Endothelial dysfunction after bone marrow transplantation: Increase of soluble thrombomodulin and PAI-1 in patients with multiple transplant-related complications

Abstract

Multiple transplant-related complications (MTRC) represent a severe condition after bone marrow transplantation (BMT) and are supposed to reflect systemic endothelial damage. Soluble thrombomodulin (sTM) and plasminogen activator inhibitor type-1 (PAI-1) were investigated as markers of endothelial dysfunction in 35 patients after autologous or allogeneic BMT and compared with the occurrence of the typical complications sepsis, veno-occlusive disease of the liver (VOD), graft-versus-host disease (GVHD), and capillary leakage syndrome (CLS). PAI-1 was assessed by an assay of functional activity and sTM by antigenic determination. In patients who had undergone allogeneic BMT and had no transplant-related complications (TRC), PAI-1 peaked on day +14 (20 +/- 5 units/ml), and sTM doubled in comparison to the starting range, to 60-80 ng/ml between days +14 and +49. In contrast, PAI-1 and sTM were unchanged following autologous BMT. PAI-1 was increased in sepsis, CLS, and VOD to 39-49 units/ml (p < 0.05, compared with patients without TRC), and in GVHD to 16-47 units/ml (not significant). Soluble TM increased to 63-309 ng/ml in patients with sepsis, VOD, or CLS (p < 0.05, compared with patients without TRC) and to 79-224 ng/ml in GVHD (not significant). The increase of sTM and PAI-1 was also positively correlated to the number of complications, so that in patients with three complications PAI-1 was increased 2.8-fold and sTM 3.5-fold over patients with no complications at all. We conclude that endothelial dysfunction is a feature of VOD, sepsis, CLS, and to lesser extent of GVHD and is worse in patients with multiple complications.

Engraftment syndrome: double-edged sword of hematopoietic cell transplants

“…37 Soluble thrombomodulin and plasminogen activator type 1, markers of endothelial injury are elevated in persons with capillary leak syndrome and other complications of transplantation, such as GVHD, hepatic veno-occlusive disease and sepsis. 38 Recombinant human soluble thrombomodulin has also been shown to ameliorate the vascular leak manifestations of ES. 39 As more biomarkers of GVHD are identified, 40 it may be possible to better determine how to distinguish ES from GVHD and whether they are are different or identical processes.…”

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

“…At the time of engraftment or at the onset of GVHD, VWF and TM levels were significantly increased with respect to the baseline, especially in patients with acute GVHD grades II-IV, suggesting that ECs could be injured. Nu¨rnberg et al 22 analysed levels of plasminogen activator inhibitor type 1 and TM and demonstrated that the increases in both markers correlated with the number of vascular complications (VOD, sepsis, capillary leak syndrome) and to a lesser degree with GVHD. Takatsura et al 23 did not observe any impact of TBI on VWF and TM levels.…”

Early thrombin generation and impaired fibrinolysis after SCT associate with acute GVHD

“…Plt activation is also characteristic for generalized endothelial injury, exposing phospholipid surfaces to generate thrombin, and secrete inflammatory mediators, also after SCT. [10][11][12] Some studies have focused on coagulation and fibrinolytic activities during SCT. In a study of mainly autologous transplant patients, increased coagulation activity was reported during conditioning therapy, whereas fibrinolytic mechanisms were shown to be triggered later.…”