Pediatr Blood Cancer 2014;61:1886–1887
BRIEF REPORT Liver Transplant for Congenital Factor VII Deficiency Melissa A. Acquazzino,
MD,
1
* Eric T. Rush,
MD, FAAP,
2
Ruben E. Quiros Tejeira,
Congenital factor VII (FVII) deficiency is a rare, autosomal recessive bleeding disorder with a spectrum of phenotypes ranging from asymptomatic to life-threatening intra-cranial hemorrhage (ICH). Orthotopic liver transplantation has been described for definitive treatment in a few patients with severe manifestations. We report a patient with congenital FVII deficiency and recurrent
MD,
3
and Jill C. Beck,
4 MD, MS
ICH, despite twice-weekly prophylaxis with recombinant activated FVII. At 17 months of age, he underwent an orthotopic liver transplant. He is now 1-year post-transplant, on maintenance immunosuppression with no hemorrhage or other complications. Pediatr Blood Cancer 2014;61:1886–1887. # 2014 Wiley Periodicals, Inc.
Key words: factor VII deficiency; liver transplant
INTRODUCTION Factor VII (FVII) is a vitamin-K dependent clotting factor. Activated FVII and tissue factor form a complex that initiates the extrinsic coagulation pathway. Congenital FVII deficiency is a rare, autosomal recessive bleeding disorder with prevalence of 1 in 500,000 [1]. In FVII deficiency, the prothrombin time (PT) is prolonged while the partial thromboplastin time (PTT) and platelets are normal. Diagnosis is confirmed by FVII antigen level and activity assay. Clinical manifestations are variable, ranging from asymptomatic or minor bleeding episodes to life-threatening intracranial hemorrhage (ICH). The correlation between measured FVII coagulation activity and severity of clinical symptoms is poor [1,2]. Acute bleeds in patients with congenital FVII deficiency are treated with recombinant activated FVII (rFVIIa) [3,4]. Fresh frozen plasma (FFP), prothrombin complex concentrates and plasma-derived FVII concentrates have also been used but may be associated with fluid overload, infection, and thrombosis [3]. Prophylactic rFVIIa is also used to prevent future bleeds in children with severe symptoms, including ICH, hemarthroses, gastrointestinal (GI) bleeding, recurrent epistaxis, or menorrhagia [4,5]. A 2010 review, based on expert opinion, recommends long-term prophylaxis with rFVIIa 20–30 mcg/kg, two to three times weekly [5]. Long-term use of rFVIIa is complicated by the lack of prospective studies, risk of life-threatening hemorrhage despite its use, need for long-term intra-venous access and high cost. Liver transplantation has been used in the treatment of other congenital hemostasis disorders, including hemophilia A and B and protein C deficiency [6–8]. Several case reports describe liver transplantation for severe FVII deficiency; however, the literature in this area remains scarce [9–11]. The child in this report received a liver transplant for congenital FVII deficiency after failure of prophylactic rFVIIa with recurrent ICH. He is asymptomatic and hemostatically normal 1-year post-transplant.
CASE REPORT The patient is a Guatemalan male who presented in the neonatal period with prolonged bleeding from venipuncture sites, and a single episode of GI bleeding. PT was 54 seconds, with an INR of 5.7. PTT, and platelets were normal. FVII activity and antigen were 2%, measured 72 hours after FFP administration. FVII inhibitor was undetectable. He developed Grade III intra-ventricular hemorrhage and left cerebellar hemorrhage at 2 weeks of age, which was
C
2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25008 Published online 28 February 2014 in Wiley Online Library (wileyonlinelibrary.com).
managed with rFVIIa (10 mcg/kg IV q 6 48 hours). He developed seizures, which were treated with phenobarbital. At 2 months of age, he presented to the emergency department with vomiting and feeding intolerance. He was found to have a left parenchymal hemorrhage with increased intra-cranial pressure requiring an emergency ventricular tap. Respiratory failure prompted admission to the intensive care unit. His acute bleed was managed with rFVIIa (20 mcg/kg IV q4 hours). An Ommaya reservoir was placed to manage his increased intra-cranial pressure. Long-term central venous access was established and he was started on a prophylactic regimen of rFVIIa (20 mcg/kg IV) twice weekly. A ventriculoperitoneal shunt was placed for persistent hydrocephalus at 5 months of age. At 10 months of age, he presented with irritability and emesis and was found to have a posterior fossa hemorrhage. He was treated with rFVIIa (25 mcg/kg IV q6 hours). Given his recurrent ICH despite prophylactic rFVIIa, he was listed for liver transplant. His prophylactic regimen was increased to rFVIIa (20 mcg/kg IV) three times weekly. Trough PT levels were measured periodically and ranged from 15.8 to 33.3 seconds. At 15 months of age, he had persistent epistaxis requiring medical attention and treatment, including daily rFVIIa (20 mcg/kg IV) for 3 days. At 17 months of age an orthotopic liver transplant was performed from an unrelated donor. During the transplant, he received 30 ml/kg of FFP. He did not receive pre-procedure rFVIIa due to a greater concern for hyper-coagulability with rVIIa infusion than for bleeding. The transplant was uncomplicated and resulted in normalization of his PT on post-operative day 6. He is 1-year posttransplant and remains well with no rFVIIa administration, no hemorrhage, no infection, no signs of rejection on maintenance
1
Pediatric Hematology/Oncology/BMT, Medical College of Wisconsin, Milwaukee, Wisconsin; 2Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska; 3Pediatric GI, Hepatology & Nutrition, Pediatric Liver & Intestinal Transplantation, University of Nebraska Medical Center, Omaha, Nebraska; 4Pediatric Hematology Oncology, University of Nebraska Medical Center, Omaha, Nebraska Correspondence to: Melissa A. Acquazzino, Pediatrics Hematology/ Oncology/BMT, Medical College of Wisconsin, MFRC 3018, 8701 Watertown Plank Road, Milwaukee, WI 53226. E-mail: [email protected]
Received 9 December 2013; Accepted 4 February 2014
Liver Transplant for Factor VII Deficiency immunosuppression, milestones.
and
improvement
on
developmental
DISCUSSION Management of congenital FVII deficiency varies due to the wide-spectrum of phenotypic manifestations. Acute, serious bleeding episodes are most often treated with rFVIIa replacement. For children with significant bleeding symptoms, prophylactic regimens of rFVIIa may be used. Prophylaxis with rFVIIa, (20 mcg/ kg twice weekly), did not prevent further ICH in our patient. He had significant morbidity from his disease, including seizures, hydrocephalus, VP shunt placement, developmental delay, and infectious complications. In addition, the family had the burden of line care and multiple infusions per week. While not the main driving factor to proceed to transplant, the cost of his care was very high. Prior to transplant, he was receiving three rFVIIa infusions per week at a cost of $1,270 per week for medication alone. In addition, his past bleeding episodes had required ICU admissions, frequent rFVIIa treatments, surgeries, and consultation with numerous subspecialty services. His treatment team felt that his risk from a future intra-cranial bleeding episode was greater than the risks associated with transplant, including both the short-term surgical morbidity and mortality and the long-term need for chronic immunosuppression. Factor VII is a vitamin-K dependent clotting factor that is synthesized in the liver. Several reports describe liver transplantation to treat congenital FVII deficiency. Levi reported two children with severe hemorrhagic complications, including ICH, who were successfully treated with orthotopic liver transplantation at 3 and 6 years of age. They had received intermittent FFP for acute bleeding episodes prior to transplantation. These patients had normal coagulation profiles within 48 hours of transplantation, no further hemorrhages and significant improvement in quality of life. Neither child had received prophylactic rFVIIa. Dhawan describes two children transplanted for FVII deficiency with good outcomes [9]. These patients were receiving prophylactic twice daily infusions of rFVIIa to maintain FVII trough levels of 10 m/dl. They were initially treated with hepatocyte transplantation and while their rFVIIa requirement decreased significantly, their dependence
Pediatr Blood Cancer DOI 10.1002/pbc
1887
on rFVIIa to maintain adequate trough levels persisted. Difficulties with maintaining central access lead to orthotopic liver transplantation at 7 and 8 months following hepatocyte transplant, which was well tolerated and curative. In contrast to our patient, they did not have major hemorrhage on prophylactic rFVIIa. Muiesan described segmental liver transplantation for two patients with FVII deficiency [11]. Both patients were living at a mean of 20 months follow-up post-transplant. Data about the management of their FVII deficiency pre-transplant were not included in the report.
CONCLUSION Our patient had an excellent outcome after curative orthotopic liver transplant for congenital FVII deficiency. This case adds to the small amount of literature showing good outcomes following liver transplant for severe FVII deficiency. Prophylactic rFVIIa should still be considered standard of care in patients with symptomatic FVII deficiency. However, in those patients who continue to have clinically significant bleeding episodes despite use of rFVIIa, or who cannot tolerate the infusion regimen, orthotopic liver transplant should be considered. The risk of future bleeding episodes and the burden of therapy must be weighed carefully against the risks of surgical complications and of life-long immunosuppression.
REFERENCES 1. Perry DJ. Factor VII deficiency. Br J Haematol 2002;118:689–700. 2. Triplett DA, Brandt JT, Batard M, et al. Hereditary factor VII deficiency: Heterogeneity defined by combined functional and immunochemical analysis. Blood 1985;66:1284–1287. 3. Lapecorella M, Mariani G. Factor VII deficiency: Defining the clinical picture and optimizing therapeutic options. Haemophilia 2008;14:1170–1175. 4. Mariani G, Konkle B, Ingerslev J. Congenital factor VII deficiency: Therapy with recombinant activated factor VII––A critical appraisal. Haemophilia 2006;12:19–27. 5. Todd T, Perry D. A review of long-term prophylaxis in the rare inherited coagulation factor deficiencies. Haemophilia 2010;16:569–583. 6. Fischbach P, Scharrer I. Therapeutic impact of orthotopic liver transplantation on disorders of hemostasis. Semin Thromb Hemost 1993;19:250–257. 7. Bontempo FA, Lewis JH, Gorenc TJ, et al. Liver transplantation in hemophilia A. Blood 1987;69:1721– 1724. 8. Casella J, Bontempo F, Markel H, et al. Successful treatment of homozygous protein C deficiency by hepatic transplantation. Lancet 1988;331:435–438. 9. Dhawan A, Mitry RR, Hughes RD, et al. Hepatocyte transplantation for inherited factor VII deficiency. Transplantation 2004;78:1812–1814. 10. Levi D, Pefkarou A, Fort JA, et al. Liver transplantation for factor VII deficiency. Transplantation 2001;72:1836–1837. 11. Muiesan P, Jassem W, Girlanda R, et al. Segmental liver transplantation from non-heart beating donors–– An early experience with implications for the future. Am J Transplant 2006;6:1012–1016.
BRIEF REPORT Liver Transplant for Congenital Factor VII Deficiency Melissa A. Acquazzino,
MD,
1
* Eric T. Rush,
MD, FAAP,
2
Ruben E. Quiros Tejeira,
Congenital factor VII (FVII) deficiency is a rare, autosomal recessive bleeding disorder with a spectrum of phenotypes ranging from asymptomatic to life-threatening intra-cranial hemorrhage (ICH). Orthotopic liver transplantation has been described for definitive treatment in a few patients with severe manifestations. We report a patient with congenital FVII deficiency and recurrent
MD,
3
and Jill C. Beck,
4 MD, MS
ICH, despite twice-weekly prophylaxis with recombinant activated FVII. At 17 months of age, he underwent an orthotopic liver transplant. He is now 1-year post-transplant, on maintenance immunosuppression with no hemorrhage or other complications. Pediatr Blood Cancer 2014;61:1886–1887. # 2014 Wiley Periodicals, Inc.
Key words: factor VII deficiency; liver transplant
INTRODUCTION Factor VII (FVII) is a vitamin-K dependent clotting factor. Activated FVII and tissue factor form a complex that initiates the extrinsic coagulation pathway. Congenital FVII deficiency is a rare, autosomal recessive bleeding disorder with prevalence of 1 in 500,000 [1]. In FVII deficiency, the prothrombin time (PT) is prolonged while the partial thromboplastin time (PTT) and platelets are normal. Diagnosis is confirmed by FVII antigen level and activity assay. Clinical manifestations are variable, ranging from asymptomatic or minor bleeding episodes to life-threatening intracranial hemorrhage (ICH). The correlation between measured FVII coagulation activity and severity of clinical symptoms is poor [1,2]. Acute bleeds in patients with congenital FVII deficiency are treated with recombinant activated FVII (rFVIIa) [3,4]. Fresh frozen plasma (FFP), prothrombin complex concentrates and plasma-derived FVII concentrates have also been used but may be associated with fluid overload, infection, and thrombosis [3]. Prophylactic rFVIIa is also used to prevent future bleeds in children with severe symptoms, including ICH, hemarthroses, gastrointestinal (GI) bleeding, recurrent epistaxis, or menorrhagia [4,5]. A 2010 review, based on expert opinion, recommends long-term prophylaxis with rFVIIa 20–30 mcg/kg, two to three times weekly [5]. Long-term use of rFVIIa is complicated by the lack of prospective studies, risk of life-threatening hemorrhage despite its use, need for long-term intra-venous access and high cost. Liver transplantation has been used in the treatment of other congenital hemostasis disorders, including hemophilia A and B and protein C deficiency [6–8]. Several case reports describe liver transplantation for severe FVII deficiency; however, the literature in this area remains scarce [9–11]. The child in this report received a liver transplant for congenital FVII deficiency after failure of prophylactic rFVIIa with recurrent ICH. He is asymptomatic and hemostatically normal 1-year post-transplant.
CASE REPORT The patient is a Guatemalan male who presented in the neonatal period with prolonged bleeding from venipuncture sites, and a single episode of GI bleeding. PT was 54 seconds, with an INR of 5.7. PTT, and platelets were normal. FVII activity and antigen were 2%, measured 72 hours after FFP administration. FVII inhibitor was undetectable. He developed Grade III intra-ventricular hemorrhage and left cerebellar hemorrhage at 2 weeks of age, which was
C
2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25008 Published online 28 February 2014 in Wiley Online Library (wileyonlinelibrary.com).
managed with rFVIIa (10 mcg/kg IV q 6 48 hours). He developed seizures, which were treated with phenobarbital. At 2 months of age, he presented to the emergency department with vomiting and feeding intolerance. He was found to have a left parenchymal hemorrhage with increased intra-cranial pressure requiring an emergency ventricular tap. Respiratory failure prompted admission to the intensive care unit. His acute bleed was managed with rFVIIa (20 mcg/kg IV q4 hours). An Ommaya reservoir was placed to manage his increased intra-cranial pressure. Long-term central venous access was established and he was started on a prophylactic regimen of rFVIIa (20 mcg/kg IV) twice weekly. A ventriculoperitoneal shunt was placed for persistent hydrocephalus at 5 months of age. At 10 months of age, he presented with irritability and emesis and was found to have a posterior fossa hemorrhage. He was treated with rFVIIa (25 mcg/kg IV q6 hours). Given his recurrent ICH despite prophylactic rFVIIa, he was listed for liver transplant. His prophylactic regimen was increased to rFVIIa (20 mcg/kg IV) three times weekly. Trough PT levels were measured periodically and ranged from 15.8 to 33.3 seconds. At 15 months of age, he had persistent epistaxis requiring medical attention and treatment, including daily rFVIIa (20 mcg/kg IV) for 3 days. At 17 months of age an orthotopic liver transplant was performed from an unrelated donor. During the transplant, he received 30 ml/kg of FFP. He did not receive pre-procedure rFVIIa due to a greater concern for hyper-coagulability with rVIIa infusion than for bleeding. The transplant was uncomplicated and resulted in normalization of his PT on post-operative day 6. He is 1-year posttransplant and remains well with no rFVIIa administration, no hemorrhage, no infection, no signs of rejection on maintenance
1
Pediatric Hematology/Oncology/BMT, Medical College of Wisconsin, Milwaukee, Wisconsin; 2Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska; 3Pediatric GI, Hepatology & Nutrition, Pediatric Liver & Intestinal Transplantation, University of Nebraska Medical Center, Omaha, Nebraska; 4Pediatric Hematology Oncology, University of Nebraska Medical Center, Omaha, Nebraska Correspondence to: Melissa A. Acquazzino, Pediatrics Hematology/ Oncology/BMT, Medical College of Wisconsin, MFRC 3018, 8701 Watertown Plank Road, Milwaukee, WI 53226. E-mail: [email protected]
Received 9 December 2013; Accepted 4 February 2014
Liver Transplant for Factor VII Deficiency immunosuppression, milestones.
and
improvement
on
developmental
DISCUSSION Management of congenital FVII deficiency varies due to the wide-spectrum of phenotypic manifestations. Acute, serious bleeding episodes are most often treated with rFVIIa replacement. For children with significant bleeding symptoms, prophylactic regimens of rFVIIa may be used. Prophylaxis with rFVIIa, (20 mcg/ kg twice weekly), did not prevent further ICH in our patient. He had significant morbidity from his disease, including seizures, hydrocephalus, VP shunt placement, developmental delay, and infectious complications. In addition, the family had the burden of line care and multiple infusions per week. While not the main driving factor to proceed to transplant, the cost of his care was very high. Prior to transplant, he was receiving three rFVIIa infusions per week at a cost of $1,270 per week for medication alone. In addition, his past bleeding episodes had required ICU admissions, frequent rFVIIa treatments, surgeries, and consultation with numerous subspecialty services. His treatment team felt that his risk from a future intra-cranial bleeding episode was greater than the risks associated with transplant, including both the short-term surgical morbidity and mortality and the long-term need for chronic immunosuppression. Factor VII is a vitamin-K dependent clotting factor that is synthesized in the liver. Several reports describe liver transplantation to treat congenital FVII deficiency. Levi reported two children with severe hemorrhagic complications, including ICH, who were successfully treated with orthotopic liver transplantation at 3 and 6 years of age. They had received intermittent FFP for acute bleeding episodes prior to transplantation. These patients had normal coagulation profiles within 48 hours of transplantation, no further hemorrhages and significant improvement in quality of life. Neither child had received prophylactic rFVIIa. Dhawan describes two children transplanted for FVII deficiency with good outcomes [9]. These patients were receiving prophylactic twice daily infusions of rFVIIa to maintain FVII trough levels of 10 m/dl. They were initially treated with hepatocyte transplantation and while their rFVIIa requirement decreased significantly, their dependence
Pediatr Blood Cancer DOI 10.1002/pbc
1887
on rFVIIa to maintain adequate trough levels persisted. Difficulties with maintaining central access lead to orthotopic liver transplantation at 7 and 8 months following hepatocyte transplant, which was well tolerated and curative. In contrast to our patient, they did not have major hemorrhage on prophylactic rFVIIa. Muiesan described segmental liver transplantation for two patients with FVII deficiency [11]. Both patients were living at a mean of 20 months follow-up post-transplant. Data about the management of their FVII deficiency pre-transplant were not included in the report.
CONCLUSION Our patient had an excellent outcome after curative orthotopic liver transplant for congenital FVII deficiency. This case adds to the small amount of literature showing good outcomes following liver transplant for severe FVII deficiency. Prophylactic rFVIIa should still be considered standard of care in patients with symptomatic FVII deficiency. However, in those patients who continue to have clinically significant bleeding episodes despite use of rFVIIa, or who cannot tolerate the infusion regimen, orthotopic liver transplant should be considered. The risk of future bleeding episodes and the burden of therapy must be weighed carefully against the risks of surgical complications and of life-long immunosuppression.
REFERENCES 1. Perry DJ. Factor VII deficiency. Br J Haematol 2002;118:689–700. 2. Triplett DA, Brandt JT, Batard M, et al. Hereditary factor VII deficiency: Heterogeneity defined by combined functional and immunochemical analysis. Blood 1985;66:1284–1287. 3. Lapecorella M, Mariani G. Factor VII deficiency: Defining the clinical picture and optimizing therapeutic options. Haemophilia 2008;14:1170–1175. 4. Mariani G, Konkle B, Ingerslev J. Congenital factor VII deficiency: Therapy with recombinant activated factor VII––A critical appraisal. Haemophilia 2006;12:19–27. 5. Todd T, Perry D. A review of long-term prophylaxis in the rare inherited coagulation factor deficiencies. Haemophilia 2010;16:569–583. 6. Fischbach P, Scharrer I. Therapeutic impact of orthotopic liver transplantation on disorders of hemostasis. Semin Thromb Hemost 1993;19:250–257. 7. Bontempo FA, Lewis JH, Gorenc TJ, et al. Liver transplantation in hemophilia A. Blood 1987;69:1721– 1724. 8. Casella J, Bontempo F, Markel H, et al. Successful treatment of homozygous protein C deficiency by hepatic transplantation. Lancet 1988;331:435–438. 9. Dhawan A, Mitry RR, Hughes RD, et al. Hepatocyte transplantation for inherited factor VII deficiency. Transplantation 2004;78:1812–1814. 10. Levi D, Pefkarou A, Fort JA, et al. Liver transplantation for factor VII deficiency. Transplantation 2001;72:1836–1837. 11. Muiesan P, Jassem W, Girlanda R, et al. Segmental liver transplantation from non-heart beating donors–– An early experience with implications for the future. Am J Transplant 2006;6:1012–1016.
