- Email: [email protected]
Paroxysmal Nocturnal Hæmoglobinuria
194
globinuria may occur in any hoamolytic ansemia when enough free haemoglobin is circulating, and the offer better prospects ; meanwhile they should be commonest cause of haemolytic anaemia is some left for trial in a few hands. circulating agent which destroysred cells. In do views on the of various treatments Why efficacy acquired hæmolytic aneemia a circulating antibody differ so greatly among honest and scientifically is responsible ; but in paroxysmal nocturnal haemominded men ? WILLIAMS et al.,8 in a survey of 1044 globinuria (P.N.H.) the red cell is at fault and there cases of breast cancer, have shown that there was very are no abnormal circulating haemolysins. DACm and
still in the experimental stage, are widely adopted, is it essential to make sure that they are safe and really
are
little difference in the end-results between radical and local treatment: it did not seem to matter much what was done. The reason for this may perhaps be found in the view that the great majority of carcinomata are either curable or incurable by present-day methods when they are first found. The curable carcinomata have not spread beyond their site of origin and are cured by almost any form of treatment. The incurable growths have already escaped beyond the limits of all the tested forms of treatment. Surgery, so far from prolonging life, may actually shorten it, though it may reduce discomfort. The method of treatment may thus matter only in a fairly small proportion of patientsperhaps some 10% in whom a carcinoma has spread only a short distance outside the breast. If this is so, superior results from a particular treatment in 10% of a series may be lost in a mass of variables unless enormous numbers are considered. Even then the difference, expressed as a percentage, would be small,
FIRTH1 showed that normal red cells transfused into a patient with P.N.H. survive for a normal time, and DACm and MOLLISON2 showed that when red cells from a patient with P.N.H. are transfused into a normal person they are rapidly destroyed. HAM3 found that the red cells in r.N.H. are rapidly hæmolysed in vitro in their own plasma or in normal plasma, whereas normal control cells are unaffected by either. CLAPP et awl. and CROSBY 5 have studied the plasma haemolytic system that is responsible for the excessive destruction of red blood-cells in P.N.H., and have shown that the activity of this system depends on a balance between two heemolytic factors, stable and labile, and two inhibitory factors, also stable and labile ; calcium and magnesium ions are also essential factors. CROSBY and DAMESHEK 6 observed that the stable inhibitory factor is easily destroyed by thrombin. In-vitro tests showed that small amounts of thrombin greatly increased the haemolysis when P.N.H. cells were suspended in their own plasma; though statistically significant. It is hardly fair, but none the less necessary, and this observation has been utilised in treating the to add philosophic to technical difficulties. It is easy hæmolytic crises of the disease. The hsemolytic reaction is thought to be enzymatic ; and HARRIS to measure the quantity of life but impossible to and his co-workersconsider that it is a proteolytic In theory at least, most of us measure its quality. If so, the abnormality is probably in the would prefer not " to live a life half dead, a living reaction. death." Certainly, length of survival is not the sole stromal proteins of the cells, and this is supported yardstick for measuring success in the treatment of by the observation that other blood elementsbreast cancer. leucocytes and platelets—are also abnormal.8 In P.N.H. abnormal haemoglobins are not present in the red cells ; and there are none of the odd shapes and Nocturnal fragmented cells such as are seen in Mediterranean was first described as long ago THIS odd ansemia. Splenectomy used to be recommended in as 1911 by MARCA and NAZARI, though a P.N.H., but the results were disappointing and the really complete description was not given until present view is that the spleen plays little part in the twenty years later by MICHELI. The affected patient hæmolytic system and that splenectomy does not notices that the urine he passes when he first gets mitigate the haemolysis at all. Splenomegaly is up in the morning is a dark port-wine shade, and uncommon, until blood-transfusions are given. The usually he puts this down to " blood in the water." haemoglobinuria that is a prominent feature of the If he delays visiting his doctor until the evening disease is much commoner than in other hæmolytic and passes a specimen of urine for the doctor to diseases and shows odd variations in intensity. examine, he is astonished and disconcerted to find CROSBY 8 points out that in most hæmolytic diseases that this appears quite normal. The matter is settled the red cells are destroyed mainly in the reticulowhen the patient brings one of the first morning endothelial system (in the spleen, for instance) and specimens for examination and it is found to contain much of the released haemoglobin never gets into the haemoglobin but not red cells. The patient usually circulating blood ; but in P.N.H. most, if not all, of looks anæmic, and it is now known that nocturnal the red cells are destroyed in the blood-stream and hæmoglobinuria is always accompanied by a haemolytic the haemoglobin therefore goes directly into the type of anaemia. plasma. The " nocturnal " part of the syndrome is J. V. DACIE and his co-workers in this country, related to sleep and not to the clock ; if the patient and T. H. HAM and, more recently, W. H. CROSBY sleeps during the day, the rhythm is reversed. HAM9 in the U.S.A., have contributed much valuable inforand DACIE et apo have shown that increased acidity mation. Hæmoglobinuria occurs whenever the con1. Dacie, J. V., Firth, D. Brit. med. J. 1913, i, 626. centration of free haemoglobin in the plasma rises 2. Dacie, J. V., Mollison, P. L. Lancet, 1949, i, 390. 3. Ham, T. H. Arch. intern. Med. 1939, 64, 1271. above the threshold for renal excretion ; in normal 4. Clapp, M. P., Williams, M. J., Mende, J. L. Blood, 1952, 7, 1117. this is about 130 100 but in 5. Crosby, W. H ml., Ibid, 1953, 8, 444. mg. per persons 6. Crosby, W. H., Dameshek, W. Ibid, 1950, 5, 822. chronic hsemoglobinuria the threshold may be lower7. Harris, J. W., Jordan, W. S., Pillemer, L., Desforges, J. F. J. clin. Invest. 1951, 30, 646. about 50-100 mg. per 100 ml. Consequently hsemo’
Paroxysmal
8. Wmiams, I. G., Murley, R.
1953, ii, 787.
Hæmoglobinuria
S., Curwen,
M. P.
Brit. med. J.
8. Crosby, W. H. Blood, 1953, 8, 769. 9. Ham, T. H. New Engl. J. Med. 1937, 217, 915. 10. Dacie, J. V., Israëls, M. C. G., Wilkinson, J. F. Lancet, 1938, i, 479.
195
of the blood, which develops during sleep, increases tion of that part of the reticulo-endothelial system haemolysis in P.N.H., but probably other factors are which produces the proteins of the stroma of red responsible as well. The hæmoglobinuria varies also blood-cells and of other blood elements. with the intensity of the hæmolytic activity in the Infantile Gastro-enteritis plasma. The disease is subject to spontaneous remissions lasting several weeks ; but there are also THE death-rate from enteritis in children under long-term improvements when the whole syndrome two years of age has fallen remarkably since 1945. seems to die down, and this sort of change is probably Dr. IAN TAYLOR, in an article on p. 202, suggests that related to increased resistance of the patient’s red this is due to improved treatment, and notably cells. Excretion of hæmosiderin in the urine has more largely use of intravenous saline infusions ; general been regarded as diagnostic of P.N.H. in periods free but he out that the reduction may also be related points from hæmoglobinuria ; CROSBY and DAMESHEK,11 to the increased use of dried milk. He remarks on the however, point out that hæmosiderinuria can be of assessing individual factors, one of which, found also in other diseases associated with persistent difficulty he says, is a reduced incidence of the severe epidemic and pronounced hæmoglobinæmia. form of this disorder. 12 In a complementary article, One of the difficulties in the management of P.N.H. the L.C.C. department3 review a group is that the patients are unusually liable to transfusion of cases in public-health infants admitted in 1949-50 to hospitals reactions and to a hæmolytic crisis after administra- in two London areas. They find that the incidence tion of drugs and in other circumstances. The was higher in the larger families and in those with reaction after transfusion is not due to the usual sort social conditions. Many such families of incompatibility, because it is the patient’s own subaverage utilised residential nurseries, where the risk of gastrored cells and not the donor cells that are destroyed ; enteritis was relatively great ; and they were unusually DAMESHEK and NEBER 12 found that the agent liable to domestic upsets as a result of which infants responsible is in the donor’s plasma, and these had to be looked after by someone other than their post-transfusion hæmolytic reactions can be avoided mother and were therefore particularly exposed to by washing the donor cells. Among drugs that have infection. (In Canada, by contrast, socio-economic caused, or been followed by, hæmolytic reactions are factors do not seem to bear on the incidence of the the arsenicals and substances of the nitrogen-mustard disease.2) The L.C.C. workers report that, in the case group. Various foods, including fish and meat,8 of illegitimate children, financial need may result in the are reported to have provoked crises. Anxiety abandonment of as they The treatment early seems to be responsible in other cases. an emphasise, is important preventive factor. of P.N.H. is not easy. Splenectomy has been tried rightly WOLFISH2 found that in less than 1% of the cases of and abandoned. Blood-transfusion does no more than admitted to the Hospital for Sick tide the patient over the immediate hæmolytic gastro-enteritis Children in Toronto was the infant entirely breast-fed crisis, and sometimes may actually make things when the symptoms first developed ; and the Oxford worse; then transfusion of washed red cells, with 4 also showed that full breast-feeding was all its attendant technical difficulties, has to be used. survey for necessary protection. Ross and her colleagues 5 6 tried success. have been without Since Many drugs in Glasgow have noted this, and have found that P.N.H. is not due to excessive antibody activity, it is faeces from fully breast-fed infar:<;,..have a predominot surprising that corticotrophin and cortisone have flora of 5-5 to 5-0, lactobacillary failed to influence the anæmia. Adrenaline, however, nating whereas the faeces from artificially fed infants have a can inhibit a crisis temporarily. A different line of pH of 7-0 to 9-0. Ross has also established that a treatment is based on the observation that thrombin feed leads to loss of the lactoformation causes destruction of the heat-stable single supplementary element and a rise in the pH of the fæces P.N.H. inhibitory factor. CROSBY 8 points out that bacillary which no further dietary change will reverse, and that this leads to increased P.N.H. hæmolytic activity with hexosamine is in human milk but absent destruction of P.N.H. red cells and also of P.N.H. from cow’s milk.present This is supported by the work of platelets. The destruction of platelets releases GYÖRGY,7 who isolated from human milk N-acetyl thromboplastin ; this will be followed by the con- glucosamine, which is a specific growth factor for version of some prothrombin to thrombin, and the Lactobacillus bifidus. thrombin will then destroy more P.N.H. inhibitor ; CRUICKSHANK6 has observed that a third of the so a cycle is set up. Anticoagulants of the dicoumarol admitted to hospital with enteritis come type break this cycle at the stage of prothrombin- patients from institutions. In 68% of the cases reviewed in thrombin conversion, and dicoumarol has been given the L.C.C. report the patient had been in communal to patients with P.N.H. in an attempt to slow the accommodation, a outpatient department, hæmolysis. Sometimes this treatment is successful ; or a welfare centre ;hospital and almost half of the patients and dicoumarol, or the related drugs ethyl biscoumhad been in contact with other children with diarrhcea. acetate (’Tromexan’) and phenylindanedione are The report says that half the infants sent to hospital worth trying. Heparin must not be used, because with a diagnosis of gastro-enteritis were found on in the plasma concentrations obtained clinically it admission to have the disease very mildly or not at all. actually increases hæmolysis. The practitioner who is handicapped in his treatment All these points are discussed in detail by CROSBY,8 1. Smith, J. J. Path. Bact. 1953, 66, 503. who points out that we still have no clue to the 2. Wolfish, M. G. J. Pediat. 1953, 43, 675. 3. Scott, J. A. Brit. J. prev. soc. Med. 1953, 7, 194. of the disease. The ætiology present hypothesis 4. Stewart, A., Westropp, C. Brit. med. J. 1953, ii, 305. is that it is caused by a more or less permanent altera5. Ross, C. A. C. Brit. J. Nutr. 1953, 7, 259.
breast-feeding-which,
and a pH
11. Crosby, W. H., Dameshek, W. J. Lab. clin. Med. 1951, 38, 829. 12. Dameshek, W., Neber, J. Blood, 1950, 5, 129.
6. Ross, C. A. C., Dawes, E. Lancet (in the press). 7. György, P. Pediatrics, 1953, 11, 98. 8. Cruickshank, R. S. Lancet, 1953, ii, 185.
globinuria may occur in any hoamolytic ansemia when enough free haemoglobin is circulating, and the offer better prospects ; meanwhile they should be commonest cause of haemolytic anaemia is some left for trial in a few hands. circulating agent which destroysred cells. In do views on the of various treatments Why efficacy acquired hæmolytic aneemia a circulating antibody differ so greatly among honest and scientifically is responsible ; but in paroxysmal nocturnal haemominded men ? WILLIAMS et al.,8 in a survey of 1044 globinuria (P.N.H.) the red cell is at fault and there cases of breast cancer, have shown that there was very are no abnormal circulating haemolysins. DACm and
still in the experimental stage, are widely adopted, is it essential to make sure that they are safe and really
are
little difference in the end-results between radical and local treatment: it did not seem to matter much what was done. The reason for this may perhaps be found in the view that the great majority of carcinomata are either curable or incurable by present-day methods when they are first found. The curable carcinomata have not spread beyond their site of origin and are cured by almost any form of treatment. The incurable growths have already escaped beyond the limits of all the tested forms of treatment. Surgery, so far from prolonging life, may actually shorten it, though it may reduce discomfort. The method of treatment may thus matter only in a fairly small proportion of patientsperhaps some 10% in whom a carcinoma has spread only a short distance outside the breast. If this is so, superior results from a particular treatment in 10% of a series may be lost in a mass of variables unless enormous numbers are considered. Even then the difference, expressed as a percentage, would be small,
FIRTH1 showed that normal red cells transfused into a patient with P.N.H. survive for a normal time, and DACm and MOLLISON2 showed that when red cells from a patient with P.N.H. are transfused into a normal person they are rapidly destroyed. HAM3 found that the red cells in r.N.H. are rapidly hæmolysed in vitro in their own plasma or in normal plasma, whereas normal control cells are unaffected by either. CLAPP et awl. and CROSBY 5 have studied the plasma haemolytic system that is responsible for the excessive destruction of red blood-cells in P.N.H., and have shown that the activity of this system depends on a balance between two heemolytic factors, stable and labile, and two inhibitory factors, also stable and labile ; calcium and magnesium ions are also essential factors. CROSBY and DAMESHEK 6 observed that the stable inhibitory factor is easily destroyed by thrombin. In-vitro tests showed that small amounts of thrombin greatly increased the haemolysis when P.N.H. cells were suspended in their own plasma; though statistically significant. It is hardly fair, but none the less necessary, and this observation has been utilised in treating the to add philosophic to technical difficulties. It is easy hæmolytic crises of the disease. The hsemolytic reaction is thought to be enzymatic ; and HARRIS to measure the quantity of life but impossible to and his co-workersconsider that it is a proteolytic In theory at least, most of us measure its quality. If so, the abnormality is probably in the would prefer not " to live a life half dead, a living reaction. death." Certainly, length of survival is not the sole stromal proteins of the cells, and this is supported yardstick for measuring success in the treatment of by the observation that other blood elementsbreast cancer. leucocytes and platelets—are also abnormal.8 In P.N.H. abnormal haemoglobins are not present in the red cells ; and there are none of the odd shapes and Nocturnal fragmented cells such as are seen in Mediterranean was first described as long ago THIS odd ansemia. Splenectomy used to be recommended in as 1911 by MARCA and NAZARI, though a P.N.H., but the results were disappointing and the really complete description was not given until present view is that the spleen plays little part in the twenty years later by MICHELI. The affected patient hæmolytic system and that splenectomy does not notices that the urine he passes when he first gets mitigate the haemolysis at all. Splenomegaly is up in the morning is a dark port-wine shade, and uncommon, until blood-transfusions are given. The usually he puts this down to " blood in the water." haemoglobinuria that is a prominent feature of the If he delays visiting his doctor until the evening disease is much commoner than in other hæmolytic and passes a specimen of urine for the doctor to diseases and shows odd variations in intensity. examine, he is astonished and disconcerted to find CROSBY 8 points out that in most hæmolytic diseases that this appears quite normal. The matter is settled the red cells are destroyed mainly in the reticulowhen the patient brings one of the first morning endothelial system (in the spleen, for instance) and specimens for examination and it is found to contain much of the released haemoglobin never gets into the haemoglobin but not red cells. The patient usually circulating blood ; but in P.N.H. most, if not all, of looks anæmic, and it is now known that nocturnal the red cells are destroyed in the blood-stream and hæmoglobinuria is always accompanied by a haemolytic the haemoglobin therefore goes directly into the type of anaemia. plasma. The " nocturnal " part of the syndrome is J. V. DACIE and his co-workers in this country, related to sleep and not to the clock ; if the patient and T. H. HAM and, more recently, W. H. CROSBY sleeps during the day, the rhythm is reversed. HAM9 in the U.S.A., have contributed much valuable inforand DACIE et apo have shown that increased acidity mation. Hæmoglobinuria occurs whenever the con1. Dacie, J. V., Firth, D. Brit. med. J. 1913, i, 626. centration of free haemoglobin in the plasma rises 2. Dacie, J. V., Mollison, P. L. Lancet, 1949, i, 390. 3. Ham, T. H. Arch. intern. Med. 1939, 64, 1271. above the threshold for renal excretion ; in normal 4. Clapp, M. P., Williams, M. J., Mende, J. L. Blood, 1952, 7, 1117. this is about 130 100 but in 5. Crosby, W. H ml., Ibid, 1953, 8, 444. mg. per persons 6. Crosby, W. H., Dameshek, W. Ibid, 1950, 5, 822. chronic hsemoglobinuria the threshold may be lower7. Harris, J. W., Jordan, W. S., Pillemer, L., Desforges, J. F. J. clin. Invest. 1951, 30, 646. about 50-100 mg. per 100 ml. Consequently hsemo’
Paroxysmal
8. Wmiams, I. G., Murley, R.
1953, ii, 787.
Hæmoglobinuria
S., Curwen,
M. P.
Brit. med. J.
8. Crosby, W. H. Blood, 1953, 8, 769. 9. Ham, T. H. New Engl. J. Med. 1937, 217, 915. 10. Dacie, J. V., Israëls, M. C. G., Wilkinson, J. F. Lancet, 1938, i, 479.
195
of the blood, which develops during sleep, increases tion of that part of the reticulo-endothelial system haemolysis in P.N.H., but probably other factors are which produces the proteins of the stroma of red responsible as well. The hæmoglobinuria varies also blood-cells and of other blood elements. with the intensity of the hæmolytic activity in the Infantile Gastro-enteritis plasma. The disease is subject to spontaneous remissions lasting several weeks ; but there are also THE death-rate from enteritis in children under long-term improvements when the whole syndrome two years of age has fallen remarkably since 1945. seems to die down, and this sort of change is probably Dr. IAN TAYLOR, in an article on p. 202, suggests that related to increased resistance of the patient’s red this is due to improved treatment, and notably cells. Excretion of hæmosiderin in the urine has more largely use of intravenous saline infusions ; general been regarded as diagnostic of P.N.H. in periods free but he out that the reduction may also be related points from hæmoglobinuria ; CROSBY and DAMESHEK,11 to the increased use of dried milk. He remarks on the however, point out that hæmosiderinuria can be of assessing individual factors, one of which, found also in other diseases associated with persistent difficulty he says, is a reduced incidence of the severe epidemic and pronounced hæmoglobinæmia. form of this disorder. 12 In a complementary article, One of the difficulties in the management of P.N.H. the L.C.C. department3 review a group is that the patients are unusually liable to transfusion of cases in public-health infants admitted in 1949-50 to hospitals reactions and to a hæmolytic crisis after administra- in two London areas. They find that the incidence tion of drugs and in other circumstances. The was higher in the larger families and in those with reaction after transfusion is not due to the usual sort social conditions. Many such families of incompatibility, because it is the patient’s own subaverage utilised residential nurseries, where the risk of gastrored cells and not the donor cells that are destroyed ; enteritis was relatively great ; and they were unusually DAMESHEK and NEBER 12 found that the agent liable to domestic upsets as a result of which infants responsible is in the donor’s plasma, and these had to be looked after by someone other than their post-transfusion hæmolytic reactions can be avoided mother and were therefore particularly exposed to by washing the donor cells. Among drugs that have infection. (In Canada, by contrast, socio-economic caused, or been followed by, hæmolytic reactions are factors do not seem to bear on the incidence of the the arsenicals and substances of the nitrogen-mustard disease.2) The L.C.C. workers report that, in the case group. Various foods, including fish and meat,8 of illegitimate children, financial need may result in the are reported to have provoked crises. Anxiety abandonment of as they The treatment early seems to be responsible in other cases. an emphasise, is important preventive factor. of P.N.H. is not easy. Splenectomy has been tried rightly WOLFISH2 found that in less than 1% of the cases of and abandoned. Blood-transfusion does no more than admitted to the Hospital for Sick tide the patient over the immediate hæmolytic gastro-enteritis Children in Toronto was the infant entirely breast-fed crisis, and sometimes may actually make things when the symptoms first developed ; and the Oxford worse; then transfusion of washed red cells, with 4 also showed that full breast-feeding was all its attendant technical difficulties, has to be used. survey for necessary protection. Ross and her colleagues 5 6 tried success. have been without Since Many drugs in Glasgow have noted this, and have found that P.N.H. is not due to excessive antibody activity, it is faeces from fully breast-fed infar:<;,..have a predominot surprising that corticotrophin and cortisone have flora of 5-5 to 5-0, lactobacillary failed to influence the anæmia. Adrenaline, however, nating whereas the faeces from artificially fed infants have a can inhibit a crisis temporarily. A different line of pH of 7-0 to 9-0. Ross has also established that a treatment is based on the observation that thrombin feed leads to loss of the lactoformation causes destruction of the heat-stable single supplementary element and a rise in the pH of the fæces P.N.H. inhibitory factor. CROSBY 8 points out that bacillary which no further dietary change will reverse, and that this leads to increased P.N.H. hæmolytic activity with hexosamine is in human milk but absent destruction of P.N.H. red cells and also of P.N.H. from cow’s milk.present This is supported by the work of platelets. The destruction of platelets releases GYÖRGY,7 who isolated from human milk N-acetyl thromboplastin ; this will be followed by the con- glucosamine, which is a specific growth factor for version of some prothrombin to thrombin, and the Lactobacillus bifidus. thrombin will then destroy more P.N.H. inhibitor ; CRUICKSHANK6 has observed that a third of the so a cycle is set up. Anticoagulants of the dicoumarol admitted to hospital with enteritis come type break this cycle at the stage of prothrombin- patients from institutions. In 68% of the cases reviewed in thrombin conversion, and dicoumarol has been given the L.C.C. report the patient had been in communal to patients with P.N.H. in an attempt to slow the accommodation, a outpatient department, hæmolysis. Sometimes this treatment is successful ; or a welfare centre ;hospital and almost half of the patients and dicoumarol, or the related drugs ethyl biscoumhad been in contact with other children with diarrhcea. acetate (’Tromexan’) and phenylindanedione are The report says that half the infants sent to hospital worth trying. Heparin must not be used, because with a diagnosis of gastro-enteritis were found on in the plasma concentrations obtained clinically it admission to have the disease very mildly or not at all. actually increases hæmolysis. The practitioner who is handicapped in his treatment All these points are discussed in detail by CROSBY,8 1. Smith, J. J. Path. Bact. 1953, 66, 503. who points out that we still have no clue to the 2. Wolfish, M. G. J. Pediat. 1953, 43, 675. 3. Scott, J. A. Brit. J. prev. soc. Med. 1953, 7, 194. of the disease. The ætiology present hypothesis 4. Stewart, A., Westropp, C. Brit. med. J. 1953, ii, 305. is that it is caused by a more or less permanent altera5. Ross, C. A. C. Brit. J. Nutr. 1953, 7, 259.
breast-feeding-which,
and a pH
11. Crosby, W. H., Dameshek, W. J. Lab. clin. Med. 1951, 38, 829. 12. Dameshek, W., Neber, J. Blood, 1950, 5, 129.
6. Ross, C. A. C., Dawes, E. Lancet (in the press). 7. György, P. Pediatrics, 1953, 11, 98. 8. Cruickshank, R. S. Lancet, 1953, ii, 185.