Heparin reversal with protamine sulfate after Percutaneous Hepatic Perfusion (PHP): is less more?

Percutaneous hepatic perfusion (PHP) is a palliative intraarterial therapy for unresectable hepatic malignancies. During PHP, high-dose melphalan is infused via the hepatic artery to saturate tumor in the liver with the chemotherapeutic substance. The venous hepatic blood is filtered by an extracorporeal melphalan specific filtration system. Blood clotting in the extracorporeal filter system is prevented by administering unfractionated heparin (UFH) in high doses, which might be reversed with protamine sulfate after the procedure. Aim of this retrospective two-center-study was to analyze the potential effect of UFH reversal with protamine sulfate on complication rates following PHP.

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_PROTAMINE); 13 patients/21 PHP in group_{REDUCED_PROTAMINE} received a reduced amount of protamine, and 28 patients/43 PHP did not receive UFH reversal with protamine (group_{NO_PROTAMINE}). Periinterventional clinical reports, findings and laboratory values were retrospectively evaluated. Complications and adverse events were classified according to Common Terminology Criteria for Adverse Events (CTCAEv5.0).

Thromboembolic events were recorded after 10 PHP procedures (5%) in group_PROTAMINE, six of which (3%) were major events (CTCAE grade 3-5). No (0%) thromboembolic events were recorded in group_{REDUCED_PROTAMINE} and group_{NO_PROTAMINE}. Hemorrhagic events were registered after 24 PHP (13%) in group_PROTAMINE, two of which (1%) were major (CTCAE grade 3-4). In group_{REDUCED_PROTAMINE}, only minor bleeding events were recorded, and one major hemorrhagic event was documented in group_{NO_PROTAMINE} (2%). There was a significant difference between the percentage of post-interventional thrombopenia in group_PROTAMINE (39%) and group_{REDUCED_PROTAMINE} (14%) versus group_{NO_PROTAMINE} (23%) (p=.00024). In group_PROTAMINE one patient suffered from a severe anaphylactic shock after the administration of protamine.

Our retrospective study implies that there might be a link between the practice of protamine sulfate administration to reverse the full hemodilutive effect of UFH after PHP and the post-interventional risk of thromboembolic events as well as clinically significant thrombopenia. Our data suggest that the standard use of protamine sulfate after PHP in low-risk patients without clinical signs of active bleeding should be critically re-evaluated.