- Email: [email protected]
CONGENITAL FOLATE-DEPENDENT MEGALOBLASTIC ANÆMIA OF UNKNOWN ÆTIOLOGY
262
veloped. The patient died a few days later. At necropsy the diagnosis of histiocytic medullary reticulosis was confirmed and
was
found
to
involve mediastinal and mesenteric
lymph-
nodes, spleen, liver, and bone-marrow. An immature teratoma in the anterior mediastinum and acute hepatic necrosis were also noted. Possible cases of malignant histiocytosis related to inmunosuppressive therapy are those of Clark and Dawson9 and Shreiner!O Both reports related to acute lymphoblastic leukaemia in which Robb-Smith’s disease was diagnosed after induction treatment. Our case would seem to be the first in which this rare disease has been found in a recipient of an allograft.
Postgraduate "Farreras
School of
Hæmatology
Valenti",
Department of Pathology, and Kidney Transplant Unit, Hospital Clinico y Provincial, Barcelona -11, Spain
L. HERNÁNDEZ-NIETO
J. A. BOMBI A. CARALPS J. M. ARANALDE
IMMUNOLOGICAL INERTIA OF VIVIPARITY SIR,-In commenting upon pregnancy, your editorial
on
where the real action is. The partners in pregnancy, mother and fetus, fail to reject each other, although they are capable of doing so after parturition and of rejecting unrelated tissues during pregnancy. In a number of species when skin grafts can be exchanged between the partners during pregnancy or immediately post partum, they often survive without rejection or after an abortive rejection process. This immunological inertia of viviparity2-l4is partner specific, mutual, and temporary, indicating that bodies of precise information about individual tissue specificities-presumably HLA antigen profiles-have been exchanged between the partners. This clearly leads, in many cases at least, to specific suppression of rejection reactions. Thus the real action takes place within the lymphoreticular systems of mothers and fetuses, and there is little need to postulate active immunological participation of trophoblast, except possibly for a time shortly after implantation and before development of the fetal lymphoreticular system. It is comprehension of the mechanisms of immunological inertia and of their kinetics that is likely to yield information exploitable in cancer. The statement that fetal escape from rejection depends largely upon properties of the trophoblast, which you do not define, is not acceptable. The many findings of generalisedH-17 and of partner-directed 18--21 immunosuppression in fetuses and young offspring and in mothers are ignored. Also you attempt to draw correlations amongst hydatidiform mole, choriocarcinoma, and viviparity, whilst failing to emphasise the very important differences amongst these biological systems. Although mechanisms with similarities may exist therein, and in abortions and pre-eclampsia, 22 -24 it is not possible at present to characterise them precisely. Thus blanket statements about undefined properties of the trophoblast are mis-
malignant trophoblast’ diverts attention from
-
and an insupportable basis for constructing a stateabout the significance of recent advances in HLA typing and choriocarcinoma.
leading ment
Surgical Division, Royal Infirmary,
J. MAXWELL ANDERSON
Glasgow G4 0SF
CONGENITAL FOLATE-DEPENDENT MEGALOBLASTIC ANÆMIA OF UNKNOWN ÆTIOLOGY a moderately retarded girl congenital familial megaloblastic anaemia for 15 years by giving her large doses of folic acid to maintain a normal clinical status. She was the product of a consanguineous marriage, and a sister died of severe anaemia in 1959. At age 1 month megaloblastic anxmia was noted. It failed to respond to parenteral vitamin B12 associated with small ("physiological") doses of folinic acid. Only with large ("pharmacological") doses of oral folic acid or parenteral folinic acid was recovery complete. Therefore, permanent therapy with oral folic acid (5 mg daily) was prescribed. Vitamin B,2 (1000 jj.g weekly) was added to folic acid to prevent possible neurological disturbances.’ Discontinuation of vitamin B,, had no
SIR,-We have been treating
with
a
of
clinical or haematological effects. When the patient was 13 vears old, a progressive irritability was the first manifestation of a severe megaloblastic ansmia which failed to respond to her usual dosage (5 mg daily) of folic acid. At this time the patient had severe anaemia (Hb 6g/dl), leukopenia (2.3x 109/1), and thrombocytopenia (70x 109/1). Severe purpura, epistaxis, and progressive diminution of vision were noted. Her bone-marrow picture was strikingly megaloblastic. Treatment with parenteral folinic acid (’Leucovorin’) at doses of 20 mg daily was started. After 20 days she had a complete remission of clinical and haematotogical symptoms. When her Hb reached 14 g/dl therapy was continued with oral folic acid (20 mg daily) and vitamin B12 (1000 p.g weekly). In February, 1975, when the patient was 15, treatment was discontinued for 1 month. Her Hb fell to 6.5 g/dl and her bone-marrow showed intense megaloblastic features. Her serum-vitamin-B,2 was 440 pg/ml and her serum-folic-acid was 6 ng/ml. R.B.c. folates were up to 1480 ng/ml. Urine 4-amino-5imidapole carboxamide was absent and there was no abnormal aminoacid pattern in either plasma or urine. Oroticaciduria was not found. Treatment was reinstated with parenteral leucovorin (32 mg daily). A high reticulocyte response was followed by a complete remission of clinical and haematologica! symptoms. When Hb reached normal level, therapy was continued with oral folic acid (30 mg daily) and vitamin B12 (1000 jg weekly). The patient is still receiving folic acid and remains clinically well and haematologically normal. Mental retardation and diminution of vision have not got worse. Our patient does not have a deficiency of either vitamin Bu or folic acid since her serum levels were normal while not on treatment. The increased R.B.c. folate while on folic acid indicated that she does not have an.intracellular deficiency of folic acid. The lack of response to parenteral physiological doses of folinic acid indicates that she is able to reduce folinic acid normally. Some rare megaloblastic ansemias associated with1 either oroticaciduria, 1-5 formiminotransferase deficiency,"
15. Hill, C. A., Finn, R., Denye, V. Br. med. J. 1973, iii, 513. 16. Kasakura, S. J. Immun. 1971, 107, 1296. 17. Stimson, W. H. Clin. exp. Immun. 1976, 25, 199. 18. Ceppellini, R., Bonnard, G. D., Coppo, F., Miggiano, V. C., Pospish, M., Curtoni, E. S., Pellegrino, M. Transplant. Proc. 1971, 3, 58. 19. Hellstrom, K. E. Hellstrom, I. Brawn, J. Nature, 1969, 224, 914. 20. Leventhal, B. G., Buell, D. N., Yankee, R., Rogentine, G. N. Terasaki, P. Proc. 5th Leucocyte Culture Conf. 1970, p. 473. 21. Youtananukorn, V., Matangkasombut, P. Nature new Biol. 1973, 242, 110. 22. Berne, B. H. Fed Proc. 1974, 33, 290. 23. Stimson, W. H. I.R.C.S. med. Sci. 1973, (73-3) 17-1-3. 24. Than, G. N., Csaba, I. F., Karg, N. J., Szabo, D. G., Novak, P. F. ibid. 1975b, 3, 94.
1. Will J. J., Mueller, J. F., Brodine, C., Kiely, C. E., Friedman, B., Hawkins, V. R., Dutra, J., Vilter, R. W. J. Lab. clin. Med. 1959, 53, 22. 2. Heinle, R. W., Welch, A. D. Am. med. Ass. 1947, 133, 739. 3. Huguley, C. M., Bain, J. A., Rivers, S. L., Scoggins, R. B. Blood, 1959,14, 615. 4. Bercroft, D. M., Philips, L. I. Br. med. J. 1965, i, 547. 5. Haggard, M. E., Lockhard, L. H. Am. J. Dis. Child. 1967, 113, 733. 6. Arakawa, T., Ohara, K., Kudo, Z., Tada, K., Hayashi, T., Mizuno, T. Tohoku. J. exp. med. 1963, 80, 370. 7. Arakawa, T., Takahashi, Y., Ogasawara, J., Hayashi, T., Chiba, R., Wada, Y., Tada, K., Mizuno, T., Okamura, T., Yoshida, T. Ann. Paediat. 1965, 205, 1.
9. Clark, B. S., Dawson, P. J. Am. J. Med 1969, 47, 314. 10. Shreiner, D. P. J. Am. med. Ass. 1975, 231, 838. 11. Lancet, 1976, ii, 1232. 12. Anderson, J. M. Nature, 1966, 206, 786. 13. Anderson, J. M. Proc. R. Soc. B. 1970, 176, 115. 14. Anderson, J. M. Nature’s Transplant: the Transplantation
Immunology
Viviparity; p. 45. London, 1972.
263
N’-methyltetrahydrofolate transferase deficiency, or increased need for thiamine9 have been reported in children. These ansmias are unresponsive to folic acid or vitamin B, Z. Lampkin et at.’" described two cases of congenital familial megaloblastic anaemia responsive only to folic acid and vitamin B12 given together in large doses, even though neither deficiency could be demonstrated in their patients. Our patient responded to large doses of folic or folinic acid given alone; addition of vitamin B12 was not necessary. Discontinuation of folic acid results promptly in a megaloblastic anaemia. The biochemical defect in this megaloblastic anaemia could lie in the conversion of dU.M.P. to T.M.P. necessary for D.N.A. synthesis, as presumed by Lampkin et al. 10 The spectacular recovery from megaloblastic anaemia upon administration of folic acid seems to exclude a congenital deficiency of the enzyme thymidylate synthetase. However, a binding defect of the enzyme so that the steric relationship with her coenzyme (tetrahydrofolic acid) is impaired seems to be a possibility. Postgraduate School of Hæmatology "Farreras Valenti", Hospital Clinico y Provincial, Central University of Barcelona,
J. VIVES MANE
Barcelona 11, Spain
C. ROZMAN
J. L. VIVES-CORRONS
FACTOR-VIII COMPLEX FETAL GROWTH RETARDATION, AND TOXÆMIA
SIR,-We greatly appreciated the letter from Dr Howie and others (Aug. 14, p. 323) on the use of coagulation tests to predict the clinical progress of pre-eclampsia. We have studied the levels of factor vin in this condition, and our results strongly suggest that the dosage of factor-vm-related antigen is a more sensitive index than the assessment of factor-vni procoagulant activity in predicting the fetal prognosis. Four groups of pregnant women were studied: (A) 14 patients without any symptom of toxaemia but with idiopathic fetal growth retardation; (B) 17 patients with symptoms of toxsmia in the last weeks of pregnancy but without further fetal growth retardation; (C) 16 patients with early toxaemia and subsequent fetal growth retardation (followed, in 6 cases, by perinatal death); and (D) 72 control pregnant women who had no signs of toxaemia or fetal growth retardation. Each patient was studied at least once during pregnancy, at delivery, 8. Arakawa, T., Narishawa, K., Tanno, K., Ohara, K., Higashi, O., Homda, Y., Tamura, T., Wada, Y., Mizuno, T., Hayashi, T. Tohoku. J. exp. Med. 1967, 93, 1. 9. Rogers, L. E., Porter, E. S., Sidbury, J. B. J. Pediat. 1969, 74, 494. 10. Lampkin, B. C., Pyesmany, A., Hyman, C. B., Hammond, D. Blood, 1971, 11
37, 515. Weiss, H. J., Hoyer L. W., Rickles, vest. 1973, 52, 2708.
F.
R., Varma, A., Rogers, J. J. clin.
In-
and 48 h later. Factor-VIII procoagulant activity (vmc), von Willebrand factor (VIIIVW.F.), and vm-related antigen (viiirag) were measured, respectively, by the one-stage assay, the ristocetin assay as described by Weiss,’ and Laurell’s immuno-
electrophoresis.1 The results are summarised in the table. As previously described,13-15 in all four groups studied, the three components of factor-vm complex increased during pregnancy, reached a maximum at delivery, and then fell within 48 h. In group A the results for vm rAg, VIII VW.F., and VIIIC were nearly identical to controls. In group B only the values for viiirag during the 35th-40th week were significantly different from controls. In group C the values for vmrAg/vmvw.F. were different from controls as early as the 28th-34th week. These significant differences are in keeping with the onset of toxaemic symptoms and in 2 cases they preceded the onset of clinical toxaemia. Many workers3 16 17 have pointed out a similar discrepancy between VIIIrAg/VIIIVW.F. and VIIIC (ratio VIIIC/VIIIrAg <1). So far, the exact significance of this is not clear. However, two hypotheses can be suggested-a molecular abnormality of factor viiirag or a partial inactivation of factor vm by thrombin in the case of disseminated intravascular coagulation. Histological studies on placentas in toxaemia show signs of chronic ischaemia, arterial thrombosis, or infarcts.18 The earlier the ohset of toxaemia, the more severe is the fetal growth retardation. Similar changes have been seen in other disorders-including glomerulonephritis/9 chronic arteritis obliterans, diabetes, and sepsis.ll Since it has been demonstrated that synthesis of VIIIfAg/VIIIVW.F. (but not vine) occurs in endothelial cells,19 it can be postulated that the increased level of VIIIrAg/VIIIVW.F. is an indicator of the severity of placental
damage. This work was supported by a grant from Delegation GénéraJe a la Recherche Scientifique et Technique (no: 75-7-0950). Laboratoire d’Hémostase, Centre de Transfusion Sanguine, Toulouse
Service de Gynécologie-obstétrique, Hôpital de la Grave, Toulouse, Cedex 31052, France
B. BONEU R. BIERME
A. FOURNIE G. PONTONNIER
12. 13. 14.
Laurell, C. B. Analyt. Biochem. 1966, 15, 45. Bennet, B., Ratnoff, O. D. J. Lab. clin. Med. 1973, 80, 256. Nilsson, I. M., Hedner, U., Astedt, B., Gennser, G., Jacobson, L, Holmberg, L., Ohrlander, S. Acta obstet. gynœc. scand. 1975, 54, 491. 15. Van Royen, E. A., Flier, O. T., Ten-cate, J. W. Lancet, 1974, ii, 657. 16. Bensoussan, D., Levy-Toledano, S., Passa, P., Caen, J., Canivet, J. Diabetologica, 1975, 2, 307. 17. Holmberg, L., Nilsson, I. M. Scand. J. Hœmat. 1974, 12, 221. 18. Bonnar, J., Redman, C. W. G., Sheppard, B. L. Eur. J. Obstet. Gynec. repro. Biol. 1975, 5, 123. 19. Jaffe, E. A., Hoyer, L. W., Nachman, R. L. J. clin. Invest: 1973, 52, 2757. 20. Ekeberg, M., Nilsson, I. M. Lancet, 1975, i, 1111. 21. Boneu, B., Abbal, M., Plante, J., Bierme, R. ibid. p. 1430.
AVERAGE PLASMA-LEVELS OF COMPONENTS OF FACTOR-VIII COMPLEX
*p<0.005
p<0.001 Results are expressed as mean and (in parentheses) confidence interval at 95%. Values for groups A, B, and C were compared to controls using the Fisher test.
(%)
IN TOXAEMIC AND NORMAL PREGNANCY
veloped. The patient died a few days later. At necropsy the diagnosis of histiocytic medullary reticulosis was confirmed and
was
found
to
involve mediastinal and mesenteric
lymph-
nodes, spleen, liver, and bone-marrow. An immature teratoma in the anterior mediastinum and acute hepatic necrosis were also noted. Possible cases of malignant histiocytosis related to inmunosuppressive therapy are those of Clark and Dawson9 and Shreiner!O Both reports related to acute lymphoblastic leukaemia in which Robb-Smith’s disease was diagnosed after induction treatment. Our case would seem to be the first in which this rare disease has been found in a recipient of an allograft.
Postgraduate "Farreras
School of
Hæmatology
Valenti",
Department of Pathology, and Kidney Transplant Unit, Hospital Clinico y Provincial, Barcelona -11, Spain
L. HERNÁNDEZ-NIETO
J. A. BOMBI A. CARALPS J. M. ARANALDE
IMMUNOLOGICAL INERTIA OF VIVIPARITY SIR,-In commenting upon pregnancy, your editorial
on
where the real action is. The partners in pregnancy, mother and fetus, fail to reject each other, although they are capable of doing so after parturition and of rejecting unrelated tissues during pregnancy. In a number of species when skin grafts can be exchanged between the partners during pregnancy or immediately post partum, they often survive without rejection or after an abortive rejection process. This immunological inertia of viviparity2-l4is partner specific, mutual, and temporary, indicating that bodies of precise information about individual tissue specificities-presumably HLA antigen profiles-have been exchanged between the partners. This clearly leads, in many cases at least, to specific suppression of rejection reactions. Thus the real action takes place within the lymphoreticular systems of mothers and fetuses, and there is little need to postulate active immunological participation of trophoblast, except possibly for a time shortly after implantation and before development of the fetal lymphoreticular system. It is comprehension of the mechanisms of immunological inertia and of their kinetics that is likely to yield information exploitable in cancer. The statement that fetal escape from rejection depends largely upon properties of the trophoblast, which you do not define, is not acceptable. The many findings of generalisedH-17 and of partner-directed 18--21 immunosuppression in fetuses and young offspring and in mothers are ignored. Also you attempt to draw correlations amongst hydatidiform mole, choriocarcinoma, and viviparity, whilst failing to emphasise the very important differences amongst these biological systems. Although mechanisms with similarities may exist therein, and in abortions and pre-eclampsia, 22 -24 it is not possible at present to characterise them precisely. Thus blanket statements about undefined properties of the trophoblast are mis-
malignant trophoblast’ diverts attention from
-
and an insupportable basis for constructing a stateabout the significance of recent advances in HLA typing and choriocarcinoma.
leading ment
Surgical Division, Royal Infirmary,
J. MAXWELL ANDERSON
Glasgow G4 0SF
CONGENITAL FOLATE-DEPENDENT MEGALOBLASTIC ANÆMIA OF UNKNOWN ÆTIOLOGY a moderately retarded girl congenital familial megaloblastic anaemia for 15 years by giving her large doses of folic acid to maintain a normal clinical status. She was the product of a consanguineous marriage, and a sister died of severe anaemia in 1959. At age 1 month megaloblastic anxmia was noted. It failed to respond to parenteral vitamin B12 associated with small ("physiological") doses of folinic acid. Only with large ("pharmacological") doses of oral folic acid or parenteral folinic acid was recovery complete. Therefore, permanent therapy with oral folic acid (5 mg daily) was prescribed. Vitamin B,2 (1000 jj.g weekly) was added to folic acid to prevent possible neurological disturbances.’ Discontinuation of vitamin B,, had no
SIR,-We have been treating
with
a
of
clinical or haematological effects. When the patient was 13 vears old, a progressive irritability was the first manifestation of a severe megaloblastic ansmia which failed to respond to her usual dosage (5 mg daily) of folic acid. At this time the patient had severe anaemia (Hb 6g/dl), leukopenia (2.3x 109/1), and thrombocytopenia (70x 109/1). Severe purpura, epistaxis, and progressive diminution of vision were noted. Her bone-marrow picture was strikingly megaloblastic. Treatment with parenteral folinic acid (’Leucovorin’) at doses of 20 mg daily was started. After 20 days she had a complete remission of clinical and haematotogical symptoms. When her Hb reached 14 g/dl therapy was continued with oral folic acid (20 mg daily) and vitamin B12 (1000 p.g weekly). In February, 1975, when the patient was 15, treatment was discontinued for 1 month. Her Hb fell to 6.5 g/dl and her bone-marrow showed intense megaloblastic features. Her serum-vitamin-B,2 was 440 pg/ml and her serum-folic-acid was 6 ng/ml. R.B.c. folates were up to 1480 ng/ml. Urine 4-amino-5imidapole carboxamide was absent and there was no abnormal aminoacid pattern in either plasma or urine. Oroticaciduria was not found. Treatment was reinstated with parenteral leucovorin (32 mg daily). A high reticulocyte response was followed by a complete remission of clinical and haematologica! symptoms. When Hb reached normal level, therapy was continued with oral folic acid (30 mg daily) and vitamin B12 (1000 jg weekly). The patient is still receiving folic acid and remains clinically well and haematologically normal. Mental retardation and diminution of vision have not got worse. Our patient does not have a deficiency of either vitamin Bu or folic acid since her serum levels were normal while not on treatment. The increased R.B.c. folate while on folic acid indicated that she does not have an.intracellular deficiency of folic acid. The lack of response to parenteral physiological doses of folinic acid indicates that she is able to reduce folinic acid normally. Some rare megaloblastic ansemias associated with1 either oroticaciduria, 1-5 formiminotransferase deficiency,"
15. Hill, C. A., Finn, R., Denye, V. Br. med. J. 1973, iii, 513. 16. Kasakura, S. J. Immun. 1971, 107, 1296. 17. Stimson, W. H. Clin. exp. Immun. 1976, 25, 199. 18. Ceppellini, R., Bonnard, G. D., Coppo, F., Miggiano, V. C., Pospish, M., Curtoni, E. S., Pellegrino, M. Transplant. Proc. 1971, 3, 58. 19. Hellstrom, K. E. Hellstrom, I. Brawn, J. Nature, 1969, 224, 914. 20. Leventhal, B. G., Buell, D. N., Yankee, R., Rogentine, G. N. Terasaki, P. Proc. 5th Leucocyte Culture Conf. 1970, p. 473. 21. Youtananukorn, V., Matangkasombut, P. Nature new Biol. 1973, 242, 110. 22. Berne, B. H. Fed Proc. 1974, 33, 290. 23. Stimson, W. H. I.R.C.S. med. Sci. 1973, (73-3) 17-1-3. 24. Than, G. N., Csaba, I. F., Karg, N. J., Szabo, D. G., Novak, P. F. ibid. 1975b, 3, 94.
1. Will J. J., Mueller, J. F., Brodine, C., Kiely, C. E., Friedman, B., Hawkins, V. R., Dutra, J., Vilter, R. W. J. Lab. clin. Med. 1959, 53, 22. 2. Heinle, R. W., Welch, A. D. Am. med. Ass. 1947, 133, 739. 3. Huguley, C. M., Bain, J. A., Rivers, S. L., Scoggins, R. B. Blood, 1959,14, 615. 4. Bercroft, D. M., Philips, L. I. Br. med. J. 1965, i, 547. 5. Haggard, M. E., Lockhard, L. H. Am. J. Dis. Child. 1967, 113, 733. 6. Arakawa, T., Ohara, K., Kudo, Z., Tada, K., Hayashi, T., Mizuno, T. Tohoku. J. exp. med. 1963, 80, 370. 7. Arakawa, T., Takahashi, Y., Ogasawara, J., Hayashi, T., Chiba, R., Wada, Y., Tada, K., Mizuno, T., Okamura, T., Yoshida, T. Ann. Paediat. 1965, 205, 1.
9. Clark, B. S., Dawson, P. J. Am. J. Med 1969, 47, 314. 10. Shreiner, D. P. J. Am. med. Ass. 1975, 231, 838. 11. Lancet, 1976, ii, 1232. 12. Anderson, J. M. Nature, 1966, 206, 786. 13. Anderson, J. M. Proc. R. Soc. B. 1970, 176, 115. 14. Anderson, J. M. Nature’s Transplant: the Transplantation
Immunology
Viviparity; p. 45. London, 1972.
263
N’-methyltetrahydrofolate transferase deficiency, or increased need for thiamine9 have been reported in children. These ansmias are unresponsive to folic acid or vitamin B, Z. Lampkin et at.’" described two cases of congenital familial megaloblastic anaemia responsive only to folic acid and vitamin B12 given together in large doses, even though neither deficiency could be demonstrated in their patients. Our patient responded to large doses of folic or folinic acid given alone; addition of vitamin B12 was not necessary. Discontinuation of folic acid results promptly in a megaloblastic anaemia. The biochemical defect in this megaloblastic anaemia could lie in the conversion of dU.M.P. to T.M.P. necessary for D.N.A. synthesis, as presumed by Lampkin et al. 10 The spectacular recovery from megaloblastic anaemia upon administration of folic acid seems to exclude a congenital deficiency of the enzyme thymidylate synthetase. However, a binding defect of the enzyme so that the steric relationship with her coenzyme (tetrahydrofolic acid) is impaired seems to be a possibility. Postgraduate School of Hæmatology "Farreras Valenti", Hospital Clinico y Provincial, Central University of Barcelona,
J. VIVES MANE
Barcelona 11, Spain
C. ROZMAN
J. L. VIVES-CORRONS
FACTOR-VIII COMPLEX FETAL GROWTH RETARDATION, AND TOXÆMIA
SIR,-We greatly appreciated the letter from Dr Howie and others (Aug. 14, p. 323) on the use of coagulation tests to predict the clinical progress of pre-eclampsia. We have studied the levels of factor vin in this condition, and our results strongly suggest that the dosage of factor-vm-related antigen is a more sensitive index than the assessment of factor-vni procoagulant activity in predicting the fetal prognosis. Four groups of pregnant women were studied: (A) 14 patients without any symptom of toxaemia but with idiopathic fetal growth retardation; (B) 17 patients with symptoms of toxsmia in the last weeks of pregnancy but without further fetal growth retardation; (C) 16 patients with early toxaemia and subsequent fetal growth retardation (followed, in 6 cases, by perinatal death); and (D) 72 control pregnant women who had no signs of toxaemia or fetal growth retardation. Each patient was studied at least once during pregnancy, at delivery, 8. Arakawa, T., Narishawa, K., Tanno, K., Ohara, K., Higashi, O., Homda, Y., Tamura, T., Wada, Y., Mizuno, T., Hayashi, T. Tohoku. J. exp. Med. 1967, 93, 1. 9. Rogers, L. E., Porter, E. S., Sidbury, J. B. J. Pediat. 1969, 74, 494. 10. Lampkin, B. C., Pyesmany, A., Hyman, C. B., Hammond, D. Blood, 1971, 11
37, 515. Weiss, H. J., Hoyer L. W., Rickles, vest. 1973, 52, 2708.
F.
R., Varma, A., Rogers, J. J. clin.
In-
and 48 h later. Factor-VIII procoagulant activity (vmc), von Willebrand factor (VIIIVW.F.), and vm-related antigen (viiirag) were measured, respectively, by the one-stage assay, the ristocetin assay as described by Weiss,’ and Laurell’s immuno-
electrophoresis.1 The results are summarised in the table. As previously described,13-15 in all four groups studied, the three components of factor-vm complex increased during pregnancy, reached a maximum at delivery, and then fell within 48 h. In group A the results for vm rAg, VIII VW.F., and VIIIC were nearly identical to controls. In group B only the values for viiirag during the 35th-40th week were significantly different from controls. In group C the values for vmrAg/vmvw.F. were different from controls as early as the 28th-34th week. These significant differences are in keeping with the onset of toxaemic symptoms and in 2 cases they preceded the onset of clinical toxaemia. Many workers3 16 17 have pointed out a similar discrepancy between VIIIrAg/VIIIVW.F. and VIIIC (ratio VIIIC/VIIIrAg <1). So far, the exact significance of this is not clear. However, two hypotheses can be suggested-a molecular abnormality of factor viiirag or a partial inactivation of factor vm by thrombin in the case of disseminated intravascular coagulation. Histological studies on placentas in toxaemia show signs of chronic ischaemia, arterial thrombosis, or infarcts.18 The earlier the ohset of toxaemia, the more severe is the fetal growth retardation. Similar changes have been seen in other disorders-including glomerulonephritis/9 chronic arteritis obliterans, diabetes, and sepsis.ll Since it has been demonstrated that synthesis of VIIIfAg/VIIIVW.F. (but not vine) occurs in endothelial cells,19 it can be postulated that the increased level of VIIIrAg/VIIIVW.F. is an indicator of the severity of placental
damage. This work was supported by a grant from Delegation GénéraJe a la Recherche Scientifique et Technique (no: 75-7-0950). Laboratoire d’Hémostase, Centre de Transfusion Sanguine, Toulouse
Service de Gynécologie-obstétrique, Hôpital de la Grave, Toulouse, Cedex 31052, France
B. BONEU R. BIERME
A. FOURNIE G. PONTONNIER
12. 13. 14.
Laurell, C. B. Analyt. Biochem. 1966, 15, 45. Bennet, B., Ratnoff, O. D. J. Lab. clin. Med. 1973, 80, 256. Nilsson, I. M., Hedner, U., Astedt, B., Gennser, G., Jacobson, L, Holmberg, L., Ohrlander, S. Acta obstet. gynœc. scand. 1975, 54, 491. 15. Van Royen, E. A., Flier, O. T., Ten-cate, J. W. Lancet, 1974, ii, 657. 16. Bensoussan, D., Levy-Toledano, S., Passa, P., Caen, J., Canivet, J. Diabetologica, 1975, 2, 307. 17. Holmberg, L., Nilsson, I. M. Scand. J. Hœmat. 1974, 12, 221. 18. Bonnar, J., Redman, C. W. G., Sheppard, B. L. Eur. J. Obstet. Gynec. repro. Biol. 1975, 5, 123. 19. Jaffe, E. A., Hoyer, L. W., Nachman, R. L. J. clin. Invest: 1973, 52, 2757. 20. Ekeberg, M., Nilsson, I. M. Lancet, 1975, i, 1111. 21. Boneu, B., Abbal, M., Plante, J., Bierme, R. ibid. p. 1430.
AVERAGE PLASMA-LEVELS OF COMPONENTS OF FACTOR-VIII COMPLEX
*p<0.005
p<0.001 Results are expressed as mean and (in parentheses) confidence interval at 95%. Values for groups A, B, and C were compared to controls using the Fisher test.
(%)
IN TOXAEMIC AND NORMAL PREGNANCY