Blur
Blut (1990) 61:295-297
© Springer-Verlag 1990
Original article Inferior vena cava thrombosis in a child with nephroblastoma and combined deficiency of antithrombin III and free protein S Franziska Demarmels 1, Annette Ridolfi Liithy 2, Andreas Hirt 2, Miha Furlan ~, and Bernhard Lfimmle 1 1 Central Hematology Laboratory and 2 Department of Pediatrics, Inselspital, University of Bern, Bern, Switzerland Received April 3, 1990/Accepted September 14, 1990
Summary. A 31/z-year-old girl developed t h r o m b o s i s of the inferior caval a n d renal veins several weeks after complete resection o f a n e p h r o b l a s t o m a . H e r m o t h e r h a d suffered from p u l m o n a r y e m b o l i s m at the age of 18 years. Familial a n t i t h r o m b i n III deficiency a n d persistently lowered free protein S levels in the proposita were found. It is a s s u m e d that the c o m b i n a t i o n of these two regulatory defects of hemostasis c o n t r i b u t e d to the early occurrence o f this severe t h r o m b o t i c event. Key words: Caval vein t h r o m b o s i s - N e p h r o b l a s t o m a A n t i t h r o m b i n III deficiency -
P r o t e i n S deficiency
Introduction T h r o m b o e m b o l i c events are rare in c h i l d h o o d [12]. Most often they are associated with venous catheters, plaster casts, t r a u m a , infections such as osteomyelitis or with vascular m a l f o r m a t i o n s . F u r t h e r m o r e , t h r o m b o e m b o lism is a well-known c o m p l i c a t i o n of the nephrotic synd r o m e a n d of several chronic i n f l a m m a t o r y diseases such as systemic lupus erythematosus, ulcerative colitis, C r o h n ' s disease a n d Behget's disease. Prognosis of h o m o cystinuria is largely i n f l u e n c e d by venous, arterial a n d microvascular thrombosis occurring in a b o u t 50% o f cases. T h r o m b o e m b o l i s m a c c o m p a n y i n g neoplastic disease is well recognized in adults [3] b u t seems to be i n f r e q u e n t in children. A n exception, however, is n e p h r o b l a s t o m a ( W i l m s - t u m o r ) which in a b o u t 5 % is complicated by occlusion o f the inferior caval or renal vein due to neoplastic tissue infiltrating a n d obstructing the vessel [11]. I n this report we describe a child who developed t h r o m b o s i s of the inferior caval a n d renal vein several weeks after o p e r a t i o n of a n e p h r o b l a s t o m a . C o a g u l a t i o n studies revealed a hereditary a n t i t h r o m b i n III deficiency
Offprint requests to: E Demarmels, Central Hematology Laboratory, Inselspital, University of Bern, CH-3010 Bern, Switzerland
a n d a persistently low free protein S level. We assume that a n t i t h r o m b i n III deficiency a n d / o r low p l a s m a levels of free protein S m a y have c o n t r i b u t e d to the severe t h r o m botic disease in this child whose renal t u m o r h a d b e e n completely resected.
Case report In February 1988, the 31A-year-oldgirl B.L. complaining of abdominal pain was admitted to our hospital for suspicion of appendicitis. Appendectomy was performed, and having found a normal appendix the girl was discharged seven days later with the diagnosis of "enteritis". Three weeks later she was rehospitalized because of abdominal pain. She presented with ballooned, tense abdomen. Abdominal ultrasonography showed a tumor of the right kidney. On March 8th 1988 nephrectomy was performed. Intraoperatively the inferior vena cava was found to be displaced to the left side but was free of neoplastic tissue as was the right renal vein. Histological examination of the tumor weighing 900 g revealed a nephroblastoma of the blastemale type without perforation of the renal capsule. Chemotherapy according to the National Wilms tumor study protocol (NWTS 4) with cyclic administration of actinomycin D and vincristine was started and continued throughout the time of observation. Seven weeks after nephrectomy, on April 26th, the girl complained for the first time of pain in the left thigh. Two days later she was admitted to hospital with fever of 39°C and a swollen and warm left thigh. Ultrasonography of the diffusely tender abdomen revealed a swollen left kidney. Serum creatinine was elevated to 109 pmol/1 (normal, 23-62 pmol/1) and urinalysis showed microscopic hematuria, cylindruria and moderate proteinuria. Computed tomography of the abdomen revealed thrombotic occlusion of both the inferior caval vein as well as the left renal vein. Anticoagulant therapy by continuous intravenous infusion of heparin was initiated and after three weeks was switched to acenocoumarol. Three months later, ultrasonography showed a near normalized size of the left kidney but still a partial occlusion of the inferior vena cava. On September 12th, anticoagulation was stopped. In February 1989, the patient suffered from rethrombosis with complete occlusion of the inferior caval vein. Anticoagulant therapy by intravenous heparin and later with phenprocoumon was resumed and continued up to date. The 28-year-old mother of the proposita had suffered from a single pulmonary embolism at the age of 18 years, and her maternal grandmother had recurrent deep leg vein thrombosis. Hemostatic evaluation of the proposita and her parents was performed.
E Demarmels et al.: Combined antithrombin III and protein S deficiency
296
o f PS from the free to the b o u n d form, possibly at least in part as a consequence o f the high C 4 b B P levels.
Methods Complete blood count (STKR, Coulter S +, Miami Lakes, Florida) and routine coagulation profile including prothrombin time (PT), activated partial thromhoplastin time (aPTT), thrombin time (TT) and fibrinogen were performed by standard procedures [14]. Antithrombin tII (AT III) activity (Kabi, Stockholm, Sweden), plasminogen activity (Kabi) and protein C (PC) activity [9} (Behring, Marburg, FRG) were assayed using commercial test kits. AT Ill antigen, PC antigen and C4b-binding protein (C4bBP) were measured by electroimmunoassay using 1.5% agarose and commercial rabbit antisera (Behring). Free protein S (PS0 was measured by electroimmunoassay of the supernatant after precipitation of plasma proteins with 5.4o70 polyethylene glycol 6,000 [41 and protein S complexed with C4b-binding protein (PSb)was measured in the redisolved precipitate as previously described in detail [t4]. Total PS was calculated according to the equation: PStotal= 0.4×PSf (%) + 0.6XPS b (07"0) based on the finding that in normal human plasma (NHP) 40% of the PS circulate free and 60% are complexed with C4bBP [6].
Discussion
Results Initial coagulation studies o f the proposita B.L, revealed a platelet count o f 304 x 109/1 (normal, 125 to 320 × 109/1), P T 100% (normal, 70% to 13007o), a P T T 46 s (normal, 4 0 - 6 0 s), T T 12 s (normal, 12 to 15 s) and fibrinogen 3.6 g / l (normal, 1.5 to 3 g/l). The values o f AT III, PC, PS and plasminogen are shown in Table 1. Persistently low values o f AT I I I activity and antigen were compatible with antithrombin I I I deficiency type 1. Moreover, PSf was repeatedly f o u n d to be decreased, whereas PSb was high normal. Calculated total PS was 1 0 7 % - 1 0 9 % as c o m p a r e d to total PS in N H R C4b-binding protein was slightly increased. The patient's m o t h e r had similar AT I I I activity and antigen levels (Table 2) confirming the heredity o f the deficiency, whereas her PS was normal. The father showed n o r m a l values for AT I I I as well as for PS. Thus, PSf deficiency in the child was no t proven to be hereditary and low PSf m a y have been due to a shift
We describe a 3V2-year-old girl who developed a thrombosis o f the inferior caval and left renal veins after complete resection o f a right-sided nephroblastoma. Her m o t h e r had suffered f r o m a p u l m o n a r y embolism at the age o f 18 years. This pointed to the possibility o f a hereditary thrombophilia. Hereditary thrombophilia m a y be caused by deficiency o f antithrombin III, protein C, protein S and p r o b a b l y by deficiency o f heparin cofactor II as well as by dysfibrinogenemia. In addition, a familial tendency to thrombotic disease may be due to deficiency of plasminogen or tissue plasminogen activator or to increase o f plasminogen activator inhibitor resulting in impaired fibrinolysis. O u r patient had hereditary AT I I I deficiency type I, as evidenced by parallel decrease of activity and antigen levels in her and her m o t h e r ' s plasma. The anticoagulatory effect o f AT I I I is mainly due to inhibition o f thrombin, and hereditary deficiency leads to recurrem thromboembolism, mainly deep leg vein thrombosis, often complicated by p u l m o n a r y embolism, and less frequently to thrombosis of inferior caval, mesenteric, axillary or superficial veins [10]. In addition, the patient had low values of free PS representing the anticoagu!antly active fraction of this protein which exists also in an inactive f o r m complexed to C4b-binding protein [4, 7]. PSf serves as a cofactor for the anticoagulant and profibrinolytic effect o f activated PC. Functional abnormalities o f PS arise from either absence o f the protein or from redistribution o f the protein with decrease o f the free form in favor o f the b o u n d f o r m [4]. The latter situation was present in our patient and was probably due at least in part to increased levels o f C4bBP. Thus, low PSf values in the proposita may not represent a hereditary but rather an
Table 1. Laboratory findings in the proposita
Prothrombin time INR Antithrombin III activity antigen Protein C Protein S free bound totaF C4b-binding protein Plasminogen
19.05.88a
03.10.88
03.02.89 b
16.05.89 13
19.06.89 13
Normal range
~ 100%
~ 100070
~ 100%
41% 1.9
--
70%-130°/0
51%
66 % 51%
---
---
80 % - 120% 80% - 120% 65070-135% 70%-140% 65%--165%
--
--
-. 78% 33% 157% 107% -146%
-.
64 % .
. 38°7o > 100070 -145070 .
. .
. 42% 153%
.
109070
.
165% .
.
a Acute thrombosis b Rethrombosis c Total protein S was calculated from protein S free and protein S bound as described in "Methods" 13 Phenprocoumon treatment; INR, International normalized ratio
70%-150% 7007o-130%
F. Demarmels et al.: Combined antithrombin III and protein S deficiency Table 2. Laboratory findings from the mother
Prothrombin time Antithrombin lII activity antigen Protein C Protein S free bound total a C4b-binding protein Plasminogen
29.03.89
05.05.89
Normal range
> 100%
> 100%
70%-130%
52% -142% 67% 140% 111% 156% 115%
55% 39% -75% 113% 98% ---
80%-120% 80%- 120% 65%-135% 70%-140% 65%-165%
297
itself a n d i m m o b i l i s a t i o n in the postoperative phase may have c o n t r i b u t e d to the t h r o m b o t i c event in this child. O u r case d e m o n s t r a t e s that t h r o m b o e m b o l i s m m a y occur even in early c h i l d h o o d a n d that l a b o r a t o r y evidence for t h r o m b o p h i l i a has to be sought.
Acknowledgment. The secretarial help of Mrs Martha Loosli is gratefully acknowledged
References 70% 150% 70°70-130%
a Total protein S was calculated as described in "Methods"
acquired deficiency. No e x p l a n a t i o n for the persistingly high C 4 b B P levels was evident. F u r t h e r m o r e , a n increased affinity of o u r p a t i e n t ' s PS for C 4 b B P could not be excluded. The clinical consequence of PSf deficiency consists in a tendency to recurrent venous t h r o m b o e m b o lism [5], a n d according to newer reports [14] also to arterial thrombosis, especially o f cerebral arteries. T h e first t h r o m b o t i c events in AT III a n d PS deficiency usually occur in early a d u l t h o o d or middle age, whereas there are only few reports of venous or arterial t h r o m b o s i s in early c h i l d h o o d [1, 8, 13]. O u r p a t i e n t with hereditary AT III deficiency represents a n extraordinary case in terms of the very early m a n i f e s t a t i o n a n d in terms of the localizat i o n of the thrombosis. P r o b a b l y the most i m p o r t a n t reason for the early m a n i f e s t a t i o n is the coexistence of AT III deficiency with a partial, possibly acquired deficiency of PS arising from a n altered ratio of the free to the b o u n d form. We c o u l d n ' t find any reports in the literature a b o u t a direct association of neoplastic disease with PS or AT III deficiency. The i n d u c t i o n of AT III deficiency by L-Asparaginase is well k n o w n [2], b u t n o similar effect o n AT III or PS has been reported for the chemotherapeutic agents administered to our patient. I n a d d i t i o n to hereditary AT III deficiency a n d altered ratio of PSf/PSb, some t h r o m b o g e n i c factors have to be considered in conn e c t i o n with our case: E x p l o r a t i o n of the vena cava inferior a n d o f the renal vein o n the occasion of n e p h r e c t o m y could have resulted in endothelial d a m a g e with local activation of the hemostatic system. F u r t h e r m o r e , surgery
1. Ambruso DR, Jacobson L J, Hathaway WE (1980) Inherited antithrombin III deficiency and cerebral thrombosis in a child. Pediatrics 65: 125-131 2. Bauer KA, Teitel JM, Rosenberg RD (1983) L-Asparaginase induced antithrombin IIt deficiency. Evidence against the production of a hypercoagulable state. Thromb Res 29:437-442 3. Bell WR. Starksen NF, Tong S. Porterfield JK (1985) Trousseau's Syndrome. Am J Med 79:423-429 4. Comp PC, Doray D, Patton D, Esmon CT (1986) An abnormal plasma distribution of protein S occurs in functional protein S deficiency. Blood 67:504-508 5. Comp PC, Esmon CT (1984) Recurrent venous thromboembolism in patients with a partial deficiency of protein S. N Engl J Med 311:1524-1528 6. Dahlb~tck B (1984) Interaction between vitamin K-dependent protein S and the complement protein, C4b-binding protein. Semin Thromb Hemost 10:139-148 7. Esmon CT (1987) The regulation of natural anticoagulant pathways. Science 235:1348-1352 8. Israels SJ, Seshia SS (1987~ Childhood stroke associated with protein C or S deficiency. J Pediatr 111:562-564 9. Martinoli JL, Stocker K (1986) Fast functional protein C assay using Protac, a novel protein C activator. Thromb Res 43: 253-264 10. Michiels J J, von Vliet HH (1984) Hereditary antithrombin III deficiency and venous thrombosis. Neth J Med 27:226-232 11. Orget J, Dore B, Ollivier H, Cirot T, Aubert J (1985) Le thrombus cave infdrieur dans le ndphroblastome de l'enfant. Ann Urol 19:420-422 12. Robin M, Boyer C (1987) Causes des thromboses vemeuses de l'enfant et de l'adolescent en dehors de la p6riode ndonatale. Arch Fr Pediatr 44:467-472 13. Sas G, Blask6 G. Petr6 I, Griffin JH (1985) A protein S deficient family with portal vein thrombosis. Thromb Haemost 54: 724 14. Thommen D, Buhrfeind E, Felix R, Sulzer I, Furlan M, Lfimmle B (1989) Htimostaseparameter bei 55 Patienten mit venOsen und/oder arteriellen Thromboembolien. Schweiz Med Wochenschr 119:493-499
Blut (1990) 61:295-297
© Springer-Verlag 1990
Original article Inferior vena cava thrombosis in a child with nephroblastoma and combined deficiency of antithrombin III and free protein S Franziska Demarmels 1, Annette Ridolfi Liithy 2, Andreas Hirt 2, Miha Furlan ~, and Bernhard Lfimmle 1 1 Central Hematology Laboratory and 2 Department of Pediatrics, Inselspital, University of Bern, Bern, Switzerland Received April 3, 1990/Accepted September 14, 1990
Summary. A 31/z-year-old girl developed t h r o m b o s i s of the inferior caval a n d renal veins several weeks after complete resection o f a n e p h r o b l a s t o m a . H e r m o t h e r h a d suffered from p u l m o n a r y e m b o l i s m at the age of 18 years. Familial a n t i t h r o m b i n III deficiency a n d persistently lowered free protein S levels in the proposita were found. It is a s s u m e d that the c o m b i n a t i o n of these two regulatory defects of hemostasis c o n t r i b u t e d to the early occurrence o f this severe t h r o m b o t i c event. Key words: Caval vein t h r o m b o s i s - N e p h r o b l a s t o m a A n t i t h r o m b i n III deficiency -
P r o t e i n S deficiency
Introduction T h r o m b o e m b o l i c events are rare in c h i l d h o o d [12]. Most often they are associated with venous catheters, plaster casts, t r a u m a , infections such as osteomyelitis or with vascular m a l f o r m a t i o n s . F u r t h e r m o r e , t h r o m b o e m b o lism is a well-known c o m p l i c a t i o n of the nephrotic synd r o m e a n d of several chronic i n f l a m m a t o r y diseases such as systemic lupus erythematosus, ulcerative colitis, C r o h n ' s disease a n d Behget's disease. Prognosis of h o m o cystinuria is largely i n f l u e n c e d by venous, arterial a n d microvascular thrombosis occurring in a b o u t 50% o f cases. T h r o m b o e m b o l i s m a c c o m p a n y i n g neoplastic disease is well recognized in adults [3] b u t seems to be i n f r e q u e n t in children. A n exception, however, is n e p h r o b l a s t o m a ( W i l m s - t u m o r ) which in a b o u t 5 % is complicated by occlusion o f the inferior caval or renal vein due to neoplastic tissue infiltrating a n d obstructing the vessel [11]. I n this report we describe a child who developed t h r o m b o s i s of the inferior caval a n d renal vein several weeks after o p e r a t i o n of a n e p h r o b l a s t o m a . C o a g u l a t i o n studies revealed a hereditary a n t i t h r o m b i n III deficiency
Offprint requests to: E Demarmels, Central Hematology Laboratory, Inselspital, University of Bern, CH-3010 Bern, Switzerland
a n d a persistently low free protein S level. We assume that a n t i t h r o m b i n III deficiency a n d / o r low p l a s m a levels of free protein S m a y have c o n t r i b u t e d to the severe t h r o m botic disease in this child whose renal t u m o r h a d b e e n completely resected.
Case report In February 1988, the 31A-year-oldgirl B.L. complaining of abdominal pain was admitted to our hospital for suspicion of appendicitis. Appendectomy was performed, and having found a normal appendix the girl was discharged seven days later with the diagnosis of "enteritis". Three weeks later she was rehospitalized because of abdominal pain. She presented with ballooned, tense abdomen. Abdominal ultrasonography showed a tumor of the right kidney. On March 8th 1988 nephrectomy was performed. Intraoperatively the inferior vena cava was found to be displaced to the left side but was free of neoplastic tissue as was the right renal vein. Histological examination of the tumor weighing 900 g revealed a nephroblastoma of the blastemale type without perforation of the renal capsule. Chemotherapy according to the National Wilms tumor study protocol (NWTS 4) with cyclic administration of actinomycin D and vincristine was started and continued throughout the time of observation. Seven weeks after nephrectomy, on April 26th, the girl complained for the first time of pain in the left thigh. Two days later she was admitted to hospital with fever of 39°C and a swollen and warm left thigh. Ultrasonography of the diffusely tender abdomen revealed a swollen left kidney. Serum creatinine was elevated to 109 pmol/1 (normal, 23-62 pmol/1) and urinalysis showed microscopic hematuria, cylindruria and moderate proteinuria. Computed tomography of the abdomen revealed thrombotic occlusion of both the inferior caval vein as well as the left renal vein. Anticoagulant therapy by continuous intravenous infusion of heparin was initiated and after three weeks was switched to acenocoumarol. Three months later, ultrasonography showed a near normalized size of the left kidney but still a partial occlusion of the inferior vena cava. On September 12th, anticoagulation was stopped. In February 1989, the patient suffered from rethrombosis with complete occlusion of the inferior caval vein. Anticoagulant therapy by intravenous heparin and later with phenprocoumon was resumed and continued up to date. The 28-year-old mother of the proposita had suffered from a single pulmonary embolism at the age of 18 years, and her maternal grandmother had recurrent deep leg vein thrombosis. Hemostatic evaluation of the proposita and her parents was performed.
E Demarmels et al.: Combined antithrombin III and protein S deficiency
296
o f PS from the free to the b o u n d form, possibly at least in part as a consequence o f the high C 4 b B P levels.
Methods Complete blood count (STKR, Coulter S +, Miami Lakes, Florida) and routine coagulation profile including prothrombin time (PT), activated partial thromhoplastin time (aPTT), thrombin time (TT) and fibrinogen were performed by standard procedures [14]. Antithrombin tII (AT III) activity (Kabi, Stockholm, Sweden), plasminogen activity (Kabi) and protein C (PC) activity [9} (Behring, Marburg, FRG) were assayed using commercial test kits. AT Ill antigen, PC antigen and C4b-binding protein (C4bBP) were measured by electroimmunoassay using 1.5% agarose and commercial rabbit antisera (Behring). Free protein S (PS0 was measured by electroimmunoassay of the supernatant after precipitation of plasma proteins with 5.4o70 polyethylene glycol 6,000 [41 and protein S complexed with C4b-binding protein (PSb)was measured in the redisolved precipitate as previously described in detail [t4]. Total PS was calculated according to the equation: PStotal= 0.4×PSf (%) + 0.6XPS b (07"0) based on the finding that in normal human plasma (NHP) 40% of the PS circulate free and 60% are complexed with C4bBP [6].
Discussion
Results Initial coagulation studies o f the proposita B.L, revealed a platelet count o f 304 x 109/1 (normal, 125 to 320 × 109/1), P T 100% (normal, 70% to 13007o), a P T T 46 s (normal, 4 0 - 6 0 s), T T 12 s (normal, 12 to 15 s) and fibrinogen 3.6 g / l (normal, 1.5 to 3 g/l). The values o f AT III, PC, PS and plasminogen are shown in Table 1. Persistently low values o f AT I I I activity and antigen were compatible with antithrombin I I I deficiency type 1. Moreover, PSf was repeatedly f o u n d to be decreased, whereas PSb was high normal. Calculated total PS was 1 0 7 % - 1 0 9 % as c o m p a r e d to total PS in N H R C4b-binding protein was slightly increased. The patient's m o t h e r had similar AT I I I activity and antigen levels (Table 2) confirming the heredity o f the deficiency, whereas her PS was normal. The father showed n o r m a l values for AT I I I as well as for PS. Thus, PSf deficiency in the child was no t proven to be hereditary and low PSf m a y have been due to a shift
We describe a 3V2-year-old girl who developed a thrombosis o f the inferior caval and left renal veins after complete resection o f a right-sided nephroblastoma. Her m o t h e r had suffered f r o m a p u l m o n a r y embolism at the age o f 18 years. This pointed to the possibility o f a hereditary thrombophilia. Hereditary thrombophilia m a y be caused by deficiency o f antithrombin III, protein C, protein S and p r o b a b l y by deficiency o f heparin cofactor II as well as by dysfibrinogenemia. In addition, a familial tendency to thrombotic disease may be due to deficiency of plasminogen or tissue plasminogen activator or to increase o f plasminogen activator inhibitor resulting in impaired fibrinolysis. O u r patient had hereditary AT I I I deficiency type I, as evidenced by parallel decrease of activity and antigen levels in her and her m o t h e r ' s plasma. The anticoagulatory effect o f AT I I I is mainly due to inhibition o f thrombin, and hereditary deficiency leads to recurrem thromboembolism, mainly deep leg vein thrombosis, often complicated by p u l m o n a r y embolism, and less frequently to thrombosis of inferior caval, mesenteric, axillary or superficial veins [10]. In addition, the patient had low values of free PS representing the anticoagu!antly active fraction of this protein which exists also in an inactive f o r m complexed to C4b-binding protein [4, 7]. PSf serves as a cofactor for the anticoagulant and profibrinolytic effect o f activated PC. Functional abnormalities o f PS arise from either absence o f the protein or from redistribution o f the protein with decrease o f the free form in favor o f the b o u n d f o r m [4]. The latter situation was present in our patient and was probably due at least in part to increased levels o f C4bBP. Thus, low PSf values in the proposita may not represent a hereditary but rather an
Table 1. Laboratory findings in the proposita
Prothrombin time INR Antithrombin III activity antigen Protein C Protein S free bound totaF C4b-binding protein Plasminogen
19.05.88a
03.10.88
03.02.89 b
16.05.89 13
19.06.89 13
Normal range
~ 100%
~ 100070
~ 100%
41% 1.9
--
70%-130°/0
51%
66 % 51%
---
---
80 % - 120% 80% - 120% 65070-135% 70%-140% 65%--165%
--
--
-. 78% 33% 157% 107% -146%
-.
64 % .
. 38°7o > 100070 -145070 .
. .
. 42% 153%
.
109070
.
165% .
.
a Acute thrombosis b Rethrombosis c Total protein S was calculated from protein S free and protein S bound as described in "Methods" 13 Phenprocoumon treatment; INR, International normalized ratio
70%-150% 7007o-130%
F. Demarmels et al.: Combined antithrombin III and protein S deficiency Table 2. Laboratory findings from the mother
Prothrombin time Antithrombin lII activity antigen Protein C Protein S free bound total a C4b-binding protein Plasminogen
29.03.89
05.05.89
Normal range
> 100%
> 100%
70%-130%
52% -142% 67% 140% 111% 156% 115%
55% 39% -75% 113% 98% ---
80%-120% 80%- 120% 65%-135% 70%-140% 65%-165%
297
itself a n d i m m o b i l i s a t i o n in the postoperative phase may have c o n t r i b u t e d to the t h r o m b o t i c event in this child. O u r case d e m o n s t r a t e s that t h r o m b o e m b o l i s m m a y occur even in early c h i l d h o o d a n d that l a b o r a t o r y evidence for t h r o m b o p h i l i a has to be sought.
Acknowledgment. The secretarial help of Mrs Martha Loosli is gratefully acknowledged
References 70% 150% 70°70-130%
a Total protein S was calculated as described in "Methods"
acquired deficiency. No e x p l a n a t i o n for the persistingly high C 4 b B P levels was evident. F u r t h e r m o r e , a n increased affinity of o u r p a t i e n t ' s PS for C 4 b B P could not be excluded. The clinical consequence of PSf deficiency consists in a tendency to recurrent venous t h r o m b o e m b o lism [5], a n d according to newer reports [14] also to arterial thrombosis, especially o f cerebral arteries. T h e first t h r o m b o t i c events in AT III a n d PS deficiency usually occur in early a d u l t h o o d or middle age, whereas there are only few reports of venous or arterial t h r o m b o s i s in early c h i l d h o o d [1, 8, 13]. O u r p a t i e n t with hereditary AT III deficiency represents a n extraordinary case in terms of the very early m a n i f e s t a t i o n a n d in terms of the localizat i o n of the thrombosis. P r o b a b l y the most i m p o r t a n t reason for the early m a n i f e s t a t i o n is the coexistence of AT III deficiency with a partial, possibly acquired deficiency of PS arising from a n altered ratio of the free to the b o u n d form. We c o u l d n ' t find any reports in the literature a b o u t a direct association of neoplastic disease with PS or AT III deficiency. The i n d u c t i o n of AT III deficiency by L-Asparaginase is well k n o w n [2], b u t n o similar effect o n AT III or PS has been reported for the chemotherapeutic agents administered to our patient. I n a d d i t i o n to hereditary AT III deficiency a n d altered ratio of PSf/PSb, some t h r o m b o g e n i c factors have to be considered in conn e c t i o n with our case: E x p l o r a t i o n of the vena cava inferior a n d o f the renal vein o n the occasion of n e p h r e c t o m y could have resulted in endothelial d a m a g e with local activation of the hemostatic system. F u r t h e r m o r e , surgery
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