- Email: [email protected]
HEPARIN IN PREVENTION OF THROMBOSIS
327 factor is employed for the determination of the actual serumdigoxin levels in such patients. Digoxin and digitoxin values were determined in 14 patients receiving digitoxin, using commercially available kits for the R.I.A. of digoxin and digitoxin (Schwarz/Mann). A linear relationship was observed between the serumdigitoxin levels and their degree of cross-reaction with the digoxin values (see accompanying figure), with a correlation coefficient (r) of 0-884. The actual serum digoxin levels in patients on digoxin, but with residual digitoxin levels, therefore, can be calculated as follows: Da=Do-Di Di =0-0886 T Da =Do-0-0886 T Da: Actual digoxin level (ng./ml.). Di: Interference of digitoxin with R.I.A. of digoxin through cross-reaction (ng./ml.). Do: Digoxin level observed by R.I.A. of digoxin (ng./ml.). T: Digitoxin level assayed by R.I.A. of digitoxin (ng./ml.).
This approach may be helpful in the evaluation of digitoxin interference with digoxin levels in critical clinical conditions. °
Department of Pathology, University of Texas Medical Branch, Galveston, Texas 77550, U.S.A.
H. KUNO-SAKAI
H. SAKAI S. E. RITZMANN.
DUPUYTREN’S CONTRACTURE
SIR,-Your annotation (July 22, p. 170) states that this condition was first described by the Baron Dupuytren in 1834. However, earlier correspondence in these columns1 established that " the merit of having first demonstrated the true knowledge of this affection, is not at least to be attributed to the justly celebrated French surgeon ". Henry Cline, of St. Thomas’s Hospital, London, accurately described the nature and effective treatment of this contracture in 1808. Like your previous correspondent I have " no motive but the cause of truth in penning the above; I hope it will not be ascribed to any invidious feeling ". Plymouth General Hospital.
K. R. HUNTER.
down products will need
Regional Immunology Laboratory, East Birmingham Hospital, Birmingham 9.
easily detectable breakdown products in fresh plasma (predominantly a2D or C3d) have shown normal C3 catabolism. The possible explanations for this are dis-
Windsor, J. Lancet, 1833-34, ii, 501. Alper, C. A., Rosen, F. S. J. clin. Invest. 1967, 46, 2021. 3. Sliwinski, A. J., Zvaifler, N. J. Clin. exp. Immun. 1972, 11, 21. 4. Peters, D. K., Martin, Angela, Weinstein, A., Cameron, J. S., Barratt, T. M., Lachmann, P. J. ibid. p. 311. 1. 2.
out in to the other is
the same known.
R. A. THOMPSON.
surgery. Mr. Charnley has apparently abandoned this practice, because one patient died with severe haemoptysis. However, this patient was also receiving dextran. Not only can dextran per se cause serious bleeding, but in combination with heparin it might be expected to affect haemostasis, these two agents have a synergistic effect on the clotting system,! and, moreover, dextran reduces platelet aggregation and adhesiveness 2,3-mechanisms which are of prime importance in preventing bleeding in the heparinised patient. Indeed, in our heparin package-leaflet we warn against the concurrent administration of drugs which interfere with platelet aggregation. Furthermore, we would add that there is no reason to suppose that the Dale-
Laidlaw clotting-time test will reveal a haemostatic defect involving platelet function. It was disappointing to read that Mr. Charnley also experienced an incident of fatal pulmonary embolism in a heparinised patient (who was also receiving dextran), but this is consistent with the experience of others. 4,6 It seems that, while there can no longer be any reasonable doubt that prophylactic heparin, in its present form, is largely beneficial, its value in major hip surgery remains to be established. However, it is to be hoped that this particular issue will in no way obscure the careful work of others 6-11 who continue to demonstrate that, in general surgical
least, heparin provides considerable protection against damaging, and potentially lethal, postoperative complication.
patients
at
a
Weddel Pharmaceuticals Ltd.,
SHERRIDAN L. STOCK MICHAEL RADCLIFFE LEE.
HEPARIN IN PREVENTION OF THROMBOSIS
SiR,—The highly significant reports of Kakkar and his associates on the use of low-dose heparin for the prevention of postoperative thrombosis have evoked such a mass of correspondence that I hesitate to add to it. There are three factors, however, which have been ignored or skirted in their recent publications in The Lancet. 12, 13 The first is that the normal response of the clotting 1. 2. 3. 4. 5.
and
cussed in the references cited, but measurement of complement metabolism and in-vitro quantitation of break-
be carried
PROPHYLAXIS OF POSTOPERATIVE EMBOLISM were disturbed to read Mr. John Charnley’s. SIR,-We letter (July 15, p. 134) describing his experience with small doses of heparin given subcutaneously, pre- and postoperatively, to prevent the thromboembolic sequelae of
14 West Smithfield, London EC1A 9HY.
RAISED COMPLEMENT IN NEPHRITIS SIR,-Dr. Versey and his colleagues, in their comment (July 29, p. 229) on the paper by Dr. Gabriel and coworkers on serum hasmolytic complement levels in nephritis (July 8, p. 55), assert that the measurement of complement (C3 and C4) breakdown products by their crossed-electrophoresis technique is of greater value in patient management than measuring C3 and C4 levels themselves. They will undoubtedly provide evidence of this in due course. However, they imply that their measurements are an index of complement utilisation, and provide information comparable to the study of complement metabolism. There is no evidence that this is so. Quite apart from the argument over whether small quantities of breakdown products seen after electrophoresis are really present in vivo, or are in-vitro artefacts, studies 2-4 of patients with low C3 levels
to
patients before the relation of one
6. 7. 8. 9. 10.
11. 12. 13.
W. G., Brewer, S. S. Acta chir. scand. 1968, suppl. 387, p. 53. Dhall, D. P., Bennett, P. N., Matheson, N. A. ibid. p. 75. Bennett, P. N., Dhall, D. P., McKenzie, F. N., Matheson, N. A. Lancet, 1966, ii, 1001. Le Vay, D. ibid. July 29, 1972, p. 230. Kakkar, V. V., Corrigan, T., Spindler, J., Fossard, D. P., Flute, P. T., Crellin, R. Q., Wessler, S., Yin, E. T. ibid. July 15, 1972, p. 101. Sharnoff, J. G., Kass, H. H., Mistica, B. A. Surgery Gynec. Obstet. 1962, 115, 75. Sharnoff, J. G., DeBlasio, G. Lancet, 1970, ii, 1006. Kakkar, V. V., Field, E. S., Nicolaides, A. N., Flute, P. T., Wessler, S., Yin, E. T. ibid. 1971, ii, 669. Williams, H. T. ibid. p. 950. Gordon-Smith, I. C., Grundy, D. J., Le Quesne, L. P., Newcombe, J. F., Bramble, F. J. ibid. 1972, i, 1133. Nicolaides, A. N., et al. Br. J. Surg. (in the press). Lancet, 1971, ii, 669. ibid. July 15, 1972, p. 101.
Bloom,
328
equilibrium to stress is a prolongation of clotting-time, whether produced by adrenaline, corticotrophin, or surgical trauma. 14 The small doses of heparin given postoperatively can accentuate this physiological response and may in fact produce bleeding such as Mr. Charnley reports.15 This is the reason why we for many years-twenty to be exactused a sensitised clotting-time to measure the physiological This " anecdotal " experience led us to fluctuation. 16 administer subcutaneous heparin for three days before operation and not during or after it, using 200 units per kg. weight as a daily dose. In cases of massive trauma, the patient’s anticoagulant and fibrinolytic response can be readily followed by the heparin clotting-time without having to resort to time-consuming and expensive laboratory determinations not available to all clinicians. I am well aware of the wan smile or the raised eyebrow of the hsematologist, coagulationist, or fibrinolyticist. Where are the 13 clotting factors, where are the platelet factors, the fibrin split products ? Where are the coagulation profiles which are expanding by leaps and bounds ? Where is the negative charge of the red cells, where is platelet adhesiveness,
aggregation,
This
or
clumping ?
be an overall screening procedure applicable to large segments of the population in community hospitals or small group clinics. The second point is that the mast cells can truly be saturated by heparin and released by stressors such as corticotrophin and nitrogen mustard, and on surgical stress.17 This concept is vastly different from using small doses of heparin to inactivate the activated factor x or some test was meant to
other factors. I should therefore like to re-emphasise the concept of heparin tolerance 18 which varies not only between individuals but in the same individual from day to day. The bodily defence against thromboembolism can be most effectively bolstered by heparin, but the set dosage and the timing of administration may need modification to obtain even better results than have been reported. And finally, rather than stress the hypercoagulable postoperative state as we too have done in the past, it might be well to think about defective fibrinolysis as we have studied it with the heparin clotting-time before and after venous
stasis. 19
Rush-Presbyterian-St. Luke’s Medical Center, 1725 West Harrison Street, Chicago, Illinois 60612.
GEZA
DE
TAKATS.
RAISED SERUM-ALKALINE-PHOSPHATASE LEVELS IN POLYMYALGIA RHEUMATICA SIR,- I was very interested to read the letter of Dr. Hall and Dr. Hargreaves (July 1, p. 48), because I reported a similar finding to the 12th International Congress of Rheumatology in Prague in 1969 (abstract 440). I have now observed a raised serum-alkaline-phosphatase in approximately 30 patients with the polymyalgia-rheumatica syndrome, only 1 of whom had histologically confirmed cranial arteritis. In about 50% of the cases there was evidence of other hepatic dysfunction, especially a raised level of serum-5-nucleotidase. Some cases have had mitochondrial antibodies, but none have had overt liver disease. In only 1 case was a liver biopsy performed (after the acute phase was settling) and the findings were non-specific. There has been no evidence of the phosphatase being of bone
oricin.
In
all
cases
14. Surgery, St. Louis, 1952, 31, 13. 15. Lancet, July 15, 1972, p. 134. 16. J. Am. med. Ass. 1951, 146, 370. 17. Surgery, St. Louis, 1958, 44, 312. 18. Surgery Gynec. Obstet. 1943, 77, 31. 19. Surgery, St. Louis, 1971, 70, 318.
the
alkaline-nhosnhatase
improved and deteriorated in parallel with the erythrocytesedimentation rate, both improving dramatically when steroids were given. In my experience, in only a minority of cases of polymyalgia rheumatica is serum-alkaline-phosphatase raised (perhaps 20%) on presentation. I have been unable to find evidence as to whether the is just one manifestation of a primary " rheumatic " disorder, or whether the polymyalgia syndrome is sometimes a manifestation of primary biliary cirrhosis or other subclinical hepatic disease.
hepatic dysfunction
Department of Physical Medicine and Rheumatology, Chase Farm Hospital, Enfield, Middlesex EN2 8JL.
E. N. GLICK.
DIPLOMA IN TROPICAL CHILD HEALTH
SIR,-Obviously your comments1 on a new tropical diploma have stimulated responses from academicians mainly devoted to the teaching of medical graduates, mostly foreign, who apply for places in such courses. From the more modest position of a foreign doctor now holding two British tropical diplomas I would like to suggest that both sides of the controversy have valid points. Although I did not come from the " sterling area " it soon became apparent that some fellow students needed the etters, or at least the prestige of the certificate of attendance, either to consolidate their positions at home or to For some reason attempt to climb the ladder faster. memberships were particularly cherished. During my own limited experience I witnessed many interesting features, such as:
(a) " Developed ", inexperienced lecturers, themselves with outlook on international medical care and public health, attempting to educate more experienced, mature, travelled
a narrow
-
-
foreigners. (b) Foreign students whose trip and
course of study seemed the result of political or family pressures at home than of a genuine desire for learning or a reasonable fair award. These students tended to be less than highly proficient in English and demanded an easy curriculum which would reinforce their previous routines, assumptions, and knowledge. (c) At the same time many educational sequences were well established and illustrated with material accumulated over the years. They were well organised and displayed by experienced teachers and reliable laboratory and ancillary technical personnel. (d) Particularly gifted teachers who proved to be solid in their competence and genuine interest in the welfare of tropical peoples. As a counterpart, a few of the staff seemed to be more interested in leaving a good personal impression with the students. Perhaps they mainly cared about their own prestige and career advancement. (e) Some of us felt a constant undercurrent of a belief that no medical education could possibly match the excellence of British and some American or Commonwealth medical schools. (f) Many of us foreigners, nevertheless, found our professional and private lives enriched with the experience of studying and living in Britain.
be
to
more
In this context your correspondents point out rightly the useful aspects of tropical education in this country. the possibilities of abHowever, rather than increasing sorbing the expertise of " developed " countries in formal settings, could more resources be directed to basic and applied research in tropical problems ? This country of yours has an enormous wealth of scientifically trained personnel, competent technicians, and longestablished research facilities which many tropical countries are likely to match considerably later than the establishment and consolidation of indigenous formal courses. What can do more for the welfare of the impoverished masses in the tropics ? A single important scientific dis1.
Lancet, June 17, 1972, p. 1323; ibid. July 1, p. 28; ibid. July 15, p. 124.
This approach may be helpful in the evaluation of digitoxin interference with digoxin levels in critical clinical conditions. °
Department of Pathology, University of Texas Medical Branch, Galveston, Texas 77550, U.S.A.
H. KUNO-SAKAI
H. SAKAI S. E. RITZMANN.
DUPUYTREN’S CONTRACTURE
SIR,-Your annotation (July 22, p. 170) states that this condition was first described by the Baron Dupuytren in 1834. However, earlier correspondence in these columns1 established that " the merit of having first demonstrated the true knowledge of this affection, is not at least to be attributed to the justly celebrated French surgeon ". Henry Cline, of St. Thomas’s Hospital, London, accurately described the nature and effective treatment of this contracture in 1808. Like your previous correspondent I have " no motive but the cause of truth in penning the above; I hope it will not be ascribed to any invidious feeling ". Plymouth General Hospital.
K. R. HUNTER.
down products will need
Regional Immunology Laboratory, East Birmingham Hospital, Birmingham 9.
easily detectable breakdown products in fresh plasma (predominantly a2D or C3d) have shown normal C3 catabolism. The possible explanations for this are dis-
Windsor, J. Lancet, 1833-34, ii, 501. Alper, C. A., Rosen, F. S. J. clin. Invest. 1967, 46, 2021. 3. Sliwinski, A. J., Zvaifler, N. J. Clin. exp. Immun. 1972, 11, 21. 4. Peters, D. K., Martin, Angela, Weinstein, A., Cameron, J. S., Barratt, T. M., Lachmann, P. J. ibid. p. 311. 1. 2.
out in to the other is
the same known.
R. A. THOMPSON.
surgery. Mr. Charnley has apparently abandoned this practice, because one patient died with severe haemoptysis. However, this patient was also receiving dextran. Not only can dextran per se cause serious bleeding, but in combination with heparin it might be expected to affect haemostasis, these two agents have a synergistic effect on the clotting system,! and, moreover, dextran reduces platelet aggregation and adhesiveness 2,3-mechanisms which are of prime importance in preventing bleeding in the heparinised patient. Indeed, in our heparin package-leaflet we warn against the concurrent administration of drugs which interfere with platelet aggregation. Furthermore, we would add that there is no reason to suppose that the Dale-
Laidlaw clotting-time test will reveal a haemostatic defect involving platelet function. It was disappointing to read that Mr. Charnley also experienced an incident of fatal pulmonary embolism in a heparinised patient (who was also receiving dextran), but this is consistent with the experience of others. 4,6 It seems that, while there can no longer be any reasonable doubt that prophylactic heparin, in its present form, is largely beneficial, its value in major hip surgery remains to be established. However, it is to be hoped that this particular issue will in no way obscure the careful work of others 6-11 who continue to demonstrate that, in general surgical
least, heparin provides considerable protection against damaging, and potentially lethal, postoperative complication.
patients
at
a
Weddel Pharmaceuticals Ltd.,
SHERRIDAN L. STOCK MICHAEL RADCLIFFE LEE.
HEPARIN IN PREVENTION OF THROMBOSIS
SiR,—The highly significant reports of Kakkar and his associates on the use of low-dose heparin for the prevention of postoperative thrombosis have evoked such a mass of correspondence that I hesitate to add to it. There are three factors, however, which have been ignored or skirted in their recent publications in The Lancet. 12, 13 The first is that the normal response of the clotting 1. 2. 3. 4. 5.
and
cussed in the references cited, but measurement of complement metabolism and in-vitro quantitation of break-
be carried
PROPHYLAXIS OF POSTOPERATIVE EMBOLISM were disturbed to read Mr. John Charnley’s. SIR,-We letter (July 15, p. 134) describing his experience with small doses of heparin given subcutaneously, pre- and postoperatively, to prevent the thromboembolic sequelae of
14 West Smithfield, London EC1A 9HY.
RAISED COMPLEMENT IN NEPHRITIS SIR,-Dr. Versey and his colleagues, in their comment (July 29, p. 229) on the paper by Dr. Gabriel and coworkers on serum hasmolytic complement levels in nephritis (July 8, p. 55), assert that the measurement of complement (C3 and C4) breakdown products by their crossed-electrophoresis technique is of greater value in patient management than measuring C3 and C4 levels themselves. They will undoubtedly provide evidence of this in due course. However, they imply that their measurements are an index of complement utilisation, and provide information comparable to the study of complement metabolism. There is no evidence that this is so. Quite apart from the argument over whether small quantities of breakdown products seen after electrophoresis are really present in vivo, or are in-vitro artefacts, studies 2-4 of patients with low C3 levels
to
patients before the relation of one
6. 7. 8. 9. 10.
11. 12. 13.
W. G., Brewer, S. S. Acta chir. scand. 1968, suppl. 387, p. 53. Dhall, D. P., Bennett, P. N., Matheson, N. A. ibid. p. 75. Bennett, P. N., Dhall, D. P., McKenzie, F. N., Matheson, N. A. Lancet, 1966, ii, 1001. Le Vay, D. ibid. July 29, 1972, p. 230. Kakkar, V. V., Corrigan, T., Spindler, J., Fossard, D. P., Flute, P. T., Crellin, R. Q., Wessler, S., Yin, E. T. ibid. July 15, 1972, p. 101. Sharnoff, J. G., Kass, H. H., Mistica, B. A. Surgery Gynec. Obstet. 1962, 115, 75. Sharnoff, J. G., DeBlasio, G. Lancet, 1970, ii, 1006. Kakkar, V. V., Field, E. S., Nicolaides, A. N., Flute, P. T., Wessler, S., Yin, E. T. ibid. 1971, ii, 669. Williams, H. T. ibid. p. 950. Gordon-Smith, I. C., Grundy, D. J., Le Quesne, L. P., Newcombe, J. F., Bramble, F. J. ibid. 1972, i, 1133. Nicolaides, A. N., et al. Br. J. Surg. (in the press). Lancet, 1971, ii, 669. ibid. July 15, 1972, p. 101.
Bloom,
328
equilibrium to stress is a prolongation of clotting-time, whether produced by adrenaline, corticotrophin, or surgical trauma. 14 The small doses of heparin given postoperatively can accentuate this physiological response and may in fact produce bleeding such as Mr. Charnley reports.15 This is the reason why we for many years-twenty to be exactused a sensitised clotting-time to measure the physiological This " anecdotal " experience led us to fluctuation. 16 administer subcutaneous heparin for three days before operation and not during or after it, using 200 units per kg. weight as a daily dose. In cases of massive trauma, the patient’s anticoagulant and fibrinolytic response can be readily followed by the heparin clotting-time without having to resort to time-consuming and expensive laboratory determinations not available to all clinicians. I am well aware of the wan smile or the raised eyebrow of the hsematologist, coagulationist, or fibrinolyticist. Where are the 13 clotting factors, where are the platelet factors, the fibrin split products ? Where are the coagulation profiles which are expanding by leaps and bounds ? Where is the negative charge of the red cells, where is platelet adhesiveness,
aggregation,
This
or
clumping ?
be an overall screening procedure applicable to large segments of the population in community hospitals or small group clinics. The second point is that the mast cells can truly be saturated by heparin and released by stressors such as corticotrophin and nitrogen mustard, and on surgical stress.17 This concept is vastly different from using small doses of heparin to inactivate the activated factor x or some test was meant to
other factors. I should therefore like to re-emphasise the concept of heparin tolerance 18 which varies not only between individuals but in the same individual from day to day. The bodily defence against thromboembolism can be most effectively bolstered by heparin, but the set dosage and the timing of administration may need modification to obtain even better results than have been reported. And finally, rather than stress the hypercoagulable postoperative state as we too have done in the past, it might be well to think about defective fibrinolysis as we have studied it with the heparin clotting-time before and after venous
stasis. 19
Rush-Presbyterian-St. Luke’s Medical Center, 1725 West Harrison Street, Chicago, Illinois 60612.
GEZA
DE
TAKATS.
RAISED SERUM-ALKALINE-PHOSPHATASE LEVELS IN POLYMYALGIA RHEUMATICA SIR,- I was very interested to read the letter of Dr. Hall and Dr. Hargreaves (July 1, p. 48), because I reported a similar finding to the 12th International Congress of Rheumatology in Prague in 1969 (abstract 440). I have now observed a raised serum-alkaline-phosphatase in approximately 30 patients with the polymyalgia-rheumatica syndrome, only 1 of whom had histologically confirmed cranial arteritis. In about 50% of the cases there was evidence of other hepatic dysfunction, especially a raised level of serum-5-nucleotidase. Some cases have had mitochondrial antibodies, but none have had overt liver disease. In only 1 case was a liver biopsy performed (after the acute phase was settling) and the findings were non-specific. There has been no evidence of the phosphatase being of bone
oricin.
In
all
cases
14. Surgery, St. Louis, 1952, 31, 13. 15. Lancet, July 15, 1972, p. 134. 16. J. Am. med. Ass. 1951, 146, 370. 17. Surgery, St. Louis, 1958, 44, 312. 18. Surgery Gynec. Obstet. 1943, 77, 31. 19. Surgery, St. Louis, 1971, 70, 318.
the
alkaline-nhosnhatase
improved and deteriorated in parallel with the erythrocytesedimentation rate, both improving dramatically when steroids were given. In my experience, in only a minority of cases of polymyalgia rheumatica is serum-alkaline-phosphatase raised (perhaps 20%) on presentation. I have been unable to find evidence as to whether the is just one manifestation of a primary " rheumatic " disorder, or whether the polymyalgia syndrome is sometimes a manifestation of primary biliary cirrhosis or other subclinical hepatic disease.
hepatic dysfunction
Department of Physical Medicine and Rheumatology, Chase Farm Hospital, Enfield, Middlesex EN2 8JL.
E. N. GLICK.
DIPLOMA IN TROPICAL CHILD HEALTH
SIR,-Obviously your comments1 on a new tropical diploma have stimulated responses from academicians mainly devoted to the teaching of medical graduates, mostly foreign, who apply for places in such courses. From the more modest position of a foreign doctor now holding two British tropical diplomas I would like to suggest that both sides of the controversy have valid points. Although I did not come from the " sterling area " it soon became apparent that some fellow students needed the etters, or at least the prestige of the certificate of attendance, either to consolidate their positions at home or to For some reason attempt to climb the ladder faster. memberships were particularly cherished. During my own limited experience I witnessed many interesting features, such as:
(a) " Developed ", inexperienced lecturers, themselves with outlook on international medical care and public health, attempting to educate more experienced, mature, travelled
a narrow
-
-
foreigners. (b) Foreign students whose trip and
course of study seemed the result of political or family pressures at home than of a genuine desire for learning or a reasonable fair award. These students tended to be less than highly proficient in English and demanded an easy curriculum which would reinforce their previous routines, assumptions, and knowledge. (c) At the same time many educational sequences were well established and illustrated with material accumulated over the years. They were well organised and displayed by experienced teachers and reliable laboratory and ancillary technical personnel. (d) Particularly gifted teachers who proved to be solid in their competence and genuine interest in the welfare of tropical peoples. As a counterpart, a few of the staff seemed to be more interested in leaving a good personal impression with the students. Perhaps they mainly cared about their own prestige and career advancement. (e) Some of us felt a constant undercurrent of a belief that no medical education could possibly match the excellence of British and some American or Commonwealth medical schools. (f) Many of us foreigners, nevertheless, found our professional and private lives enriched with the experience of studying and living in Britain.
be
to
more
In this context your correspondents point out rightly the useful aspects of tropical education in this country. the possibilities of abHowever, rather than increasing sorbing the expertise of " developed " countries in formal settings, could more resources be directed to basic and applied research in tropical problems ? This country of yours has an enormous wealth of scientifically trained personnel, competent technicians, and longestablished research facilities which many tropical countries are likely to match considerably later than the establishment and consolidation of indigenous formal courses. What can do more for the welfare of the impoverished masses in the tropics ? A single important scientific dis1.
Lancet, June 17, 1972, p. 1323; ibid. July 1, p. 28; ibid. July 15, p. 124.