854 The
following day the baby was operated on and Nissen’s was performed. After the operation the baby extubated and the remainder of the postoperative course uneventful. The baby is now 10 months old and doing
120 ml of clear fluid
fundoplication
diorespiratory
was
cessful.
was
arrest
Discussion
well. Case 2 A male Arab baby was born at home after a normal pregnancy. Delivery was normal and birth-weight was 3000 g. The baby did not pass meconium and 3 days after birth was admit-
ted to hospital where the imperforate anus was treated by anoplasty. Since then the baby continued to have constipation, abdominal distention, and occasional vomiting and had bowel movements once in 10-20 days. The baby was referred to our hospital for evaluation when he was 10 months old. Examination on admission showed a well-developed baby weighing 7300 g. The abdomen was moderately distended but no other abnormality was found. Hirschsprung’s disease was diagnosed after barium enema and suction biopsy from the rectum and the infant was operated upon. At laparotomy an aganglionic segment of large bowel was found to extend up to the sigmoid colon. Sigmoid-loop colostomy was performed. Because of difficulties in infusing into a peripheral vein, percutaneous cannulation of the right internal jugular vein was done one day after operation. The i.v. line was connected to an infusion pump. 12 h later severe respiratory distress developed. Pronounced cyanosis and intercostal and subcostal retraction were noted. Diminished air-entry was heard over the right lung field. Chest X-ray revealed a markedly widened mediastinum and fluid in the right pleural cavity. The cannula was immediately removed from the internal jugular vein, and
Preliminary
Communication
ANTITHROMBIN-III TRANSFUSION IN DISSEMINATED INTRAVASCULAR COAGULATION CHARLES S. P. JENKINS JAN. W. TEN CATE
HANS G. SCHIPPER LAURENS H. KAHLÉ
Hæmostasis, Department of Hæmatology, University Hospital Wilhelmina Gasthuis, Amsterdam, The Division of
If extravasation occurs, the infusion pump will cause continuous infiltration and rising pressure in closed compartments. In peripheral infusions this may result in severe cellular damage to skin and subcutaneous tissues, and skin grafting may be needed.2 In central-vein infusions mediastinal extravasation may occur. Pressure building up in the mediastinum results in serious respiratory disturbances, and if these are not detected in time, impaired venous return may lead to death. Case 1 required assisted ventilation via an endotracheal tube because of serious respiratory disturbance, and in case 2 pronounced respiratory distress was followed by cardio-
respiratory arrest. The use of infusion pumps to regulate infusions via central veins seems to be especially dangerous in neonates and infants. Infusion in such patients should be controlled by devices which do not develop pressure, and work only on gravity. Requests for reprints
Three
with
patients
a severe
bleeding
disorder and disseminated intravascular coagulation were effectively treated with human antithrombin-III concentrates. This treatment, followed by administration of prothrombin complex and platelet suspensions, resulted in a normal hæmostasis, which was maintained during clinical investigations and surgery. INTRODUCTION
potent inhibitor of actifactors.’ Heparin binds to the lysine
ANTITHROMBIN-III
(AT-III)
is
a
vated coagulation residues of the AT-III molecule, resulting in a complex with a greater affinity for both thrombin and factor xa than that of AT-III alone.22 Heparin infusion has been reported to result in a reduction of AT-III activity,3 which may promote thrombosis. We have observed that thrombosis can occur under- heparin therapy when AT-m activity is low, even at sufficiently prolonged kaolin-cephalin time.4 Thus heparin may be either less effective or even hazardous when AT-III is deficient. AT-III deficiency is seen in liver cirrhosis, intravascular coagulation,6and nephrotic
should be addressed
to
M.S.
REFERENCES 1. Berlatzky, Y., Freund, 2. Lancet, 1976, i, 291.
H., Schiller,
M. Z. Kinderchir.
1976, 18, 231.
It also occurs as a rare inherited defect.’ Patients with low AT-III activities and thrombosis would benefit if AT-III levels could be raised to within normal limits before the start of heparin therapy. We describe here three patients with intravascular coagulation and a severe haemorrhagic diathesis in whom infusion of human AT-111 which had been activated in vitro by a low dose of heparin, followed by infusion of coagulation-factor concentrates and platelet suspensions, induced a near-normal haemostatic state.
syndrome.7
PATIENTS
Netherlands
Summary
aspirated by pleural puncture. Cardeveloped and resuscitation was unsuc-
was
Patient A.-A 54-year-old man with liver cirrhosis was admitted for recurrent gastrointestinal bleeding. Endoscopy revealed bleeding oesophageal varices. During observation bleeding recurred, and the coagulation status deteroriated. Blood cultures, which were not obtained until after operation, were positive for Pseudomonas ceruginosa, a known inducer of intravascular coagulation. The antibiotic therapy started postoperatively could therefore not account for the improvement in his haemostatic state before surgery. He underwent left-sided thoracotomy and ligation of the cesophageal varices without haemostatic complications. The further postoperative course
complicated by recurrent gastrointestinal bleeding and high fever. He died from cardiopulmonary complications on the eighth postoperative day. Patient B.-A 72-year-old woman developed progressive jaundice and a severe haemorrhagic diathesis induced by intravascular coagulation. After correction of the haemostatic defect computer-tomographic scanning of the liver suggested the presence of metastases. Necropsy revealed the primary tumour to be a pancreatic carcinoma. Patient C.-A 34-year-old pregnant woman with progressive pain in the liver region underwent a caesarean section because of a decreasing fetal heart-rate due to the sudden development of shock. During surgery, a massive amount of blood was found in the peritoneal cavity. A ruptured subcapsular haematoma was present in the right lobe of the liver. Severe was
855 TABLE II——CHANGES IN BLOOD-VALUES IN PATIENT B
intravascular coagulation contributed to intra-abdominal blood-loss after surgery. Bleeding was controlled by treatment of the intravascular coagulation, and further improvement of the haemostatic state was achieved by transfusion of fresh blood. Further observations revealed that the symptoms presented by the patient were due to essential hypertension. METHODS
activity was measured on an automated kinetic and substrate analyser (Vitatron, Dieren, The Netherenzyme lands). 5 jjd diluted plasma (0-05 ml plasma, 0-33 ml phosphate-buffered saline pH 7-4) was incubated with 0.5ml reaction buffer containing 1000 u/1 heparin, 300 N.I.H. u/1 thrombin, and 75 thrombin-inhibitor units/I aprotinin at 23 °C for 6.5 min. After addition of 0.05 ml ’Chromozym TH’ (1.5 mmol/1) the increase in absorbance per minute is calculated automatically and compared with a reference curve obtained from dilutions of normal plasma.9-12 Other coagulation assays were performed according to standard methods. 13 1500-1725 u human AT-III was dissolved in 50 ml distilled water and activated in vitro before infusion by the addition of AT-III
Infusion of
donors),
500 u 150 u AT-iii +
1500
u AT-m + 500 u heparin; (2) cryoprecipitate (20 (20 donors), and platelets (8 donors); (3) 1500 U AT-III heparin; (4) 1500 U AT-III + 6000 u heparin (in 10 h); (5)
(1)
P.P.S.B. +
900 u heparin/h.
TABLE HI——CHANGES IN BLOOD-VALUES
IN
PATIENT C
heparin (500-1500 u; ’Thromboliquine’, Organon, Oss, The Netherlands). Prothrombin complex (P.P.S.B.) was purchased from the central laboratory of the blood-transfusion service of the Dutch Red Cross, Amsterdam. RESULTS
The critical states of the three patients resulted from different pathological conditions. However, each patient demonstrated intravascular coagulation, with low levels of fibrinogen, a positive ethanol-gelation test, low platelet-count, and low levels of AT-III. The poor haemostatic states were improved after therapy including infusions of human AT-111 concentrates and of human AT-III concentrates activated in vitro with heparin. Patient A.-Infusion with AT-III concentrates (1650 u) increased AT-III activity from 37 to 64%; prothrombin complex (P.P.S.B., 20 donors) was then administered within 20 min and the activities of factors n and x rose almost to normal levels (table I). Fresh-frozen plasma (3 donors), as a source of factor v and fibrinogen, was infused continuously over a period of 2 hours. Because the ethanol-gelation test was still positive, a second infusion of AT-III concentrates (1650 u) was administered. On this occasion AT-m was activated in vitro with heparin (500 u) before infusion. The ethanol-gelation test became negative and remained so during and immediately after the operation. Because the fibrinogen concentration was normal and the level of
fibrinogen/fibrin degradation products low, a false-negative ethanol-gelation test was improbable.14 Hsemostasis was further improved to near normal by infusion of cryoprecipitate as a source of fibrinogen (20 donors) and fresh platelets (8 donors) (table I).
Infusion of (1) platelets
(8 donors); (2) 1725
u AT-m +
1000
u
heparin;
(3) P.P.S.B. (20 donors). Patient B.-1500 U AT-III activated in vitro with 500 heparin increased AT-m activity from 26 to 78%. Transfusion of prothrombin complex (P.P.s.B., 20 donors), cryoprecipitate (20 donors), and platelet suspensions (8 donors) resulted in a striking. improvement of the haemostatic state. However, the ethanol-gelation test remained positive (table 11). A second infusion of activated AT-III concentrates was given as the activity had decreased to 59%, and an equal amount of activated AT-III (1500 U AT-III and 6000 u heparin) was continuously transfused over 10 hours. During this period AT-m activity was stable, indicating an overall AT-111 consumption of about 1500 u in 10 hours (table u). The ethanol-gelation test remained positive, and the other coagulation parameters remained stable. The ethanolgelation test became negative during continuous infusion of more activated AT-III (150 u AT-III and 900 u heparin/h) and remained so when infusion of heparin alone (750 u/h), in the presence of an optimum heparincofactor activity, was continued (table n). Patient C.-Immediately before infusion of AT-III concentrates the ethanol-gelation test became negative. However, the coagulation factors still remained low u
TABLE I-VALUES IN PATIENT A AFTER TREATMENT WITH AT-111 CONCENTRATE
Infusion of
(1)
1650
U
AT-III;
(2)
P.P.S.B.
(20 donors); (3) 1650
U AT-III +
500
u
heparin, cryoprecipitate (20 donors),
and
platelets (8 donors).
856
(table III). Infusion of activated AT-III concentrates (1725 U AT-III and 1000 u heparin) raised AT-III activity from 56 to 106%. Factor-ii activity rose to 97% after infusion of prothrombin complex (P.P.S.B., 20 donors) (table III). The patient’s haemostatic state was further improved and maintained by transfusion of fresh blood. The bleeding abated in the next 24 hours. DISCUSSION
activity may be easily monitored,9 this find approach may increasing application.
because
AT-Iii
We are indebted to Marian Paap and Marianne Schaap for the coagulation assays and to Prof. Vreeken and Dr R. Goudsmit for their critical reading of this article. We are grateful for the cooperation of our colleagues in the departments of internal medicine and surgery at the Sint Lucas Ziekenhuis and Wilhelmina Gasthuis, Amsterdam. Human AT-Ill concentrates were generously provided by Kabivitrum, Amsterdam. Requests for reprints should be addressed to J.W.T.C.
The three patients described here, although presenting different pathologies, all had intravascular coagulation with low levels of AT-III. AT-III is a known inhibitor of activated coagulation factors’ and can be deficient in disseminated intravascular coagulation.6 In view of this, the patients were infused with AT-III concentrates, this treatment being thought advantageous compared with conventional heparin therapy, since heparin alone may be ineffective at low levels of AT-III (heparin cofactor
activity). Heparin diminishes AT-III levels,3 and low levels of ATIII could then promote intravascular coagulation. We have recently reported our observations on a patient with low AT-III levels who had coagulation complications during haemodialysis despite sufficient heparinisation as indicated by the kaolin clotting-time.4 During intravascular coagulation levels of coagulation factors may fall. Infusion of prothrombin complex in patients with intravascular coagulation and low levels of AT-III may maintain this process as well as increase the risk of thrombosis (unpublished observations); raising AT-III levels is necessary to minimise such complications. It was also considered advantageous to first activate AT-III in vitro by the addition of a small amount of heparin before infusion. Heparin-AT-III complexes inhibit activated coagulation factors at a faster rate than AT-III alone.2 In this manner, less heparin is lost by interaction with other plasma proteins. We found this approach effective in the treatment of intravascular coagulation in our patients. In one patient (B), the ethanolgelation test was negative only after prolonged heparinisation once plasma-AT-III levels had been returned to normal. The stimulus of intravascular coagulation in this patient was highly potent, as indicated by the consumption of 1500 U AT-III during a 10-hour period. Although in patient C the ethanol-gelation test was negative just before infusion of AT-III concentrates, the AT-III level and the levels of the coagulation factors were low. In view of this, the patient was treated in the same way as the others, since the optimum haemostatic state would contribute to the control of this patient’s severe intra-abdominal bleeding. In all three patients presented, after AT-III levels had been made normal, normal or near normal levels of coagulation factors and platelets could be maintained. In this way the bleeding tendencies were controlled, and further clinical investigations and surgery in one patient (A) were undertaken under good hsemostatic conditions. The haemostatic state of all three patients improved within a short time of correction of AT-III activity. Although correction of AT-III levels is advocated, the basic therapy for intravascular coagulation still depends on the primary cause. Therefore raising AT-III levels should be thought of as an additional therapy in the treatment of patients with intravascular coagulation. As more human AT-III concentrate becomes available and
REFERENCES 1. 2.
Abildgaard, U. Scand. J. clin. Lab. Invest. 1967, 19, Abildgaard, U. ibid. 1968, 21, 89.
190.
Marciniak, E., Gockerman, J. Lancet, 1977, ii, 581. Schipper, H. G., Kahlé, L. H., Jenkins, C. S. P., ten Cate, J. W., Veenhof, C., Sinaasappel, M. ibid. 1978, i, 209. 5. Von Kaulla, E., von Kaulla, K. N. Am.J. clin. Path. 1967, 48, 69.
3. 4.
6. 7.
Bick, R., Kovacs, I., Fekete, L. Thromb. Res. 1976, 8, 745. Kaufmann, R. H., Graeff, J. de, Brutel de la Riviere, G., Es, J. Med. 1976, 60, 1048.
8. 9.
Egeberg, O.
Thromb. Diath.
L. van, Am.
hæmorrh. 1965, 13, 516.
Kahlé, L. H., Schipper, H. G., Jenkins, C. S. P.,
ten
Cate, J. W. Thromb.
Res. (in the press). 10.
Blomback, M., Blomback, B., Olsson, P., Svendssen, L. Thromb. Res. 1974,
5, 621. Odegard, O. R. ibid. 1975, 7, 351. Odegard, O. R., Lie, M., Abildgard, U. Thromb. Res. 1975, 6, 287. Biggs, R. Human Blood Coagulation, Hæmostasis and Thrombosis; p. 504. Oxford, 1976. 14. Gerrits, W. B. J. Thesis, University of Amsterdam, 1974. 11. 12. 13.
SELECTIVE DEFICIENCY OF
3-&bgr;-D-GALACTOSYLTRANSFERASE (T-TRANSFERASE) IN
Tn-POLYAGGLUTINABLE ERYTHROCYTES
J. P. CARTRON G. ANDREU
J. CARTRON CH. SALMON
Groupe U76 de Recherches de l’INSERM et Service d’Immunologie du Centre National de Transfusion Sanguine, 75739 Paris, France
G. W. G. BIRD
Regional Blood Transfusion Service, Birmingham B15 2SG
single genetic defect in membrane synthesis—namely, a deficiency of 3-&bgr;-Dgalactosyltransferas—can account for the serological and physicochemical properties of Tn-polyagglutinable erythrocytes.
Summary
A
Tn-polyagglutinability (persistent mixed-field polyagglutinability) is an acquired condition in which there are two erythrocyte populations; one is normal and in the other the Tn cryptantigen is exposed.’ Anti-Tn is present in most normal human adult sera. The condition may be associated with haemolytic ansemia, and, since leucocytes and platelets are similarly affected, there is usually leucopenia and thrombocytopenia.1 Tn polyagglutinability may be associated with leukmmiaand may indeed be a preleukaemic state.3 The Tn receptor may also be exposed in the cells of breast and other cancers.There has therefore been much interest in the molecular basis of Tn polyagglutin-
ability.5-’ Tn is
an
intermediate stage in the
biosynthesis of the
following day the baby was operated on and Nissen’s was performed. After the operation the baby extubated and the remainder of the postoperative course uneventful. The baby is now 10 months old and doing
120 ml of clear fluid
fundoplication
diorespiratory
was
cessful.
was
arrest
Discussion
well. Case 2 A male Arab baby was born at home after a normal pregnancy. Delivery was normal and birth-weight was 3000 g. The baby did not pass meconium and 3 days after birth was admit-
ted to hospital where the imperforate anus was treated by anoplasty. Since then the baby continued to have constipation, abdominal distention, and occasional vomiting and had bowel movements once in 10-20 days. The baby was referred to our hospital for evaluation when he was 10 months old. Examination on admission showed a well-developed baby weighing 7300 g. The abdomen was moderately distended but no other abnormality was found. Hirschsprung’s disease was diagnosed after barium enema and suction biopsy from the rectum and the infant was operated upon. At laparotomy an aganglionic segment of large bowel was found to extend up to the sigmoid colon. Sigmoid-loop colostomy was performed. Because of difficulties in infusing into a peripheral vein, percutaneous cannulation of the right internal jugular vein was done one day after operation. The i.v. line was connected to an infusion pump. 12 h later severe respiratory distress developed. Pronounced cyanosis and intercostal and subcostal retraction were noted. Diminished air-entry was heard over the right lung field. Chest X-ray revealed a markedly widened mediastinum and fluid in the right pleural cavity. The cannula was immediately removed from the internal jugular vein, and
Preliminary
Communication
ANTITHROMBIN-III TRANSFUSION IN DISSEMINATED INTRAVASCULAR COAGULATION CHARLES S. P. JENKINS JAN. W. TEN CATE
HANS G. SCHIPPER LAURENS H. KAHLÉ
Hæmostasis, Department of Hæmatology, University Hospital Wilhelmina Gasthuis, Amsterdam, The Division of
If extravasation occurs, the infusion pump will cause continuous infiltration and rising pressure in closed compartments. In peripheral infusions this may result in severe cellular damage to skin and subcutaneous tissues, and skin grafting may be needed.2 In central-vein infusions mediastinal extravasation may occur. Pressure building up in the mediastinum results in serious respiratory disturbances, and if these are not detected in time, impaired venous return may lead to death. Case 1 required assisted ventilation via an endotracheal tube because of serious respiratory disturbance, and in case 2 pronounced respiratory distress was followed by cardio-
respiratory arrest. The use of infusion pumps to regulate infusions via central veins seems to be especially dangerous in neonates and infants. Infusion in such patients should be controlled by devices which do not develop pressure, and work only on gravity. Requests for reprints
Three
with
patients
a severe
bleeding
disorder and disseminated intravascular coagulation were effectively treated with human antithrombin-III concentrates. This treatment, followed by administration of prothrombin complex and platelet suspensions, resulted in a normal hæmostasis, which was maintained during clinical investigations and surgery. INTRODUCTION
potent inhibitor of actifactors.’ Heparin binds to the lysine
ANTITHROMBIN-III
(AT-III)
is
a
vated coagulation residues of the AT-III molecule, resulting in a complex with a greater affinity for both thrombin and factor xa than that of AT-III alone.22 Heparin infusion has been reported to result in a reduction of AT-III activity,3 which may promote thrombosis. We have observed that thrombosis can occur under- heparin therapy when AT-m activity is low, even at sufficiently prolonged kaolin-cephalin time.4 Thus heparin may be either less effective or even hazardous when AT-III is deficient. AT-III deficiency is seen in liver cirrhosis, intravascular coagulation,6and nephrotic
should be addressed
to
M.S.
REFERENCES 1. Berlatzky, Y., Freund, 2. Lancet, 1976, i, 291.
H., Schiller,
M. Z. Kinderchir.
1976, 18, 231.
It also occurs as a rare inherited defect.’ Patients with low AT-III activities and thrombosis would benefit if AT-III levels could be raised to within normal limits before the start of heparin therapy. We describe here three patients with intravascular coagulation and a severe haemorrhagic diathesis in whom infusion of human AT-111 which had been activated in vitro by a low dose of heparin, followed by infusion of coagulation-factor concentrates and platelet suspensions, induced a near-normal haemostatic state.
syndrome.7
PATIENTS
Netherlands
Summary
aspirated by pleural puncture. Cardeveloped and resuscitation was unsuc-
was
Patient A.-A 54-year-old man with liver cirrhosis was admitted for recurrent gastrointestinal bleeding. Endoscopy revealed bleeding oesophageal varices. During observation bleeding recurred, and the coagulation status deteroriated. Blood cultures, which were not obtained until after operation, were positive for Pseudomonas ceruginosa, a known inducer of intravascular coagulation. The antibiotic therapy started postoperatively could therefore not account for the improvement in his haemostatic state before surgery. He underwent left-sided thoracotomy and ligation of the cesophageal varices without haemostatic complications. The further postoperative course
complicated by recurrent gastrointestinal bleeding and high fever. He died from cardiopulmonary complications on the eighth postoperative day. Patient B.-A 72-year-old woman developed progressive jaundice and a severe haemorrhagic diathesis induced by intravascular coagulation. After correction of the haemostatic defect computer-tomographic scanning of the liver suggested the presence of metastases. Necropsy revealed the primary tumour to be a pancreatic carcinoma. Patient C.-A 34-year-old pregnant woman with progressive pain in the liver region underwent a caesarean section because of a decreasing fetal heart-rate due to the sudden development of shock. During surgery, a massive amount of blood was found in the peritoneal cavity. A ruptured subcapsular haematoma was present in the right lobe of the liver. Severe was
855 TABLE II——CHANGES IN BLOOD-VALUES IN PATIENT B
intravascular coagulation contributed to intra-abdominal blood-loss after surgery. Bleeding was controlled by treatment of the intravascular coagulation, and further improvement of the haemostatic state was achieved by transfusion of fresh blood. Further observations revealed that the symptoms presented by the patient were due to essential hypertension. METHODS
activity was measured on an automated kinetic and substrate analyser (Vitatron, Dieren, The Netherenzyme lands). 5 jjd diluted plasma (0-05 ml plasma, 0-33 ml phosphate-buffered saline pH 7-4) was incubated with 0.5ml reaction buffer containing 1000 u/1 heparin, 300 N.I.H. u/1 thrombin, and 75 thrombin-inhibitor units/I aprotinin at 23 °C for 6.5 min. After addition of 0.05 ml ’Chromozym TH’ (1.5 mmol/1) the increase in absorbance per minute is calculated automatically and compared with a reference curve obtained from dilutions of normal plasma.9-12 Other coagulation assays were performed according to standard methods. 13 1500-1725 u human AT-III was dissolved in 50 ml distilled water and activated in vitro before infusion by the addition of AT-III
Infusion of
donors),
500 u 150 u AT-iii +
1500
u AT-m + 500 u heparin; (2) cryoprecipitate (20 (20 donors), and platelets (8 donors); (3) 1500 U AT-III heparin; (4) 1500 U AT-III + 6000 u heparin (in 10 h); (5)
(1)
P.P.S.B. +
900 u heparin/h.
TABLE HI——CHANGES IN BLOOD-VALUES
IN
PATIENT C
heparin (500-1500 u; ’Thromboliquine’, Organon, Oss, The Netherlands). Prothrombin complex (P.P.S.B.) was purchased from the central laboratory of the blood-transfusion service of the Dutch Red Cross, Amsterdam. RESULTS
The critical states of the three patients resulted from different pathological conditions. However, each patient demonstrated intravascular coagulation, with low levels of fibrinogen, a positive ethanol-gelation test, low platelet-count, and low levels of AT-III. The poor haemostatic states were improved after therapy including infusions of human AT-111 concentrates and of human AT-III concentrates activated in vitro with heparin. Patient A.-Infusion with AT-III concentrates (1650 u) increased AT-III activity from 37 to 64%; prothrombin complex (P.P.S.B., 20 donors) was then administered within 20 min and the activities of factors n and x rose almost to normal levels (table I). Fresh-frozen plasma (3 donors), as a source of factor v and fibrinogen, was infused continuously over a period of 2 hours. Because the ethanol-gelation test was still positive, a second infusion of AT-III concentrates (1650 u) was administered. On this occasion AT-m was activated in vitro with heparin (500 u) before infusion. The ethanol-gelation test became negative and remained so during and immediately after the operation. Because the fibrinogen concentration was normal and the level of
fibrinogen/fibrin degradation products low, a false-negative ethanol-gelation test was improbable.14 Hsemostasis was further improved to near normal by infusion of cryoprecipitate as a source of fibrinogen (20 donors) and fresh platelets (8 donors) (table I).
Infusion of (1) platelets
(8 donors); (2) 1725
u AT-m +
1000
u
heparin;
(3) P.P.S.B. (20 donors). Patient B.-1500 U AT-III activated in vitro with 500 heparin increased AT-m activity from 26 to 78%. Transfusion of prothrombin complex (P.P.s.B., 20 donors), cryoprecipitate (20 donors), and platelet suspensions (8 donors) resulted in a striking. improvement of the haemostatic state. However, the ethanol-gelation test remained positive (table 11). A second infusion of activated AT-III concentrates was given as the activity had decreased to 59%, and an equal amount of activated AT-III (1500 U AT-III and 6000 u heparin) was continuously transfused over 10 hours. During this period AT-m activity was stable, indicating an overall AT-111 consumption of about 1500 u in 10 hours (table u). The ethanol-gelation test remained positive, and the other coagulation parameters remained stable. The ethanolgelation test became negative during continuous infusion of more activated AT-III (150 u AT-III and 900 u heparin/h) and remained so when infusion of heparin alone (750 u/h), in the presence of an optimum heparincofactor activity, was continued (table n). Patient C.-Immediately before infusion of AT-III concentrates the ethanol-gelation test became negative. However, the coagulation factors still remained low u
TABLE I-VALUES IN PATIENT A AFTER TREATMENT WITH AT-111 CONCENTRATE
Infusion of
(1)
1650
U
AT-III;
(2)
P.P.S.B.
(20 donors); (3) 1650
U AT-III +
500
u
heparin, cryoprecipitate (20 donors),
and
platelets (8 donors).
856
(table III). Infusion of activated AT-III concentrates (1725 U AT-III and 1000 u heparin) raised AT-III activity from 56 to 106%. Factor-ii activity rose to 97% after infusion of prothrombin complex (P.P.S.B., 20 donors) (table III). The patient’s haemostatic state was further improved and maintained by transfusion of fresh blood. The bleeding abated in the next 24 hours. DISCUSSION
activity may be easily monitored,9 this find approach may increasing application.
because
AT-Iii
We are indebted to Marian Paap and Marianne Schaap for the coagulation assays and to Prof. Vreeken and Dr R. Goudsmit for their critical reading of this article. We are grateful for the cooperation of our colleagues in the departments of internal medicine and surgery at the Sint Lucas Ziekenhuis and Wilhelmina Gasthuis, Amsterdam. Human AT-Ill concentrates were generously provided by Kabivitrum, Amsterdam. Requests for reprints should be addressed to J.W.T.C.
The three patients described here, although presenting different pathologies, all had intravascular coagulation with low levels of AT-III. AT-III is a known inhibitor of activated coagulation factors’ and can be deficient in disseminated intravascular coagulation.6 In view of this, the patients were infused with AT-III concentrates, this treatment being thought advantageous compared with conventional heparin therapy, since heparin alone may be ineffective at low levels of AT-III (heparin cofactor
activity). Heparin diminishes AT-III levels,3 and low levels of ATIII could then promote intravascular coagulation. We have recently reported our observations on a patient with low AT-III levels who had coagulation complications during haemodialysis despite sufficient heparinisation as indicated by the kaolin clotting-time.4 During intravascular coagulation levels of coagulation factors may fall. Infusion of prothrombin complex in patients with intravascular coagulation and low levels of AT-III may maintain this process as well as increase the risk of thrombosis (unpublished observations); raising AT-III levels is necessary to minimise such complications. It was also considered advantageous to first activate AT-III in vitro by the addition of a small amount of heparin before infusion. Heparin-AT-III complexes inhibit activated coagulation factors at a faster rate than AT-III alone.2 In this manner, less heparin is lost by interaction with other plasma proteins. We found this approach effective in the treatment of intravascular coagulation in our patients. In one patient (B), the ethanolgelation test was negative only after prolonged heparinisation once plasma-AT-III levels had been returned to normal. The stimulus of intravascular coagulation in this patient was highly potent, as indicated by the consumption of 1500 U AT-III during a 10-hour period. Although in patient C the ethanol-gelation test was negative just before infusion of AT-III concentrates, the AT-III level and the levels of the coagulation factors were low. In view of this, the patient was treated in the same way as the others, since the optimum haemostatic state would contribute to the control of this patient’s severe intra-abdominal bleeding. In all three patients presented, after AT-III levels had been made normal, normal or near normal levels of coagulation factors and platelets could be maintained. In this way the bleeding tendencies were controlled, and further clinical investigations and surgery in one patient (A) were undertaken under good hsemostatic conditions. The haemostatic state of all three patients improved within a short time of correction of AT-III activity. Although correction of AT-III levels is advocated, the basic therapy for intravascular coagulation still depends on the primary cause. Therefore raising AT-III levels should be thought of as an additional therapy in the treatment of patients with intravascular coagulation. As more human AT-III concentrate becomes available and
REFERENCES 1. 2.
Abildgaard, U. Scand. J. clin. Lab. Invest. 1967, 19, Abildgaard, U. ibid. 1968, 21, 89.
190.
Marciniak, E., Gockerman, J. Lancet, 1977, ii, 581. Schipper, H. G., Kahlé, L. H., Jenkins, C. S. P., ten Cate, J. W., Veenhof, C., Sinaasappel, M. ibid. 1978, i, 209. 5. Von Kaulla, E., von Kaulla, K. N. Am.J. clin. Path. 1967, 48, 69.
3. 4.
6. 7.
Bick, R., Kovacs, I., Fekete, L. Thromb. Res. 1976, 8, 745. Kaufmann, R. H., Graeff, J. de, Brutel de la Riviere, G., Es, J. Med. 1976, 60, 1048.
8. 9.
Egeberg, O.
Thromb. Diath.
L. van, Am.
hæmorrh. 1965, 13, 516.
Kahlé, L. H., Schipper, H. G., Jenkins, C. S. P.,
ten
Cate, J. W. Thromb.
Res. (in the press). 10.
Blomback, M., Blomback, B., Olsson, P., Svendssen, L. Thromb. Res. 1974,
5, 621. Odegard, O. R. ibid. 1975, 7, 351. Odegard, O. R., Lie, M., Abildgard, U. Thromb. Res. 1975, 6, 287. Biggs, R. Human Blood Coagulation, Hæmostasis and Thrombosis; p. 504. Oxford, 1976. 14. Gerrits, W. B. J. Thesis, University of Amsterdam, 1974. 11. 12. 13.
SELECTIVE DEFICIENCY OF
3-&bgr;-D-GALACTOSYLTRANSFERASE (T-TRANSFERASE) IN
Tn-POLYAGGLUTINABLE ERYTHROCYTES
J. P. CARTRON G. ANDREU
J. CARTRON CH. SALMON
Groupe U76 de Recherches de l’INSERM et Service d’Immunologie du Centre National de Transfusion Sanguine, 75739 Paris, France
G. W. G. BIRD
Regional Blood Transfusion Service, Birmingham B15 2SG
single genetic defect in membrane synthesis—namely, a deficiency of 3-&bgr;-Dgalactosyltransferas—can account for the serological and physicochemical properties of Tn-polyagglutinable erythrocytes.
Summary
A
Tn-polyagglutinability (persistent mixed-field polyagglutinability) is an acquired condition in which there are two erythrocyte populations; one is normal and in the other the Tn cryptantigen is exposed.’ Anti-Tn is present in most normal human adult sera. The condition may be associated with haemolytic ansemia, and, since leucocytes and platelets are similarly affected, there is usually leucopenia and thrombocytopenia.1 Tn polyagglutinability may be associated with leukmmiaand may indeed be a preleukaemic state.3 The Tn receptor may also be exposed in the cells of breast and other cancers.There has therefore been much interest in the molecular basis of Tn polyagglutin-
ability.5-’ Tn is
an
intermediate stage in the
biosynthesis of the
