The role of the endothelium in the short-term complications of hematopoietic SCT.

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Abstract

In this review, we analyse the role of the endothelium in the development of several complications that appear soon after haematopoietic SCT (HSCT). Once it had been demonstrated that sinusoidal damage is the initiating event of the sinusoidal obstruction syndrome, it was considered that other short-term complications with overlapping clinical manifestations, such as capillary leak syndrome, engraftment syndrome, transplant-associated microangiopathy, diffuse alveolar haemorrhage and idiopathic pneumonia syndrome, could have an endothelial origin. During HSCT, endothelial cells (ECs) are activated and damaged by several factors, including conditioning, cytokines released by damaged tissues, endotoxins translocated through damaged mucosa, drugs used in the procedure, the engraftment, and--in the allogeneic setting--immunological reactions. The different clinical syndromes that occur could be determined by the predominant phenotypic change in the ECs and the location of this change (organ dependant or systemic). Several translational studies have provided evidence of this endothelial dysfunction on the basis of analysis of soluble markers, soluble forms of adhesion molecules, the enumeration of circulating ECs and microparticles, and morphologic and functional changes induced in cultured ECs. This increased knowledge has opened up a wide range of potential pharmacologic interventions to prevent or treat endothelial damage and, consequently, to improve the outcome of patients receiving HSCT.

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Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients.

G B McDonald, M Hinds, L Fisher … (1993)

To determine the incidence and clinical course of veno-occlusive disease of the liver (VOD) after bone marrow transplantation and to analyze risk factors for severe VOD. Cohort study of 355 consecutive patients. A bone marrow transplantation center. Each patient was prospectively evaluated for VOD, and many risk factors for severe VOD were analyzed using logistic regression models. The relation of VOD to renal and cardiopulmonary failure was analyzed using time-dependent proportional hazards models. Veno-occlusive disease developed in 190 of 355 patients (54%; 95% CI, 48% to 59%): Fifty-four patients had severe VOD and 136 had mild or moderate VOD. Independent variables derived from a multivariate model for predicting severe VOD included elevated transaminase values before transplantation (relative risk, 4.6; P < 0.0001); vancomycin therapy during cytoreductive therapy (relative risk, 2.9; P = 0.003); cytoreductive therapy with a high-dose regimen (relative risk, 2.8; P = 0.01); acyclovir therapy before transplantation (relative risk, 4.8; P = 0.02); mismatched or unrelated donor marrow (relative risk, 2.4; P = 0.02); and previous radiation therapy to the abdomen (relative risk, 2.2; P = 0.04). Vancomycin therapy was a marker for persistent fever. Multiorgan failure was more frequent among patients with VOD and usually followed the onset of liver disease. Veno-occlusive disease, which developed in 54% of bone marrow transplant recipients, is frequently associated with renal and cardiopulmonary failure. Pretransplant transaminase elevations, use of high-dose cytoreductive therapy, and persistent fever during cytoreductive therapy are independent predictors of severe VOD.

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Venoocclusive disease of the liver following bone marrow transplantation.

H G Braine, L L Sensenbrenner, Wouter Vogel … (1987)

Review of 235 consecutive patients undergoing bone marrow transplantation was performed in order to define the clinical syndrome of venoocclusive disease of the liver (VOD) in these patients. Analysis of all patients with histologically proven VOD revealed a consistent clinical syndrome of liver dysfunction occurring within the first 3 weeks after marrow infusion. This was characterized by hyperbilirubinemia peaking at greater than or equal to 2 mg/dl with at least 2 of 3 other findings: hepatomegaly, ascites, and 5% or greater weight gain. VOD developed in 22% (52 of 235). A persistently elevated aspartate aminotransferase (SGOT) prior to transplant was associated with an increased risk of developing VOD by multivariate analysis (P = 0.0003), and acute leukemia in first remission was associated with a decreased risk (P = 0.02). Neither the preparative regimen (busulfan and cyclophosphamide versus cyclophosphamide and total body irradiation) nor the type of graft (allogeneic versus autologous) influenced the occurrence. Twenty-four of these 52 patients (47%) died with VOD (10% of the entire group). This makes VOD the third leading cause of death in our allogeneic graft recipients, and the second leading cause in our patients receiving autologous transplants. VOD is a common complication of bone marrow transplantation and has a specific clinical presentation, which usually allows diagnosis without the need of liver biopsy.

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Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease).

Laurie DeLeve, Howard Shulman, George McDonald (2002)

The term veno-occlusive disease of the liver refers to a form of toxic liver injury characterized clinically by the development of hepatomegaly, ascites, and jaundice, and histologically by diffuse damage in the centrilobular zone of the liver. The cardinal histologic features of this injury are marked sinusoidal fibrosis, necrosis of pericentral hepatocytes, and narrowing and eventual fibrosis of central veins. Recent studies suggest that the primary site of the toxic injury is sinusoidal endothelial cells, followed by a series of biologic processes that lead to circulatory compromise of centrilobular hepatocytes, fibrosis, and obstruction of liver blood flow. Thus we propose a more appropriate name for this form of liver injury--sinusoidal obstruction syndrome. This review encompasses historical perspectives, clinical manifestations of sinusoidal obstruction syndrome in the setting of hematopoietic cell transplantation, histologic features of centrilobular injury, and a discussion of the pathophysiology of sinusoidal injury, based on both animal and clinical investigations.