Evaluation of Endothelial Damage in Sinusoidal Obstructive Syndrome

Introduction: Sinusoidal Obstructive Syndrome (SOS) is a complication derived from the endothelial damage associated to hematopoietic stem-cell transplant (HSCT) conditioning. Although its appearance is highly dependent on patient risk factors, it has an estimated prevalence of 14% and is associated with a high morbidity and with mortality rates than can ascend to 90% at day +100 of transplant in severe cases. New methods to early diagnose SOS are needed in order to minimize the incidence and severity of SOS.

Here we present preliminary results of our single center prospective study that aims to measure and validate a panel of biomarkers in plasma [L-Ficolin, hyaluronic acid (HA), vascular adhesion molecule-1 (VCAM1) and plasminogen activator inhibitor-1 (PAI-1)] which have been recently described to be prognostic of the development of SOS (Akil et al, Biol. Blood Marrow Transplant. 21, 1739-1745, 2015).

Methods: Twenty-one adult patients undergoing HSCT were recruited (median age 43.5 years old, 20-68), 15 men and 6 women. Three patients (14%) were diagnosed of SOS and received defibrotide (Gentium/Jazz Pharmaceutical) treatment. Diagnosis of SOS was performed based on the Seattle and Baltimore modified Criteria.

Citrated blood samples from all patients were obtained before starting conditioning regimen (V0), and at infusion day (V1), 7 (V2) and 14 (V3) after infusion. Three additional samples (V4, V5 and V6) were drawn from those patients with SOS (just before defibrotide and 7 and 14 days after treatment with defibrotide). Samples were centrifuged twice at 23°C (15 min at 1,500 g, and 2 min at 13,000 g) and aliquots were stored at -80ºC until analysis.

Phosphatidylserine-MP (Ph-MP) and tissue factor-MP (TF-MP) dependent procoagulant activities were determined with the ZYMUPHEN kits. VCAM1, PAI-1, L-Ficolin and HA concentrations were measured by ELISA.

Data from the routine laboratory analysis were also registered.

Statistical analyses was performed with SPSS software. Values of p≤0.05 were considered statistically significant.

Results : Considering transplant type, 9 were autologous and 9 allogenic in controls, and 3 allogenic in SOS; donor type were 3 unrelated, 6 related and 3 haploidentical in controls, and 3 related and 2 haploidentical in SOS. Conditioning regimen intensity was 7 full, 2 reduced, 8 with busulfan and 1 with total body irradiation in controls and 3 reduced and 2 with busulfan in SOS group. Controls received 2(1-4) previous chemotherapy lines whereas SOS group received 3(2-9).

Regarding diseases, 4 presented acute myeloblastic leukemia, 2 acute lymphoblastic leukemia, 3 multiple myeloma, 3 non-Hodgkin's lymphoma and 6 Hodgkin's disease in control group whereas in SOS group 1 had acute myeloblastic leukemia, 1 myelodysplastic syndrome and 1 non-Hodgkin's lymphoma.

As observed, occurrence of SOS did not seem to be related to either the malignant disease or number of chemotherapy drugs employed for its treatment or donor type and conditioning regimen.

L-Ficolin, a complement activator involved in homeostatic clearance of mitochondria in the liver, seemed to diminished in the SOS group at V3 (wo SOS : 1025±923 ng/mL ; SOS : 680±817 ng/mL). Nevertheless, this diminution was not significant probably due to the few patients with SOS.

No differences were observed between patients without and with SOS in plasma levels of markers of endothelial damage VCAM1, PAI-1 and HA, this last a direct indicator of hepatic sinusoidal endothelial cell function.

Procoagulant activity associated to Ph-MP was lower in patients with SOS (p=0.023) whereas that associated to TF-MP was unaffected.

Plasma levels of VCAM1 and HA increased along time in both groups. After treatment with defibrotide these values achieved steady levels in SOS patients (V4 and V5). On the other hand, PAI-1 did not change over time.

SOS patients presented at V3 higher total bilirrubin (wo SOS: 0.86±0.53 mg/dL; SOS: 2.31±0.18 mg/dL, p=0.008) and lower albumin levels (wo SOS: 3.5±0.3 g/dL; SOS: 2.7±0.1 g/dL)

Conclusions: Our results indicate that endothelial damage is present in all patients undergoing HSCT and that treatment of SOS patients with defibrotide might restrain this injury. Due to the low number of patients included so far, we cannot conclude anything about the value of biomarkers proposed to serve as predictors of SOS onset. Our study is still open and recruiting patients.

This work was supported by Jazz Pharmaceutical