PEDIATRICS Vol. 111 No. 1 January 2003, pp. 167-170
Bleeding Tendency in Children With Alagille Syndrome
* Service d’Hépatologie pédiatrique
Laboratoire d’Hématologie, Hôpital de Bicêtre, Le Kremlin Bicêtre Cedex, France
Unité INSERM 347, Le Kremlin Bicêtre Cedex, France
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ABSTRACT |
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Objective. Spontaneous intracranial bleeding is now a widely recognized complication and cause of mortality in patients with Alagille syndrome. The pathogenesis of intracranial bleeding in these patients remains unclear. The aim of the study was to look for other sites of bleeding in these patients that could suggest a factor of multiorgan morbidity.
Methods. The records of 174 patients with Alagille syndrome were reviewed, and 38 (22%) patients without liver failure who experienced hemorrhage that led to a drop in hemoglobin level of at least 3 g/dL or to blood transfusion were identified.
Results. In 38 patients, 49 bleeding episodes occurred at a median age of 3.75 years (range: 1 month–27 years). Seventeen patients had 23 episodes of spontaneous bleeding; 21 patients bled during surgery or other medical procedures, and 5 among these 21 patients also had a spontaneous bleeding episode. Nine patients bled at least twice. Median platelets count and prothrombin time were normal. Severe cholestasis existed in 33 patients. One patient has a deletion of the 20p12 region, and 13 of 17 patients studied have a JAGGED1 mutation. Blood transfusion was necessary in 23 patients. Eight patients died secondary to bleeding (4 after surgery, 2 after gastrointestinal bleeding, 1 after needle liver biopsy, and 1 after intracranial bleeding).
Conclusion. These results suggest that patients with Alagille syndrome are at special risk for bleeding; this should be taken into account before deciding on an invasive procedure. The mechanism of the bleeding is still unclear; the role of hypercholesterolemia cannot be excluded, but it may be speculated that JAGGED1 signaling abnormalities may impair the hemostatic function.
Key Words: Alagille syndrome • hemorrhage • JAGGED1 • hemostasism
Abbreviations: AGS • Alagille syndrome
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Intracranial bleeding is now a recognized complication in patients with Alagille syndrome (AGS). The incidence of intracranial bleeding in AGS may be as high as 14%.1 Deaths secondary to intracranial hemorrhage range from 1.7% to 25% of the overall mortality as reported recently in large series.1–4 Pathogenesis of intracranial bleeding is still unclear but may be related to JAGGED1 gene expression in the dural plexus.5 Because JAGGED1 is expressed in both arterial endothelium and megakaryocytes and regulates cell–cell interactions and cell matrix alterations during endothelium injury,6,7 we investigated whether bleeding may involve other sites. This report describes 38 patients who had AGS without liver failure and presented with severe hemorrhage either spontaneous or complicating medical procedures.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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From 1960 to 2000, 174 children with AGS were investigated in this unit. In this retrospective study, the charts of these children were reviewed to identify patients who experienced severe hemorrhagic complications without biological signs of liver failure. Thirty-eight patients (27 boys) were identified. All data concerning clinical findings, laboratory data, tests results (echocardiograms, radiographs, endoscopic examinations), and histologic data were obtained by reviewing medical records. One child who had bled during the neonatal period was excluded because of vitamin K deficiency existing after birth. Severe hemorrhage was considered whenever a blood transfusion was necessary or a drop in hemoglobin level of at least 3 g/dL was observed. Peptic ulcer bleeding was confirmed by endoscopic exploration, ruling out portal hypertensive gastropathy. Bleeding time (Ivy); prothrombin time; thrombin time; activated partial thromboplastin time; 1-stage factor V, II, VII, and X clotting activities; and fibrinogen levels (Clauss) were systematically performed. FVIII, von Willebrand factor antigen and ristocetin cofactor activity assays, and ex vivo platelet aggregation studies were performed in 5 cases. Chronic cholestasis was defined as persisting elevation of serum concentration of conjugated bilirubin (>17 µmol/L or 1.0 mg/dL) for longer than 6 months. Liver failure was defined by the combination of hypoalbuminemia (<35 g/L) and prolonged prothrombin time (
70%). Patients with severe chronic cholestasis had intramuscular administration of fat-soluble vitamins. Regarding vitamin K repletion, 10 mg of vitamin K1 was given intramuscularly every 2 weeks. Eighteen patients were screened for the presence of heterozygous mutations in the JAGGED1 gene.
Statistical Analysis
Comparison of proportions was made by use of 
2 test, with Yates correction if indicated. All statistical tests were 2-tailed, and P < .05 was taken to be significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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The 38 patients reported in this series experienced 49 bleeding episodes at a median age of 3.75 years (range: 1 month–27 years). Twenty of the 38 children displayed all clinical features of AGS; 13 and 5 displayed 4 and 3 features, respectively. Neonatal cholestasis was the initial clinical sign of the disease in all but 5 children who presented with jaundice after the age of 6 months. Median age at diagnosis was 10 months (range: 1 month–6 years). Paucity of interlobular bile ducts was present in all liver specimens of 32 patients who underwent liver biopsy. Two or more minor features were observed and are indicated in Table 1 . Hemorrhage occurred during surgical and other medical procedures (n = 21) or spontaneously (n = 28). Five of 21 patients who bled during surgery also experienced spontaneous bleeding. The remaining 23 spontaneous bleedings occurred in 17 patients. Thirteen of these 17 patients had a single spontaneous bleeding episode, but 4 presented with altogether 10 episodes. Eight patients bled from 2 different sites, and 1 patient bled from 3 different sites. Three of these 9 patients who bled from different sites experienced intracranial hemorrhage. The causes of spontaneous bleeding and results of laboratory tests at the moment of bleeding are shown in Tables 2 and 3, respectively. Thirteen of the 23 patients who required blood transfusions underwent surgical or medical procedures. All patients who underwent surgical procedures or invasive investigations were in good general condition with no signs of infection or multiple organ dysfunction. Of 14 patients who had received a transplant in this series, only 1 bled after orthotopic liver transplantation. This patient who had bled after renal biopsy at age 3.5 years underwent a successful orthotopic liver transplantation at age 17.5 years and presented with menorrhagia that required blood transfusions at age 20. Hormone tests were normal, and the menorrhagia was considered to be of functional origin. Of the 4 patients who bled after kidney needle biopsy, 1 had small kidneys and in the other 3 both kidneys were normal in size, shape, and location.
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Bleeding was lethal for 8 patients: during surgery in 4, after gastrointestinal bleeding in 2, after second intracranial bleeding in 1, and after liver biopsy in 1. The patient who died after liver biopsy, a 3.5-year-old girl, presented with acute shock 5 hours after needle liver biopsy that was not responsive to emergency resuscitation; postmortem examination showed hemoperitoneum and hematoma on the liver surface. The hemoglobin concentration performed systematically 2 hours after the biopsy had shown a hemoglobin level identical to the preprocedure level. Bleeding accounted for 14% of the overall mortality rate in the group of 174 patients, and 1.7% represented the percentage of deaths as a result of intracranial bleeding alone.
Four children underwent surgery for intracranial bleeding that occurred at ages ranging from 19 months to 6 years. Three of these children had a single episode of intracranial hemorrhage, but the fourth child had 2 episodes. Bone fracture was found in only 1 of them. Head injury was the result of a sudden fall from still-standing position in all instances. Loss of consciousness was not detected at the moment or after falling. All children survived after bleeding except for the child who had 2 episodes. No postmortem examination of the brain was done in this child.
At the moment of bleeding, all patients but 5 had severe chronic cholestasis, but only 2 patients had normal blood cholesterol levels. Ten patients displayed histologically proven cirrhosis. Seven patients presented with grade 1 esophageal varices without signs of portal hypertensive gastropathy. A moderate thrombocytopenia (platelet count ranging between 80 and 150 x 109/L) was found in 8 of 33 patients; bleeding time was normal (2–4 minutes) in the 31 patients tested. Ex vivo platelet aggregation study was normal in the 5 patients tested. Four of these 5 patients also had normal levels of FVIII and von Willebrand factor levels. Prothrombin time and levels of factors V, II, VII, and X and fibrinogen were normal in 35 of 36 patients tested; in 1 case, the FV level was 0.56 IU/mL, with normal levels of fibrinogen, FII, FVII, and FX. Therefore, the bleeding and/or requirement for transfusion was deemed extremely unusual for the type of procedures, especially when considering that the common preoperative hemostasis investigations were normal in virtually all patients(Table 3) .
Heart defects and other vascular features were found in 24 of 38 patients of this group and in 44 other patients of the group of 136 children who had AGS and did not present with hemorrhagic complications. Cardiac surgery was necessary for treatment in 9 patients from each group. Cardiovascular manifestations, apart from pulmonary stenosis, were more frequent in patients with hemorrhagic complications (63%) than in patients without hemorrhagic complications (32%; P = .0006) as well as cardiac surgery (24% and 6.7%, respectively; P = .0059).
One patient has an unbalanced translocation with deletion of the 20p12 region, and 13 of 17 patients studied have a JAGGED1 mutation. Twelve mutations led to premature stop codon, and only 1 is a missense mutation. They occur in exons 1, 2, 5, 6, 7, 16, 20, and 24.8 There is no difference between patients who bled and the whole series in frequency of detection of JAGGED1 mutations.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Unexplained intracranial bleeding is now a widely recognized complication and cause of mortality in patients with AGS. Hemorrhage originating from other sites has not been described as a factor of morbidity. We report that hemorrhagic complications occurred in 38 (22%) of 174 patients and have contributed in 14% of overall mortality rate (including only 1 death secondary to intracranial bleeding). Therefore, bleeding tendency significantly contributes to the morbidity and mortality in patients with AGS and is multisystemic. The risk must be taken into account before any invasive procedure is conducted, because bleeding was lethal in 4 patients during surgery and in 1 after liver needle biopsy.
Chronic severe cholestasis and cirrhosis existing in patients with AGS may be a contributing factor to their hemorrhagic risk. In this series, none of the patients presented with significant coagulation abnormalities, and it is very unlikely that their bleeding tendency was related to an increased fibrinolysis activation without any subsequent FV or fibrinogen level decrease. Coagulopathy existed only in 2 of 20 patients reported with intracranial bleeding.1–3 Coagulation defect related to liver condition, as seen in end-stage liver disease, cannot be solely held responsible for bleeding in the patients reported here.
In this series, median age of bleeding was 3.75 years, suggesting a correlation with severe cholestasis and hypercholesterolemia, which are most prevalent in the early school-age years. The role of the abnormal lipoprotein pattern observed in patients with AGS cannot be ruled out even if 5 patients were not jaundiced at the moment of bleeding and 2 other patients had normal levels of blood cholesterol. Indeed apolipoprotein E–rich high-density lipoprotein particles may inhibit platelet aggregation and decrease thrombus formation.9,10
It has been previously reported that patients with intracranial bleeding had other manifestations suggesting vascular compromise.3 Our series confirms this finding because cardiovascular abnormalities were significantly more frequent in patients who bled. It has been known for a long time that excessive bleeding tendency may complicate congenital cardiac defects.11 Moreover, cerebrovascular abnormalities may be associated with a variety of congenital heart disorders and cause intracranial bleeding.12 It cannot be ruled out that pathogenesis of bleeding tendency in AGS belongs to the same phenomena and is unspecific.
In another way, it has been suggested that a different defect in Notch signaling pathway may be present in patients with intracranial bleeding.3 Because most of the patients studied have JAGGED1 mutations, involvement of another defect is unlikely. Besides, no genotype/phenotype correlation could be established. Moreover, JAGGED1 is widely expressed in endothelial cells, which play a pivotal role both in hemostasis and in angiogenesis.7 The expression of JAGGED1 in megakaryocytes6 may also be relevant in that respect. Thus, it could be speculated that defects in Notch signaling pathway may impair both angiogenesis and hemostasis and then bleeding tendency may be specific to AGS. This hypothesis may parallel the role of hemostatic protease receptors during development of the vascular system evidenced by knockout mice models.13
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ACKNOWLEDGMENTS |
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We thank Dr Marie Dreyfus, an expert in coagulation, for assistance in the analysis of hematologic results.
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FOOTNOTES |
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Received for publication Mar 26, 2002; Accepted Jul 26, 2002.
Reprint requests to (P.L.) Service d’Hépatologie pédiatrique, Hôpital de Bicêtre, 78 rue du Général Leclerc, F-94275 Le Kremlin Bicêtre Cedex, France. E-mail: hadchoue{at}kb.inserm.fr
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PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics
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