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Factor XI deficiency in an Ashkenazi Jewish child, causing severe postoperative hemorrhage
Factor
XI Deficiency
in an Ashkenazi Jewish Child, Postoperative Hemorrhage By David J. Weinstock Baltimore,
l Although inherited coagulation factor deficiencies with negative bleeding histories are rare, cases such as the one presented herein may not be diagnosed at the time of surgery and may experience severe hemostatic problems postoperatively. It may be prudent to obtain an activated partial thromboplastin time preoperatively for all Ashkenazi Jews, including those with a negative history for a hemostatic disorder, because of the high incidence of factor Xl deficiency in their population. Surgeons and anesthesiologists should be aware of the existence of this and other uncommon hemostatic disorders and their treatment when faced with serious, apparently unexplained postoperative hemorrhage. Copyright 0 1995 by W,B, Saunders Company
INDEX WORDS: life-threatening
Factor Xl, hemophilia hemorrhage.
C, Ashkenazi
Jews,
EMOPHILIA C (factor XI deficiency) is an uncommon disorder. It occurs in approximately 3% of all patients with hemophilia. The disorder usually does not present with clinical bleeding before adulthood; thus, the general practitioner and even the pediatric hematologist might not see an affected child during his or her entire career. We report this case not only because of the rarity of the disorder, but also because a carefully taken history is often negative for a hemostatis disorder.
H
CASE REPORT A 3-year-old boy who was well, except for mild signs of obstructive sleep apnea, was scheduled for a tonsilectomy and adenoidectomy at another hospital. There was no history in the patient or any family member of an unusual bleeding tendency. Both parents are Ashkenazi Jews. A preoperative complete blood count and prothrombin time (PT) were normal. The activated partial thromboplastin time (aPIT) was 56 seconds (control, 33 seconds). The estimated amount of blood loss during surgery was minimal. Postoperatively the patient was extubated but experienced mild to moderate continuous bleeding from the nose and mouth. Examination showed no one single site of bleeding. The child was transferred to the pediatric intensive care unit at our hospital, because no local measures could control the bleeding. PT and From the Divisions of Critical Care Medicine and HematologyOrzcology, Department of Pediati’cs, Sinai Hospital of Baltimore, Baltimore, MD. Address reprint requests to David J. Weinstock, MD, Director, Pediatric Critical Care Medicine, Shady Grove Adventist Hospital, 9901 Medical Center Dr, Rockville, MD 20850. Copytight 0 1995 by W! B. Saunders Company 0022-3468l95i3012-0033$03.00l0
1746
Causing
Severe
and Allen D. Schwartz Maryland aPTT were obtained again and found to be 11 seconds and 43 seconds, respectively. The platelet count, fibrinogen level, ristocetin cofactor assay, and d-dimer level were all normal. A coagulation factor analysis showed a factor VIII level of 78% (normal, 50% to 150%), and a factor IX level of 60% (normal, 50% to 150%). However, the factor XI level was less than 2% (normal, 65% to 150%). The hemoglobin concentration had decreased to 5.3 g/dL from the preoperative level of 13.0 g/dL. The child was given packed red blood cells (15 mL/kg) and fresh frozen plasma (FFP) (20 mL/kg). This increased the factor XI activity level to 56% and the hemoglobin concentration to 8 g/dL. The bleeding from the surgical site slowed and finally stopped after approximately 24 hours. There was no postoperative airway obstruction. The child was treated with FFP (20 mL/kg) every other day for 1 week, with treatment being completed as an outpatient. Family members had factor analysis performed. The patient’s mother had a factor XI activity level of 47%, his father had a factor XI activity level of 58%, and his sister had a factor XI activity of 65%. Normal activity values in our laboratory are 65% to 150%. The test has approximately 10% error per determination in our laboratory. DISCUSSION
Factor XI, or plasma thromboplastin antecedent (PTA), is produced in the liver, and the gene that codes for its production is located on chromosome 4.i It is activated from the zymogen into the protease form by factor XIIa. Once activated, factor XIa converts the zymogen factor IX (Christmas factor) into the protease factor IXa, which then initiates the remainder of the intrinsic coagulation cascade. This pathway is measured by the aPTT. Therefore aPTT is prolonged in patients with factor XI deficiency. aPTT also is prolonged in those with factor VIII deficienq (hemophilia A), factor IX deficiency (hemophilia B), or factor XII deficiency. The PT should be normal in all of these disorders. Patients with factor XI deficiency seldom have an aPTT as prolonged as that of patients with factor VIII or IX deficiency, even when the levels of factor XI are very 10w.~ The severity of clinical bleeding3 also correlates poorIy with factor XI levels; patients with a “severe” deficiency may have little or no excess bleeding even during major surgery. In fact, the bleeding may vary in the same patient after similar challenges.4 The deficiency is most common among Ashkenazi Jews (3 per 1,000) in Israel? It also has occurred in non-Jewish patients, but is extremely rare-about one per million.6 In contrast with other coagulation factor deficien-
Jaurnaloffediatrk
.Swgery,
Vol30,
No 12 (December),
1995: pp 1746-1747
FACTOR
1747
Xl DEFICIENCY
ties, factor XI is not contained in cryoprecipitate or prothrombin complex. High-purity factor XI concentrates have been studied, but they have the danger of being thrombogenic.’ Therefore, the treatment of bleeding caused by this disorder is with fresh frozen plasma. Bleeding can be controlled with plasma concentrations of 10 to 20 U/dL. The half-life of factor XI is greater than 48 hours. A dose of 1 U/kg increases the plasma level of factor XI activity by 2 U/dL. The treatment of bleeding thus can be handled with 15 mL/kg of FFP, to achieve a plasma concentration of about 30 U/dL. The issue of whether or not to routinely perform
coagulation screening on all patients who will undergo elective surgery remains controversial. Most physicians believe that the best screening test is a thorough history and physical examination. Objective study of the impact of preoperative laboratory screening has yielded mixed results. One study by Rappaport* indicated some utibty of screening, whereas other studies show no usefulness at all.9,1oWe recommend the preoperative screening of all Ashkenazi Jews, the population at highest risk for factor XI deficiency, to avoid the possibility of life-threatening postoperative hemorrhage. This is best accomplished by obtaining aPTT preoperatively.
REFERENCES 1. Kato A, Asaki R, et al: Factor XI gene (Fll) is located on the distal end of the long arm of human chromosome 4. Cytogenet Cell Genet 52:77-79, 1989 2. Scott CF, Sinha D, et al: Amidolytic assay of human factor XI in plasma: Comparison with a coagulant assay and a new, rapid radioimmunoassay. Blood 63:42-44,1984 3. Kitchens CS: Factor XI: a review of its biochemistry and deficiency. Semin Thromb Hemost 17:55-58, 1991 4. Bolton-Maggs PHB, Young-Wang-Yin B, McGraw AH, et al: Inheritance and bleeding in factor Xl deficiency. Br J Haematol 69:521-522, 1988 5. Seligsohn U: High gene frequency of factor XI (PTA) deficiency in Ashkenazi Jews. Blood 51:1223-1225,197s
6. Harker LA Hemostasis Manual, ed 2. Philadelphia, F.A. Davis, 1974, p 28 7. Mannucci PM, Bauer KA, Santagostino E, et al: Activation of the coagulation cascade after infusion of a factor XI concentrate in congenitally deficient patients. Blood 84:1314-1317, 1994 8. Rapaport SE: preoperative hemostatic evaluation: Which tests, if any? Blood 61:229-230, 1983 9. Manning SC, Beste D, McBride T, et al: An assessment of preoperative coagulation screening for tonsillectomy and adenoidectomy. Int J Pediatr Otolrhinolaryngoll3:237-238,1987 10. Kaplan EB, Sheiner LB, Boeckmann AJ, et al: The usefulness of preoperative laboratory screening. JAMA 253:3576-3577, 1985
XI Deficiency
in an Ashkenazi Jewish Child, Postoperative Hemorrhage By David J. Weinstock Baltimore,
l Although inherited coagulation factor deficiencies with negative bleeding histories are rare, cases such as the one presented herein may not be diagnosed at the time of surgery and may experience severe hemostatic problems postoperatively. It may be prudent to obtain an activated partial thromboplastin time preoperatively for all Ashkenazi Jews, including those with a negative history for a hemostatic disorder, because of the high incidence of factor Xl deficiency in their population. Surgeons and anesthesiologists should be aware of the existence of this and other uncommon hemostatic disorders and their treatment when faced with serious, apparently unexplained postoperative hemorrhage. Copyright 0 1995 by W,B, Saunders Company
INDEX WORDS: life-threatening
Factor Xl, hemophilia hemorrhage.
C, Ashkenazi
Jews,
EMOPHILIA C (factor XI deficiency) is an uncommon disorder. It occurs in approximately 3% of all patients with hemophilia. The disorder usually does not present with clinical bleeding before adulthood; thus, the general practitioner and even the pediatric hematologist might not see an affected child during his or her entire career. We report this case not only because of the rarity of the disorder, but also because a carefully taken history is often negative for a hemostatis disorder.
H
CASE REPORT A 3-year-old boy who was well, except for mild signs of obstructive sleep apnea, was scheduled for a tonsilectomy and adenoidectomy at another hospital. There was no history in the patient or any family member of an unusual bleeding tendency. Both parents are Ashkenazi Jews. A preoperative complete blood count and prothrombin time (PT) were normal. The activated partial thromboplastin time (aPIT) was 56 seconds (control, 33 seconds). The estimated amount of blood loss during surgery was minimal. Postoperatively the patient was extubated but experienced mild to moderate continuous bleeding from the nose and mouth. Examination showed no one single site of bleeding. The child was transferred to the pediatric intensive care unit at our hospital, because no local measures could control the bleeding. PT and From the Divisions of Critical Care Medicine and HematologyOrzcology, Department of Pediati’cs, Sinai Hospital of Baltimore, Baltimore, MD. Address reprint requests to David J. Weinstock, MD, Director, Pediatric Critical Care Medicine, Shady Grove Adventist Hospital, 9901 Medical Center Dr, Rockville, MD 20850. Copytight 0 1995 by W! B. Saunders Company 0022-3468l95i3012-0033$03.00l0
1746
Causing
Severe
and Allen D. Schwartz Maryland aPTT were obtained again and found to be 11 seconds and 43 seconds, respectively. The platelet count, fibrinogen level, ristocetin cofactor assay, and d-dimer level were all normal. A coagulation factor analysis showed a factor VIII level of 78% (normal, 50% to 150%), and a factor IX level of 60% (normal, 50% to 150%). However, the factor XI level was less than 2% (normal, 65% to 150%). The hemoglobin concentration had decreased to 5.3 g/dL from the preoperative level of 13.0 g/dL. The child was given packed red blood cells (15 mL/kg) and fresh frozen plasma (FFP) (20 mL/kg). This increased the factor XI activity level to 56% and the hemoglobin concentration to 8 g/dL. The bleeding from the surgical site slowed and finally stopped after approximately 24 hours. There was no postoperative airway obstruction. The child was treated with FFP (20 mL/kg) every other day for 1 week, with treatment being completed as an outpatient. Family members had factor analysis performed. The patient’s mother had a factor XI activity level of 47%, his father had a factor XI activity level of 58%, and his sister had a factor XI activity of 65%. Normal activity values in our laboratory are 65% to 150%. The test has approximately 10% error per determination in our laboratory. DISCUSSION
Factor XI, or plasma thromboplastin antecedent (PTA), is produced in the liver, and the gene that codes for its production is located on chromosome 4.i It is activated from the zymogen into the protease form by factor XIIa. Once activated, factor XIa converts the zymogen factor IX (Christmas factor) into the protease factor IXa, which then initiates the remainder of the intrinsic coagulation cascade. This pathway is measured by the aPTT. Therefore aPTT is prolonged in patients with factor XI deficiency. aPTT also is prolonged in those with factor VIII deficienq (hemophilia A), factor IX deficiency (hemophilia B), or factor XII deficiency. The PT should be normal in all of these disorders. Patients with factor XI deficiency seldom have an aPTT as prolonged as that of patients with factor VIII or IX deficiency, even when the levels of factor XI are very 10w.~ The severity of clinical bleeding3 also correlates poorIy with factor XI levels; patients with a “severe” deficiency may have little or no excess bleeding even during major surgery. In fact, the bleeding may vary in the same patient after similar challenges.4 The deficiency is most common among Ashkenazi Jews (3 per 1,000) in Israel? It also has occurred in non-Jewish patients, but is extremely rare-about one per million.6 In contrast with other coagulation factor deficien-
Jaurnaloffediatrk
.Swgery,
Vol30,
No 12 (December),
1995: pp 1746-1747
FACTOR
1747
Xl DEFICIENCY
ties, factor XI is not contained in cryoprecipitate or prothrombin complex. High-purity factor XI concentrates have been studied, but they have the danger of being thrombogenic.’ Therefore, the treatment of bleeding caused by this disorder is with fresh frozen plasma. Bleeding can be controlled with plasma concentrations of 10 to 20 U/dL. The half-life of factor XI is greater than 48 hours. A dose of 1 U/kg increases the plasma level of factor XI activity by 2 U/dL. The treatment of bleeding thus can be handled with 15 mL/kg of FFP, to achieve a plasma concentration of about 30 U/dL. The issue of whether or not to routinely perform
coagulation screening on all patients who will undergo elective surgery remains controversial. Most physicians believe that the best screening test is a thorough history and physical examination. Objective study of the impact of preoperative laboratory screening has yielded mixed results. One study by Rappaport* indicated some utibty of screening, whereas other studies show no usefulness at all.9,1oWe recommend the preoperative screening of all Ashkenazi Jews, the population at highest risk for factor XI deficiency, to avoid the possibility of life-threatening postoperative hemorrhage. This is best accomplished by obtaining aPTT preoperatively.
REFERENCES 1. Kato A, Asaki R, et al: Factor XI gene (Fll) is located on the distal end of the long arm of human chromosome 4. Cytogenet Cell Genet 52:77-79, 1989 2. Scott CF, Sinha D, et al: Amidolytic assay of human factor XI in plasma: Comparison with a coagulant assay and a new, rapid radioimmunoassay. Blood 63:42-44,1984 3. Kitchens CS: Factor XI: a review of its biochemistry and deficiency. Semin Thromb Hemost 17:55-58, 1991 4. Bolton-Maggs PHB, Young-Wang-Yin B, McGraw AH, et al: Inheritance and bleeding in factor Xl deficiency. Br J Haematol 69:521-522, 1988 5. Seligsohn U: High gene frequency of factor XI (PTA) deficiency in Ashkenazi Jews. Blood 51:1223-1225,197s
6. Harker LA Hemostasis Manual, ed 2. Philadelphia, F.A. Davis, 1974, p 28 7. Mannucci PM, Bauer KA, Santagostino E, et al: Activation of the coagulation cascade after infusion of a factor XI concentrate in congenitally deficient patients. Blood 84:1314-1317, 1994 8. Rapaport SE: preoperative hemostatic evaluation: Which tests, if any? Blood 61:229-230, 1983 9. Manning SC, Beste D, McBride T, et al: An assessment of preoperative coagulation screening for tonsillectomy and adenoidectomy. Int J Pediatr Otolrhinolaryngoll3:237-238,1987 10. Kaplan EB, Sheiner LB, Boeckmann AJ, et al: The usefulness of preoperative laboratory screening. JAMA 253:3576-3577, 1985