Objectives: Thrombophilia has been implicated in posttransplant thrombosis. Data concerning the impact of thrombophilia on thrombotic risk in renal graft recipients are inconclusive. We evaluated whether identification of thrombophilia in patients during pretransplant laboratory screening was a predictor of posttransplant outcomes.
Materials and Methods: We conducted a prospective single-center longitudinal study that included adult recipients who underwent kidney transplant from January 2011 to December 2017. Cardiovascular risk factors, personal history of thrombosis, and data concerning kidney transplant episodes were recorded. Before kidney transplant, all patients were systematically screened for thrombophilia. For thrombophilia screening for antithrombin, protein C, protein S deficiencies, and activated protein C resistance, reagents from Stago were used (Stachrom AT, Staclot Protein C, Staclot Protein S, and Staclot APCR). The endpoint was a thrombotic event within 2 years after kidney transplant.
Results: Among 75 end-stage renal disease candidates for kidney transplant, 46 kidney transplant recipients were screened for thrombophilia. Thirty-six of the patients were men. The median age was 37 years (interquartile range, 33-43 years). Renal replacement therapy (36 hemodialysis and 10 peritoneal dialysis) was started in all patients. Forty-five patients received a kidney from a living donor. Among the 46 patients, 4 (9%) had a thrombophilia abnormality (3 with protein C deficiency and 1 with activated protein C resistance). Thrombotic events occurred during the follow-up in 7 cases (15%) with no anterior thrombophilia abnormality; 2 of these concerned the kidney transplant. Only 1 patient had loss of kidney graft immediately after kidney transplant. There was no association between pretransplant thrombophilia and posttransplant thrombotic events.
Conclusions: Our results suggest that the utility of universal, comprehensive preoperative thrombophilia testing is not beneficial to determine risk of postoperative thrombosis. Thrombophilia testing may be considered in a select population with a history of pretransplant thrombotic events.
Key words : Cardiovascular risk, Posttransplant thrombotic events, Renal failure, Thrombosis
Thrombotic events are a serious complication in kidney transplant (KT) patients. These events include not only ordinary localizations such as pulmonary embolism and deep vein thrombosis but also graft artery and graft vein thrombosis, which may compromise graft survival.1,2 It has been reported that thrombotic events can occur at any time but are more frequent in the 6 months after KT.3 Several studies have suggested risk factors related to the patient’s underlying kidney disease, recipient and donor characteristics, surgical technique, immediate postoperative outcomes, and immunosuppressive treatment.1,4,5 Thrombotic risks increase in patients with hereditary or acquired thrombophilia.6,7 However, given the frequency of acquired thrombophilia in patients with end-stage renal disease (ESRD),8 inherited thrombophilia remains problematic. Therefore, pretransplant screening for thrombophilia has been adopted by several transplant teams.9 However, relevance of thrombophilia screening for KT remains controversial.10 In fact, inclusion criteria, analysis methods for thrombophilic markers, duration of follow-up periods, and effects on therapeutic approach all lack standardization.
The aim of our study was to evaluate whether identification of thrombophilia in patients during pretransplant laboratory screening is a predictor of poor posttransplant outcomes.
Materials and Methods
We conducted a prospective, single-center, longitudinal study of adult patients awaiting KT from January 2011 to December 2017. All KT candidate recipients were systematically screened for inherited thrombophilia. Clinical data were obtained from medical records and standardized. These data included cardiovascular risk factors, personal history of thrombosis, and details of KT procedure (type of donor, details of immunosuppression, age of donors and recipients, cold ischemia time, surgical difficulty, and immediate postoperative complications). The outcomes of interest were thrombotic events or graft rejection within 2 years post-KT. Patients with missing data were excluded.
Peripheral venous blood was drawn into tubes containing citrate (3.2%, 9:1). Platelet-poor plasma was obtained after a double centrifugation at 2500 g for 10 minutes. Aliquots were stored at -80 °C for less than 30 days and immediately thawed before analysis.
For laboratory investigation, we used reagents from Stago (Stachrom AT, Staclot Protein C, Staclot Protein S, and Staclot APCR) to conduct screening for antithrombin, protein C deficiency, protein S deficiency, and activated protein C resistance. All laboratory assays were performed on a fully automated STA analyzer (Stago). The presence of inherited thrombophilia was considered only if repeated tests showed persistently abnormal results (antithrombin < 80%, protein C deficiency < 70%, protein S deficiency < 55%, or activated protein C resistance < 120 seconds) and/or if the abnormal defect was shown in family investigation.
Patients were regularly followed up during routine visits. All thrombotic events within the 2 years post-KT were recorded (deep vein, superficial vein, fistula, or artery thrombosis; pulmonary embolism; graft vein or graft artery thrombosis).
This study was approved by the local ethics committee. Approved written informed consent was obtained from all patients included in this study.
Categorical variables are expressed as percentages. Continuous variables are expressed as median values with interquartile ranges. Comparisons of categorical variables were tested by the chi-square test or the Fisher test, as appropriate. Comparisons of quantitative variables were performed with the Mann- Whitney U test. P < .05 was considered statistically significant. All statistical analyses were performed with SPSS 20.0 software.
During the study period, 75 ESRD patients underwent KT. After exclusion of patients with missing data, 46 KT recipients screened for thrombophilia were included. The median age was 37 years (interquartile range, 33-43 years). Thirty-six patients were men.
At least 1 cardiovascular risk factor was identified in 31 patients, as follows: arterial hypertension (n = 24), diabetes (n = 7), hyperlipidemia (n = 1), and smoking (n = 15).
A history of systemic lupus erythematosus and hemolytic uremic syndrome was identified in 2 patients. None of the 46 recipients had a history of thrombotic events or antiphospholipid syndrome.
Chronic glomerular nephropathy was the main cause of ESRD (n = 16; 35%). Renal replacement therapy (36 patients on hemodialysis and 10 on peritoneal dialysis) was started in all patients at a median age of 30 years. Forty-five patients received a kidney from a living donor.
All patients received induction with steroid, thymoglobulin, and mycophenolate mofetil followed by tacrolimus, mycophenolate mofetil, and prednisone as maintenance treatment. All patients also received thromboprophylaxis with heparin calcium at a dose of 7500 IU per 0.3 mL twice daily during the 5 days after KT.
Among the 46 KT recipients, 4 patients (9%) had thrombophilia (3 with protein C deficiency, and 1 with activated protein C resistance). Analysis of demographic and clinical data in patients with and without thrombophilia did not show any statistically significant difference (Table 1). In addition, data related to KT were comparable between the 2 groups. Pretransplant thrombotic events were not recorded in any groups (Table 2).
There were 7 thrombotic events (15%) during the follow-up period. Two of these concerned the KT; ie, a patient with no thrombophilia had loss of kidney graft immediately after transplant (Table 3, patient 7), and the other patient was surgically resuscitated (Table 3, patient 3). There was no association between pre-KT thrombophilia and post-KT thrombotic events. Only 1 patient received a deceased donor graft, without any complication (Table 4).
It is well known that thrombotic events are associated with poor outcomes in KT, especially when it concerns a renal graft. Therefore, identification of patients with thrombotic risk factors may avoid this potential problem. Our study concerned 46 KT recipients who benefited from systematic thrombophilia screening before KT. Of these 46 patients, only 4 (9%) had thrombophilia (1 patient with activated protein C resistance; 3 patients with protein C deficiency). None had a post-KT thrombotic event. Furthermore, postoperative thrombotic events were identified in 7 patients (15%) with no inherited thrombophilia. To the best of our knowledge, our study is the first to focus on the relevance of thrombophilia screening in adult KT recipients. However, this study has some limitations, mainly the monocentric character of the study, as well as the lack of data for factor V Leiden and prothrombin gene mutations.
Several studies reported a prevalence of thrombophilia ranging from 5% to 16%.11-13 The reported rates are different among studies because of the heterogeneity of studied thrombophilia markers. Morrissey and colleagues11 reported 10 patients (4%) with thrombophilia among 235 KT recipients. However, all 10 patients had acquired thrombophilia (lupus anticoagulant, elevated anticardiolipin).11 Dick and colleagues12 found thrombophilia in 3 patients among 18 pediatric KT recipients (2 patients with protein S deficiency; 1 patient with factor V Leiden).
Higher rates were reported in studies that included screening for acquired thrombophilia such as elevated homocysteine and factor VIII levels or lupus anticoagulant as a laboratory workup; in a study by Bock and colleagues, 36 patients (36%) had thrombophilia (decreased protein S and antithrombin activities were found in 9 and 2 cases, respectively; elevated homocysteine in 21 cases; and heterozygosity of factor V Leiden in 4 cases).3 It should be noted that thrombophilia markers were not controlled in these studies, which could lead to an overestimation of inherited thrombophilia.
Vascular events were reported in 15% of patients in this study. Two patients (4%) had thrombotic events involving the graft. Similar rates were reported in several studies.3,10,11 Bock and colleagues reported 2% graft loss from thrombosis in 100 recipients.3
No KT recipient with positive thrombophilia experienced a thrombotic event. Few previous studies have evaluated the association between thrombophilia and thrombotic events. In a cohort of 36 children, 10 thrombotic complications were recorded in 10 children, and there was no association between thrombophilia and postoperative thrombotic events.3 Thrombotic events were associated in this study with the history of focal segmental glomerulosclerosis.3
Other factors were reported to be associated with thrombotic risk, such as immunosuppressive agents used to prevent rejection, peritoneal dialysis, deceased donor, and surgical difficulties.14
In summary, this study showed no association between thrombophilia and thrombotic events after KT. Thus, there is no relevance to systematic thrombophilia screening in adults awaiting KT. History of thrombotic events or known familial thrombophilia may influence the decision to screen for thrombophilia. Furthermore, the impact of these laboratory findings on thromboprophylaxis strategies remains unknown.
Volume : 19
Issue : 3
Pages : 212 - 216
DOI : 10.6002/ect.2020.0234
From the 1Hematology Department, La Rabta Hospital, Tunis, Tunisia; the
2Nephrology-Dialysis-Kidney Transplantation Department, La Rabta Hospital, Tunis
Tunisia; and the 3Faculty of Medicine of Tunis, Tunis University El Manar,
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest. The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Corresponding author: Bahri Dhouha, Hematology Department, La Rabta Hospital, Jabbari Street 1007, Tunis, Tunisia
Phone: +216 54 771 435
Table 1. Demographic and Clinical Characteristics of Recipients With and Without Thrombophilia
Table 2. Data Related To Kidney Transplant in Recipients With and Without Thrombophilia
Table 3. Characteristics of Patients With Vascular Events Occurring After Kidney Transplant
Table 4. Relationship of Donor to Recipient