Post Partum Haemorrhage: prepartum plasmin and thrombin generation is similar in women with and without PPH

Introduction: Eight women die from PPH every hour wordldwide, thus causing 1/3 of all maternal deaths. As many of these women have no known prepartum risk factors, we need to better understand the pathophysiology of PPH. Our group recently identified PREpartum FXIII activity (FXIII; Haslinger et al., JTH, 2020) and the platelet count (Brun et al., TMH, 2023) to be strongly associated with POSTpartum blood loss. Studies in surgery and trauma have shown loss of FXIII to be very prevalent and relevant for the respective clinical outcome. However, other data suggest that increased fibrinolysis (Gruneberg et al., Front Med, 2023) or decreased thrombin generation (de Moreuil et al., JTH, 2023) might be relevant to PPH development. We thus quantified prepartum plasmin (plasmin-antiplasmin complexes, PAP) and thrombin generation (Prothrombin fragments 1+2, F1+2) in the PPH1300 study.

Method: Evaluating 677 women with vaginal delivery, immediate prepartum PAP and F1+2 were determined with commercially available ELISA assays on a DSX ELISA automation, all performed according to the suggestions of the manufacturers. Statistical procedures are given with results.

Results: 486 women (71.8%) remained without PPH, 146 (21.6%) developed non-severe (<1000 ml/24h) and 45 (6.6%) severe (≥1000 ml/24h) PPH. There were no significant differences between women without PPH, with non-severe or severe PPH, neither for PAP (p=0.19, [Fig. 1]) nor F1+2 (p=0.24, [Fig. 2], Kruskal-Wallis testing). Pooling of women with any type of PPH for evaluation did not change the results.

Fig. 1 PAP complexes PAP complexes measured immediately prepartum are not different in women who will or will not develop PPH.

Fig. 2 Prothrombin fragments F1+2 Prothrombin fragments F1+2 measured immediately prepartum are not different in women who will or will not develop PPH.

Conclusion: In this to date largest prospective observation study, we find no indication that women developing PPH have increased fibrinolytic activity or decreased thrombin generation prepartum. This bears some important implications.

First, it supports the notion that antifibrinolytics are unlikely to be helpful prophylactically, i.e. before increased bleeding occurs. It does not imply that antifibrinolytics should be withheld once increased bleeding occurs, as shown by the WOMAN trial.

Second, these data show that women developing PPH do not have reduction in prepartum thrombin generation. This does not exclude that decreased thrombin generation might occur late during PPH, e.g. through dilution due to volume therapy.

Third, these observations give further credit to the idea that prepartum FXIII is indeed an important and early modulator of postpartum blood loss.

To sum up, our data indicate that both, women who go on to develop PPH and those who do not develop PPH show comparable plasmin and thrombin generation immediately prepartum. It seems thus unlikely that fibrinolytic activity or thrombin generation are relevant or predictive factors in the prepartum situation; or that they contribute to the early development of PPH. This, however, does not preclude that they can play a role after PPH started, which remains to be elucidated.