- Email: [email protected]
THROMBOTIC TENDENCY IN SYSTEMIC LUPUS ERYTHEMATOSUS
719 ALCOHOL AND NORMALITY
SIR,-Dr Marmot and his colleagues (March 14, p. 580) claim to show that "a moderate consumption of alcohol is associated with longevity but that small increases above that are associated with shortening of life". Their study does not justify this conclusion. They derive their data from a surveyl of male civil servants undertaken to test a quite different hypothesis, and their study suffers from all the defects inherent in trying to make data collected for one purpose serve another. Their estimate of alcohol consumption is taken from a postal survey of a sample of men who recorded the "food items" consumed over a three-day period (Sunday, Monday, and Tuesday). Would any epidemiologist set out to estimate the daily alcohol consumption of the British man without including Saturday night? Marmot et al. concede that "Heavy bias would arise if heavy drinkers failed to report their use of alcohol". If? Is it not more than likely that they would? Admitting the possibility that a bias exists does not absolve investigators from their responsibility of avoiding it, and, if they cannot because they are processing old data, then surely they should stop there. They tell us that a "quadratic relationship" accounts for the differences in mortality between categories of alcohol consumption (table I). Since thereis no significant difference in mortality between categories in the 40-49-year-old age group, I presume that this relationship refers only to the 838 men in the 50-59 and 60-64 age groups, of whom 88 died over the 10 years of the follow-up. Had Marmot et al. set out to test the hypothesis that "consumption of a moderate amount of alcohol is associated with longevity", would they have settled for (and would we have accepted) such a very small sample on which to base conclusions? To end their report by suggesting that their results support a "safe limit" of consumption of 35 g of alcohol a day is preposterous. Their results may deserve reporting briefly, as a spur to a proper study, but to hallow them by publication as an Original Article in The Lancet means not only that they will be cited as definitive but also that there will inevitably be popular headlines of the "Doctors say a Pint is Good for You" variety. Perhaps this is just the sort of smokescreen the Tobacco Research Council, who paid for the study, wanted in order to divert the public’s attention from the damage done by cigarette smoking. Health Centre,
Newport, Dyfed SA42 0TJ
depleted intraplatelet serotoninand large platelet-aggregating immune complexes in sera of these patients. Platelet aggregation thresholds for ADP and collagen were normal, but that for AA strikingly reduced (p<0 0 1) compared with healthy control and patients with minimal change nephropathy. The ability of plasma to generate PGI2-like activity was normal in fifteen of sixteen patients without lupus anticoagulant but plasma from two of three patients with lupus anticoagulant showed a marked defect in ability to stimulate PGI2 production, as reported by Carreras et al. These data suggest that an important thrombotic tendency is present in most lupus patients in association with degranulated and serotonin-depleted platelets even when a nephrotic syndrome is not present. In addition, a few patients demonstrate reduced ability to generate PGI2 from endothelium, as reported in the case of Carreras et al. These two abnormalities, if present together (for example, in patients with lupus "anticoagulant"), could lead to clinically important thrombosis, as described by Carreras et al. and Slater. The possibility arises that the reduced threshold for platelet aggregation induced by AA may result from change in platelet membrane lipids, occurring as a result of immune complex-platelet We have found
J. C. BIGNALL
THROMBOTIC TENDENCY IN SYSTEMIC LUPUS ERYTHEMATOSUS
SIR,-The paper by Dr Carreras and colleagues (Jan. 31, p. 244) and Dr Slater’s letter (Feb. 14, p. 393) are of great interest. Thrombosis is a well known complication of systemic lupus erythematosus (SLE) with2 or without3 the anti-phospholipid "lupus" anticoagulant, and Kant et al. have demonstrated that glomerular capillary thrombi are the best histological prognostic index in lupus nephritis. In an investigation to be published elsewhere we studied twentythree patients with SLE and nephritis, none of whom were either nephrotic or uraemic, including three patients with "lupus" anticoagulant.5We measured aggregation thresholds of peripheral blood platelets to ADP, collagen, and arachidonic acid (AA), intraplatelet serotonin concentrations, the ability of plasma to stimulate prostacyclin (PGI2) like activity from rat aortic rings, and the presence of circulating platelet-aggregating immune complexes. 1 Reid
DD, Bret GZ, Hamilton PJS, Jarrett RJ, Keen H, Rose G. Cardiorespiratory disease and diabetes among middle-aged male civil servants: a study of screening and intervention. Lancet 1974, i: 469-73. 2 Mueh JR, Herbst KD, Rappaport SS. Thrombosis in patients with the lupus anticoagulant. Ann Intern Med 1980; 92: 159. 3. Dubois EL. Systemic lupus erythematosus. Los Angeles: University of Southern California Press, 1976. 4. Kant KS, Pollak VE, Weiss MA, Glueck HI, Miller MA, Hess EV. Glomerular thrombosis in systemic lupus erythematosus: Prevalence and significance. Medicim
(Baltimore) (in press). 5 Williams H, Laurent R, Gibson T. The lupus coagulation inhibitor and venous thrombosis. a report of four cases. Clin Lab Haematol 1980; 2: 139-44
amounts of
interaction in the circulation. In support of this suggestion, we found a strong correlation between the titre of platelet-aggregating immune complexes in serum and the threshold for irreversible platelet aggregation in response to AA, in our patients with SLE. As suggested by Slater, such patients might benefit from antiplatelet therapy. In four out of five additional patients with lupus nephritis who were on antiplatelet agents (four on dipyridamole, 10 mg/kg over 24 h in three doses, one on indomethacin 100 mg in 24 h) we observed a normal (one patient) or increased (three patients) platelet aggregation threshold for AA. Renal Unit,
Guy’s Hospital, London SE1 9RT; Division of Nephrology and Dialysis,
Ospedale Riuniti, Bergamo, Italy; and Mario Negri Institute, Milan
D. MARCHESI A. PARBTANI G. FRAMPTON M. LIVIO G. REMUZZI J. S. CAMERON
EFFECT OF DIPYRIDAMOLE ON PROTEINURIA OF NEPHROTIC SYNDROME
SiR,-Bang et al.1 suggested that enhanced platelet aggregation in glomerular renal disease may arise as a consequence of loss in the urine of plasma proteins responsible for inhibition of aggregation. Yoshida and Aoki found that the main mechanism responsible for the potentation of platelet aggregation is the release of arachidonic acid from platelet membrane phospholipids via activation of phospholipase A2, and enhanced platelet aggregation in the nephrotic syndrome was at least partly attributable to an increased availability of2 arachidonic acid released secondary to hypo-
albuminaemia.2
We wondered if dipyridamole (’Persantin’; Boehringer Ingelheim) would be of value in this situation: this drug inhibits platelet aggregation,3the release reaction, and biosynthesis ofthromboxane A2 in platelets.4 Dipyridamole could thus have an inhibitory effect in proteinuria. In a serologically well stabilised case of lupus nephritis dipyridamole brought about a prompt, unequivocal remission of a
6. Parbtani
A, Frampton G, Yewdall V, Kasai N, Cameron JS. Platelet and plasma serotonin concentrations in glomerulonephritis III. The nephritis of systemic lupus erythematosus. Clin Nephrol 1980; 14: 164-72. 7. Kasai N, Parbtani A, Yewdall V, Shepherd P, Verroust P, Cameron JS. Platelet aggregating immune complexes in glomerulonephritis. Clin Exp Immunol 1981; 43: 64-72. 1. Bang NU, Trygstad CW, Schroeder JE, Heidenreich RO, Csiscko BM. Enhanced platelet function in glomerular renal disease. J Lab Clin Med 1973, 81: 651-60. 2. Yoshida N, Aoki N. Release of arachidonic acid from human platelets: a key role for the potentiation of platelet aggregability in normal subjects as well as in those with nephrotic syndrome Blood 1978; 52: 969-77. 3. Emmons PR, Harrison MJG, Honour AJ. Effect of dipyridamole on human platelet behaviour. Lancet 1965; ii: 603-06. 4. Best LC, McGuire MB, Jones PBB, Holland TK, Preston FE, Segal DS, Russell RGG. Mode of action of dipyridamole on human platelets. Thrombos Res 1979, 16: 367-79.
SIR,-Dr Marmot and his colleagues (March 14, p. 580) claim to show that "a moderate consumption of alcohol is associated with longevity but that small increases above that are associated with shortening of life". Their study does not justify this conclusion. They derive their data from a surveyl of male civil servants undertaken to test a quite different hypothesis, and their study suffers from all the defects inherent in trying to make data collected for one purpose serve another. Their estimate of alcohol consumption is taken from a postal survey of a sample of men who recorded the "food items" consumed over a three-day period (Sunday, Monday, and Tuesday). Would any epidemiologist set out to estimate the daily alcohol consumption of the British man without including Saturday night? Marmot et al. concede that "Heavy bias would arise if heavy drinkers failed to report their use of alcohol". If? Is it not more than likely that they would? Admitting the possibility that a bias exists does not absolve investigators from their responsibility of avoiding it, and, if they cannot because they are processing old data, then surely they should stop there. They tell us that a "quadratic relationship" accounts for the differences in mortality between categories of alcohol consumption (table I). Since thereis no significant difference in mortality between categories in the 40-49-year-old age group, I presume that this relationship refers only to the 838 men in the 50-59 and 60-64 age groups, of whom 88 died over the 10 years of the follow-up. Had Marmot et al. set out to test the hypothesis that "consumption of a moderate amount of alcohol is associated with longevity", would they have settled for (and would we have accepted) such a very small sample on which to base conclusions? To end their report by suggesting that their results support a "safe limit" of consumption of 35 g of alcohol a day is preposterous. Their results may deserve reporting briefly, as a spur to a proper study, but to hallow them by publication as an Original Article in The Lancet means not only that they will be cited as definitive but also that there will inevitably be popular headlines of the "Doctors say a Pint is Good for You" variety. Perhaps this is just the sort of smokescreen the Tobacco Research Council, who paid for the study, wanted in order to divert the public’s attention from the damage done by cigarette smoking. Health Centre,
Newport, Dyfed SA42 0TJ
depleted intraplatelet serotoninand large platelet-aggregating immune complexes in sera of these patients. Platelet aggregation thresholds for ADP and collagen were normal, but that for AA strikingly reduced (p<0 0 1) compared with healthy control and patients with minimal change nephropathy. The ability of plasma to generate PGI2-like activity was normal in fifteen of sixteen patients without lupus anticoagulant but plasma from two of three patients with lupus anticoagulant showed a marked defect in ability to stimulate PGI2 production, as reported by Carreras et al. These data suggest that an important thrombotic tendency is present in most lupus patients in association with degranulated and serotonin-depleted platelets even when a nephrotic syndrome is not present. In addition, a few patients demonstrate reduced ability to generate PGI2 from endothelium, as reported in the case of Carreras et al. These two abnormalities, if present together (for example, in patients with lupus "anticoagulant"), could lead to clinically important thrombosis, as described by Carreras et al. and Slater. The possibility arises that the reduced threshold for platelet aggregation induced by AA may result from change in platelet membrane lipids, occurring as a result of immune complex-platelet We have found
J. C. BIGNALL
THROMBOTIC TENDENCY IN SYSTEMIC LUPUS ERYTHEMATOSUS
SIR,-The paper by Dr Carreras and colleagues (Jan. 31, p. 244) and Dr Slater’s letter (Feb. 14, p. 393) are of great interest. Thrombosis is a well known complication of systemic lupus erythematosus (SLE) with2 or without3 the anti-phospholipid "lupus" anticoagulant, and Kant et al. have demonstrated that glomerular capillary thrombi are the best histological prognostic index in lupus nephritis. In an investigation to be published elsewhere we studied twentythree patients with SLE and nephritis, none of whom were either nephrotic or uraemic, including three patients with "lupus" anticoagulant.5We measured aggregation thresholds of peripheral blood platelets to ADP, collagen, and arachidonic acid (AA), intraplatelet serotonin concentrations, the ability of plasma to stimulate prostacyclin (PGI2) like activity from rat aortic rings, and the presence of circulating platelet-aggregating immune complexes. 1 Reid
DD, Bret GZ, Hamilton PJS, Jarrett RJ, Keen H, Rose G. Cardiorespiratory disease and diabetes among middle-aged male civil servants: a study of screening and intervention. Lancet 1974, i: 469-73. 2 Mueh JR, Herbst KD, Rappaport SS. Thrombosis in patients with the lupus anticoagulant. Ann Intern Med 1980; 92: 159. 3. Dubois EL. Systemic lupus erythematosus. Los Angeles: University of Southern California Press, 1976. 4. Kant KS, Pollak VE, Weiss MA, Glueck HI, Miller MA, Hess EV. Glomerular thrombosis in systemic lupus erythematosus: Prevalence and significance. Medicim
(Baltimore) (in press). 5 Williams H, Laurent R, Gibson T. The lupus coagulation inhibitor and venous thrombosis. a report of four cases. Clin Lab Haematol 1980; 2: 139-44
amounts of
interaction in the circulation. In support of this suggestion, we found a strong correlation between the titre of platelet-aggregating immune complexes in serum and the threshold for irreversible platelet aggregation in response to AA, in our patients with SLE. As suggested by Slater, such patients might benefit from antiplatelet therapy. In four out of five additional patients with lupus nephritis who were on antiplatelet agents (four on dipyridamole, 10 mg/kg over 24 h in three doses, one on indomethacin 100 mg in 24 h) we observed a normal (one patient) or increased (three patients) platelet aggregation threshold for AA. Renal Unit,
Guy’s Hospital, London SE1 9RT; Division of Nephrology and Dialysis,
Ospedale Riuniti, Bergamo, Italy; and Mario Negri Institute, Milan
D. MARCHESI A. PARBTANI G. FRAMPTON M. LIVIO G. REMUZZI J. S. CAMERON
EFFECT OF DIPYRIDAMOLE ON PROTEINURIA OF NEPHROTIC SYNDROME
SiR,-Bang et al.1 suggested that enhanced platelet aggregation in glomerular renal disease may arise as a consequence of loss in the urine of plasma proteins responsible for inhibition of aggregation. Yoshida and Aoki found that the main mechanism responsible for the potentation of platelet aggregation is the release of arachidonic acid from platelet membrane phospholipids via activation of phospholipase A2, and enhanced platelet aggregation in the nephrotic syndrome was at least partly attributable to an increased availability of2 arachidonic acid released secondary to hypo-
albuminaemia.2
We wondered if dipyridamole (’Persantin’; Boehringer Ingelheim) would be of value in this situation: this drug inhibits platelet aggregation,3the release reaction, and biosynthesis ofthromboxane A2 in platelets.4 Dipyridamole could thus have an inhibitory effect in proteinuria. In a serologically well stabilised case of lupus nephritis dipyridamole brought about a prompt, unequivocal remission of a
6. Parbtani
A, Frampton G, Yewdall V, Kasai N, Cameron JS. Platelet and plasma serotonin concentrations in glomerulonephritis III. The nephritis of systemic lupus erythematosus. Clin Nephrol 1980; 14: 164-72. 7. Kasai N, Parbtani A, Yewdall V, Shepherd P, Verroust P, Cameron JS. Platelet aggregating immune complexes in glomerulonephritis. Clin Exp Immunol 1981; 43: 64-72. 1. Bang NU, Trygstad CW, Schroeder JE, Heidenreich RO, Csiscko BM. Enhanced platelet function in glomerular renal disease. J Lab Clin Med 1973, 81: 651-60. 2. Yoshida N, Aoki N. Release of arachidonic acid from human platelets: a key role for the potentiation of platelet aggregability in normal subjects as well as in those with nephrotic syndrome Blood 1978; 52: 969-77. 3. Emmons PR, Harrison MJG, Honour AJ. Effect of dipyridamole on human platelet behaviour. Lancet 1965; ii: 603-06. 4. Best LC, McGuire MB, Jones PBB, Holland TK, Preston FE, Segal DS, Russell RGG. Mode of action of dipyridamole on human platelets. Thrombos Res 1979, 16: 367-79.