Pediatr Transplantation 2015: 19: E126–E129
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12526
Renal transplantation experience in a patient with factor V Leiden homozygous, MTHFR C677T heterozygous, and PAI heterozygous mutation G€ ulhan B, Tavil B, G€ umr€ uk F, Aki TF, Topaloglu R. (2015) Renal transplantation experience in a patient with factor V Leiden homozygous, MTHFR C677T heterozygous, and PAI heterozygous mutation. Pediatr Transplant, 19: E126–E129. DOI: 10.1111/ petr.12526. Abstract: Vascular complications are important causes of allograft loss in renal transplantation. A two and a half-month-old boy was diagnosed with posterior urethral valve and progressed to end-stage renal disease at eight yr of age. During the HD period, a central venous catheter was replaced three times for repeated thrombosis. The boy was found to be homozygous for FVL and heterozygous for both MTHFR (C677T) and PAI. At the age of 12, renal transplantation was performed from a deceased donor. Postoperative anticoagulation therapy was initiated with continuous intravenous administration of heparin at the dose of 10 IU/kg/h. HD was performed for the first three days. By the fourth day of transplantation, his urine output had increased gradually. Heparin infusion was continued for 18 days during hospitalization at the same dosage. Thereafter, he was discharged with LMWH. On the third month after transplantation, his serum creatinine level was 1.1 mg/dL and eGFR was 75.7 mL/min/ 1.73 m2. He has still been using LMWH, and his eGFR was 78.7 mL/ min/1.73 m2 eight months after transplantation. Postoperative lowdose heparin treatment is a safe strategy for managing a patient with multiple thrombotic risk factors.
Vascular complications are the most common non-immunological cause of allograft loss in renal transplantation. Recently, in pediatric renal transplantation, vascular thrombosis was reported to account for 9.8% of all graft failures (1). Young age of donor and recipient, multiple small donor vessels, prolonged cold ischemia time (>24 h), and arterial hypotension are the main risk factors for thrombosis (2, 3). In addition to the plurality of causes for vascular thrombosis, inherited and acquired risk factors promote the development of thrombosis.
Abbreviations: APC, activated protein C; CAN, chronic allograft nephropathy; eGFR, estimated GFR; FVL, factor V Leiden; HD, hemodialysis; LMWH, low molecular weight heparin; MTHFR, 5,10-methylenetetrahydrofolate reductase; PAI-1, plasminogen activator inhibitor-1.
E126
Bora G€ulhan1, Bet€ul Tavil2, Fatma G€umr€uk2, Tuncay F. Aki3 and Rezan Topaloglu1 1
Department of Pediatric Nephrology, Faculty of Medicine, Hacettepe University, Sıhhiye, Ankara, Turkey, 2Department of Pediatric Hematology, Faculty of Medicine, Hacettepe University, Sıhhiye, Ankara, Turkey, 3Department Urology, Faculty of Medicine, Hacettepe University, Sıhhiye, Ankara, Turkey
Key words: factor V Leiden – thrombophilia – renal transplantation Bora G€ulhan, Department of Pediatric Nephrology, Faculty of Medicine, Hacettepe University, Sıhhiye, Ankara 06100, Turkey Tel.: +90 312 305 1246/+90 536 461 3759 Fax: +90 312 309 4232 E-mail: [email protected] Accepted for publication 17 April 2015
Protein C and S deficiency, antithrombin deficiency, FVL, and prothrombin 20210A gene mutations are common risk factors for thrombosis (4). Although the overall prevalence of FVL mutation in Turkish population is 7.6%, homozygous FVL is quite rare (5). Mutant factor V is resistant to degradation by APC, and this predisposes the patient to thrombosis. Besides FVL, PAI-1 plays a central role in the regulation of the fibrinolytic enzyme system, and mutations in PAI-1 system cause inhibition of fibrinolysis and produce a risk of thrombosis (6). Apart from thrombophilic mutations, mutations in genes coding MTHFR enzyme cause an increase in total homocysteine plasma concentration which is associated with premature arteriolosclerosis and endothelium degeneration (7). In this case report, the renal transplantation experience of a child with homozygous FVL, het-
Renal transplantation with thrombophilia
erozygous MTHFR C677T, and heterozygous PAI gene mutations is presented. Case
A two-month-old boy admitted to the local hospital complained of decreased urine output, and he was diagnosed as bilateral hydroureteronephrosis. He was referred to our hospital for further investigation. Voiding cystourethrogram showed posterior urethral valve. Valve resection was performed when he was two and a half months of age. When he was eight yr of age, he progressed to end-stage renal failure. Both the patient and his family preferred HD as renal replacement therapy. During the HD period, a central venous catheter was replaced three times for repeated thrombosis. Despite flushes with tissue plasminogen activators prior to HD, some HD sessions had to be terminated preliminarily due to catheter blocks. Therefore, a thorough evaluation of the coagulation system was performed. The boy was found to be homozygous for FVL and heterozygous for both MTHFR (C677T) and PAI. His factor V level was 135% (reference 70– 120%), and factor VII level was 176% (reference 70–130%; Table 1). At the age of 12, renal transplantation was performed from a deceased donor (donor was a 54-yr-old male with HLA 2 Ag mismatches), and cold ischemia time was 16 h. The graft was anastomosed to the recipient’s right external iliac vessels. Immunosuppression consisted of basiliximab as induction and tacrolimus, prednisolone, and mycophenolate mofetil as maintenance therapy. Postoperative anticoagulation therapy was initiated with continuous intravenous administration of heparin at the dosage of 10 IU/kg/h. His urine output was below 0.5 mL/kg/h, and HD was performed for the first three days. Recurrent Doppler USG investigation of the transplant artery and vein was negative for any sign of thrombosis. Graft biopsy during the surgery revealed global sclerosis in 15% of the glomeruli, minimal edema on the interstitial areas, mild segmental hyalinosis in some arterioles, and fibrin thrombus on the hilar arteriole of a global sclerotic glomerulus. By the fourth day of transplantation, his urine output had increased gradually. Heparin infusion was continued for 18 days during hospitalization at the same dosage. Thereafter, he was discharged with LMWH. LMWH was administered at a dosage of 1 mg/kg/day. Recurrent transplant artery Doppler USG did not show any sign of thrombosis. The dose of LMWH was adjusted according to antifactor Xa levels. On the third month after transplantation, his serum creati-
nine level was 1.1 mg/dL and eGFR was Diethylene triamine 75.7 mL/min/1.73 m2. penta-acetic acid scintigraphy revealed normal perfusion, concentration, and excretion function of the graft. Follow-up serum and urine viral serologies for BK, JC, and CMV were all negative. He has still been using LMWH, prednisolone, mycophenolate mofetil, and tacrolimus treatment, and his eGFR was 78.7 mL/min/1.73 m2, eight months after transplantation. LMWH treatment will be continued until one yr after transplantation. Discussion
In renal transplantation, coagulation system disorders have been associated with an increased incidence of graft loss and impaired graft function (8–10). Data related to renal transplantation and thrombophilia are mostly based on adult literature. Pediatric experience is rare in this area (11, 12). Herein, we presented the renal transplantation experience of a patient with multiple thrombotic risk factors including FVL homozygous, MTHFR C677T heterozygous, and PAI 4G/5G heterozygous mutations. FVL is a gain of function mutation that causes the substitution of glutamine to arginine at the Arg506 cleavage site. This single amino acid substitution leads to resistance of factor Va to APC binding and favors thrombin generation. APC is an anticoagulant protein that inactivates procoagulant factor Va and VIIIa and prevents thrombin formation. FVL is the most commonly Table 1. Coagulation parameters of the patient with increased factor V, VII, VIII levels and decreased protein S activity Test
Result (reference)
aPTT INR Fibrinogen Thrombin time Antittrombin III activity Factor V Factor VII Factor VIII Factor IX Factor X Factor XI Factor XII Factor XIII Anticardiolipin IgM/IgG Antiphospholipid IgM/IgG Homocysteine Protein S activity Protein C activity
23.8 sn 0.96 341 mg/dL (219–403) 17.7 (16.6–22.5) 108% (80–120) 135% (70–120) 176% (70–130) 155% (70–150) 105% (60–170) 120% (70–120) 128% (70–150) 95% (70–150) 100% (80–130) Negative/Negative Negative/Negative 11.27 lmol/L (
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12526
Renal transplantation experience in a patient with factor V Leiden homozygous, MTHFR C677T heterozygous, and PAI heterozygous mutation G€ ulhan B, Tavil B, G€ umr€ uk F, Aki TF, Topaloglu R. (2015) Renal transplantation experience in a patient with factor V Leiden homozygous, MTHFR C677T heterozygous, and PAI heterozygous mutation. Pediatr Transplant, 19: E126–E129. DOI: 10.1111/ petr.12526. Abstract: Vascular complications are important causes of allograft loss in renal transplantation. A two and a half-month-old boy was diagnosed with posterior urethral valve and progressed to end-stage renal disease at eight yr of age. During the HD period, a central venous catheter was replaced three times for repeated thrombosis. The boy was found to be homozygous for FVL and heterozygous for both MTHFR (C677T) and PAI. At the age of 12, renal transplantation was performed from a deceased donor. Postoperative anticoagulation therapy was initiated with continuous intravenous administration of heparin at the dose of 10 IU/kg/h. HD was performed for the first three days. By the fourth day of transplantation, his urine output had increased gradually. Heparin infusion was continued for 18 days during hospitalization at the same dosage. Thereafter, he was discharged with LMWH. On the third month after transplantation, his serum creatinine level was 1.1 mg/dL and eGFR was 75.7 mL/min/ 1.73 m2. He has still been using LMWH, and his eGFR was 78.7 mL/ min/1.73 m2 eight months after transplantation. Postoperative lowdose heparin treatment is a safe strategy for managing a patient with multiple thrombotic risk factors.
Vascular complications are the most common non-immunological cause of allograft loss in renal transplantation. Recently, in pediatric renal transplantation, vascular thrombosis was reported to account for 9.8% of all graft failures (1). Young age of donor and recipient, multiple small donor vessels, prolonged cold ischemia time (>24 h), and arterial hypotension are the main risk factors for thrombosis (2, 3). In addition to the plurality of causes for vascular thrombosis, inherited and acquired risk factors promote the development of thrombosis.
Abbreviations: APC, activated protein C; CAN, chronic allograft nephropathy; eGFR, estimated GFR; FVL, factor V Leiden; HD, hemodialysis; LMWH, low molecular weight heparin; MTHFR, 5,10-methylenetetrahydrofolate reductase; PAI-1, plasminogen activator inhibitor-1.
E126
Bora G€ulhan1, Bet€ul Tavil2, Fatma G€umr€uk2, Tuncay F. Aki3 and Rezan Topaloglu1 1
Department of Pediatric Nephrology, Faculty of Medicine, Hacettepe University, Sıhhiye, Ankara, Turkey, 2Department of Pediatric Hematology, Faculty of Medicine, Hacettepe University, Sıhhiye, Ankara, Turkey, 3Department Urology, Faculty of Medicine, Hacettepe University, Sıhhiye, Ankara, Turkey
Key words: factor V Leiden – thrombophilia – renal transplantation Bora G€ulhan, Department of Pediatric Nephrology, Faculty of Medicine, Hacettepe University, Sıhhiye, Ankara 06100, Turkey Tel.: +90 312 305 1246/+90 536 461 3759 Fax: +90 312 309 4232 E-mail: [email protected] Accepted for publication 17 April 2015
Protein C and S deficiency, antithrombin deficiency, FVL, and prothrombin 20210A gene mutations are common risk factors for thrombosis (4). Although the overall prevalence of FVL mutation in Turkish population is 7.6%, homozygous FVL is quite rare (5). Mutant factor V is resistant to degradation by APC, and this predisposes the patient to thrombosis. Besides FVL, PAI-1 plays a central role in the regulation of the fibrinolytic enzyme system, and mutations in PAI-1 system cause inhibition of fibrinolysis and produce a risk of thrombosis (6). Apart from thrombophilic mutations, mutations in genes coding MTHFR enzyme cause an increase in total homocysteine plasma concentration which is associated with premature arteriolosclerosis and endothelium degeneration (7). In this case report, the renal transplantation experience of a child with homozygous FVL, het-
Renal transplantation with thrombophilia
erozygous MTHFR C677T, and heterozygous PAI gene mutations is presented. Case
A two-month-old boy admitted to the local hospital complained of decreased urine output, and he was diagnosed as bilateral hydroureteronephrosis. He was referred to our hospital for further investigation. Voiding cystourethrogram showed posterior urethral valve. Valve resection was performed when he was two and a half months of age. When he was eight yr of age, he progressed to end-stage renal failure. Both the patient and his family preferred HD as renal replacement therapy. During the HD period, a central venous catheter was replaced three times for repeated thrombosis. Despite flushes with tissue plasminogen activators prior to HD, some HD sessions had to be terminated preliminarily due to catheter blocks. Therefore, a thorough evaluation of the coagulation system was performed. The boy was found to be homozygous for FVL and heterozygous for both MTHFR (C677T) and PAI. His factor V level was 135% (reference 70– 120%), and factor VII level was 176% (reference 70–130%; Table 1). At the age of 12, renal transplantation was performed from a deceased donor (donor was a 54-yr-old male with HLA 2 Ag mismatches), and cold ischemia time was 16 h. The graft was anastomosed to the recipient’s right external iliac vessels. Immunosuppression consisted of basiliximab as induction and tacrolimus, prednisolone, and mycophenolate mofetil as maintenance therapy. Postoperative anticoagulation therapy was initiated with continuous intravenous administration of heparin at the dosage of 10 IU/kg/h. His urine output was below 0.5 mL/kg/h, and HD was performed for the first three days. Recurrent Doppler USG investigation of the transplant artery and vein was negative for any sign of thrombosis. Graft biopsy during the surgery revealed global sclerosis in 15% of the glomeruli, minimal edema on the interstitial areas, mild segmental hyalinosis in some arterioles, and fibrin thrombus on the hilar arteriole of a global sclerotic glomerulus. By the fourth day of transplantation, his urine output had increased gradually. Heparin infusion was continued for 18 days during hospitalization at the same dosage. Thereafter, he was discharged with LMWH. LMWH was administered at a dosage of 1 mg/kg/day. Recurrent transplant artery Doppler USG did not show any sign of thrombosis. The dose of LMWH was adjusted according to antifactor Xa levels. On the third month after transplantation, his serum creati-
nine level was 1.1 mg/dL and eGFR was Diethylene triamine 75.7 mL/min/1.73 m2. penta-acetic acid scintigraphy revealed normal perfusion, concentration, and excretion function of the graft. Follow-up serum and urine viral serologies for BK, JC, and CMV were all negative. He has still been using LMWH, prednisolone, mycophenolate mofetil, and tacrolimus treatment, and his eGFR was 78.7 mL/min/1.73 m2, eight months after transplantation. LMWH treatment will be continued until one yr after transplantation. Discussion
In renal transplantation, coagulation system disorders have been associated with an increased incidence of graft loss and impaired graft function (8–10). Data related to renal transplantation and thrombophilia are mostly based on adult literature. Pediatric experience is rare in this area (11, 12). Herein, we presented the renal transplantation experience of a patient with multiple thrombotic risk factors including FVL homozygous, MTHFR C677T heterozygous, and PAI 4G/5G heterozygous mutations. FVL is a gain of function mutation that causes the substitution of glutamine to arginine at the Arg506 cleavage site. This single amino acid substitution leads to resistance of factor Va to APC binding and favors thrombin generation. APC is an anticoagulant protein that inactivates procoagulant factor Va and VIIIa and prevents thrombin formation. FVL is the most commonly Table 1. Coagulation parameters of the patient with increased factor V, VII, VIII levels and decreased protein S activity Test
Result (reference)
aPTT INR Fibrinogen Thrombin time Antittrombin III activity Factor V Factor VII Factor VIII Factor IX Factor X Factor XI Factor XII Factor XIII Anticardiolipin IgM/IgG Antiphospholipid IgM/IgG Homocysteine Protein S activity Protein C activity
23.8 sn 0.96 341 mg/dL (219–403) 17.7 (16.6–22.5) 108% (80–120) 135% (70–120) 176% (70–130) 155% (70–150) 105% (60–170) 120% (70–120) 128% (70–150) 95% (70–150) 100% (80–130) Negative/Negative Negative/Negative 11.27 lmol/L (
