**5. Danaparoid prophylaxis of post-transplant thrombotic disorders**

The diagnosis of SOS is usually based on the Baltimore or Seattle criteria, and not every publication**—**especially single case reports or meeting abstracts, reveals which was used. The main difference between these two diagnostic guidelines is the inclusion of hyperbilirubinemia in the former. This seemingly small difference can result in great differences in important outcome events such as TRM, OS and MOD/MOF frequencies [108] when applied within the same population cohort. The European Society for Blood and Marrow Transplantation (EBMT) has attempted to rationalise this by applying the two sets of criteria to early and late SOS since hyperbilirubinemia is often absent in late SOS but a grey area remains and the change has yet to be clinically validated. Such validation is necessary since it appears to have a great influence on disease progression and the outcomes of specific treatment modalities.

#### **5.1 Population exposure**

Danaparoid has been evaluated in at least 524 patients for the prevention of SOS and/or TA-TMA after HSCT. All eight reports [108–115] come from Japan. Malignancies, particularly haematogenous cancers, formed about 80% of the reasons for HSCT. The non-malignant reasons were mainly aplastic anaemia, adrenoleukodystrophy and mucopolysaccharidoses. The subjects presented with a wide spectrum of underlying clinical disorders and had followed a course of chemotherapy (the conditioning regimen) or radiotherapy. In addition they had or were still receiving prophylaxis against GvHD and a cocktail of prophylactic medication

to prevent BMT rejection and infection. Many of these drugs cause SOS or TA-TMA because of their hepato- and renal toxicity.

Japanese investigators have compared danaparoid use in both indications with standard prophylaxis using AT and/or ursodeoxycholic acid (UDCA) with or without antithrombotic co-medication. Defibrotide (DF) the standard therapy for SOS/ TA-TMA treatment is also increasingly used for their prevention but there has not been a direct comparison with danaparoid.

The 197 patients in 2 comparative studies were adults [108] or mostly adults (median age 48 years, range 16–70 years) [109], as was one of the single cases reported [115]. The remaining studies and case reports of 326 patients were performed exclusively or mostly in children (age range < 1–18 years). In the only two studies with data males appeared to predominate (64.2%).
