Thrombophilia due to activated protein C resistance (Leiden mutation) is the most common inherited thrombophilic disorder with 5% incidence in whites. Renal transplant of these patients entails a risk of vascular thrombosis soon after the transplant; and acute rejection episodes and graft loss within the first year. We present a case of a successful living-related renal transplant in man with a recent history of repeat episodes of vascular access thrombosis attributed to inherited thrombophilia (heterozygosity for factor V mutation Q506 and homozygosity for mutation T677 for methylene-tetrahydrofolate reductase). Transplant recipient was administered anticoagulation therapy with low molecular weight heparin pre- and postoperatively. No thrombotic or hemorrhagic events occurred posttransplant. A high suspicion of thrombophilic disorders in patients with end-stage renal disease with vascular access thrombotic events should be screened further to prevent failure of a subsequent renal transplant. Inherited thrombophilic disorders may not exclude living-related kidney transplant provided that anticoagulation therapy is admin-istered perioperatively.
Key words : Renal transplant, Thrombophilia, Renal allograft thrombosis, Arteriovenous fistula thrombosis, Factor V-Leiden
Vascular complications are relatively rare in renal transplant; however, coexistence of inherited throm-bophilic disorders predispose to thromboembolic episodes that may compromise a potential renal transplant.1 These patients are at high risk of developing severe complications after renal transplant, which may lead to early transplant loss.2-4 Acute rejection has been reported in 71% of renal transplant recipients with thrombophilic disorders.4 Cerebral and coronary vascular disease as well as throm-boembolic episodes, including vascular occlusive events of the graft, in this group of patients have risen to 67%.5 Early graft loss within the first year after transplant was 55.6%.2,6 Delayed graft function and chronic graft dysfunction also have been reported.
Thrombophilia due to factor V-Leiden mutations is the commonest inherited thrombophilic disorder with 5% prevalence in white people that belong to a larger group of coagulopathies regarding the resistance to protein C.1,7 Specifically, inheritance of factor V-Leiden (FVL) mutation may increase the risk of renal allograft thrombosis by approximately 4 times.8 Placement of arginine instead of glutamine at residue 506 leads to a defective molecule of factor V that hinders combination to activated protein C and thus inhibits normal creation of thrombi. It presents with idiopathic deep venous thrombosis in hetero-zygotic carriers. Thrombotic episodes may involve arteries in homozygotics.1 Mutations of methylene-tetrahydrofolate reductase (MTHFR) causes hyper-homocysteinemia, which may trigger arteriovenous fistula thrombosis in patients who are undergoing haemodialysis.9 In addition, homozygosity in T677 mutation in the MTHFR gene that causes hyper-homocysteinemia, is thought to be an independent risk factor for venous thromboembolism.8 Coexistence of both mutations regarding FVL and MTHFR and their involvement to renal allograft thrombosis, remains unknown.
We present a successful living-related renal transplant in a recipient with inherited thrombophilia because of heterozygosity for mutation of factor V Q506 and homozygosity for mutation T677 for MTHFR.
A 65-year-old man with end-stage renal disease due to hypertensive nephrosclerosis was admitted for preemptive renal transplant from living-related donor (his sister). The recipient had a recent history of 3 episodes of vascular access thrombosis. Two months before his admission, an arteriovenous fistula was created on the right wrist that was thrombosed 10 days later. The second episode occurred 1 month later, when an arteriovenous graft was thrombosed. During an attempt of surgical recanalization of the graft, it was observed that thrombi created at hoc. Because it was suspected that a thrombophilic disorder was present, a full thrombophilic screening was performed including protein C, protein S, antithrombin III (AT3), lupus anticoagulant screening, activated protein C resistance, homocysteine, factor V (Leiden), prothrombin G20210 mutation (G20210A), international normalized ratio (INR), activated partial throm-boplastin time, and prothrombin time. The screening revealed that the patient had a heterozygotic mutation for FVL and homozygosity for mutation in T677 gene for MTHFR (Table 1). The latter resulted in hyperhomocysteinemia 60 μmol/L (normal values, 4-11.1 μmol/L). Administration of folic acid preoperatively normalized homocysteine levels (8 μmol/L).
A living-related donor was his 62-year-old sister, whose thrombophilia screening just revealed heterozygosity for mutation in T677 gene for MTHFR, which constitutes no clinical coagulopathy provided. She had normal serum levels of homocysteine (11.9 μmol/L).
Donor and recipient had the same blood type O Rhesus positive. Human leukocyte antigen typing showed that they had 3 human leukocyte antigen matches (A24, B55, DR11). They were both informed of the risks of acute rejection, vascular thrombosis as well as the low graft survival rate the first year in addition to the risk of hemorrhage during the operation or during the early postoperative period considering the continuous anticoagulation treatment and provided full consent to proceed with transplant operation.
Following diagnosis of thrombophilia, the recipient commenced treatment with low dose of low molecular weight heparin, enoxaparin 40 mg twice daily, owing to end-stage renal disease. Anti-Xa levels 4 hours after administration were monitored closely to titrate optimal dosage based on target anti-Xa levels 0.4 to 1 IU. The optimal dosage for our recipient was enoxaparin 40 mg twice daily. Four hours before the onset of transplant surgical operation, the recipient received enoxaparin 40 mg and at the time that graft’s vessels were anastomosed anti-Xa levels were 0.46 IU/mL, value close to the lowest therapeutic threshold. The recipient’s induction immunosuppression regimen included basiliximab and methylprednisolone 500 mg at the time of reperfusion. On the first day after the transplant, the maintenance immunosuppressive regimen included tacrolimus 1 mg/kg twice daily, mycophenolate mofetil 1 g/day, and corticosteroids (initially methylprednisolone 250 mg, and subse-quently prednisolone, tapering schema: reduction 25 mg every day). The transplant operation was completed successfully with immediate renal graft function. The first postoperative day urine output was 4.5 L.
The anticoagulant therapy postoperatively continued with enoxaparin doses titrated to anti-Xa levels (Figure 1). Serum creatinine levels reduced quickly, requiring frequent enoxaparin dose adjustment. On the seventh day after transplant, the patient’s serum creatinine was 1.3 mg/dL and enoxaparin was increased to 60 mg twice daily. Gradual substitution with acenocoumarol began targeting INR 2-3. When INR was within the therapeutic range, enoxaparin was discontinued. No vascular complication or hemorrhage occurred. The recipient was discharged on 26th postoperative day with excellent renal graft function.
Inherited thrombophilia should be suspected in end-stage renal disease patients with a history of throm-botic episodes of vascular accesses, complications that are usually attributed to poor surgical tech-niques. Furthermore, a history of deep venous thrombosis, multiple miscarriages, or other thrombo-embolic episodes including acute rejection in previous renal transplant may raise suspicion of inherited coagulopathy. Once a thrombophilic disorder is diagnosed, anticoagulation therapy should be administered for life. When the disorder is diagnosed in pretransplant assessment, antico-agulation therapy must be initiated immediately.10,11
Low molecular weight heparin, unfractionated heparin, or warfarin may be used in doses that provide therapeutic effect. Because of renal deficiency, titration and individualization of doses are necessary to achieve target therapeutic levels, which differ depending on the anticoagulant agent used.10,11 Repeated measurements either of anti Xa levels or aPTT or INR, and hence dose titration, are necessary not only to prevent thrombotic events perioperatively but also, to prevent postoperative hemorrhage in recipients with thrombophilic disorders.12,13
In children with thrombophilia the incidence of graft thrombosis is higher than adults considering the fact that renal transplant in children with end-stage renal disease has already 11.6% risk of acute graft thrombosis.14 Children with end-stage renal disease and coexistent hypercoagulable disorders underwent successful living-related kidney trans-plants receiving proper perioperative antico-agulation therapy.15 The overall graft survival in such patients was comparable to group of patients without thrombophilic disorder.14 Ekberg and associates found that acute rejection in recipients with factor V R506Q mutation experienced early graft loss because of vascular rejection of the graft attributed to histologic changes including endo-theliosis and fibrinoid vascular changes associated with FV genotype.6 Studies have shown that recipients with hypercoagulable disorders have a significantly higher risk of early graft failure apart from thromboembolic events and acute rejection.16 Long-term graft survival is higher when antico-agulants are administered prophylactically.17
Genetic analysis has shown that single nucleotide polymorphisms seem to have no statistically significant association with acute rejections, except from factor V mutation Q506.18 Further larger studies are required to evaluate the role of antithrombotic treatment in acute rejection episodes in throm-bophilic recipients with different single nucleotide polymorphisms.
In our case, a living-related renal transplant was performed successfully in a recipient with thrombo-philic disorder. Pretransplant evaluation revealed inherited thrombophilia suspected from the recent history of vascular access thrombosis. Antico-agulation therapy used perioperatively and intense monitoring of anticoagulants effects were performed, balancing the risk of thrombosis versus hemorrhage.
Patients with a history of repeated thromboembolic episodes should be screened for thrombophilic disorders. Recommendations are required for antico-agulation therapy in renal transplant candidates with inherited thrombophilia based on prospective studies.
Volume : 15
Issue : 1
Pages : 96 - 99
DOI : 10.6002/ect.2014.0255
From the 1First Department of Surgery Transplant Unit,
Evangelismos General Hospital of Athens, Greece; the 2Laboratory of
Hematology, Evangelismos General Hospital of Athens, Greece; and the 3Biomedical
Research Foundation of the Academy of Athens
Acknowledgements: The authors declare that they have no sources of funding for this study, and they have no conflicts of interest to declare.
Corresponding author: Spiros Drakopoulos, First Department of Surgery – Transplant Unit, Evangelismos General Hospital of Athens, Greece, 45-47 Ipsilantou Street, Athens 10676, Greece
Phone: +30 210 720 5446
Fax: +30 210 723 3421
Table 1. Screening for Thrombophilia the Renal Transplant Candidate
Figure 1. Enoxaparine’s Dose Regulation Dependent With Allograft’s Function