Abstract
Introduction: We earlier showed prepartum F XIII to be the main coagulation component to influence postpartum blood loss (PPBL) over fibrinogen (FIB), F II and platelet count (Haslinger, JTH, 2020). We offered a first explanation to align these findings with the current concept of PPH genesis (Korte, Blood Suppl. 1, 2024), including increased prepartum D-dimer (DD) and a prolonged second stage of labor (SSL). However, questions on the relevance of the amount of prepartum thrombin, plasmin, fibrin generation and fibrin degradation and the interaction with other clinical (risk) factors with regard to pathophysiology (and thus potentially therapy) remain.
Methods: Our prospective study on PPH (≥500 ml PPBL / 24h, WHO) is registered with ClinicalTrials.gov (NCT02604602). Here, we describe results on and relationships between measured blood loss (MBL), prepartum concentrations of Prothrombin Fragments (thrombin generation, F1+2), PAP complexes (plasmin generation, PAP), DD (resulting from thrombin and plasmin generation), SSL, age, BMI, parity and gestation age (GA), in 1308 women with vaginal deliveries (VD, n=676) and c-section (CS, n=632). Data were used as available; the smallest set was for F1+2 (n=1258). Statistics (MedCalc 23.3.2) are given with results
Results: Median prepartum F1+2 (pmol/L) or PAP (µg/L) were similar in women with vs without PPH, both in CS (F1+2: 584 vs 596, p=0.092 / PAP: 465 vs 436, p=0.619) and VD (F1+2: 615 vs 588, p=0.108 / PAP: 464 vs 471, p=0.703, Kruskal-Wallis test); DD (mg/L) was significantly increased in women developing PPH, both in CS (median [IQR] 1.59 [1.19-2.30] vs 1.34 [1.05-1.94], p=0.0002) and VD (1.66 [1.34-2.32] vs 1.54 [1.24-2.01], p=0.008); so was µg DD generated per µg PAP, both in CS (340 [243-535] vs 322 [237-457], p=0.044) and VD (392 [290-515] vs 339 [253-463], p=0.003. Women developing PPH had a longer median SSL (minutes; CS not evaluated; VD 71 [21-141] vs 46 [17-114], p=0.004); and a slightly higher GA (d) with CS (269 [266-276] vs 268 [265-272], p=0.039), not VD (282 vs 280, p=0.250). All other clinical parameters were similar in women with or without PPH, independent of CS or VD (age, BMI, parity; all p>0.137).
All of the mentioned prepartum parameters were included in multiple regression analyses (separately for CS and VD) with MBL as dependent variable. DD (CS/VD: p=0.006/0.012), BMI (CS/VD: p=0.044/0.008), and SSL (VD P=0.003/CS not evaluated) influenced the extent of MBL, while the other parameters (F1+2, PAP, age, parity and GA) did not.
Conclusions: These results from this to date largest prospective observational study on PPH indicate that prepartum thrombin and plasmin generation are likely not independently related to postpartum blood loss, irrespective of the mode of delivery (VD or CS). This does not preclude that thrombin or plasmin generation might play a role in the later course of a developing PPH. Increased prepartum DD, however, is associated with increased postpartum blood loss, both in VD and CS. Although the different behaviors of prepartum F1+2, PAP and DD might appear counterintuitive at first sight, it seems to fit well with our earlier results: at nominally and statistically comparable prepartum plasmin and thrombin generation (and FIB levels, not shown), lower FXIII levels (Haslinger, JTH, 2020) likely mediate a reduced antifibrinolytic resistance through decreased α2-antiplasmin linking (Fraser, Blood, 2011), resulting in higher DD concentrations, as evidenced here by the higher amount of DD generated per µg PAP in women developing PPH.
The results of the multivariate analysis (MBL depending on prepartum DD, SSL and BMI) support our postulate that these variables set the stage for a possible coagulopathy, followed by a progressive consumption of coagulation factors (mostly FXIII), finally resulting in PPH; such a mechanism might be relevant in a considerable amount of women who do not display a “classical” reason for a PPH, especially uterine atony (Korte, Blood Suppl. 1, 2024).
Our data seem to suggest that prophylactic antifibrinolytic therapy and early stimuli of thrombin generation are unlikely to be helpful: no dysbalance can be detected between women with or without future PPH, neither with VD nor CS. Thus, early during PPH development, other therapeutic approaches should be evaluated. Whether antifibrinolytics and/or thrombin generation stimuli might be helpful during the later course of a PPH remains to be elucidated.
