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A Complete Histologic Approach to Gastrointestinal Biopsy From Hematopoietic Stem Cell Transplant Patients With Evidence of Transplant-Associated Gastrointestinal Thrombotic Microangiopathy.

Thrombotic microangiopathy (TMA) is characterized by microvascular endothelial cell injury and associated thrombosis. Thrombotic microangiopathy is best known as the main pathologic feature of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome in the kidney. (1) However, the same pattern of microvascular injury occurs in many other conditions, including systemic sclerosis, lupus nephritis, acute radiation injury, calcineurin inhibitor toxicity, and infections, and in association with rejection of solid organs in allograft transplant. Thrombotic microangiopathy can occur systemically in many organs, including the lungs, skin, and gastrointestinal (GI) tract. (2)

Transplant-associated TMA (TA-TMA) is a recognized complication of hematopoietic stem cell transplant (HSCT). (2) Transplant-associated TMA has been reported in both autologous and allogeneic HSCT. (3) Chemotherapeutic agents, radiation, infections, immunosuppressive medications, and graft-versus-host disease (GVHD) have all been shown to either contribute to or worsen the endothelial damage seen in TA-TMA. A high-risk phenotype of TA-TMA marked by significant nephrotic-range proteinuria and complement activation can potentially involve the GI tract, and a growing body of evidence exposes this diagnosis as a real threat contributing to poor patient survival. (4,5) Intestinal TA-TMA (iTMA) presents with a constellation of clinical symptoms, similar in nature to acute intestinal GVHD (iGVHD), infections, or drug-induced colitis. (6,7) Therefore, defining histologic criteria is crucial for clinicians to make management decisions that improve overall outcome.

The purpose of this paper is to present detailed descriptions of iTMA, targeting a clinical transplant and pathology audience who may encounter GI mucosal biopsy specimens from HSCT patients presenting with severe GI symptoms, where the differential diagnosis includes infections and GVHD. It is of the utmost importance that the intestinal vasculature, including capillaries of the lamina propria (LP), be fully assessed when reviewing biopsies from HSCT recipients. The discovery of features consistent with iTMA has immediate implications for clinical management that could improve outcome and survival.

PATHOPHYSIOLOGY AND CLINICAL FEATURES

Intestinal TA-TMA is one of the manifestations of systemic TA-TMA. Clinicians and researchers continue to delineate clearer diagnostic criteria for TA-TMA, using a combination of serum laboratory testing and clinical parameters. Serum markers of TA-TMA include elevated lactate dehydrogenase, de novo thrombocytopenia not explained by other post-HSCT complications, Coombs test-negative hemolytic anemia (often hallmarked by increased free plasma hemoglobin and decreased haptoglobin), peripheral schistocytes, and signs of renal dysfunction (proteinuria and elevated creatinine). Transplant-associated TMA may worsen to include dysfunction in multiple organ systems. (6) Patients may have systemic hypertension that is refractory to multiple agents, hypoxemia and respiratory distress from pulmonary hypertension resulting from the injury of lung microvasculature, pericardial effusion or tamponade from pericarditis, and unexplained neurologic dysfunction. (8-11)

Previous retrospective reports have estimated the incidence of TA-TMA at 5% to 10%, possibly capturing only the most severe TMA cases. (12-14) In a prospective trial with routine screening of laboratory markers, 39% of HSCT recipients were found to meet the diagnosis of TA-TMA. (6) About half of these patients presented with TA-TMA-associated multi-organ injury. This study identified a subset of patients with a high-risk TA-TMA (hrTA-TMA) phenotype, associated with considerable morbidity and mortality. These patients presented with nephrotic-range proteinuria (an elevated protein to creatinine ratio >2 mg/mg), usually in the absence of persistent hypoalbuminemia, and activation of the terminal complement complex, characterized by an elevation of soluble C5b-9 in blood. In this study, 10 of 39 TA-TMA patients (25.6%) were found to have hrTA-TMA together with significant GI bleeding associated with abdominal pain. (2,6) Deleterious microangiopathic changes in the GI vasculature likely contributed to their symptoms.

Many transplant centers conclude that GI symptoms of bleeding and pain are explained by refractory grade 3 to 4 iGVHD, infection, and/or drug-associated gastroenteritis. Intestinal GVHD is also hallmarked by voluminous diarrhea and cramping. However, once GVHD treatment is initiated and diarrhea subsides, some patients experience persistent severe abdominal pain due to TA-TMA-associated ischemia and GI bleeding, requiring significant narcotic use and frequent blood transfusion support. Additionally, patients with iTMA often pass sloughed mucosal lining per rectum. Inamoto et al (15) retrospectively reviewed HSCT patients who had received endoscopies for significant GI symptoms. In this study, individuals with iTMA experienced intestinal bleeding that did not respond to immunosuppressive therapies targeting GVHD. The authors concluded that iTMA is underdiagnosed and might even be more prevalent than iGVHD. Our own group showed that patients with both iGVHD and iTMA more commonly experience bleeding and pain than patients with iGVHD alone. (7) Other reports have also pointed out the significance of severe abdominal pain requiring heavy narcotic use and bleeding with frequent transfusions after resolution of diarrhea as a hallmark of ongoing iTMA. (16-18)

Immunosuppressive agents such as calcineurin inhibitors used to prevent and actively treat GVHD may worsen TA-TMA. Indeed, patients with iTMA who may be mislabeled as having refractory acute iGVHD may have worse outcomes when calcineurin inhibitors are continued. Symptoms of iTMA have been successfully reversed in patients whose calcineurin inhibitors are discontinued and replaced by other medications. Fujino et al (19) successfully initiated and then reversed histologic and clinical signs of iTMA in rats exposed to tacrolimus. Additional clinical reports have shown that calcineurin inhibitors contribute to the development of systemic TMA in both humans and animals after both HSCT and solid organ transplantation. (20-23) However, the very real risk of exacerbating acute GVHD as a result of lowering or even discontinuing certain immunosuppressive agents underscores the need for careful pathologic study of bowel wall biopsies to delineate signs of ongoing iGVHD and/or iTMA.

Despite the known effects of medications like calcineurin inhibitors, the exact mechanism of histopathologic damage in iTMA remains largely unknown. Luft et al (24) proposed a model in which certain patients' initial endothelial insult is secondary to a T-cell-mediated (GVHD-related) mechanism of action followed by further damage secondary to a progressive microangiopathy. Patients were shown to have elevated markers, including angiopoietin 2, chemokine IL-8, hepatocyte growth factor, soluble thrombomodulin, and serum nitrates. Some of these markers may be elevated even prior to transplant, and may be prognostic markers for poorer outcome. However, histologically proven iTMA has been documented in both the autologous stem cell and solid organ transplant settings, where an alloreactive T-cell-mediated GVHD is highly unlikely. (3,22,23) Despite this, endothelial damage within the gut is likely an extension of systemic terminal complement activation, a published finding in patients with hrTA-TMA in both the allogeneic and autologous settings. As such, GI symptoms consistent with iTMA have been treated successfully with terminal complement blockers. (2,4,25,26)

PATHOLOGY

Morphologic Features

Renal disease was one of the first manifestations reported in TA-TMA patients and histologic analysis was found to be helpful when assessing the severity. (27-31) Patients with systemic TA-TMA can present with iTMA with or without renal involvement. (2) Although the pathogenesis of TA-TMA in HSCT patients is not fully understood, the histologic hallmark of both renal TMA and iTMA is endothelial cell injury. The same histologic approach used to evaluate renal TA-TMA is useful to assess iTMA. Histologic analysis typically displays various degrees of endothelial cell injury, with or without hemorrhage and thrombosis of capillaries, arterioles, and arteries; the features of the vessels are similar to those seen in renal TA-TMA. (2,32,33) Endoscopic examination, in which GI mucosal biopsies are taken, is standard procedure in most transplant centers to help determine the cause of GI symptoms post-HSCT. Histology of the mesenteric vasculature (small to middle-sized arteries) in resection specimens from these patients has been reported to display intimal hyperplasia, myxoid degeneration of the vessel walls, endothelial irregularities, thrombi, and expansion of the subendothelial spaces with the deposition of intraluminal fibrin. (21,34-36)

Currently, histologic analysis is performed mainly to assess for the presence or absence of iGVHD, infections, and drug-related changes. Detailed microscopic examination of mucosal vasculature for iTMA is not commonly performed because of the clinical focus on iGVHD. Gastrointestinal mucosal biopsies usually contain mucosa with surface and crypt epithelium as well as LP. Biopsies often do not contain deeper structures, such as the submucosa or muscularis layers, in which larger vessels (arterioles and arteries) have been used to fully appreciate changes indicative of iTMA. The concern that biopsy samples from endoscopy may not contain sufficient vasculature for assessing iTMA is frequent. However, multiple transplant centers have presented endoscopic and histologic data and findings from capillaries in the LP. Indeed, biopsies from post-HSCT patients experiencing pain and bleeding can show a significant presence of iTMA. (7,15-17,37,38)

Nishida et al (17) published findings of 16 HSCT patients found to have histopathologic findings consistent with iTMA. Seven patients died, and postmortem analysis of GI tissues displayed fibrinoid necrosis of terminal arterioles within the deep mucosa, extravasation of fragmented red blood cells (RBCs) around affected vessels, and extensive crypt depletion in the tip of mucosal folds. Endoscopic examination of 9 patients showed features consistent with iGVHD, such as edematous and erythematous mucosa with areas of ulcer and bleeding. However, careful review of histologic findings identified iTMA. Histologic features included frequent perivascular hemorrhages with hemosiderin and capillary thrombosis, both granular and hyaline in appearance, which were confirmed as platelet associated using immunostaining for CD41a and von Willebrand factor. Narimatsu et al (16) reported on their experience of 123 cord blood HSCT patients, with 7 exhibiting signs of iTMA. Pathologic diagnosis was based on the presence of all 3 of the following histologic signs: widening of subendothelium with myxoid degeneration, intraluminal thrombus formation, and fibrinoid necrosis of terminal arterioles. Inamoto et al (15) claimed that 92% of HSCT patients who underwent endoscopic biopsies had findings consistent with iTMA. The histologic diagnostic criteria of iTMA were not well defined in this report. However, the same histopathologic criteria were applied to a work published later by Yamada-Fujiwara et al, (38) which analyzed treatment strategies for patients with iTMA and/or GVHD. The histopathologic features used in both these publications included the presence of endothelial cell swelling, endothelial cell denudation, noninflammatory crypt loss, wedge-shaped segmental ischemic injury, and interstitial edema with perivascular hemorrhage of fragmented RBCs. The presence of incomplete regeneration and residual neuroendocrine cells has been suggested as an additional identifier for iTMA. (15) Stains for chromogranin A, CD56, or synaptophysin were used to delineate these features; however, the clinical utility is unclear. The presence of thrombi was not required for an iTMA diagnosis.

Our group reported GI biopsy findings in 50 post-HSCT patients using 8 histologic criteria accrued from the publications mentioned above. Patients were divided into 3 clinical study groups based on the presence or absence of systemic hrTA-TMA and clinical iGVHD. Six of 8 histologic features, including endothelial cell separation, intraluminal schistocytes, intraluminal fibrin, intraluminal microthrombi, loss of glands, and mucosal denudation, were statistically increased in patients who met all the parameters for hrTA-TMA. Intravascular microthrombi were seen in 26.5% of patients with hrTA-TMA and iGVHD, a feature exclusive to patients with hrTA-TMA and not seen in patients with iGVHD who did not have hrTA-TMA. Perivascular mucosal hemorrhages and endothelial cell swelling were seen more commonly in patients with hrTA-TMA, but these differences did not reach statistical significance. Our study showed that specific histologic criteria were useful to assess and diagnose iTMA in patients suffering from significant abdominal pain and GI bleeding requiring frequent transfusions. (7)

Below we provide a detailed pathologic description of the histologic features of iTMA. The features are also summarized in Table 1.

Perivascular Mucosal Hemorrhage.--Perivascular mucosal hemorrhage is defined as perivascular RBC extravasation from capillaries into the interstitium of the LP. It is important to distinguish this from procedure-related hemorrhage, which is typically diffuse in distribution, is located in the LP close to the surface epithelium, and contains fresh, relatively intact RBCs. In contrast, perivascular mucosal hemorrhage associated with iTMA typically contains fragmented and/or degenerated RBCs. The hemorrhages can present in a patchy distribution at and/or close to the disrupted blood vessels located in the LP (Figure 1, A through C). At times, capillaries can appear totally effaced and replaced by hemorrhage. Remote hemorrhage can be replaced by hemosiderin, and the areas may be infiltrated by hemosiderin-laden histiocytes (Figure 1, D).

Endothelial Cell Swelling.--Endothelial cell swelling is defined as nuclear enlargement of the endothelial cells of the LP capillaries. We use a tentative criterion defining swelling as nuclear width of approximately more than 3 times wider than the normal width of endothelial nuclei in more than 50% of the LP capillaries (Figure 2, A and B). Figure 2, C, shows an atrophic gland with thinned epithelial cells and apoptotic bodies, which should not be confused with a vessel exhibiting endothelial cell swelling.

Endothelial Cell Separation.--Endothelial cell separation is defined as endothelial cell detachment from the basement membrane in LP capillaries. As seen in glomerular capillaries in cases with renal TMA, separation of the endothelium from the underlying basement membrane and production of new basement membrane layer(s) are also seen in iTMA, which leads to a double-contour appearance of the capillary walls (Figure 3, A and B, arrows). We consider that a biopsy includes this feature when at least 1 LP or submucosal capillary exhibits endothelial cell separation.

Intraluminal Schistocytes.--Intraluminal schistocytes are defined by the presence of fragmented and/or degenerated RBCs within the LP capillaries. We consider that a biopsy includes this feature when fragmented RBCs make up more than 50% of total RBCs observed in at least 50% of the LP capillaries (Figure 4, A through C).

Intraluminal Fibrin.--Intraluminal fibrin is defined by the presence of fibrin material in at least 1 capillary in the LP and/or submucosa. The fibrin material is frequently present in the space between the separated endothelial cells and the underlying basement membrane (Figure 5, A through C). The fibrin material is sometimes admixed with fragmented RBCs (Figure 5, A, arrows) and is often present in the space between the separated endothelial cells and the basement membrane (Figure 5, B and C, arrowheads). Condensed intraluminal serum protein material, which is a thinner, paler pink, translucent material, needs to be clearly differentiated from true intraluminal fibrin.

Intraluminal Microthrombi.--Intraluminal microthrombi are defined by the presence of thrombi with or without organization, occluding at least 1 capillary or small arteriole in the LP and/or submucosa (Figure 6, A and B). The endothelial cells may appear necrotic and denuded (Figure 6, B).

Loss of Glands.--We define loss of glands as an unequivocal count of greater than 50% reduction in the number of observed glands. Gastrointestinal biopsies should contain approximately 50 to 60 glands, 20 to 30 glands, and 10 to 20 glands per high-power field (X400) in the gastric fundus, gastric antrum, and colon, respectively. Spaces between glands are usually markedly widened, and the intervening stroma shows fibroplasia with or without hyalinization (Figure 7, A and B). Frequent crypt epithelial apoptosis and atrophic, vanishing glands are also commonly seen in iGVHD. However, observing loss of glandular architecture in the context of the vascular findings described herein should warrant conservative consideration of iTMA as a primary or additional pathology for evolving clinical symptoms.

Mucosal Denudation.--Mucosal denudation is defined as the removal or loss of surface epithelium in at least 1 tissue fragment. Distinguishing this from mucosal detachment directly associated with the endoscopic procedure can be challenging. However, mucosal denudation from iTMA is often associated with significant gland loss and the appearance of a single layer of regenerative enterocytes and a fibrotic and/or hyalinized interstitial stroma in the LP (Figure 7, A and B). Denuded surface replaced by a single layer of regenerative enterocytes is also shown in Figure 7, A and B (arrows). These features are likely representative of a subacute or chronic phase of ischemia and can also be seen in iGVHD and severe drug-induced mucosal injury. Denudation of mucosa in the context of vascular findings described herein should warrant conservative consideration of iTMA as a primary pathology for evolving clinical symptoms.

Immunostains.--Evaluation for histologic findings diagnostic of TMA requires only staining with routine hematoxylin-eosin; additional stains are unnecessary. Despite this, previous studies have shown immunostaining for markers of clot formation (CD41, von Willebrand factor), and markers to assess the degree of crypt neuroendocrine cell degeneration (chromogranin A, CD56, or synaptophysin) may be helpful. However, the clinical importance of these stains is not clear.

Complement activation is a well-studied mechanism contributing to TA-TMA. Staining for deposition of various complement components in the endothelial linings may be informative. Immunostains for the complement component C4d in particular have appeared in studies evaluating renal TA-TMA cases. (27) Additional prospective trials are required to define the utility of immunostains in the diagnosis of iTMA.

Differential Diagnosis

Acute iGVHD.--Major histologic features of acute iGVHD include the appearance of apoptotic bodies in crypt epithelial cells, most frequently in the lower GI tract. (39-42) In more severe cases, crypt abscesses, destruction and loss of crypts, ulceration of surface epithelium, and finally total denudation of the mucosa are seen. Grading systems for acute iGVHD have been proposed (Table 2). (43,44) However, correlation with clinical manifestations and outcomes is weak, and there is no clear consensus among pathologists. (41,42,45) Many cases of iTMA may show overlapping findings consistent with high-grade iGVHD, including rather nonspecific features of mucosal injury including loss of crypts, ulceration, and mucosal denudation. Again, the histologic hallmark of iTMA is endothelial injury. The LP vasculature must be carefully examined even when features of iGVHD are appreciated.

Cytomegalovirus infection.--Cytomegalovirus (CMV) infection is a well-known complication of HSCT; it infects endothelial cells and can lead to vasculitis. (46) Therefore, patients with CMV infection may present with similar severe hematochezia secondary to ischemia caused by the endothelial injury. Infected endothelial cells are enlarged and show characteristic cytoplasmic and nuclear viral inclusions (Figure 8). Serum CMV DNA load, measured by polymerase chain reaction, can assist in clinical management but does not always correlate with evidence of GI CMV infection. Immunohistochemical stain for CMV antigen is also available, and may be used to confirm the presence of the viral products.

Drugs Associated With iTMA.--Pathologists working with HSCT patients must be aware of drugs associated with TMA. These include immunosuppressive agents used to treat and prevent GVHD, such as calcineurin inhibitors (eg, tacrolimus and cyclosporine) and sirolimus. (47) Although GI symptoms (nausea, vomiting, diarrhea, and abdominal pain) are reported, the histologic features of drug-induced iTMA have not been well studied. It is likely that these patients may exhibit findings similar or identical to what is described herein.

SUMMARY AND RECOMMENDATIONS

The histologic hallmark of iTMA is endothelial cell injury, not unlike findings seen in acute hemolytic uremic syndrome or thrombocytopenic purpura patients with renal microangiopathy. The endothelial cell injury is likely associated with complement activation. Various degrees of endothelial cell injury are present in iTMA and range from endothelial cell swelling or separation to necrotic microangiopathy in severe cases. Injured endothelial cells induce the coagulation cascade and the involved vessel is engulfed by intraluminal fibrin, which can be observed in biopsies. Some vessels may be totally occluded, exhibiting microthrombi. Intraluminal microthrombi may be a sign exclusive to TATMA patients with a high-risk phenotype. We believe the histologic features described above are useful to systematically assess and diagnose iTMA. Accurate identification of iTMA patients will allow for appropriate management changes that may improve outcome and overall survival. Pathologists reviewing HSCT patients' endoscopic biopsies must evaluate both epithelial and endothelial compartments, and must be familiar with the clinical changes associated with iTMA, iGVHD, and GI viral infections.

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Mikako Warren, MD; Sonata Jodele, MD; Christopher Dandoy, MD; Kasiani C. Myers, MD; Gregory Wallace, MD; Adam Nelson, MBBS; Javier El-Bietar, MD

Accepted for publication February 9, 2017.

Published as an Early Online Release August 10, 2017.

From the Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California (Dr Warren); and the Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (Drs Jodele, Dandoy, Myers, Wallace, Nelson, and El-Bietar).

Dr Jodele served as a consultant for a Novartis (Basel, Switzerland) clinical trial and has a US provisional patent application for methods and compositions related to transplant-associated thrombotic microangiopathy. The other authors have no relevant financial interest in the products or companies described in this article.

Reprints: Mikako Warren, MD, Children's Hospital Los Angeles, 4650 Sunset Blvd, MS 43, Los Angeles, CA 90027 (email: miwarren@ chla.usc.edu).

Please Note: Illustration(s) are not available due to copyright restrictions

Caption: Figure 1. Perivascular mucosal hemorrhage (gastrointestinal biopsies from high-risk transplant-associated thrombotic microangiopathy patients). A, Stomach. B, Stomach. C, Colon. D, Stomach. Perivascular mucosal hemorrhage is defined as red blood cell (RBC) extravasation from lamina propria capillaries (A through C). Unlike procedure-related hemorrhage, this appears in a patchy distribution at and/or close to where the disrupted vessels are located and contains fragmented and/or degenerated RBCs. Remote hemorrhage can be replaced by hemosiderin, and the areas may be infiltrated by hemosiderin-laden histiocytes (D, arrowheads) (hematoxylin-eosin, original magnifications X200 [A] and X400 [B through D]).

Caption: Figure 2. Endothelial cell swelling (gastrointestinal biopsies from high-risk transplant-associated thrombotic microangiopathy patients). A, Stomach. B, Stomach. C, Colon. Endothelial cell swelling is defined by enlargement of endothelial cells of the lamina propria capillaries (A [arrowhead] and B). C, An atrophic gland with thinned epithelial cells and apoptotic bodies, which should not be confused with a vessel exhibiting endothelial cell swelling (hematoxylin-eosin, original magnifications X200 [A] and X400 [B and C]).

Caption: Figure 3. Endothelial cell separation (gastrointestinal biopsies from high-risk transplant-associated thrombotic microangiopathy patients). A, Colon. B, Colon. Endothelial cell separation is defined by endothelial cell detachment from the basement membrane (A and B, arrows) and can take a double contour appearance. An atrophic gland is also present (A, arrowhead) (hematoxylin-eosin, original magnification X400).

Caption: Figure 4. Intraluminal schistocytes (gastrointestinal biopsies from high-risk transplant-associated thrombotic microangiopathy patients). A, Colon. B, Colon. C, Colon. Intraluminal schistocytes are defined by the presence of fragmented and/or degenerated red blood cells within the lamina propria (LP) capillaries (A through C). The LP capillaries, seen here transversely (A) and in cross section (B and C), also show prominent endothelial cell swelling. A vanishing atrophic gland is also present (C, arrowhead) (hematoxylin-eosin, original magnification X400).

Caption: Figure 5. Intraluminal fibrin (gastrointestinal biopsies from high-risk transplant-associated thrombotic microangiopathy patients). A, Stomach. B, Colon. C, Colon. Intraluminal fibrin is defined by the presence of fibrin material within the lamina propria capillaries. The fibrin material is sometimes admixed with fragmented red blood cells (A, arrows). The fibrin material is often present in the space between the separated endothelial cells and the basement membrane (B and C, arrowheads). The capillaries also show prominent endothelial cell swelling (hematoxylin-eosin, original magnification X400).

Caption: Figure 6. Intraluminal microthrombi (gastrointestinal biopsies from high-risk transplant-associated thrombotic microangiopathy patients). A, Stomach. B, Colon. Intraluminal microthrombi are defined by the presence of fibrin material occluding the lamina propria capillaries (A and B, arrows). The endothelial cells can appear necrotic and denuded in the capillaries (B) (hematoxylin-eosin, original magnification X200).

Caption: Figure 7. Loss of glands and mucosal denudation (gastrointestinal biopsies from high-risk transplant-associated thrombotic microangiopathy patients). A, Colon. B, Colon. Loss of glands is delineated by vanishing and atrophic glands. Spaces between glands are markedly widened and intervening stroma show fibroplasia (A and B). Mucosal denudation is defined by denudation of surface epithelium, which is often replaced by a single layer of regenerative enterocytes (A and B, arrows) (hematoxylin-eosin, original magnification X100).

Caption: Figure 8. Cytomegalovirus-associated colitis (biopsy from a hematopoietic stem cell transplant recipient). Colon. The endothelial cells are enlarged with both cytoplasmic (arrow) and nuclear (arrowheads) viral inclusions (hematoxylin-eosin, original magnification X400).
Table 1. Summary of Histologic Criteria of Intestinal
Thrombotic Microangiopathy

Histologic             Definition                   Source, y
Criteria

Perivascular    Patchy interstitial         El-Bietar et al, (7)
mucosal         hemorrhage containing       2015;Inamoto et al, (15)
hemorrhage      fragmented and-or           2009;Narimatsu et al,
                degenerated RBCs at and     (16) 2005; Nishida et al,
                close to where LP           (17) 2004; Yamamoto et
                capillaries are             al, (18) 2009;Hewamana et
                located;remote hemorrhage   al, (34) 2009
                can be replaced by
                hemosiderin and the area
                can be infiltrated by
                hemosiderin-laden
                macrophages.

Endothelial     Presence of endothelial     El-Bietar et al, (7)
cell swelling   nuclear enlargement of LP   2015;Inamoto et al, (15)
                capillaries (>3X normal     2009; Yamamoto et al,
                nuclear size in >50% of     (18) 2009
                LP capillaries).

Endothelial     Endothelial cell            El-Bietar et al, (7)
cell            detachment from the         2015;Inamoto et al, (15)
separation      basement membrane in at     2009; Narimatsu et al,
                least 1 capillary in LP     (16) 2005
                and/or submucosa in a
                biopsy.

Intraluminal    Presence of fragmented      El-Bietar et al, (7)
schistocytes    and/or degenerated RBCs     2015;Yamamoto et al, (18)
                (schistocytes) within LP    2009
                capillaries;>50% of RBCs
                should be schistocytes in
                at least 50% of
                capillaries.

Intraluminal    Fibrin material in at       El-Bietar et al, (7)
fibrin          least 1 capillary or        2015;Narimatsu et al,
                arteriole in LP and/or      (16) 2005;Nishida et al,
                submucosa in a biopsy.      (17) 2004

Intraluminal    Presence of thrombus with   El-Bietar et al, (7)
microthrombi    or without organization     2015;Inamoto et al, (15)
                occluding at least 1        2009; Narimatsu et al,
                capillary or arteriole in   (16) 2005; Nishida et al,
                LP and/or submucosa in a    (17) 2004; Yamamoto et
                biopsy.                     al, (18) 2009

Loss of         An unequivocal count of     El-Bietar et al, (7)
glands          >50% reduction in the       2015;Inamoto et al, (15)
                number of observed          2009; Nishida et al, (17)
                glands;in addition, the     2004; Yamamoto et al,
                spaces between glands are   (18) 2009
                markedly widened with
                intervening stroma, which
                is often florotic.

Mucosal         Denudation of surface       El-Bietar et al, (7)
denudation      epithelium in at least 1    2015;Inamoto et al, (15)
                tissue fragment.            2009; Hewamana et al,
                                            (34) 2009

Abbreviations: LP, lamina propria;RBC, red blood cell.

Table 2. Grading Schema for Intestinal Graft-Versus-Host Diseasea

Grade                           Description

1       Epithelial cell necrosis in the form of crypt apoptotic
        cells in an often noncontiguous pattern;minimal criterion is
        a single or rare apoptotic crypt cell with or without
        accompanying adjacent lymphocytic infiltrate.

2       Noncontiguous crypt loss;the appearance of apoptotic crypt
        abscess with dilated walls lined by thinned epithelium
        devoid of mucin. There may be the presence of lymphocytes,
        neutrophils, or eosinophils infiltrating the interstitium,
        crypt abscess, or crypt wall.

3       Crypt loss involving contiguous stretches of mucosa with
        some focal ulceration.

4       Mucosal denudation, widespread ulceration, and extensive
        loss of surface epithelium-crypts resulting in empty
        expanses of lamina propria;there may be granulation tissue,
        areas of hemorrhage, or dilated small vessels with reactive-
        appearing endothelium with or without infiltration of a
        mixed population of leukocytes.
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Author:Warren, Mikako; Jodele, Sonata; Dandoy, Christopher; Myers, Kasiani C.; Wallace, Gregory; Nelson, Ad
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Report
Date:Nov 1, 2017
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