- Email: [email protected]
Antithymocyte Antibody–Induced Coagulopathy in Renal Transplant Recipients
Antithymocyte Antibody–Induced Coagulopathy in Renal Transplant Recipients N.F. Siparsky, R. Klein, L.F. Kushnir, M.H. Gallichio, and D.J. Conti ABSTRACT Background. Antithymocyte antibody (ATA) remains the most commonly used induction immunosuppressive agent in renal transplantation (RT). To date, few case reports of ATA-induced coagulopathy exist. Methods. We performed a single-center, retrospective analysis of renal transplant recipients (RTRs) who underwent RT followed by ATA therapy between 2007 and 2011. The protocol used for deceased donor and unrelated living donor recipient immunosuppression was Thymoglobulin (TMG), methylprednisolone, Cellcept, Prograf, and Rapamune. In related living donor recipients, Simulect (SIM) was substituted for TMG. The international normalized ratio (INR) was routinely checked on days 0 and 2, and thereafter at the discretion of the surgeon. RTRs were transfused packed red blood cells (PRBCs) or fresh frozen plasma (FFP) at the discretion of the surgeon. Results. During the study period, 257 RTs were performed at our institution. The following 18 RTR were excluded: simultaneous kidney and pancreas transplant recipients (4), RTRs on warfarin at the time of admission (2), RTRs who received OKT3 (2), and RTRs with INR ⱖ 1.2 at the time of admission (10). Of the remaining 239 RTR, 208 (87%) underwent TMG induction therapy; 31 RTR (13%) underwent SIM induction therapy. The mean INR peaked in both groups on day 4 but was higher in TMG recipients (TMG 1.35, SIM 1.20). FFP was transfused in 65 TMG (31%) and 3 SIM (10%) recipients (P ⫽ .01); PRBCs were transfused in 88 TMG (44%) and 6 SIM (19%) recipients (P ⫽ .02). No patients returned to the operating room for bleeding complications within 7 days of RT. Patient age, gender, ethnicity, and diabetes status were not statistically significant factors in the development of coagulopathy. Conclusion. TMG administration is associated with coagulopathy. Using an INR screening protocol and an aggressive transfusion protocol, bleeding complications associated with coagulopathy can be avoided in this higher-risk group. NTITHYMOCYTE antibody (ATA) is commonly used for induction therapy in deceased donor renal transplantation (RT) as well as living donor RT.1 Although it remains to be approved for this use by the United States Food and Drug Administration, ATA is widely used for induction therapy because of its efficacy in preventing allograft rejection and promoting allograft tolerance in both living donor and deceased donor RT.2,3 ATA is a potent polyclonal antibody therapy with numerous well-described acute and long-term effects. Early case series dating back to the 1960s reported transfusion reactions using horse-derived antilymphocyte globulin of vari-
A
able severity in every recipient, ranging from fever to anaphylaxis.4 The equine preparation5 is currently available under the trademark Atgam® (Pfizer; New York,
From the Section of Transplantation, Department of Surgery, Albany Medical College (N.F.S., R.K., M.H.G., D.J.C.), Albany, NY; and the South Jersey Regional Medical Center Physicians of Southern New Jersey (L.K.), Vineland, NJ. Address reprint requests to Nicole F. Siparsky, MD, Department of Surgery, Section of Transplantation, Albany Medical College, 47 New Scotland Ave., MC61GE, Albany, NY 12208. E-mail: [email protected]
© 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter http://dx.doi.org/10.1016/j.transproceed.2012.10.057
Transplantation Proceedings, 45, 1531–1534 (2013)
1531
1532
SIPARSKY, KLEIN, KUSHNIR ET AL
New York); it is licensed for the treatment of aplastic anemia and it is not commonly used in RT. Today, the most commonly used antibody preparation in RT induction therapy is the rabbit variety of ATA, anti-thymocyte globulin (rabbit), which is available under the trademark Thymoglobulin® (TMG) and is manufactured by Genzyme (Cambridge, MA). Acute transfusion reactions with ATA remain common, including acute cytokine release syndrome. At the hematologic level, lymphopenia and thrombocytopenia are also routinely observed.6 However, to date, few case reports of ATA-induced coagulopathy exist in the solid organ transplantation literature.7 METHODS Participant Selection
Immunosuppression Protocol The induction protocol used for deceased donor and unrelated living donor recipients was TMG at 5 mg/kg in divided doses over days 1 through 6, and methylprednisolone 1000 mg in divided doses over days 1 through 6. In related living donor recipients, Simulect® (SIM) which is manufactured by Novartis (East Hanover, NJ), was substituted for TMG (40 mg in divided doses on days 0 and 4). For recipients with an ATA allergy, OKT3 was administered. Most patients underwent an early steroid withdrawal with cessation of steroids on postoperative day 6. In most cases, maintenance immunotherapy consisted of mycophenolate mofetil (Cellcept® by Genentech; San Francisco, CA), tacrolimus (Prograf® by Astellas; Northbrook, IL), and sirolimus (Rapamune® by Pfizer; New York, New York). Oral methylprednisolone therapy was substituted for sirolimus in patients who were receiving steroids before transplantation, suffered from delayed graft function, or whose underlying renal disorder was focal segmental glomerulosclerosis. Mean INR by Day
1.40 1.35
Mean INR
Data for Figure 1 Thymoglobulin 0.98 1.03 1.1 1.22 1.35 1.26 1.17 1.16
Day 0 1 2 3 4 5 6 7
1.25 1.20 1.15 1.10 1.05 1.00 0.95
Simulect 0.99 1.05 1.05 1.18 1.2 1.13 1.1 1.2
0.90 0
1
Transfusion
FFP PRBC
Thymoglobulin
Simulect
P Value
65 (31%) 88 (42%)
3 (10%) 6 (19%)
.01 .02
Coagulopathy Screening and Treatment Protocol The INR was routinely checked on days 0 and 2, and thereafter at the discretion of the surgeon (Figure 1). To avoid complications of bleeding and anemia, patients were transfused fresh frozen plasma (FFP) and red blood cells (RBC) at the discretion of the surgeon (Table 1).
Statistical Analysis
We performed a single-center, retrospective analysis of renal transplant recipients (RTRs) who underwent RT at our institution between 2007 and 2011. All RTRs underwent induction during or immediately after RT using a combination of antibody and corticosteroid therapy. All RTRs were considered for inclusion in the study. The following exclusion criteria were applied to these patients: simultaneous kidney and pancreas transplant recipients, those who had warfarin therapy at the time of admission, those administered Muromonab-CD3 (Orthoclone OKT3® by Janssen Pharmaceutica; no longer available in the United States) induction therapy, and those with and international normalized ratio (INR) ⱖ 1.2 at the time of admission.
1.30
Table 1. Transfusion After Renal Transplantation (Days 1 Through 7)
2
3
4
5
6
Postoperave Day Thymoglobulin
Simulect
Fig 1. Mean international normalized ratio.
7
The patient demographics, laboratory values, warfarin status, and donor type were compared between TMG and SIM recipients. A Student t test and chi-squared test were used to compare means and proportions across categories. All statistical analyses were performed using Stata software version 11.1® (Statacorp; College Station, TX).
RESULTS Demographics
During the study period, 247 RT were performed at our institution; 18 of these were excluded because they met one or more exclusion criteria: simultaneous kidney and pancreas transplant recipient (n ⫽ 4), warfarin therapy at the time of admission (n ⫽ 2), OKT3 induction therapy (n ⫽ 2), or INR ⱖ 1.2 at the time of admission (n ⫽ 10). Patient age, gender, ethnicity, and diabetes status were not statistically significant factors in the development of TMG coagulopathy. The demographics of the two groups based on induction therapy are displayed in Table 2. Induction Therapy and Coagulopathy
Of the remaining 239 recipients, 208 patients (87%) underwent TMG induction therapy, whereas 31 patients (13%) underwent SIM induction therapy. TMG efficacy was determined by the severity of lymphocyte (LYM) depletion observed in the first 7 days after RT. Persistent LYM depletion was observed from days 0 to 7 in TMG recipients (⌬LYM ⫽ 19%; P ⫽ .00), whereas early LYM reconstitution was observed in the SIM group (⌬LYM ⫽ 4%; P ⫽ .02). A change in the mean INR was observed in the TMG group from days 0 to 2 (⌬INR2 ⫽ 0.12, P ⫽ .00) and from days 0 to 3 (⌬INR3 ⫽ 0.23, P ⫽ 0.00). The mean INR peaked in both groups on day 4; the peak mean INR was higher in TMG recipients (TMG 1.31, SIM 1.07). The peak mean INR was ⱖ 1.3 in 71 (33%) and 3 (9%) of TMG and SIM recipients, respectively (P ⫽ 0.01). The peak mean INR was ⱖ 1.5 in 43 (20%) and 1 (3%) of TMG and SIM recipients, respectively (P ⫽ .02). The trends in INR for the two groups based on induction therapy are displayed in Table 3 and Fig 1.
ATA-INDUCED COAGULOPATHY
1533
Table 2. Patient Demographics Demographic Variable
Average age (y) Male Diabetes Ethnicity White African American Other
Thymoglobulin (n ⫽ 208)
Simulect (n ⫽ 31)
51.7 123 (59%) 66 (66%)
46.6 22 (71%) 13 (41%)
166 (80%) 23 (11%) 19 (9%)
28 (90%) 2 (7%) 1 (3%)
P Value
.37 .21 .26 .36
FFP was transfused in 65 TMG (31%) and 3 SIM (10%) recipients within 1 week of surgery (P ⫽ .01). Packed RBCs (PRBCs) were transfused in 88 TMG recipients (42%) and 6 SIM recipients (19%). The rates of transfusion of PRBC and FFP are displayed in Table 1. No patients returned to the operating room for bleeding complications within 7 days of transplantation. DISCUSSION
Few case reports of ATA-induced coagulopathy exist in the solid organ transplantation literature. In 1996, Trivedi et al described two cases of coagulopathy during equine ATA therapy, which is no longer used for induction therapy in RT. The remainder of reported cases can be found in the hematopoietic stem cell transplantation (HSCT) literature.8 In one series of 12 patients reported by Weber,9 rabbit ATA therapy was associated with a host of coagulation derangements, including an increase in D-dimer, tissue factor, thrombin-antithrombin III complex, and thrombomodulin. However, in the Weber series, no global coagulation abnormality was detected. This pattern was attributed to disseminated intravascular coagulation (DIC) in the setting of HSCT. It is difficult to draw parallels between solid organ and HSCT recipients using this limited data and hypothesis. However, cytokine release syndrome is a common side effect of ATA transfusion. In critically ill patients, cytokine release is associated with derangements in fibrinolysis and coagulation, similarly attributed to DIC. It has been suggested by Pihusch10 that disturbances in coagulation after ATA administration in HSCT can be attributed to DIC, much like DIC is observed in critically ill patients. He cites reduced antithrombin levels, lengthening of the prothrombin time, and elevated D-dimer levels within 24 hours of administration of ATA in his argument. We were unable to identify any case reports detailing this phenomenon in solid organ transplantation recipients. It would be difficult to ascertain the cause of derangements of these compounds in the postsurgical patient, in whom an elevation in D-dimer levels and an elevation in cytokine levels is routinely observed. Bleeding diathesis is common in the renal failure population. In most patients, this phenomenon is multifactorial. First, uremic platelet dysfunction is a universal phenomenon. Second, rapid volume loading occurs at the time of
transplantation, leading a dilution of clotting factors which results in dilutional coagulopathy. Third, the administration of heparin during dialysis may result in coagulopathy at the time of, or shortly after, surgery. Fourth, most patients with renal failure also suffer from coronary or peripheral arterioocclusive disease. Such patients are often prescribed antiplatelet agents (eg, aspirin or clopidogrel) which cause further platelet dysfunction. Finally, some patients fail to thrive on dialysis; these malnourished patients may suffer from coagulopathy due to vitamin K deficiency. These issues might place a patient at risk for TMG-associated coagulopathy after RT. However, we were unable to show this relationship. Using screening INR, we were unable to identify a statistically significant trend between preoperative INR and postoperative coagulopathy in the study group. Our INR screening protocol was effective in showing TMG-associated coagulopathy in RTRs. Similarly, our INR screening protocol, combined with aggressive FFP and PRBC transfusion, appeared to be effective in preventing post-transplantation bleeding requiring reoperation. With this protocol, 68 patients (28.5%) received FFP within 1 week of surgery, 94 patients (39%) received PRBC within 1 week of surgery, and no patient returned to the operating room for bleeding. There are a number of limitations to this study. First, this is not a prospective, randomized, blinded trial. Our patient population is a small one, derived from a single-center experience in a retrospective fashion. Second, the surgeon’s decision to use FFP transfusion was not a standardized one; it depended on variables such as comorbid conditions (eg, obesity), procurement conditions (eg, donation after cardiac death, long ischemia time), or transplantation conditions (eg, narrow arterial anastomosis, low recipient blood pressure). A standard FFP transfusion dosing schedule was not used. Fourth, we used a warfarin-free protocol for wait-listed patients who were in competitive range for organ offers; transplant candidates were transitioned from warfarin to high-dose twice daily subcutaneous heparin to avoid medication-induced coagulopathy during, and immediately after transplantation. In this way, we excluded few patients from our study group. For programs that have transplantation patients who take warfarin, this protocol might not be efficacious. Finally, further studies will be needed to corroborate our findings and to elucidate this phenomenon at a molecular level. Table 3. Trends in INR INR Trend
Thymoglobulin
Simulect
⌬ INR (day 0 to day 2) ⌬ INR (day 0 to day 3) Mean INR peak Peak INR ⱖ 1.3 Peak INR ⱖ 1.5
0.12 (P ⫽ .00))
0.05 (P ⫽ .28)
0.23 (P ⫽ .00)
0.18 (P ⫽ .19)
1.31 (day 4) n ⫽ 71 (55%) n ⫽ 43 (20%)
1.07 (day 4) n ⫽ 3 (9%) n ⫽ 1 (3%)
Abbreviation: INR, international normalized ratio.
P Value
.01 .03
1534
REFERENCES 1. Gaber A, Knight R, Patel S, Gaber L. A review of the evidence for use of thymoglobulin induction in renal transplantation. Transplant Proc. 2010;42:1395–1400. 2. Gaber A, Matas A, Henry M, Brennan D, Stevens R, Kapur S, et al. Antithymocyte globulin induction in living donor renal transplant recipients: final report of the TAILOR Registry. Transplantation. 2012;94(4):331–337. 3. Wagner S, Brennan D. Induction therapy in renal transplant recipients: how convincing is the current evidence? Drugs. 2012; 72(5):671– 683. 4. Starzl T, Marchioro T, Hutchison D, Porter K, Cerilli G, et al. The clinical use of antilymphocyte globulin in renal homotransplantations. Transplantation. 1967;5:1100 –1105. 5. Starzl T, Brettschneider L, Penn I, Schmidt R, Bell P, et al. A trial with heterologous antilymphocyte globulin in man. Transplant Proc. 1969;1(1):448 – 454.
SIPARSKY, KLEIN, KUSHNIR ET AL 6. Moicean A, Popp A, Sinescu I. Thymoglobulin—new approaches to optimal outcomes. J Med Life. 2009;2(3):319 –324. 7. Trivedi H, Lal S, Gupta N, Ross G Jr. Atgam associated coagulopathy in renal transplant patients: a report of two unusual cases. Int J Artif Organs. 1996;19(8):448 – 450. 8. Pihusch R, Holler E, Muhlbayer D, Gohring P, Stotzer O, Pihusch M, et al. The impact of antithymocyte globulin on shortterm toxicity after allogeneic stem cell transplantation. Bone Marrow Transplant. 2002;30(6):347–354. 9. Weber M, Kroger N, Langer F, Hansen A, Zabelina T, et al. Non-overt disseminated intravascular coagulation in patients during treatment with antithymocyte globulin for unrelated allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2003;31(9):817– 822. 10. Pihusch M. Bleeding complications after hematopoietic stem cell transplantation. Semin Hematolo 2004;41(1:supp 1):93–100.
A
able severity in every recipient, ranging from fever to anaphylaxis.4 The equine preparation5 is currently available under the trademark Atgam® (Pfizer; New York,
From the Section of Transplantation, Department of Surgery, Albany Medical College (N.F.S., R.K., M.H.G., D.J.C.), Albany, NY; and the South Jersey Regional Medical Center Physicians of Southern New Jersey (L.K.), Vineland, NJ. Address reprint requests to Nicole F. Siparsky, MD, Department of Surgery, Section of Transplantation, Albany Medical College, 47 New Scotland Ave., MC61GE, Albany, NY 12208. E-mail: [email protected]
© 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter http://dx.doi.org/10.1016/j.transproceed.2012.10.057
Transplantation Proceedings, 45, 1531–1534 (2013)
1531
1532
SIPARSKY, KLEIN, KUSHNIR ET AL
New York); it is licensed for the treatment of aplastic anemia and it is not commonly used in RT. Today, the most commonly used antibody preparation in RT induction therapy is the rabbit variety of ATA, anti-thymocyte globulin (rabbit), which is available under the trademark Thymoglobulin® (TMG) and is manufactured by Genzyme (Cambridge, MA). Acute transfusion reactions with ATA remain common, including acute cytokine release syndrome. At the hematologic level, lymphopenia and thrombocytopenia are also routinely observed.6 However, to date, few case reports of ATA-induced coagulopathy exist in the solid organ transplantation literature.7 METHODS Participant Selection
Immunosuppression Protocol The induction protocol used for deceased donor and unrelated living donor recipients was TMG at 5 mg/kg in divided doses over days 1 through 6, and methylprednisolone 1000 mg in divided doses over days 1 through 6. In related living donor recipients, Simulect® (SIM) which is manufactured by Novartis (East Hanover, NJ), was substituted for TMG (40 mg in divided doses on days 0 and 4). For recipients with an ATA allergy, OKT3 was administered. Most patients underwent an early steroid withdrawal with cessation of steroids on postoperative day 6. In most cases, maintenance immunotherapy consisted of mycophenolate mofetil (Cellcept® by Genentech; San Francisco, CA), tacrolimus (Prograf® by Astellas; Northbrook, IL), and sirolimus (Rapamune® by Pfizer; New York, New York). Oral methylprednisolone therapy was substituted for sirolimus in patients who were receiving steroids before transplantation, suffered from delayed graft function, or whose underlying renal disorder was focal segmental glomerulosclerosis. Mean INR by Day
1.40 1.35
Mean INR
Data for Figure 1 Thymoglobulin 0.98 1.03 1.1 1.22 1.35 1.26 1.17 1.16
Day 0 1 2 3 4 5 6 7
1.25 1.20 1.15 1.10 1.05 1.00 0.95
Simulect 0.99 1.05 1.05 1.18 1.2 1.13 1.1 1.2
0.90 0
1
Transfusion
FFP PRBC
Thymoglobulin
Simulect
P Value
65 (31%) 88 (42%)
3 (10%) 6 (19%)
.01 .02
Coagulopathy Screening and Treatment Protocol The INR was routinely checked on days 0 and 2, and thereafter at the discretion of the surgeon (Figure 1). To avoid complications of bleeding and anemia, patients were transfused fresh frozen plasma (FFP) and red blood cells (RBC) at the discretion of the surgeon (Table 1).
Statistical Analysis
We performed a single-center, retrospective analysis of renal transplant recipients (RTRs) who underwent RT at our institution between 2007 and 2011. All RTRs underwent induction during or immediately after RT using a combination of antibody and corticosteroid therapy. All RTRs were considered for inclusion in the study. The following exclusion criteria were applied to these patients: simultaneous kidney and pancreas transplant recipients, those who had warfarin therapy at the time of admission, those administered Muromonab-CD3 (Orthoclone OKT3® by Janssen Pharmaceutica; no longer available in the United States) induction therapy, and those with and international normalized ratio (INR) ⱖ 1.2 at the time of admission.
1.30
Table 1. Transfusion After Renal Transplantation (Days 1 Through 7)
2
3
4
5
6
Postoperave Day Thymoglobulin
Simulect
Fig 1. Mean international normalized ratio.
7
The patient demographics, laboratory values, warfarin status, and donor type were compared between TMG and SIM recipients. A Student t test and chi-squared test were used to compare means and proportions across categories. All statistical analyses were performed using Stata software version 11.1® (Statacorp; College Station, TX).
RESULTS Demographics
During the study period, 247 RT were performed at our institution; 18 of these were excluded because they met one or more exclusion criteria: simultaneous kidney and pancreas transplant recipient (n ⫽ 4), warfarin therapy at the time of admission (n ⫽ 2), OKT3 induction therapy (n ⫽ 2), or INR ⱖ 1.2 at the time of admission (n ⫽ 10). Patient age, gender, ethnicity, and diabetes status were not statistically significant factors in the development of TMG coagulopathy. The demographics of the two groups based on induction therapy are displayed in Table 2. Induction Therapy and Coagulopathy
Of the remaining 239 recipients, 208 patients (87%) underwent TMG induction therapy, whereas 31 patients (13%) underwent SIM induction therapy. TMG efficacy was determined by the severity of lymphocyte (LYM) depletion observed in the first 7 days after RT. Persistent LYM depletion was observed from days 0 to 7 in TMG recipients (⌬LYM ⫽ 19%; P ⫽ .00), whereas early LYM reconstitution was observed in the SIM group (⌬LYM ⫽ 4%; P ⫽ .02). A change in the mean INR was observed in the TMG group from days 0 to 2 (⌬INR2 ⫽ 0.12, P ⫽ .00) and from days 0 to 3 (⌬INR3 ⫽ 0.23, P ⫽ 0.00). The mean INR peaked in both groups on day 4; the peak mean INR was higher in TMG recipients (TMG 1.31, SIM 1.07). The peak mean INR was ⱖ 1.3 in 71 (33%) and 3 (9%) of TMG and SIM recipients, respectively (P ⫽ 0.01). The peak mean INR was ⱖ 1.5 in 43 (20%) and 1 (3%) of TMG and SIM recipients, respectively (P ⫽ .02). The trends in INR for the two groups based on induction therapy are displayed in Table 3 and Fig 1.
ATA-INDUCED COAGULOPATHY
1533
Table 2. Patient Demographics Demographic Variable
Average age (y) Male Diabetes Ethnicity White African American Other
Thymoglobulin (n ⫽ 208)
Simulect (n ⫽ 31)
51.7 123 (59%) 66 (66%)
46.6 22 (71%) 13 (41%)
166 (80%) 23 (11%) 19 (9%)
28 (90%) 2 (7%) 1 (3%)
P Value
.37 .21 .26 .36
FFP was transfused in 65 TMG (31%) and 3 SIM (10%) recipients within 1 week of surgery (P ⫽ .01). Packed RBCs (PRBCs) were transfused in 88 TMG recipients (42%) and 6 SIM recipients (19%). The rates of transfusion of PRBC and FFP are displayed in Table 1. No patients returned to the operating room for bleeding complications within 7 days of transplantation. DISCUSSION
Few case reports of ATA-induced coagulopathy exist in the solid organ transplantation literature. In 1996, Trivedi et al described two cases of coagulopathy during equine ATA therapy, which is no longer used for induction therapy in RT. The remainder of reported cases can be found in the hematopoietic stem cell transplantation (HSCT) literature.8 In one series of 12 patients reported by Weber,9 rabbit ATA therapy was associated with a host of coagulation derangements, including an increase in D-dimer, tissue factor, thrombin-antithrombin III complex, and thrombomodulin. However, in the Weber series, no global coagulation abnormality was detected. This pattern was attributed to disseminated intravascular coagulation (DIC) in the setting of HSCT. It is difficult to draw parallels between solid organ and HSCT recipients using this limited data and hypothesis. However, cytokine release syndrome is a common side effect of ATA transfusion. In critically ill patients, cytokine release is associated with derangements in fibrinolysis and coagulation, similarly attributed to DIC. It has been suggested by Pihusch10 that disturbances in coagulation after ATA administration in HSCT can be attributed to DIC, much like DIC is observed in critically ill patients. He cites reduced antithrombin levels, lengthening of the prothrombin time, and elevated D-dimer levels within 24 hours of administration of ATA in his argument. We were unable to identify any case reports detailing this phenomenon in solid organ transplantation recipients. It would be difficult to ascertain the cause of derangements of these compounds in the postsurgical patient, in whom an elevation in D-dimer levels and an elevation in cytokine levels is routinely observed. Bleeding diathesis is common in the renal failure population. In most patients, this phenomenon is multifactorial. First, uremic platelet dysfunction is a universal phenomenon. Second, rapid volume loading occurs at the time of
transplantation, leading a dilution of clotting factors which results in dilutional coagulopathy. Third, the administration of heparin during dialysis may result in coagulopathy at the time of, or shortly after, surgery. Fourth, most patients with renal failure also suffer from coronary or peripheral arterioocclusive disease. Such patients are often prescribed antiplatelet agents (eg, aspirin or clopidogrel) which cause further platelet dysfunction. Finally, some patients fail to thrive on dialysis; these malnourished patients may suffer from coagulopathy due to vitamin K deficiency. These issues might place a patient at risk for TMG-associated coagulopathy after RT. However, we were unable to show this relationship. Using screening INR, we were unable to identify a statistically significant trend between preoperative INR and postoperative coagulopathy in the study group. Our INR screening protocol was effective in showing TMG-associated coagulopathy in RTRs. Similarly, our INR screening protocol, combined with aggressive FFP and PRBC transfusion, appeared to be effective in preventing post-transplantation bleeding requiring reoperation. With this protocol, 68 patients (28.5%) received FFP within 1 week of surgery, 94 patients (39%) received PRBC within 1 week of surgery, and no patient returned to the operating room for bleeding. There are a number of limitations to this study. First, this is not a prospective, randomized, blinded trial. Our patient population is a small one, derived from a single-center experience in a retrospective fashion. Second, the surgeon’s decision to use FFP transfusion was not a standardized one; it depended on variables such as comorbid conditions (eg, obesity), procurement conditions (eg, donation after cardiac death, long ischemia time), or transplantation conditions (eg, narrow arterial anastomosis, low recipient blood pressure). A standard FFP transfusion dosing schedule was not used. Fourth, we used a warfarin-free protocol for wait-listed patients who were in competitive range for organ offers; transplant candidates were transitioned from warfarin to high-dose twice daily subcutaneous heparin to avoid medication-induced coagulopathy during, and immediately after transplantation. In this way, we excluded few patients from our study group. For programs that have transplantation patients who take warfarin, this protocol might not be efficacious. Finally, further studies will be needed to corroborate our findings and to elucidate this phenomenon at a molecular level. Table 3. Trends in INR INR Trend
Thymoglobulin
Simulect
⌬ INR (day 0 to day 2) ⌬ INR (day 0 to day 3) Mean INR peak Peak INR ⱖ 1.3 Peak INR ⱖ 1.5
0.12 (P ⫽ .00))
0.05 (P ⫽ .28)
0.23 (P ⫽ .00)
0.18 (P ⫽ .19)
1.31 (day 4) n ⫽ 71 (55%) n ⫽ 43 (20%)
1.07 (day 4) n ⫽ 3 (9%) n ⫽ 1 (3%)
Abbreviation: INR, international normalized ratio.
P Value
.01 .03
1534
REFERENCES 1. Gaber A, Knight R, Patel S, Gaber L. A review of the evidence for use of thymoglobulin induction in renal transplantation. Transplant Proc. 2010;42:1395–1400. 2. Gaber A, Matas A, Henry M, Brennan D, Stevens R, Kapur S, et al. Antithymocyte globulin induction in living donor renal transplant recipients: final report of the TAILOR Registry. Transplantation. 2012;94(4):331–337. 3. Wagner S, Brennan D. Induction therapy in renal transplant recipients: how convincing is the current evidence? Drugs. 2012; 72(5):671– 683. 4. Starzl T, Marchioro T, Hutchison D, Porter K, Cerilli G, et al. The clinical use of antilymphocyte globulin in renal homotransplantations. Transplantation. 1967;5:1100 –1105. 5. Starzl T, Brettschneider L, Penn I, Schmidt R, Bell P, et al. A trial with heterologous antilymphocyte globulin in man. Transplant Proc. 1969;1(1):448 – 454.
SIPARSKY, KLEIN, KUSHNIR ET AL 6. Moicean A, Popp A, Sinescu I. Thymoglobulin—new approaches to optimal outcomes. J Med Life. 2009;2(3):319 –324. 7. Trivedi H, Lal S, Gupta N, Ross G Jr. Atgam associated coagulopathy in renal transplant patients: a report of two unusual cases. Int J Artif Organs. 1996;19(8):448 – 450. 8. Pihusch R, Holler E, Muhlbayer D, Gohring P, Stotzer O, Pihusch M, et al. The impact of antithymocyte globulin on shortterm toxicity after allogeneic stem cell transplantation. Bone Marrow Transplant. 2002;30(6):347–354. 9. Weber M, Kroger N, Langer F, Hansen A, Zabelina T, et al. Non-overt disseminated intravascular coagulation in patients during treatment with antithymocyte globulin for unrelated allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2003;31(9):817– 822. 10. Pihusch M. Bleeding complications after hematopoietic stem cell transplantation. Semin Hematolo 2004;41(1:supp 1):93–100.