Early Treatment with H12-(ADP)-liposomes Ameliorates Post-partum Hemorrhage with Coagulopathy Caused by Amniotic Fluid Embolism in Rabbits

Background: Amniotic fluid embolism is an unpredictable and sometimes lethal complication of childbirth. H12-(ADP)-liposomes, which were developed as a platelet substitute, may be useful to control postpartum hemorrhage with consumptive coagulopathy. Objective: To establish a hemodynamically stable amniotic fluid embolism animal model and evaluate the efficacy of H12-(ADP)-liposome infusion in the initial management of postpartum hemorrhage complicated with amniotic fluid embolism-involved coagulopathy. Study Design: Pregnant New Zealand white rabbits (28th day of pregnancy/normal gestation period 29–35 days) underwent cesarean section, followed by intravenous administration of amniotic fluid (a total of 3.0 mL administered in 4 doses over 9 min). Thereafter, uncontrolled postpartum hemorrhage was induced by transecting the right mid-artery and concomitant vein in the myometrium. After initial bleeding for 5 min, rabbits received isovolemic fluid resuscitation through the femoral vein with an equivalent volume of blood loss every 5 min for 60 min. The transfusion regimens included platelet-rich plasma, platelet-poor plasma, and a bolus injection of H12-(ADP)-liposomes followed by platelet-poor plasma transfusion (n = 8 rabbits per group). Sixty minutes after initiation of bleeding, rabbits received surgical hemostasis by ligation of bleeding vessels, except in cases with spontaneous hemostasis. Results: Administration of amniotic fluid caused thrombocytopenia (56 ± 3 × 103/μL) and prolonged both clotting time (before administration: 130 ± 3 to 171 ± 5 s) and prothrombin time (4.5 ± 0.1 to 4.7 ± 0.1 s). After the initial 5 min-bleeding in the rabbits, the mean arterial pressure fell to 43 ± 2 mmHg. Platelet-poor plasma transfusion alone further prolonged clotting time and prothrombin time at 60 min (192 ± 10, 5.2 ± 0.1 s, respectively) with decreasing mean arterial pressure to less than 40 mmHg. By contrast, injection with H12-(ADP)-liposomes followed by platelet-poor plasma transfusion reduced the prolonged clotting time (153 ± 5 s) and prothrombin time (4.9 ± 0.1 s) similar to platelet-rich plasma transfusion (154 ± 11, 4.9 ± 0.1 s, respectively) at 60 min. These rabbits maintained a mean arterial pressure of more than 45 mmHg throughout the experiment. H12-(ADP)-liposome infusion/platelet-poor plasma transfusion as well as platelet-rich plasma transfusion yielded spontaneous hemostasis in 4 out of 8 rabbits, whereas platelet-poor plasma did not stop bleeding in any of the rabbits. The total blood loss was 59 ± 17 mL in the H12-(ADP)-liposomes/platelet-poor plasma group, which was half of that in the platelet-poor plasma group (124 ± 10 mL). Conclusions: H12-(ADP)-liposome infusion may be effective in the initial management of postpartum hemorrhage complicated with amniotic fluid embolism, resulting in mitigation of consumptive coagulopathy. Amniotic fluid embolism is an unpredictable complication of childbirth and occurs suddenly even in low-risk pregnancies. We propose initial fluid resuscitation with H12-(ADP)-liposomes, an artificial substitute for platelets, to prevent consumptive coagulopathy in hemorrhagic animal models with amniotic fluid embolism (AFE). Animals treated with H12-(ADP)-liposomes/PPP infusion or with PRP transfusion showed reduced total blood loss compared with PPP infusion. H12-(ADP)-liposomes/PPP infusion achieved spontaneous hemostasis of arterial bleeding in half of the animals, similar to PRP transfusion. We established a new rabbit hemorrhagic model simulating AFE that showed moderate consumptive coagulopathy at late gestation. Early H12-(ADP)-liposome treatment may prevent exacerbating coagulopathy (overt DIC).