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Acquired Factor XI Deficiency: A Rare Complication After Liver Transplantation
Acquired Factor XI Deficiency: A Rare Complication After Liver Transplantation Y. Yankol*, N. Mecit, T. Kanmaz, K. Acarli, and M. Kalayoglu Organ Transplantation Center, Sisli Memorial Hospital, Istanbul, Turkey
ABSTRACT Background. A majority of coagulation factors are synthesized in the liver. Factor XI (FXI) deficiency (Rosenthal syndrome) is one of the rare inherited coagulation disorders with an extremely low risk of transmission by liver transplantation (LT). Case Report. We report here the case of a 50-year-old man who unknowingly acquired FXI deficiency by LT. During 1 year of post-transplant follow-up, his activated partial thromboplastin time (aPTT) remained prolonged, but he did not develop bleeding complications. The patient required retransplantation due to chronic rejection and is currently doing well 4 years after his first liver transplantation. Conclusions. The presence of a prolonged aPTT in a deceased donor should raise suspicion for the presence of rare coagulation factor deficiencies. During urgent, lifesaving procedures such as LT, it may be impossible to avoid transmission. Awareness of this possibility will allow early detection and management.
L
IVER TRANSPLANTATION (LT) has become the treatment of choice for patients with end-stage chronic liver disease (ESLD) and acute liver failure, as well as for the treatment of select malignancies and metabolic disorders. However, LT may be associated with transmission of rare undiagnosed infections and various deficiencies of proteins synthesized by the liver, especially during deceased donor (DD) LT. Transmission of congenital clotting factor deficiencies is a rare occurrence following LT. Factor XI (FXI) deficiency is a rare inherited coagulation disorder, with a prevalence of severe deficiency in approximately 1:1,000,000 in most populations [1]. To our knowledge, only 2 cases of FXI deficiency acquired by LT have been reported in the literature [2,3]. We present here a case of unknowingly acquired FXI deficiencyda rare, autosomal recessive inherited coagulation disorderdby DD LT. CASE REPORT The recipient, a 50-year-old man, developed ESLD secondary to alcoholic liver disease, with grade 2e3 hepatic encephalopathy and ascites. He was on the waiting list for 3 months. At the time of transplantation he had an activated partial thromboplastin time (aPTT) of 40.0 sec, international normalized ratio (INR) of 1.5 and creatinine of 1.8 mg/dL. There was no personal or family history of bleeding disorder prior to the diagnosis of ESLD. ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 47, 179e181 (2015)
The donor was a 59-year-old man with a declaration of brain death after spontaneous intracranial hemorrhage. At the time the donor liver was offered to our patient, the donor had a normal INR and prothrombin time (PT), with normal liver enzymes. All the blood test results were normal with the exception of creatinine, which was 5.4 mg/dL. During the offer period the donor became unstable, and the decision was urgently made to consider the patient a suitable liver donor. The liver was the only organ procured from this donor. The donor surgery was uneventful and no abnormalities were noted. The liver transplant operation was performed in 10 hours, with 7.5 hours’ cold ischemia time, and required transfusion of 16 units packed red blood cells and 18 units fresh frozen plasma (FFP). The liver functioned well postoperatively and the patient was extubated in the operating room. The patient was in the intensive care unit for 3 days and received an immunosuppressive protocol consisting of tacrolimus, mycophenolate mofetil, and steroids starting on postoperative day (POD) 1. Aspirin was started at the same time. No blood or FFP was required during this time period. The patient’s postoperative blood tests quickly returned to normal levels during the first week postoperatively. On POD 7, an isolated increase was noted in his aPTT level, reached 71.0 sec on POD 12. Other blood
*Address correspondence to Yucel Yankol, MD, Sisli Memorial Hospital, Organ Transplantation Center, Piyalepasa Bulvari, Okmeydani-Sisli, 34385, Istanbul, Turkey. E-mail: yyankol@ yahoo.com 0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2014.10.042
179
180 tests were normal during this time period. The patient underwent testing in an attempt to diagnose the cause of the isolated increase in aPTT, and the aspirin was stopped. FXI deficiency was diagnosed with the 19% (normal range 50e150%). FactorVIII (FVIII) and factor IX (FIX) were normal. He was discharged with an aPTT level of 71.0 sec, with all other blood test results in the normal range. After learning of this diagnosis, we reviewed the blood tests, which were performed on the donor at the donor hospital, and noted an aPTT level of 56.0 sec during the first admission that was unannounced during the liver offer. In the first year after transplantation, the recipient had no problems, with an aPTT level between 60.0 and 120.0 sec during this follow-up period. After 1 year, the number of liver enzymes started to increase. A liver biopsy was performed, and 1 year posttransplantation, the diagnosis of chronic rejection was made. Attempts to treat this chronic rejection were unsuccessful, and the patient underwent liver retransplantation from a deceased donor 14 months after his first liver transplant. He had an uncomplicated course and is currently doing well 3 years after retransplantation.
DISCUSSION
DDs are still the most important organ supply for LT. Selection of healthy donor organs is essential for successful LT. During live liver donor evaluation, all required blood tests and imaging studies are completed prior to live liver donation to minimize risk to the donor and recipient. The risk of transmission of an infection or of deficiencies in proteins synthesized by the liver from a live donor to a recipient is extremely rare. Conversely, in DD LT there is a higher risk of transmission due to the limitations of DD evaluation. The transmission of human immunodeficiency virus and hepatitis C virus infections from DD during the window period is an ongoing important discussion. After a head injury, large amounts of tissue thromboplastin are released, possibly resulting in hemostatic activation with abnormalities in aPTT and PT levels. In this situation, it may be difficult to detect pre-existing synthetic defects of coagulation factors in the DD liver [4]. In addition, there have been recently published reports about transmission of various deficiencies of proteins synthesized by the liver from DD, including protein C, protein S, FVII, FXII, and FXI deficiencies [2e6]. FXI is a plasma glycoprotein involved in the early phases of blood coagulation cascade. FXI deficiency was first described in 1953 as a mild to moderate bleeding disorder by Rosenthal and colleagues [7]. Although FXI is a rare coagulation disorder in most populations with a prevalence of approximately 1:1,000,000 population, its frequency is remarkably high in Ashkenazi Jews (prevalence of 1:450). Recent studies suggest that the prevalence of mild deficiency may be higher than previously known. Severe deficiency is defined as FXI activity in plasma of less than 20%. Most bleeding manifestations in severe deficiency are related to injury or surgery, and patients do not bleed spontaneously. Some patients do not bleed during an injury. The diagnosis of FXI deficiency is usually made incidentally during presurgical workup when a prolonged APTT is noted. It is rarely diagnosed due to injury-related
YANKOL, MECIT, KANMAZ ET AL
bleeding [1]. In our recipient, the isolated aPTT elevation was recognized 7 days after transplantation without any history of bleeding, and the FXI was noted to be 19%. The different diagnoses of the causes of isolated prolonged aPTT when INR and platelet count are normal may include heparin use, lupus anticoagulation, von Willebrand’s disease, prekallikrein, high molecular kininogen, FVII, FIX, FXI, and FXII deficiencies. FVII, FIX, and FXI have clinical importance due to their bleeding risk. Others have no clinical significance [1]. In our patient, all blood tests and coagulation factor levels were normal except FXI. Although we did not obtain an FXI level in the recipient prior to liver transplantation, many blood tests showed a normal pre-transplant aPTT level. Our donor was a Turkish man whose family does not have any history or knowledge of a coagulation disorder in him or his family, with his only known aPTT level of 56.0 sec. During the recipient’s 1 year of close monitoring prior to the diagnosis of chronic rejection, this situation did not cause a serious problem. Since a high level of FXI is known to be associated with thrombotic events, careful evaluation and treatment are required during prophylactic treatments before surgery and during treatment after bleeding. Available treatments for FXI deficiency are FFP, FXI concentrates, recombinant FVIIa, and oral antifibrinolytic agents (tranexamic acid, aminocaproic acid) [1]. The half-life of FXI is 50 to 80 hours [3]. During this patient’s first liver transplant operation, 18 units of FFT were transfused. This could be the reason for his normal aPTT level during the first 6 postoperative days following transplantation. Any discussion of treatment options also should include the 2 reported cases of correction of FXI deficiency after LT [8,9]. LT has the potential to transfer genetic and metabolic disorders. Although there is no specific screening procedure recommended for detection of these rare inherited genetic and metabolic disorders in donors with the absence of medical or family history, it is important for the medical staff to be aware of the possibility of transmission. If diagnosed, these disorders should be relative contraindications. On the other hand, every donor liver is very important and may save a life, especially in regions without an adequate organ supply from deceased donors. If there is no recent history of abnormal bleeding in the donor or the donor’s family, an isolated prolonged aPTT or PT should not be a contraindication to transplantation, as stated in previous reports.
REFERENCES [1] Duga S, Salomon O. Congenital factor XI deficiency: an update. Semin Thromb Hemost 2013;39:621e31. [2] Dzik WH, Arkin CF, Jenkins RL. Transfer of congenital factor XI deficiency from a donor to a recipient by liver transplantation. N Engl J Med 1987;316:1217e8. [3] Clarkson K, Rosenfeld B, Fair J, Klein A, Bell W. Factor XI deficiency acquired by liver transplantation. Ann Intern Med 1991;115:877e9.
FXI DEFICIENCY AFTER LIVER TRANSPLANTATION [4] Guy SR, Magliocca JF, Fruchtman S, et al. Transmission of factor VII deficiency through liver transplantation. Transpl Int 1999;12:278e80. [5] Schuetze SM, Linenberger M. Acquired protein S deficiency with multiple thrombotic complications after orthotopic liver transplant. Transplantation 1999;67:1366e9. [6] Cransac M, Carles J, Bernard PH, et al. Heterozygous protein C deficiency and dysfibrinogenemia acquired by liver transplantation. Transpl Int 1995;8:307e11.
181 [7] Rosenthal RL, Dreskin OH, Rosenthal N. New hemophilialike disease caused by deficiency of a third plasma thromboplastin factor. Proc Soc Exp Biol Med 1953;82:171e4. [8] Simpson E, Gillett G, Makris M. Liver transplantation for factor XI deficiency: cure before diagnosis. Haemophilia 2008;14: 649e50. [9] Ghosh N, Marotta PJ, McAlister VC. Correction of factor XI deficiency by liver transplantation. N Engl J Med 2005;352: 2357e8.
ABSTRACT Background. A majority of coagulation factors are synthesized in the liver. Factor XI (FXI) deficiency (Rosenthal syndrome) is one of the rare inherited coagulation disorders with an extremely low risk of transmission by liver transplantation (LT). Case Report. We report here the case of a 50-year-old man who unknowingly acquired FXI deficiency by LT. During 1 year of post-transplant follow-up, his activated partial thromboplastin time (aPTT) remained prolonged, but he did not develop bleeding complications. The patient required retransplantation due to chronic rejection and is currently doing well 4 years after his first liver transplantation. Conclusions. The presence of a prolonged aPTT in a deceased donor should raise suspicion for the presence of rare coagulation factor deficiencies. During urgent, lifesaving procedures such as LT, it may be impossible to avoid transmission. Awareness of this possibility will allow early detection and management.
L
IVER TRANSPLANTATION (LT) has become the treatment of choice for patients with end-stage chronic liver disease (ESLD) and acute liver failure, as well as for the treatment of select malignancies and metabolic disorders. However, LT may be associated with transmission of rare undiagnosed infections and various deficiencies of proteins synthesized by the liver, especially during deceased donor (DD) LT. Transmission of congenital clotting factor deficiencies is a rare occurrence following LT. Factor XI (FXI) deficiency is a rare inherited coagulation disorder, with a prevalence of severe deficiency in approximately 1:1,000,000 in most populations [1]. To our knowledge, only 2 cases of FXI deficiency acquired by LT have been reported in the literature [2,3]. We present here a case of unknowingly acquired FXI deficiencyda rare, autosomal recessive inherited coagulation disorderdby DD LT. CASE REPORT The recipient, a 50-year-old man, developed ESLD secondary to alcoholic liver disease, with grade 2e3 hepatic encephalopathy and ascites. He was on the waiting list for 3 months. At the time of transplantation he had an activated partial thromboplastin time (aPTT) of 40.0 sec, international normalized ratio (INR) of 1.5 and creatinine of 1.8 mg/dL. There was no personal or family history of bleeding disorder prior to the diagnosis of ESLD. ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 47, 179e181 (2015)
The donor was a 59-year-old man with a declaration of brain death after spontaneous intracranial hemorrhage. At the time the donor liver was offered to our patient, the donor had a normal INR and prothrombin time (PT), with normal liver enzymes. All the blood test results were normal with the exception of creatinine, which was 5.4 mg/dL. During the offer period the donor became unstable, and the decision was urgently made to consider the patient a suitable liver donor. The liver was the only organ procured from this donor. The donor surgery was uneventful and no abnormalities were noted. The liver transplant operation was performed in 10 hours, with 7.5 hours’ cold ischemia time, and required transfusion of 16 units packed red blood cells and 18 units fresh frozen plasma (FFP). The liver functioned well postoperatively and the patient was extubated in the operating room. The patient was in the intensive care unit for 3 days and received an immunosuppressive protocol consisting of tacrolimus, mycophenolate mofetil, and steroids starting on postoperative day (POD) 1. Aspirin was started at the same time. No blood or FFP was required during this time period. The patient’s postoperative blood tests quickly returned to normal levels during the first week postoperatively. On POD 7, an isolated increase was noted in his aPTT level, reached 71.0 sec on POD 12. Other blood
*Address correspondence to Yucel Yankol, MD, Sisli Memorial Hospital, Organ Transplantation Center, Piyalepasa Bulvari, Okmeydani-Sisli, 34385, Istanbul, Turkey. E-mail: yyankol@ yahoo.com 0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2014.10.042
179
180 tests were normal during this time period. The patient underwent testing in an attempt to diagnose the cause of the isolated increase in aPTT, and the aspirin was stopped. FXI deficiency was diagnosed with the 19% (normal range 50e150%). FactorVIII (FVIII) and factor IX (FIX) were normal. He was discharged with an aPTT level of 71.0 sec, with all other blood test results in the normal range. After learning of this diagnosis, we reviewed the blood tests, which were performed on the donor at the donor hospital, and noted an aPTT level of 56.0 sec during the first admission that was unannounced during the liver offer. In the first year after transplantation, the recipient had no problems, with an aPTT level between 60.0 and 120.0 sec during this follow-up period. After 1 year, the number of liver enzymes started to increase. A liver biopsy was performed, and 1 year posttransplantation, the diagnosis of chronic rejection was made. Attempts to treat this chronic rejection were unsuccessful, and the patient underwent liver retransplantation from a deceased donor 14 months after his first liver transplant. He had an uncomplicated course and is currently doing well 3 years after retransplantation.
DISCUSSION
DDs are still the most important organ supply for LT. Selection of healthy donor organs is essential for successful LT. During live liver donor evaluation, all required blood tests and imaging studies are completed prior to live liver donation to minimize risk to the donor and recipient. The risk of transmission of an infection or of deficiencies in proteins synthesized by the liver from a live donor to a recipient is extremely rare. Conversely, in DD LT there is a higher risk of transmission due to the limitations of DD evaluation. The transmission of human immunodeficiency virus and hepatitis C virus infections from DD during the window period is an ongoing important discussion. After a head injury, large amounts of tissue thromboplastin are released, possibly resulting in hemostatic activation with abnormalities in aPTT and PT levels. In this situation, it may be difficult to detect pre-existing synthetic defects of coagulation factors in the DD liver [4]. In addition, there have been recently published reports about transmission of various deficiencies of proteins synthesized by the liver from DD, including protein C, protein S, FVII, FXII, and FXI deficiencies [2e6]. FXI is a plasma glycoprotein involved in the early phases of blood coagulation cascade. FXI deficiency was first described in 1953 as a mild to moderate bleeding disorder by Rosenthal and colleagues [7]. Although FXI is a rare coagulation disorder in most populations with a prevalence of approximately 1:1,000,000 population, its frequency is remarkably high in Ashkenazi Jews (prevalence of 1:450). Recent studies suggest that the prevalence of mild deficiency may be higher than previously known. Severe deficiency is defined as FXI activity in plasma of less than 20%. Most bleeding manifestations in severe deficiency are related to injury or surgery, and patients do not bleed spontaneously. Some patients do not bleed during an injury. The diagnosis of FXI deficiency is usually made incidentally during presurgical workup when a prolonged APTT is noted. It is rarely diagnosed due to injury-related
YANKOL, MECIT, KANMAZ ET AL
bleeding [1]. In our recipient, the isolated aPTT elevation was recognized 7 days after transplantation without any history of bleeding, and the FXI was noted to be 19%. The different diagnoses of the causes of isolated prolonged aPTT when INR and platelet count are normal may include heparin use, lupus anticoagulation, von Willebrand’s disease, prekallikrein, high molecular kininogen, FVII, FIX, FXI, and FXII deficiencies. FVII, FIX, and FXI have clinical importance due to their bleeding risk. Others have no clinical significance [1]. In our patient, all blood tests and coagulation factor levels were normal except FXI. Although we did not obtain an FXI level in the recipient prior to liver transplantation, many blood tests showed a normal pre-transplant aPTT level. Our donor was a Turkish man whose family does not have any history or knowledge of a coagulation disorder in him or his family, with his only known aPTT level of 56.0 sec. During the recipient’s 1 year of close monitoring prior to the diagnosis of chronic rejection, this situation did not cause a serious problem. Since a high level of FXI is known to be associated with thrombotic events, careful evaluation and treatment are required during prophylactic treatments before surgery and during treatment after bleeding. Available treatments for FXI deficiency are FFP, FXI concentrates, recombinant FVIIa, and oral antifibrinolytic agents (tranexamic acid, aminocaproic acid) [1]. The half-life of FXI is 50 to 80 hours [3]. During this patient’s first liver transplant operation, 18 units of FFT were transfused. This could be the reason for his normal aPTT level during the first 6 postoperative days following transplantation. Any discussion of treatment options also should include the 2 reported cases of correction of FXI deficiency after LT [8,9]. LT has the potential to transfer genetic and metabolic disorders. Although there is no specific screening procedure recommended for detection of these rare inherited genetic and metabolic disorders in donors with the absence of medical or family history, it is important for the medical staff to be aware of the possibility of transmission. If diagnosed, these disorders should be relative contraindications. On the other hand, every donor liver is very important and may save a life, especially in regions without an adequate organ supply from deceased donors. If there is no recent history of abnormal bleeding in the donor or the donor’s family, an isolated prolonged aPTT or PT should not be a contraindication to transplantation, as stated in previous reports.
REFERENCES [1] Duga S, Salomon O. Congenital factor XI deficiency: an update. Semin Thromb Hemost 2013;39:621e31. [2] Dzik WH, Arkin CF, Jenkins RL. Transfer of congenital factor XI deficiency from a donor to a recipient by liver transplantation. N Engl J Med 1987;316:1217e8. [3] Clarkson K, Rosenfeld B, Fair J, Klein A, Bell W. Factor XI deficiency acquired by liver transplantation. Ann Intern Med 1991;115:877e9.
FXI DEFICIENCY AFTER LIVER TRANSPLANTATION [4] Guy SR, Magliocca JF, Fruchtman S, et al. Transmission of factor VII deficiency through liver transplantation. Transpl Int 1999;12:278e80. [5] Schuetze SM, Linenberger M. Acquired protein S deficiency with multiple thrombotic complications after orthotopic liver transplant. Transplantation 1999;67:1366e9. [6] Cransac M, Carles J, Bernard PH, et al. Heterozygous protein C deficiency and dysfibrinogenemia acquired by liver transplantation. Transpl Int 1995;8:307e11.
181 [7] Rosenthal RL, Dreskin OH, Rosenthal N. New hemophilialike disease caused by deficiency of a third plasma thromboplastin factor. Proc Soc Exp Biol Med 1953;82:171e4. [8] Simpson E, Gillett G, Makris M. Liver transplantation for factor XI deficiency: cure before diagnosis. Haemophilia 2008;14: 649e50. [9] Ghosh N, Marotta PJ, McAlister VC. Correction of factor XI deficiency by liver transplantation. N Engl J Med 2005;352: 2357e8.