- Email: [email protected]
Distribution of Transplantation-Associated Thrombotic Microangiopathy (TA-TMA) and Comparison between Renal TA-TMA and Intestinal TA-TMA: Autopsy Study
ARTICLE IN PRESS Biol Blood Marrow Transplant && (2019) &&&&&&
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Distribution of X XTransplantation-Associated Thrombotic Microangiopathy (TA-TMA) and Comparison between Renal TA-TMA and Intestinal TA-TMA: Autopsy Study
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21X XRin XD YamadaD12X X , D23X XTetsuo NemotoD224X X , D25X XKazuteru OhashiD26X3X , D27X XAkiko TonookaD28X1X , D29X XShin-ichiro HoriguchiD1230X X , D231X XToru MotoiD23X1X , D23X XTsunekazu HishimaD234X1,X *
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Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan 2 Department of Pathology, Showa University Northern Yokohama Hospital, Kanagawa, Japan 3 Department of Hematology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
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74 Article history: Received 26 March 2019 Accepted 21 August 2019
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Keywords: Hematopoietic stem cell transplantation Thrombotic microangiopathy Transplantation-associated thrombotic microangiopathy Graft-versus-host disease Autopsy
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A B S T R A C T Transplantation-associated thrombotic microangiopathy (TA-TMA) is an important complication of hematopoietic stem cell transplantation. To date, information regarding the organs that are affected by TA-TMA as confirmed histologically remains limited; the clinicopathologicD237X Xdifferences between renal TA-TMA and intestinal TA-TMA have not been examined despite being the well-known and commonly affected sites of TA-TMA. We therefore examined 165 autopsied patients after hematopoietic stem cell transplantation and compared the clinicopathologicD238X fX actors of renal and intestinal TA-TMA. It was clear that 38 (23%) of our patients had TA-TMA. In the TA-TMA cases, the kidney (61%) and intestine (53%) were commonly affected, and the ileum and right colon were vulnerable. Other organs that we found to be affected by TA-TMA included the stomach (8%), gallbladder (5%), and oral cavity, pharynx, esophagus, liver, heart, urinary bladder, and ureter (all at 3%), and symptoms thought to be caused by TA-TMA of these organs were not observed in any patient. Histologically, TA-TMA only affected the arteriole, or small arteries, regardless of the organ, and the veins or larger arteries were not affected at all. In the kidney, the glomerular capillary was also affected, D239X X and mesangiolysis and double contours of the basement membranes were often in evidence. The histologicD240X X overlap of renal and intestinal TA-TMA was rare (13%), and the patients in the intestinal TA-TMA group exhibited more frequency of a history of intestinal acute graft-versus-host disease (GVHD) during the clinical courseD241X X compared with that of the renal TA-TMA group (80% versus D24X X 22%, P = .0016). D243X X Although TA-TMA can affect many other organs, the frequency of these ancillary events was low, and the clinical effect may have been small. Our results suggest that in comparison to renal TA-TMA, intestinal GVHD could be more closely associated with intestinal TA-TMA as a risk factor. © 2019 Published by Elsevier Inc. on behalf of the American Society for Transplantation and Cellular Therapy
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INTRODUCTION Thrombotic microangiopathy (TMA) is a syndrome caused by small-Dvessel 24X X endothelial injury and clinically characterized by microangiopathic hemolytic anemia, elevated serum lactate dehydrogenase level, thrombocytopenia, and multiorgan injury [1]. Multiple factors can be the cause of a primary TMA [1]. ADAMTS13 deficiency-mediated TMA or Shiga toxin-mediated TMA are representative, and they have been familiarly called the thrombotic thrombocytopenic purpuraD245X X and Shiga toxin-related hemolytic uremic syndromeD,246X X respectively [2,3]. Secondary TMA can occur in underlying diseases, including
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Financial disclosure: See Acknowledgments on page 11. * Correspondence and reprint requests: Tsunekazu Hishima, X D X epartment of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan. E-mail address: [email protected] (T. Hishima).
infection, cancer, pregnancy, hypertension, and autoimmune diseases. Of particular interest here, transplantation-associated TMA (TA-TMA) is an increasingly recognizedD247X X and occasionally life-threatingD248X X complication of hematopoietic stem cell transplantation (HSCT) [1,4,5]. TA-TMA most commonly affects the kidneys, resulting in renal dysfunction, proteinuria, and hypertension [4-7]. Other organs that have been reported as targets of TA-TMA include the lungs, intestines, and brain, where symptoms include pulmonary hypertension, abdominal pain and bleeding, and various neurologic manifestations [4,8-15]. Clinical criteria proposed by the Blood and Marrow Transplant Clinical Trial Network and the European Group for Blood and Marrow Transplantation have been used in the diagnosis of TA-TMA [16,17], but the unfortunate limitations of the diagnostic sensitivity of these protocols have D249X X been noted [18,19]. D250X X Because there can also be several complications, including graft-versus-host disease (GVHD), infection, and radiationD,251X X as
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https://doi.org/10.1016/j.bbmt.2019.08.025 1083-8791/© 2019 Published by Elsevier Inc. on behalf of the American Society for Transplantation and Cellular Therapy
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well as chemotherapy-related toxicity contributing to organ dysfunction in HSCT patients, making accurate clinical decisions regarding whether symptoms are resulting from TATMA or something else entirely is often difficult. Diagnoses based on histologicD25X X analysis have been shown to enable the development of an objective evaluation of endothelial injury and the exclusion of other treatable causes. Previous studies that used D253X X histologicD254X Xmethods to determine the presence of TATMA were mainly based on biopsDy 25X X specimensD256X X and limited D257X X to kidneys and intestines [6,7,9-13,20]. In considerable contrast, autopsy can enable a systemic evaluation of TA-TMA. From a detailed review of 35 autopsied patients with TA-TMA, based on numerous articles published between 1966 and 2003, George et al. [21] indicated that most descriptions were very brief and only renal TA-TMA was described in almost all patients. Two detailed autopsy studies of 20 and 15 cases have been reported recently [22,23], but D258X X the distribution of this condition across organs other than the kidney and intestine was almost never mentioned. Although TA-TMA can affect blood vessels in the whole body, information regarding the organs, other than the kidney and intestine, that D259X X are affected by TATMA as confirmed histologically remains limited to date. Another important drawback in the existing literature is that although the kidneys and intestines are a common target of TA-TMA, the overlap of how or how often renal TA-TMA and intestinal TA-TMA might be jointly in evidence has not been described in previous autopsied cases [21-23]. From a biopsy study of intestinal TA-TMA, 9% of those diagnosed with intestinal TA-TMA showed renal dysfunction [11], and this outcome suggested that renal TA-TMA rarely coexists with intestinal TA-TMA. However, to date, a rigorous comparison between them has not been undertaken. Our aim here was to retrospectively examine a large number of autopsied patients after HSCT to clarify the systemic distribution of TA-TMA and compare the clinicopathologicD260X Xfactors of renal versus intestinal TA-TMA.
153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181
MATERIALS AND METHODS Patients Between January 1, 1994, and January 31, 2017, 1458 patients underwent HSCT at the Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, and 165 of them were autopsied. We obtained information regarding numerous clinical factors from the relevant hospital records, including age, sex, D261X X life span after HSCT, primary disease, donor source, stem cell source, HLA match status, conditioning regimen, radiation status, GVHD prophylaxis, the history of intestinal biopsy carried out when the patients were alive, any history of acute GVHD during the clinical courseD26X X that D263X X was diagnosed and graded on the basis of the consensus criteria at the time [24], and the clinical suspicion of TA-TMA, which was based on laboratory and/or intestinal biopsy findings. If applicable, the onset of acute GVHD and TA-TMA during the clinical course was also recorded. Information regarding the last HSCT was used in 33 patients who underwent HSCT several times. The Institutional Review Board of The Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital approved this study (approval number: 2125). Autopsy Review D264X X As part of our investigation, we sampled 1 D265X X section from each organ, including the esophagus, stomach, small intestine, large intestine, gallbladder, pancreas, spleen, urinary bladder, tongue, submandibular gland, thyroid gland, and bone marrow. In addition, 2 D26X X sections were sampled from each side of the heart, liver, and kidney. Five sections were sampled from each lobe of the lung. One section was sampled from the prostate and testis in males and from the uterus and ovaries in females. Sections of brain were available in 64 of our 165 autopsied patients, and multiple sections were sampled. In addition to above routine sections, additional elements were appropriately sampled as prompted by macroscopic findings. All sections were formalinD267X Xfixed, paraffinD268X X embedded, and stained with hematoxylin and eosin. In addition, a section of the kidney was routinely stained with periodic acid SchiffD269X X and in some cases also stained with periodic acid methenamine silver. A section of the lung was routinely stained using Elastica van Gieson.
We based a diagnosis of TA-TMA on the histologicD270X X findings, including endothelial cell separation, a widening of the subendothelial space with myxoid degeneration, an intraluminal fibrin, intraluminal microthrombi, intraluminal schistocytes, or fibrinoid necrosis [10,20,22]. Mesangiolysis or double contours of basement membranes were also regarded as histologicD271X X findings of TMA in the kidney [22]. Because D27X X each histologicD273X fi X nding was also observed in various conditions, such as intraluminal microthrombi in disseminated intravascular coagulation [25], fibrinoid necrosis in various vasculitis [26], and mesangiolysis and double contours of the basement membranes in diabetic nephropathy [27], a combination of histologicD274X fi X ndings was required for the diagnosis of TA-TMA. Sequential histologicD275X X findings, such as from endothelial cell separation through a widening of the subendothelial space to an intraluminal fibrin in the subendothelial space, directly reflect endothelial injury, and such findings are considered the characteristics of TMA. Thus, these findings were considered important in the diagnosis of TA-TMA. Two pathologists (R.Y. and T.H.), blinded to each patient’s clinical data, reviewed the autopsy sections, and a consensus was reached. We also recorded any indications of residual primary disease and other complications associated with HSCT, including sinusoidal obstruction syndromeD276X X[28], active GVHD [29], and infection. Bacterial or fungal infections were confirmed by periodic acid SchiffD27X sX tain or Grocott’s methenamine silver stain, respectively. Toxoplasma gondi, cytomegalovirus (CMV), herpes simplex virusD,278X X and adenovirusD279X X infection were confirmed using immunohistochemistry. Epstein-Barr virus (EBV) infection was confirmed by EBV-encoded small RNAD280X X in situ hybridization.
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Statistical Analysis D281X X FisherD28X e X xact test and the Wilcoxon rank-sum test were used to compare categorical variables and continuous variables, respectively. Statistical significance was defined as P D283X X < D284X X .05. D285X X All statistical analyzes were performed with EZR (Saitama Medical Center, Jichi Medical University, Shimotsuke, JapanD;286X X Kanda, 2012) [30], which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria, version 3.4.0). More precisely, it is a modified version of R commander (version 2.3-2) that was designed to add statistical functions frequently used in biostatistics.
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183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 204 205 206 207 208 209 210 211
RESULTS In total, 38 patients (23%) were diagnosed with TA-TMA based on our autopsy findings, and their clinical characteristics and autopsy results are detailed in Table 1.
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Patient Characteristics D287X X Clinical characteristics of patients with TA-TMA are summarized in Table 2. The median age was 45 years (range, 11D28X Xto 62 years), and 25 male (66%)D289X X and 13 female patients (34%) were included. The median duration after HSCT was 192 days (range, 28D290X X to 1530 days). The primary diseases involved were acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and myelodysplastic syndromeD291X X in 16 (42%), 13 (34%), 4 (11%), and 2 (5%) patients, D29X X respectively. We also found cases of chronic lymphocytic leukemia/small lymphocytic lymphoma, malignant lymphoma, and aplastic anemia in 1 D293X X patient each. The donor was related in 11 patients (29%) and unrelated in 27 cases (71%). No patients underwent autologous transplantation. The stem cell source was bone marrow in 26 patients (68%), peripheral blood in 8 (21%), and cord blood in 4 cases (11%). HLA was matched in 17 patients (45%) and mismatched in 21 patients (55%). The conditioning regimen was myeloablative in 31 patients (82%) and nonDmye294X X loablative in 7 cases (18%). At least one of the calcineurin inhibitors, including cyclosporin (CSP) or tacrolimus D295X X (TAC), was used as GVHD prophylaxis. CSP, TAC, or CSP + TAC was used in 19 (50%), 17 (45%), and 2 patients (5%) respectively. A history of acute GVHD during the clinical course was observed in 33 patients (87%). The median onset of acute GVHD was 15 (rangeD,296X X 7D297X X to 68) days after HSCT. Intestinal biopsy was performed in 18 patients when they were aliveD,298X X and from this effort, 17 were diagnosed with intestinal GVHD. Based on the histologicD29X X findings [13,20], including the regional loss of glands, marked hemosiderin deposits, or intraluminal microthrombi, the possible coexistence of intestinal TA-TMA was
217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246
247 248
Table 1 Clinical Characteristics and Autopsy Results of Patients with TA-TMAD25X X
249 250
Clinical Characteristics Case No.
Age, yr/Sex
Duration after HSCT
Primary Disease
Donor Source
HLA Match Status
Conditioning Regimen
Radiation Status
GVHD Prophylaxis
Acute GVHD*
Diagnosis based on Intestinal Biopsy
Residual Primary Disease
Site of TA-TMA
SOS
Active GVHD
Infection
Cause of Death
Renal TA-TMA group
1
51/M
309
ALL
uBMT
Mismatch
Myeloablative
TBI
TAC/MTX
I (2/0/0)
GVHD
+
Kidney
Bacteria (systemic)
Sepsis (bacteria)
251 252 253 254 255
Autopsy Results
Characteristic
151
AML
uBMT
Mismatch
Myeloablative
TBI
TAC/MTX
I (2/0/0)
NP
Kidney
Fungus (lung)
DAD
67
AML
uBMT
Mismatch
Myeloablative
None
TAC/MTX
III (3/0/3)
NP
Kidney
Bacteria (systemic)
Sepsis (bacteria)
4
46/F
791
AML
uBMT
Mismatch
Myeloablative
TBI
TAC/MTX
II (0/1/0)
GVHD + CMV
Kidney
Bacteria (lung)
DAD
260
5
58/F
511
ALL
uBMT
Mismatch
Myeloablative
TBI
TAC/MTX
I (2/0/0)
NP
Kidney
Renal TA-TMA
261
6
51/M
976
AML
uBMT
Full match
Myeloablative
TBI
CSP/MTX
None
NP
+
Kidney
BKVy (urinary bladder)
Hemorrhagic cystitis (BKV)
7
58/F
373
AML
uBMT
Mismatch
Nonmyeloablative
TBI
TAC/MTX
II (3/0/0)
GVHD
+
Kidney
CMV (transverse colon), HSV (oral cavity, esophagus, trachea), fungus (systemic)
Sepsis (fungus)
8
52/M
1530
ALL
uBMT
Mismatch
Myeloablative
TBI
TAC/MTX
I (2/0/0)
GVHD
Kidney
Bacteria (lung)
Pneumonia (bacteria)
9
26/M
1523
ML
rPBSCT
Full match
Myeloablative
TBI
CSP/MTX
I (1/0/0)
NP
Kidney
Pneumothorax, IP
10
27/F
431
ALL
uBMT
Full match
Myeloablative
TBI
CSP/MTX
I (2/0/0)
NP
+
Kidney
Relapse, IP
11
53/M
515
ALL
rPBSCT
Full match
Myeloablative
TBI
CSP/MTX
None
NP
Kidney
Bacteria (lung)z
Renal TA-TMA
12
39/M
137
ALL
uCBT
Mismatch
Myeloablative
TBI
CSP/MTX
I (2/0/0)
NP
Kidney
Liver
GVHD (liver)
13
28/F
151
ALL
དྷBMT
Full match
Myeloablative
TBI
CSP/MTX
II (3/0/0)
NP
Kidney
Skin
Renal TA-TMA
14
40/F
882
CML
uBMT
Full match
Myeloablative
TLI
CSP/MTX
III (2/0/2)
NP
Kidney
Liver
Fungus (systemic)
Sepsis (fungus)
15
36/M
315
AA
uBMT
Full match
Nonmyeloablative
TLI
CSP/MTX
II (2/0/1)
NP
Kidney
Fungus (systemic)
Alveolar hemorrhage
16
45/M
246
CML
uBMT
Mismatch
Myeloablative
TLI
TAC/MTX
II (3/0/1)
NP
Kidney
Stomach, duodenum, liver
CMV (ileum), bacteria (lung), fungus (lung)
Pneumonia (fungus)
17
30/M
349
ALL
rBMT
Full match
Myeloablative
TBI
CSP/MTX
I (1/0/0)
GVHD
Kidney
CMV (stomach, small intestine, large intestine)
Gastrointestinal hemorrhage
18
23/M
28
ALL
uBMT
Full match
Myeloablative
TLI
CSP/MTX
None
NP
Kidney
Large intestine
Fungus (lung), bacteria (esophagus, large intestine)
GVHD (gut)
257 258 259
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(continued)
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3
4
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Table 1 (Continued)
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Clinical Characteristics
Autopsy Results
Age, yr/Sex
Duration after HSCT
Primary Disease
Donor Source
HLA Match Status
Conditioning Regimen
Radiation Status
GVHD Prophylaxis
Acute GVHD*
Diagnosis based on Intestinal Biopsy
Residual Primary Disease
Site of TA-TMA
SOS
Active GVHD
Infection
Cause of Death
Renal and intestinal TA-TMA group
19
43/F
44
CLL/SLL
uCBT
Mismatch
Nonmyeloablative
None
TAC/MMF /MTX
None
Nonspecific
+
Kidney, jejunum
ADV (liver), fungus (systemic)
Relapse, sepsis (fungus)
20
49/M
318
AML
rPBSCT
Mismatch
Nonmyeloablative
TBI
TAC/MMF
II (3/0/0)
GVHD + suspected TA-TMA
+
Kidney, stomach, cecum to descending colon
Fungus (lung)
pneumonia (fungus)
21
52/M
490
ALL
rPBSCT
Full match
Myeloablative
TBI
CSP/MTX
IIIx
GVHD
Kidney, ileum
Bacteria (lung), fungus (lung)
IP
22
34/M
109
AML
uBMT
Mismatch
Myeloablative
TBI
TAC/MTX
IV (3/4/3)
NP
+
Kidney, stomach, ileum, ascending colon to transverse colon
CMV (stomach, ileum), bacteria (lung, pleura), fungus (lung)
Pneumonia (bacteria)
23
44/F
334
CML
uBMT
Mismatch
Myeloablative
TLI
CSP/MTX
III (2/0/2)
NP
Kidney, esophagus, pharynx, ileum, liver
Bacteria (systemic)
intestinal TATMA
24
23/M
116
ALL
rPBSCT
Full match
Myeloablative
TBI
TAC/MTX
II (3/0/1)
GVHD + suspected TA-TMA
+
Ileum to cecum
Bacteria (systemic)
pneumonia (bacteria)
25
50/M
65
AML
uBMT
Mismatch
Myeloablative
TBI
TAC/MTX
III (3/0/2)
GVHD
Duodenum to rectum, heart, oral cavity
Protozoan (systemic)
Sepsis (protozoan)
26
60/F
198
AML
uCBT
Mismatch
Nonmyeloablative
TBI
TAC/MTX
II (1/0/1)
GVHD + suspected TA-TMA
Ileum to ascending colon, gallbladder
EBV (ileum)║
Cerebral ischemia
27
25/F
75
AML
rPBSCT
Mismatch
Myeloablative
TBI
TAC
III (2/0/3)
GVHD + suspected TA-TMA
Duodenum, ileum, gallbladder, ureter, urinary bladder
+
Large intestine, liver
Intra-abdominal hemorrhage
28
45/M
133
MDS
uCBT
Mismatch
Nonmyeloablative
TBI
CSP/MMF
III (3/0/4)
GVHD + CMV
Ileum to ascending colon
CMV (ileum, adrenal gland)
Pulmonary embolism
29
62/M
93
AML
rPBSCT
Full match
Nonmyeloablative
TBI
CSP/MTX
III (2/0/2)
GVHD + CMV
Jejunum to ileum
Esophagus, liver
Intestinal TATMA, GVHD (liver)
332
30
60/M
118
MDS
uBMT
Full match
Myeloablative
None
TAC/MTX
I (1/0/0)
NP
Ileum
DAD
333
31
40/F
61
ALL
uBMT
Mismatch
Myeloablative
TBI
TAC/MTX
III (2/0/4)
GVHD
Ileum
Intestinal TATMA
32
45/M
188
AML
rPBSCT
Full match
Myeloablative
TBI
CSP
None
NP
+
Ascending colon
Fungus (lung)
Pneumonia (fungus)
295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319
Intestinal TA-TMA group
320 321 322 323 324 325 326 327 328 329 330 331
334 335 336
(continued)
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Characteristic
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Table 1 (Continued)
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Clinical Characteristics Characteristic
Primary Disease
Donor Source
HLA Match Status
Conditioning Regimen
Radiation Status
GVHD Prophylaxis
Acute GVHD*
Diagnosis based on Intestinal Biopsy
Residual Primary Disease
Site of TA-TMA
SOS
Active GVHD
Infection
Cause of Death
343
33
54/M
113
AML
uBMT
Mismatch
Myeloablative
TLI
CSP/TAC/ MTX
IV (4/4/3)
NP
Ileum
Skin, liver
CMV (systemic), EBV (systemic)x
Intestinal TATMA, GVHD (liver)
34
30/M
70
AML
uBMT
Full match
Myeloablative
None
CSP/MTX
IV (4/0/3)
NP
Ileum
Skin, liver
CMV (adrenal gland), HSV (oral cavity)
Intestinal TA-TMA
35
42/F
195
CML
uBMT
Full match
Myeloablative
None
CSP/TAC/MTX
I (2/0/0)
GVHD
Stomach, duodenum to ileum
Fungus (lung)
Intestinal TA-TMA
36
19/F
138
AML
uBMT
Mismatch
Myeloablative
TLI
CSP/MTX
III (2/0/2)
NP
Ileum
Liver
CMV (lung)
GVHD (liver)
37
31/M
218
AML
uBMT
Full match
Myeloablative
TLI
CSP/MTX
III (3/0/4)
GVHD
Jejunum to rectum
+
Liver
Fungus (systemic)
cerebral hemorrhage (fungus)
38
11/M
63
ALL
rBMT
Mismatch
Myeloablative
None
CSP/MTX
IV (1/0/3)
GVHD + CMV
Duodenum to ileum
Skin, liver, small intestine
CMV (small intestine, rectum)
Intestinal TA-TMA, GVHD (gut), cerebral hemorrhage
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SOS indicates sinusoidal obstruction syndrome; ALL, acute lymphoblastic leukemia; uBMT, unrelated bone marrow transplantation; TBI, total body irradiation; TLI, total lymphoid irradiation; MTX, XXX ;X X AML, acute myeloid leukemia; NP, not performed; DAD, diffuse alveolar damage; BKV, BK virus; HSV, herpes simplex virus; ML, malignant lymphoma; rPBSCT, related peripheral blood stem cell transplantation; IP, interstitial pneumonia; CML, chronic myeloid leukemia; AA, aplastic anemia; CLL/SLL, chronic lymphocytic leukemia/small lymphocytic leukemia; ADV, adenovirus; MDS, myelodysplastic syndrome; uCBT, unrelated core blood transplantation; MMF, XXX .X X * Grade (skin/liver/gut). y Detected in urine during lifetime using polymerase chain reaction. z Mycobacterium infection confirmed by Ziehl-Neelsen stain. x Details of GVHD were not available. ║ Post-transplant lymphoproliferative disorder.
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Duration after HSCT
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Age, yr/Sex
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Autopsy Results
Case No.
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Table 2 Clinical Characteristics of Patients D26X X with TA-TMAD27X X
384
Feature
385
Age, median, and range (yr)
386
Sex
387 388 389 390 391
Table 3 Site of TA-TMAD28X X Value 45 (11-62)
447 448
Site of TA-TMA
Number (%)
449
Kidney
23 (61D)29X X
450
Intestine
20 (53D)30X X
Male
25 (66)
Small intestine
18 (47D)31X X
Female
13 (34)
Duodenum
4 (11D)32X X
Jejunum
6 (16D)3X X
Duration after HSCT, median, and range (d)
192 (28-1530)
Primary disease
Ileum
17 (45D)34X X
451 452 453 454 455 456
AML
16 (42)
Large intestine
8 (21D)35X X
ALL
13 (34)
Right colon
8 (21D)36X X
394
CML
4 (11)
Left colon or rectum
3 (8D)37X X
395
CLL/SLL
1 (3)
Stomach
3 (8D)38X X
396
MDS
2 (5)
Gallbladder
2 (5D)39X X
397
ML
1 (3)
Oral cavity
1 (3D)40X X
462
398
AA
1 (3)
Pharynx
1 (3D)41X X
463
Esophagus
1 (3D)42X X
464
392 393
399
Donor source
457 458 459 460 461
400
Related
11 (29)
Liver
1 (3D)43X X
465
401
Unrelated
27 (71)
Heart
1 (3D)4X X
466
Urinary bladder
1 (3D)45X X
467
Ureter
1 (3D)46X X
468
402
Stem cell source
403
Bone marrow
404
Peripheral blood
8 (21)
469
Cord blood
4 (11)
470
405 406 407 408 409 410 411 412 413
26 (68)
HLA match status Full match
17 (45)
Mismatch
21 (55)
Conditioning regimen Myeloablative Nonmyeloablative
31 (82) 7 (18)
Radiation status
414
TBI
24 (63)
415
TLI
8 (21)
416
None
6 (16)
417
GVHD prophylaxis
418
CSP (+ other)
19 (50)
419
TAC (+ other)
17 (45)
420
CSP + TAC (+ other)
2 (5)
421
A history of acute GVHD during the clinical course
33 (87)
422
Onset of acute GVHD after HSCT, median and range (d)*
15 (7-68)
423
Clinical suspicion of TA-TMA
13 (34)
424
Onset of TA-TMA after HSCT, median and range (d)
57 (17-472)
425 426
Values are presented as number (%) unless otherwise indicated. * In 1 patient, information about the onset of GVHD was not available.
427 428 429 430 431 432 433 434 435 436 437 438 439 440 441
suspected in 4 patients. Moreover, CMV infection coexisted in an additional 4 D30X X patients. TA-TMA was clinically suspected in 13 patients (34%) based on laboratory findings and/or intestinal biopsy. The median onset of clinically suspected TA-TMA was 57 (rangeD,301X X 17D302X tX o 472) days after HSCT. Regarding the symptoms of TA-TMA, 1 D30X X patient exhibited elevated levels of serum creatinine thought D304X X to be caused by renal TA-TMA. Nine patients had digestive symptoms, including diarrhea, bloody stool, or abdominal pain, but intestinal TA-TMA was considered the cause of symptoms in only 2 D305X X patients due to the coexistence of intestinal GVHD during the clinical course. Remarkably, symptoms thought to be caused by TA-TMA of other organs were not found in any patients.
442 443 444 445 446
Autopsy Findings D306X X of TA-TMA The sites of TA-TMA are shown in Table 3. TA-TMA was most commonly observed in the kidney (23 patients, 61%), followed by the intestine (20 patients, 53%), stomach (3 patients,
471
8%), gallbladder (2 patients, 5%), and then the oral cavity, pharynx, esophagus, liver, heart, urinary bladder, and ureter (respectively 1 patient each, 3%). In the gut, the small intestine was the more commonly affected area (18 patients, 47%) compared with D307X X the large intestine (8 patients, 21%), and the ileum was almost always affected (17 patients, 45%). In the large intestine, the right colon was impacted in all cases. TA-TMA of the brain was not found. Histologically, TA-TMA affected the arteriole, or small arteries, regardless of the organ, and yet the vein and larger arteries were not affected at all. In the kidney, the glomerular capillary, vascular pole, and arteriole were mainly affected (Figure 1A). Mesangiolysis and double contours of basement membranes were often observed (Figure 1B). Intraluminal microthrombi and intraluminal schistocytes were occasionally noted in the affected vascular system (Figure 1C). By comparison, the interlobular artery was less affected. D308X X In the digestive system, TA-TMA produced several macroscopic findings, including redness, edema, erosion, or ulcer, in response to the degree of vascular damage (Figure 1D). Almost all ulcers were limited to the submucosa and the muscularis propria was rarely involved. We found that perforation did not occur in all patients and that TA-TMA was observed in only the submucosa, except for few cases in which the mucosal arteriole was also affected (Figure 1E,F). The vessels in the muscularis propria or subserosa were not affected even in the case where TA-TMA was the cause of a fatal hemorrhage. TA-TMA of the gallbladder represented erosion or ulcers (Figure 2A), and a few small arteries in the subserosa were affected in the gallbladder (Figure 2B,C). TA-TMA of the urinary bladder and ureter represented mild hemorrhage cystitis (Figure 2D), and a few arterioles and small arteries in the mucosa or muscularis propria were affected (Figure 2E,F)D309X X but rarely observed in the perivesical tissue. In other organs, including the oral cavity, tongue, liver, and heart, TA-TMA was not detected macroscopically and only a few arterioles were affected. It was confirmed that of the 38 patients, 7 D310X X died of TA-TMA. Four of these were intestinal TA-TMA, and 3 D31X X were renal TATMA. It was considered that intestinal TA-TMA may have been one of the causes of death for the additional 3 D312X X patients.
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512
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610
546
611
547
612
548
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549
614
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551
616
552
617
553
618
554
619
555
620
556
621
557
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558
623
559
624 625
560 561 562 563 564 565
Figure 1. Common sites affected by TA-TMA. (DA) 1X X Renal arteriole showed endothelial cell separation, widening of the subendothelial space, intraluminal fibrin, and intraluminal microthrombi. (DB) 2X X Glomerular change including mesangiolysis and double contours of the basement membranes were often found. (DC) 3X X Intraluminal schistocytes were occasionally observed in the affected glomerular capillary. (DD) 4X X Ulcers of the ilium resulted from TA-TMA. (DE) 5X X Some submucosal arterioles and small arteries under the ulcer of the ileum were affected by TA-TMA. (DF) 6X X Submucosal small arteries of the ileum showed endothelial cell separation, widening of the subendothelial space, and intraluminal fibrin. (DA) 7X X Periodic acid Schiff stain, D8X X (DB) 9X X periodic acid methenamine silver stain, and (DC, 10X X E, D1X X F) D12X X hematoxylin D13X X and eosin stain.
568 569 570 571 572 573 574 575 576
627 628 629 630 631
566 567
626
Related HistologicD31X F X indings from Autopsy D314X X Other histologicD315X X findings from the autopsies are summarized in Table 4. Residual primary disease and sinusoidal obstruction syndromeD316X X were observed in 9 (24%) and 2 (5%) of our patients, respectively. Active GVHD was observed in 12 patients (32%) during the autopsy. The liver, skin, small intestine, large intestine, esophagus, and stomach were affected in 10 (31%), 4 (11%), 2 (5%), 2 (5%), 1 (3%), and 1 (3%)D,317X X respectively. Most patients showed histologicD318X X findings of focal or systemic infection (29 patients, 76%). Focal viral infection was observed
in 11 patients (29%), most of which involved CMV infections (8 patients, 21%). In addition, herpes simplex virusD319X X infection was detected in 2 (5%) patients, while adenovirusD320X X and EBV infections represented post-transplant lymphoproliferative disordersD,321X X and the BK virus was observed D32X X in only 1 D32X X (3%) patient. Systemic CMV and EBV infections representing post-transplant lymphoproliferative disorderDs324X X were also observed in 1 D325X X (3%) patient. Bacterial or fungal infection was observed in 20 cases (53%). We observed focal infection in 11 patients (29%), almost all of which took the form of pneumonitis or aspergilloma.
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642
707
643
708
644
709
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646
711
647
712
648
713
649
714
650
715
651
716
652
717
653
718
654
719
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720
656
721
657
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658
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724
660
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661
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664
729
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731
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733
669
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673
738
674
739
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690 691 692 693 694 695
Figure 2. Uncommon sites affected by TA-TMA. (DA) 14X X Erosion and ulcers of the gallbladder resulting from TA-TMA. (DB) 15X X A few small arteries in the subserosa of the gallbladder were affected by TA-TMA. (DC) 16X X Small arteries in the subserosa of the gallbladder showed endothelial cell separation, widening of the subendothelial space with myxoid degeneration, and intraluminal fibrin. (DD) 17X X Mild hemorrhage cystitis resulted from TA-TMA. (DE) 18X X A few arterioles and small arteries in the mucosa or muscularis propria of the urinary bladder were affected by TA-TMA, and hemorrhage was found in the surrounding stroma. (DF) 19X X Mucosal arterioles of the urinary bladder showed endothelial cell separation, widening of the subendothelial space, and intraluminal fibrin. (D20XB, X C, D21X X E, D2X X F) D23X X Hematoxylin D24X X and eosin stain.
698 699
Systemic infection was noted in 9 patients (24%), whereas D326X X systemic protozoal infection (Toxoplasma gondii) was observed in only 1 D327X X case (3%).
700 701 702 703 704 705 706
757 758 759 760 761
696 697
756
Comparison between the Renal D328X X and the Intestinal D329X X TA-TMA D30XGroups X All of our patients had TA-TMA in either the kidney or intestine, and only 5 (13%) had both. As a result, our 38 D31Xpatients X were mainly classified into 2 groups, renal [18] and intestinal [15]. A comparison between these 2 sets of patients
is presented in Table 5. Clinically, the renal TA-TMA group statistically showed a longer duration after HSCT (361 versus D32X X 116 days, P = .D006) 3X X and less frequency of a history of intestinal acute GVHD during the clinical course (22% versus D34X X 80%, P = .D0016). 35X X Intestinal biopsy was performed in 5 patients in the renal and 10 from the intestinal TA-TMA group when they were still alive. All 15 patients were diagnosed with intestinal acute GVHD, and the coexistence of intestinal TA-TMA was suspected in 4 patients in the intestinal TA-TMA group. Autopsy findings showed that only patients in the intestinal
762 763 764 765 766 767 768 769 770 771
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Table 4 Related HistologicD47X FX indings from AutopsyD48X X
774
HistologicD49X Findings D50X X
775
Residual primary disease
776
9 (24D)51X X
SOS
777
2 (5D)52X X
Active GVHD
778 779 780 781
Number (%)
12 (32D)53X X
Liver
10 (31D)54X X
Skin
4 (11D)5X X
Small intestine
2 (5D)56X X
Large intestine
2 (5D)57X X
Esophagus
1 (3D)58X X
784
Stomach
1 (3D)59X X
785
Infection
29 (76D)60X X
786
Virus (focal/systemic)
11 (29D)/1 61X X (3D)62X X
787
Bacterium and/or fungus (focal/systemic)
11 (29D)/9(24D 63X X 64X)X
788
Protozoan (systemic)
782 783
1 (3D)65X X
789 790 791 792 793
TA-TMA group had TA-TMA in sites other than the kidney and intestine. No significant differences were observed regarding other factors.
794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836
DISCUSSION To our knowledge, this is the largest study of TA-TMA based on histologicD36X X findings using autopsied patients where both a systemic evaluation and a detailed histologicD37X X examination were performed. In this effort, 23% of the cases were diagnosed with TA-TMA. Two previous autopsy studies showed that the frequency of TA-TMA was 40% [22,23]. One found no statistically significant differences in clinicopathologicD38X X factors, and the other reported a close association with the history of acute GVHD during the clinical course, similar to the results we also observed in this study. We found that TA-TMA most commonly affected the kidney, and this is consistent with 2 previous autopsy studies, which also showed the same general outcome [22,23]. Siami et al. [22] observed that the kidney was involved in all 8 patients having TA-TMA, out of 20 autopsied cases. Goyama et al. [23] detected that 1 D39X X patient had renal TA-TMA and 5 were suspected to have renal TA-TMA from a total of 15 autopsied patients. In the current study, fully 53% of our cases had intestinal TA-TMA. As several previous investigations have noted, mainly based on biopsies of intestinal TA-TMA cases [9-13,20,23], the intestine is one of most common target areas of TA-TMA. The ileum was the most commonly affected area, D340Xand X the right-sided colon was also vulnerable, which is consistent with a previous study that was based on intestinal biopsies [11]. Macroscopically, intestinal TA-TMA showed nonspecific varied findings, and a precise differentiation from other complications, including GVHD and CMV infection, was very difficult. The submucosal arteriole seems to have been the preferred site of intestinal TA-TMA, and this observation is consistent with a previous study based on intestinal biopsies [9]. The resulting ulcers were limited to the submucosa and rarely reached the muscularis propria. However, a case where the intestinal TA-TMA involved the mesenteric artery and caused perforation was also reported [5,31,32]. Previous studies histologically confirmed that TA-TMA can also involve the lung, esophagus, stomach, heart, pancreas, and liver, but these observations were not explained in detail, and the clinical effects remain unknown [5,8,13,20-22]. Our analysis here is the first report histologically confirming that the gallbladder, oral cavity, pharynx, urinary bladder, and ureter can also be sites of TA-TMA. Although the frequency was low, and the
9
clinical effect may be small, it is now clear that organs other than the kidney and intestine can be affected by TA-TMA. We did not detect TA-TMA of the brain, even though neurologicD341X X symptoms are common in patients clinically considered to have TA-TMA, and neurologic dysfunction is included in one of the clinical diagnostic criteria. It has been widely regarded that the most common TA-TMA-related brain injury is likely due to acute uncontrolled TA-TMA-associated hypertension, including posterior reversible encephalopathy syndrome (PRES) [4,14-16]. We found that 2 of our patients had a history of PRES, and we were able to obtain the brain tissue from 1 D342X X of these cases. Any histologicD34X X findings suggesting that PRES was not detected were likely due to the improvement following the therapy [33]. This study did not specifically include systemic TA-TMA; however, Goyama et al. [23] reported 2 autopsied patients who had systemic TA-TMA, although the distribution of TA-TMA was not described. To the best of our knowledge, a case of a patient who was histologically proven to have both renal and intestinal TA-TMA has not been previously reported; this study could detect only D34X5X patients with this combination, although it must be understood that both renal and intestinal biopsy are not always performed and diagnosing intestinal TA-TMA via intestinal biopsy is often challenging. In comparison between the renal TA-TMA group and intestinal TA-TMA group, duration after HSCT was significantly longer and the history of intestinal acute GVHD during the clinical course was significantly less frequent in the renal TA-TMA group compared with those in the intestinal TATMA group. Moreover, nonDrenal 345X X and nonDintestinal 346X X TA-TMAs were noted only in the intestinal TA-TMA group. Duration after HSCT is probably not considered D347X X important because there are few TA-TMA-related deaths in the current study. The deviation of nonDrenal 348X X and nonDintestinal 349X X TA-TMA is also assumed to be due to the small sample size because a previous study found that a few of the autopsied patients who had renal TA-TMA were also reported to be having nonDrenal 350X X and nonDintestinal 351X X TA-TMA [22]. Several risk factors have been considered regarding TA-TMA, including conditioning agents, radiation, calcineurin inhibitors, infection, and GVHD [23,34-42]. However, the results were conflicting, and the degree to which any of these factors affects the occurrence or the progression of TATMA in individuals is still remarkably unclear. The current study suggested that in comparison to renal TA-TMA, intestinal GVHD could be more closely associated with intestinal TATMA as a risk factor; although active intestinal GVHD was almost not observed during the autopsies due to the long duration from the HSCT (medianD,352X X 192 days). The association between TA-TMA and these risk factors has generally been examined as a whole, and the relationship with the affected organ has not been considered. It has been widely recognized that different etiologies showed different distributions of TMA in patients with other types of TMA; for example, Shiga toxinrelated hemolytic uremic syndromeD35X X typically results in renal dysfunction, but thrombotic thrombocytopenic purpuraD354X X rarely does [1], and the effect of risk factors on TA-TMA could be different among various organs. The important question is: how is intestinal GVHD associated D35X X with intestinal TA-TMA? Further D356X X studies are needed to clarify this. This study has several limitations. First, not all patients who D357X X had an HSCT were autopsied, which can potentially involve selection bias. Second, many patients in their terminal stage had several complications, which could have resulted in abnormal laboratory data and symptoms. Thus, the frequency and risk factors involving TA-TMA simply cannot be compared with other clinical studies of the general population after
837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 901
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Table 5 Comparison between Renal TA-TMA Group and Intestinal TA-TMA GroupD6X X
904
Feature
905
Clinical characteristics
906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923
Age, median, and range (Dyr) 68X X Male/Dfemale 73X X Duration after HSCT, median and range (dD)80X X
Intestinal TA-TMA (n = 15) 42 (11D-62) 70X X
12 (67D)D74X X /6 75 X (33D)76X X
10 (67D)D7X X /5 78 X (33D)79X X
361 (28D-1530) 81X X
116 (61D-218) 82X X
95 X (7D)96X X 9 (60D)D92X X /3 93 X (20D)D94X X /1
MDSD/MLD 97X X /AA 98X X
0 (0D)D9X X /1 10 X (6D)D10X X /1 102 X (6D)103X X
2 (13D)D104X X /0 105 X (0D)D106X X /0 107 X (0D)108X X
4 (22D)D1X X /14 12 X (78D)13X X
5 (33D)D14X X /10 15 X (67D)16X X D17X X .43
Stem cell source 15 (83D)19X X
9 (60D)120X X
D12X X Peripheral blood
2 (11D)12X X
4 (27D)123X X
D124X X Cord blood
1 (6D)125X X
2 (13D)126X X
9 (50D)D130X X /9 13 X (50D)132X X
D140X X NonD 14X X 142XyeloabD mD X 143X X lative
12 (80D)139X X
2 (7D)14X X
3 (20D)145X X
TBID/TLI 147X X or otherD/D148X X none 149 X
13 (72D)D150X X /4 15 X (22D)D152X X /1 153 X (6D)154X X
GVHD prophylaxis
929
CSP (+ other)
10 (56D)16X X
7 (47D)162X X
TAC (+ other)
8 (44D)163X X
6 (40D)164X X
930 931 932 933 934 935 936 937
0 (0D)165X X
2 (13D)16X X 14 (93D)168X X
D169X X Skin
14 (78D)170X X
14 (93D)17X X
D173X X Liver
1 (6D)174X X
1 (7D)175X X
D176X X Gut
4 (22D)17X X
12 (80D)178X X
976 977 979 980 981 982
986 988 990 991 992
D160X X .41
16 (89D)167X X
CSP + TAC (+ other) A history of acute GVHD during the clinical course
975
989
158 X (27D)159X X 8 (53D)D15X X /3 156 X (20D)D157X X /4
928
974
987
D146X X .31
Radiation status
973
985
D136X X .64 16 (89D)138X X
972
984
7 (47D)D13X X /8 134 X (53D)135X X
Conditioning regimen
971
983
D127X X .85
HLA match status
925
969
978 D109X X .70
Donor source
D128X X Full matchD/mismatch 129X X
D83X X .006 D84X X .078
5 (28D)D87X X /9 8 X (50D)D89X X /2 90 X (7D)91X X
D18X X Bone marrow
D71X X .83 1
AMLD/ALLD 85X X 86X X /CML
RelatedD/unrelated 10X X
P Value D67X X
970 46 (23D-59) 69X X
Primary disease
D137X X Myeloablative
927
968 Renal TA-TMA (n = 18)
D72X X Sex
924 926
967
993 994 995 996
1 D172X X .35 1 D179X X .0016
Autopsy results
997 998 999 1000 1001 1002
938
Residual primary disease
4 (22D)180X X
2 (13D)18X X
D182X X .66
939
Other sites of TA-TMA (except the kidney and intestine)
0 (0D)183X X
4 (27D)184X X
D185X X .033
1004
940
Serositis
5 (28D)186X X
0 (0D)187X X
D18X X .049
1005
941
SOS
0 (0D)189X X
2 (13D)190X X
D19X X .20
1006
942
Active GVHD
5 (28D)192X X
7 (47D)193X X
D194X X .30
1007
943
D195X X Intestine
2 (7D)196X X
2 (13D)197X X
1
1008
13 (72D)198X X
11 (61D)19X X
1
1009
D20X X FocalD 201X X
4 (22D)20X X
5 (33D)203X X
D204X X .70
D205X X SystemicD 206X X
0 (0D)207X X
1 (7D)208X X
D209X X .45
FocalD210X X
6 (33D)21X X
2 (13D)21X X
D213X X .24
Systemic D214X X
5 (28D)215X X
2 (13D)216X X
D217X X .41
Protozoan (systemic)
0 (0D)218X X
1 (7D)219X X
D20X X .45
944
Infection
945
Virus
946 947 948 949 950 951 952 953
1010
Bacteria and/or fungus
Values are presented as number (%) unless otherwise indicated. Information about the renal and intestinal TMA overlap group (n = 5) is not included in Table 5.
956 957 958 959 960 961 962 963 964 965 966
1011 1012 1013 1014 1015 1016 1017 1018 1019
954 955
1003
HSCT, and the clinical effect of TA-TMA may be substantially underestimated. Third, various histologic criteria of intestinal TA-TMA have been proposed in biopsy studies [10,20,22], but it is often difficult to evaluate endothelial injury of the capillary in the lamina propria and other mucosal findings associated with TA-TMAD358X X due to the autolytic damage in autopsy specimens. Consequently, there is a significant possibility of underestimating the actual frequency of intestinal TA-TMA. Finally, our patients were autopsied after a comparatively long duration from HSCT (medianD,359X X 192 days), especially in the renal TA-TMA group (medianD,360X X 361 days). The onset of TA-TMA was usually within 150 days after HSCT [17], and an early
manifestation of TA-TMA may produce quite different data. However, our results are meaningful in terms of reliability, because of their confirmation by histologicD361X X findings and systemic evaluations, which can help exclude other complications that might clinically mimic TA-TMA and detect mild TA-TMA not producing major clinical manifestations and laboratory data.
1020 1021 1022 1023 1024 1025 1026 1027
CONCLUSIONS Here we systemically evaluated TA-TMA in the largest number of autopsied patients who had undergone an HSCT. We then found that the kidney and intestine were commonly
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affectedD362X Xand that the ileum and right colon were vulnerable. It was also evident that other organs, including the stomach, gallbladder, oral cavity, pharynx, esophagus, liver, heart, urinary bladder, and ureter, can be affected by TA-TMA, although the frequencies involved were low and the clinical effects may be small. We also found that the histologicD36X o X verlap of renal TATMA and intestinal TA-TMA was rare; in comparison to renal TA-TMA, intestinal GVHD could be more closely associated with intestinal TA-TMA as a risk factor.
1041 1042 1043 1044 1045 1046 1047 1048
ACKNOWLEDGMENTS The authors thank Mikiko Hada for tremendous support on summarizing clinical data. Financial disclosure: The authors have nothing to disclose. Conflict of interest statement: There are no conflicts of interest to report.
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REFERENCES 1. George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med. 2014;371:654–666. 2. Furlan M, Robles R, Galbusera M, et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med. 1998;339:1578–1584. 3. Karmali MA, Petric M, Lim C, Fleming PC, Arbus GS, Lior H. The association between idiopathic hemolytic uremic syndrome and infection by verotoxin-producing Escherichia coli. J Infect Dis. 1985;151:775–782. 4. Jodele S, Laskin BL, Dandoy CE, et al. A new paradigm: Diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury. Blood Rev. 2015;29:191–204. 5. Laskin BL, Goebel J, Davies SM, Jodele S. Small vessels, big trouble in the kidneys and beyond: hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Blood. 2011;118:1452–1462. 6. Hingorani S. Chronic kidney disease in long-term survivors of hematopoietic cell transplantation: epidemiology, pathogenesis, and treatment. J Am Soc Nephrol. 2006;17:1995–2005. 7. Troxell ML, Pilapil M, Miklos DB, Higgins JP, Kambham N. Renal pathology in hematopoietic cell transplantation recipients. Mod Pathol. 2008;21:396–406. 8. Dandoy CE, Hirsch R, Chima R, Davies SM, Jodele S. Pulmonary hypertension after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2013;19:1546–1556. 9. Nishida T, Hamaguchi M, Hirabayashi N, et al. Intestinal thrombotic microangiopathy after allogeneic bone marrow transplantation: a clinical imitator of acute enteric graft-versus-host disease. Bone Marrow Transplant. 2004;33:1143–1150. 10. Narimatsu H, Kami M, Hara S, et al. Intestinal thrombotic microangiopathy following reduced-intensity umbilical cord blood transplantation. Bone Marrow Transplant. 2005;36:517–523. 11. Inamoto Y, Ito M, Suzuki R, et al. Clinicopathological manifestations and treatment of intestinal transplant-associated microangiopathy. Bone Marrow Transplant. 2009;44:43–49. 12. Yamada-Fujiwara M, Miyamura K, Fujiwara T, et al. Diagnosis of intestinal graft-versus-host disease and thrombotic microangiopathy after allogeneic stem cell transplantation Tohoku. J Exp Med. 2012;227:31–37. 13. El-Bietar J, Warren M, Dandoy C, et al. Histologic features of intestinal thrombotic microangiopathy in pediatric and young adult patients after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2015;21:1994–2001. 14. Fuge R, Bird JM, Fraser A, et al. The clinical features, risk factors and outcome of thrombotic thrombocytopenic purpura occurring after bone marrow transplantation. Br J Haematol. 2001;113:58–64. 15. Martinez MT, Bucher Ch, Stussi G, et al. Transplant-associated microangiopathy (TAM) in recipients of allogeneic hematopoietic stem cell transplants. Bone Marrow Transplant. 2005;36:993–1000. 16. Ho VT, Cutler C, Carter S, et al. Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2005;11:571–575. 17. Ruutu T, Barosi G, Benjamin RJ, et al. Diagnostic criteria for hematopoietic stem cell transplant-associated microangiopathy: results of a consensus process by an International Working Group. Haematologica. 2007;92:95–100. 18. Kennedy GA, Bleakley S, Butler J, Mudie K, Kearey N, Durrant S. Posttransplant thrombotic microangiopathy: sensitivity of proposed new diagnostic criteria. Transfusion. 2009;49:1884–1889.
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19. Cho BS, Yahng SA, Lee SE, et al. Validation of recently proposed consensus criteria for thrombotic microangiopathy after allogeneic hematopoietic stem-cell transplantation. Transplantation. 2010;90:918–926. 20. Warren M, Jodele S, Dandoy C, et al. A complete histologic approach to gastrointestinal biopsy from hematopoietic stem cell transplant patients with evidence of transplant-associated gastrointestinal thrombotic microangiopathy. Arch Pathol Lab Med. 2017;141:1558–1566. 21. George JN, Li X, McMinn JR, Terrell DR, Vesely SK, Selby GB. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: a diagnostic dilemma. Transfusion. 2004;44:294–304. 22. Siami K, Kojouri K, Swisher KK, Selby GB, George JN, Laszik ZG. Thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation: an autopsy study. Transplantation. 2008;85:22–28. 23. Goyama S, Takeuchi K, Kanda Y, et al. Post-transplant endothelial disorder after hematopoietic SCT: a blinded autopsy study. Bone Marrow Transplant. 2012;47:1243–1245. 24. Przepiorka D, Weisdorf D, Martin P, et al. Consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15:825–828. 25. Ohashi R, Ishii H, Naito Z, Shimizu A. Morphological spectrum of renal pathology and its correlation to clinical features in patients with disseminated intravascular coagulation: a study involving a series of 21 autopsy cases. Pathol Int. 2014;64:443–452. 26. Jennette JC, Falk RJ, Bacon PA, et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65:1–11. 27. Furuichi K, Yuzawa Y, Shimizu M, et al. Nationwide multicentre kidney biopsy study of Japanese patients with type 2 diabetes. Nephrol Dial Transplant. 2018;33:138–148. 28. McDonald GB. Hepatobiliary complications of hematopoietic cell transplantation, 40 years on. Hepatology. 2010;51:1450–1460. 29. Shulman HM, Kleiner D, Lee SJ, et al. Histopathologic diagnosis of chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: II. Pathology Working Group Report. Biol Blood Marrow Transplant. 2006;12:31–47. 30. Kanda Y. Investigation of the freely-available easy-to-use software “EZR” (Easy R) for medical statistics. Bone Marrow Transplant. 2013;48:452–458. 31. Hewamana S, Austen B, Murray J, Johnson S, Wilson K. Intestinal perforation secondary to haematopoietic stem cell transplant associated thrombotic microangiopathy. Eur J Haematol. 2009;83:277. 32. Aljitawi OS, Rodriguez L, Madan R, Ganguly S, Abhyankar S, McGuirk JP. Late-onset intestinal perforation in the setting of posttransplantation microangiopathy: a case report. Transplant Proc. 2010;42:3892–3893. 33. Bartynski WS. Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and clinical features. Am J Neuroradiol. 2008;29:1036–1042. 34. Fassas AB, Buddharaju LN, Rapoport A, et al. Fatal disseminated adenoviral infection associated with thrombotic thrombocytopenic purpura after allogeneic bone marrow transplantation. Leuk Lymphoma. 2001;42:801–804. 35. Takatsuka H, Wakae T, Mori A, et al. Endothelial damage caused by cytomegalovirus and human herpesvirus-6. Bone Marrow Transplant. 2003;31:475–479. 36. Nakamae H, Yamane T, Hasegawa T, et al. Risk factor analysis for thrombotic microangiopathy after reduced-intensity or myeloablative allogeneic hematopoietic stem cell transplantation. Am J Hematol. 2006;81:525–531. 37. Platzbecker U, von Bonin M, Goekkurt E, et al. Graft-versus-host disease prophylaxis with everolimus and tacrolimus is associated with a high incidence of sinusoidal obstruction syndrome and microangiopathy: results of the EVTAC trial. Biol Blood Marrow Transplant. 2009;15(10):1–108. 38. Changsirikulchai S, Myerson D, Guthrie KA, McDonald GB, Alpers CE, Hingorani SR. Renal thrombotic microangiopathy after hematopoietic cell transplant: role of GVHD in pathogenesis. Clin J Am Soc Nephrol. 2009;4:345–353. re P, Fillet G, Beguin Y. Comparison of 39. Willems E, Baron F, Seidel L, Fre thrombotic microangiopathy after allogeneic hematopoietic cell transplantation with high-dose or nonmyeloablative conditioning. Bone Marrow Transplant. 2010;45:689–693. 40. Li A, Wu Q, Davis C, et al. Transplant-associated thrombotic microangiopathy is a multifactorial disease unresponsive to immunosuppressant withdrawal. Biol Blood Marrow Transplant. 2019;25:570–576. 41. Kraft S, Bollinger N, Bodenmann B, et al. High mortality in hematopoietic stem cell transplant-associated thrombotic microangiopathy with and without concomitant acute graft-versus-host disease. Bone Marrow Transplant. 2019;54:540–548. 42. Gavriilaki E, Sakellari I, Batsis I, et al. Transplant-associated thrombotic microangiopathy: incidence, prognostic factors, morbidity, and mortality in allogeneic hematopoietic cell transplantation. Clin Transplant. 2018;32: e13371.
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Distribution of X XTransplantation-Associated Thrombotic Microangiopathy (TA-TMA) and Comparison between Renal TA-TMA and Intestinal TA-TMA: Autopsy Study
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21X XRin XD YamadaD12X X , D23X XTetsuo NemotoD224X X , D25X XKazuteru OhashiD26X3X , D27X XAkiko TonookaD28X1X , D29X XShin-ichiro HoriguchiD1230X X , D231X XToru MotoiD23X1X , D23X XTsunekazu HishimaD234X1,X *
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Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan 2 Department of Pathology, Showa University Northern Yokohama Hospital, Kanagawa, Japan 3 Department of Hematology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
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74 Article history: Received 26 March 2019 Accepted 21 August 2019
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Keywords: Hematopoietic stem cell transplantation Thrombotic microangiopathy Transplantation-associated thrombotic microangiopathy Graft-versus-host disease Autopsy
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A B S T R A C T Transplantation-associated thrombotic microangiopathy (TA-TMA) is an important complication of hematopoietic stem cell transplantation. To date, information regarding the organs that are affected by TA-TMA as confirmed histologically remains limited; the clinicopathologicD237X Xdifferences between renal TA-TMA and intestinal TA-TMA have not been examined despite being the well-known and commonly affected sites of TA-TMA. We therefore examined 165 autopsied patients after hematopoietic stem cell transplantation and compared the clinicopathologicD238X fX actors of renal and intestinal TA-TMA. It was clear that 38 (23%) of our patients had TA-TMA. In the TA-TMA cases, the kidney (61%) and intestine (53%) were commonly affected, and the ileum and right colon were vulnerable. Other organs that we found to be affected by TA-TMA included the stomach (8%), gallbladder (5%), and oral cavity, pharynx, esophagus, liver, heart, urinary bladder, and ureter (all at 3%), and symptoms thought to be caused by TA-TMA of these organs were not observed in any patient. Histologically, TA-TMA only affected the arteriole, or small arteries, regardless of the organ, and the veins or larger arteries were not affected at all. In the kidney, the glomerular capillary was also affected, D239X X and mesangiolysis and double contours of the basement membranes were often in evidence. The histologicD240X X overlap of renal and intestinal TA-TMA was rare (13%), and the patients in the intestinal TA-TMA group exhibited more frequency of a history of intestinal acute graft-versus-host disease (GVHD) during the clinical courseD241X X compared with that of the renal TA-TMA group (80% versus D24X X 22%, P = .0016). D243X X Although TA-TMA can affect many other organs, the frequency of these ancillary events was low, and the clinical effect may have been small. Our results suggest that in comparison to renal TA-TMA, intestinal GVHD could be more closely associated with intestinal TA-TMA as a risk factor. © 2019 Published by Elsevier Inc. on behalf of the American Society for Transplantation and Cellular Therapy
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INTRODUCTION Thrombotic microangiopathy (TMA) is a syndrome caused by small-Dvessel 24X X endothelial injury and clinically characterized by microangiopathic hemolytic anemia, elevated serum lactate dehydrogenase level, thrombocytopenia, and multiorgan injury [1]. Multiple factors can be the cause of a primary TMA [1]. ADAMTS13 deficiency-mediated TMA or Shiga toxin-mediated TMA are representative, and they have been familiarly called the thrombotic thrombocytopenic purpuraD245X X and Shiga toxin-related hemolytic uremic syndromeD,246X X respectively [2,3]. Secondary TMA can occur in underlying diseases, including
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Financial disclosure: See Acknowledgments on page 11. * Correspondence and reprint requests: Tsunekazu Hishima, X D X epartment of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan. E-mail address: [email protected] (T. Hishima).
infection, cancer, pregnancy, hypertension, and autoimmune diseases. Of particular interest here, transplantation-associated TMA (TA-TMA) is an increasingly recognizedD247X X and occasionally life-threatingD248X X complication of hematopoietic stem cell transplantation (HSCT) [1,4,5]. TA-TMA most commonly affects the kidneys, resulting in renal dysfunction, proteinuria, and hypertension [4-7]. Other organs that have been reported as targets of TA-TMA include the lungs, intestines, and brain, where symptoms include pulmonary hypertension, abdominal pain and bleeding, and various neurologic manifestations [4,8-15]. Clinical criteria proposed by the Blood and Marrow Transplant Clinical Trial Network and the European Group for Blood and Marrow Transplantation have been used in the diagnosis of TA-TMA [16,17], but the unfortunate limitations of the diagnostic sensitivity of these protocols have D249X X been noted [18,19]. D250X X Because there can also be several complications, including graft-versus-host disease (GVHD), infection, and radiationD,251X X as
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well as chemotherapy-related toxicity contributing to organ dysfunction in HSCT patients, making accurate clinical decisions regarding whether symptoms are resulting from TATMA or something else entirely is often difficult. Diagnoses based on histologicD25X X analysis have been shown to enable the development of an objective evaluation of endothelial injury and the exclusion of other treatable causes. Previous studies that used D253X X histologicD254X Xmethods to determine the presence of TATMA were mainly based on biopsDy 25X X specimensD256X X and limited D257X X to kidneys and intestines [6,7,9-13,20]. In considerable contrast, autopsy can enable a systemic evaluation of TA-TMA. From a detailed review of 35 autopsied patients with TA-TMA, based on numerous articles published between 1966 and 2003, George et al. [21] indicated that most descriptions were very brief and only renal TA-TMA was described in almost all patients. Two detailed autopsy studies of 20 and 15 cases have been reported recently [22,23], but D258X X the distribution of this condition across organs other than the kidney and intestine was almost never mentioned. Although TA-TMA can affect blood vessels in the whole body, information regarding the organs, other than the kidney and intestine, that D259X X are affected by TATMA as confirmed histologically remains limited to date. Another important drawback in the existing literature is that although the kidneys and intestines are a common target of TA-TMA, the overlap of how or how often renal TA-TMA and intestinal TA-TMA might be jointly in evidence has not been described in previous autopsied cases [21-23]. From a biopsy study of intestinal TA-TMA, 9% of those diagnosed with intestinal TA-TMA showed renal dysfunction [11], and this outcome suggested that renal TA-TMA rarely coexists with intestinal TA-TMA. However, to date, a rigorous comparison between them has not been undertaken. Our aim here was to retrospectively examine a large number of autopsied patients after HSCT to clarify the systemic distribution of TA-TMA and compare the clinicopathologicD260X Xfactors of renal versus intestinal TA-TMA.
153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181
MATERIALS AND METHODS Patients Between January 1, 1994, and January 31, 2017, 1458 patients underwent HSCT at the Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, and 165 of them were autopsied. We obtained information regarding numerous clinical factors from the relevant hospital records, including age, sex, D261X X life span after HSCT, primary disease, donor source, stem cell source, HLA match status, conditioning regimen, radiation status, GVHD prophylaxis, the history of intestinal biopsy carried out when the patients were alive, any history of acute GVHD during the clinical courseD26X X that D263X X was diagnosed and graded on the basis of the consensus criteria at the time [24], and the clinical suspicion of TA-TMA, which was based on laboratory and/or intestinal biopsy findings. If applicable, the onset of acute GVHD and TA-TMA during the clinical course was also recorded. Information regarding the last HSCT was used in 33 patients who underwent HSCT several times. The Institutional Review Board of The Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital approved this study (approval number: 2125). Autopsy Review D264X X As part of our investigation, we sampled 1 D265X X section from each organ, including the esophagus, stomach, small intestine, large intestine, gallbladder, pancreas, spleen, urinary bladder, tongue, submandibular gland, thyroid gland, and bone marrow. In addition, 2 D26X X sections were sampled from each side of the heart, liver, and kidney. Five sections were sampled from each lobe of the lung. One section was sampled from the prostate and testis in males and from the uterus and ovaries in females. Sections of brain were available in 64 of our 165 autopsied patients, and multiple sections were sampled. In addition to above routine sections, additional elements were appropriately sampled as prompted by macroscopic findings. All sections were formalinD267X Xfixed, paraffinD268X X embedded, and stained with hematoxylin and eosin. In addition, a section of the kidney was routinely stained with periodic acid SchiffD269X X and in some cases also stained with periodic acid methenamine silver. A section of the lung was routinely stained using Elastica van Gieson.
We based a diagnosis of TA-TMA on the histologicD270X X findings, including endothelial cell separation, a widening of the subendothelial space with myxoid degeneration, an intraluminal fibrin, intraluminal microthrombi, intraluminal schistocytes, or fibrinoid necrosis [10,20,22]. Mesangiolysis or double contours of basement membranes were also regarded as histologicD271X X findings of TMA in the kidney [22]. Because D27X X each histologicD273X fi X nding was also observed in various conditions, such as intraluminal microthrombi in disseminated intravascular coagulation [25], fibrinoid necrosis in various vasculitis [26], and mesangiolysis and double contours of the basement membranes in diabetic nephropathy [27], a combination of histologicD274X fi X ndings was required for the diagnosis of TA-TMA. Sequential histologicD275X X findings, such as from endothelial cell separation through a widening of the subendothelial space to an intraluminal fibrin in the subendothelial space, directly reflect endothelial injury, and such findings are considered the characteristics of TMA. Thus, these findings were considered important in the diagnosis of TA-TMA. Two pathologists (R.Y. and T.H.), blinded to each patient’s clinical data, reviewed the autopsy sections, and a consensus was reached. We also recorded any indications of residual primary disease and other complications associated with HSCT, including sinusoidal obstruction syndromeD276X X[28], active GVHD [29], and infection. Bacterial or fungal infections were confirmed by periodic acid SchiffD27X sX tain or Grocott’s methenamine silver stain, respectively. Toxoplasma gondi, cytomegalovirus (CMV), herpes simplex virusD,278X X and adenovirusD279X X infection were confirmed using immunohistochemistry. Epstein-Barr virus (EBV) infection was confirmed by EBV-encoded small RNAD280X X in situ hybridization.
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Statistical Analysis D281X X FisherD28X e X xact test and the Wilcoxon rank-sum test were used to compare categorical variables and continuous variables, respectively. Statistical significance was defined as P D283X X < D284X X .05. D285X X All statistical analyzes were performed with EZR (Saitama Medical Center, Jichi Medical University, Shimotsuke, JapanD;286X X Kanda, 2012) [30], which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria, version 3.4.0). More precisely, it is a modified version of R commander (version 2.3-2) that was designed to add statistical functions frequently used in biostatistics.
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RESULTS In total, 38 patients (23%) were diagnosed with TA-TMA based on our autopsy findings, and their clinical characteristics and autopsy results are detailed in Table 1.
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Patient Characteristics D287X X Clinical characteristics of patients with TA-TMA are summarized in Table 2. The median age was 45 years (range, 11D28X Xto 62 years), and 25 male (66%)D289X X and 13 female patients (34%) were included. The median duration after HSCT was 192 days (range, 28D290X X to 1530 days). The primary diseases involved were acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and myelodysplastic syndromeD291X X in 16 (42%), 13 (34%), 4 (11%), and 2 (5%) patients, D29X X respectively. We also found cases of chronic lymphocytic leukemia/small lymphocytic lymphoma, malignant lymphoma, and aplastic anemia in 1 D293X X patient each. The donor was related in 11 patients (29%) and unrelated in 27 cases (71%). No patients underwent autologous transplantation. The stem cell source was bone marrow in 26 patients (68%), peripheral blood in 8 (21%), and cord blood in 4 cases (11%). HLA was matched in 17 patients (45%) and mismatched in 21 patients (55%). The conditioning regimen was myeloablative in 31 patients (82%) and nonDmye294X X loablative in 7 cases (18%). At least one of the calcineurin inhibitors, including cyclosporin (CSP) or tacrolimus D295X X (TAC), was used as GVHD prophylaxis. CSP, TAC, or CSP + TAC was used in 19 (50%), 17 (45%), and 2 patients (5%) respectively. A history of acute GVHD during the clinical course was observed in 33 patients (87%). The median onset of acute GVHD was 15 (rangeD,296X X 7D297X X to 68) days after HSCT. Intestinal biopsy was performed in 18 patients when they were aliveD,298X X and from this effort, 17 were diagnosed with intestinal GVHD. Based on the histologicD29X X findings [13,20], including the regional loss of glands, marked hemosiderin deposits, or intraluminal microthrombi, the possible coexistence of intestinal TA-TMA was
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Table 1 Clinical Characteristics and Autopsy Results of Patients with TA-TMAD25X X
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Clinical Characteristics Case No.
Age, yr/Sex
Duration after HSCT
Primary Disease
Donor Source
HLA Match Status
Conditioning Regimen
Radiation Status
GVHD Prophylaxis
Acute GVHD*
Diagnosis based on Intestinal Biopsy
Residual Primary Disease
Site of TA-TMA
SOS
Active GVHD
Infection
Cause of Death
Renal TA-TMA group
1
51/M
309
ALL
uBMT
Mismatch
Myeloablative
TBI
TAC/MTX
I (2/0/0)
GVHD
+
Kidney
Bacteria (systemic)
Sepsis (bacteria)
251 252 253 254 255
Autopsy Results
Characteristic
151
AML
uBMT
Mismatch
Myeloablative
TBI
TAC/MTX
I (2/0/0)
NP
Kidney
Fungus (lung)
DAD
67
AML
uBMT
Mismatch
Myeloablative
None
TAC/MTX
III (3/0/3)
NP
Kidney
Bacteria (systemic)
Sepsis (bacteria)
4
46/F
791
AML
uBMT
Mismatch
Myeloablative
TBI
TAC/MTX
II (0/1/0)
GVHD + CMV
Kidney
Bacteria (lung)
DAD
260
5
58/F
511
ALL
uBMT
Mismatch
Myeloablative
TBI
TAC/MTX
I (2/0/0)
NP
Kidney
Renal TA-TMA
261
6
51/M
976
AML
uBMT
Full match
Myeloablative
TBI
CSP/MTX
None
NP
+
Kidney
BKVy (urinary bladder)
Hemorrhagic cystitis (BKV)
7
58/F
373
AML
uBMT
Mismatch
Nonmyeloablative
TBI
TAC/MTX
II (3/0/0)
GVHD
+
Kidney
CMV (transverse colon), HSV (oral cavity, esophagus, trachea), fungus (systemic)
Sepsis (fungus)
8
52/M
1530
ALL
uBMT
Mismatch
Myeloablative
TBI
TAC/MTX
I (2/0/0)
GVHD
Kidney
Bacteria (lung)
Pneumonia (bacteria)
9
26/M
1523
ML
rPBSCT
Full match
Myeloablative
TBI
CSP/MTX
I (1/0/0)
NP
Kidney
Pneumothorax, IP
10
27/F
431
ALL
uBMT
Full match
Myeloablative
TBI
CSP/MTX
I (2/0/0)
NP
+
Kidney
Relapse, IP
11
53/M
515
ALL
rPBSCT
Full match
Myeloablative
TBI
CSP/MTX
None
NP
Kidney
Bacteria (lung)z
Renal TA-TMA
12
39/M
137
ALL
uCBT
Mismatch
Myeloablative
TBI
CSP/MTX
I (2/0/0)
NP
Kidney
Liver
GVHD (liver)
13
28/F
151
ALL
དྷBMT
Full match
Myeloablative
TBI
CSP/MTX
II (3/0/0)
NP
Kidney
Skin
Renal TA-TMA
14
40/F
882
CML
uBMT
Full match
Myeloablative
TLI
CSP/MTX
III (2/0/2)
NP
Kidney
Liver
Fungus (systemic)
Sepsis (fungus)
15
36/M
315
AA
uBMT
Full match
Nonmyeloablative
TLI
CSP/MTX
II (2/0/1)
NP
Kidney
Fungus (systemic)
Alveolar hemorrhage
16
45/M
246
CML
uBMT
Mismatch
Myeloablative
TLI
TAC/MTX
II (3/0/1)
NP
Kidney
Stomach, duodenum, liver
CMV (ileum), bacteria (lung), fungus (lung)
Pneumonia (fungus)
17
30/M
349
ALL
rBMT
Full match
Myeloablative
TBI
CSP/MTX
I (1/0/0)
GVHD
Kidney
CMV (stomach, small intestine, large intestine)
Gastrointestinal hemorrhage
18
23/M
28
ALL
uBMT
Full match
Myeloablative
TLI
CSP/MTX
None
NP
Kidney
Large intestine
Fungus (lung), bacteria (esophagus, large intestine)
GVHD (gut)
257 258 259
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(continued)
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256
3
4
292
Table 1 (Continued)
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Clinical Characteristics
Autopsy Results
Age, yr/Sex
Duration after HSCT
Primary Disease
Donor Source
HLA Match Status
Conditioning Regimen
Radiation Status
GVHD Prophylaxis
Acute GVHD*
Diagnosis based on Intestinal Biopsy
Residual Primary Disease
Site of TA-TMA
SOS
Active GVHD
Infection
Cause of Death
Renal and intestinal TA-TMA group
19
43/F
44
CLL/SLL
uCBT
Mismatch
Nonmyeloablative
None
TAC/MMF /MTX
None
Nonspecific
+
Kidney, jejunum
ADV (liver), fungus (systemic)
Relapse, sepsis (fungus)
20
49/M
318
AML
rPBSCT
Mismatch
Nonmyeloablative
TBI
TAC/MMF
II (3/0/0)
GVHD + suspected TA-TMA
+
Kidney, stomach, cecum to descending colon
Fungus (lung)
pneumonia (fungus)
21
52/M
490
ALL
rPBSCT
Full match
Myeloablative
TBI
CSP/MTX
IIIx
GVHD
Kidney, ileum
Bacteria (lung), fungus (lung)
IP
22
34/M
109
AML
uBMT
Mismatch
Myeloablative
TBI
TAC/MTX
IV (3/4/3)
NP
+
Kidney, stomach, ileum, ascending colon to transverse colon
CMV (stomach, ileum), bacteria (lung, pleura), fungus (lung)
Pneumonia (bacteria)
23
44/F
334
CML
uBMT
Mismatch
Myeloablative
TLI
CSP/MTX
III (2/0/2)
NP
Kidney, esophagus, pharynx, ileum, liver
Bacteria (systemic)
intestinal TATMA
24
23/M
116
ALL
rPBSCT
Full match
Myeloablative
TBI
TAC/MTX
II (3/0/1)
GVHD + suspected TA-TMA
+
Ileum to cecum
Bacteria (systemic)
pneumonia (bacteria)
25
50/M
65
AML
uBMT
Mismatch
Myeloablative
TBI
TAC/MTX
III (3/0/2)
GVHD
Duodenum to rectum, heart, oral cavity
Protozoan (systemic)
Sepsis (protozoan)
26
60/F
198
AML
uCBT
Mismatch
Nonmyeloablative
TBI
TAC/MTX
II (1/0/1)
GVHD + suspected TA-TMA
Ileum to ascending colon, gallbladder
EBV (ileum)║
Cerebral ischemia
27
25/F
75
AML
rPBSCT
Mismatch
Myeloablative
TBI
TAC
III (2/0/3)
GVHD + suspected TA-TMA
Duodenum, ileum, gallbladder, ureter, urinary bladder
+
Large intestine, liver
Intra-abdominal hemorrhage
28
45/M
133
MDS
uCBT
Mismatch
Nonmyeloablative
TBI
CSP/MMF
III (3/0/4)
GVHD + CMV
Ileum to ascending colon
CMV (ileum, adrenal gland)
Pulmonary embolism
29
62/M
93
AML
rPBSCT
Full match
Nonmyeloablative
TBI
CSP/MTX
III (2/0/2)
GVHD + CMV
Jejunum to ileum
Esophagus, liver
Intestinal TATMA, GVHD (liver)
332
30
60/M
118
MDS
uBMT
Full match
Myeloablative
None
TAC/MTX
I (1/0/0)
NP
Ileum
DAD
333
31
40/F
61
ALL
uBMT
Mismatch
Myeloablative
TBI
TAC/MTX
III (2/0/4)
GVHD
Ileum
Intestinal TATMA
32
45/M
188
AML
rPBSCT
Full match
Myeloablative
TBI
CSP
None
NP
+
Ascending colon
Fungus (lung)
Pneumonia (fungus)
295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319
Intestinal TA-TMA group
320 321 322 323 324 325 326 327 328 329 330 331
334 335 336
(continued)
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Characteristic
337
Table 1 (Continued)
338 339 340
Clinical Characteristics Characteristic
Primary Disease
Donor Source
HLA Match Status
Conditioning Regimen
Radiation Status
GVHD Prophylaxis
Acute GVHD*
Diagnosis based on Intestinal Biopsy
Residual Primary Disease
Site of TA-TMA
SOS
Active GVHD
Infection
Cause of Death
343
33
54/M
113
AML
uBMT
Mismatch
Myeloablative
TLI
CSP/TAC/ MTX
IV (4/4/3)
NP
Ileum
Skin, liver
CMV (systemic), EBV (systemic)x
Intestinal TATMA, GVHD (liver)
34
30/M
70
AML
uBMT
Full match
Myeloablative
None
CSP/MTX
IV (4/0/3)
NP
Ileum
Skin, liver
CMV (adrenal gland), HSV (oral cavity)
Intestinal TA-TMA
35
42/F
195
CML
uBMT
Full match
Myeloablative
None
CSP/TAC/MTX
I (2/0/0)
GVHD
Stomach, duodenum to ileum
Fungus (lung)
Intestinal TA-TMA
36
19/F
138
AML
uBMT
Mismatch
Myeloablative
TLI
CSP/MTX
III (2/0/2)
NP
Ileum
Liver
CMV (lung)
GVHD (liver)
37
31/M
218
AML
uBMT
Full match
Myeloablative
TLI
CSP/MTX
III (3/0/4)
GVHD
Jejunum to rectum
+
Liver
Fungus (systemic)
cerebral hemorrhage (fungus)
38
11/M
63
ALL
rBMT
Mismatch
Myeloablative
None
CSP/MTX
IV (1/0/3)
GVHD + CMV
Duodenum to ileum
Skin, liver, small intestine
CMV (small intestine, rectum)
Intestinal TA-TMA, GVHD (gut), cerebral hemorrhage
344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359Q4 360
361Q5 362 363 364 365 366 367 368 369
SOS indicates sinusoidal obstruction syndrome; ALL, acute lymphoblastic leukemia; uBMT, unrelated bone marrow transplantation; TBI, total body irradiation; TLI, total lymphoid irradiation; MTX, XXX ;X X AML, acute myeloid leukemia; NP, not performed; DAD, diffuse alveolar damage; BKV, BK virus; HSV, herpes simplex virus; ML, malignant lymphoma; rPBSCT, related peripheral blood stem cell transplantation; IP, interstitial pneumonia; CML, chronic myeloid leukemia; AA, aplastic anemia; CLL/SLL, chronic lymphocytic leukemia/small lymphocytic leukemia; ADV, adenovirus; MDS, myelodysplastic syndrome; uCBT, unrelated core blood transplantation; MMF, XXX .X X * Grade (skin/liver/gut). y Detected in urine during lifetime using polymerase chain reaction. z Mycobacterium infection confirmed by Ziehl-Neelsen stain. x Details of GVHD were not available. ║ Post-transplant lymphoproliferative disorder.
370 371 372 373 374 375 376 377 378 379 380 381
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Age, yr/Sex
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Autopsy Results
Case No.
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382 383
Table 2 Clinical Characteristics of Patients D26X X with TA-TMAD27X X
384
Feature
385
Age, median, and range (yr)
386
Sex
387 388 389 390 391
Table 3 Site of TA-TMAD28X X Value 45 (11-62)
447 448
Site of TA-TMA
Number (%)
449
Kidney
23 (61D)29X X
450
Intestine
20 (53D)30X X
Male
25 (66)
Small intestine
18 (47D)31X X
Female
13 (34)
Duodenum
4 (11D)32X X
Jejunum
6 (16D)3X X
Duration after HSCT, median, and range (d)
192 (28-1530)
Primary disease
Ileum
17 (45D)34X X
451 452 453 454 455 456
AML
16 (42)
Large intestine
8 (21D)35X X
ALL
13 (34)
Right colon
8 (21D)36X X
394
CML
4 (11)
Left colon or rectum
3 (8D)37X X
395
CLL/SLL
1 (3)
Stomach
3 (8D)38X X
396
MDS
2 (5)
Gallbladder
2 (5D)39X X
397
ML
1 (3)
Oral cavity
1 (3D)40X X
462
398
AA
1 (3)
Pharynx
1 (3D)41X X
463
Esophagus
1 (3D)42X X
464
392 393
399
Donor source
457 458 459 460 461
400
Related
11 (29)
Liver
1 (3D)43X X
465
401
Unrelated
27 (71)
Heart
1 (3D)4X X
466
Urinary bladder
1 (3D)45X X
467
Ureter
1 (3D)46X X
468
402
Stem cell source
403
Bone marrow
404
Peripheral blood
8 (21)
469
Cord blood
4 (11)
470
405 406 407 408 409 410 411 412 413
26 (68)
HLA match status Full match
17 (45)
Mismatch
21 (55)
Conditioning regimen Myeloablative Nonmyeloablative
31 (82) 7 (18)
Radiation status
414
TBI
24 (63)
415
TLI
8 (21)
416
None
6 (16)
417
GVHD prophylaxis
418
CSP (+ other)
19 (50)
419
TAC (+ other)
17 (45)
420
CSP + TAC (+ other)
2 (5)
421
A history of acute GVHD during the clinical course
33 (87)
422
Onset of acute GVHD after HSCT, median and range (d)*
15 (7-68)
423
Clinical suspicion of TA-TMA
13 (34)
424
Onset of TA-TMA after HSCT, median and range (d)
57 (17-472)
425 426
Values are presented as number (%) unless otherwise indicated. * In 1 patient, information about the onset of GVHD was not available.
427 428 429 430 431 432 433 434 435 436 437 438 439 440 441
suspected in 4 patients. Moreover, CMV infection coexisted in an additional 4 D30X X patients. TA-TMA was clinically suspected in 13 patients (34%) based on laboratory findings and/or intestinal biopsy. The median onset of clinically suspected TA-TMA was 57 (rangeD,301X X 17D302X tX o 472) days after HSCT. Regarding the symptoms of TA-TMA, 1 D30X X patient exhibited elevated levels of serum creatinine thought D304X X to be caused by renal TA-TMA. Nine patients had digestive symptoms, including diarrhea, bloody stool, or abdominal pain, but intestinal TA-TMA was considered the cause of symptoms in only 2 D305X X patients due to the coexistence of intestinal GVHD during the clinical course. Remarkably, symptoms thought to be caused by TA-TMA of other organs were not found in any patients.
442 443 444 445 446
Autopsy Findings D306X X of TA-TMA The sites of TA-TMA are shown in Table 3. TA-TMA was most commonly observed in the kidney (23 patients, 61%), followed by the intestine (20 patients, 53%), stomach (3 patients,
471
8%), gallbladder (2 patients, 5%), and then the oral cavity, pharynx, esophagus, liver, heart, urinary bladder, and ureter (respectively 1 patient each, 3%). In the gut, the small intestine was the more commonly affected area (18 patients, 47%) compared with D307X X the large intestine (8 patients, 21%), and the ileum was almost always affected (17 patients, 45%). In the large intestine, the right colon was impacted in all cases. TA-TMA of the brain was not found. Histologically, TA-TMA affected the arteriole, or small arteries, regardless of the organ, and yet the vein and larger arteries were not affected at all. In the kidney, the glomerular capillary, vascular pole, and arteriole were mainly affected (Figure 1A). Mesangiolysis and double contours of basement membranes were often observed (Figure 1B). Intraluminal microthrombi and intraluminal schistocytes were occasionally noted in the affected vascular system (Figure 1C). By comparison, the interlobular artery was less affected. D308X X In the digestive system, TA-TMA produced several macroscopic findings, including redness, edema, erosion, or ulcer, in response to the degree of vascular damage (Figure 1D). Almost all ulcers were limited to the submucosa and the muscularis propria was rarely involved. We found that perforation did not occur in all patients and that TA-TMA was observed in only the submucosa, except for few cases in which the mucosal arteriole was also affected (Figure 1E,F). The vessels in the muscularis propria or subserosa were not affected even in the case where TA-TMA was the cause of a fatal hemorrhage. TA-TMA of the gallbladder represented erosion or ulcers (Figure 2A), and a few small arteries in the subserosa were affected in the gallbladder (Figure 2B,C). TA-TMA of the urinary bladder and ureter represented mild hemorrhage cystitis (Figure 2D), and a few arterioles and small arteries in the mucosa or muscularis propria were affected (Figure 2E,F)D309X X but rarely observed in the perivesical tissue. In other organs, including the oral cavity, tongue, liver, and heart, TA-TMA was not detected macroscopically and only a few arterioles were affected. It was confirmed that of the 38 patients, 7 D310X X died of TA-TMA. Four of these were intestinal TA-TMA, and 3 D31X X were renal TATMA. It was considered that intestinal TA-TMA may have been one of the causes of death for the additional 3 D312X X patients.
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520
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521
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525
590
526
591
527
592
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595
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596
532
597
533
598
534
599
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603
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605
541
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611
547
612
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549
614
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616
552
617
553
618
554
619
555
620
556
621
557
622
558
623
559
624 625
560 561 562 563 564 565
Figure 1. Common sites affected by TA-TMA. (DA) 1X X Renal arteriole showed endothelial cell separation, widening of the subendothelial space, intraluminal fibrin, and intraluminal microthrombi. (DB) 2X X Glomerular change including mesangiolysis and double contours of the basement membranes were often found. (DC) 3X X Intraluminal schistocytes were occasionally observed in the affected glomerular capillary. (DD) 4X X Ulcers of the ilium resulted from TA-TMA. (DE) 5X X Some submucosal arterioles and small arteries under the ulcer of the ileum were affected by TA-TMA. (DF) 6X X Submucosal small arteries of the ileum showed endothelial cell separation, widening of the subendothelial space, and intraluminal fibrin. (DA) 7X X Periodic acid Schiff stain, D8X X (DB) 9X X periodic acid methenamine silver stain, and (DC, 10X X E, D1X X F) D12X X hematoxylin D13X X and eosin stain.
568 569 570 571 572 573 574 575 576
627 628 629 630 631
566 567
626
Related HistologicD31X F X indings from Autopsy D314X X Other histologicD315X X findings from the autopsies are summarized in Table 4. Residual primary disease and sinusoidal obstruction syndromeD316X X were observed in 9 (24%) and 2 (5%) of our patients, respectively. Active GVHD was observed in 12 patients (32%) during the autopsy. The liver, skin, small intestine, large intestine, esophagus, and stomach were affected in 10 (31%), 4 (11%), 2 (5%), 2 (5%), 1 (3%), and 1 (3%)D,317X X respectively. Most patients showed histologicD318X X findings of focal or systemic infection (29 patients, 76%). Focal viral infection was observed
in 11 patients (29%), most of which involved CMV infections (8 patients, 21%). In addition, herpes simplex virusD319X X infection was detected in 2 (5%) patients, while adenovirusD320X X and EBV infections represented post-transplant lymphoproliferative disordersD,321X X and the BK virus was observed D32X X in only 1 D32X X (3%) patient. Systemic CMV and EBV infections representing post-transplant lymphoproliferative disorderDs324X X were also observed in 1 D325X X (3%) patient. Bacterial or fungal infection was observed in 20 cases (53%). We observed focal infection in 11 patients (29%), almost all of which took the form of pneumonitis or aspergilloma.
632 633 634 635 636 637 638 639 640 641
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642
707
643
708
644
709
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648
713
649
714
650
715
651
716
652
717
653
718
654
719
655
720
656
721
657
722
658
723
659
724
660
725
661
726
662
727
663
728
664
729
665
730
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731
667
732
668
733
669
734
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735
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673
738
674
739
675
740
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741
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742
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679
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745
681
746
682
747
683
748
684
749
685
750
686
751
687
752
688
753
689
754 755
690 691 692 693 694 695
Figure 2. Uncommon sites affected by TA-TMA. (DA) 14X X Erosion and ulcers of the gallbladder resulting from TA-TMA. (DB) 15X X A few small arteries in the subserosa of the gallbladder were affected by TA-TMA. (DC) 16X X Small arteries in the subserosa of the gallbladder showed endothelial cell separation, widening of the subendothelial space with myxoid degeneration, and intraluminal fibrin. (DD) 17X X Mild hemorrhage cystitis resulted from TA-TMA. (DE) 18X X A few arterioles and small arteries in the mucosa or muscularis propria of the urinary bladder were affected by TA-TMA, and hemorrhage was found in the surrounding stroma. (DF) 19X X Mucosal arterioles of the urinary bladder showed endothelial cell separation, widening of the subendothelial space, and intraluminal fibrin. (D20XB, X C, D21X X E, D2X X F) D23X X Hematoxylin D24X X and eosin stain.
698 699
Systemic infection was noted in 9 patients (24%), whereas D326X X systemic protozoal infection (Toxoplasma gondii) was observed in only 1 D327X X case (3%).
700 701 702 703 704 705 706
757 758 759 760 761
696 697
756
Comparison between the Renal D328X X and the Intestinal D329X X TA-TMA D30XGroups X All of our patients had TA-TMA in either the kidney or intestine, and only 5 (13%) had both. As a result, our 38 D31Xpatients X were mainly classified into 2 groups, renal [18] and intestinal [15]. A comparison between these 2 sets of patients
is presented in Table 5. Clinically, the renal TA-TMA group statistically showed a longer duration after HSCT (361 versus D32X X 116 days, P = .D006) 3X X and less frequency of a history of intestinal acute GVHD during the clinical course (22% versus D34X X 80%, P = .D0016). 35X X Intestinal biopsy was performed in 5 patients in the renal and 10 from the intestinal TA-TMA group when they were still alive. All 15 patients were diagnosed with intestinal acute GVHD, and the coexistence of intestinal TA-TMA was suspected in 4 patients in the intestinal TA-TMA group. Autopsy findings showed that only patients in the intestinal
762 763 764 765 766 767 768 769 770 771
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Table 4 Related HistologicD47X FX indings from AutopsyD48X X
774
HistologicD49X Findings D50X X
775
Residual primary disease
776
9 (24D)51X X
SOS
777
2 (5D)52X X
Active GVHD
778 779 780 781
Number (%)
12 (32D)53X X
Liver
10 (31D)54X X
Skin
4 (11D)5X X
Small intestine
2 (5D)56X X
Large intestine
2 (5D)57X X
Esophagus
1 (3D)58X X
784
Stomach
1 (3D)59X X
785
Infection
29 (76D)60X X
786
Virus (focal/systemic)
11 (29D)/1 61X X (3D)62X X
787
Bacterium and/or fungus (focal/systemic)
11 (29D)/9(24D 63X X 64X)X
788
Protozoan (systemic)
782 783
1 (3D)65X X
789 790 791 792 793
TA-TMA group had TA-TMA in sites other than the kidney and intestine. No significant differences were observed regarding other factors.
794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836
DISCUSSION To our knowledge, this is the largest study of TA-TMA based on histologicD36X X findings using autopsied patients where both a systemic evaluation and a detailed histologicD37X X examination were performed. In this effort, 23% of the cases were diagnosed with TA-TMA. Two previous autopsy studies showed that the frequency of TA-TMA was 40% [22,23]. One found no statistically significant differences in clinicopathologicD38X X factors, and the other reported a close association with the history of acute GVHD during the clinical course, similar to the results we also observed in this study. We found that TA-TMA most commonly affected the kidney, and this is consistent with 2 previous autopsy studies, which also showed the same general outcome [22,23]. Siami et al. [22] observed that the kidney was involved in all 8 patients having TA-TMA, out of 20 autopsied cases. Goyama et al. [23] detected that 1 D39X X patient had renal TA-TMA and 5 were suspected to have renal TA-TMA from a total of 15 autopsied patients. In the current study, fully 53% of our cases had intestinal TA-TMA. As several previous investigations have noted, mainly based on biopsies of intestinal TA-TMA cases [9-13,20,23], the intestine is one of most common target areas of TA-TMA. The ileum was the most commonly affected area, D340Xand X the right-sided colon was also vulnerable, which is consistent with a previous study that was based on intestinal biopsies [11]. Macroscopically, intestinal TA-TMA showed nonspecific varied findings, and a precise differentiation from other complications, including GVHD and CMV infection, was very difficult. The submucosal arteriole seems to have been the preferred site of intestinal TA-TMA, and this observation is consistent with a previous study based on intestinal biopsies [9]. The resulting ulcers were limited to the submucosa and rarely reached the muscularis propria. However, a case where the intestinal TA-TMA involved the mesenteric artery and caused perforation was also reported [5,31,32]. Previous studies histologically confirmed that TA-TMA can also involve the lung, esophagus, stomach, heart, pancreas, and liver, but these observations were not explained in detail, and the clinical effects remain unknown [5,8,13,20-22]. Our analysis here is the first report histologically confirming that the gallbladder, oral cavity, pharynx, urinary bladder, and ureter can also be sites of TA-TMA. Although the frequency was low, and the
9
clinical effect may be small, it is now clear that organs other than the kidney and intestine can be affected by TA-TMA. We did not detect TA-TMA of the brain, even though neurologicD341X X symptoms are common in patients clinically considered to have TA-TMA, and neurologic dysfunction is included in one of the clinical diagnostic criteria. It has been widely regarded that the most common TA-TMA-related brain injury is likely due to acute uncontrolled TA-TMA-associated hypertension, including posterior reversible encephalopathy syndrome (PRES) [4,14-16]. We found that 2 of our patients had a history of PRES, and we were able to obtain the brain tissue from 1 D342X X of these cases. Any histologicD34X X findings suggesting that PRES was not detected were likely due to the improvement following the therapy [33]. This study did not specifically include systemic TA-TMA; however, Goyama et al. [23] reported 2 autopsied patients who had systemic TA-TMA, although the distribution of TA-TMA was not described. To the best of our knowledge, a case of a patient who was histologically proven to have both renal and intestinal TA-TMA has not been previously reported; this study could detect only D34X5X patients with this combination, although it must be understood that both renal and intestinal biopsy are not always performed and diagnosing intestinal TA-TMA via intestinal biopsy is often challenging. In comparison between the renal TA-TMA group and intestinal TA-TMA group, duration after HSCT was significantly longer and the history of intestinal acute GVHD during the clinical course was significantly less frequent in the renal TA-TMA group compared with those in the intestinal TATMA group. Moreover, nonDrenal 345X X and nonDintestinal 346X X TA-TMAs were noted only in the intestinal TA-TMA group. Duration after HSCT is probably not considered D347X X important because there are few TA-TMA-related deaths in the current study. The deviation of nonDrenal 348X X and nonDintestinal 349X X TA-TMA is also assumed to be due to the small sample size because a previous study found that a few of the autopsied patients who had renal TA-TMA were also reported to be having nonDrenal 350X X and nonDintestinal 351X X TA-TMA [22]. Several risk factors have been considered regarding TA-TMA, including conditioning agents, radiation, calcineurin inhibitors, infection, and GVHD [23,34-42]. However, the results were conflicting, and the degree to which any of these factors affects the occurrence or the progression of TATMA in individuals is still remarkably unclear. The current study suggested that in comparison to renal TA-TMA, intestinal GVHD could be more closely associated with intestinal TATMA as a risk factor; although active intestinal GVHD was almost not observed during the autopsies due to the long duration from the HSCT (medianD,352X X 192 days). The association between TA-TMA and these risk factors has generally been examined as a whole, and the relationship with the affected organ has not been considered. It has been widely recognized that different etiologies showed different distributions of TMA in patients with other types of TMA; for example, Shiga toxinrelated hemolytic uremic syndromeD35X X typically results in renal dysfunction, but thrombotic thrombocytopenic purpuraD354X X rarely does [1], and the effect of risk factors on TA-TMA could be different among various organs. The important question is: how is intestinal GVHD associated D35X X with intestinal TA-TMA? Further D356X X studies are needed to clarify this. This study has several limitations. First, not all patients who D357X X had an HSCT were autopsied, which can potentially involve selection bias. Second, many patients in their terminal stage had several complications, which could have resulted in abnormal laboratory data and symptoms. Thus, the frequency and risk factors involving TA-TMA simply cannot be compared with other clinical studies of the general population after
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Table 5 Comparison between Renal TA-TMA Group and Intestinal TA-TMA GroupD6X X
904
Feature
905
Clinical characteristics
906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923
Age, median, and range (Dyr) 68X X Male/Dfemale 73X X Duration after HSCT, median and range (dD)80X X
Intestinal TA-TMA (n = 15) 42 (11D-62) 70X X
12 (67D)D74X X /6 75 X (33D)76X X
10 (67D)D7X X /5 78 X (33D)79X X
361 (28D-1530) 81X X
116 (61D-218) 82X X
95 X (7D)96X X 9 (60D)D92X X /3 93 X (20D)D94X X /1
MDSD/MLD 97X X /AA 98X X
0 (0D)D9X X /1 10 X (6D)D10X X /1 102 X (6D)103X X
2 (13D)D104X X /0 105 X (0D)D106X X /0 107 X (0D)108X X
4 (22D)D1X X /14 12 X (78D)13X X
5 (33D)D14X X /10 15 X (67D)16X X D17X X .43
Stem cell source 15 (83D)19X X
9 (60D)120X X
D12X X Peripheral blood
2 (11D)12X X
4 (27D)123X X
D124X X Cord blood
1 (6D)125X X
2 (13D)126X X
9 (50D)D130X X /9 13 X (50D)132X X
D140X X NonD 14X X 142XyeloabD mD X 143X X lative
12 (80D)139X X
2 (7D)14X X
3 (20D)145X X
TBID/TLI 147X X or otherD/D148X X none 149 X
13 (72D)D150X X /4 15 X (22D)D152X X /1 153 X (6D)154X X
GVHD prophylaxis
929
CSP (+ other)
10 (56D)16X X
7 (47D)162X X
TAC (+ other)
8 (44D)163X X
6 (40D)164X X
930 931 932 933 934 935 936 937
0 (0D)165X X
2 (13D)16X X 14 (93D)168X X
D169X X Skin
14 (78D)170X X
14 (93D)17X X
D173X X Liver
1 (6D)174X X
1 (7D)175X X
D176X X Gut
4 (22D)17X X
12 (80D)178X X
976 977 979 980 981 982
986 988 990 991 992
D160X X .41
16 (89D)167X X
CSP + TAC (+ other) A history of acute GVHD during the clinical course
975
989
158 X (27D)159X X 8 (53D)D15X X /3 156 X (20D)D157X X /4
928
974
987
D146X X .31
Radiation status
973
985
D136X X .64 16 (89D)138X X
972
984
7 (47D)D13X X /8 134 X (53D)135X X
Conditioning regimen
971
983
D127X X .85
HLA match status
925
969
978 D109X X .70
Donor source
D128X X Full matchD/mismatch 129X X
D83X X .006 D84X X .078
5 (28D)D87X X /9 8 X (50D)D89X X /2 90 X (7D)91X X
D18X X Bone marrow
D71X X .83 1
AMLD/ALLD 85X X 86X X /CML
RelatedD/unrelated 10X X
P Value D67X X
970 46 (23D-59) 69X X
Primary disease
D137X X Myeloablative
927
968 Renal TA-TMA (n = 18)
D72X X Sex
924 926
967
993 994 995 996
1 D172X X .35 1 D179X X .0016
Autopsy results
997 998 999 1000 1001 1002
938
Residual primary disease
4 (22D)180X X
2 (13D)18X X
D182X X .66
939
Other sites of TA-TMA (except the kidney and intestine)
0 (0D)183X X
4 (27D)184X X
D185X X .033
1004
940
Serositis
5 (28D)186X X
0 (0D)187X X
D18X X .049
1005
941
SOS
0 (0D)189X X
2 (13D)190X X
D19X X .20
1006
942
Active GVHD
5 (28D)192X X
7 (47D)193X X
D194X X .30
1007
943
D195X X Intestine
2 (7D)196X X
2 (13D)197X X
1
1008
13 (72D)198X X
11 (61D)19X X
1
1009
D20X X FocalD 201X X
4 (22D)20X X
5 (33D)203X X
D204X X .70
D205X X SystemicD 206X X
0 (0D)207X X
1 (7D)208X X
D209X X .45
FocalD210X X
6 (33D)21X X
2 (13D)21X X
D213X X .24
Systemic D214X X
5 (28D)215X X
2 (13D)216X X
D217X X .41
Protozoan (systemic)
0 (0D)218X X
1 (7D)219X X
D20X X .45
944
Infection
945
Virus
946 947 948 949 950 951 952 953
1010
Bacteria and/or fungus
Values are presented as number (%) unless otherwise indicated. Information about the renal and intestinal TMA overlap group (n = 5) is not included in Table 5.
956 957 958 959 960 961 962 963 964 965 966
1011 1012 1013 1014 1015 1016 1017 1018 1019
954 955
1003
HSCT, and the clinical effect of TA-TMA may be substantially underestimated. Third, various histologic criteria of intestinal TA-TMA have been proposed in biopsy studies [10,20,22], but it is often difficult to evaluate endothelial injury of the capillary in the lamina propria and other mucosal findings associated with TA-TMAD358X X due to the autolytic damage in autopsy specimens. Consequently, there is a significant possibility of underestimating the actual frequency of intestinal TA-TMA. Finally, our patients were autopsied after a comparatively long duration from HSCT (medianD,359X X 192 days), especially in the renal TA-TMA group (medianD,360X X 361 days). The onset of TA-TMA was usually within 150 days after HSCT [17], and an early
manifestation of TA-TMA may produce quite different data. However, our results are meaningful in terms of reliability, because of their confirmation by histologicD361X X findings and systemic evaluations, which can help exclude other complications that might clinically mimic TA-TMA and detect mild TA-TMA not producing major clinical manifestations and laboratory data.
1020 1021 1022 1023 1024 1025 1026 1027
CONCLUSIONS Here we systemically evaluated TA-TMA in the largest number of autopsied patients who had undergone an HSCT. We then found that the kidney and intestine were commonly
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ARTICLE IN PRESS R. Yamada et al. / Biol Blood Marrow Transplant && (2019) &&&&&&
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affectedD362X Xand that the ileum and right colon were vulnerable. It was also evident that other organs, including the stomach, gallbladder, oral cavity, pharynx, esophagus, liver, heart, urinary bladder, and ureter, can be affected by TA-TMA, although the frequencies involved were low and the clinical effects may be small. We also found that the histologicD36X o X verlap of renal TATMA and intestinal TA-TMA was rare; in comparison to renal TA-TMA, intestinal GVHD could be more closely associated with intestinal TA-TMA as a risk factor.
1041 1042 1043 1044 1045 1046 1047 1048
ACKNOWLEDGMENTS The authors thank Mikiko Hada for tremendous support on summarizing clinical data. Financial disclosure: The authors have nothing to disclose. Conflict of interest statement: There are no conflicts of interest to report.
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