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Pregnancy in a Patient With Hepatic Artery Thrombosis After Liver Transplantation: A Case Report
Pregnancy in a Patient With Hepatic Artery Thrombosis After Liver Transplantation: A Case Report O. Troninaa,*, N. Mikołajczyka, B. Pietrzakb, M. Pacholczykc, and M. Durlika a Department of Transplantation Medicine and Nephrology, Transplantation Institute, bFirst Department of Obstetrics and Gynecology, and cDepartment of General Surgery and Transplantology, Transplantation Institute, Medical University of Warsaw, Warszawa, Poland
ABSTRACT Background. Hepatic artery thrombosis (HAT) increases the risk of complications and mortality after liver transplantation. The incidence for HAT is increased in patients with risk factors (vascular reconstructions, coagulation disorders and acute rejection episodes amongst others). Early retransplantation improves the prognosis for patients, but owing to lack of donors, surgical and interventional radiologic attempts to restore the patency of hepatic artery are made. The prognosis for the liver and the patient can also be improved by the development of collateral circulation. Case Report. We describe a case of a 30-year-old woman with hepatic failure owing to Wilson disease. Liver transplantation with the use of vascular conduit made of donor’s iliac arteries was complicated by an early HAT. Heterozygous factor V Leiden mutation was confirmed in the patient. Despite surgical and radiologic attempts to restore patency and despite treatment with fractioned heparin and aspirin, the hepatic artery remained occluded. Retransplantation was not considered, even though the patient was planning a pregnancy. After 1 year of observation of stable liver function, conversion from mycophenolate mofetil to azathioprine treatment, the patient was given consent for a high-risk pregnancy. Discussion. The course of pregnancy was uneventful, with normal liver function parameters, without pathological bleedings. The patient was treated with doses of enoxaparin adjusted for the patient’s weight. In the 34th week, owing to increasing concentration of bile acids, the pregnancy ended with a cesarean section. The newborn had 10-point APGAR score.
H
EPATIC ARTERY THROMBOSIS (HAT) substantially increases the risk of complications and mortality after liver transplantation [1,2]. It is the second main reason, after primary nonfunction, for early failure and loss of liver allografts. The incidence of HAT is increased in patients with risk factors [1e4]. Surgical or radiologic attempts to restore the patency of hepatic artery, although not always successful, can prevent the development of severe infection and biliary tract pathologies. It seems that only early retransplantation improves the long-term prognosis [1,2,5]. There are no guidelines for the treatment of HAT in the literature. Each patient has to be managed and treated individually. Herein we have presented a case of a patient after liver transplantation with early HAT, after failed surgical and radiologic attempts to restore hepatic artery patency, treated with low-molecular-weight heparin and aspirin, with
an uneventful course of pregnancy and no adverse effects on the newborn. CASE REPORT A 30-year-old woman with liver cirrhosis owing to Wilson disease underwent liver transplantation in 2010. Because of the lack of the hepatic artery in the recipient, a vascular conduit was created, with the use of iliac arteries of the donor, connecting the aorta (below renal arteries) and the donor’s liver artery. The blood flow through hepatic artery was monitored daily. On the posttransplantation day 4, Doppler ultrasonography showed no blood flow through the hepatic artery. The patient was qualified for urgent surgery. Thrombosis of the conduit *Address correspondence to Olga Tronina, MD, Klinika Medycyny Transplantacyjnej i Nefrologii, Instytut Transplantologii WUM, 02-006 Warszawa, ul. Nowogrodzka 59, Poland. E-mail: [email protected]
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/14 http://dx.doi.org/10.1016/j.transproceed.2014.09.021
Transplantation Proceedings, 46, 2929e2931 (2014)
2929
2930 was confirmed intraoperatively and a thrombectomy was performed. In the following days, blood flow through the hepatic artery was sustained. The patient was given prophylaxis with aspirin and low-molecular-weight heparin (1 1 mg/kg body mass). The perioperative period was complicated by 2 acute rejection episodes treated with intravenous methylprednisolone infusions and adding a third immunosuppressive agent (mycophenolate mofetil) to the immunosuppressive regimen. Liver histopathology showed no signs of ischemia. Cholangiography showed no signs of biliary tract pathologies. The patient was discharged home with the recommendation of follow-up in the Transplantations Outpatient Clinic. We excluded the presence of lupus anticoagulant, immunoglobulin (Ig)G and IgM anticardiolipine antibodies, antithrombin activity disorders, coagulophatic abnormalities, protein C and free protein S antigen activity disorders, and mutation G20210A of the prothrombin gene, as potential reasons for coagulation disorders. Heterozygous factor V Leiden mutation was confirmed. Two months after transplantation, we observed a rise in liver function parameters, especially cholestatic ones. We performed computed tomographic angiography, which showed only narrow collateral blood flow with HAT despite anticoagulation prophylaxis. The patient was disqualified from further surgical treatment. After a council with specialists in interventional radiology, the patient was qualified for fibrinolytic treatment. She was also given enoxaparin in therapeutic doses of 2 1 mg/kg body mass. The fibrinolysis was performed in 2 stages on December 16 and 17, 2010. Angiography confirmed HAT with a patent stump of the conduit. Recanalization of the hepatic artery with balloon diameters of 4 and 5 mm was performed. Control angiography showed residual thrombi with segmental dissection of the artery. Recombined tissue activator of plasminogen (15 mg) was given. On the following day, through a catheter that was left in the lumen of the artery, 2 XPERT stents were implanted with good effect (XPERT 6 60 distally, 8 60 proximally). Owing to risk of bleeding, the closing of a 5mm false aneurysm was postponed and ultimately never performed. Diagnostic imaging performed 1 week after the procedure showed proper blood flow through hepatic artery. Two months after the procedure, late bleeding from the place of insertion of the catheter occurred. The site was surgically revised, 4 U of packed red blood cells and 2 U of freshly frozen plasma were transfused. A control nuclear magnetic resonance showed a HAT with rich collateral blood flow. Owing to stable liver function parameters, no signs of biliary tract ischemia, and previous history the patient was disqualified from further treatment. Urgent retransplantation was not considered, although the patient had been planning a pregnancy. After 1 year of observation of stable liver function and conversion from mycophenolate mofetil to azathioprine, the patient was given consent to attempt a high-risk pregnancy. The course of pregnancy was uneventful up to the 34th week. We observed normal liver function parameters, without pathologic bleeding. The patient was treated with doses of enoxaparin adjusted for the weight. In her 34th week, owing to increasing concentrations of bile acids, the patient underwent a cesarean section. No bleeding complications were observed. The newborn was assessed as 10 points on the APGAR scale and was monitored, for the first few days, in the neonatal ICU owing to being an early born. At 6 months, we observed good liver function parameters; liver ultrasonography liver shows no pathologies and the patient is in a good general state.
DISCUSSION
HAT occurs in 3% to 11% of liver transplant recipients and increases the risk of early injury to the transplanted organ,
TRONINA, MIKOŁAJCZYK, PIETRZAK ET AL
biliary complications, severe infections, loss of the organ, and even death (30% in early HAT) [2,5,6]. Risk factors for HAT are vascular reconstructions, medical procedures on the vessels, genetic and acquired coagulation disorders (thrombophilia, patients with hepatic cell carcinomas), acute rejections, cytomegalovirus incompatibility of the donor and recipient, and extended ischemia time of the liver [2]. Fan et al [3] describe a 100% occurrence of HAT in patients with factor V Leiden mutation and with a reconstruction of the hepatic artery with the use of a vascular conduit (vs 30% in patients with reconstruction but without the mutation). They also describes a 10-fold increase in risk in patients with factor V Leiden mutation (30%) compared with patients without coagulation disorders (3.8%) [3]. The formation of collateral circulation, which starts at 2 weeks posttransplantation, can improve the fate of the transplanted liver and the patient’s survival [2,5]. There are no guidelines for treatment of patients with risk factors for HAT. In the first posttransplant days, patients are monitored with repeated Doppler ultrasonography. In case of any suspicion of pathologies an angio-CT is performed [2,5,6]. Most patients with HAT (75%) undergo some attempt to restore patency of the hepatic artery. The success rate of the procedures largely depends on the protocol of ultrasound screening (66.1% if daily scans are performed vs 44.9% if less often) [2,5]. Retransplantation, owing to the risk of bleeding after interventional radiology procedures, remains the treatment of choice for HAT. It is performed in 50% of primary cases and in 30.3% of patients after previous revascularization [2]. In female liver transplant recipients, pregnancy should be planned postponed for 1 to 2 years after transplantation, and only with stable liver function [7,8] and after appropriate preparations, such as discontinuing potentially teratogenic treatments. Thanks to strict care in specialized transplant centers, the live birth rate and miscarriage rate are better in liver recipients than in general population (76.9% and 15.6% vs 66.7% and 17.1%, respectively) [8] despite an increased risk for obstetric complications, including preeclampsia (27% vs 8%) and gestational diabetes (21.9% vs 5.1%) [7,8]. After liver transplantation, patients also have an increased risk of perinatal complications. Cesarean sections (44.6% vs 31.9%,), premature birth (39.4% vs 12.5%). and low birth weight (2886 vs 3298 g) are more common than in the general population [8]. Additional risk factors, such as increased risk for acute rejection, reactivation of hepatitis B and C infections, bacterial infections, kidney injury, or a possibility of bleeding in patients receiving anticoagulation treatment or prophylaxis, also play in important role [7,8]. Treatment with vitamin K antagonists is contraindicated in pregnancy owing to teratogenic effect, increased risk of bleeding, and increased risk for pregnancy loss [9,10]. New-generation drugs such as thrombin inhibitors and direct inhibitors of factor Xa are also not advised [10]. Therapy with low-molecular-weight heparins with doses adjusted for the stage of pregnancy, body mass, increased renal clearance, and increased volume
PREGNANCY WITH POSTTRANSPLANT HAT
of distribution, is safe and efficient in pregnant women [9,11]. There is no need to monitor concentrations of antiXa factor because it does not increase the treatments success rate and is not useful in predicting bleedings or recurrence of thrombosis [10]. Aspirin (150 mg/d) is a safe treatment, even though it crosses the placenta [9]. Therapeutic success in patients with multiple risk factors is possible only if there is a strict cooperation in a team of specialists. REFERENCES [1] Pareja E, Cortes M, Navarro R, et al. Vascular complications after orthotopic liver transplantation: hepatic artery thrombosis. Transplant Proc 2010;42:2970e2. [2] Bekker J, Ploem S, de Jong KP. Early hepatic artery thrombosis after liver transplantation: a systematic review of the incidence, outcome and risk factors. Am J Transplant 2009;9:746e57. [3] Fan J, Nishida S, Selvaggi G, et al. Factor V Leiden mutation is a risk factor for hepatic artery thrombosis in liver transplantation. Transplant Proc 2013;45:1990e3.
2931 [4] Hibi T, Levi DM, Fukazawa K, et al. Long-term deleterious effects of aortohepatic conduits in primary liver transplantation: proceed with caution. Liver Transpl 2013;19:916e25. [5] Singhal A, Stokes K, Sebastian A, et al. Endovascular treatment of hepatic artery thrombosis following liver transplantation. Transpl Int 2010;23:245e56. [6] Vrochides D, Hassanain M, Metrakos P, et al. Re-vascularization may not increase graft survival after hepatic artery thrombosis in liver transplant recipients. Hippokratia 2010;14:115e8. [7] Alvaro E, Jimenez LC, Palomo I, et al. Pregnancy and orthotopic liver transplantation. Transplant Proc 2013;45:1966e8. [8] Deshpande NA, James NT, Kucirka LM, et al. Pregnancy outcomes of liver transplant recipients: a systematic review and meta-analysis. Liver Transpl 2012;18:621e9. [9] Yurdakök M. Fetal and neonatal effects of anticoagulants used in pregnancy: a review. Turk J Pediatr 2012;54:207e15. [10] Singhal A, Mukherjee I, Stokes K, et al. Continuous intraarterial thrombolysis for early hepatic artery thrombosis following liver transplantation: case report. Vasc Endovascular Surg 2010;44: 134e8. [11] Kim HB. Urgent revascularization for hepatic artery thrombosis: maybe good for the few, definitely good for the many. Liver Transpl 2010;16:812e4.
ABSTRACT Background. Hepatic artery thrombosis (HAT) increases the risk of complications and mortality after liver transplantation. The incidence for HAT is increased in patients with risk factors (vascular reconstructions, coagulation disorders and acute rejection episodes amongst others). Early retransplantation improves the prognosis for patients, but owing to lack of donors, surgical and interventional radiologic attempts to restore the patency of hepatic artery are made. The prognosis for the liver and the patient can also be improved by the development of collateral circulation. Case Report. We describe a case of a 30-year-old woman with hepatic failure owing to Wilson disease. Liver transplantation with the use of vascular conduit made of donor’s iliac arteries was complicated by an early HAT. Heterozygous factor V Leiden mutation was confirmed in the patient. Despite surgical and radiologic attempts to restore patency and despite treatment with fractioned heparin and aspirin, the hepatic artery remained occluded. Retransplantation was not considered, even though the patient was planning a pregnancy. After 1 year of observation of stable liver function, conversion from mycophenolate mofetil to azathioprine treatment, the patient was given consent for a high-risk pregnancy. Discussion. The course of pregnancy was uneventful, with normal liver function parameters, without pathological bleedings. The patient was treated with doses of enoxaparin adjusted for the patient’s weight. In the 34th week, owing to increasing concentration of bile acids, the pregnancy ended with a cesarean section. The newborn had 10-point APGAR score.
H
EPATIC ARTERY THROMBOSIS (HAT) substantially increases the risk of complications and mortality after liver transplantation [1,2]. It is the second main reason, after primary nonfunction, for early failure and loss of liver allografts. The incidence of HAT is increased in patients with risk factors [1e4]. Surgical or radiologic attempts to restore the patency of hepatic artery, although not always successful, can prevent the development of severe infection and biliary tract pathologies. It seems that only early retransplantation improves the long-term prognosis [1,2,5]. There are no guidelines for the treatment of HAT in the literature. Each patient has to be managed and treated individually. Herein we have presented a case of a patient after liver transplantation with early HAT, after failed surgical and radiologic attempts to restore hepatic artery patency, treated with low-molecular-weight heparin and aspirin, with
an uneventful course of pregnancy and no adverse effects on the newborn. CASE REPORT A 30-year-old woman with liver cirrhosis owing to Wilson disease underwent liver transplantation in 2010. Because of the lack of the hepatic artery in the recipient, a vascular conduit was created, with the use of iliac arteries of the donor, connecting the aorta (below renal arteries) and the donor’s liver artery. The blood flow through hepatic artery was monitored daily. On the posttransplantation day 4, Doppler ultrasonography showed no blood flow through the hepatic artery. The patient was qualified for urgent surgery. Thrombosis of the conduit *Address correspondence to Olga Tronina, MD, Klinika Medycyny Transplantacyjnej i Nefrologii, Instytut Transplantologii WUM, 02-006 Warszawa, ul. Nowogrodzka 59, Poland. E-mail: [email protected]
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/14 http://dx.doi.org/10.1016/j.transproceed.2014.09.021
Transplantation Proceedings, 46, 2929e2931 (2014)
2929
2930 was confirmed intraoperatively and a thrombectomy was performed. In the following days, blood flow through the hepatic artery was sustained. The patient was given prophylaxis with aspirin and low-molecular-weight heparin (1 1 mg/kg body mass). The perioperative period was complicated by 2 acute rejection episodes treated with intravenous methylprednisolone infusions and adding a third immunosuppressive agent (mycophenolate mofetil) to the immunosuppressive regimen. Liver histopathology showed no signs of ischemia. Cholangiography showed no signs of biliary tract pathologies. The patient was discharged home with the recommendation of follow-up in the Transplantations Outpatient Clinic. We excluded the presence of lupus anticoagulant, immunoglobulin (Ig)G and IgM anticardiolipine antibodies, antithrombin activity disorders, coagulophatic abnormalities, protein C and free protein S antigen activity disorders, and mutation G20210A of the prothrombin gene, as potential reasons for coagulation disorders. Heterozygous factor V Leiden mutation was confirmed. Two months after transplantation, we observed a rise in liver function parameters, especially cholestatic ones. We performed computed tomographic angiography, which showed only narrow collateral blood flow with HAT despite anticoagulation prophylaxis. The patient was disqualified from further surgical treatment. After a council with specialists in interventional radiology, the patient was qualified for fibrinolytic treatment. She was also given enoxaparin in therapeutic doses of 2 1 mg/kg body mass. The fibrinolysis was performed in 2 stages on December 16 and 17, 2010. Angiography confirmed HAT with a patent stump of the conduit. Recanalization of the hepatic artery with balloon diameters of 4 and 5 mm was performed. Control angiography showed residual thrombi with segmental dissection of the artery. Recombined tissue activator of plasminogen (15 mg) was given. On the following day, through a catheter that was left in the lumen of the artery, 2 XPERT stents were implanted with good effect (XPERT 6 60 distally, 8 60 proximally). Owing to risk of bleeding, the closing of a 5mm false aneurysm was postponed and ultimately never performed. Diagnostic imaging performed 1 week after the procedure showed proper blood flow through hepatic artery. Two months after the procedure, late bleeding from the place of insertion of the catheter occurred. The site was surgically revised, 4 U of packed red blood cells and 2 U of freshly frozen plasma were transfused. A control nuclear magnetic resonance showed a HAT with rich collateral blood flow. Owing to stable liver function parameters, no signs of biliary tract ischemia, and previous history the patient was disqualified from further treatment. Urgent retransplantation was not considered, although the patient had been planning a pregnancy. After 1 year of observation of stable liver function and conversion from mycophenolate mofetil to azathioprine, the patient was given consent to attempt a high-risk pregnancy. The course of pregnancy was uneventful up to the 34th week. We observed normal liver function parameters, without pathologic bleeding. The patient was treated with doses of enoxaparin adjusted for the weight. In her 34th week, owing to increasing concentrations of bile acids, the patient underwent a cesarean section. No bleeding complications were observed. The newborn was assessed as 10 points on the APGAR scale and was monitored, for the first few days, in the neonatal ICU owing to being an early born. At 6 months, we observed good liver function parameters; liver ultrasonography liver shows no pathologies and the patient is in a good general state.
DISCUSSION
HAT occurs in 3% to 11% of liver transplant recipients and increases the risk of early injury to the transplanted organ,
TRONINA, MIKOŁAJCZYK, PIETRZAK ET AL
biliary complications, severe infections, loss of the organ, and even death (30% in early HAT) [2,5,6]. Risk factors for HAT are vascular reconstructions, medical procedures on the vessels, genetic and acquired coagulation disorders (thrombophilia, patients with hepatic cell carcinomas), acute rejections, cytomegalovirus incompatibility of the donor and recipient, and extended ischemia time of the liver [2]. Fan et al [3] describe a 100% occurrence of HAT in patients with factor V Leiden mutation and with a reconstruction of the hepatic artery with the use of a vascular conduit (vs 30% in patients with reconstruction but without the mutation). They also describes a 10-fold increase in risk in patients with factor V Leiden mutation (30%) compared with patients without coagulation disorders (3.8%) [3]. The formation of collateral circulation, which starts at 2 weeks posttransplantation, can improve the fate of the transplanted liver and the patient’s survival [2,5]. There are no guidelines for treatment of patients with risk factors for HAT. In the first posttransplant days, patients are monitored with repeated Doppler ultrasonography. In case of any suspicion of pathologies an angio-CT is performed [2,5,6]. Most patients with HAT (75%) undergo some attempt to restore patency of the hepatic artery. The success rate of the procedures largely depends on the protocol of ultrasound screening (66.1% if daily scans are performed vs 44.9% if less often) [2,5]. Retransplantation, owing to the risk of bleeding after interventional radiology procedures, remains the treatment of choice for HAT. It is performed in 50% of primary cases and in 30.3% of patients after previous revascularization [2]. In female liver transplant recipients, pregnancy should be planned postponed for 1 to 2 years after transplantation, and only with stable liver function [7,8] and after appropriate preparations, such as discontinuing potentially teratogenic treatments. Thanks to strict care in specialized transplant centers, the live birth rate and miscarriage rate are better in liver recipients than in general population (76.9% and 15.6% vs 66.7% and 17.1%, respectively) [8] despite an increased risk for obstetric complications, including preeclampsia (27% vs 8%) and gestational diabetes (21.9% vs 5.1%) [7,8]. After liver transplantation, patients also have an increased risk of perinatal complications. Cesarean sections (44.6% vs 31.9%,), premature birth (39.4% vs 12.5%). and low birth weight (2886 vs 3298 g) are more common than in the general population [8]. Additional risk factors, such as increased risk for acute rejection, reactivation of hepatitis B and C infections, bacterial infections, kidney injury, or a possibility of bleeding in patients receiving anticoagulation treatment or prophylaxis, also play in important role [7,8]. Treatment with vitamin K antagonists is contraindicated in pregnancy owing to teratogenic effect, increased risk of bleeding, and increased risk for pregnancy loss [9,10]. New-generation drugs such as thrombin inhibitors and direct inhibitors of factor Xa are also not advised [10]. Therapy with low-molecular-weight heparins with doses adjusted for the stage of pregnancy, body mass, increased renal clearance, and increased volume
PREGNANCY WITH POSTTRANSPLANT HAT
of distribution, is safe and efficient in pregnant women [9,11]. There is no need to monitor concentrations of antiXa factor because it does not increase the treatments success rate and is not useful in predicting bleedings or recurrence of thrombosis [10]. Aspirin (150 mg/d) is a safe treatment, even though it crosses the placenta [9]. Therapeutic success in patients with multiple risk factors is possible only if there is a strict cooperation in a team of specialists. REFERENCES [1] Pareja E, Cortes M, Navarro R, et al. Vascular complications after orthotopic liver transplantation: hepatic artery thrombosis. Transplant Proc 2010;42:2970e2. [2] Bekker J, Ploem S, de Jong KP. Early hepatic artery thrombosis after liver transplantation: a systematic review of the incidence, outcome and risk factors. Am J Transplant 2009;9:746e57. [3] Fan J, Nishida S, Selvaggi G, et al. Factor V Leiden mutation is a risk factor for hepatic artery thrombosis in liver transplantation. Transplant Proc 2013;45:1990e3.
2931 [4] Hibi T, Levi DM, Fukazawa K, et al. Long-term deleterious effects of aortohepatic conduits in primary liver transplantation: proceed with caution. Liver Transpl 2013;19:916e25. [5] Singhal A, Stokes K, Sebastian A, et al. Endovascular treatment of hepatic artery thrombosis following liver transplantation. Transpl Int 2010;23:245e56. [6] Vrochides D, Hassanain M, Metrakos P, et al. Re-vascularization may not increase graft survival after hepatic artery thrombosis in liver transplant recipients. Hippokratia 2010;14:115e8. [7] Alvaro E, Jimenez LC, Palomo I, et al. Pregnancy and orthotopic liver transplantation. Transplant Proc 2013;45:1966e8. [8] Deshpande NA, James NT, Kucirka LM, et al. Pregnancy outcomes of liver transplant recipients: a systematic review and meta-analysis. Liver Transpl 2012;18:621e9. [9] Yurdakök M. Fetal and neonatal effects of anticoagulants used in pregnancy: a review. Turk J Pediatr 2012;54:207e15. [10] Singhal A, Mukherjee I, Stokes K, et al. Continuous intraarterial thrombolysis for early hepatic artery thrombosis following liver transplantation: case report. Vasc Endovascular Surg 2010;44: 134e8. [11] Kim HB. Urgent revascularization for hepatic artery thrombosis: maybe good for the few, definitely good for the many. Liver Transpl 2010;16:812e4.