**6.2 Ursodeoxycholic acid**

UDCA, currently the most widely used drug for SOS prevention, is a natural bile acid that is capable of reducing the toxicity of its companion bile acids in cholestatic liver diseases. In inflammatory disorders it can 'attenuate the pro-inflammatory cytokine environment through decreased expression of TNF-α, interleukins 1 and 2, and interferon-γ, thereby minimising endothelial injury occurring in HSCT associated with the cytokine storm [117]. UDCA is safe and not only lowers the frequency of SOS but also of TRM and appears to have a small effect in reducing the development


*Dan = danaparoid, DF = defibrotide, GvHD = graft v host disease, (LMW)H = low and unfractionated heparins, MB = major bleeding, nd = no or unclear data, OS = outcome survival, SOS = sinusoidal obstruction syndrome, TA-TMA transplant associated thrombotic microangiopathy, TRM = treatment related mortality, UDCA = ursodeoxycholic acid.*

*1 From* **Table 9**

*2 From* **Table 9** *and additional data from non-danaparoid studies.*

*3 Assessed at either D + 100 and/or 2–5 years after HSCT, OS was 100% for danaparoid + UDCA.*

*4 Assessed at D + 100 after HSCT.*

*5 From Refs. [119, 120]*

*6 From Ref. [121]*

**Table 10.** *Pooled results of SOS prophylaxis studies.* of GvHD [118]. It is occasionally used in combination with UFH and LMWHs but there is little evidence that they improve its efficacy. Outcomes of UDCA use shown in **Table 10** are derived from several studies and reviews [117–120, 122].

#### **6.3 Defibrotide**

This oligodesoxyribonucleotide extracted from porcine intestinal mucosa has numerous antithrombotic, EC protective, fibrinolytic, anti-ischaemic and angiogenic activities. Its clear benefits for the treatment of SOS have led to approval by the FDA for this indication. More recently DF has been investigated for SOS prevention with mixed results [121, 123–127]. The inter-study variance may be due to the different dosing regimens used (including occasional co-medication with UDCA) and different intervals between diagnosis and DF treatment initiation. Greater success has been reported using initiating DF earlier [128] after SOS diagnosis or combining it with UDCA [129].

#### **6.4 Results**

The outcomes of non-danaparoid studies with UDCA and DF for the prevention of SOS (and where mentioned TA-TMA) are summarised and compared with danaparoid in **Table 10**. The data for danaparoid only and in combination with UDCA have been separated because of the apparent greater. Impact of comedication with UDCA on the frequencies of TRM and GvHD. For many studies it is unclear to what extent TA-TMA might have been present and therefore contributed to caused morbidity or death since it was mentioned. In addition not all parameters were assessed in all studies hence percentages are based only on the available data. The frequency of haemorrhages with DF in several studies [130, 131] has been as high as 22%, but in one study [130] was the same as the unspecified controls. So there remains some confusion regarding its safety.

Interestingly the danaparoid efficacy appears to be better in children than in adults, perhaps related to the use of a higher dosing intensity/kg body weight.
