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ARTERIAL-GRAFT PATENCY, PLATELET ADHESIVENESS, AND ANTICOAGULANTS
496
angiogram in our article. Macroscopically the shrivelled area of cavitary infarction looked orange-brown, and microscopic examination revealed abundant blood-pigment in the macro.. phage cells. These findings suggest that a hammrrhapc cerebral infarction was present, and had possibly resulted from restoration of circulation in a previously occluded (ischsmic; ;
territory.2* P. M. DALAL
Cerebrovascular Study Group, Central Research Laboratory, Bai Yamunabai Laxmanrao Nair Charitable Hospital, Bombay 8, India.
(a) Brain-specimen injected with Micropaque ’ showing shrivelled area
of cerebral infarction.
Arrows denote recanalised vessels
not seen
in first
antemortem
angiogram. A non-filling blood-vessel containing firmly adherent pearly-white material (? organised embolic fragment) is encircled. (b) Angiographic pattern of (a) on X-ray examination.
non-filling of the parietal branches of the left middle cerebral artery, and another cerebral angiogram, on the 8th day after the ictus, showed normal circulation (see fig. 3a and b in our article 1); this arterial recanalisation was thought to be the result of spontaneous embolic clot lysis. The patient made no significant recovery from his severe neurological deficit and was kept under observation in an infirmary. 2 years after the above incident, the patient complained of severe substernal pain, collapsed, and died instantaneously. Necropsy revealed an old anteroseptal myocardial infarction and an old renal infarction. In addition, there was an orangebrown cavitary area of softening in the central and cortical territories of the left middle cerebral artery; all cerebral vessels were patent and remarkably free from atherosclerosis. After ligation of the left anterior cerebral artery and the left posterior communicating branch of the posterior cerebral artery, a postmortem injection, under low pressure, revealed normal filling of the previously occluded branches of the left middle cerebral artery (figure a), as had been visualised in the second antemortem angiogram in our article with the vascular pattern of which this postmortem angiogram (figure b) agrees very
closely. We hope
that this information will clearly establish the fact restoration of angiographic circulation resulted from recanalisation of occluded vessels, rather than from retrograde collateral flow. In view of the extensive area of cerebral infarction, in the deep as well as the superficial cortical territories, it is logical to conclude that initially the embolus lodged in the stem of the left middle cerebral artery and subsequently migrated, after fragmentation, into the middle-cerebral branches, as was shown in the first antemortem that the
antemortem
P. M. SHAH C. K. DESHPANDE S. C. SHETH.
ARTERIAL-GRAFT PATENCY, PLATELET ADHESIVENESS, AND ANTICOAGULANTS SIR,-Mr. Evans and Professor Irvine (Aug. 13) do not takf into consideration the most recent findings on platelet adhesive. ness, and other very significant facts which are extremell important, particularly in vascular surgery. Prof. B. G. Shafiroff and 1,4 my own5 further studies to which I have referred previously,and my workwith Prof C. W. Lillehei, have shown that adenosine triphosphate (A.T.P,, is probably one of the most important activators of profibrinogenolysin and profibrinolysin, and therefore of fibrinolysis, The first breakdown product of A.T.P. is adenosine diphosphate (A.D.P.) ; Hardisty and Huttonhave shown that fibrinogenis a cofactor needed for A.D.P. to cause platelet aggregation, but without A.D.P. fibrinogen can cause this, as has been confirmed and amplified (independently at the same time) by Kopec et aJ,1 My co-workers and I have shown that A.T.P. not only dissolves the platelet clot, but reverses calcification in the vessel wall, and also prevents clot formation (this has been confirmed by others); this is also true of A.M.P. The two breakdown produce of A.T.P., A.D.P. and adenosine monophosphate (A.M.P.), can be converted to A.T.P. by phosphorylation-for this vitamin E in mixed form is needed (which is not presently available in England), and probably vitamin B(pyridoxine) can do this. The level of fibrinogen in plasma is most important in the aggregation of platelets, and the higher the level of fibrinogen the more rapid is the clot formation; with vascular disease have very high blood-fibrinogen values-levels of 8001600 mg. per 100 ml. have been observed in severe cases ina few hundred patients. Kay et al.10 in 1950 by using oc-tocopherol postoperativelyin major surgery in 238 patients were able to prevent, in all of them, formation of thrombi and emboli-these occurred in 18 (8%) of the patients, some of whom died, in a similar control group. Prof. B. G. Shafiroff and I have shown that vitamin E in mixed form, and certain ot-tocopherols are activators of profibrinogenolysin and profibrinolysin and together with other coenzymes, such as pyridoxine and nicotinic acid, have decalcified vessels and other tissues and reversed essend "
"
patients
’
hypertension in over 200 patients. Fatty meals of cholesterol and/or saturated fat and, as I 5 was the first to show, cigarette-smoke inhalation are inhibitors of fibrinolysis. It is now well established that heparin and other anticoagulants do not activate fibrinolysis and therefore cannot dissolve the clot, and cannot even prevent clot formation in certain cases-most probably when the fibrinogen level is above say 800 mg. per 100 ml.
Endarterectomy has
a
permanent
place in therapy of pen
Fisher, C. M., Adams, R. D. J. Neuropath. exp. Neurol. 1951, 10. 92 Dalal, P. M., Shah, P. M., Aiyar, R. R. Lancet, 1965, ii, 358. Misirlioglu, Y. I., Shafiroff, B. G. Circulation, 1964, 30, suppl. 3, pp 20, 22. 5. Misirlioglu, Y. I. Summary, 1964, 16, 67; Lecture given at the Univ Hospital, Brooklyn, New York, on June 18, 1964. 6. Misirlioglu, Y. I. Lancet, 1965, ii, 850; ibid. 1966, i, 821. 7. Misirlioglu, Y. I., Lillehei, C. W. Angiology, 1962, 13, 185; Thr Diath. hœmorrh. 1962, 8, 542; J. Am. med. Ass. 1963, 184, 211 8. Hardisty, R. M., Hutton, R. A. Nature, Lond. 1966, 210, 644. 9. Kopec, M., Budzynski, A., Stachurska, J., Wegrzynowiez, Z., Kowak E. Thromb. Diath. Hœmorrh. 1966, 15, 476. 10. Kay, J. H., Balla, G. A., Hutton, S. B., Ochsner, A. New Orl. surg. J. 1950, 103, 116. 2. 3. 4.
497 vascular disease-the patency of the vessels can be maintained by activators of fibrinolysis which are non-toxic, have no serious side-effects, and are very cheap in the United States. Y. I. MISIRLIOGLU.
pheral
FIRST-AID FOR HÆMORRHAGE SiR,—! was fortunate to be guided by Mr. London, whose letterappeared recently, in the treatment of haemorrhage, and my military experience confirms the value of his observations. In many cases of military wounds involving major arteries seen in the past year-e.g., wounds of subscapular, superior gluteal, anterior tibial, anterior femoral, peroneal, and iliac arteries= first-aid treatment by pressure over the bleeding-point was effective in all instances except the last, a gunshot wound which proved rapidly fatal. I would add, however, that the first field dressing used by the British Army is unsurpassed for this purpose. I would have thought that its use could be considered by civilian first-aiders. Military Hospital, Terendak, R. SCOTT. c/o G.P.O. Malacca, Malaysia.
A CLINICAL STUDY OF SURGICAL SHOCK SiR—Mr. Pierce (July 30) rightly points out the different effects of " dextran " and " low-molecular-weight dextran " (L.M.w.D.) on total peripheral resistance and the clotting mechanism. But patients in endotoxin shock-e.g., with peritonitis-are invariably hypovolmmic from dehydration. It would be dangerous to treat such patients with L.M.W.D. alone, since this would result in an extremely high urinary dextran concentration and urinary viscosity, with subsequent impairment of urine flow. These patients should first have their hypovolsmia corrected by the infusion of a dextran"with an clinical average molecular weight of about 70,000-e.g., dextran"(’ Macrodex ’), which remains in the circulation longer,’ and has an erythrocyte-aggregating capacity no greater than normal plasma,4 and hence would not unduly increase the total peripheral resistance. Having restored the blood-volume, L.M.W.D. may then be used to improve tissue perfusion by
lowering blood-viscosity. Brighton and Lewes Hospital Group, Brighton.
R. YEO.
PAIN IN OSTEOARTHRITIC JOINTS SiR,-Your leading article6 on osteoarthrosis, a similar communication last year, and the subsequent correspondence in these columns serve well to underline the present ignorance of pain mechanisms in the so-called degenerative processes which affect connective tissues. Because pain is the principal reason why patients with osteoarthritic joints seek medical aid, a deeper understanding of the mechanisms involved is highly desirable; such knowledge would allow a more scientific approach to treatment than is currently feasible. The available therapeutic armamentarium is based mainly on empirical
of widely different procedures pain relief. One clinical observation is
provide,
up to
a
point,
effective
pertinent to the problem. Not infrequently one sees patients who, on the first postoperative day after a high-femoral osteotomy, clearly state that their pain has completely disappeared. Usually patients can differentiate wound pain from their preoperative discomfort. This almost immediate relief of pain can hardly be attributed to such reasons as the short period of bed rest. It is difficult to reconcile this observation with the proposed theories of the mechanisms of pain in the osteoarthritic hip. Blood-vessels and their accompanying nerves will be divided at the site of the osteotomy, but those which enter the femoral head will be totally undamaged unless some form of nail-plate fixation is used. The acetabulum also is the site of pathological changes, however, and the vascular and nerve-supplies to this region are far removed from the surgical field in a conventional osteotomy. Theories of pain mechanisms in osteoarthritic joints will have to accommodate the obvious but often neglected fact that there are two sides to every articulation. The bewildering complexity of the problem is accentuated when one considers the postoperative course. Although there may be radiographic improvement (e.g., decrease in cyst size and increased joint-space) after highfemoral osteotomy, the hip-joint (both sides) remains arthritic, and yet a significant proportion of the patients have complete and apparently permanent relief of pain. Department of Orthopedics, University of Washington School of Medicine, T. K. F. TAYLOR. Seattle, Washington 98105.
FLUORIDES AND THE LOCOMOTOR SYSTEM
SIR,-Your editorial commenton my joint case-study of fluorosis with radiculomyelopathy2 prompts this reply on several issues. You posed the question: " Was the renal damage a consequence of anterior nerve-root pressure interfering with bladder control, or had longstanding renal disease caused the polyuria and polydipsia ? On his first admission to hospital, urological studies disclosed that the patient had a functional bladder-neck obstruction. The slightly abnormal results of urinary-tract function studies noted at this time did not change appreciably after a period of 12 years. If a significant pyelonephritis had existed before this initial examination, it seems likely that with the additive factors of obstruction and repeated infection a more rapid deterioration of renal function would have occurred during the subsequent 12-year interval. My colleagues and I would not argue the point, however, that the "
1. 2.
Lancet, 1966, i, 1194. Sauerbrunn, B. J. L., Ryan, C. M., Shaw, J. F. Ann. intern. Med. 1965, 63, 1074.
grounds. As far
as can be determined by clinical and radiological criteria, there are no detectable differences between the asymptomatic and the symptomatic osteoarthritic joint: histological, histochemical, and biochemical studies have provided similar negative results. The vertebral column often
presents
a
comparable enigma. This suggests that it is highly "
"
unlikely that a simple mechanism is responsible for pain in the osteoarthritic hip. Further, it is well known that a number 1. 2. 3.
London, P. S. Lancet, 1966, i, 1329. Bergentz, S. E., Falkheden, T., Olson, S. Ann. Surg. 1965, 161, 582. Gruber, V. F., Bergentz, S. E., Fritjofsson, A. Rheomacrodex— Reports of Symposia: vOL. I; p. 13. London, 1964. 4. Hint, H. ibid. p. 2.2. 5. Lancet, 1966, i, 1357. 6. ibid. 1965, i, 947.
Fluorosis in: (a) radius and ulna, showing striking bony overgrowth, thickening of cortex, and periosteal proliferation; (b) tibia and fibula, showing bony overgrowth and sclerotic excrescences.
angiogram in our article. Macroscopically the shrivelled area of cavitary infarction looked orange-brown, and microscopic examination revealed abundant blood-pigment in the macro.. phage cells. These findings suggest that a hammrrhapc cerebral infarction was present, and had possibly resulted from restoration of circulation in a previously occluded (ischsmic; ;
territory.2* P. M. DALAL
Cerebrovascular Study Group, Central Research Laboratory, Bai Yamunabai Laxmanrao Nair Charitable Hospital, Bombay 8, India.
(a) Brain-specimen injected with Micropaque ’ showing shrivelled area
of cerebral infarction.
Arrows denote recanalised vessels
not seen
in first
antemortem
angiogram. A non-filling blood-vessel containing firmly adherent pearly-white material (? organised embolic fragment) is encircled. (b) Angiographic pattern of (a) on X-ray examination.
non-filling of the parietal branches of the left middle cerebral artery, and another cerebral angiogram, on the 8th day after the ictus, showed normal circulation (see fig. 3a and b in our article 1); this arterial recanalisation was thought to be the result of spontaneous embolic clot lysis. The patient made no significant recovery from his severe neurological deficit and was kept under observation in an infirmary. 2 years after the above incident, the patient complained of severe substernal pain, collapsed, and died instantaneously. Necropsy revealed an old anteroseptal myocardial infarction and an old renal infarction. In addition, there was an orangebrown cavitary area of softening in the central and cortical territories of the left middle cerebral artery; all cerebral vessels were patent and remarkably free from atherosclerosis. After ligation of the left anterior cerebral artery and the left posterior communicating branch of the posterior cerebral artery, a postmortem injection, under low pressure, revealed normal filling of the previously occluded branches of the left middle cerebral artery (figure a), as had been visualised in the second antemortem angiogram in our article with the vascular pattern of which this postmortem angiogram (figure b) agrees very
closely. We hope
that this information will clearly establish the fact restoration of angiographic circulation resulted from recanalisation of occluded vessels, rather than from retrograde collateral flow. In view of the extensive area of cerebral infarction, in the deep as well as the superficial cortical territories, it is logical to conclude that initially the embolus lodged in the stem of the left middle cerebral artery and subsequently migrated, after fragmentation, into the middle-cerebral branches, as was shown in the first antemortem that the
antemortem
P. M. SHAH C. K. DESHPANDE S. C. SHETH.
ARTERIAL-GRAFT PATENCY, PLATELET ADHESIVENESS, AND ANTICOAGULANTS SIR,-Mr. Evans and Professor Irvine (Aug. 13) do not takf into consideration the most recent findings on platelet adhesive. ness, and other very significant facts which are extremell important, particularly in vascular surgery. Prof. B. G. Shafiroff and 1,4 my own5 further studies to which I have referred previously,and my workwith Prof C. W. Lillehei, have shown that adenosine triphosphate (A.T.P,, is probably one of the most important activators of profibrinogenolysin and profibrinolysin, and therefore of fibrinolysis, The first breakdown product of A.T.P. is adenosine diphosphate (A.D.P.) ; Hardisty and Huttonhave shown that fibrinogenis a cofactor needed for A.D.P. to cause platelet aggregation, but without A.D.P. fibrinogen can cause this, as has been confirmed and amplified (independently at the same time) by Kopec et aJ,1 My co-workers and I have shown that A.T.P. not only dissolves the platelet clot, but reverses calcification in the vessel wall, and also prevents clot formation (this has been confirmed by others); this is also true of A.M.P. The two breakdown produce of A.T.P., A.D.P. and adenosine monophosphate (A.M.P.), can be converted to A.T.P. by phosphorylation-for this vitamin E in mixed form is needed (which is not presently available in England), and probably vitamin B(pyridoxine) can do this. The level of fibrinogen in plasma is most important in the aggregation of platelets, and the higher the level of fibrinogen the more rapid is the clot formation; with vascular disease have very high blood-fibrinogen values-levels of 8001600 mg. per 100 ml. have been observed in severe cases ina few hundred patients. Kay et al.10 in 1950 by using oc-tocopherol postoperativelyin major surgery in 238 patients were able to prevent, in all of them, formation of thrombi and emboli-these occurred in 18 (8%) of the patients, some of whom died, in a similar control group. Prof. B. G. Shafiroff and I have shown that vitamin E in mixed form, and certain ot-tocopherols are activators of profibrinogenolysin and profibrinolysin and together with other coenzymes, such as pyridoxine and nicotinic acid, have decalcified vessels and other tissues and reversed essend "
"
patients
’
hypertension in over 200 patients. Fatty meals of cholesterol and/or saturated fat and, as I 5 was the first to show, cigarette-smoke inhalation are inhibitors of fibrinolysis. It is now well established that heparin and other anticoagulants do not activate fibrinolysis and therefore cannot dissolve the clot, and cannot even prevent clot formation in certain cases-most probably when the fibrinogen level is above say 800 mg. per 100 ml.
Endarterectomy has
a
permanent
place in therapy of pen
Fisher, C. M., Adams, R. D. J. Neuropath. exp. Neurol. 1951, 10. 92 Dalal, P. M., Shah, P. M., Aiyar, R. R. Lancet, 1965, ii, 358. Misirlioglu, Y. I., Shafiroff, B. G. Circulation, 1964, 30, suppl. 3, pp 20, 22. 5. Misirlioglu, Y. I. Summary, 1964, 16, 67; Lecture given at the Univ Hospital, Brooklyn, New York, on June 18, 1964. 6. Misirlioglu, Y. I. Lancet, 1965, ii, 850; ibid. 1966, i, 821. 7. Misirlioglu, Y. I., Lillehei, C. W. Angiology, 1962, 13, 185; Thr Diath. hœmorrh. 1962, 8, 542; J. Am. med. Ass. 1963, 184, 211 8. Hardisty, R. M., Hutton, R. A. Nature, Lond. 1966, 210, 644. 9. Kopec, M., Budzynski, A., Stachurska, J., Wegrzynowiez, Z., Kowak E. Thromb. Diath. Hœmorrh. 1966, 15, 476. 10. Kay, J. H., Balla, G. A., Hutton, S. B., Ochsner, A. New Orl. surg. J. 1950, 103, 116. 2. 3. 4.
497 vascular disease-the patency of the vessels can be maintained by activators of fibrinolysis which are non-toxic, have no serious side-effects, and are very cheap in the United States. Y. I. MISIRLIOGLU.
pheral
FIRST-AID FOR HÆMORRHAGE SiR,—! was fortunate to be guided by Mr. London, whose letterappeared recently, in the treatment of haemorrhage, and my military experience confirms the value of his observations. In many cases of military wounds involving major arteries seen in the past year-e.g., wounds of subscapular, superior gluteal, anterior tibial, anterior femoral, peroneal, and iliac arteries= first-aid treatment by pressure over the bleeding-point was effective in all instances except the last, a gunshot wound which proved rapidly fatal. I would add, however, that the first field dressing used by the British Army is unsurpassed for this purpose. I would have thought that its use could be considered by civilian first-aiders. Military Hospital, Terendak, R. SCOTT. c/o G.P.O. Malacca, Malaysia.
A CLINICAL STUDY OF SURGICAL SHOCK SiR—Mr. Pierce (July 30) rightly points out the different effects of " dextran " and " low-molecular-weight dextran " (L.M.w.D.) on total peripheral resistance and the clotting mechanism. But patients in endotoxin shock-e.g., with peritonitis-are invariably hypovolmmic from dehydration. It would be dangerous to treat such patients with L.M.W.D. alone, since this would result in an extremely high urinary dextran concentration and urinary viscosity, with subsequent impairment of urine flow. These patients should first have their hypovolsmia corrected by the infusion of a dextran"with an clinical average molecular weight of about 70,000-e.g., dextran"(’ Macrodex ’), which remains in the circulation longer,’ and has an erythrocyte-aggregating capacity no greater than normal plasma,4 and hence would not unduly increase the total peripheral resistance. Having restored the blood-volume, L.M.W.D. may then be used to improve tissue perfusion by
lowering blood-viscosity. Brighton and Lewes Hospital Group, Brighton.
R. YEO.
PAIN IN OSTEOARTHRITIC JOINTS SiR,-Your leading article6 on osteoarthrosis, a similar communication last year, and the subsequent correspondence in these columns serve well to underline the present ignorance of pain mechanisms in the so-called degenerative processes which affect connective tissues. Because pain is the principal reason why patients with osteoarthritic joints seek medical aid, a deeper understanding of the mechanisms involved is highly desirable; such knowledge would allow a more scientific approach to treatment than is currently feasible. The available therapeutic armamentarium is based mainly on empirical
of widely different procedures pain relief. One clinical observation is
provide,
up to
a
point,
effective
pertinent to the problem. Not infrequently one sees patients who, on the first postoperative day after a high-femoral osteotomy, clearly state that their pain has completely disappeared. Usually patients can differentiate wound pain from their preoperative discomfort. This almost immediate relief of pain can hardly be attributed to such reasons as the short period of bed rest. It is difficult to reconcile this observation with the proposed theories of the mechanisms of pain in the osteoarthritic hip. Blood-vessels and their accompanying nerves will be divided at the site of the osteotomy, but those which enter the femoral head will be totally undamaged unless some form of nail-plate fixation is used. The acetabulum also is the site of pathological changes, however, and the vascular and nerve-supplies to this region are far removed from the surgical field in a conventional osteotomy. Theories of pain mechanisms in osteoarthritic joints will have to accommodate the obvious but often neglected fact that there are two sides to every articulation. The bewildering complexity of the problem is accentuated when one considers the postoperative course. Although there may be radiographic improvement (e.g., decrease in cyst size and increased joint-space) after highfemoral osteotomy, the hip-joint (both sides) remains arthritic, and yet a significant proportion of the patients have complete and apparently permanent relief of pain. Department of Orthopedics, University of Washington School of Medicine, T. K. F. TAYLOR. Seattle, Washington 98105.
FLUORIDES AND THE LOCOMOTOR SYSTEM
SIR,-Your editorial commenton my joint case-study of fluorosis with radiculomyelopathy2 prompts this reply on several issues. You posed the question: " Was the renal damage a consequence of anterior nerve-root pressure interfering with bladder control, or had longstanding renal disease caused the polyuria and polydipsia ? On his first admission to hospital, urological studies disclosed that the patient had a functional bladder-neck obstruction. The slightly abnormal results of urinary-tract function studies noted at this time did not change appreciably after a period of 12 years. If a significant pyelonephritis had existed before this initial examination, it seems likely that with the additive factors of obstruction and repeated infection a more rapid deterioration of renal function would have occurred during the subsequent 12-year interval. My colleagues and I would not argue the point, however, that the "
1. 2.
Lancet, 1966, i, 1194. Sauerbrunn, B. J. L., Ryan, C. M., Shaw, J. F. Ann. intern. Med. 1965, 63, 1074.
grounds. As far
as can be determined by clinical and radiological criteria, there are no detectable differences between the asymptomatic and the symptomatic osteoarthritic joint: histological, histochemical, and biochemical studies have provided similar negative results. The vertebral column often
presents
a
comparable enigma. This suggests that it is highly "
"
unlikely that a simple mechanism is responsible for pain in the osteoarthritic hip. Further, it is well known that a number 1. 2. 3.
London, P. S. Lancet, 1966, i, 1329. Bergentz, S. E., Falkheden, T., Olson, S. Ann. Surg. 1965, 161, 582. Gruber, V. F., Bergentz, S. E., Fritjofsson, A. Rheomacrodex— Reports of Symposia: vOL. I; p. 13. London, 1964. 4. Hint, H. ibid. p. 2.2. 5. Lancet, 1966, i, 1357. 6. ibid. 1965, i, 947.
Fluorosis in: (a) radius and ulna, showing striking bony overgrowth, thickening of cortex, and periosteal proliferation; (b) tibia and fibula, showing bony overgrowth and sclerotic excrescences.