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Keywords:

  • asymptomatic venous thromboembolism;
  • oral anticoagulant therapy;
  • renal transplant recipients;
  • symptomatic venous thromboembolism;
  • venous thromboembolism recurrence

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

Summary. Background: Venous thromboembolism (VTE) is one of the thrombotic complications that can occur in patients receiving renal transplantation (RT). The prevalence of VTE in RT patients is, however, undefined. Objectives: To evaluate the rate of a first episode of VTE in a series of 538 consecutive RT recipients admitted to our institution, the timing of occurrence of the thromboembolic events after transplantation, and the rate of recurrence after thromboprophylaxis withdrawal. Risk factors for recurrence were also evaluated, particularly in relation to the type of the first event (symptomatic or asymptomatic). Results: During follow-up, 47 of 518 patients (28 males, 19 females; 9.1%) developed a first episode of VTE at a median time of 17 months (range 1–165 months) after kidney transplantation. Cancer was associated with the occurrence of VTE (odds ratio 4.8). Seventeen of 43 patients (39.5%) with deep vein thrombosis were asymptomatic and the diagnosis was made during routine ultrasound examination. Twenty-two patients (46.8%) experienced a recurrence of VTE. A relevant rate of recurrence was documented amongst patients with a first episode of both symptomatic (53%) and asymptomatic (23.5%) VTE. Conclusion: This study confirms that RT patients are at high risk of symptomatic and asymptomatic VTE and that this risk persists even after several years. Patients who experience VTE are at high risk of recurrence after thromboprophylaxis withdrawal.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

Venous thromboembolism (VTE) is one of the thrombotic complications that occurs in patients receiving renal transplantation (RT). Thromboembolism is strongly correlated with the surgery procedure. However, it is well known that in RT patients there is an imbalance of the hemostatic system, leading to a persistent hypercoagulable state [1–5] that may play a role in later events. The nature of clotting activation is probably multifactorial, in part owing to classic risk factors, in part owing to specific factors related to RT. However, studies dealing with VTE in RT recipients are scarce and report contradictory data; thus, the real frequency of VTE in RT patients is undefined [6–11]. In this population of high-risk patients there is probably an underestimation of the disease, in particular in relation to the occurrence of asymptomatic episodes. A high rate of asymptomatic VTE has been reported in acute medical patients at high risk [12–13] and asymptomatic proximal deep vein thrombosis (DVT) has been related to pulmonary embolism (PE) [14–15] and mortality [16], thus indicating the clinical relevance of the diagnosis of these events. In a previous report we demonstrated an elevated rate of recurrence in RT patients who had a first episode of VTE after withdrawal of thromboprophylaxis [11], underlining that a previous VTE event in the RT patient remains a persistent risk factor for the occurrence of new episodes.

The aims of our study were to evaluate the rate of a first episode of VTE in a series of consecutive patients with RT, the timing of occurrence of the thromboembolic events after transplantation, and the rate of recurrence after thromboprophylaxis withdrawal. Risk factors for recurrence were also evaluated, particularly in relation to the type of the first event (symptomatic or asymptomatic).

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

Patients

This is a follow-up observational cohort study conducted on 538 consecutive RT recipients admitted to our institution from January 1990 to September 2005. Patients were treated in the Renal Unit and follow-up control visits were planned according to American Society of Nephrology guidelines [17]. Twenty patients were lost at follow-up.

All clinical and laboratory data concerning RT recipients admitted to our Renal Unit since 1990 were registered following routine practice at our institution. All patients received low-dose subcutaneous unfractionated heparin or low-molecular-weight heparin (LMWH) as thromboprophylactic treatment for the first 3 months after renal transplantation. Color duplex ultrasonography (DUS) was performed periodically after renal transplantation. DUS was scheduled after 1 week, 1 month, 3 months, 6 months, 12 months and then once yearly in all patients. During follow-up, episodes of DVT of the limbs and/or PE were recorded. DVT was diagnosed by DUS [18]. The diagnosis of PE was based on the combination of clinical probability, chest radiography and perfusion-ventilation lung scanning [19,20].

Venous thromboembolic events were systematically recorded soon after their validation by the physicians responsible; treatment was based on the administration of i.v. unfractionated heparin given at dosages aimed to obtain an activated partial thromboplastin time value in the therapeutic range (normal value 1.5–2.5). Secondary prophylaxis after DVT was based either on the administration of standard oral anticoagulation (International Normalized Ratio 2.0–3.0) or on LMWH 4000 to 6000 IU once a day. The length of secondary prophylaxis was at least 3 months.

Laboratory investigations

All patients with thrombosis underwent laboratory screening for inherited thrombophilia and antiphospholipid antibodies, after completion of anticoagulant treatment. Blood samples were collected to detect the presence of thrombophilia [antithrombin (AT), protein C (PC), free protein S (PS), G20210A prothrombin gene variant, factor (F) V Leiden, homocysteine, lupus anticoagulant, anticardiolipin antibodies, FVIII]. Laboratory methods have been previously described [21,22]. FVIII was measured by a clotting method using FVIII:C-deficient plasma (DADE Behring, Marburg, Germany). Hyperhomocysteinemia (>30 μmol L−1) was defined according to Hankey et al. [23]. Systematic laboratory investigation was carried out only in the patients who suffered thrombosis.

At the time of VTE diagnosis we measured creatinine levels (mg dL−1), daily proteinuria (g 24h−1) and we used creatinine clearance per 24 h to estimate the glomerular filtration rate (GFR), which was standardized to a body surface area of 1.73 cm2.

Evidence of cytomegalovirus (CMV) viremia was investigated in peripheral blood using a semiquantitative polymerase chain reaction assay [24].

Statistical analysis

Statistical analysis was performed by the SPSS (Chicago, IL, USA) software for Windows (version 10.0).

Results are expressed as median and range because of their skewed distribution. Preliminary statistical analysis was performed using the Wilcoxon signed rank test or Fisher's exact test (categorical data). The non-parametric Mann–Whitney U-test was used for comparisons between single groups. A univariate analysis was performed to evaluate the relationship between cancer and the occurrence of the first episode of VTE. Odds ratios (OR) are given with their 95% confidence intervals (CI) and a value of P < 0.05 was chosen for statistical significance.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

From 1990 to September 2005 we followed 518 patients after RT [334 males and 184 females, median age at transplantation 47 years (range 18–69 years)]. During follow-up, 47 patients (28 males, 19 females; 9.1%) developed a first episode of VTE [median age at VTE 58 years (range 24–79 years)]. The clinical characteristics and etiology of patients’ end-stage kidney disease that led to RT are described in Table 1. Patients who experienced VTE had undergone RT at an older age with respect to the other patients: the median age at transplantation was 55 years (range 24–68 years) in this group and 46 years (range 18–69 years) in patients without VTE (P = 0.000) (Table 1). Patients were treated with oral anticoagulants in 32 cases and with LMWH in 15 cases for a mean time of 6 months (range 3–43 months). The total period of antithrombotic treatment was 41 patient-years and during this period five bleeding complications were recorded (rate 12.2 per 100 patient-years): two patients had muscle hematomas and three had gastrointestinal bleeding (among whom two patients were being treated with LMWH and three with oral anticoagulant treatment). Hematologic and solid cancer were present in 31 (6.6%) RT patients without VTE and in 12 (25.5%) RT patients with VTE (P = 0.000) (Table 1). A univariate analysis showed that the presence of cancer was associated with the occurrence of VTE with OR 4.8 (95% CI 2.3–10.1; P = 0.000). Characteristics of VTE events are reported in Table 2. Forty-three patients had DVT of the lower limbs (34 proximal and nine distal) and four patients had PE. The thrombotic events developed a median time of 17 months (range 1–165 months) after kidney transplantation. Ten patients (21%) suffered from VTE in the first 3 months post-RT, eight (17%) from 3 to 6 months post-RT, five (11%) from 6 to 12 months, seven (15%) from 1 to 4 years and 17 (36%) more than 4 years post-RT (Fig. 1). Seventeen of 43 patients (39.5%) with DVT were asymptomatic and the diagnosis was made during routine ultrasound examination. Among the 47 patients with VTE, 22 (46.8%) experienced a recurrence of VTE after the withdrawal of antithrombotic treatment. No difference was found in the rate of recurrent VTE events in relation to the type of the first episode (spontaneous or with transient risk factor). Four patients remain on treatment for the following reasons: one for a prosthetic mechanical aortic heart valve; two for atrial fibrillation; and one for a recent VTE episode. Seven patients died: five of cancer, one of pulmonary infection and one due to heart failure. There were no deaths caused by hemorrhagic complication.

Table 1.  Characteristics of patients with renal transplantation
 All patientsPatients without VTEPatients with VTE
  1. *P = 0.000 vs. patients without venous thromboembolism (VTE).

Number51847147
Males/females334/184306/16528/19
Age (years) at transplantation 47 (18–69) 46 (18–69)55 (24–68)*
Malignancy 43 (8.3%) 31 (6.6%)12 (25.5%)*
Underlying renal disease
 Polycystic kidney disease  93 (19.8%)14 (29.8%)
 Glomerulonephritis 201 (42.7%)14 (29.8%)
 Various other/specified   7 (1.4%) 4 (8.5%)
 Interstitial nephritis  49 (10.3%) 7 (14.9%)
 Unspecified 111 (23.7%) 8 (17.0%)
 Diabetes mellitus  10 (2.1%) 0
Table 2.  Characteristics of venous thromboembolism episode
All patients47
Deep vein thrombosis43 (92%)
Pulmonary embolism4 (8%)
Spontaneous events30 (63%)
With transient risk factors17 (36%)
Symptomatic26 (61%)
Ultrasound diagnosis17 (39%)
Recurrence22 (46.8%)
image

Figure 1. Time of occurrence of first venous thromboembolism event after renal transplantation.

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Thrombophilia was investigated in RT VTE patients. No cases of AT, PC, PS deficiency nor antiphospholipid antibodies were found. One patient had G20210A prothrombin gene variant, two patients had FV Leiden mutation, 11 patients had hyperhomocysteinemia, 37 of 47 patients had FVIII levels >150% and 15 of 47 patients had elevated serum levels of lipoprotein(a).

Renal transplantation VTE patients had median serum creatinine levels of 1.4 mg dL−1 (0.9–2.9) and GFR of 65 mL min−1 1.73 cm−2 (17–122). In patients with VTE, 25 of 47 (54%) were overweight [defined as body mass index (BMI) > 25]. History of acute CMV infection was recorded in 16 of 47 (34%) and 10 of 47 (21%) patients suffered from lymphocele as a consequence of RT.

We analyzed the characteristics of the 22 RT VTE patients who had recurrent VTE. No differences were found vs. patients without recurrence in relation to cancer, BMI > 25, history of acute CMV infection or presence of lymphocele. In addition, no differences were found with regard to thrombophilia markers. Creatinine serum levels, GFR and proteinuria were also similar in the two groups of patients. No statistically significant differences were found in the rate of recurrence in relation to the type of the first event (spontaneous or with a transient risk factor). The rate of recurrence was similar among patients with proximal and distal DVT [14/34 (41.2%) and 4/9 (44.4%) respectively]. All four patients with PE experienced recurrence after thromboprophylaxis withdrawal. A relevant rate of recurrence was documented amongst patients with either a first symptomatic (53%) episode or an asymptomatic (24%) first episode.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References

This study reports a 9.1% incidence of DVT of the lower limbs and/or PE in a large cohort of patients with renal transplantation. The higher incidence of these thrombotic complications in RT patients with respect to subjects with normal renal function is well-known, however the incidence reported in other studies varies widely, ranging from 0.6 to 25% [6–8,11]. Recently, a retrospective cohort study [10] conducted on the United States National Registry found a 1.5% incidence of VTE in approximately 28 000 patients followed for 3 years. However, it is possible that this study produced an underestimation of disease prevalence because it was conducted on Medicare claims and with a short follow-up. In our population, more than 40% of cases occurred after the third year of follow-up. Similar to our data, in a retrospective study on 480 RT patients followed for more than 10 years, Allen et al. [9] showed an incidence of 8.3%. Another retrospective study [7] performed in 125 transplanted patients with a high prevalence of diabetes mellitus (31%), differing from our cohort (2.1%), reported a VTE incidence of 8.8% after a follow-up period of only 1 year. However, most of VTE episodes occurred in diabetic patients, whereas the incidence in non-diabetic patients was 3.5%. Thus, these data cannot be directly compared with ours.

In our series of consecutive patients, all diagnosed symptomatic and asymptomatic thrombotic events were systematically recorded over the past 15 years. The inclusion of unselected patients consecutively diagnosed and the systematic investigation for possible asymptomatic VTE renders our cohort representative of the RT patient population. Nevertheless, even the present investigation is susceptible to underestimation, as a number of minor asymptomatic occlusive events occurring and resolving in the period between two consecutive DUS could have been missed. A notable finding of our study is the elevated number of asymptomatic VTE events (39%), diagnosed by DUS examination performed in routine tests. The incidence of asymptomatic VTE events in high-risk patients has been reported in several studies [16,25–28]. In particular, in the PREVENT study [16], conducted on acutely ill medical patients at high risk for VTE, cases of asymptomatic proximal DVT represented approximately two-thirds of all observed events [13]. Asymptomatic proximal DVT events are widely accepted as being clinically relevant [29]. In addition, symptomatic and asymptomatic proximal DVT are closely linked to the risk of PE [14,15]. The relevance of asymptomatic proximal DVT and its relation to mortality have been previously emphasized [16]. DVT is considered to be the pathophysiological precursor of the late post-thrombotic syndrome [30] and the occurrence of post-thrombotic syndrome is also significantly correlated with asymptomatic DVT [28]. The clinical relevance of VTE-related problems is the rationale for the routine practice of performing DUS surveillance in asymptomatic high-risk patients [16]. DUS is the most universally accepted test for the diagnosis of symptomatic lower limb DVT, because of its wide availability, non-invasivity and repeatibility [31,32]. An increasing number of clinical trials in thromboprophylaxis have used US outcomes. Although in asymptomatic patients DUS has a reduced sensitivity [33], this test nonethless allowed us to detect 17 asymptomatic events. Thus, it is reasonable to assume that in our series we had an underestimation of the prevalence of the disease. The relevance of asymptomatic events is also underlined by the rate of recurrences. Although rate of recurrence of VTE in asymptomatic patients was lower than that found in symptomatic patients, recurrences were present in a not-negligible percentage (24%) of patients with a first asymptomatic event. In addition, the limited number of PE events in our series could be related to the routine period DUS tests performed in our institution in RT recipients that may allow the detection and treatment of asymptomatic events.

When we analyzed the timing of occurrence of VTE events after RT, approximately one-fifth of the patients developed the event in the first 3 months after surgery as a consequence of the operation. However, the occurrence of VTE events later than this appears to be related to other factors. Many reports have been published on clotting alterations in patients with renal disease; the increased risk of thrombotic events is multifactorial and is related to specific conditions of RT. Alterations of hemostasis have been demonstrated in relation to the immunosuppressive treatment used in these patients, in particular to calcineurin inhibitors [5]. In addition, the occurrence of acute CMV infection is reported as a risk factor for the occurrence of VTE [5]. Pretransplant dialysis modality, recurrent proteinuria and posttransplant erytrocytosis have also been associated with a hypercoagulable state [5]. Hyperhomocysteinemia is frequently found in RT patients, and increasing evidence exists that homocysteine may affect the coagulation system. Hyperhomocysteinemia has been shown to be associated with cardiovascular risk in RT patients [34].

The high incidence of cancer in RT patients is another important condition that predisposes to thrombosis. In our series 25.5% of patients who developed a first episode of VTE were affected by solid or hematological tumors, as compared with 6.7% of RT patients without VTE. Malignancy is a thrombophilic condition and there is clinical evidence that patients with cancer have a significantly increased risk of thrombosis [35]. Our data confirm the thrombophilic role of cancer in RT patients too.

In a previous study [11] we demonstrated a high incidence of recurrent VTE after antithrombotic prophylaxis withdrawal in RT patients with a previous episode of VTE. This risk was significantly higher (OR 10) than in patients with a previous episode of VTE with normal renal function. In the present study we have confirmed this observation, with 22 of 47 recurrent events recorded. Surprisingly, there was no difference in recurrence rate for patients with and without cancer. In addition, there was no significant difference in the rate of recurrence in relation to the type of first episode (symptomatic or asymptomatic, and spontaneous or with transient risk factor) or renal function. The prevalence of thrombophilia markers was not different in patients with and without recurrence. However, this result is not surprising because a lack of correlation between thrombophilia and recurrence has been already demonstrated in patients with VTE with normal renal function [36,37]. The high incidence of recurrence in RT patients confirmed the existence of a hypercoagulable state in these patients, and the lengthy time period in which recurrences occurred suggests an extensive persistence of this hypercoagulable state.

The high risk of VTE recurrence in RT patients requires strategies for its prevention and possibly the need for prolonged, probably life-long, treatment. The perspective of long-term antithrombotic treatment implies, at the moment, the use of coumarins with the need for a careful evaluation of risk/benefit ratio. A high rate of bleeding events was found in our patients, in spite of the short time of exposure to oral anticoagulant therapy. Longer observation periods are required to obtain an adequate evaluation, in order to establish the optimal oral anticoagulant therapy duration in these patients. In the near future, the availability of new antithrombotic drugs might offer further therapeutic opportunities for secondary VTE prophylaxis in patients with RT.

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  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References
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