S. S. J. Bone Jt Surg. 1952, 34B, 599. Marin, H. M., Lemieux, J., Mueller, L. Surgery Gynec. Obstet. 1961, 113, 293.
-the reduction of thrombosis achieved by early mobilisation and active physiotherapy after operation. Lately, intermittent pneumatic compression of the calf muscles during and after surgery has also been shown to reduce postoperative thrombosis, as assessed by the
1-nbrinogen test.33,34 Nevertheless, none of these precautions offers complete protection, and calf compression is valueless in patients with malignant disease. 33 Thus, venous stasis cannot be the whole answer.
Hypercoagulability of blood is a sequel to surgery, and several drugs prevent some of the coagulation changes. Slow-release heparin reduces deep venous thrombosis (as detected by125I-fibrinogen) both in general surgical patients 35 and in patients with acute myocardial infarction. 36 There is, however, an increased risk of wound haemorrhage, and one series of patients having operations for hip fracture seemed not to benefit at all.35 Acetylsalicylic acid, which in a dose of 1-5 g. daily inhibits platelet aggregation, reduces venous thrombosis but increases bleeding from a surgical wound. 371 Dextran 70 both inhibits platelet aggregation and improves peripheral blood-flow, and when given perioperatively it reduces the risk of venous thrombosis even in patients with malignant disease .31 But hsematoma and excessive oedema of the wound are more common than with other agents, and there may be allergic reactions. The large volumes of dextran recommended by some workers are contraindicated in patients with cardiac or renal failure.39 Changes in the vessel wall have received least attention. Vascular endothelium is known to release plasminogen activator’40,4and one suggestion is that damage to the vessel wall interferes with release of this fibrinolytic agent, thus allowing thrombosis to start. However, the sharp decrease in fibrinolytic activity immediately after operation does not correlate with subsequent venous thrombosis, 4 2 and stimulation of fibrinolytic activity with phenformin and ethylaestrenol, before and after operation, does not prevent thrombosis.433 None of the prophylactic measures for venous thrombosis provides complete protection without complications, and none seems suitable for routine use in all hospital patients. Furthermore, there is still no evidence that they reduce fatal pulmonary embolism. Thus, at present there is no complete explanation of the pathogenesis of venous thrombosis. Is Virchow’s triad still valid, after 120 years ? It has proved an invaluable concept, but perhaps we should now be looking harder at the normal vessel wall and at the biochemical responses of the body to trauma. 33.
34. 35. 36. 37. 38. 39. 40. 41. 42.
43.
Hills, N. H., Pflug, J. J., Jeyasingh, K., Boardman, L., Calnan, J. S. Br. med. J. 1972, i, 131. Ruckley, C. V., Clark, W. B., McGregor, A. B. M., Prescott, R. J. Abst. IV int. Congr. Thromb. Hœmostasis, Vienna, 1973, p. 282. Gallus, A. S., Hirsh, J., Turpie, A. G. G., Tuttle, R. ibid. p. 276. Warlow, C., Beattie, A. G., McIntosh, R., Terry, G., Ogston, D., Douglas, A. S. ibid. p. 275. Zekert, F., Kohn, P., Vormittag, E. ibid. p. 281. Bonnar, J., Walsh, J. J., Haddon, M. ibid. p. 278. Evarts, C. M. ibid. p. 279. Todd, A. S. J. Path. Bact. 1959, 78, 281. Warren, B. A. Br. J. exp. Path. 1963, 44, 365. Allan, N. C., Webber, R. G., Macintyre, I. M. C., Crispin, J. R., Ruckley, C. V. Abst. IV int. Congr. Thromb. Hœmostasis, Vienna, 1973, p. 163. Fossard, D. P., Corrigan, T. P., Field, E. S., Friend, J., Kakkar, V. V., Flute, P. T. ibid. p. 283.