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Prophylactic anticoagulation in heterozygous protein C deficiency
754
status at
birth. In view of the accumulated evidence and the
long-term consequences of a mistake at this stage of life,6it might be prudent to consider the DHA option or at least supplementation of pregnant women given aspirin with omega-3 fatty acids. Institute of Brain
Chemistry
and Human Nutrition,
Hackney Hospital, London E9 6BE, UK
M. A. CRAWFORD
1. Leaf
AA, Leighfield MJ, Casteloe KL, Crawford MA. Long chain polyunsaturated fatty adds in fetal growth. Early Hum Dev 1992; 30: 183-91. 2. Farquharson J, Cockbum F, Patrick AW, Jamieson E, Logan RW. Infant cerebral cortex phospholipid fatty-acid composition and diet. Lancet 1992; 340: 810-13. 3. Bjerve KF, Thoresen L, Boona K, et al. Clinical studies with alpha-linolenic acid and long chain n-3 fatty acids. Nutrition 1992; 8: 130-32. 4. Birch DG, Birch EE, Hoffman DR, Uauy RD. Retinal development in very-lowbirth-weight infants fed diets differing in omega-3 fatty acids. Invest Ophthalm Visual Sci 1992; 33: 21-32. 5. Olsen FO, Sorensen JD, Secher
NJ, et al. Randomised controlled trial of effect of fish-oil supplementation on pregnancy duration. Lancet 1992; 339: 1003-07. 6. Scottish Low Birthweight Group. The Scottish low birthweight study I, survival, growth, neuromotor and sensory impairment. Arch Dis Child 1992; 67: 675-86.
Treatment of
hypophosphataemia
Allaart and colleagues’ report draws attention to the association between venous thromboembolic episodes, heterozygous protein C deficiency, and acute precipitating events such as operation, trauma, or childbirth. We have noted a similar association in two healthy young women who had been using oral contraceptives for several years without complications: one developed an iliofemoral deep vein thrombosis while recovering from chickenpox, and the other had a pulmonary embolism after tonsillectomy. Precipitating events were identified in about half the thromboembolic episodes in Allaart and colleagues’ study; this information was obtained by interviewing patients, often several years after these episodes. We suspect that in a prospective study more such precipitating events would be identified. On the basis of our findings and those of Sagar et aP we have suggested that women taking oral contraceptives who undergo elective surgery should be given prophylactic heparin.4 We believe that this approach could be applied to otherpredisposing conditions such as heterozygous protein C deficiency. The dilemma to which Allaart et al allude in their final paragraph might be resolved by the use of such selective, rather than continuous, prophylaxis. Groote Schuur Hospital, Cape Town 7925, South Africa
RORY J. FARRELL JENNIFER LAMB
SIR,-Dr Coyle (Oct 17, p 977) and Dr Young (Feb 6, p 374) and
colleagues’ reports are to be welcomed because hypophosphataemia is poorly recognised in hospital patientsmore so, the treatment of severe hypophosphataemia. However, there is one point that should be emphasised with respect to patients with severe hypophosphataemia that was not brought out in these letters; this is the association of other electrolyte disturbances with hypophosphataemia. Vannatta et all in their original paper, about treatment of low plasma phosphate, described the association of severe hypophosphataemia with hypomagnesaemia and mentioned that plasma magnesium should also be measured in these patients. Crook2 has shown an association of hypokalaemia in patients with severe hypophosphataemia. These electrolyte disturbances may need correction in their own right. their
,
Clinical
Chemistry, Guy’s Hospital, London SE1 9RT, UK
MARTIN CROOK
JB, Whang R, Papper S. Efficacy of intravenous phosphate therapy in the severely hypophosphataemic patient. Arch Intern Med 1981; 141: 885-67. Crook M. Hypophosphataemia in a hospital population and the incidence of concomitant hypokalaemia. Ann Clin Biochem 1992; 29: 64-66.
1. Vannatta 2.
Prophylactic anticoagulation in heterozygous protein C deficiency SIR,-Dr Allaart and colleagues (Jan 16, p 134) report an association between heterozygous protein C deficiency and increased risk of venous thromboembolism. However, by use of both genetic markers and a functional assay for protein C activity, they show that 15% of heterozygotes have normal protein C activity. Furthermore, despite the correlation between the gene carrier state and venous thromboembolism, they did not find a correlation between thrombosis and protein C activity. Much of the difficulty in establishing the clinical significance of heterozygous protein C deficiency arises from the fact that it is a chronic state (similar to other risk factors such as obesity, smoking, and oral contraceptive use), whereas deep vein thrombosis and pulmonary embolism are acute events. The combination of symptomless protein C deficiency and oral contraceptive use resulted in the early development of venous thrombosis in an identical twin study,1 and a similar finding has been reported in antithrombin III deficiency.2 Allaart and co-workers record a moderate but non-significant increase in venous thrombotic events associated with a history of oral contraceptive use. This finding was, however, based on an analysis of all participants; the risk ratios for oral contraceptive use among protein C deficiency heterozygotes and their normal relatives might differ substantially. Furthermore, Allaart’s analysis is based on a history of oral contraceptive use at any time in the past, rather than on any temporal association between a thromboembolic event and oral contraception.
Girolami A, Simioni P, Sartori MT, Zanardi S. Oral contraceptives caused thrombosis in a monoovular twin with protein C deficiency, while the other, without medication, remained asymptomatic. Blood Coag Fibrinol 1992; 3: 119-20. 2. Girolami A, Stevanato F, Lazzaro AR. Bilateral iliofemoral thrombophlebitis after ten 1.
contraceptive pills in a 25-year-old woman with antithrombin III deficiency. Acta 3. 4.
Haematol 1988; 79: 118-19. Sagar S, Stamatakis JD, Thomas DP, Kakkar VV. Oral contraceptives, antithrombin III activity and postoperative deep vein thrombosis. Lancet 1976; i: 509-11. Farrell RJ, Lamb J. Should the pill be stopped preoperatively? BMJ 1988; 296: 1066.
Ifosfamide and exacerbation of cisplatininduced hearing loss SiR,—Qspladn can cause permanent, bilateral hearing loss.’ Studies of factors that may exacerbate toxicity (environmental sources of noise,2 aminoglycoside antibiotics,3 central nervous system irradiation1.4) have not looked at the potential effects of other chemotherapeutic agents used with cisplatin. Ifosfamide is combined with cisplatin in many common adult and paediatric cancers, including germ cell tumours, small cell and non-small cell lung cancer, cervical and ovarian carcinoma, neuroblastoma, and osteosarcoma.
To assess whether ifosfamide exacerbates cisplatin-induced hearing loss, we compared patients with osteosarcoma treated with both drugs in the OS-86 study5 (1986-91) with patients who received cisplatin-based therapy without ifosfamide in the MIOS protocol6 (1982-86). Both protocols specified the same dose of cisplatin (four courses of 100 mg/m2 each) and similar schedules of high-dose methotrexate and doxorubicin. OS-86 specified five cycles of ifosfamide (8 g/m2 per cycle) whereas MIOS stipulated five cycles of bleomycin, cyclophosphamide,and dactinomycin. Prospective audiological assessments were available for 47 of 51 OS-86 patients (92%) and 31 of 41 MIOS patients (76%). Testing was done in a sound-proofed room with either a Beltone 200C or a
GSI16 audiometer. In both studies, changes in hearing thresholds were first observed after patients had received cumulative doses of 200 mg/m2. After receiving the full cisplatin dose of 400 mg/m2, all 0 S-86 patients had greater than 50 dB hearing loss at 8000 Hz and many had changes in hearing thresholds at 4000 and 6000 Hz. Deficits at these thresholds were significantly greater than those in MIOS patients (Wilcoxon rank-sum test, figure). A multivariate mixed-effects model detected similar significant differences between the two groups (data not shown). Post-treatment hearing loss sufficient to require amplification (defined by a hearing thresholds 30 dB at 2000 or 3000 Hz) was significantly more frequent among OS-86 patients than the MIOS patients (12 of 25 vs 4 of 24 evaluable cases; p 0.03, Fisher’s exact test). Thus the observed differences in hearing thresholds had functional impact. Concurrent ifosfamide therapy can exacerbate cisplatin-induced hearing loss. That this effect is not simply additive is suggested by =
status at
birth. In view of the accumulated evidence and the
long-term consequences of a mistake at this stage of life,6it might be prudent to consider the DHA option or at least supplementation of pregnant women given aspirin with omega-3 fatty acids. Institute of Brain
Chemistry
and Human Nutrition,
Hackney Hospital, London E9 6BE, UK
M. A. CRAWFORD
1. Leaf
AA, Leighfield MJ, Casteloe KL, Crawford MA. Long chain polyunsaturated fatty adds in fetal growth. Early Hum Dev 1992; 30: 183-91. 2. Farquharson J, Cockbum F, Patrick AW, Jamieson E, Logan RW. Infant cerebral cortex phospholipid fatty-acid composition and diet. Lancet 1992; 340: 810-13. 3. Bjerve KF, Thoresen L, Boona K, et al. Clinical studies with alpha-linolenic acid and long chain n-3 fatty acids. Nutrition 1992; 8: 130-32. 4. Birch DG, Birch EE, Hoffman DR, Uauy RD. Retinal development in very-lowbirth-weight infants fed diets differing in omega-3 fatty acids. Invest Ophthalm Visual Sci 1992; 33: 21-32. 5. Olsen FO, Sorensen JD, Secher
NJ, et al. Randomised controlled trial of effect of fish-oil supplementation on pregnancy duration. Lancet 1992; 339: 1003-07. 6. Scottish Low Birthweight Group. The Scottish low birthweight study I, survival, growth, neuromotor and sensory impairment. Arch Dis Child 1992; 67: 675-86.
Treatment of
hypophosphataemia
Allaart and colleagues’ report draws attention to the association between venous thromboembolic episodes, heterozygous protein C deficiency, and acute precipitating events such as operation, trauma, or childbirth. We have noted a similar association in two healthy young women who had been using oral contraceptives for several years without complications: one developed an iliofemoral deep vein thrombosis while recovering from chickenpox, and the other had a pulmonary embolism after tonsillectomy. Precipitating events were identified in about half the thromboembolic episodes in Allaart and colleagues’ study; this information was obtained by interviewing patients, often several years after these episodes. We suspect that in a prospective study more such precipitating events would be identified. On the basis of our findings and those of Sagar et aP we have suggested that women taking oral contraceptives who undergo elective surgery should be given prophylactic heparin.4 We believe that this approach could be applied to otherpredisposing conditions such as heterozygous protein C deficiency. The dilemma to which Allaart et al allude in their final paragraph might be resolved by the use of such selective, rather than continuous, prophylaxis. Groote Schuur Hospital, Cape Town 7925, South Africa
RORY J. FARRELL JENNIFER LAMB
SIR,-Dr Coyle (Oct 17, p 977) and Dr Young (Feb 6, p 374) and
colleagues’ reports are to be welcomed because hypophosphataemia is poorly recognised in hospital patientsmore so, the treatment of severe hypophosphataemia. However, there is one point that should be emphasised with respect to patients with severe hypophosphataemia that was not brought out in these letters; this is the association of other electrolyte disturbances with hypophosphataemia. Vannatta et all in their original paper, about treatment of low plasma phosphate, described the association of severe hypophosphataemia with hypomagnesaemia and mentioned that plasma magnesium should also be measured in these patients. Crook2 has shown an association of hypokalaemia in patients with severe hypophosphataemia. These electrolyte disturbances may need correction in their own right. their
,
Clinical
Chemistry, Guy’s Hospital, London SE1 9RT, UK
MARTIN CROOK
JB, Whang R, Papper S. Efficacy of intravenous phosphate therapy in the severely hypophosphataemic patient. Arch Intern Med 1981; 141: 885-67. Crook M. Hypophosphataemia in a hospital population and the incidence of concomitant hypokalaemia. Ann Clin Biochem 1992; 29: 64-66.
1. Vannatta 2.
Prophylactic anticoagulation in heterozygous protein C deficiency SIR,-Dr Allaart and colleagues (Jan 16, p 134) report an association between heterozygous protein C deficiency and increased risk of venous thromboembolism. However, by use of both genetic markers and a functional assay for protein C activity, they show that 15% of heterozygotes have normal protein C activity. Furthermore, despite the correlation between the gene carrier state and venous thromboembolism, they did not find a correlation between thrombosis and protein C activity. Much of the difficulty in establishing the clinical significance of heterozygous protein C deficiency arises from the fact that it is a chronic state (similar to other risk factors such as obesity, smoking, and oral contraceptive use), whereas deep vein thrombosis and pulmonary embolism are acute events. The combination of symptomless protein C deficiency and oral contraceptive use resulted in the early development of venous thrombosis in an identical twin study,1 and a similar finding has been reported in antithrombin III deficiency.2 Allaart and co-workers record a moderate but non-significant increase in venous thrombotic events associated with a history of oral contraceptive use. This finding was, however, based on an analysis of all participants; the risk ratios for oral contraceptive use among protein C deficiency heterozygotes and their normal relatives might differ substantially. Furthermore, Allaart’s analysis is based on a history of oral contraceptive use at any time in the past, rather than on any temporal association between a thromboembolic event and oral contraception.
Girolami A, Simioni P, Sartori MT, Zanardi S. Oral contraceptives caused thrombosis in a monoovular twin with protein C deficiency, while the other, without medication, remained asymptomatic. Blood Coag Fibrinol 1992; 3: 119-20. 2. Girolami A, Stevanato F, Lazzaro AR. Bilateral iliofemoral thrombophlebitis after ten 1.
contraceptive pills in a 25-year-old woman with antithrombin III deficiency. Acta 3. 4.
Haematol 1988; 79: 118-19. Sagar S, Stamatakis JD, Thomas DP, Kakkar VV. Oral contraceptives, antithrombin III activity and postoperative deep vein thrombosis. Lancet 1976; i: 509-11. Farrell RJ, Lamb J. Should the pill be stopped preoperatively? BMJ 1988; 296: 1066.
Ifosfamide and exacerbation of cisplatininduced hearing loss SiR,—Qspladn can cause permanent, bilateral hearing loss.’ Studies of factors that may exacerbate toxicity (environmental sources of noise,2 aminoglycoside antibiotics,3 central nervous system irradiation1.4) have not looked at the potential effects of other chemotherapeutic agents used with cisplatin. Ifosfamide is combined with cisplatin in many common adult and paediatric cancers, including germ cell tumours, small cell and non-small cell lung cancer, cervical and ovarian carcinoma, neuroblastoma, and osteosarcoma.
To assess whether ifosfamide exacerbates cisplatin-induced hearing loss, we compared patients with osteosarcoma treated with both drugs in the OS-86 study5 (1986-91) with patients who received cisplatin-based therapy without ifosfamide in the MIOS protocol6 (1982-86). Both protocols specified the same dose of cisplatin (four courses of 100 mg/m2 each) and similar schedules of high-dose methotrexate and doxorubicin. OS-86 specified five cycles of ifosfamide (8 g/m2 per cycle) whereas MIOS stipulated five cycles of bleomycin, cyclophosphamide,and dactinomycin. Prospective audiological assessments were available for 47 of 51 OS-86 patients (92%) and 31 of 41 MIOS patients (76%). Testing was done in a sound-proofed room with either a Beltone 200C or a
GSI16 audiometer. In both studies, changes in hearing thresholds were first observed after patients had received cumulative doses of 200 mg/m2. After receiving the full cisplatin dose of 400 mg/m2, all 0 S-86 patients had greater than 50 dB hearing loss at 8000 Hz and many had changes in hearing thresholds at 4000 and 6000 Hz. Deficits at these thresholds were significantly greater than those in MIOS patients (Wilcoxon rank-sum test, figure). A multivariate mixed-effects model detected similar significant differences between the two groups (data not shown). Post-treatment hearing loss sufficient to require amplification (defined by a hearing thresholds 30 dB at 2000 or 3000 Hz) was significantly more frequent among OS-86 patients than the MIOS patients (12 of 25 vs 4 of 24 evaluable cases; p 0.03, Fisher’s exact test). Thus the observed differences in hearing thresholds had functional impact. Concurrent ifosfamide therapy can exacerbate cisplatin-induced hearing loss. That this effect is not simply additive is suggested by =