Histologic Features of Intestinal Thrombotic Microangiopathy in Patients with High Risk TMA after HSCT

Introduction

We showed that high risk transplant-associated thrombotic microangiopathy (TMA) can present with multisystem involvement and has poor outcome after HSCT with <20% 1-year survival (Jodele, Blood 2014). TMA may involve intestinal vasculature and can present with bleeding and ischemic colitis.  There are no established pathologic criteria for diagnosis of intestinal TMA (iTMA).  The goal of our study was to review available tissue specimens obtained after HSCT in order to identify histologic features of iTMA.

Methods

Fifty consecutive HSCT patients who underwent endoscopy for gastrointestinal symptoms were evaluated for histopathologic signs of iTMA using 8 histologic criteria described in literature: mucosal hemorrhages, loss of glands, schistocytes, fibrinoid debris in the vessel lumen, intravascular microthrombi, endothelial cell swelling, endothelial cell separation and total denudation of mucosa (Figure).  The reviewing pathologist was blinded to patients' clinical history.  Histologic markers were listed as present or absent. For patients having multiple evaluations after HSCT, the first diagnostic tissue sample was used for this study.   Patients were divided into 3 clinical groups based on the presence or absence of systemic TMA and intestinal graft versus host disease (iGVHD): TMA/iGVHD, no TMA/iGVHD, and noTMA/no iGVHD. Systemic TMA was diagnosed using rigorous clinical and diagnostic criteria.  Comparison among the groups was done using Fisher exact test.

Results

Fifteen patients (30%) had a clinical diagnosis of systemic TMA. Out of 35 patients without TMA, 21 had clinical and histologic evidence of gut GVHD while 14 did not.  Incidence of stage 3-4 gut GVHD was similar in the TMA/iGVHD and noTMA/iGVHD groups (79% vs 64%). All histologic signs of iTMA except for mucosal hemorrhages and endothelial cell swelling were significantly more common in patients with systemic TMA (p<0.05). Intravascular thrombi were exclusively seen only in patients with systemic TMA (Table).

Conclusions

We identified histologic features of iTMA that can be used to delineate vascular injury of the bowel in patients with TMA after HSCT.  Recognition of these histological signs in patients with gastrointestinal symptoms after HSCT may guide clinical decisions.

Table: Histologic features in patients with TMA and without

HSCT patients with gastrointestinal symptoms (n=50)
	TMA/iGVDH n=15	No TMA/iGVDH n=21	No TMA/no iGVDH n=14	p=value
Mucosal hemorrhages	12 (80%)	11 (52.4%)	5 (36%)	0.057
Loss of glands	11 (73.3%)	8 (38%)	0 (0%)	<0.0001
Intravascular schistocytes	10 (66.7%)	5 (23.8%)	3 (21.4%)	0.016
Intravascular fibrinoid debris	8 (53.3%)	2 (9.55%)	2 (14%)	0.008
Intravascular microthrombi	4 (26.6%)	0 (0%)	0 (0%)	0.010
Endothelial cell swelling	13 (86.6%)	13 (61.9%)	7 (50%)	0.086
Endothelial cell separation	8 (53.3%)	3 (14.3%)	1 (7%)	0.007
Total denudation of mucosa	7 (46.7%)	3 (14.3%)	0 (0%)	0.005