Histologic Features of Intestinal Thrombotic Microangiopathy in Pediatric and Young Adult Patients after Hematopoietic Stem Cell Transplantation

Abstract

High-risk transplantation-associated thrombotic microangiopathy (TMA) can present with multisystem involvement and is associated with a poor outcome after hematopoietic stem cell transplantation (HSCT), with < 20% 1-year survival. TMA may involve the intestinal vasculature and can present with bleeding and ischemic colitis. There are no established pathologic criteria for the diagnosis of intestinal TMA (iTMA). The goal of our study was to identify histologic features of iTMA and describe associated clinical features. We evaluated endoscopic samples from 50 consecutive HSCT patients for 8 histopathologic signs of iTMA and compared findings in 3 clinical groups based on the presence or absence of systemic high-risk TMA (hrTMA) and the presence or absence of clinically staged intestinal graft-versus-host disease (iGVHD): TMA/iGVHD, no TMA/iGVHD, and no TMA/no iGVHD. Thirty percent of the study subjects had a clinical diagnosis of systemic hrTMA. On histology, loss of glands, intraluminal schistocytes, intraluminal fibrin, intraluminal microthrombi, endothelial cell separation, and total denudation of mucosa were significantly more common in the hrTMA group (P < .05). Intravascular thrombi were seen exclusively in patients with hrTMA. Mucosal hemorrhages and endothelial cell swelling were more common in hrTMA patients but this difference did not reach statistical significance. Patients with hrTMA were more likely to experience significant abdominal pain and gastrointestinal bleeding requiring multiple blood transfusions (P < .05). Our study shows that HSCT patients with systemic hrTMA can have significant bowel vascular injury that can be identified using defined histologic criteria. Recognition of these histologic signs in post-transplantation patients with significant gastrointestinal symptoms may guide clinical decisions.

Keywords: Endothelial injury; Graft-versus-host disease TA-TMA; Intestinal thrombotic microangiopathy; Thrombotic microangiopathy (TMA).

Figure 1

Histologic samples showing mucosal hemorrhage (H&E, biopsies from 4 iTMA patients, A–C: colon, original magnification ×100, ×400, ×600, respectively, D: stomach, ×400). (A) Patchy distribution of fragmented RBC extravasation located at and/or close to the disrupted capillaries in the lamina propria. (B–C) Capillaries demonstrate fragmented RBC extravasation with partial (B, black arrow) and total (C, clear arrow) disruption of the wall. (D) Hemosiderin deposits (stained brown) and hemosiderin-laden macrophages represent remote mucosal hemorrhage. Nikon Eclipse 80i, 10x/0.30, 40x/0.75, 60x/0.85, Diagnostic Instruments 14.2 Color Mosaic, Spot software.

Figure 2

Histologic samples showing loss of glands and mucosal denudation (H&E, biopsies from 3 iTMA patients, A–B: colon, original magnification ×100, C: colon, original magnification ×200). (A–C) The surface epithelium is denuded. The lamina propria shows significant (> 50%) gland loss, appears fibrotic (B, asterisk), and is partially replaced by regenerated epithelium (C, black arrows). Nikon Eclipse 80i, 10x/0.30, 20/0.75, Diagnostic Instruments 14.2 Color Mosaic, Spot software.

Figure 3

Histologic samples showing intraluminal schistocytes, fibrin and microthrombi as well as endothelial cell swelling and separation. (A–B) Intraluminal schistocytes (H&E, biopsies from 2 iTMA patients, colon, original magnification ×400). Fragmented and degenerated RBCs (asterisk) are present within the capillaries. (C–D) Intraluminal fibrin (H&E, biopsies from 2 iTMA patients, C: esophagus, original magnification ×400, D: colon, original magnification ×400). Capillaries demonstrate fibrin debris in the lumen. Note the fibrin is present in the space between separated endothelial cells (black arrows) and the basement membrane. (E–F) Intraluminal microthrombi (H&E, biopsies from 2 iTMA patients, colon, original magnification ×400). Capillaries are totally occluded by fibrin (clear arrow). (G) Endothelial cell swelling (H&E, biopsies from 2 iTMA patients, colon, original magnification ×400). Capillaries are lined by endothelial cells (asterisk) with enlarged nuclei > 3 times wider than the normal nuclei. (H) Endothelial cell separation (H&E, biopsies from 2 iTMA patients, colon, original magnification ×400). The endothelial cells are separated from the basement membrane (double arrow). Nikon Eclipse 80i, 40x/0.75, Diagnostic Instruments 14.2 Color Mosaic, Spot software.