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of adhesion molecules, release of chemokines, production of growth fac-
tors, and activation of coagulation factors. Higher doses of irradiation
cause endothelial injury in a dose-dependent manner [8] . Radiation with
7.5 Gy was found to induce persistent anatomic changes in the endothe-
lium, including intracellular edema and occlusion of microvascular lumens
by edematous ECs [9] .
The effects of cyclophosphamide and busulfan on ECs were investigated in
murine models of allo-HSCT. Cyclophosphamide (120 mg/kg) and busulfan
(16 mg/kg) caused endothelial damage, as determined by structural changes
in transmission electron microscopy and by an increased number of cir-
culating endothelial cells [10,11] . Furthermore, preclinical studies demon-
strate that frequently used immunosuppressants, such as cyclosporin A and
Sirolimus, have direct cytotoxic effects on ECs [12,13] . Tacrolimus (FK506)
also has extensive toxic effects on ECs and has been used in a rat model
to induce intestinal thrombotic microangiopathy. In this study, rats were
examined histopathologically after FK506 injection using light and elec-
tron microscopy as well as immunohistochemistry. Hemorrhagic lesions
with multifocal erosions and crypt loss were found in the small intestines
of Tacrolimus-treated animals. Electron microscopy demonstrated degen-
erative swelling of ECs and platelet aggregates adhering to the vessel walls.
The extent of intestinal injury was proportional to the whole-blood levels of
Tacrolimus [14] .
481
Human studies confirm preclinical results and show that the intensity of
the conditioning regimen correlates positively with endothelial damage.
Patients who received reduced-intensity conditioning had significantly lower
circulating EC numbers, which are used as a surrogate marker for endothe-
lial injury, compared with allo-HSCT recipients who received standard con-
ditioning [15] . A high-intensity conditioning regimen correlated positively
with an increase in seromarkers of EC damage, such as von Willebrand factor
(VWF), ADAMTS-13 activity, sVCAM-1, and sTNFR1 [16] . Severe endothelial
damage, defined by high levels of circulating cyclic GMP, was a negative pre-
dictive factor for survival after HSCT, highlighting the clinical significance
of endothelial damage for patients undergoing allo-HSCT [17] . Clinical data
show that calcineurin inhibitors, in particular cyclosporin A, may further
aggravate endothelial damage caused by the conditioning regimen. Mor-
phological and biochemical changes indicative of generalized endothelial
damage were found in approximately 80% of allo-HSCT recipients treated
with cyclosporin for prophylaxis of GVHD [18] . Similar endothelial changes
have been reported in renal transplant recipients receiving cyclosporin [19] .
However, results of subsequent clinical studies confirm preclinical results
and demonstrate that various immunosuppressants increase the risk for
endothelial complications, as opposed to exclusively calcineurin inhibi-
tors. The highest endothelial toxicity has been observed when multiple
immunosuppressants were combined. A microangiopathic syndrome was
observed in roughly 20% of patients receiving a combination of cyclosporin
and methylprednisolone for GVHD prophylaxis [20] . Another clinical study
found approximately 10% severe microangiopathy after combined use of
cyclosporin, methotrexate, and glucocorticoids as GVHD prophylaxis [21] .
In patients receiving Sirolimus, a mammalian target of rapamycin inhibitor,
an increase in serological markers for endothelial injury on the day prior to
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