Protocol Version 1.1 was approved on 11 Jun 2012 and applied to all study centers in the US. Major changes included: - Removing age restriction of ≥3 years old to comply with PREA Requirements - Removing weight restriction of <20 kg - Excluding mild bleeding subjects from Preliminary Part (I). In addition, the inclusion criteria referring to the type of bleeding for both parts of the study aligned so that only subjects with moderate bleeding intensity are enrolled - Adjusting the assumed screen failure rates in Preliminary Part (I) - Adjusting sample size calculations based on new reference data - Adjusting drop-out rate assumptions based on the lesser likelihood of subject withdrawal during the short intra-operative period - Excluding subjects with previous known sensitivity to heparin or protamine components to reduce the risk for the safety of the participating subjects - Addition of exclusion criteria #10 for subjects with recent surgical procedures to reduce risk for subjects & confounding factors for safety evaluation - Polymerization time (vessel clamping period) increased from 1 to 2 min in accordance with new reference data - Clarification that FS Grifols application at sites other than the TBS is disallowed - 3-min timepoint after start of treatment application was removed due to the extension of polymerization time to 2 min - Removing the IO vital sign measurements at 3 & 7 min - Addition of the time point of TEnd2 for documentation of the actual end time of FS Grifols reapplication - Addition of the procedure for sponsor evaluation and unblinding of reportable cases from the blinded part of the study (Primary Part [II]) - Reducing pediatric blood sampling requirements for the safety of subjects <30 kg

Protocol Version 1.2 was approved on 24 Oct 2012 and applied to all study centers in the US. Major changes included: • Addition of TStart2 time point due to the FDA’s request to capture times of study drug reapplication, if applicable.

Protocol Version 2.0 was approved on 23 Aug 2013 and applied to all study centers in the US. Major changes included: - Overall study duration increased from 17 to 48 total months - Clarification that subjects must have Hgb ≥9 g/dL at baseline within 24 hours prior to the surgical procedure - Clarification that females who were pregnant or nursing a child at baseline (within 24 hours prior to the surgical procedure) were excluded from the study. Laboratory testing for determination of the subject’s eligibility was to be performed locally at the site - Expanded the list of acceptable surgical procedures to include testing of FS Grifols in bypass grafting at additional anatomic locations with larger vessels - Removing exclusion criterion #6 (Known [documented] previous exposure to thrombin-containing [bovine, human or recombinant] products) to allow testing of FS Grifols in subjects who were previously exposed to other thrombin products - Clarification for Day 0 recording of vital signs at 2, 4, & 6 hours after TCompletion - Clarification that the maximum total volume of FS Grifols allowed to be applied at the TBS would be approximately 12 mL (equivalent to the full content of 2 FS Grifols kits) - Reducing the number of Post-Operative Visits by removing visits on Post-Operative Days 1 & 3 - Shifting the following procedures from Post-Operative Days 1 and 3 to Post-Operative Day 2: coagulation panel (INR and aPTT ratio), CBC, and serum clinical chemistry -Clarification of laboratory panels for pediatric sampling.

Protocol Version 3.0 was approved on 16 Jan 2014 The key update to this protocol amendment was the addition of approximately 6 study centers in 2 new countries, Hungary and Serbia. An additional major change included: • Removing the Month 6 Visit for virus safety testing after study drug administration. Removing the Month 6 Visit shortened the observation period from 6 months to 3 months and also shortened the subject’s expected length of participation period from 7 months to 4 months.

Protocol Version 3.1 was approved on 25 Mar 2014 and applied to all study centers in Hungary. This country-specific protocol amendment was implemented to include the exclusion criterion (listed below) required by Hungary’s national competent authority. • Have known (documented) history of thrombophilia. • Have known (documented) history of IgA deficiency.

Protocol Version 4.0 and Version 4.1 were approved on 16 Dec 2014. The key update to Protocol Version 4.0 was the addition of approximately 6 study centers in 1 new country, Russia. Version 4.1 applied to all study centers in Hungary. The major changes included: - Decreasing the Hgb levels criterion from ≥9.0 g/dL to ≥8.0 g/dL at baseline (within 24 hours prior to surgical procedure) to allow the enrollment of subjects with lower Hgb levels (eg, subjects receiving chemotherapy prior to surgery or pediatric subjects) that otherwise would be screening failures. Laboratory testing for determination of subject’s eligibility was performed locally at the investigative study center. - Updating the FS Grifols shelf-life from 1 year to 2 years when stored at a temperature of ≤-18ºC (≤-0.40ºF). - Clarification that baseline central laboratory samples could be drawn shortly after anesthesia, but before the start of surgery.

Protocol Version 4.2 was approved on 31 Mar 2015 and applied to all study centers in Russia. The major changed included: • Removal of pediatric subjects in the study.