•Clarified that AEs and outcome data were to be collected on Day+30 and Day+100 post-HSCT. • Included additional information related to recording of AEs recording, including details on relationship to study drug. • Updated criteria used to define complete response (CR).

•Modified the eligibility criteria by removing the requirement for patients to demonstrate MOF prior to enrollment and to be eligible only following HSCT - patients could meet eligibility criteria following chemotherapy. • The requirement for VOD before Day+35 and MOF (as applicable) by Day+45 was removed allowing patients with late onset VOD to be treated. • Clarified the duration of treatment to allow continued treatment until the patient achieved a CR or until hospital discharge. •Hemodynamic instability was modified to include the requirement for 2 or more pressors (not including renal doses of dopamine). • Discontinuation criteria were modified to permit patients who required multiple pressors after defibrotide to continue on defibrotide. (As long as the patient could maintain his/her mean arterial pressure within 1 standard deviation of age-adjusted controls). • Introduced a cost recovery program.

•Introduced a new formulation (paraben preservatives removed, glass vials instead of glass ampoules) and container closure system for defibrotide. • Reintroduced the comparison of the Historical Control arm of the Phase 3 study 2005-01 and the patients enrolled under Protocol 2006-05 who met eligibility criteria of Protocol 2005-01, regarding Day+100 survival and CR (Note: this analysis had been removed in Amendment 2 when entry criteria were broadened). • Included a reporting window of ± 3 days and ± 7 days for Day+30 and Day+100 assessments, respectively. • Allowed an increased number of enrolled patients (from 100-200 to 200-300 patients).

• Added pregnancy to the contraindications to the use of defibrotide.

Allowed enrollment of patients with a VOD diagnosis based on modified Seattle Criteria, in addition to those fulfilling Baltimore criteria (elevation of total bilirubin to 2.0 mg/dL or higher was no longer mandatory). • Increased the number of enrolled patients (from 200-300 patients to approximately 600 patients).

•Increased the number of patients to be enrolled (from 600 to 1000). • Changed the end of treatment with defibrotide from achievement of CR or until discharge from the hospital to until signs and symptoms of VOD resolved. • Removed comparison to historical control from Protocol 2005-01. • Added disallowance of any medication that increased the risk of hemorrhage. • Changed exclusion criterion regarding hemodynamic stability to include a recommendation for adult patients. • Added option of contact without return visit to clinic for follow-up at Day +30 and Day +100 post-HSCT. • Widened the acceptable concentration range for defibrotide solution for infusion due to new stability data.