Thrombotic Microangiopathy in Patients with Allogeneic Hematopoietic Stem Cell Transplantation

Background : Transplantation-associated thrombotic microangiopathy (TMA) is infrequent but devastating complications after allogeneic hematopoietic stem cell transplantation (HSCT). However, there were no widely accepted criteria for the definition of TMA. Recently, the Blood and Marrow Transplants Clinical Trials Network (BMT CTN) and International Working Group (IWG) proposed a definition for TMA with some differences. The BMT CTN defined TMA as an increased number of schistocytes (³ 2/high power field (HPF)) and elevated lactate dehydrogenase (LDH), concurrent renal and/or neurologic dysfunction, and negative Coombs’ test results. On the other hand, the IWG defined TMA by adding prolonged or progressive thrombocytopenia, a decrease in hemoglobin and serum haptoglobin concentration instead of concurrent renal and/or neurologic dysfunction and negative Coombs’ test results. In addition, the value of an increased number of schistocytes (³4% or ³ 8/HPF) for diagnosis of TMA by IWG is higher than that by BMT CTN (³ 2/HPF). Until now, there has been no report to validate both criteria for TMA.

Patients and Methods : We retrospectively examined 672 consecutive patients (median age 34 years, range 15–68) who underwent allogeneic HSCT from matched sibling donor (n = 442) and alternative donor (n = 230) at Catholic HSCT Center between January 2002 and December 2006 to analyze the role of some predicting factors for the incidence and outcome of TMA after HSCT and to validate two recently proposed criteria for TMA. We defined TMA as an increased number of schistocytes (³ 2/HPF), elevated LDH, prolonged or progressive thrombocytopenia, a decrease in hemoglobin and serum haptoglobin concentration, and negative Coombs’ test results (O-TMA). O-TMA with renal and/or neurologic dysfunction was compatible with TMA defined by BMT CTN (B-TMA), and O-TMA with increased number of schistocytes over 8/HPF was compatible with TMA defined by IWG (I-TMA). TMA-associated death was defined as the interval from the onset of TMA to death which was associated with TMA without a relapse from underlying diseases after the onset of TMA.

Results : Among 672 patients, 85 patients (13%) developed O-TMA including 41 patients (6%) with B-TMA and 17 patients (3%) with I-TMA. On multivariate analysis, TMA occurrence was higher in patients with older age (P = 0.001), mismatched human leukocyte antigen (P < 0.001), and acute graft-versus-host disease (GVHD) ³ grade II (P < 0.001) for O-TMA, in patients with older age (P = 0.002), advanced disease status at HSCT (P = 0.005), and acute GVHD ³ grade II (P < 0.001) for B-TMA, and advanced disease status at HSCT (P = 0.017) and acute GVHD ³ grade III (P < 0.001) for I-TMA. In patients with O-TMA, patients with renal dysfunction (hazard ratio 4.03, 95% CI 2.38–6.83, P < 0.001) and/or concurrent veno-occlusive disease (hazard ratio 3.16, 95% CI 1.50–6.62, P = 0.002) proved to have significantly decreased overall survival by multivariate analysis. In addition, the presence of renal dysfunction was the only significant factor associated with increased TMA-associated death (hazard ratio 11.61, 95% CI 4.79–28.16, P < 0.001). Maximal schistocytes count over 8/HPF and other factors including sex mismatch, acute GVHD ³ grade III, advanced disease status at HSCT, maximal LDH over 1298 IU/l, neurologic dysfunction, and concurrent cytomegalo virus infection that were significant on univariate analysis failed to show the significance relationship on multivariate analysis.

Conclusions : This study identifies which patients are more prone to developing TMA after allogeneic HSCT according to three definitions for TMA (O-TMA, B-TMA and I-TMA). Notably, using multivariate analysis in patients with O-TMA, this retrospective study shows the importance of renal dysfunction compared to the maximal number of schistocytes count, which suggests that there are possible shortcomings of the definition by I-TMA that can miss out those with schistocytes count less than 8/HPF who may need early detection as a TMA. The proposed definitions of TMA need to be modified and be validated with prospective studies.