Acute obstetric coagulopathy: need for innovation Open Access

Previously, Collins et al identified distinct coagulopathic changes in a subset of women with severe postpartum hemorrhage (PPH; defined by blood loss >2000 mL) and high plasmin/antiplasmin ratio (>25 000 ng/mL), which the authors coined as acute obstetric coagulopathy (AOC).¹ In this issue of Blood Advances, further characterization of severe PPH with AOC by Collins et al² revealed pronounced fibrino(geno)lysis, as well as factor V (FV) cleavage and FVIII reduction (expressed as diminished FVIII/von Willebrand factor ratio). These findings are reminiscent of coagulation changes in early trauma-induced coagulopathy (TIC) and are noteworthy because they signify a critical step forward in the dissection of coagulopathic changes exacerbating PPH.

To date, little thought has been given to what extent features of obstetric coagulopathy may emulate or differ from TIC or disseminated intravascular coagulation (DIC) or whether obstetric coagulopathy may be its own entity altogether. The lack of insight into the internal processes of coagulopathy related to PPH have limited the advancement of targeted interventions to curb bleeding and maternal mortality. Knowledge acquisition related to obstetric coagulopathy has been slow, probably because funding for research to impact women’s health is notoriously lacking.³ Over the last 30 years, only 2 new medicines have been introduced into the armamentarium to treat PPH, namely heat-stable carbetocin (uterotonic) and tranexamic acid (antifibrinolytic), demonstrating a stark innovation deficit (World Health Organization Postpartum Hemorrhage Summit, 2023). To put things into perspective, PPH is on the rise in the United States,⁴ estimated to be responsible for ∼30% to 80% of maternal mortality worldwide, taking many hundreds of maternal lives daily; and even if survived, PPH often causes severe maternal morbidity for years to follow.⁵ 

This background sets the stage for the importance of the report by Collins et al.² Observations in a subset of 12 women with severe PPH and AOC provide a window into specific coagulopathic changes, which in turn may accelerate hemostatic impairment. In general, PPH is defined fairly uniformly by professional societies as blood loss of ≥500 to 1000 mL. However, it is easily conceivable that volume, rate of hemorrhage, and clinical circumstances may affect coagulopathic changes, influencing the severity of PPH. Therefore, one may conjecture that “no bleeding is alike.” PPH is commonly described to be facilitated by the “4 Ts,”⁶ referring to “tone, trauma, tissue, and thrombin (clotting),” conditions that may not always occur in isolation. Their constellation may be intertwined and affect the ensuing coagulopathy accordingly. Therefore, in the setting of “no bleeding is alike,” a “one-size-fits-all” coagulopathy may not pertain in the presence of dynamic fluctuations over time. For instance, coagulopathy associated with PPH and amniotic fluid embolism or placental abruption may resemble DIC⁷ and be quite different from PPH associated with uterine atony, trauma, clotting deficits, or other conditions. Currently, there are no conclusive data available to predict coagulopathic changes during PPH based on the underlying “T.” Although hypofibrinogenemia appears to be a unifying hallmark in PPH irrespective of cause, with fibrinogen levels <200 mg/dL bearing a high risk for PPH,¹ other defining characteristics are less well understood.

Here, Collins et al² describe specific coagulopathic changes in 12 women with severe PPH and AOC, compared to 21 women with severe PPH without AOC. The women belong to a cohort of 518 women with PPH recruited through the Obstetric Bleeding Study Plus (REC16/WA/0282). Although the primary causes of bleeding (atony, surgical/trauma, placental abruption, placenta accreta/previa, retained products of conception, amniotic fluid embolus, and unknown causes) and total measured blood loss were comparable between the 2 groups, the AOC group experienced massive fibrino(geno)lysis with degradation of FV and FVIII. However, the reasons for that were not quite clear, which emphasizes the need to close the aforementioned knowledge gaps. The pronounced fibrino(geno)lytic phenotype was demonstrated by low fibrinogen levels, high levels of d-dimer and other fibrin and fibrinogen degradation products, as well as enhanced tissue plasminogen activator (tPA)–initiated plasmin generation. In contrast, thrombin generation, FII, and FX remained more or less unaffected, exposing features more aligned with early TIC rather than DIC, although some overlap cannot be excluded.⁸ Of note, the incidence of uterine atony was relatively low (∼8%), suggesting a lesser propensity for “tone” and higher propensity for “tissue” and “trauma” as the root cause of PPH. This is noteworthy and may explain why coagulopathic features differed, for example, from another cohort of 81 women with PPH,⁹ in whom markedly low thrombin generation, increased tPA, and clot breakdown resistance were reported, along with relatively lower fibrinogen levels than controls. However, blood loss in this cohort appeared much less (median 1280 mL), and uterine atony was present in 74% of cases, suggesting that “T” context and severity of PPH may truly matter, with additional research urgently needed.

Because the coagulopathic features of AOC appear to be similar or overlapping with early TIC, it is important to mention that TIC is increasingly recognized as a distinct coagulopathic process, characterized by early and selective depletion of FV and FVIII through activation of protein C,¹⁰ as well as dysregulated fibrinolysis.⁸ The accelerated protein C activation is probably caused by trauma-related endotheliopathy,⁸ which may also be invoked in AOC if “tissue” and/or “trauma” prevail as underlying etiologies for PPH. Mechanistically, this may have future therapeutic implications because there is momentum for emerging agents that intersect the protein C pathway as a targeted approach to ablate coagulopathy and bleeding.¹⁰ In summary, Collins et al provide an important contribution to our understanding of obstetric coagulopathy, which appears multifaceted, with an urgent need for further in-depth studies, including innovative animal models, to accelerate the field.

Conflict-of-interest disclosure: A.v.D. has received honoraria for participating in scientific advisory boards, consulting, and speaking engagements from BioMarin, Regeneron, Pfizer, Bioverativ/Sanofi, CSL Behring, Novo Nordisk, Spark Therapeutics, Genentech, and uniQure, and is a cofounder and member of the board of directors of Hematherix LLC, a Biotech company, which is developing ^SuperFVa therapy for bleeding complications. B.C.J. declares no competing financial interests.