Post Partum Haemorrhage (PPH): Time to Change Perception of Pathophysiology and Approach to Therapy? Uterine Atony in Developing PPH Is Rare with Disturbances of Coagulation Being Early and Frequent

Introduction: Traditionally, uterine atony (UA, 70% of cases), lacerations (LAC, 20%) and retained placenta (PLAC, 10%) are established etiologies of PPH. We showed earlier (Haslinger, JTH, 2020) prepartum F XIII to be the main coagulation component to influence postpartum blood loss, over fibrinogen (FIB), F II and platelet count (PLT). Whether the current concept of PPH can be aligned with these findings is unclear. A non-severe PPH (nsPPH, 500 - 1000 ml) always precedes any severe PPH (sPPH, > 1000 ml); nsPPH thus likely harbors information on the genesis of sPPH. For elucidation, we examined the peripartum course of various coagulation components in various settings and their association with PPH etiologies, specifically UA.

Methods: This prospective study on PPH in more than 1300 parturient women is registered with ClinicalTrials.gov (NCT02604602). Here, 677 women not undergoing cesarean section (CS, as pathophysiology of PPH in CS likely differs from non-CS) are evaluated.

Prepartum D-dimer (DD) and peripartum courses of FIB, PLT, F II and F XIII (ratio from two samples taken within 36 h post- and prepartum) were determined with standard procedures. A validated device measured the blood loss (MBL), duration of the 2^nd stage of labor (SSL) and presence (or absence) of nsPPH, sPPH, UA, LAC and PLAC were noted. For PPH with or without UA, LAC or PLAC, observed vs expected frequencies were compared. Statistics (MedCalc 22.013) are given with results

Results: Prepartum DD was significantly increased in women developing PHH (+8% vs no PPH by median, Mann-Whitney; +15% by 10% trimmed mean, Yuan-Welch; all p < 0.0096). Women developing PPH had a longer median SSL (+ 54% vs no PPH, Mann-Whitney, p < 0.004).

Of all components, F XIII was the one most sensitive to consumption/loss overall, compared to prepartum results (- 13% w/o PPH vs -21% w/ PPH , p<0.0001, Mann-Whitney) and in all (10/10) peripartum subsettings evaluated (no potential etiologies, any of three potential etiologies or multiple potential etiologies, all with and without PPH). In these subsettings, FXIII loss was significantly higher compared to that of FIB or PLT (2/10 subsettings); FIB and PLT (1/10); and FIB and PLT and F II (7/10).

In nsPPH (n=146), UA was significantly less frequent than expected (10.3% vs 70%, p < 0.0001); however, LAC (20.5% vs 20%) and PLAC (12.3 % vs 10%) showed expected frequencies. Singular etiologies were present in 35.6% of PPH, multiple etiologies in 3.5%. Importantly, 60.9% of women with nsPPH showed none of the traditionally known etiologies. Similarly, a strong trend for UA to be less frequent than expected was seen in sPPH (57.8% vs 70%, p = 0.074, z statistics).

Conclusions: This - to date largest - prospective observational study on PPH pathophysiology indicates that in women developing PPH later on, increased prepartum DD is present before a prolonged SSL occurs. FXIII is the coagulation component most sensitive to loss and consumption in any peripartum setting (from women without PPH to women with PPH and multiple known etiologies), significantly more sensitive than FBG, PLT and F II. In combination, these observations seem a logical and likely explanation for the increased consumption/loss of coagulation factors and the resulting haemostatic insufficiency when PPH develops, even in the absence of traditional etiologies like UA.

Contrary to the traditional concept, our results suggest UA not to be the primary driver of PPH, as most women with nsPPH were without UA (and UA also seemed less frequent in sPPH than assumed until now). We thus speculate that UA in sPPH tends to follow the development of PPH, rather than vice versa. Overall, ~ 60% of women with nsPPH did not exhibit any of the traditionally established PPH etiologies.

In summary, our data suggest that most women developing PPH display a pathophysiology that differs from current concepts: increased prepartum coagulation activation and a prolonged SSL are followed by increased loss of coagulation factors, predominantly F XIII, and bleeding. This is independent from UA in most women to begin with. Progressive deterioration of haemostasis reflects the progression of PPH (with a later increase in prevalence of UA).

Consequently, early procoagulant support to prevent women with nsPPH from progressing to sPPH needs to be evaluated. Given our results (and negative results of intervention trials with FIB), F XIII should be evaluated.

Korte:Werfen: Other: travel support; stago: Honoraria, Research Funding; Sobi: Honoraria, Other: travel support; Novo Nordisk: Consultancy; Beckman Coulter: Other: travel support; CSL Behring: Honoraria, Research Funding.