Heparin Reversal With Protamine Sulfate After Percutaneous Hepatic Perfusion (PHP): How Much Is Too Much?

Purpose: Percutaneous hepatic perfusion (PHP) is a palliative intraarterial therapy approach for unresectable hepatic malignancies. During PHP, high dose chemotherapeutic melphalan is saturating the liver parenchyma and an extracorporeal hemofiltration extracts excess melphalan. Blood clotting in the extracorporeal filter system is prevented by administering unfractionated heparin (UFH), which can be reversed with protamine after the procedure. Aim of this retrospective two-center-study was to analyze the potential effect of UFH reversal with protamine on complication rates following PHP.

Materials and Methods: All patients receiving PHP treatment between 10/2014 and 04/2021 were classified according to their intraprocedural coagulation management: 92 patients/192 PHP received full UFH reversal with protamine (group_PRO); 13 patients/21 PHP in group_REDPRO received a reduced amount of protamine and 28 patients/43 PHP did not receive UFH reversal with protamine (group_NOPRO). Periinterventional clinical reports, findings and laboratory values were retrospectively evaluated. Complications and adverse events were classified according to CTCAEv5.0.

Results: Thromboembolic events were recorded after 10 PHP procedures (5%) in group_PRO, six of which (3%) were major events (CTCAE grade 3-5). No (0%) thromboembolic events were recorded in group_REDPRO and group_NOPRO. After in total 24/192 PHP (13%), patients in group_PRO suffered from hemorrhagic events, two of which (1%) were major (CTCAE grade 3-4). In group_REDPRO, only minor bleeding events were recorded, and one major hemorrhagic event was documented in group_NOPRO (2%). There was a statistically significant difference between the post-interventional platelet count of group_PRO (39%), group_REDPRO(14%) and group_NOPRO (23%) (group_PROvs. _REDPRO: p< .00001; group_PRO vs. _NOPRO: p< 0.05; group_REDPRO vs. _NOPRO: p< 0.05). In group_PRO one patient suffered from a severe anaphylactic shock after the administration of protamine.

Conclusion: Our study implies that the use of protamine to reverse the hemodilutive effect of UFH after PHP might increase the risk of thromboembolic events as well as clinically significant post-interventional thrombopenia. We suggest that a paradigm shift regarding the standard use of protamine after PHP in low-risk patients without clinical signs of active bleeding should urgently be discussed.