Annals o f Clinical & Laboratory Science, vol. 30, no. 1, 2000 75

Acute Renal Artery and Vein Thrombosis after Renal Transplant, Associated with a Short Partial Thromboplastin Time and Factor V Leiden Mutation

Nabil Guirguis, Milos N. Budisavljevic, Sally Self, P. R. Rajagopalan, and John LazarchickDepartments of Medicine, Pathology and Laboratory Medicine, and Surgery,Medical University of South Carolina, Charleston, South Carolina

Abstract. Renal graft thrombosis is a rare but devastating complication of renal transplantation. It accounts for one-third to one-half of early graft losses. We report a patient with acute renal artery and vein thrombosis associated with abnormally short activated partial thromboplastin time (aPTT) and factor V Leiden mutation. Vascular thrombosis developed on the ninth post-transplant day and led to a graft loss. Before transplantation, the patient had three episodes of thrombosis of arteriovenous access for hemodialysis. Our case illustrates the importance of investigating pretransplant patients for hypercoagulable states, particularly those with short aPTT.

Keywords: Renal artery thrombosis, renal vein thrombosis, cadaveric renal transplant, short activated partial thromboplastin time, factor V Leiden mutation.

Introduction

Renal vascular thrombosis is an uncommon but serious complication of renal transplantation and usually occurs in the early postoperative period [1]. The most common causes are faulty surgical anastomosis, severe (hyper)acute rejection, multiple donor vessels, pediatric donors, and progression of stenosis to thrombosis [2,3]. Although Heidenreich, et al evaluated the prevalence of the presence of major hereditary and acquired risk factors of thrombophilia and acute rejection in renal allograft recipients, they did not include any patients with a shortened aPTT as a risk factor [4]. We present a case o f acute renal graft loss due to extensive thrombosis of the renal artery and vein in a patient w ith a hypercoagulable state associated w ith a repeatedly short aPTT and the presence of factor V Leiden mutation.

Address correspondence to John Lazarchick, M .D ., D epartm ent of Pathology and Laboratory Medicine, Medical University of South Carolina, 171 Ashley Ave., Charleston, SC 29525; Tel: 843 792 2933; Fax: 843 792 1248; E-mail: lazarj@musc.ed

Case report.

A 30-year old white female with endstage renal disease secondary to Alport’s syndrome received a cadaveric renal transplant. Her pretransplant laboratory data included potassium 4.5 mM/1, total CO2 19 mM/L, urea nitrogen 60 m g/d l, creatinine 12.9 m g/dl, ph osp h oru s 8.4 m g /d l, h em o g lo b in 9.7 g /d l, hem atocrit 28.5% , p la te le ts 1 9 3 ,0 0 0 /m m 3 , prothrom bin tim e 11.7 sec, and aPTT 22.3 sec (reference range: 22.8-33.5 sec). Following trans­plantation, she had immediate graft function with progressive decrease o f serum creatinine to 3.6 mg/dl at discharge from the hospital eight days later. She was started on cyclosporin on the second day post­transplant. Her other medications were prednisone, m ycophenolate m ofetil, acyclovir, nystatin, and sulfamethoxazole/trimethoprim.

On the ninth day post-transplant, she developed gross hematuria, severe abdominal pain, fever, and tenderness over the transplanted kidney. Her urine output decreased from >3 L/24 hr at the time of discharge from the hospital to approximately 1 L/24 hr, which was the volume that she voided before the

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76 Annals o f Clinical & Laboratory Science

renal transplant. Laboratory data included potassium6.4 mM/L, urea nitrogen 103 mg/dl, creatinine 6.0 mg/dl, hematocrit 22.6%, platelets 145,000/mm^, prothrombin time 12.6 sec, and aPTT 15.5 sec. She underwent urgent surgical exploration and was found to have a nonviable renal graft. A transplant nephrectom y was perform ed. M icroscopic examination demonstrated thrombi within the renal vein and artery (Fig. 1) and signs o f acute tubular necrosis. No evidence of acute rejection was found (Fig. 2).

The patient’s past medical history was remarkable for three episodes of thrombosis of A-V access for hemodialysis. Evaluation of her coagulation profile performed after the transplant nephrectomy revealed normal fibrinogen, antithrombin III, protein S, and protein C (both antigen and functional). Tests for lupus anticoagulants and antiphospholipid antibodies were negative. Analysis of genomic DNA with PCR using specific primers indicated the presence of both guanine and adenine at nucleotide 1691, consistent with heterozygous factor V Leiden.

Discussion

Thrombosis of the transplant renal artery and vein is an uncommon complication occurring in 0.5% to 6.2% of renal transplants [2,3]. It usually occurs within several weeks post-transplantation, and almost always results in loss of the graft. Renal graft thrombosis is responsible for one-third to one-half of early graft losses [3]. The only clinical feature of renal graft artery thrombosis is oliguria or anuria with deteriorating renal function, while venous thrombosis is usually associated in addition with hematuria and a painful swollen graft that may progress to rupture and hemorrhage [ 1 ]. The reported causes and conditions associated with renal graft vascular thrombosis are summarized in Table 1.

In this report we present a case of acute renal graft loss due to thrombosis of the renal artery and vein in a patient with a short aPTT and a mutation in factor V (factor V Leiden). Factor V Leiden is a genetic defect (point mutation) in the factor V molecule that confers resistance to proteolysis by activated protein C. The prevalence of the factor V Leiden genotype is 5.7% of U.S.A. Caucasian and 1.2% of African-American populations [5]. It was found in 20% of unselected

Table 1. Causes and conditions associated with renal transplant vascular thrombosis (modified from [2-4]).

Surgical Technical errorsVessel torsion, kinking, or compression

Donor relatedMultiple donor vesselsDiscrepancy in size of donor and recipient vessels Preservation injury Prolonged ischemia times Older and very young donor grafts Female donor grafts Donor’s right kidney

Recipient related Hypotension Volume depletion Diabetes mellitusHigh platelet count and dysfunction Lupus anticoagulants Past history of venous thrombosis “Acceptable” positive crossmatch Renal artery atheroma and stenosis Hyperacute or acute rejection Extension of iliofemoral thrombosis Pediatric recipients Higher preoperative hemoglobin Membranous glomerulonephritis CAPD as pretransplant dialysis mode Prior native nephrectomy

Controversial cyclosporinOKT3 antibody induction therapy

patients evaluated for the first episode of venous thrombosis [6]. Factor V Leiden mutation is the most common abnormality detected in individuals studied for familial thrombophilia [7]. Carriers of this mutation have a 40% cumulative incidence of recurrent venous thromboses within eight years [8].

While the association of factor V Leiden mutation with venous thrombosis is well established, data for arterial thromboses are still not clear, but they may occur in young individuals and in association with other risk factors. Factor V Leiden m utation is associated with a 5- to 10-fold increase in relative risk of venous thrombosis, and the presence of additional risk factors (eg, heterozygous protein C or S deficiency, oral contraceptives, postoperative state) raises the

Renal graft thrombosis 77

Fig. 1. Section o f renal vein (A) and renal artery (B) dem onstrating throm bosis. There is no evidence o f arteritis. (O riginal m agnification 5x, H & E .)

Fig. 2 . Photom icrograph o f k idney show ing no evidence o f rejection. N o interstitial hem orrhage is present. There is tubular d ila tation w ith epithelia l sim plification com patib le w ith ischem ia-ind uced acute tubular necrosis. (O riginal m agnification 5x, H & E .)

78 Annals o f Clinical & Laboratory Science

relative risk of thrombosis 35- to 50-fold. Clearly, hereditary thrombophilic factors (deficiencies of protein C or S, or the presence of factor V Leiden) increase the risk of acute renal allograft rejection. O f the 97 transplant recipients in the Heidenreich, et al study [4], 46 had acute allograft rejection. Fifteen of these patients (8 of 10 with factor V Leiden, 1 of 4 with protein C deficiency, 2 of 2 with protein S deficiency, and 4 of 5 with AT-III deficiency) had rejection associated with a thrombophilic risk factor. In the other 31 patients who showed acute graft rejection, no clotting abnormality was found. In addition, no patient in either group had simultaneous renal artery and vein thrombosis.

A very short aPTT in our patient could be the contributing factor. It was recorded on five separate occasions yielding values of 21.2,22.3,18.5,15.2, and 15-5 sec (reference range: 22.8-33.5 sec). This remarkable consistency excludes artificial effects as a cause of short aPTT. Short aPTT has been reported as a sign of hypercoagulable state [9]. This may reflect the presence of circulating factors Xa, or thrombin, resulting from the coagulation pathway being activated, or early degradation products which are rapidly clottable by thrombin. No association between short aPTT and any specific hypercoagulable state has been described. This is the first documentation o f a markedly shortened aPTT, noted multiple times, and renal artery and vein thrombosis. We believe that the presence of the factor V Leiden mutation and the short aPTT contributed to the vascular graft thrombosis in our patient.

It is unlikely that any other previously described cause of graft vessel thrombosis played a significant role in our case. The patient had an immediate graft function with improving urine output and serum creatinine; no apparent defect of vascular anastomosis was found at the time of nephrectomy, and no signs of rejection were found on histologic examination of the removed graft. A contribution of immunosuppressive therapy to the development of acute graft thrombosis has been challenged [5]. In fact, two recent studies did not find any association between primary renal graft: thrombosis and immunosuppressive agents [2,3]. The usual signs of cyclosporin toxicity, (ie, thrombotic microangiopathy, isometric vacuoles, or arteriolar hyalinosis) were absent.

Conclusion

In conclusion, our case illustrates the importance of a short aPTT in the pretransplant laboratory evaluation. At this point, it may be premature to suggest an extensive coagulation work-up, including assay for factor V Leiden, in patients with short aPTT. Our observation, however, indicates a need for further investigation. We are studying the significance of short aPTT in kidney transplant and dialysis populations.

References

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