- Email: [email protected]
Heparin-induced thrombocytopenia in a child
Volume 121 Number 1
experience with this and other patients is needed to determine whether this outcome is due to early initiation of benzoate a n d / o r D M therapy or to variability in phenotype. REFERENCES 1. Nyhan WL. Nonketotic hyperglycinemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease. 6th ed. New York: McGraw-Hill, 1989:74353. 2. Ransom BR. Possible pathophysiology of neurologic abnormalities associated with nonketotic hyperglycinemia [Letter]. N Engl J Med 1976;294:1295-6. 3. McDonald JW, Johnston MV. Non-ketotie hyperglycinemia: pathophysiological role of the N-methyl-D-aspartate type amino acid receptors [Letter]. Ann Neurol 1990;27:449-50. 4. Wolff JA, Kulovich S, Yu AL, Qiao C-N, Nyhan WL. The effectiveness of benzoate in the rnanagement of seizures in nonketotic hyperglycinemia. Am J Dis Child 1986;140:596-602. 5. Prince DA, Feeser HR. Dextromethorphan protects against cerebral infarction in a rat model of hypoxia-ischemia. Neurosci Lett 1988;85:291-6. 6. Ferkany JW, Borosky SA, Clissold DB, Pontecorvo MJ. Dextromethorphan inhibits NMDA-induced convulsions. Eur J Pharmacol 1988;151:151-4.
Detromethorphan and benzoate for hyperglycinemia
1 35
7. Gitzelmann R, Steinmann B, Otten A, et al. Non-ketotic hyperglycinemia treated with strychnine, a glycine receptor antagonist. Helvetica Pediatrica Acta 1978;32:517-25. 8. Von Wendt L, Simila S, Saukkonen A-L, Koivisto M. Failure of strychnine treatment during the neonatal period in three Finnish children with nonketotic hyperglycinemia. Pediatrics 1980;65:1166-9. 9. Carson NAJ. Non-ketotic hyperglycinemia: a review of 70 patients. J Inherited Metab Dis 1982;5(suppl 2):126-8. 10. McDonald JW, Johnston MV. Physiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain Res Rev 1990;15:41-70. 11. Sklow B, Goldberg MP, Choi DW. High concentration of glycine potentiate cortical neuronal injury produced by combined oxygen-glucose deprivation in vivo [Abstract]. Neurology 1991 ;41 (suppl 1):227. 12. McDonald JW, Silverstein FS, Johnston MV. Neurotoxicity of N-methyl-D-aspartate is markedly enhanced in developing rat central nervous system. Brain Res 1988;459:200-3. 13. Ohya Y, Ochi N, Mizutani N, Hayakawa C, Watanabe K. Nonketotic hyperglycinemia: treatment with NMDA antagonist and consideration of neuropathogenesis. Pediatr Neurol 1991;7:65-8.
Clinical and laboratory observations Heparin-induced thrombocytopenia in a child C h a r l e s P o t t e r , MD, J o a n C o x Gill, MD, J. Paul S c o t t , MD, a n d J a n i c e G. M c F a r l a n d , MD From the Department of Pediatrics, Medical College of Wisconsin, and the Blood Research institute, Blood Center of Southeastern Wisconsin, Milwaukee
We describe a case of t h r o m b o c y t o p e n i a and d e e p venous thrombosis in a boy who received heparin to maintain p a t e n c y of a central venous catheter. M e a surement of the release of serotonin l a b e l e d with carbon 14 confirmed the prese n c e of heparin-induced thrombocytopenia. Children receiving heparin thera p y should be monitored for the possibility of heparin-induced thrombocytopenia. (J PEDIATR1992;121:135-8)
Heparin-induced thrombocytopenia occurs in two forms: a nonimmune-based mild thrombocytopenia beginning soon after heparin administration and an immune-mediated se-
Submitted for publication May 23, 1991; accepted Jan. 17, 1992. Reprint requests: Joan Cox Gill, MD, Great Lakes Hemophilia Foundation, P.O. Box 13127, Wauwatosa, WI 53212-0127. 9/22/36387
vere thrombocytopenia with onset several days after heparin therapy is initiated.l-3 This latter form, when accompanied by limb- and life-threatening arterial thromboses in 10% to 20% of cases, is termed heparin-induced thrombosis and thrombocytopenia syndrome. 1-5 Although H I T occurs in as many as 5% of adults treated with heparin, it has been reported only once in the pediatric age group. 6 We describe a case of H I T in a boy who had thrombosis of the left subclavian vein and right calf veins.
13 6
Clinical and laboratory observations
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POST-OPERATION DATE Figure. Course of thrombocytopenia in a boy receiving heparin flushes to maintain catheter patency after cardiac surgery. Arrows indicate platelet transfusions and horizontal bars depict heparin exposure.
METHODS A n intact-platelet E L I S A was used to detect the presence of d r u g - i n d e p e n d e n t antibodies, as previously described. 7, 8 M e a s u r e m e n t of the release of serotonin labeled with carbon 14 was used to confirm the diagnosis of HIT. 1'2'4 Briefly, the release of serotonin from 14C-serotonin-loaded platelets added to control a n d patient sera was m e a s u r e d in the absence of heparin a n d with 0.1 U and 100 U of heparin per milliliter. Release of >20% of label with 0.1 U heparin per milliliter and of <20% with 100 U / m l was considered a positive result. Assays were run in duplicate; a n o r m a l control s e r u m a n d two well-characterized control sera t h a t repeatedly d e m o n s t r a t e d 85% to 100% release of serotonin at the heparin concentration of 0.1 U / m l , with no release at 100 U / m l , were tested with each assay. CASE REPORT A 13-year-old white boy was first exposed to heparin at 1 month of age during a Waterston shunt procedure for tricuspid atresia; heparin was also used to maintain catheter patency during the postoperative period. His platelet count decreased slightly on the first postoperative day but then returned to normal. At 8 years of age the patient underwent closure of the Waterston
shunt and a right Blalock shunt procedure was performed. He was again given heparin during cardiopulmonary bypass. Heparin flushes of intravenous catheters were continued for 1 week after operation. The patient's platelet count decreased to 109,000 cells/#l on the day after operation and the next day fell to 95,000 cells/~zl from a preoperative level of 216,000 cells/#l. The platelet count quickly recovered to >100,000 cells/#l but fell again to 93,000 cells//A at the pafi~ent's discharge on the tenth postoperative day. Two days later the patient was readmitted with transient left-sided hemiparesis and aspirin therapy was initiated. Right subclavian steal syndrome was diagnosed and the right vertebral
ELISA HIT
Enzyme-linked immunosorbent assay Heparin-induced thrombocytopenia
artery was ligated. The patient received heparinized saline flushes of intravenous catheters for the next week. Three days after the arterial ligation he had right-sided hemiparesis consistent with a cerebral vascular accident in the left hemisphere. Multiple bilateral areas of cerebral calcification, reflecting an older process, were noted on computed tomographic scan, but findings of cerebral flow study, cranial computed tomography, and echocardiography were not consistent with emboli, thrombi, or vegetations. A venogram of the lower extremities appeared normal. The platelet count was
Volume 121 Number 1
115,000 cells/#l at readmission, increased to 154,000 cells/tzl 3 days after the arterial ligation, and was 196,000 cells/tzl at the patient's discharge. At 13 years of age the patient underwent closure of his Blalock shunt. Preoperative laboratory values included a platelet count of 168,000 cells//zl, a fibrinogen value of 225 mg/dl, fibrin and fibrinogen degradation products < 10 units, a prothrombin time of 1Z8 seconds, and a partial thromboplastin time of 28.8 seconds; hemoglobin level and hematocrit remained normal throughout this hospitalization. The patient was given 2000 U of heparin during cardiopulmonary bypass and received 8 units of random-donor platelets during the procedure. Patency of the intravenous catheters was maintained for the next 8 days with 20 U of heparin every 3 hours. Heparin administration, platelet transfusions, and platelet counts are shown in the Figure. On the eighth postoperative day, the patient had edema of the left upper extremity. Thrombosis of the left subclavian vein at the central line site and deep venous thrombosis of the right calf were diagnosed by venography. Protein C, protein S, antithrombin III, and plasminogen values were decreased but returned to normal after resolution of the thrombi. Because the patient's platelet count had fallen to 70,000 cells/#l and did not improve with platelet transfusion, the diagnosis of HIT was considered. The intact-platelet ELISA demonstrated plateletreactive antibody in the serum and results of the serotonin-release test were positive (Table). Heparin therapy was discontinued; treatment with warfarin at a dose of 5 mg daily and aspirin at a dose of 60 mg daily was started. Results of the serotonin-release test were again positive on the next day (Table). The lowest platelet count, 52,000 cells/~d, was recorded on the eleventh postoperative day; after this, platelet counts rose each day, reaching 101,000 cells/~d on the thirteenth day and 202,000 cells/ul on the sixteenth day. During the patient's hospitalization, all blood cultures remained sterile. There was no laboratory evidence of disseminated intravascular coagulation. The patient was discharged on the thirty-fifth postoperative day and continued to receive warfarin and aspirin. Seventy-five days after the discontinuation of heparin therapy, results of the serotonin-release test for HIT and the intact-platelet ELISA for platelet antibody were negative (Table). The patient continues to have partial subclavian vein obstruction and his platelet counts are normal. The patient's neurologic status has been stable, but he has residual hemiparesis and developmental delay as a sequela of his cerebrovascular accident at the age of 8 years. DISCUSSION Two forms of H I T have been described. A nonimmune, transient thrombocytopenia, H I T type I, occurs immediately after initiation of heparin therapy and is not associated with sequelae despite the continuation of heparin therapy.I, 4 In contrast to the simple clearance of agglutinated platelets caused by the binding of heparin in type I H I T , type II H I T is thought to be mediated by the development of heparin-dependent IgG or I g M antibodies that bind to the Fc receptor on the platelet surface, causing platelet activation that may lead to limb- or life-threatening arterial platelet thrombi. 1, 2, 4, 5, 9, 10 Thrombotic complications,
Clinical and laboratory observations
13 7
Table. ~4C-Serotonin release from platelets incubated in patient serum at various times Day 8 9 83
No heparin
0.1 U heparin per milliliter
100 U heparin per milliliter
0 0 0
78 68 1
18 1 3
Figures represent percentage of serotonin release at given concentration of heparin.
which are seen in approximately 10% to 20% of persons with type II HIT, include acute myocardial infarction, cerebral infarction, and limb amputation.i, 2, 4, 5, 9 Severe and unexpected venous thrombosis, which has also occurred during heparin therapy, is increasingly considered to be part of the syndrome.I, 2, 4 The onset of thrombocytopenia in type II H I T usually occurs within 2 to 15 days after the initiation of heparin therapy; platelet counts range between 40,000 and 60,000 cells/~zl. 1, 4 The specificity of the laboratory diagnosis of H I T has improved to approximately 99% with the use of the t4C-serotonin-release test. 1, 4 Measurable amounts of ~4C-serotonin are released from platelets activated in the presence of patient serum and therapeutic concentrations of heparin, When high concentrations of heparin are used 14C-serotonin is not released, presumably because the free antiheparin antibodies are bound by the heparin and thus cannot bind to Fc receptors. Positive release of serotonin at high heparin concentrations suggests the presence of autoantibody or of non-heparin-dependent, drug-dependent antibody. Heparin-dependent antibodies typically disappear from the patient's serum within several weeks after the discontinuation of heparin therapy. W e believe that our patient had H I T because of his typical course of consumptive thrombocytopenia with resolution after the discontinuation of heparin therapy, the positive results of the serotonin-release test in the presence of therapeutic but not higher concentrations of heparin at appropriate times during the illness, and the lack of other causes of thrombocytopenia. The serious thrombotic complication seen in our patient may not have been directly caused by H I T . However, platelet activation associated with H I T may have increased the risk of thrombosis from endothelial damage by the catheter tip in the superior vena cava. Whether the cerebrovascular accident that occurred after the patient's second operative procedure with exposure to heparin was due to H I T is unclear. At that time, the pattern of thrombocytopenia was not consistent with that reported in patients with H I T type II and no studies were performed to confirm the diagnosis. Several explanations are possible for the lack of reports
13 8
Clinical and laboratory observations
of this entity in children. Heparin is used much less frequently in this age group and is usually given in the setting of cardiopulmonary bypass, extracorporeal membrane oxygenation, or dialysis, which may not necessitate prolonged exposure to heparin. 5 Many children are also treated during infancy and may not have an immune system competent to mount an immune response. It is also possible that, because children do not have other risk factors for thrombosis, thrombosis may not occur as frequently and thrombocytopenia may be overlooked or attributed to other, nonspecific causes, such as suspected but unproved infection. We conclude that HIT may occur in the pediatric age group and recommend that platelet counts be monitored in children receiving heparin therapy. Clinicians should remain aware of this possibility in children who have thrombocytopenia while receiving heparin therapy. Diagnostic studies to rule out thrombosis and a 14C-serotonin-release test should be carried out in patients with any symptoms suggestive of thrombosis. Prospective studies of children receiving heparin therapy are warranted and will better define this drug-induced complication in the pediatric age group.
The Journal of Pediatrics July 1992
REFERENCES
1. Warkentin TE, Kelton JG. Heparin and platelets. Hematol Oncol Clin North Am 1990;4:243-64. 2. Warkentin TE, Kelton JG. Heparin-induced thrombocytopenia. Annu Rev Med 1989;40:31-44. 3. Miller ML. Heparin-induced thrombocytopenia. Cleve Clin J Med 1989;56:483-90. 4. Warkentin TE, Kelton JG. Heparin-indueed thrombocytopenia. In: Coller BS, ed. Progress in hemostasis and thrombosis. Philadelphia: WB Saunders, 1991:1-34. 5. Bell WR. Heparin-associated thrombocytopenia and thrombosis. J Lab Clin Med 1988;111:600-5. 6. Oriot D, Wolfe M, Wood C, et al. Severe thrombocytopenia induced by heparin in an infant with acute myocarditis. Arch Fr Pediatr 1990;47:357-9. 7. Howe SE, Lynch DM, Lynch JM. An enzyme-linked immunosorbent assay for the quantification of serum platelet-bindable IgG. Transfusion 1984;24:348-52. 8. Schiffer CA, Young V. Detection of platelet antibody using a micro-enzyme-linkedimmunosorbent assay (ELISA). Blood 1983;61:811-7. 9. Cola C, Ansel J. Heparin-induced thrombocytopenia and arterial thrombosis: alternative therapies. Am Heart J 1990; 118:368-74. 10. Kelton JG, Sheridan D, Santos A, et al. Heparin-induced thrombocytopenia:laboratory studies. Blood 1988;72:925-30.
Effects of ursodeoxycholic acid on liver function in patients with cystic fibrosis and chronic cholestasis C. G a l a b e r t , PhD, J. C. M o n t e t , PhD, D. L e n g r a n d , A. L e c u i r e , C. S o t t a , C. F i g a r e l l a , PhD, MD, a n d J. P. C h a z a l e t t e , MD From the Laboratoire de Biochimie et Centre d'Etudes et Recherches sur la Mucoviscidose, H6pital Ren6e Sabran (Hopitaux de Lyon) Glens, Hy~res, France, Groupe de Recherche sur les Glandes Exocrines (INSERM), Marseille, France, and Laboratoire de Biochimie, H6pital de la Croix Rousse (Hopitaux de Lyon), Lyon, France
Ursodeoxycholic acid, 10 to 20 m g / k g per day, was administered for I year to 22 patients with cystic fibrosis and chronic cholestasis, resulting in significantly improved liver enzyme values. However, evidence of cholestasis continued, as shown by the pattern of alkaline phosphatase isoenzymes. (J PEDIATR1992;121: 138-41) Exocrine secretions in patients with cystic fibrosis are generally dehydrated because of an epithelial transport defect. The abnormal biliary secretion is considered an important Supported by grants from the Association Fran~aise.de Lutte contre la Mucoviscidoseand the Caisse R6gionale d~:A~suranceMaladie du Sud-Est. Submitted for publication Aug. 7, 1991; accepted Feb. 3, 1992. Reprint requests: C. Galabert, PhD, Laboratoire de Biologic, Hopital Ren6e Sabran (Hopitaux de Lyon) Giens, 83406, Hy6res Cedex, France. 9/26/36785
factor in the hepatopathy in CF, 1causing inspissation in the biliary ductules, which leads to plug formation, cholestasis, subsequent .inflammation, duetular proliferation, and finally focal biliary cirrhosis and multilobular cirrhosis. 2 Additionally, bile acid malabsorption and fecal loss of taurine lead to the enrichment of bile with hydrophobic, potentially cytotoxic bile acids) Ursodeoxycholic acid, a hydrophilic bile acid 4 with potent choleretic properties, 5 has been shown to protect the hepatocyte against the cytotoxic effects of hydrophobic bile acids.6, 7 Recently UDCA was proposed for the treatment
experience with this and other patients is needed to determine whether this outcome is due to early initiation of benzoate a n d / o r D M therapy or to variability in phenotype. REFERENCES 1. Nyhan WL. Nonketotic hyperglycinemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease. 6th ed. New York: McGraw-Hill, 1989:74353. 2. Ransom BR. Possible pathophysiology of neurologic abnormalities associated with nonketotic hyperglycinemia [Letter]. N Engl J Med 1976;294:1295-6. 3. McDonald JW, Johnston MV. Non-ketotie hyperglycinemia: pathophysiological role of the N-methyl-D-aspartate type amino acid receptors [Letter]. Ann Neurol 1990;27:449-50. 4. Wolff JA, Kulovich S, Yu AL, Qiao C-N, Nyhan WL. The effectiveness of benzoate in the rnanagement of seizures in nonketotic hyperglycinemia. Am J Dis Child 1986;140:596-602. 5. Prince DA, Feeser HR. Dextromethorphan protects against cerebral infarction in a rat model of hypoxia-ischemia. Neurosci Lett 1988;85:291-6. 6. Ferkany JW, Borosky SA, Clissold DB, Pontecorvo MJ. Dextromethorphan inhibits NMDA-induced convulsions. Eur J Pharmacol 1988;151:151-4.
Detromethorphan and benzoate for hyperglycinemia
1 35
7. Gitzelmann R, Steinmann B, Otten A, et al. Non-ketotic hyperglycinemia treated with strychnine, a glycine receptor antagonist. Helvetica Pediatrica Acta 1978;32:517-25. 8. Von Wendt L, Simila S, Saukkonen A-L, Koivisto M. Failure of strychnine treatment during the neonatal period in three Finnish children with nonketotic hyperglycinemia. Pediatrics 1980;65:1166-9. 9. Carson NAJ. Non-ketotic hyperglycinemia: a review of 70 patients. J Inherited Metab Dis 1982;5(suppl 2):126-8. 10. McDonald JW, Johnston MV. Physiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain Res Rev 1990;15:41-70. 11. Sklow B, Goldberg MP, Choi DW. High concentration of glycine potentiate cortical neuronal injury produced by combined oxygen-glucose deprivation in vivo [Abstract]. Neurology 1991 ;41 (suppl 1):227. 12. McDonald JW, Silverstein FS, Johnston MV. Neurotoxicity of N-methyl-D-aspartate is markedly enhanced in developing rat central nervous system. Brain Res 1988;459:200-3. 13. Ohya Y, Ochi N, Mizutani N, Hayakawa C, Watanabe K. Nonketotic hyperglycinemia: treatment with NMDA antagonist and consideration of neuropathogenesis. Pediatr Neurol 1991;7:65-8.
Clinical and laboratory observations Heparin-induced thrombocytopenia in a child C h a r l e s P o t t e r , MD, J o a n C o x Gill, MD, J. Paul S c o t t , MD, a n d J a n i c e G. M c F a r l a n d , MD From the Department of Pediatrics, Medical College of Wisconsin, and the Blood Research institute, Blood Center of Southeastern Wisconsin, Milwaukee
We describe a case of t h r o m b o c y t o p e n i a and d e e p venous thrombosis in a boy who received heparin to maintain p a t e n c y of a central venous catheter. M e a surement of the release of serotonin l a b e l e d with carbon 14 confirmed the prese n c e of heparin-induced thrombocytopenia. Children receiving heparin thera p y should be monitored for the possibility of heparin-induced thrombocytopenia. (J PEDIATR1992;121:135-8)
Heparin-induced thrombocytopenia occurs in two forms: a nonimmune-based mild thrombocytopenia beginning soon after heparin administration and an immune-mediated se-
Submitted for publication May 23, 1991; accepted Jan. 17, 1992. Reprint requests: Joan Cox Gill, MD, Great Lakes Hemophilia Foundation, P.O. Box 13127, Wauwatosa, WI 53212-0127. 9/22/36387
vere thrombocytopenia with onset several days after heparin therapy is initiated.l-3 This latter form, when accompanied by limb- and life-threatening arterial thromboses in 10% to 20% of cases, is termed heparin-induced thrombosis and thrombocytopenia syndrome. 1-5 Although H I T occurs in as many as 5% of adults treated with heparin, it has been reported only once in the pediatric age group. 6 We describe a case of H I T in a boy who had thrombosis of the left subclavian vein and right calf veins.
13 6
Clinical and laboratory observations
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POST-OPERATION DATE Figure. Course of thrombocytopenia in a boy receiving heparin flushes to maintain catheter patency after cardiac surgery. Arrows indicate platelet transfusions and horizontal bars depict heparin exposure.
METHODS A n intact-platelet E L I S A was used to detect the presence of d r u g - i n d e p e n d e n t antibodies, as previously described. 7, 8 M e a s u r e m e n t of the release of serotonin labeled with carbon 14 was used to confirm the diagnosis of HIT. 1'2'4 Briefly, the release of serotonin from 14C-serotonin-loaded platelets added to control a n d patient sera was m e a s u r e d in the absence of heparin a n d with 0.1 U and 100 U of heparin per milliliter. Release of >20% of label with 0.1 U heparin per milliliter and of <20% with 100 U / m l was considered a positive result. Assays were run in duplicate; a n o r m a l control s e r u m a n d two well-characterized control sera t h a t repeatedly d e m o n s t r a t e d 85% to 100% release of serotonin at the heparin concentration of 0.1 U / m l , with no release at 100 U / m l , were tested with each assay. CASE REPORT A 13-year-old white boy was first exposed to heparin at 1 month of age during a Waterston shunt procedure for tricuspid atresia; heparin was also used to maintain catheter patency during the postoperative period. His platelet count decreased slightly on the first postoperative day but then returned to normal. At 8 years of age the patient underwent closure of the Waterston
shunt and a right Blalock shunt procedure was performed. He was again given heparin during cardiopulmonary bypass. Heparin flushes of intravenous catheters were continued for 1 week after operation. The patient's platelet count decreased to 109,000 cells/#l on the day after operation and the next day fell to 95,000 cells/~zl from a preoperative level of 216,000 cells/#l. The platelet count quickly recovered to >100,000 cells/#l but fell again to 93,000 cells//A at the pafi~ent's discharge on the tenth postoperative day. Two days later the patient was readmitted with transient left-sided hemiparesis and aspirin therapy was initiated. Right subclavian steal syndrome was diagnosed and the right vertebral
ELISA HIT
Enzyme-linked immunosorbent assay Heparin-induced thrombocytopenia
artery was ligated. The patient received heparinized saline flushes of intravenous catheters for the next week. Three days after the arterial ligation he had right-sided hemiparesis consistent with a cerebral vascular accident in the left hemisphere. Multiple bilateral areas of cerebral calcification, reflecting an older process, were noted on computed tomographic scan, but findings of cerebral flow study, cranial computed tomography, and echocardiography were not consistent with emboli, thrombi, or vegetations. A venogram of the lower extremities appeared normal. The platelet count was
Volume 121 Number 1
115,000 cells/#l at readmission, increased to 154,000 cells/tzl 3 days after the arterial ligation, and was 196,000 cells/tzl at the patient's discharge. At 13 years of age the patient underwent closure of his Blalock shunt. Preoperative laboratory values included a platelet count of 168,000 cells//zl, a fibrinogen value of 225 mg/dl, fibrin and fibrinogen degradation products < 10 units, a prothrombin time of 1Z8 seconds, and a partial thromboplastin time of 28.8 seconds; hemoglobin level and hematocrit remained normal throughout this hospitalization. The patient was given 2000 U of heparin during cardiopulmonary bypass and received 8 units of random-donor platelets during the procedure. Patency of the intravenous catheters was maintained for the next 8 days with 20 U of heparin every 3 hours. Heparin administration, platelet transfusions, and platelet counts are shown in the Figure. On the eighth postoperative day, the patient had edema of the left upper extremity. Thrombosis of the left subclavian vein at the central line site and deep venous thrombosis of the right calf were diagnosed by venography. Protein C, protein S, antithrombin III, and plasminogen values were decreased but returned to normal after resolution of the thrombi. Because the patient's platelet count had fallen to 70,000 cells/#l and did not improve with platelet transfusion, the diagnosis of HIT was considered. The intact-platelet ELISA demonstrated plateletreactive antibody in the serum and results of the serotonin-release test were positive (Table). Heparin therapy was discontinued; treatment with warfarin at a dose of 5 mg daily and aspirin at a dose of 60 mg daily was started. Results of the serotonin-release test were again positive on the next day (Table). The lowest platelet count, 52,000 cells/~d, was recorded on the eleventh postoperative day; after this, platelet counts rose each day, reaching 101,000 cells/~d on the thirteenth day and 202,000 cells/ul on the sixteenth day. During the patient's hospitalization, all blood cultures remained sterile. There was no laboratory evidence of disseminated intravascular coagulation. The patient was discharged on the thirty-fifth postoperative day and continued to receive warfarin and aspirin. Seventy-five days after the discontinuation of heparin therapy, results of the serotonin-release test for HIT and the intact-platelet ELISA for platelet antibody were negative (Table). The patient continues to have partial subclavian vein obstruction and his platelet counts are normal. The patient's neurologic status has been stable, but he has residual hemiparesis and developmental delay as a sequela of his cerebrovascular accident at the age of 8 years. DISCUSSION Two forms of H I T have been described. A nonimmune, transient thrombocytopenia, H I T type I, occurs immediately after initiation of heparin therapy and is not associated with sequelae despite the continuation of heparin therapy.I, 4 In contrast to the simple clearance of agglutinated platelets caused by the binding of heparin in type I H I T , type II H I T is thought to be mediated by the development of heparin-dependent IgG or I g M antibodies that bind to the Fc receptor on the platelet surface, causing platelet activation that may lead to limb- or life-threatening arterial platelet thrombi. 1, 2, 4, 5, 9, 10 Thrombotic complications,
Clinical and laboratory observations
13 7
Table. ~4C-Serotonin release from platelets incubated in patient serum at various times Day 8 9 83
No heparin
0.1 U heparin per milliliter
100 U heparin per milliliter
0 0 0
78 68 1
18 1 3
Figures represent percentage of serotonin release at given concentration of heparin.
which are seen in approximately 10% to 20% of persons with type II HIT, include acute myocardial infarction, cerebral infarction, and limb amputation.i, 2, 4, 5, 9 Severe and unexpected venous thrombosis, which has also occurred during heparin therapy, is increasingly considered to be part of the syndrome.I, 2, 4 The onset of thrombocytopenia in type II H I T usually occurs within 2 to 15 days after the initiation of heparin therapy; platelet counts range between 40,000 and 60,000 cells/~zl. 1, 4 The specificity of the laboratory diagnosis of H I T has improved to approximately 99% with the use of the t4C-serotonin-release test. 1, 4 Measurable amounts of ~4C-serotonin are released from platelets activated in the presence of patient serum and therapeutic concentrations of heparin, When high concentrations of heparin are used 14C-serotonin is not released, presumably because the free antiheparin antibodies are bound by the heparin and thus cannot bind to Fc receptors. Positive release of serotonin at high heparin concentrations suggests the presence of autoantibody or of non-heparin-dependent, drug-dependent antibody. Heparin-dependent antibodies typically disappear from the patient's serum within several weeks after the discontinuation of heparin therapy. W e believe that our patient had H I T because of his typical course of consumptive thrombocytopenia with resolution after the discontinuation of heparin therapy, the positive results of the serotonin-release test in the presence of therapeutic but not higher concentrations of heparin at appropriate times during the illness, and the lack of other causes of thrombocytopenia. The serious thrombotic complication seen in our patient may not have been directly caused by H I T . However, platelet activation associated with H I T may have increased the risk of thrombosis from endothelial damage by the catheter tip in the superior vena cava. Whether the cerebrovascular accident that occurred after the patient's second operative procedure with exposure to heparin was due to H I T is unclear. At that time, the pattern of thrombocytopenia was not consistent with that reported in patients with H I T type II and no studies were performed to confirm the diagnosis. Several explanations are possible for the lack of reports
13 8
Clinical and laboratory observations
of this entity in children. Heparin is used much less frequently in this age group and is usually given in the setting of cardiopulmonary bypass, extracorporeal membrane oxygenation, or dialysis, which may not necessitate prolonged exposure to heparin. 5 Many children are also treated during infancy and may not have an immune system competent to mount an immune response. It is also possible that, because children do not have other risk factors for thrombosis, thrombosis may not occur as frequently and thrombocytopenia may be overlooked or attributed to other, nonspecific causes, such as suspected but unproved infection. We conclude that HIT may occur in the pediatric age group and recommend that platelet counts be monitored in children receiving heparin therapy. Clinicians should remain aware of this possibility in children who have thrombocytopenia while receiving heparin therapy. Diagnostic studies to rule out thrombosis and a 14C-serotonin-release test should be carried out in patients with any symptoms suggestive of thrombosis. Prospective studies of children receiving heparin therapy are warranted and will better define this drug-induced complication in the pediatric age group.
The Journal of Pediatrics July 1992
REFERENCES
1. Warkentin TE, Kelton JG. Heparin and platelets. Hematol Oncol Clin North Am 1990;4:243-64. 2. Warkentin TE, Kelton JG. Heparin-induced thrombocytopenia. Annu Rev Med 1989;40:31-44. 3. Miller ML. Heparin-induced thrombocytopenia. Cleve Clin J Med 1989;56:483-90. 4. Warkentin TE, Kelton JG. Heparin-indueed thrombocytopenia. In: Coller BS, ed. Progress in hemostasis and thrombosis. Philadelphia: WB Saunders, 1991:1-34. 5. Bell WR. Heparin-associated thrombocytopenia and thrombosis. J Lab Clin Med 1988;111:600-5. 6. Oriot D, Wolfe M, Wood C, et al. Severe thrombocytopenia induced by heparin in an infant with acute myocarditis. Arch Fr Pediatr 1990;47:357-9. 7. Howe SE, Lynch DM, Lynch JM. An enzyme-linked immunosorbent assay for the quantification of serum platelet-bindable IgG. Transfusion 1984;24:348-52. 8. Schiffer CA, Young V. Detection of platelet antibody using a micro-enzyme-linkedimmunosorbent assay (ELISA). Blood 1983;61:811-7. 9. Cola C, Ansel J. Heparin-induced thrombocytopenia and arterial thrombosis: alternative therapies. Am Heart J 1990; 118:368-74. 10. Kelton JG, Sheridan D, Santos A, et al. Heparin-induced thrombocytopenia:laboratory studies. Blood 1988;72:925-30.
Effects of ursodeoxycholic acid on liver function in patients with cystic fibrosis and chronic cholestasis C. G a l a b e r t , PhD, J. C. M o n t e t , PhD, D. L e n g r a n d , A. L e c u i r e , C. S o t t a , C. F i g a r e l l a , PhD, MD, a n d J. P. C h a z a l e t t e , MD From the Laboratoire de Biochimie et Centre d'Etudes et Recherches sur la Mucoviscidose, H6pital Ren6e Sabran (Hopitaux de Lyon) Glens, Hy~res, France, Groupe de Recherche sur les Glandes Exocrines (INSERM), Marseille, France, and Laboratoire de Biochimie, H6pital de la Croix Rousse (Hopitaux de Lyon), Lyon, France
Ursodeoxycholic acid, 10 to 20 m g / k g per day, was administered for I year to 22 patients with cystic fibrosis and chronic cholestasis, resulting in significantly improved liver enzyme values. However, evidence of cholestasis continued, as shown by the pattern of alkaline phosphatase isoenzymes. (J PEDIATR1992;121: 138-41) Exocrine secretions in patients with cystic fibrosis are generally dehydrated because of an epithelial transport defect. The abnormal biliary secretion is considered an important Supported by grants from the Association Fran~aise.de Lutte contre la Mucoviscidoseand the Caisse R6gionale d~:A~suranceMaladie du Sud-Est. Submitted for publication Aug. 7, 1991; accepted Feb. 3, 1992. Reprint requests: C. Galabert, PhD, Laboratoire de Biologic, Hopital Ren6e Sabran (Hopitaux de Lyon) Giens, 83406, Hy6res Cedex, France. 9/26/36785
factor in the hepatopathy in CF, 1causing inspissation in the biliary ductules, which leads to plug formation, cholestasis, subsequent .inflammation, duetular proliferation, and finally focal biliary cirrhosis and multilobular cirrhosis. 2 Additionally, bile acid malabsorption and fecal loss of taurine lead to the enrichment of bile with hydrophobic, potentially cytotoxic bile acids) Ursodeoxycholic acid, a hydrophilic bile acid 4 with potent choleretic properties, 5 has been shown to protect the hepatocyte against the cytotoxic effects of hydrophobic bile acids.6, 7 Recently UDCA was proposed for the treatment