REVIEW

C URRENT
OPINION Coagulation management and transfusion in
massive postpartum hemorrhage
Christina Massoth a, Manuel Wenk b, Patrick Meybohm c and Peter Kranke c

Purpose of Review
Excessive bleeding during and following childbirth remains one of the leading causes of maternal mortality.
Recent findings
Current guidelines differ in definitions and recommendations on managing transfusion and hemostasis in
massive postpartum hemorrhage (PPH). Insights gained from trauma-induced coagulopathy are not directly
transferable to the obstetric population due to gestational alterations and a differing pathophysiology.
Summary
Factor deficiency is uncommon at the beginning of most etiologies of PPH but will eventually develop from
consumption and depletion in the absence of bleeding control. The sensitivity of point-of-care tests for
fibrinolysis is too low and may delay treatment, therefore tranexamic acid should be started early at
diagnosis even without signs for hyperfibrinolysis. Transfusion management may be initiated empirically,
but is best to be guided by laboratory and viscoelastic assay results as soon as possible.
Hypofibrinogenemia is well detected by point-of-care tests, thus substitution may be tailored to individual
needs, while reliable thresholds for fresh frozen plasma (FFP) and specific components are yet to be
defined. In case of factor deficiency, prothrombin complex concentrate or lyophilized plasma allow for a
more rapid restoration of coagulation than FFP. If bleeding and hemostasis are under control, a timely
anticoagulation may be necessary.
Keywords
cesarean section, coagulopathy, uterine atony, vaginal birth

INTRODUCTION traumatic injuries and preexisting or pregnancy-

Over the last 25 years global efforts have brought
about a decline in maternal mortality by 44%. Yet,
an estimated 800 women are dying daily in the
course of pregnancy and childbirth, resulting in
approximately 300 000 potentially avoidable deaths
per year [1].
There is a disparity between high and low- to
middle-income countries, reflected in maternal
mortality rates ranging from 12 per 100 000 live
births to as much as 546 per 100 000 in regions of
sub-Saharan Africa [1]. Accounting for about 16% of
deaths in developed countries and 27% worldwide,
postpartum hemorrhage (PPH) remains the leading
cause of maternal mortality from a global perspec-
tive [2].
Uterine atony, characterized by insufficient
muscular compression and vasoconstriction of
exposed vessels after separation of the placenta,
occurs as the primary driver of life-threatening
bleeding in up to 80% of cases [3]. Less frequent
etiologies include placenta accreta spectrum,
associated coagulopathies such as von Willebrand’s
disease and disseminated intravascular coagulation
as reflected by the mnemonic 4Ts – Tonus, Tissue,
Trauma, Thrombin [4].
Multiparity, cesarean section, preeclampsia and
maternal age
35 years have been recognized as
factors associated with an increased risk of bleed-
ing complications [5]. Overall, the value of the
individual consideration of predictors for PPH is
a
Department of Anesthesiology, Intensive Care and Pain Medicine,
unster, bDepartment of Anesthesiology and Inten-
University Hospital M€
sive Care, Clemenshospital M€ unster and cDepartment of
unster, M€
Anaesthesiology, Intensive Care, Emergency and Pain Medicine Uni-
versity Hospital Wuerzburg, Wuerzburg, Germany
Correspondence to Peter Kranke, Univ.-Prof. Dr med. Department of
Anaesthesiology, Intensive Care, Emergency and Pain Medicine, Uni-
versity Hospital Wuerzburg, Oberduerrbacher Str. 6, 97080 Wuerzburg,
Germany. Tel: +49 931 201 30050; e-mail: kranke_p@ukw.de
Curr Opin Anesthesiol 2023, 36:281–287
DOI:10.1097/ACO.0000000000001258

0952-7907 Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved. www.co-anesthesiology.com

Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.

Obstetric and gynecological anesthesia
KEY POINTS
 Massive postpartum hemorrhage is still a leading cause
of maternal death but lacks consensual definitions
and recommendations.
 Although transfusion and coagulation management
may be initiated empirically, the specific hemostatic
constellations resulting from gestational alterations
demand a customized treatment.
 Early assessment of viscoelastic assays complemented
by laboratory testing will allow for targeted rapid
restoration of coagulation levels.
controversially discussed, so that in the meantime
artificial intelligence (AI) techniques and machine
learning have also been used in order to improve
prediction [6].
DEFINITION
Postpartum hemorrhage is usually diagnosed after a
certain amount of blood loss after delivery, differ-
entiated as primary if occurring within 24 h after
birth or secondary after 24 h up to 12 weeks [7]. Still,
there is no consensual quantitative definition of
PPH. Traditional classifications, such as the WHO
criteria, term a blood loss
500 ml after birth as PPH
and stage bleeding volumes beyond 1000 ml as
severe. Others differentiate by birth mode and
define PPH as bleeding volume of
500 ml following
vaginal delivery and
1000 ml after cesarean section
[8,9]. The American College of Obstetricians and
Gynecologists (ACOG) demands, irrespective of
the birth mode, a bleeding volume of at least
1000 ml or, alternatively, clinical signs of hypovo-
lemia [10]. The term ‘massive PPH’ is exclusively
used by the NATA-guidelines (Network for the
Advancement of Patient Blood Management,
Hemostasis and Thrombosis) and refers to an
ongoing blood loss of >2500 ml or hypovolemic
shock [11]. Massive hemorrhage, in general, is
roughly defined as the need for more than four units
of packed red blood cells within the first hour or >10
units within 24 h [12]. However, these boundaries
are hardly universally applicable; the use of blood-
saving measures such as intraoperative cell salvage
blur and confuse strict definitions.
Regardless of these heterogeneous definitions,
critical blood loss after childbirth remains an under-
recognized condition. Visual assessments of bleed-
ing volumes are low in accuracy and should be
enhanced by pictorial algorithms and actual meas-
urements using calibrated collectors or the weighing
of cloths and drapes to avoid the detrimental
282 www.co-anesthesiology.com
Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
consequences of delayed or improper management
such as hysterectomy, hypovolemic shock, end
organ damage and cardiac arrest [13,14].
For this reason, some guidelines recommend
assuming PPH if only the suspicion is raised and
taking into account typical shock signs (lactate, pH,
base excess) or the shock index [9].
PATHOPHYSIOLOGY
It is critical to notice that physiological changes of
late pregnancy include a rise in heart rate and
alveolar ventilation and may thus very well mask
the clinical signs of hypovolemia even with an
excessive blood loss of 25–30% [15].
Still, gestational alterations also come with a
prothrombotic state at term to limit peripartum
bleeding by upregulation of almost all coagulation
factors and decreased fibrinolysis [16]. While the
thrombocyte count may fall from the second tri-
mester due to the expansion in plasma volume,
consecutive hemodilution, and increased clearance
rates, fibrinogen levels rise by factor two from base-
line to a range between 3.73 and 6.19 g/dl [17,18].
Even on the basis of viscoelastic methods, the norm
value distribution, which often deviates from the
population of nonpregnant women, must be taken
into account [19].
Impaired hemostasis and fibrinolysis occur at
an early stage in the massively bleeding trauma
patient due to the more extensive tissue injury and
associated endothelial activation and inflamma-
tory response. In contrast, early coagulopathy is
uncommon during the initial phase of PPH, except
for particular but rare conditions such as amniotic
fluid embolism, placental abruption or preexisting
coagulopathies [12,20]. However, when untreated,
ongoing blood loss will eventually result in factor
deficiency and fibrinolysis due to depletion, con-
sumption and hemodilution from resuscitation
with crystalloids and colloids. While thrombin-
generating factors may be used more than once,
fibrinogen will be the first to fall from consump-
tion [16].
GENERAL CONSIDERATIONS OF
COAGULATION MANAGEMENT
The main priority of coagulation management for
the multidisciplinary team is to identify the patho-
physiology of PPH and to implement measures to
control and stop the bleeding, such as the admin-
istration of uterotonics, surgical exploration or even
temporary aortic compression.
Anemia, acidosis and hypothermia each accel-
erate the downward spiral of coagulopathy by
Volume 36  Number 3  June 2023
 Coagulation management and transfusion in massive postpartum hemorrhage Massoth et al.
impairing clot formation and strength and
require timely optimization, with target values of
hemoglobin of 7–9 g/dl, pH >7.2 and a temperature
of >36.58C during uncontrolled bleeding [21].
Ionized calcium plays an essential role in hemo-
stasis and contributes as factor IV by activating several
coagulation factors to clot formation and strengthen-
ing. An in vitro study suggests decreased calcium levels
may also impair oxytocin-induced uterine contrac-
tility [22]. A retrospective analysis of 406 PPH cases
from an 11-year period found even slightly reduced
calcium concentrations below 1.16 mmol/l to be
independently associated with an increased risk of
severe bleeding, with an odds ratio (OR) of 1.97 [95%
confidence interval (CI) 1.25–3.1, P ¼ 0.003) for each
&
0.1 mmol/l decrease [23 ].
Despite early concerns for an increased risk of
amniotic fluid embolism and fetal red cell sensitiza-
tion, an increasing body of evidence supports the
use of autologous transfusion of intraoperative cell
salvage in obstetric bleeding.
A retrospective analysis of 1170 cases reported
a median reinfusion volume of 231 (154–306 [80–
1690]) ml and found the implementation of
cell salvage to be safe and associated with a decrease
in RBC transfusion from 1.4% to 0.4% over a 10-
year period [24]. A large observational study com-
paring 11 322 cases of cesarean section before the
implementation of intraoperative cell salvage with
17 456 cases postimplementation reported no
increase in adverse events with a reinfusion rate
of 47% (757 patients). Although autologous trans-
fusion significantly reduced the intraoperative
administration of RBC [difference 0.7%, 95% CI
0.1% to 1.4%; P ¼ .03), the postoperative rate
remained unchanged (difference 0.2%, 95% CI,
0.4% to 0.7%; P ¼ 0.56) [25].
Nevertheless, if available, cell salvage is a safe
and viable option for transfusion management not
only in massive PPH and is recommended (1C) by
current guidelines [11,26].
This is especially true for caesarean delivery. The
use of cell salvage in spontaneous births is practiced
only very sporadically [27,28].
TRANEXAMIC ACID
Except for rare conditions such as amniotic fluid
embolism, early development of fibrinolysis might
not occur as regularly in obstetrics as in the setting
of trauma-associated hemorrhage, and there is a
paucity of data on different phenotypes and timing
of fibrinolytic activity. A single-center study retro-
spectively assessed thromboelastography results of
118 women with PPH and failed to detect elevated
fibrinolytic activity [29].
0952-7907 Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
Other trials identified a positive kinetic of fibri-
nolytic biomarkers such as plasmin-antiplasmin
complexes or D-dimers, accumulating as a break-
down product of cross-linked fibrin in patients with
significant obstetric bleeding without antifibrino-
lytic treatment. These findings suggest an insuffi-
cient sensitivity of viscoelastic assays to detect
&&
hyperfibrinolysis in this setting [30,31 ].
Throughout the last decade, the antifibrinolytic
drug tranexamic acid (TXA) has gained wide popu-
larity in preventing and managing various settings
of heavy bleeding. TXA binds as a competitive
antagonist at the lysin receptor of plasminogen
and inhibits the tissue plasminogen activator- or
urokinase-induced conversion to plasmin and, thus
the plasmin-mediated proteolysis of fibrin and asso-
ciated inflammatory pathways.
The 2017 landmark WOMAN-trial randomized
20 060 parturients with an estimated bleeding vol-
ume of >500 ml after vaginal or >1000 ml after
cesarean delivery to receive either 1 g TXA or pla-
cebo. Although both treatment arms did not differ
regarding the primary composite endpoint death
from all causes or hysterectomy, death from bleed-
ing was significantly reduced with TXA [1.5% vs.
1.9%; P ¼ 0.045; relative risk (RR) 0.81 95% CI (0.65–
1.0)]. Still, the generalizability remains limited to
the fact the trial was primarily conducted in low- to
middle-resource settings [32].
To find the optimal dose to inhibit fibrinolysis,
the recent multicenter TRACES trial randomized 175
women with a bleeding volume of more than 800 ml
after cesarean section to receive a dosage of 1 g TXA,
0.5 g TXA or placebo. Although a dose of 1 g but not
0.5 g significantly reduced levels of fibrinolysis
markers, these findings were not correlated with
improved clinical outcomes, as patients in all three
treatment arms did not differ in duration or amount
of bleeding or the incidence of life-threatening
&&
blood loss above 2500 ml [31 ].
Two large multicenter randomized controlled
trials assessed the effect of preventive treatment
with TXA compared to placebo on the incidence
of PPH: In the TRAAP- study with 4079 randomized
parturients undergoing vaginal delivery, TXA was
not associated with a reduction of the primary out-
come, a blood loss of at least 500 ml (8.1% vs. 9.8%;
RR 0.83 95% CI 0.68–1.01, P ¼ 0.07) [33]. The
TRAAP-2 trial, including 4551 randomized women
undergoing cesarean section, reported a reduction
in the primary outcome PPH of at least 1000 ml or
need of transfusion [26.7% vs. 31.6%, aRR 0.84; 95%
CI (0.75–0.94, P ¼ 0.003]. However, blood loss was
only about 100 ml less with TXA and transfusion
rates, or any other secondary outcomes did not
differ between groups [34].
www.co-anesthesiology.com 283
Obstetric and gynecological anesthesia
To treat PPH, 1 g TXA effectively reduces fibri-
nolytic activity, but the impact on prevention
seems less meaningful and has to be counterbal-
anced against adverse events. For this reason, var-
ious guidelines have so far rejected prophylactic
administration, although in the course of caesar-
ean section deliveries with a high risk of PPH,
current evidence suggests benefits of early (pro-
phylactic) use (e.g. after separation of the child)
[35,36]. Although TXA does not seem to increase
the risk of thromboembolic events, it is associated
with higher rates of postoperative nausea and
vomiting [33,34]. Given the now widespread avail-
ability in obstetric departments, a recent World
Health Organization warning reported rising num-
bers of inadvertent intrathecal injections of TXA
with disastrous effects due to the substance’s
inherent neurotoxicity, associated with mortality
&
rates of 50% [37 ].
TRANSFUSION
The European Society of Anaesthesiology and Inten-
sive Care guideline for the management of severe
perioperative bleeding recommends a target hemo-
globin level of 7–9 g/dl for the actively bleeding
patient, while the platelet count should be above
75 to 100x109/l [38,39]. Empirical treatment using
transfusion protocols and fixed shock packs with a
4:4:1 ratio of blood: plasma: platelets may be appro-
priate for the initial management of massive uncon-
trolled bleeding [38,40].
However, this approach results in a high load of
plasma infusion, associated with an increased risk
for adverse events [41,42]. Considering the physio-
logical prothrombotic state of term pregnant
women, factor deficiency at the beginning of mas-
sive transfusion is uncommon but may be pro-
moted by high dosages of fresh frozen plasma
(FFP) of nonpregnant donors, causing inadvertent
dilution [43].
To allow for an early and targeted replacement
of factor deficiencies, blood samples for hemostasis
testing need to be collected as soon as possible.
Given the long turnaround times of laboratory
assessments, repetitive use of viscoelastic hemo-
static assays such as thromboelastography (TEG)
or thromboelastometry (ROTEM) appears favorable
to guide further hemostatic treatment.
A recent prospective observational study com-
pared ROTEM results with laboratory assessments of
hemostasis of 521 women with postpartum blood
loss of at least 1000 ml. In this cohort, hypofibrino-
genemia <2 g/l occurred as the most common factor
deficiency in 5% of patients and was reliably
detected by FIBTEM A5 with an area-under-the-
284 www.co-anesthesiology.com
Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
receiver operator characteristic curve of 0.96 (95%
CI 0.94–0.98, P < 0.001), a sensitivity of 0.76 and a
specificity of 0.96. However, EXTEM clotting time
(CT) and PLTEM performed poorly in detecting
factor deficiency reflected by prolonged prothrom-
bin time (1.5x times) or thrombocytopenia
<75  109/l with a sensitivity of 0.33 and 0.3 and
&
a specificity of 0.97 and 0.99, respectively [44 ].
Similarly, TEG identified low fibrinogen levels suc-
cessfully but cannot reliably indicate prolonged
prothrombin time, while data on the detection of
critically reduced platelet counts are inconsistent
[45,46]. Consequently, viscoelastic hemostatic
assays are a valuable component to guide coagula-
tion management and to initiate fibrinogen replace-
ment in particular. Still, they leave uncertainty
when to transfuse fresh frozen plasma or platelets
and cannot provide the additional information on
prothrombin time/INR and activated partial throm-
boplastin time gathered from traditional laboratory
tests. Pragmatic approaches recommend FFP dos-
ages of 15–20 ml/kg in abnormal hemostatic tests
or EXTEM CT >75 s [11,19].
Several TEG- or ROTEM-guided algorithms for
massive hemorrhage have been proposed, but high-
quality evidence for an actual impact on patient
outcomes is lacking so far [47–49].
Currently, in our own institutions the threshold
for the point-of care diagnostic devices to apply
fibrinogen is 12 mm (FIBTEM A 5), while an EXTEM
Clotting time >75 may indicate the need for pro-
thrombin complex concentrate [50].
FIBRINOGEN
Low fibrinogen levels at baseline have been identi-
fied as an independent predictor of bleeding severity
in postpartum bleeding. In a prospective multicen-
ter study including 128 parturients with PPH, the
authors reported a negative predictive value for a
fibrinogen level >4 g/l at the start of uterotonic
treatment and an OR for progression into severe
bleeding of 2.63 [95% CI (1.66–4.16) P < 0.0001]
for each 1 g/l decrease in fibrinogen [51].
A posthoc analysis of 738 PPH cases described the
OR of severe bleeding to be 1.9 [95% CI (1.16–3.09)] if
fibrinogen levels at diagnosis range between 2 and
3 g/l and to increase to as much as 11.99 [95% CI
(2.56–56.06)] with fibrinogen levels below 2 g/l [52].
Consequently, The British RCOG (Royal College
of Obstetricians and Gynaecologists) guidelines rec-
ommend maintaining plasma fibrinogen concentra-
tion at a minimum level of 2 g/l, equivalent to a
FIBTEM MCF below 12 mm [48,53].
FFP is not ideal for managing hypofibrinogene-
mia as it contains only low concentrations of
Volume 36  Number 3  June 2023
 Coagulation management and transfusion in massive postpartum hemorrhage Massoth et al.
fibrinogen and requires the administration of high
volumes. Replacement of 2 g fibrinogen equals
already a total amount of 1000 ml in FFP. To avoid
complications of circulatory overload, alternative
substances such as cryoprecipitate and fibrinogen
concentrate are more favorable in dosage-volume-
relation (transfusion associated cardiac overload,
TRACO) and associated with a lower risk of infec-
tious transmission and risk for Transfusion Related
Acute Lung Injury (TRALI) [16].
Three recent RCTs assessed the impact of early
fibrinogen substitution on patient outcomes in PPH.
The FIB-PPH randomized 249 parturients with
severe PPH [mean blood loss 1459 (SD 476) ml] to
receive preemptively 2 g fibrinogen or placebo, irre-
spective of the plasma fibrinogen concentration at
that time. Although the administration of fibrino-
gen turned out safe in terms of thromboembolic
events, it was not associated with a reduction in
the primary endpoint postpartum blood transfusion
[20% vs. 22%; RR 0.95 (95%CI (0.58–1.54) P ¼ 0.88]
or any other prespecified endpoints [54]. Similarly,
the OBS2-study randomly assigned 55 subjects with
a blood loss of 1000–1500 ml and FIBTEM A5
<15 mm to receive fibrinogen concentrate in a dos-
age to increase FIBTEM A5 above 22m or placebo.
Most recently, the multicenter FIDEL-trial random-
ized 437 patients needing a switch in prostaglandins
for ongoing bleeding after delivery to the adminis-
tration of 3 g fibrinogen or placebo. Although fibri-
nogen infusion did prevent a decrease in plasma
fibrinogen levels, it was not associated with
decreased transfusion rates (23.4% vs. 25.0%; OR
1.01, P ¼ 0.98) or fall in Hb level >4 g/dl (19.1% vs.
19.5%; OR 1.02; P ¼ 0.95) [55 ].
&&
Early or preemptive fibrinogen substitution with
still high concentrations at baseline did not seem to
improve patient outcomes. Therefore, a targeted
replacement might not be necessary at FIBTEM lev-
els >12 mm or plasma levels between 2 and 2.5 g/l.
Dosing recommendations range from 30 to 60 mg/
kg body weight, considering that approximately
0.5 g fibrinogen is about to raise MCF by 1 mm in
a 70 kg patient [56].
FACTOR REPLACEMENT
Prothrombin complex concentrates (PCC) contain
the vitamin-K-dependent clotting factors II, VII, IX,
X and protein S and C, a composition designed for a
rapid reversal of vitamin K antagonists. There is a
paucity of data on the role of PCC in PPH, and some
guidelines strictly advocate against their use for safety
concerns [11,57]. Others suggest the administration
of PCC with a dose of 20–30 IU/kg as an alternative to
FFP or lyophilized plasma in constellations of
0952-7907 Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
adequate fibrinogen replacement and abnormal pro-
thrombin time/INR or severe ongoing blood loss
[9,58]. However, studies are warranted to determine
the potential beneficial effects of PPH against the risk
of venous thromboembolism.
Factor XIII is also referred to as fibrin stabilizing
factor, providing mechanical clot strength and
fibrinolytic resistance.
A recent prospective cohort study assessing pre-
partum coagulation factor levels in a total of 1300
women found factor XIII activity to be strongly asso-
ciated with the incidence of PPH. The authors
reported a factor activity below 50% to increase the
probability of PPH beyond 50% [59]. Consistently,
another observational trial including 548 subjects
identified low prepartum factor XIII levels as an inde-
pendent risk factor for bleeding after delivery with a
mean of 79.33% (SD 15.5) in women with PPH and
86.45% (SD 14.6) in those without (P ¼ 0.001) [60].
Although data on factor XIII replacement is scarce,
some guidelines suggest the administration of 30 IU
/kg body weight in conditions of significant defi-
ciency and ongoing bleeding [9,11,38]. At least it
seems advisable to monitor this factor, especially in
the case of more pronounced or prolonged bleeding.
Recombinant activated factor VIIa has been rec-
ognized as efficient in terminating PPH refractory to
escalated uterotonic therapy and sufficient hemo-
static management. In therapeutic dosages of about
60 to 90 mg/kg body weight, it operates as a direct
activator of factor X and induces a thrombin burst
[61,62]. It was only recently authorized by the Euro-
pean Medicines Agency (EMA) for the treatment of
severe PPH refractory to uterotonic bleeding control
and may be considered on a case-by-case decision
[9]. However, large-scale data from the obstetric
population are lacking, and safety concerns for an
increased risk of arterial thromboembolic events
remain [63].
CONCLUSION
The devastating consequences of severe hemor-
rhage after delivery remain an issue of unabated
priority. The lack of consensus of various recently
published guidelines highlights the need for uni-
form definitions and recommendations. The upre-
gulation of coagulation factors at term impedes
empirical treatment of massive bleeding. As the
obstetric population will clearly benefit from a
targeted, personalized treatment, there is an urgent
need to find sensible point-of-care thresholds when
to administer or withhold FFP, platelets and spe-
cific coagulation factors and to a lesser extent pro-
thrombin complex concentrate and factor XIII
(Fig. 1). As long as there is no good data on outcome
www.co-anesthesiology.com 285
Obstetric and gynecological anesthesia

Basic Precondions Anfibrinolysis Diagnosc Transfusion Targets Refractory Bleeding

• Temperature >36.5°C Point-of-Care • Hb 7 to 9g/dl
Iniate transfusion protocol • Platelets >75 to 100x109/l
• pH >7.2 • BGA unl diagnosc available
• Ca2+ > 1.16mmol/l • TEG/ROTEM • Fibrinogen > 2 to 2.5g/l
1g Tranexamic Acid Consider rF VIIa
Laboratory Tests FIBTEM A5 >12mm
RBC:FFP:Platelets 4:4:1 • EXTEM Ct < 75 sec.
Consider Cell Salvage • Platelets
• aPTT, PT • PT/aPTT prolongaon
• Fibrinogen <1.5 x mes baseline
• F XIII >60%

FIGURE 1. Flowchart of hemostatic and transfusion management in PPH. PPH, postpartum hemorrhage.

9. Annecke T, Lier H, Girard T, et al. Peripartum hemorrhage, diagnostics and

under different coagulation management regi-
mens, clinicians should focus on a quick and easy
normalization of established coagulation levels or
POC limits.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
C.M., P.K., M.W. declares no conflict of interest. P.M.’s
Department received research grants from the German
Research Foundation (ME 3559/1-1, ME 3559/3-1, ME
6094/3-2), BMBF (01KG1815), BMG (ZMVI1-
2520DAT10E); P.M. received honoraria for scientific
lectures from Biotest AG, CSL Behring, Haemonetics,
Pharmacosmos GmbH, Vifor Pharma, Werfen GmbH.
P.K. received honoraria for scientific lectures from CSL
Behring, TEVARatiopharm, Fresenius, Vifor Pharma
and Pharmacosmos GmbH.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
1. Alkema L, Chou D, Hogan D, et al. Global, regional, and national levels and
trends in maternal mortality between 1990 and 2015 with scenario-based
projections to 2030: a systematic analysis by the UN Maternal Mortality
Estimation Inter-Agency Group. Lancet 2016; 387:462–474.
2. Say L, Chou D, Gemmill A, et al. Global causes of maternal death: a WHO
systematic analysis. Lancet Glob Health 2014; 2:e323–e333.
3. Bateman BT, Berman MF, Riley LE, Leffert LR. The epidemiology of post-
partum hemorrhage in a large, nationwide sample of deliveries. Anesth Analg
2010; 110:1368–1373.
4. Widmer M, Piaggio G, Hofmeyr GJ, et al. Maternal characteristics and causes
associated with refractory postpartum haemorrhage after vaginal birth: a
secondary analysis of the WHO CHAMPION trial data. BJOG 2020;
127:628–634.
5. Kramer MS, Berg C, Abenhaim H, et al. Incidence, risk factors, and temporal
trends in severe postpartum hemorrhage. Am J Obstet Gynecol 2013;
209:448.e1–448.e7.
6. Krishnamoorthy S, Liu Y, Liu K. A novel oppositional binary crow search
algorithm with optimal machine learning based postpartum hemorrhage
prediction model. BMC Pregnancy Childbirth 2022; 22:560.
7. Giouleka S, Tsakiridis I, Kalogiannidis I, et al. Postpartum hemorrhage: a com-
prehensive review of guidelines. Obstet Gynecol Surv 2022; 77:665–682.
8. Menard MK, Main EK, Currigan SM. Executive summary of the reVITALize
initiative: standardizing obstetric data definitions. Obstetr Gynecol 2014;
124:150–153.
treatment: update of the S2k guidelines AWMF 015/063 from August 2022.
Die Anaesthesiologie 2022; 71:952–958.
10. Practice bulletin no. 183: postpartum hemorrhage. Obstetr Gynecol 2017;
130:e168–e186.
11. Muñoz M, Stensballe J, Ducloy-Bouthors A-S, et al. Patient blood manage-
ment in obstetrics: prevention and treatment of postpartum haemorrhage. A
NATA consensus statement. Blood Transfus 2019; 17:112–136.
12. Moore EE, Moore HB, Kornblith LZ, et al. Trauma-induced coagulopathy. Nat
Rev Dis Primers 2021; 7:30.
13. Bose P, Regan F, Paterson-Brown S. Improving the accuracy of estimated
blood loss at obstetric haemorrhage using clinical reconstructions. BJOG
2006; 113:919–924.
14. Duthie SJ, Ven D, Yung GL, et al. Discrepancy between laboratory determina-
tion and visual estimation of blood loss during normal delivery. Eur J Obstet
Gynecol Reprod Biol 1991; 38:119–124.
15. Pacagnella RC, Souza JP, Durocher J, et al. A systematic review of the
relationship between blood loss and clinical signs. PLoS One 2013; 8:
e57594.
16. Vermeulen T, van de Velde M. The role of fibrinogen in postpartum hemor-
rhage. Best Pract Res Clin Anaesthesiol 2022; 36:399–410.
17. Cines DB, Levine LD. Thrombocytopenia in pregnancy. Blood 2017;
130:2271–2277.
18. Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory
studies: a reference table for clinicians. Obstetr Gynecol 2009; 114:1326–1331.
19. Dias JD, Butwick AJ, Hartmann J, Waters JH. Viscoelastic haemostatic point-
of-care assays in the management of postpartum haemorrhage: a narrative
review. Anaesthesia 2022; 77:700–711.
20. Stafford IA, Moaddab A, Dildy GA, et al. Amniotic fluid embolism syndrome:
analysis of the Unites States International Registry. Am J Obstet Gynecol
MFM 2020; 2:100083.
21. Lier H, Krep H, Schroeder S, Stuber F. Preconditions of hemostasis in trauma:
a review. The influence of acidosis, hypocalcemia, anemia, and hypothermia
on functional hemostasis in trauma. J Trauma 2008; 65:951–960.
22. Talati C, Ramachandran N, Carvalho JCA, et al. The effect of extracellular
calcium on oxytocin-induced contractility in naive and oxytocin-pretreated
human myometrium in vitro. Anesth Analg 2016; 122:1498–1507.
23. Epstein D, Solomon N, Korytny A, et al. Association between ionised calcium
& and severity of postpartum haemorrhage: a retrospective cohort study. Br J
Anaesth 2021; 126:1022–1028.
This cohort study described that decreased levels of ionized calcium can identify
women at high risk for PPH.
24. Sullivan IJ, Ralph CJ. Obstetric intra-operative cell salvage: a review of an
established cell salvage service with 1170 re-infused cases. Anaesthesia
2019; 74:976–983.
25. Yan H, Hu L-Q, Wu Y, et al. The association of targeted cell salvage blood
transfusion during cesarean delivery with allogeneic packed red blood cell
transfusions in a maternity hospital in China. Anesth Analg 2018; 127:706–713.
26. Prevention and management of postpartum haemorrhage. BJOG 2017; 124:
e106–e149.
27. Phillips JM, Tamura T, Waters JH, et al. Autotransfusion of vaginally shed
blood as a novel therapy in obstetric hemorrhage: a case series. Transfusion
(Paris) 2022; 62:613–620.
28. Phillips JM, Sakamoto S, Buffie A, et al. How do I perform cell salvage during
vaginal obstetric hemorrhage? Transfusion (Paris) 2022; 62:1159–1165.
29. Arnolds DE, Scavone BM. Thromboelastographic assessment of fibrinolytic
activity in postpartum hemorrhage: a retrospective single-center observational
study. Anesth Analg 2020; 131:1373–1379.
30. Ducloy-Bouthors AS, Duhamel A, Kipnis E, et al. Postpartum haemorrhage
related early increase in D-dimers is inhibited by tranexamic acid: haemostasis
parameters of a randomized controlled open labelled trial. Br J Anaesth 2016;
116:641–648.
31. Ducloy-Bouthors A-S, Gilliot S, Kyheng M, et al. Tranexamic acid dose-
&& response relationship for antifibrinolysis in postpartum haemorrhage during
caesarean delivery: TRACES, a double-blind, placebo-controlled, multicentre,
dose-ranging biomarker study. Br J Anaesth 2022; 129:937–945.
This multicenter randomized dose-finding trial found 1 g of tranexamic acid, but not
0.5 g or placebo to significantly reduce fibrinolytic activity.

286 www.co-anesthesiology.com Volume 36  Number 3  June 2023

Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.

 Coagulation management and transfusion in massive postpartum hemorrhage Massoth et al.
32. WOMAN Trial Collaborators. Effect of early tranexamic acid administration on
mortality, hysterectomy, and other morbidities in women with postpartum
haemorrhage (WOMAN): an international, randomised, double-blind, place-
bo-controlled trial. Lancet 2017; 389:2105–2116.
33. Sentilhes L, Winer N, Azria E, et al. Tranexamic acid for the prevention of blood
loss after vaginal delivery. N Engl J Med 2018; 379:731–742.
34. Sentilhes L, Sénat Mv, le Lous M, et al. Tranexamic acid for the prevention of
blood loss after cesarean delivery. N Engl J Med 2021; 384:1623–1634.
35. Binyamin Y, Orbach-Zinger S, Gruzman I, et al. The effect of prophylactic use
of tranexamic acid for cesarean section. J Maternal-Fetal Neonat Med 2022;
35:9157–9162.
36. Shalaby MA, Maged AM, Al-Asmar A, et al. Safety and efficacy of preoperative
tranexamic acid in reducing intraoperative and postoperative blood loss in
high-risk women undergoing cesarean delivery: a randomized controlled trial.
BMC Pregnancy Childbirth 2022; 22:201.
37. Moran NF, Bishop DG, Fawcus S, et al. Tranexamic acid at cesarean delivery:
& drug-error deaths. BJOG 2023; 130:114–117.
Tranexamic acid is involved in an increasing number of maternal fatalities due to
inadvertent intrathecal injections.
38. Kozek-Langenecker SA, Ahmed AB, Afshari A, et al. Management of severe
perioperative bleeding: guidelines from the European Society of Anaesthe-
siology: First update. Eur J Anaesthesiol 2017; 34:332–395.
39. Spahn DR, Bouillon B, Cerny V, et al. The European guideline on management
of major bleeding and coagulopathy following trauma: fifth edition. Crit Care
2019; 23:98.
40. Mesar T, Larentzakis A, Dzik W, et al. Association between ratio of fresh frozen
plasma to red blood cells during massive transfusion and survival among
patients without traumatic injury. JAMA Surg 2017; 152:574–580.
41. Inaba K, Branco BC, Rhee P, et al. Impact of plasma transfusion in trauma
patients who do not require massive transfusion. J Am Coll Surg 2010;
210:957–965.
42. Watson GA, Sperry JL, Rosengart MR, et al. Fresh frozen plasma is independently
associated with a higher risk of multiple organ failure and acute respiratory
distress syndrome. J Trauma 2009; 67:221–227; discussion 228–30.
43. Collis RE, Collins PW. Haemostatic management of obstetric haemorrhage.
Anaesthesia 2015; 70:78–e28.
44. Bell SF, Roberts TCD, Freyer Martins Pereira J, et al. The sensitivity and
& specificity of rotational thromboelastometry (ROTEM) to detect coagulopathy
during moderate and severe postpartum haemorrhage: a prospective ob-
servational study. Int J Obstet Anesth 2022; 49:103238.
This observational study highlights the strengths and limitations of viscoelastic
assays to guide hemostatic management in PPH.
45. Roberts TCD, de Lloyd L, Bell SF, et al. Utility of viscoelastography with TEG
6 s to direct management of haemostasis during obstetric haemorrhage: a
prospective observational study. Int J Obstet Anesth 2021; 47:103192.
46. Rigouzzo A, Louvet N, Favier R, et al. Assessment of coagulation by throm-
boelastography during ongoing postpartum hemorrhage: a retrospective
cohort analysis. Anesth Analg 2020; 130:416–425.
47. Frigo MG, Agostini V, Brizzi A, et al. Practical approach to transfusion
management of postpartum haemorrhage. Transfus Med 2021; 31:11–15.
48. McNamara H, Kenyon C, Smith R, et al. Four years’ experience of a ROTEM1
-guided algorithm for treatment of coagulopathy in obstetric haemorrhage.
Anaesthesia 2019; 74:984–991.
0952-7907 Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
49. Bell SF, Collis RE, Pallmann P, et al. Reduction in massive postpartum
haemorrhage and red blood cell transfusion during a national quality improve-
ment project, Obstetric Bleeding Strategy for Wales, OBS Cymru: an ob-
servational study. BMC Pregnancy Childbirth 2021; 21:377.
50. Helmer P, Schlesinger T, Hottenrott S, et al. Postpartum hemorrhage: inter-
disciplinary consideration in the context of patient blood management.
Anaesthesist 2022; 71:181–189.
51. Charbit B, Mandelbrot L, Samain E, et al. The decrease of fibrinogen is an early
predictor of the severity of postpartum hemorrhage. J Thromb Haemost 2007;
5:266–273.
52. Cortet M, Deneux-Tharaux C, Dupont C, et al. Association between fibrinogen
level and severity of postpartum haemorrhage: secondary analysis of a
prospective trial. Br J Anaesth 2012; 108:984–989.
53. Collins PW, Lilley G, Bruynseels D, et al. Fibrin-based clot formation as an
early and rapid biomarker for progression of postpartum hemorrhage: a
prospective study. Blood 2014; 124:1727–1736.
54. Wikkelsø AJ, Edwards HM, Afshari A, et al. Preemptive treatment with
fibrinogen concentrate for postpartum haemorrhage: randomized controlled
trial. Br J Anaesth 2015; 114:623–633.
55. Ducloy-Bouthors A, Mercier F, Grouin J, et al. Early and systematic admin-
&& istration of fibrinogen concentrate in postpartum haemorrhage following
vaginal delivery: the FIDEL randomised controlled trial. BJOG 2021; 128:
1814–1823.
This was the largest RCT on early administration of fibrinogen in PPH so far, the
intervention had no effect on hemoglobin decrease or transfusion rate.
56. Solomon C, Pichlmaier U, Schoechl H, et al. Recovery of fibrinogen
after administration of fibrinogen concentrate to patients with severe
bleeding after cardiopulmonary bypass surgery. Br J Anaesth 2010; 104:
555–562.
57. Collins P, Abdul-Kadir R, Thachil J. Subcommittees on women’ s health
issues in thrombosis and haemostasis and on disseminated intravascular
coagulation. Management of coagulopathy associated with postpartum
hemorrhage: guidance from the SSC of the ISTH. J Thromb Haemost
2016; 14:205–210.
58. Carvalho M, Rodrigues A, Gomes M, et al. Interventional algorithms for the
control of coagulopathic bleeding in surgical, trauma, and postpartum set-
tings: recommendations from the Share Network Group. Clin Appl Thromb
Hemost 2016; 22:121–137.
59. Haslinger C, Korte W, Hothorn T, et al. The impact of prepartum factor XIII
activity on postpartum blood loss. J Thromb Haemost 2020; 18:1310–
1319.
60. Bamberg C, Mickley L, Henkelmann A, et al. The impact of antenatal factor XIII
levels on postpartum haemorrhage: a prospective observational study. Arch
Gynecol Obstet 2019; 299:421–430.
61. Welsh A, McLintock C, Gatt S, et al. Guidelines for the use of recombinant
activated factor VII in massive obstetric haemorrhage. Aust N Z J Obstet
Gynaecol 2008; 48:12–16.
62. Park SC, Yeom SR, Han SK, et al. Recombinant activated factor VII as a
second line treatment for postpartum hemorrhage. Korean J Crit Care Med
2017; 32:333–339.
63. Simpson E, Lin Y, Stanworth S, et al. Recombinant factor VIIa for the
prevention and treatment of bleeding in patients without haemophilia. Co-
chrane Database Syst Rev 2012. doi:10.1002/14651858.CD005011.pub4.
www.co-anesthesiology.com 287