- Email: [email protected]
CHRONIC INTERSTITIAL CYSTITIS AND SUBCUTANEOUS HEPARIN
1010 fell. Surprisingly, the CBZ level was essentially unchanged. Patsalos et al conclude that the side-effects were induced by CBZ-E rather than by CBZ itself. A contribution from the other drugs was not considered. CBZ side-effects are seen over a wide range of plasma drug concentrations and have been associated with plasma levels well in patients on within the so-called therapeutic range,2 combined antiepileptic drug therapy, and these adverse reactions are not related to high levels of CBZ-E. 2,4 It is surprising that a reduction in CBZ dose should have led to a selection decrease in CBZ-E concentration. The elimination half life of the epoxide after administration is considerably shorter than that of CBZ. The epoxide level during CBZ therapy depends on the rate of epoxidation of the parent drug and the rate of elimination of the metabolite. After a dose reduction of CBZ, plasma CBZ-E levels should parallel those of CBZ.5,6 In individuals the ratio between the plasma levels of the epoxide and parent drug is
especially
(a) % neutrophils containing any E coh. (b) Phagocytic mdex=(a) x mean number ofE co/ per neutrophil. Reaction medium was 3001’1 Hanks balanced salt solution, 501’1 fresh autologous serurr (complement source) containing 6010’ E cob and 310" human neutrophils. 50 Nl o either normal serum, anti-LPS gammaglobulin diluted 1:160 or normal gammaglobulir diluted 1: 160 was added and mixtures mcubated for 30 min at 37°C with gentle agitation Smears were stained with Glemsa stain and counted. Statistical analyses by paired t test- *p<0’05 compared with normal serum, **p<0’001 1 compared with normal serum and p>0-001 compared with normal IgG, tp>0-0’ compared with normal serum, :f:p
constant.7 assess
the
phagocytosis
of Escherichia coli
8
by human neutrophils
(table). Neutrophils
present in the medium lacking any IgG always had both the lowest number of ingested E coli and phagocytotic index. The medium containing LG-1 always produced the highest ingestion rate, with neutrophils in the medium containing normal human IgG (known to contain small amounts of anti-LPS IgG) having intermediate values. These findings show that in addition to destroying bacteria by complement activation, anti-LPs also increases the uptake of bacteria by phagocytic cells. The sera of some patients with gram-negative bacteraemia lacked anti-O antibodies (the main component of anti-LPS) and were also incapable of stimulating neutrophils to ingest autologous gramnegative bacteria, under conditions strongly implying a cause-andeffect relationship.9 The anti-LPS gammaglobulin used here is easily prepared by any medium-sized blood bank and may provide the anti-gram-negative bacterial antibodies lacking in such bacteraemic patients.
Supported by grants from the South African Medical Research Council. Departments of Medicine and Physiology. University of Natal, Congella 4013, South Africa; and Natal Institute of Immunology
D. PUDIFIN I. L’HOSTE J. DUURSMA S. L. GAFFIN
E, Pitsoe SB, Gaffin SL. Anti-lipopolysaccharide immunotherapy in the management of septic shock of obstetrical and gynaecological origin. Lancet 1984; i:
At the time of the CBZ dose reduction, there was a small decrease in the phenytoin dose (from 350 to 325 mg daily). This might have caused a significant fall in plasma phenytoin concentration. Phenytoin induces the epoxidation of CBZ8 and the metabolism of CBZ might have been induced to different degrees at the two phenytoin levels. If the phenytoin levels were very different on the two doses, some of the side-effects might have been due to this drug. Earlier attempts to evaluate the effects of CBZ epoxide during CBZ therapy have led to conflicting results.The most reliable assessments of the clinical effects of CBZ epoxide can be obtained by giving the epoxide to man. The metabolite been given to healthy volunteers in single doses up to 200 mg and as monotherapy to patients with trigeminal neuralgia in doses up to 1000 mg daily.9 No side-effects were observed despite peak plasma levels of CBZ-E up to 16 jamolll, which is considerably higher than the threshold for side-effects of 9 mol/1 suggested by Patsalos et al. The side-effects observed in the patient of Patsalos et al were probably due to the complex antiepileptic drug therapy. The role of CBZ-E is unclear.
has
Department of Neurology, Söder Hospital, Stockholm
TORBJÖRN TOMSON
Department of Clinical Pharmacology, Karolinska Institute, Huddinge Hospital, S-141 86 Huddinge, Sweden
LEIF BERTILSSON
1. Lachman
981-83. 2 Gaffin SL, Wells MT, Jordaan J Antilipopolysaccharide toxin therapy for whole body X-irradiation overdose. Br J Radiol (in press). 3 Zanotti AM, Gaffin SL Prophylaxis of superior mesenteric artery occlusion shock in rabbits by antilipopolysaccharide (anti-LPS) antibodies. J Surg Res 1985, 38: 113-15. 4 Gaffin SL, Robins-Browne R, Cooper R, Gregory M, Badsha N, Brock-Utne JG, Vorster BJ antibiotic effect of human and equine antiendotoxin antibody rich serum Klebsiella pneumoniae. S Afr J Sci 1982; 78: 91-92. 5. Welsh NH, Rauch A, Gaffin SL. Topical immunotherapy for pseudomonas keratitis in rabbits use of anti-lipopolysaccharide plasma. Br J Ophthalmol 1984; 8: 828-32. 6. Gaffin SL, Badsha N, Vorster BJ Properties of human lipopolysaccharide gamma globulin. specificity and protective effects. Vox Sang 1985; 48: 276-83. 7. Gaffin SL. Large-scale production of anti-negative bacterial antibodies. Lancet 1983; ii: 1420-21. 8. Van Furth R, Leijh PC, Klein F. Correlation between opsonic activity for various microorganisms and composition of gamma globulin preparations for intravenous use. J Infect Dis 1984; 149: 511-17. 9. Weinstein RJ, Young LS. Neutrophil function in gram negative rod bacteremia. The interaction between phagocytic cells, infecting organisms and humoral factors. J Clin Invest 1976; 58: 190-99.
SIDE-EFFECTS OF CARBAMAZEPINE: DRUG OR METABOLITE?
SiR,-Dr Patsalos and colleagues (Aug 31, p 496) describe
acute
a patient on combination therapy with phenytoin, carbamazepine (CBZ), and phenobarbitone. Plasma levels were said to be within the "therapeutic range", but we know of no controlled studies that establish such ranges during combination therapy.i
side-effects in
When the CBZ dose was lowered the side-effects diminished and the plasma concentration of the epoxide metabolite of CBZ (CBZ-E)
1.
Sjöqvist F Therapeutic drug monitoring: Twenty years’ experience. In: Lemberger L,
Reidenberg MM, eds. Proceedings of the Second World Conference on Clinical Pharmacology and Therapeutics. Bethesda: American Society of Pharmacology and Experimental Therapeutics, 1984: 38-63. 2. Rapeport WG. Factors influencing the relationship between carbamazepine plasma concentration and its clinical effects in patients with epilepsy, Clin Neuropharmacol 1985; 8: 141-49. 3. Kutt H, Solomon G, Wasterlain C, et al. Carbamazepine in difficult to control outpatients. Acta Neurol Scand 1975; 60 (suppl): 27-32. 4. Tomson T. Interdosage fluctuations in plasma carbamazepine concentration determine intermittent side effects. Acta Neural 1984; 41: 830-34. 5. Tomson T, Tybring G, Bertilsson L. Single-dose kinetics and metabolism of carbamazepine-10,11-epoxide. Clin Pharmacol Ther 1983; 33: 58-65 6. Rowland M, Tozer TN. Clinical pharmacokinetics: Concepts and applications. Philadelphia: Lea and Febiger, 1980. 7. Tomson T, Tybring G, Bertilsson L, Ekbom K, Rane A. Carbamazepine therapy in trigeminal neuralgia: Clinical effects in relation to plasma concentration. Arch Neurol 1980; 37: 699-703. 8. Eichelbaum M, Tomson T, Tybring G, Bertilsson L. Carbamazepine metabolism in man: Induction and pharmacogenetic aspects. Clin Pharmacokin 1985; 10: 80-90. 9. Tomson T, Bertilsson L. Potent therapeutic effect of carbamazepine-10,11-epoxide in trigeminal neuralgia. Arch Neurol 1984; 41: 598-601.
CHRONIC INTERSTITIAL CYSTITIS AND SUBCUTANEOUS HEPARIN
SIR,-Your July 20 editorial takes a pessimistic view of the current empirical methods of treatment of chronic interstitial cystitis (IC). The causes of IC remain elusive. However, the bladder lesions suggest an inflammatory process followed by extensive fibrosis as a major factor in the clinical manifestations. In this disease there be a stage of injury to the tissues of the bladder wall folby a response dominated by defective tissue repair, as suggested by deposits of fibrin on the surface of the lesions. These seems
lowed
to
1011
layers of fibrin provide a matrix for the migration and proliferation of cells participating in repair (fibroblasts and angioblasts, and certain white cells when there is an added inflammatory reaction). The retention of layers of fibrin for a long time impairs diffusion of nutrients to the connective tissue under repair, leading to incomplete repair with extensive fibrosis and scar formation 1,2 associated with disruption of adjacent layers of muscle cells and nerves, which is expressed clinically during relapses. One way to prevent this sequence might be to limit the deposition of fibrin to the amount sufficient for primary wound healing. One approach would then be to delay the formation of fibrin in a manner similar to that successfully introduced in the treatment and prophylaxis of thrombotic disorders.3 This reasoning, together with experience gained in the treatment of thrombosis-prone individuals and in patients with subcutaneous heparin,4-6prompted an attempt to treat IC with subcutaneous heparin. Pilot studies 7,8 in small groups of selected patients suggest this to be a promising approach, inviting confirmatory studies in larger series. For example, discontinuation of treatment produced a clinical relapse followed by remission when heparin administration was resumed. Section of
Coagulation and Fibrinolysis, Department of Clinical Chemistry, and Section for Thrombosis Research, South Jutland University Centre, DK-6700 Esbjerg, Denmark
high doses of heparin given intravenously could provoke a decrease and even a deficiency of plasma antithrombin III; they presumed that the low AT-III levels might induce thromboembolic episodes after cessation of heparin therapy, especially if no oral anticoagulant therapy was started. Although Lagerstedt et al state that the recurrences were at a median of 49 days, they do not specify the time of these recurrences and it is possible that the phenomenon observed by Marciniak is partly responsible for the high recurrence rate in the non-warfarin group. We believe that, on the basis of this study, no definite conclusion can be drawn about the need for secondary prevention in isolated calf vein thrombosis. Academic Medical Centre, Department of Haemostasis and 1105 AZ Amsterdam, Netherlands 1. Hull
TAGE ASTRUP
1 Astrup T. The biological significance of fibrinolysis. Lancet 1956; ii: 565-68. 2. Kwaan HC, Astrup T. Fibrinolytic activity of reparative connective tissue. J Pathol Bacteriol 1964; 87: 409. 3 Jacques LB Heparins Anionic polyelectrolyte drugs. Pharmacol Rev 1980; 31: 99-166. 4. Brandt P. Observations during the treatment of antithrombin-III deficient women with heparin and antithrombin concentrate during pregnancy, parturition, and abortion. Thromb Res 1981; 22: 15-24. 5. Jespersen J. Termination of pregnancy in a woman with hereditary antithrombin deficiency under antithrombotic protection with subcutaneous heparin and infusion of plasma Gynecol Obstet Invest 1981; 12: 267-71. 6 Jespersen J, Gram J, Kluft C, Astrup T. Protection against venous thrombosis in an antithrombin-III deficient patient suffering from episodes of arterial thrombosis requiring major surgery: Effects of oral stanozolol in combination with intravenous AT-III and/or subcutaneous heparin. Am J Clin Pathol 1985; 83: 768-71. 7 Lose G, Frandsen B, Højensgård JC, Jespersen J, Astrup T. Chronic interstitial cystitis. Increased levels of eosinophil cationic protein in sirum and urine and an ameliorating effect of subcutaneous heparin. Scand J Urol Nephrol 1983, 17: 159-61 8 Lose G, Jespersen J, Frandsen B, Højensgård, JC, Astrup T. Subcutaneous heparin in the treatment of interstitial cystitis Scand J Urol Nephrol 1985; 19: 27-9.
ORAL ANTICOAGULANTS AFTER CALF-VEIN THROMBOSIS
SIR,-On the basis of their findings Dr Lagerstedt and colleagues (Sept 7, p 515) recommend long-term oral anticoagulant treatment for patients with isolated calf vein thrombosis. Patients randomised to initial intravenous heparin treatment for 5 days followed by oral anticoagulants for three months had no recurrence during the first 90 days, whereas 8 patients (29%) randomised to intravenous heparin only for 5 days had a recurrence. Of these 8 patients, 5 had a recurrence with proximal extension and 1 had a pulmonary embolus. We are surprised by this high frequency of recurrences in the heparin-only group. In prospective studies, normal findings on repeated impedance plethysmography (IPG) were the basis for not treating patients with clinically suspected venous thrombosis. 1,2 All patients with repeated normal IPG were followed for 12 months. IPG has a high sensitivity for proximal deep-vein thrombosis (DVT) (93%) but a lower sensitivity for calf DVT (20%).3 In 66% of the patients with repeatedly normal IPG, an alternative explanation for their leg complaints could be found, leaving 33% with potential calf DVT. Recurrences in these patients with proximal extension would have been picked up by IPG during long-term follow-up. Reported recurrences, however, are 13% and 19%, respectively.I,2 The substantial discrepancy with the study by Lagerstedt may be explained by the following. Firstly, their study was not double blind. Therefore, patients randomised to the group receiving no oral anticoagulants are more likely to report with new symptoms (diagnostic suspicion bias). Secondly, the regimen for the primary treatment in this study was a 5-day course of high-dose heparin intravenously. Marciniak and Gockermanreported that similar
M. V. HUISMAN J. W. TEN GATE H. R. BULLER
RD, Hirsh J, Sackett DL, et al Replacement of venography in thrombosis by impedance plethysmography and 125I-fibrinogen
suspected venous legscanning Ann
Intern Med 1981, 94: 12-15 RD, Hirsh J, Carter CJ, et al. Diagnostic efficacy of impedance plethysmography for clinically suspected deep vein thrombosis. Ann Intern Med 1985, 102: 21-28. Hull RD, Raskob GE, LeClerc JR, et al The venous diagnosis of clinically suspected venous thrombosis Clin Chest Med 1984, 5: 439-56 Marciniak E, Gockerman JP Heparin-induced decrease in circulating antithrombin III. Lancer 1977; ii: 581-84.
2. Hull 3
JØRGEN JESPERSEN
Thrombosis,
Meibergdreef 9,
4.
INTRAVENOUS IMMUNOGLOBULIN FOR AUTOIMMUNE THROMBOCYTOPENIA OF CHILDHOOD
SIR,-Dr Imbach and colleagues (Aug 31, p 464) have compared intravenous immunoglobulin with oral corticosteroids in the management of autoimmune thrombocytopenia (ITP) of childhood. The 94 cases included in the trial were drawn from various centres throughout Europe. Imbach et al found that 80% of cases resolved1 within six months, and this is in line with our findings in 181 cases. 77% of Imbach’s patients treated with corticosteroids and 83% of those receiving immunoglobulin recovered in 1-2 weeks. These rates are not significantly different from each other or from the "response" in children in our series who received no treatment at all. Nor were the findings in their two groups different 180 and 360 dys after diagnosis. We do not consider it reasonable to classify ITP as chronic simply because the platelet count was less than 150 x 109/1180 days after diagnosis-indeed almost 20% of our cases remitted spontaneously and "permanently" even though thrombocytopenia had persisted for more than a year. Serious adverse reactions were noted in 22% of children who received immunoglobulin. Adverse effects, chiefly weight gain, were also noted in children treated with steroids, but the doses were quite high and, more important, administration was often longterm.
The main
objective of Imbach and colleagues’ trial was "to prevent potentially fatal central nervous system haemorrhage, which occurs in less than 1% of all children with ITP". They failed; 1 child died from cerebral haemorrhage despite three doses of immunoglobulin. Imbach et al have not demonstrated that IgG has anything to offer either in immediate platelet response or long-term benefit. This is an expensive treatment, whose place, if any, may be in producing a temporary increase in platelet count before surgical or other dangerous procedures. We found no benefit from steroids, either in speed of recovery or end result-nor is there any convincing published evidence elsewhere. Nonetheless we advised a 4-5 week course of prednisone 40 mg daily in all ITP presenting in childhood on the grounds that it is of proven benefit in other similar autoimmune disease, that it may have an effect on capillary fragility, and that, used in this way, its only side-effect is a temporary, modest weight gain. Department ofHaematology, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP
R. W. WALKER W. WALKER
1. Walker RW, Walker W Immune thrombocytopenia: Initial illness and long-term 316-22.
follow-up. Arch Dis Child 1984; 59:
especially
(a) % neutrophils containing any E coh. (b) Phagocytic mdex=(a) x mean number ofE co/ per neutrophil. Reaction medium was 3001’1 Hanks balanced salt solution, 501’1 fresh autologous serurr (complement source) containing 6010’ E cob and 310" human neutrophils. 50 Nl o either normal serum, anti-LPS gammaglobulin diluted 1:160 or normal gammaglobulir diluted 1: 160 was added and mixtures mcubated for 30 min at 37°C with gentle agitation Smears were stained with Glemsa stain and counted. Statistical analyses by paired t test- *p<0’05 compared with normal serum, **p<0’001 1 compared with normal serum and p>0-001 compared with normal IgG, tp>0-0’ compared with normal serum, :f:p
constant.7 assess
the
phagocytosis
of Escherichia coli
8
by human neutrophils
(table). Neutrophils
present in the medium lacking any IgG always had both the lowest number of ingested E coli and phagocytotic index. The medium containing LG-1 always produced the highest ingestion rate, with neutrophils in the medium containing normal human IgG (known to contain small amounts of anti-LPS IgG) having intermediate values. These findings show that in addition to destroying bacteria by complement activation, anti-LPs also increases the uptake of bacteria by phagocytic cells. The sera of some patients with gram-negative bacteraemia lacked anti-O antibodies (the main component of anti-LPS) and were also incapable of stimulating neutrophils to ingest autologous gramnegative bacteria, under conditions strongly implying a cause-andeffect relationship.9 The anti-LPS gammaglobulin used here is easily prepared by any medium-sized blood bank and may provide the anti-gram-negative bacterial antibodies lacking in such bacteraemic patients.
Supported by grants from the South African Medical Research Council. Departments of Medicine and Physiology. University of Natal, Congella 4013, South Africa; and Natal Institute of Immunology
D. PUDIFIN I. L’HOSTE J. DUURSMA S. L. GAFFIN
E, Pitsoe SB, Gaffin SL. Anti-lipopolysaccharide immunotherapy in the management of septic shock of obstetrical and gynaecological origin. Lancet 1984; i:
At the time of the CBZ dose reduction, there was a small decrease in the phenytoin dose (from 350 to 325 mg daily). This might have caused a significant fall in plasma phenytoin concentration. Phenytoin induces the epoxidation of CBZ8 and the metabolism of CBZ might have been induced to different degrees at the two phenytoin levels. If the phenytoin levels were very different on the two doses, some of the side-effects might have been due to this drug. Earlier attempts to evaluate the effects of CBZ epoxide during CBZ therapy have led to conflicting results.The most reliable assessments of the clinical effects of CBZ epoxide can be obtained by giving the epoxide to man. The metabolite been given to healthy volunteers in single doses up to 200 mg and as monotherapy to patients with trigeminal neuralgia in doses up to 1000 mg daily.9 No side-effects were observed despite peak plasma levels of CBZ-E up to 16 jamolll, which is considerably higher than the threshold for side-effects of 9 mol/1 suggested by Patsalos et al. The side-effects observed in the patient of Patsalos et al were probably due to the complex antiepileptic drug therapy. The role of CBZ-E is unclear.
has
Department of Neurology, Söder Hospital, Stockholm
TORBJÖRN TOMSON
Department of Clinical Pharmacology, Karolinska Institute, Huddinge Hospital, S-141 86 Huddinge, Sweden
LEIF BERTILSSON
1. Lachman
981-83. 2 Gaffin SL, Wells MT, Jordaan J Antilipopolysaccharide toxin therapy for whole body X-irradiation overdose. Br J Radiol (in press). 3 Zanotti AM, Gaffin SL Prophylaxis of superior mesenteric artery occlusion shock in rabbits by antilipopolysaccharide (anti-LPS) antibodies. J Surg Res 1985, 38: 113-15. 4 Gaffin SL, Robins-Browne R, Cooper R, Gregory M, Badsha N, Brock-Utne JG, Vorster BJ antibiotic effect of human and equine antiendotoxin antibody rich serum Klebsiella pneumoniae. S Afr J Sci 1982; 78: 91-92. 5. Welsh NH, Rauch A, Gaffin SL. Topical immunotherapy for pseudomonas keratitis in rabbits use of anti-lipopolysaccharide plasma. Br J Ophthalmol 1984; 8: 828-32. 6. Gaffin SL, Badsha N, Vorster BJ Properties of human lipopolysaccharide gamma globulin. specificity and protective effects. Vox Sang 1985; 48: 276-83. 7. Gaffin SL. Large-scale production of anti-negative bacterial antibodies. Lancet 1983; ii: 1420-21. 8. Van Furth R, Leijh PC, Klein F. Correlation between opsonic activity for various microorganisms and composition of gamma globulin preparations for intravenous use. J Infect Dis 1984; 149: 511-17. 9. Weinstein RJ, Young LS. Neutrophil function in gram negative rod bacteremia. The interaction between phagocytic cells, infecting organisms and humoral factors. J Clin Invest 1976; 58: 190-99.
SIDE-EFFECTS OF CARBAMAZEPINE: DRUG OR METABOLITE?
SiR,-Dr Patsalos and colleagues (Aug 31, p 496) describe
acute
a patient on combination therapy with phenytoin, carbamazepine (CBZ), and phenobarbitone. Plasma levels were said to be within the "therapeutic range", but we know of no controlled studies that establish such ranges during combination therapy.i
side-effects in
When the CBZ dose was lowered the side-effects diminished and the plasma concentration of the epoxide metabolite of CBZ (CBZ-E)
1.
Sjöqvist F Therapeutic drug monitoring: Twenty years’ experience. In: Lemberger L,
Reidenberg MM, eds. Proceedings of the Second World Conference on Clinical Pharmacology and Therapeutics. Bethesda: American Society of Pharmacology and Experimental Therapeutics, 1984: 38-63. 2. Rapeport WG. Factors influencing the relationship between carbamazepine plasma concentration and its clinical effects in patients with epilepsy, Clin Neuropharmacol 1985; 8: 141-49. 3. Kutt H, Solomon G, Wasterlain C, et al. Carbamazepine in difficult to control outpatients. Acta Neurol Scand 1975; 60 (suppl): 27-32. 4. Tomson T. Interdosage fluctuations in plasma carbamazepine concentration determine intermittent side effects. Acta Neural 1984; 41: 830-34. 5. Tomson T, Tybring G, Bertilsson L. Single-dose kinetics and metabolism of carbamazepine-10,11-epoxide. Clin Pharmacol Ther 1983; 33: 58-65 6. Rowland M, Tozer TN. Clinical pharmacokinetics: Concepts and applications. Philadelphia: Lea and Febiger, 1980. 7. Tomson T, Tybring G, Bertilsson L, Ekbom K, Rane A. Carbamazepine therapy in trigeminal neuralgia: Clinical effects in relation to plasma concentration. Arch Neurol 1980; 37: 699-703. 8. Eichelbaum M, Tomson T, Tybring G, Bertilsson L. Carbamazepine metabolism in man: Induction and pharmacogenetic aspects. Clin Pharmacokin 1985; 10: 80-90. 9. Tomson T, Bertilsson L. Potent therapeutic effect of carbamazepine-10,11-epoxide in trigeminal neuralgia. Arch Neurol 1984; 41: 598-601.
CHRONIC INTERSTITIAL CYSTITIS AND SUBCUTANEOUS HEPARIN
SIR,-Your July 20 editorial takes a pessimistic view of the current empirical methods of treatment of chronic interstitial cystitis (IC). The causes of IC remain elusive. However, the bladder lesions suggest an inflammatory process followed by extensive fibrosis as a major factor in the clinical manifestations. In this disease there be a stage of injury to the tissues of the bladder wall folby a response dominated by defective tissue repair, as suggested by deposits of fibrin on the surface of the lesions. These seems
lowed
to
1011
layers of fibrin provide a matrix for the migration and proliferation of cells participating in repair (fibroblasts and angioblasts, and certain white cells when there is an added inflammatory reaction). The retention of layers of fibrin for a long time impairs diffusion of nutrients to the connective tissue under repair, leading to incomplete repair with extensive fibrosis and scar formation 1,2 associated with disruption of adjacent layers of muscle cells and nerves, which is expressed clinically during relapses. One way to prevent this sequence might be to limit the deposition of fibrin to the amount sufficient for primary wound healing. One approach would then be to delay the formation of fibrin in a manner similar to that successfully introduced in the treatment and prophylaxis of thrombotic disorders.3 This reasoning, together with experience gained in the treatment of thrombosis-prone individuals and in patients with subcutaneous heparin,4-6prompted an attempt to treat IC with subcutaneous heparin. Pilot studies 7,8 in small groups of selected patients suggest this to be a promising approach, inviting confirmatory studies in larger series. For example, discontinuation of treatment produced a clinical relapse followed by remission when heparin administration was resumed. Section of
Coagulation and Fibrinolysis, Department of Clinical Chemistry, and Section for Thrombosis Research, South Jutland University Centre, DK-6700 Esbjerg, Denmark
high doses of heparin given intravenously could provoke a decrease and even a deficiency of plasma antithrombin III; they presumed that the low AT-III levels might induce thromboembolic episodes after cessation of heparin therapy, especially if no oral anticoagulant therapy was started. Although Lagerstedt et al state that the recurrences were at a median of 49 days, they do not specify the time of these recurrences and it is possible that the phenomenon observed by Marciniak is partly responsible for the high recurrence rate in the non-warfarin group. We believe that, on the basis of this study, no definite conclusion can be drawn about the need for secondary prevention in isolated calf vein thrombosis. Academic Medical Centre, Department of Haemostasis and 1105 AZ Amsterdam, Netherlands 1. Hull
TAGE ASTRUP
1 Astrup T. The biological significance of fibrinolysis. Lancet 1956; ii: 565-68. 2. Kwaan HC, Astrup T. Fibrinolytic activity of reparative connective tissue. J Pathol Bacteriol 1964; 87: 409. 3 Jacques LB Heparins Anionic polyelectrolyte drugs. Pharmacol Rev 1980; 31: 99-166. 4. Brandt P. Observations during the treatment of antithrombin-III deficient women with heparin and antithrombin concentrate during pregnancy, parturition, and abortion. Thromb Res 1981; 22: 15-24. 5. Jespersen J. Termination of pregnancy in a woman with hereditary antithrombin deficiency under antithrombotic protection with subcutaneous heparin and infusion of plasma Gynecol Obstet Invest 1981; 12: 267-71. 6 Jespersen J, Gram J, Kluft C, Astrup T. Protection against venous thrombosis in an antithrombin-III deficient patient suffering from episodes of arterial thrombosis requiring major surgery: Effects of oral stanozolol in combination with intravenous AT-III and/or subcutaneous heparin. Am J Clin Pathol 1985; 83: 768-71. 7 Lose G, Frandsen B, Højensgård JC, Jespersen J, Astrup T. Chronic interstitial cystitis. Increased levels of eosinophil cationic protein in sirum and urine and an ameliorating effect of subcutaneous heparin. Scand J Urol Nephrol 1983, 17: 159-61 8 Lose G, Jespersen J, Frandsen B, Højensgård, JC, Astrup T. Subcutaneous heparin in the treatment of interstitial cystitis Scand J Urol Nephrol 1985; 19: 27-9.
ORAL ANTICOAGULANTS AFTER CALF-VEIN THROMBOSIS
SIR,-On the basis of their findings Dr Lagerstedt and colleagues (Sept 7, p 515) recommend long-term oral anticoagulant treatment for patients with isolated calf vein thrombosis. Patients randomised to initial intravenous heparin treatment for 5 days followed by oral anticoagulants for three months had no recurrence during the first 90 days, whereas 8 patients (29%) randomised to intravenous heparin only for 5 days had a recurrence. Of these 8 patients, 5 had a recurrence with proximal extension and 1 had a pulmonary embolus. We are surprised by this high frequency of recurrences in the heparin-only group. In prospective studies, normal findings on repeated impedance plethysmography (IPG) were the basis for not treating patients with clinically suspected venous thrombosis. 1,2 All patients with repeated normal IPG were followed for 12 months. IPG has a high sensitivity for proximal deep-vein thrombosis (DVT) (93%) but a lower sensitivity for calf DVT (20%).3 In 66% of the patients with repeatedly normal IPG, an alternative explanation for their leg complaints could be found, leaving 33% with potential calf DVT. Recurrences in these patients with proximal extension would have been picked up by IPG during long-term follow-up. Reported recurrences, however, are 13% and 19%, respectively.I,2 The substantial discrepancy with the study by Lagerstedt may be explained by the following. Firstly, their study was not double blind. Therefore, patients randomised to the group receiving no oral anticoagulants are more likely to report with new symptoms (diagnostic suspicion bias). Secondly, the regimen for the primary treatment in this study was a 5-day course of high-dose heparin intravenously. Marciniak and Gockermanreported that similar
M. V. HUISMAN J. W. TEN GATE H. R. BULLER
RD, Hirsh J, Sackett DL, et al Replacement of venography in thrombosis by impedance plethysmography and 125I-fibrinogen
suspected venous legscanning Ann
Intern Med 1981, 94: 12-15 RD, Hirsh J, Carter CJ, et al. Diagnostic efficacy of impedance plethysmography for clinically suspected deep vein thrombosis. Ann Intern Med 1985, 102: 21-28. Hull RD, Raskob GE, LeClerc JR, et al The venous diagnosis of clinically suspected venous thrombosis Clin Chest Med 1984, 5: 439-56 Marciniak E, Gockerman JP Heparin-induced decrease in circulating antithrombin III. Lancer 1977; ii: 581-84.
2. Hull 3
JØRGEN JESPERSEN
Thrombosis,
Meibergdreef 9,
4.
INTRAVENOUS IMMUNOGLOBULIN FOR AUTOIMMUNE THROMBOCYTOPENIA OF CHILDHOOD
SIR,-Dr Imbach and colleagues (Aug 31, p 464) have compared intravenous immunoglobulin with oral corticosteroids in the management of autoimmune thrombocytopenia (ITP) of childhood. The 94 cases included in the trial were drawn from various centres throughout Europe. Imbach et al found that 80% of cases resolved1 within six months, and this is in line with our findings in 181 cases. 77% of Imbach’s patients treated with corticosteroids and 83% of those receiving immunoglobulin recovered in 1-2 weeks. These rates are not significantly different from each other or from the "response" in children in our series who received no treatment at all. Nor were the findings in their two groups different 180 and 360 dys after diagnosis. We do not consider it reasonable to classify ITP as chronic simply because the platelet count was less than 150 x 109/1180 days after diagnosis-indeed almost 20% of our cases remitted spontaneously and "permanently" even though thrombocytopenia had persisted for more than a year. Serious adverse reactions were noted in 22% of children who received immunoglobulin. Adverse effects, chiefly weight gain, were also noted in children treated with steroids, but the doses were quite high and, more important, administration was often longterm.
The main
objective of Imbach and colleagues’ trial was "to prevent potentially fatal central nervous system haemorrhage, which occurs in less than 1% of all children with ITP". They failed; 1 child died from cerebral haemorrhage despite three doses of immunoglobulin. Imbach et al have not demonstrated that IgG has anything to offer either in immediate platelet response or long-term benefit. This is an expensive treatment, whose place, if any, may be in producing a temporary increase in platelet count before surgical or other dangerous procedures. We found no benefit from steroids, either in speed of recovery or end result-nor is there any convincing published evidence elsewhere. Nonetheless we advised a 4-5 week course of prednisone 40 mg daily in all ITP presenting in childhood on the grounds that it is of proven benefit in other similar autoimmune disease, that it may have an effect on capillary fragility, and that, used in this way, its only side-effect is a temporary, modest weight gain. Department ofHaematology, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP
R. W. WALKER W. WALKER
1. Walker RW, Walker W Immune thrombocytopenia: Initial illness and long-term 316-22.
follow-up. Arch Dis Child 1984; 59: