Thromboembolic Risk Factors in Patients Undergoing Kidney Transplant: Implication of Abnormally Short Activated Partial Thromboplastin Time

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1 396 Annals of Clinical & Laboratory Science, vol. 33, no. 4, 2003 Thromboembolic Risk Factors in Patients Undergoing Kidney Transplant: Implication of Abnormally Short Activated Partial Thromboplastin Time Nabil G. Guirguis, 1 Chad Eicher, 1 Lynette Hock, 2 James Lynch, 2 Vicki D. Graham, 3 P. R. Rajagopalan, 3 Amal Guirguis, 3 and John Lazarchick 3 1 Internal Medicine Department and 2 Preventive and Societal Medicine Department, University of Nebraska Medical Center, Omaha, Nebraska; 3 Pathology and Transplantation Departments, Medical University of South Carolina, Charleston, South Carolina Abstract. This study was designed to examine the relationship of short activated partial thromboplastin time (aptt) and prothrombin time (PT) to the incidence of thromboembolic events, hereditary and acquired coagulation defects associated with an increased risk of thrombosis, or cardiovascular diseases in patients undergoing renal transplantation. The prevalence of these conditions in our patients (n = 436) was 55%. Forty-two percent of the patients had short aptt or PT. Multivariate analysis revealed that patients with short aptt have an odds ratio (OR) = 2.15, 95% Confidence Interval (CI) ( ) (p =0.0042), and for patients with short PT, an OR = 2.01, 95% CI ( ) (p = 0.052). Our study also suggests that other risk factors, including non-white ethnicity (98% blacks), OR =1.64, 95% CI ( ) (p = 0.047), diabetes mellitus, OR = 2.62, 95% CI ( ) (P = 0.028), and autosomal dominant polycystic kidney disease (ADPKD) (p <0.0001). Short aptt results, or probably short PT results, pre- or post-transplantation may be associated with increased risks for thromboembolism. (received 23 June 2003; accepted 2 July 2003) Keywords: activated partial thromboplastin time, prothrombin time thromboembolism, renal transplantation Introduction Address correspondence to: John Lazarchick, M.D., Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 165 Ashley Avenue, Suite 309, P.O. Box , Charleston, SC 29425, USA; tel ; fax ; lazarj@musc.edu. The most common causes of early renal allograft failure are related to the vasculature, with 1 / 3 to 1 / 2 of early graft losses due to renal graft thrombosis [1]. The incidence of venous thromboembolism in the transplant population is variable, depending on the definition used in the studies [2,3]. Humor et al [4] reported an incidence of %. The incidence of pulmonary embolism was reported to be 2-14%, with a mortality rate of % [4,5]. Inherited and acquired causes of hypercoagulable states along with other secondary causes predispose the patients to thromboembolic diseases. Risk factors for thromboembolic diseases include the presence of factor V Leiden mutation, protein S or C deficiency, lupus anticoagulant, antiphospholipid antibody, prothrombin 20210A gene mutation, anti-thrombin III deficiency, and polymorphism of plasminogen activator inhibitor-1 gene (4G/4G) in the transplanted kidney [2,3,6-12]. Heparin cofactor II deficiency, on the other hand, has been shown not to be a risk factor for thrombosis in renal allograft recipients [13]. In contrast to merely identifying a specific hypercoagulable condition as a risk factor for thrombosis, a recently published case study reported a significantly short aptt (activated partial thromboplastin time) in a renal allograft recipient who was positive for the factor V Leiden mutation and who subsequently developed renal vein and artery thrombosis along with the loss of her graft [14]. This case suggested a possible association between an abnormality in a common laboratory test (ie, the aptt) and development of thrombosis in renal graft recipients. The report prompted the present study of the significance of short aptt and PT test results in renal transplant patients /03/0400/0396 $ by the Association of Clinical Scientists, Inc.

2 Significance of short aptt in renal transplant patients 397 Material and Methods Patients. Patients (n = 598) who received cadaveric (75%) or living-related (25%) kidney grafts between January 1994 and January 1999 in the Transplant Center of The Medical University of South Carolina were investigated. At the time of data collection, the median elapsed period post-transplant was 24 mo. Of the patients, 162 were excluded because they did not have sufficient laboratory tests or sufficient clinical findings to be placed in the case or the control groups. The remaining patients were stratified pre-analysis to 241 patients in the case group that had thromboembolic diseases, coagulation defects, or cardiovascular diseases, and 195 in the control group that had no thromboembolic diseases, cardiovascular diseases, or other conditions that might increase the risk of thrombosis. Patients in the case group had at least one of the following conditions: deep venous thrombosis, recurrent access clotting, pulmonary embolism, kidney graft thrombosis, allograft pancreas thrombosis, previous use of warfarin in the absence of atrial fibrillation, hemolytic uremic syndrome, coagulation defect (protein C or protein S deficiency, antithrombin III deficiency), or objective evidence of myocardial insult (defined as a history of myocardial infarction, coronary artery bypass surgery, or coronary angioplasty). Patients in the control group did not have the above conditions or any other conditions that might increase the risk of thromboembolism. These conditions included pulmonary hypertension, questionable ventilation perfusion scan, chest pain, foot gangrene, calciphylaxis, cerebrovascular accident, extremity embolism, malignancy, foot amputation, peripheral arterial disease, vascular insufficiency of the intestine, abnormal renal transplant scan consistent with partial infarction, or avascular necrosis of hip joints. History of coumadin use was used as indirect evidence of a thrombotic event, after excluding the patients with atrial fibrillation. Methods. This study investigated the relationships of short activated partial thromboplastin (aptt) and prothrombin (PT) times to the thromboembolic events cited above, from the time that the patients were in renal failure to the time post-transplantation. The duration of the study was up to 9 years. All the patients who received kidney, or kidney and pancreas, transplants between January 1994 and January 1999 were included. Retrospectively, the hospital charts, electronic records in the patient information system, and the ICD-9 codes were scrutinized since Short aptt and PT results during this time period were recorded, as well as the laboratory reference ranges. The cases and controls were sampled during concurrent time periods. Specimens were collected from the cases from June 1993 to February 1999 and from the controls from June 1993 to January The median number of days between assay of both PT and aptt and transplant was 0, ranging from 3.6 yr pre- to 4.9 yr post-transplant for aptt, (interquartile range = 12 days), and 4.6 yr pre- to 5.1 yr post-transplant for PT (interquartile range = 1 day). The normal reference ranges for aptt and PT test results were modified periodically as reagent lots for these assays were changed in the hematology laboratory, based upon a routine protocol with blood samples from healthy volunteers (n = 20-40). The case and control samples were all analyzed at the time of sample collection and no values were obtained on frozen/thawed specimens. Measurements were performed with a coagulation analyzer (MLA 1600 instrument) throughout this study. Correlation studies were done with any new reagent compared to the old reagent. The aptt and the PT test results were considered to be short if they were less than the lower limits of the reference ranges. It is unlikely that variations in the sampling process or assay technique would bias the association under investigation, because no difference was found between the cases and controls in respect to the laboratory control values (Table 1). Statistical analysis. SAS software, version 8, was used for the data analysis. For comparison of groups, t-tests, Wilcoxon s rank sum test, and Fisher s exact test were used for univariate analysis. For multivariate analysis, multiple logistic regression was used. All tests were two-sided. The level of statistical significance was defined as p <0.05. The patients race was classified as either as white or non-white.

3 398 Annals of Clinical & Laboratory Science Table 1. Univariate analysis of the renal transplant patients characteristics and parameters. Characteristic or parameter Comparison Cases Controls p value n (%) n (%) Number (total = 436) 241 (55%) 195 (45%) Laboratory lowest reference range of PT median range Laboratory lowest reference range of aptt median range Age at renal transplant (yr) mean ± SD 42.0 ± ± Gender female 101 (42%) 96 (49%) 0.15 Race non-white 156 (65%) 107 (55%) Diabetes mellitus present 34 (14%) 12 (6%) * Assay for CMV antibodies positive 190 (80%) 135 (72%) Autosomal dominant polycystic kidney disease present 64 (27%) 18 (9%) <0.0001* *Patients in the case group had significantly higher prevalences of diabetes mellitus and autosomal dominant polycystic kidney disease (ADPKD) than the patients in the control group (p <0.05). The non-white group included 3 hispanics, 257 blacks, and 3 others. Results Table 1 contains demographic information for the cases and controls. Patients in the case group had higher prevalences of diabetes mellitus and ADPKD (p = , and <0.0001, respectively). The prevalence of at least one condition described in the case group (thromboembolic diseases, coagulation defects, or cardiovascular diseases) was 55%. Forty two percent of the entire group had a short aptt or PT. The prevalence of short aptt was 35% and that of short PT was 14%. Seven percent of the patients had both short aptt and short PT results. The prevalence of short aptt in the case and control groups was 39% and 29%, respectively. The prevalence of short PT in the case and control groups was 17% and 11%, respectively. When the prevalences of the short aptt and short PT in the case and the control groups were compared, short aptt were found to be greater in the cases (p = 0.020) and short PT was marginally greater (p=0.073) (Table 2). When the median aptt and PT of the lowest laboratory reference range values for the cases were compared to the lowest laboratory reference range values for the controls, there were no significant differences (Table 1). On the other hand, PT values for the cases (median = 11.2 sec) were significantly shorter than for the controls (median = 11.4 sec, p = 0.043). A marginal difference was found for the aptt (p = 0.072). Since some of the cases were receiving coumadin, the difference between cases and controls may be underestimated. The proportions and values of cases with normal PT and aptt would likely be lower in the absence of treatment. After adjustment for age at transplant, race (white versus non-white), gender, and diabetes mellitus, the odds ratio (OR) as an independent risk factor for thromboembolic diseases in patients with short aptt was 2.15, 95% CI ( ) (p = ), and in patients with short PT was 2.01, 95% CI ( ) (p = 0.052). Other OR values were as follows: in males = 1.76, 95% CI ( ) (p = 0.024), in non-white subjects (98% blacks) = 1.64, 95% CI ( ) (p = 0.047), and for in patients with diabetes mellitus = 2.62 ( ) (p = 0.028) (Table 3). The association

4 Significance of short aptt in renal transplant patients 399 Table 2. Comparisons between the prevalences of short PT and short aptt results in the cases and controls. Parameter Comparison Cases Controls p value n (%) n (%) Short PT (count) less than normal 41 (17%) 21 (11%) normal 199 (83%) 174 (89%) Short aptt (count) less than normal 95 (39%) 56 (29%) 0.020* normal 146 (61%) 139 (71%) *Patients in the case group had significantly higher prevalence of short aptt results than the patients in the control group (p <0.05). of autosomal dominant polycystic kidney disease (ADPKD) was highly significant in the univariate analysis (p <0.0001) (Table 1). Discussion Assays for aptt and PT are routinely performed on patients before renal transplant surgery to check for an increased risk for bleeding, but the significance of short aptt and PT results are not fully understood in this population. This paper highlights short aptt and/or PT results as indicators of increased risk for thromboembolic events in this group. This study shows that the prevalence of thromboembolic diseases, hereditary or acquired coagulation defects associated with increased risk for thrombosis, or cardiovascular diseases is very high in this population. Furthermore, it suggests that they are related to excess morbidity and probably to excess mortality observed in these patients. This paper considers other risk factors including non-white race, ADPKD, and diabetes. Diabetes mellitus was found by Ohio et al [15] to be associated with renal vein thrombosis in the kidney transplant population. The implications of thrombosis are grave and sometimes result in loss of the graft [1,14]. Moreover, the risk factors for thromboembolic diseases might be related to acute rejection and probably to long-term graft survival. A retrospective study by Heidenreich et al [16] found a relationship between hypercoagulable state risk factors and acute rejection in renal allograft recipients. Other investigators have studied the potential association between short aptt and risk of thrombosis in non-transplant populations. McKenna et al [17] conducted a prospective clinical Table 3. Multivariate analysis using logistic regression. Variables Odds ratio 95% CI p value Short PT Short appt * Age (1 yr increase) Non-white * Male * Diabetes mellitus * * p < After correcting for other risk factors, short aptt is an independent risk factor for thromboembolic diseases in renal transplant patients. trial examining a short aptt result as a risk factor for thrombosis. The study showed 10-fold increased risk of thromboembolism in study subjects with a short aptt. Edson et al [18] reported that short aptt results are indicative of increased levels of procoagulants, and the increased procoagulants were associated with thrombosis. Landi et al [19] found that short aptt results were associated with deep venous thromboses in acute stroke patients, while Gallus et al [20] found that short aptt results preand post-operation were predictive of post-operative thrombosis. In contrast to these studies, Belliveau [21] reported that upon review of clinical records it was found that patients with extremely short aptt results had a history of spontaneous bleeding. A recent study by Korte et al [22] examined the relationship between short aptt results and thrombosis. They found in a general patient population that subjects with short aptt results were at increased risk for thromboembolism.

5 400 Annals of Clinical & Laboratory Science Our previous case report [14] suggested that short aptt might be a risk factor for thrombosis in kidney transplant patients. The current study supports the importance of short aptt results, and possibly of short PT results, pre- or posttransplantation, as risk factors for thromboembolic diseases, coagulation defects, or cardiovascular diseases in the renal transplant population. Short aptt results, or probably short PT results, pre- or post-transplantation appear to carry increased risks for thromboembolic diseases or cardiovascular diseases. These are prevalent problems that are associated with high morbidity and probably with high mortality in the renal transplant population. Further investigations are needed to characterize the pre- and the post-transplant patients according to their risk factors. References 1. Bakir N, Sluiter WJ, Ploeg RJ, van Son WJ, Tegzess AM. Primary renal graft thrombosis. Nephrol Dial Transplant 1996;11: Oh J, Schaefer F, Veldmann A, Nowak G, Nowak-Gottl U, Tonshoff B, et al. Heterozygous prothrombin gene mutation: a new risk factor for early renal allograft thrombosis. Transplantation 1999;68: Ekberg H, Svensson PJ, Simanaitis M, Dahlback B. Factor V R506Q mutation (activated protein C resistance) is an additional risk factor for early renal graft loss associated with acute vascular rejection. Transplantation 2000;69: Humar A, Johnson EM, Gillingham KJ, Sutherland DE, Payne WD, Dunn DL, et al. Venous thromboembolic complications after kidney and kidney-pancreas transplantation: a multivariate analysis. Transplantation 1998;65: Arnadottir M, Bergentz SE, Bergqvist D, Husberg B, Konrad P, Lindholm T. Thromboembolic complications after renal transplantation: a retrospective analysis. World J Surg 1983;7: Irish AB, Green FR, Gray DW, Morris PJ. The factor V Leiden (R506Q) mutation and risk of thrombosis in renal transplant recipients. Transplantation 1997;64: Simioni P, Prandoni P, Lensing AW, Scudeller A, Sardella C, Prins MH, et al. The risk of recurrent venous thromboembolism in patients with an Arg506 Gln mutation in the gene for factor V (factor V Leiden). N Engl J Med 1997;336: Vaidya S, Wang CC, Gugliuzza C, Fish JC. Relative risk of post-transplant renal thrombosis in patients with antiphospholipid antibodies. Clin Transplant 1998;12: Knight RJ, Schanzer H, Rand JH, Burrows L. Renal allograft thrombosis associated with the antiphospholipid antibody syndrome. Transplantation 1995;60: Wagenknecht DR, Fastenau DR, Torry RJ, Carter CB, Haag BW, McIntyre JA. Antiphospholipid antibodies are a risk factor for early renal allograft failure: isolation of antiphospholipid antibodies from a thrombosed renal allograft. Transplant Proc 1999;31: Wang Y, Turner N, An SF, Fleming KA, Thompson EM. Gene expression of plasminogen activator inhibitor 1 in transplant kidneys complicated by renal vein thrombosis: a combined study by in-situ hybridization and immunohistochemistry. Nephrol Dial Transplant 1994;9: Penny MJ, Nankivell BJ, Disney AP, Byth K, Chapman JR. Renal graft thrombosis. A survey of 134 consecutive cases. Transplantation 1994;58: Toulon P, Moulonguet-Doleris L, Costa JM, Aiach M. Heparin cofactor II deficiency in renal allograft recipients: no correlation with the development of thrombosis. Thromb Haemost 1991;65: Guirguis N, Budisavljevic MN, Self S, Rajagopalan PR, Lazarchick J. Acute renal artery and vein thrombosis after renal transplant, associated with a short partial thromboplastin time and factor V Leiden mutation. Ann Clin Lab Sci 2000;30: Ojo AO, Hanson JA, Wolfe RA, Agodoa LY, Leavey SF, Leichtman A, et al. Dialysis modality and the risk of allograft thrombosis in adult renal transplant recipients. Kidney Int 1999;55: Heidenreich S, Dercken C, August C, Koch HG, Nowak- Gottl U. High rate of acute rejections in renal allograft recipients with thrombophilic risk factors. J Am Soc Nephrol 1998;9: McKenna R, Bachmann F, Miro-Quesada M. Thromboembolism in patients with abnormally short activated partial thromboplastin time. Thromb Haemost 1977;38: Edson JR, Krivit W, White JG. Kaolin partial thromboplastin time: high levels of procoagulants producing short clotting times or masking deficiencies of other procoagulants or low concentrations of anticoagulants. J Lab Clin Med 1967;70: Landi G, D Angelo A, Boccardi E, Candelise L, Mannucci PM, Morabito A, et al. Venous thromboembolism in acute stroke. Prognostic importance of hypercoagulability. Arch Neurol 1992;49: Gallus AS, Hirsh J, Gent M. Relevance of preoperative and postoperative blood tests to postoperative leg-vein thrombosis. Lancet 1973;2: Belliveau RR. Extremely shortened activated partial thromboplastin times. JAMA 1980;243: Korte W, Clarke S, Lefkowitz JB. Short activated partial thromboplastin times are related to increased thrombin generation and an increased risk for thromboembolism. Am J Clin Pathol 2000;113: