Coagulopatia

Best Practice & Research Clinical Obstetrics and Gynaecology 61 (2019) 106e120
Contents lists available at ScienceDirect
Best Practice & Research Clinical

Obstetrics and Gynaecology
journal homepage: www.elsevier.com/locate/bpobgyn
Managing coagulopathy following PPH

Helen McNamara*, Shuba Mallaiah
Department of Anaesthesia, Liverpool Women's NHS Trust, Crown St., Liverpool, L8 7SS, UK
a b s t r a c t
Keywords:
Postpartum haemorrhage The prothrombotic state during pregnancy protects against coa-
Coagulation gulopathy. Fibrinogen is of key importance with concentrations of
Fibrinogen 4e6 g/l in parturients preventing the majority of women with
Thromboelastometry postpartum haemorrhage developing hypofibrinogenaemia.
Pregnancy However, plasma levels below 2 g/l are strongly predictive of bleed
progression and should be maintained above this. Laboratory tests
of coagulation have a low sensitivity in major haemorrhage, and
results are not quickly available. Viscoelastometry provides rapid
results, and the FIBTEM A5 test correlates with fibrinogen levels in
PPH. Fibrinogen concentrate or cryoprecipitate is more suitable for
fibrinogen replacement in pregnancy than fresh frozen plasma.
Formulaic blood product administration results in unnecessary
treatment for the majority. Reduced morbidity with
viscoelastometry-guided blood product administration has been
demonstrated with observational studies but not with randomised
controlled trials. Further studies are needed to assess the optimal
treatment threshold and outcome benefits from targeted fibrin-
ogen replacement.
© 2019 Published by Elsevier Ltd.
Introduction
Postpartum haemorrhage (PPH) persists in being a major challenge worldwide, causing the death of
one woman every 6 min, mainly in low- and middle-income countries, despite the achievements of the
United Nations Millennium Development Goals [1] and Sustainable Development Goals programmes
[2]. Mortality in well-resourced countries is much lower but remains concerning. The MBRRACE report
* Corresponding author.
E-mail addresses: Helen.mcnamara@lwh.nhs.uk, shuba.mallaiah@nhs.net (H. McNamara).
https://doi.org/10.1016/j.bpobgyn.2019.04.002
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H. McNamara, S. Mallaiah / Best Practice & Research Clinical Obstetrics and Gynaecology 61 (2019) 106e120 107
2014e16 [3] found a rate of 0.78 deaths per 100,000 live births in England and Wales due to hae-
morrhage, having almost doubled in approximately 5 years. PPH is responsible for 80% of severe
maternal morbidity and 77% of all postpartum ICU admissions in Scotland [4]. Effective treatment relies
on teamwork, with the obstetric team focused on stopping the bleeding while anaesthetists manage
fluid resuscitation and blood transfusion. Management of coagulation is an essential component of this,
being necessary to prevent a vicious cycle of worsening bleeding and increasing coagulopathy.
Normal coagulation
Coagulation systems involve a delicate balance, protecting against life threatening haemorrhage
whilst avoiding excessive clot formation. The cell based model (Fig. 1) describes three overlapping
phases of coagulation involving a close interaction between cellular and plasma components [5].
Initiation occurs when tissue factor on damaged endothelium is exposed, activating factor VII and
others via the extrinsic pathway. The resulting small thrombin burst activates platelets that bind
factors Va, VIIIa and IXa (amplification). Activated factors on the surface of platelets make the tenase
complex (IXa, VIIIa and X), which, in turn, activates the prothrombinase complex (Xa and Va). This
converts large amounts of prothrombin into an explosive thrombin burst (propagation), ultimately
forming fibrin from fibrinogen. This final step is essential for the formation of a stable clot. Fibrinogen is
also important in binding activated platelets to one another and helps to sustain platelet aggregation.
This system is balanced by both the anticoagulant system and the fibrinolytic process, which is
activated during clot formation [6]. Anticoagulant activity occurs at the margins of injury when
thrombin binds to the endothelial receptor, thrombomodulin. This activates protein C, which along
with protein S degrades factors Va and VIIIa. Thrombin is inactivated by formation of a
thrombineantithrombin (TAT) complex, and tissue factor pathway inhibitor (TFPI) forms a complex
with tissue factor, factors VIIa and Xa, to inhibit the clotting cascade. This ensures that the clot formed
is confined to the area of injury. Fibrinolysis is an essential process by which clot is broken down.
Thrombin induces tissue plasminogen activator (t-PA), generating plasmin from plasminogen.
Fig. 1. The cell-based model of coagulation. TF, tissue factor vWF, von Willebrand factor [7].
108 H. McNamara, S. Mallaiah / Best Practice & Research Clinical Obstetrics and Gynaecology 61 (2019) 106e120
Regulation of fibrinolysis is via plasminogen activator inhibitor (PAI)-1 and thrombin activatable
fibrinolysis inhibitor.
Pregnancy changes
Multiple changes occur in the coagulation system as pregnancy progresses (Fig. 2), with the largest
changes seen at term [7,8]. While plasma volume increases by 40%, red blood cell volume increases by
only 25%, causing a physiological anaemia. Platelet count decreases, both from dilution and con-
sumption by the uteroplacental unit, but is rarely great enough to impact bleeding.
Normal nonpregnant values for fibrinogen are 2e4 g/l but increase incrementally to 4e6 g/l by the
third trimester of pregnancy [9,10]. Fibrinolytic activity is impaired, largely due to placental-derived
plasminogen activator inhibitor type 2 (PAI-2) but returns rapidly to normal following delivery. PAI-
1 also becomes markedly elevated in the third trimester. With relatively unchanged t-PA levels, this
contributes to reduced clot lysis, resulting in a 4- to 10-fold increased thrombotic risk throughout
gestation and the postpartum period [6]. The vascular bed of the placenta contains foetal trophoblast
cells, with an endothelial cell-like ability to regulate haemostasis. These cells have haemostatic
properties including tissue factor expression, altered anticoagulant function, suppression of fibrino-
lysis, and exposure of anionic phospholipids [6].
At term, the prothrombin time (PT) and activated partial thromboplastin time (aPTT) are shorter
than the (nonpregnant) normal range due to the increase in pro-coagulant factors (except factor XI),
especially fibrinogen, factor VIII, and von Willebrand factors [11,12]. The prothrombotic state at the end
of the third trimester prepares for the huge haemorrhagic challenge when the uterus, receiving
700e800 mls blood per minute, expels the foetoplacental unit leaving a large exposed placental bed. In
the majority of women, this demand is adequately met as long as the uterus remains contracted,
reducing the vascular area and ‘ligating’ the spiral arteries as they travel through the myometrium.
Fig. 2. Changes in haemostatic variables during normal pregnancy, which result in a pro-coagulant state [8].
However, a small proportion of women, approximately 2.7% in the UK [13], suffer blood losses of
approximately 1500 mls or more.
Diagnosing coagulopathy
Standard laboratory tests (SLTs)
Standard coagulation tests include prothrombin time (PT), activated partial thromboplastin time
(aPTT) and plasma fibrinogen concentration (usually measured by the Clauss method).
SLTs are performed after removal of cellular elements by centrifugation, and the end point is for-
mation of the first fibrin strands, when approximately 5% of thrombin has been generated. They
measure clot initiation but do not assess the quality and strength of the clot. Hence, they often remain
unchanged even with large blood losses and are of limited use [14,15] with turnaround times of
30e60 min, rendering the results irrelevant in a rapidly evolving haemorrhage.
Point-of-care testing
Viscoelastic haemostatic assays (VHAs) such as thromboelastography (TEG) and rotational throm-
boelastometry (ROTEM) are being increasingly used as point-of-care coagulation tests during major
haemorrhage. Thrombelastography (TEG) was first described by Hartert in 1948 [16]. Several
comprehensive systematic reviews have evaluated their use [17e19].
The working principle is similar in both (Fig. 3, Video 1). Whole blood is placed in a small gap
between a cup and a pin to which activators are added. The cup or the pin moves relative to the other
part, and as fibrin strands form, the resistance to movement due to increasing stickiness is converted to
a graphical trace. The TEG® (Haemonetics Corporation, Braintree, MA, USA) involves a rotating cup and
Fig. 3. Mechanism of thromboelastometry. As the blood clots in the cup, the restriction to movement of the pin is detected optically
and converted to a graphical trace [28].
a pin attached to a torsion wire. ROTEM® (Pentapharm GmbH, Munich, Germany) uses a pin rotating
slowly backward and forward, stabilized by ball bearings. Using whole blood represents haemostasis
in vivo, under low shear conditions that mimic the venous circulation. The whole process from initi-
ation to clot strength and breakdown is measured and displayed (Fig. 4). The TEG and ROTEM measure
similar parameters (Table 1). Earlier, the near-patient use of these devices by clinicans rather than
laboratory personnel required basic training in pipetting techniques. More recently, both manufac-
turers have introduced cartridge-based systems; TEG® 6s and the ROTEM®Sigma, designed to improve
ease of use as well as precision.
Supplementary related to this article can be found at https://doi.org/10.1016/j.bpobgyn.2019.04.
002.
Activation of clotting can be performed with a variety of different reagents, to assess specific parts of
the coagulation process. The most common tests using ROTEM are EXTEM and FIBTEM. The EXTEM is
thromboplastin-activated and assesses the extrinsic pathway. The FIBTEM involves the addition of a
platelet inhibitor (cytochalasin D) and assesses the fibrin component of the clot. Using these in parallel
can determine whether reduced clot strength is due to a problem with fibrinogen or platelets.
The FIBTEM and EXTEM A5 (amplitude at 5 min following the start of clot formation) are useful
parameters for rapid clotting assessment. They have been shown to correlate well with MCF [20,21],
60
40
20
MCF
MCF
0
Clot firmness
(mm)
0 10 20
CT Time (min)
Fig. 4. ROTEM parameters shown are clotting time (CT, the time for the start of clot formation), A5 (Amplitude at 5 min after CT),
Maximum clot firmness (MCF).
Table 1
ROTEM and TEG parameters.
Aspect of clotting assessed ROTEM® parameter TEG® parameter
Initiation Clotting time (CT) Reaction time (R-time)

Time to formation of first fibrin strands.
Concentration of coagulation factors/
inhibitors
Kinetics Alpha angle (a) K-time
Fibrin polymerisation and stabilisation of clot Clot formation time (CFT)
with platelets and FXIII
Clot strength Amplitude (A) at intervals post start of clot Maximum amplitude (MA)
Aggregation of platelets and formation of a formation, and at peak clot firmness.
stable polymerized fibrin network. Amplitude 5 min post CT (A5).
Maximum clot firmness (MCF)
Lysis Percentage reduction in amplitude Lysis (Ly)
Clot breakdown/stability. Maximum lysis (ML)
allowing results to be reported 6e7 min following the start of the test. They are most widely used in
haemorrhage treatment algorithms, where contemporaneous results are a huge advantage to the
clinician. An excellent correlation has been demonstrated between FIBTEM A5 and Clauss fibrinogen in
women with PPH, showing FIBTEM A5 to be a useful early biomarker [22,23]. A TEG-based Functional
Fibrinogen test is available using abciximab to inhibit platelet activation and has been used in pregnant
women [24]. Another ROTEM parameter often used in PPH is the EXTEM CT. A prolonged result is
indicative of global clotting factor deficiency. Fibrinolysis may be evident on VHA testing if severe and
can be confirmed using the APTEM test, which uses aprotinin to inhibit fibrinolysis. However, due to a
low sensitivity, mild degrees may not be noticeable. Fig. 5 includes examples of abnormal ROTEM
traces in obstetric patients. The hypercoagulability of pregnancy has necessitated specific reference
ranges to be determined (Table 2) [10,25,26] (see Fig. 6).
Fig. 5. ROTEM traces, EXTEM left, FIBTEM right. The blue colour depicts an amplitude >20 mm. (a, b) Trace from a normal healthy
pregnant woman. (c, d) Trace from a woman with massive PPH. Reduced clot amplitude in EXTEM and FIBTEM plus prolonged CT
signifies hypofibrinogenaemia and deficiency of other factors. (e,f) Trace from a woman with PPH following amniotic fluid embolism.
Severe reduction in amplitude, prolongation of CT and rapid tapering of the trace signify a state of DIC with overt fibrinolysis.
Table 2
Viscoelastic test values in term pregnancy and nonpregnant controls [8,9]. Values presented as mean (2SD) (TEG) and median
(IQR) (ROTEM). A5 values are author's own unpublished figures.
TEG ROTEM EXTEM ROTEM FIBTEM
R-time (min) K-time (min) MA (mm) CT (s) A5 (mm) MCF (mm) CT (s) A5 (mm) MCF (mm)
Control 6.7 (3.8e9.8) 2.0 (0.7e3.4) 61 (50e73) 51 (45e55) 41 (35e46) 59 (57e72) 51 44e53) 10 (9e12) 13 (11e16)
Term 7.0 (1e13) 2.0 (0.2e3.8) 75 (65e86) 53 (47e62) 49 (44e53) 67 (64e71) 52 (46e65) 18 (16e21) 19 (17e23)
Although NICE [27] failed to endorse the use of point of care testing in PPH in 2014 citing a lack of evidence, many studies since
then have led to their use being approved by the British Society of Haematologists and AAGBI [28,29].
Fig. 6. Algorithm for ROTEM-guided targeted fibrinogen concentrate treatment in obstetric haemorrhage (Liverpool Women's
Hospital, UK).
Coagulation changes during PPH
Fibrinogen, representing 85e90% of the whole amount by weight of plasma coagulation factors, is
the first to fall below a critical level during blood loss and haemodilution [30,31]. Coagulation tests
during PPH have demonstrated that women with severe haemorrhage have lower fibrinogen levels
than women with nonsevere PPH [14]. A large study of women with PPH >1500 ml [15] showed that
fibrinogen levels were inversely related to blood loss (r 0.48) and were significantly lower in women
who required at least 4 units RBC (2.2 g/l vs. 3.6 g/l). Platelet count has been shown to fall in severe PPH
[11,15], where transfusion of >4 units RBCs is required. In contrast to other haemostatic parameters,
aPTT and PT remain largely within the normal range even with large blood losses [11,15], indicating that
these tests are of limited value in PPH.
The majority of women with PPH do not develop significant coagulopathy. The incidence of
fibrinogen <2 g/l has been reported as 1e2/1000 deliveries [32]. A 4-year analysis of ROTEM param-
eters in a large tertiary referral unit [13] showed that of 893 women who bled 1500 ml or more, only
23% had a FIBTEM A5 12 mm (approximates to a plasma fibrinogen level of 2.2 g/l). Less common still
was a deficiency of other clotting factors, as indicated by an EXTEM CT > 100 s, seen in only 1.2%, most
of whom had suffered placental abruption with intrauterine death and also had marked hypofi-
brinogenaemia, suggesting a consumptive process.
Fibrinogen in PPH - cause or effect?
Fibrinogen levels are important during PPH, being the only factor independently associated with
ongoing severe bleeding [14]. For every 1 g/l decrease in fibrinogen, the risk of progression to severe PPH
is almost tripled. A fibrinogen level <2 g/l carries a 100% positive predictive value for progression,
whereas a level >4 g/l has a negative predictive value of 79%. A study of 738 women with severe PPH
after vaginal delivery [33] found that severe PPH was almost twice as likely if fibrinogen level at
diagnosis was 2e3 g/l and 12 times as likely if fibrinogen was <2 g/l. A fibrinogen level of <2 g/l has also
been shown to be predictive of the need for an advanced interventional procedure for haemostasis [34].
Viscoelastometric measures of fibrinogen have been shown to be highly predictive of PPH severity.
FIBTEM A5 is an independent predictor for progression to bleeds >2500 ml, with a FIBTEM A5 <10 mm
associated with more prolonged bleeds and longer stay in the high-dependency unit [22]. TEG clot
strength measures have also shown similar predictive effect [35].
Although a low fibrinogen level early in a PPH is highly predictive of severity, levels prior to blood
loss do not appear to be so. Several studies have shown that pre-partum fibrinogen, FIBTEM and
EXTEM, on admission to delivery suite did not predict PPH [36e38].
Fibrinogen may fall due to dilution, utilization or breakdown. Dilution occurs with loss of clotting
factors during haemorrhage alongside volume replacement with intravenous fluids, packed RBC or cell
saved blood [39]. Utilization occurs in the presence of any defect in the vascular system, as local clot
forms. This is exaggerated in the placental bed, being an active site of coagulation. Although placental
fibrin deposition during delivery without PPH does not appear significant [38], observational studies
suggest that dilution and fibrinogen utilization are responsible for falling levels during PPH [14,39,40].
Fibrinolysis does not appear to play a major role, only becoming excessive in a small proportion of
women where activation of clotting becomes systemic in the form of disseminated intravascular
coagulation (DIC) [11,14], seen in cases of placental abruption (particularly when large enough to result
in IUD), amniotic fluid embolism and preeclampsia [41].
Treating coagulopathy during PPH
Principles
Institution specific Major Haemorrhage Protocols (MHP), which include clinical, laboratory and
logistic responses, have been shown to reduce haemorrhage-related morbidity and transfusion re-
quirements [42].
PPH can present with alarming speed, or as a deceptively small but persistent trickle. Visual esti-
mation is inaccurate, and an objective method such as weighing blood soaked pads and bed linen is
preferred [43]. Prompt recognition and triggering the MHP will ensure that appropriate escalation
takes place. Resuscitation should start with the ABC principle. Providing oxygen by face mask (10e15 l/
min) is important to maximise oxygen delivery when circulating volume and haemoglobin concen-
tration are reduced.
Circulation requires urgent intervention, and IV access with 2 large bore (14G) cannulae and blood
samples (full blood count, coagulation screening including point of care testing if available, cross-
match, urea and electrolytes and arterial blood gas) are needed. Two litres of warmed isotonic crys-
talloid, followed by transfusion of red cells are vital. Emergency O negative blood may be needed in
severe bleeds switching to crossmatched or group specific blood when available [44]. All fluid should
be warmed and a forced air blanket used to avoid the lethal triad of hypothermia, acidosis and coa-
gulopathy. Acidosis is detected by arterial blood gas sampling and lactate measurement. Tissue
perfusion should be maintained with volume replacement as the mainstay although vasopressors may
also be required. Normal saline should be avoided as it causes hyperchloraemia, which exacerbates
acidosis, and balanced solutions such as ringers lactate are preferable. Hypocalcaemia should be cor-
rected promptly to maintain an ionized Calcium >1.0 mmol/l because calcium is an essential co-factor
for coagulation as well as maintaining vascular tone.
Coagulation products
Coagulation products may be needed to replace deficiencies. Available products include Fresh
Frozen Plasma (FFP), platelets, cryoprecipitate and fibrinogen concentrate. Tranexamic acid is also
included here.
Fresh frozen plasma (FFP)
FFP is plasma separated after donation and frozen to maintain the activity of clotting factors. It is
issued as single-donor packs and must be thawed before use. Levels vary widely between donors and
therefore in individual packs. Derived from nonpregnant donors, it has a fibrinogen level of approxi-
mately 2g/l, well below pregnant plasma levels. However, it contains additional clotting factors indi-
cated for treatment of deficiencies commonly seen in DIC. The recommended dose is 12e15 ml/kg,
which is a minimum of 4 units (>1000 mls) for a 70 kg adult [44].
Cryoprecipitate
Cryoprecipitate is manufactured by thawing FFP and centrifuging to produce a cryoglobulin rich in

fibrinogen, Factor VIII and von Willebrand factor, which is then refrozen and stored at 20 C. It
provides a concentrated source of fibrinogen (Table 3). It is available as single-donor packs or as pools
of five donations. The adult therapeutic dose is two pools, which typically increases the plasma
fibrinogen by approximately 1 g/l [44].
Fibrinogen concentrate
Fibrinogen concentrate is a pasteurized freeze-dried source of fibrinogen from donated plasma. It is

presented as a powder to be reconstituted with water, providing 1 g in 50 ml. Since April 2011, the
product RiaSTAP® (CSL Behring) has been licensed in the UK for the treatment of congenital hypofi-
brinogenaemia only. There is long-standing international experience of its effectiveness in the more
Table 3
Comparison of fibrinogen content in FFP, cryoprecipitate and fibrinogen concentrate.
Standard adult dose Volume Fibrinogen content Number of donors
FFP e 4 units 1000 ml ~2 g 4

Cryoprecipitate e 2 pooled units 360 ml ~3 g 10
Fibrinogen concentrate 150 ml 3g 30-60,000a
a
Although pooled from large numbers of donors, the production of fibrinogen concentrate includes multiple steps,
demonstrated to reduce the risk of virus transmission in addition to donor selection and screening. This includes pasteurisation
(60 C for 20 h in an aqueous solution) [45].
common setting of acquired hypofibrinogenaemia, and in many European countries, it is the main
source of fibrinogen replenishment. It is currently used only by a small number of trusts in the UK,
although it is reasonable to expect that this will increase because of its ease of administration, con-
venience of storage and standardised fibrinogen content.
Platelets
Platelets are either pooled from four whole blood donations or obtained by apheresis (whereby a
concentrated source of platelets is separated out at the point of donation from a single donor). Re-
cipients born after 1st January 1996 should receive apheresis platelets where possible. Transmission of
bacterial infection (1 in 12,000) is higher than other blood components because platelets are stored at
22 C. Transfusion should commence within 30 min of issue and be given over 30 min through a blood
administration set. Each pack of 250e350 ml should increase the platelet count by approximately
30 109/l. Some patients are refractory to platelet transfusion, failing to achieve the expected increase
in number or function. This may occur in massive haemorrhage, DIC, sepsis and secondary to some
medications. The usual lifespan of a platelet in health is 10.5 days, but this may be reduced by these
factors as well as duration of storage.
Tranexamic acid (TXA)
Tranexamic acid is an antifibrinolytic drug, which significantly reduced mortality from PPH in a
worldwide multicentre RCT [46] when 1 g was given within 3 h of delivery. As fibrinolysis is not easily
detected on laboratory or viscoelastometric testing, tranexamic acid should be given to all women on
diagnosis of PPH, in accordance with WHO recommendations.
Empiric vs. targeted blood product administration
Key goals for coagulation during PPH as set by the RCOG and AAGBI [29,47] are:
plasma fibrinogen >2 g/l.

platelet count >75 109/l; and
PT and aPTT ratio <1.5 times normal.
MHPs may recommend either formulaic use of blood products or a targeted approach responding to
evidence of coagulation deficiency on laboratory or near patient testing.
Retrospective military studies have suggested that early FFP in bleeding casualties improved out-
comes [48e50], promoting the use of RBC:FFP in a 1:1 ratio. However, survivorship bias could not be
excluded [51] and concerns exist regarding high rates of organ failure and acute respiratory distress
syndrome in patients transfused large volumes of FFP [52e54]. Nevertheless, this fixed ratio practice
has had a wide uptake in many MHPs, including those for PPH without much supporting evidence.
Products are usually supplied as ‘shock packs’ in this context, although thawing of frozen products and
transport from the laboratory to the clinical area can still cause delays.
Giving unmonitored FFP with fibrinogen levels approximately 2 g/l to parturients who maintain
higher fibrinogen levels even after a modest bleed may be counterproductive, resulting in dilution and
paradoxically lowering fibrinogen levels [55]. This could potentially exacerbate bleeding, increasing
the need for transfusion and amplifying circulatory overload.
Current national guidelines have acknowledged that administration of clotting products to all pa-
tients during haemorrhage is unwarranted and potentially harmful [29]. However, many Trusts do not
currently have VHAs and if no haemostatic results are available and bleeding is ongoing after 4 units of
RBC, FFP is recommended at a dose of 12e15 ml/kg until haemostatic test results are known [47].
Following an analysis of women with very large blood losses [11], empirical fibrinogen replacement
(given as cryoprecipitate or fibrinogen concentrate) was recommended in massive transfusion of 8
units RBC if no POCT is available.
MHPs using targeted, goal-directed correction of coagulopathy have demonstrated better outcomes.
A retrospective observational study using FIBTEM A5-guided fibrinogen concentrate resulted in a
significant reduction in all blood products, and a reduction in transfusion associated circulatory
overload, intensive care admission and a nonsignificant reduction in hysterectomy compared to pa-
tients treated with shock packs [56]. In patients with blood loss >1500 ml and FIBTEM A5 12 mm, 3 g
fibrinogen concentrate was administered if FIBTEM A5 was <7 mm or between 7 and 12mm with
ongoing or high risk of haemorrhage. The treatment algorithm used in this study (Fig. 6) recommended
FFP in patients with EXTEM CT > 100 s for treatment of deficiency of other coagulation factors and
platelets if EXTEM A5 is still low after correction of FIBTEM A5 or after 10 units of RBCs have been
transfused.
An extension of this study by a further 3 years included 32,647 deliveries and 843 women with PPH
>1500 ml [13]. The significant reduction in administration of all blood products, as well as morbidity
was maintained over the 4-year period. A total of 110 women received fibrinogen concentrate for
proven acquired hypofibrinogenaemia. Most required a single dose of 3 g, although some women
required repeated dosing up to a maximum of 18 g, given to two women with severe consumptive
coagulopathy due to placental abruption. Fibrinogen concentrate was particularly beneficial in these
women, as large volumes of FFP or cryoprecipitate would be required to provide equivalent fibrinogen.
Rapid laboratory fibrinogen results have been used [57] to guide fibrinogen concentrate treatment
in PPH, resulting in a lower blood loss and reduced FFP volumes. However, there was no difference in
red cell requirements or other outcome measures in the small number of women included.
TEG-based algorithms have been published [58] and used to guide blood product transfusion during
PPH. TEG-guided transfusion plus early surgical intervention resulted in a significant reduction in
hysterectomy, total blood loss and FFP transfusion compared with standard care [35].
Pre-emptive use of fibrinogen concentrate is not effective. In 249 women with PPH randomised to
fibrinogen concentrate 2 g or placebo without coagulation testing, there was no improvement in
outcomes [59]. Only 5 participants had a fibrinogen level <2 g, demonstrating the importance of
targeted treatment.
Although observational data support VHA-guided fibrinogen replacement during PPH, data from
RCT studies have been limited. A multicentre RCT of fibrinogen concentrate vs. placebo in PPH [60] was
designed to assess the effect of early administration of fibrinogen concentrate, to maintain fibrinogen
levels of 4 g/l (FIBTEM A5 22 mm). Patients were randomised to receive either fibrinogen concentrate
or placebo if FIBTEM A5 was <16 mm. Of the 663 women enrolled with EBL>1000 ml, only 8.7% met
this criteria. No significant reduction in transfusion requirements or blood loss was shown. However,
only a small number of women had plasma fibrinogen <2 g/l. The difference in outcome benefits
between observational and RCT data may be due to this. It is difficult to recruit patients during a life
threatening haemorrhage. Large observational datasets encompass all women, including those with
very large blood loss and severe coagulation disturbance. Their limitation is that it is not possible to
eliminate confounding factors. Hence, further RCTs are needed in PPH, designed to allow inclusion of
women with lower fibrinogen levels.
This study also analysed the potential haemostatic consequence of withholding blood products if
fibrinogen levels were unimpaired [61]. In 605 women with FIBTEM A5 >15 mm, withholding FFP did
not result in any women developing clinically significant haemostatic impairment. Subgroup analyses
suggested that a FIBTEM A5 >12 mm is adequate for haemostasis, and there was no benefit in further
increasing fibrinogen levels. In line with the observational studies, this supports the importance of
VHAs in identifying women with adequate haemostasis during haemorrhage, where potentially
harmful blood product administration may be avoided.
Ongoing work includes the OBS Cymru study (Obstetric Bleeding Strategy for Wales) [32], an all
Wales quality improvement project and research study supported by the Welsh Government. It was
launched in November 2016, and includes ROTEM-guided blood product management in addition to
other important interventions in PPH, with the aim of reducing morbidity associated with blood loss
>2500 ml, red cell transfusion, FFP transfusion and critical care admissions. Their results will be of
great interest as the project will allow assessment of this strategy on a wide scale and in units of
varying size and population.
Summary
Hypercoagulability in pregnancy prevents significant coagulopathy during postpartum haemor-

rhage in the majority of women. Plasma fibrinogen is critical during PPH, with levels below 2 g/l
leading to almost certain progression of bleeding. The RCOG and AAGBI advise goals for coagulation
during PPH as plasma fibrinogen >2 g/l, platelet count >75 109/l and PT/aPTT ratio <1.5.
Administration of blood products to all women with PPH using formulaic protocols has little
supporting evidence and represents over transfusion for the majority, with potential adverse effects.
Observational studies have demonstrated reduced transfusion and improved outcomes using
fibrinogen concentrate in women with hypofibrinogenaemia, identified by rapid viscoelastic
assessment.
The extent and nature of coagulopathy vary with severity of blood loss and aetiology. Fibrinogen
<2 g/l develops in approximately 25% of women with PPH 1500 ml. Fibrinogen concentrate and
cryoprecipitate are suitable for replenishing levels in pregnancy. FFP may be safely withheld if visco-
elastic testing demonstrates adequate coagulation. A small proportion of women, particularly those
with placental abruption, amniotic fluid embolism or massive blood loss, develop a more severe
coagulopathy. Early FFP is indicated to treat widespread clotting factor deficiency in such cases. Further
RCTs are needed to determine the optimal threshold for fibrinogen replacement, and the outcome
benefits of VHA-guided product replacement.
Practice points
Plasma fibrinogen levels should be maintained above 2 g/l in women with postpartum
haemorrhage.
Only approximately 25% of women develop significant coagulopathy during PPH of
1500 ml, indicating that formulaic treatment for the majority may be unnecessary and
potentially harmful.
Viscoelastometry can be used to provide rapid assessment of clotting, and the FIBTEM A5
(ROTEM) is a useful early biomarker of fibrinogen levels.
Fibrinogen concentrate or cryoprecipitate are more appropriate than FFP for replenishing
plasma fibrinogen.
Disseminated intravascular coagulopathy is uncommon and usually occurs in association
with placental abruption, amniotic fluid embolism or very severe haemorrhage.
Research agenda
There is very promising observational data for improved outcomes when viscoelastometry-
guided blood product administration is used in PPH, particularly when fibrinogen concen-
trate is used as a source of fibrinogen replacement. Evidence from RCTs is less supportive,
but RCTs, to date, have not been able to include sufficient numbers of women with plasma
fibrinogen <2 g/l.
Further RCTs are required, which are designed to be able to assess the outcome benefits of
this treatment strategy in all women, but especially those with acquired
hypofibrinogenaemia.
These studies should also determine the optimal treatment thresholds, dosing and choice of
blood product to maximise benefit and reduce risks, to improve morbidity and mortality
overall.
Conflict of interest
Author SM has received travel expenses and honoraria from Tem International/Werfen for talks
given in relation to viscoelastometric testing.
Acknowledgements
No funding or sponsorship has been received.
References
[1] Beattie RM, Brown NJ, Cass H. Millennium development goals progress report. Arch Dis Child 2015 Feb;100(Suppl 1).
S1eS1.
[2] UN General Assembly. Transforming our world : the 2030 Agenda for Sustainable Development. 21 October 2015. A/RES/
70/1, Available at, https://www.refworld.org/docid/57b6e3e44.html [Accessed 24 May 2019].
[3] Knight M, Bunch K, Tufnell D, Jayakody H, Shakespeare J, Kotnis R, et al. Saving lives, improving mothers' care - lessons
learned to inform maternity care from the UK and Ireland confidential enquiries into maternal deaths and morbidity
2014-16. Oxford: National Perinatal Epidemiology Unit, University of Oxford; 2018.
[4] Lennox C, Marr L, Scotland HI. Scottish confidential audit of severe maternal morbidity; reducing avoidable harm.
Healthcare Improvement Scotland; 2019.
[5] Hoffman M, Monroe DM. A cell-based model of hemostasis. Thromb Haemostasis 2001 Jun;85(6):958e65.
[6] Thachil J, Toh C-H. Disseminated intravascular coagulation in obstetric disorders and its acute haematological manage-
ment. Blood Rev 2009 Jul;23(4):167e76.
[7] Katz D, Beilin Y. Disorders of coagulation in pregnancy. Br J Anaesth 2015 Dec;115(Suppl 2). ii75e88.
[8] Solomon C, Collis RE, Collins PW. Haemostatic monitoring during postpartum haemorrhage and implications for man-
agement. Br J Anaesth 2012 Dec;109(6):851e63.
[9] Bowden F, Bhalla A, Kelly S. Changes in rotational thromboelastometry (ROTEM) parameters during the first, second and
third trimesters of pregnancy. Int J Obstetric Anaesth 2017. ed. 31(S11).
[10] Huissoud C, Carrabin N, Benchaib M, Fontaine O, Levrat A, Massignon D, et al. Coagulation assessment by rotation
thrombelastometry in normal pregnancy. Thromb Haemostasis 2009 Apr;101(4):755e61.
*[11] Green L, Knight M, Seeney F, Hopkinson C, Collins PW, Collis RE, et al. The haematological features and transfusion
management of women who required massive transfusion for major obstetric haemorrhage in the UK: a population based
study. Br J Haematol 2016 Feb;172(4):616e24. John Wiley & Sons, Ltd., (10.1111).
[12] O'Riordan MN, Higgins JR. Haemostasis in normal and abnormal pregnancy. Best Pract Res Clin Obstet Gynaecol 2003 Jun;
17(3):385e96.
*[13] McNamara H, Kenyon C, Smith R, Mallaih S, Barclay P. Four year's experience of a ROTEM® guided algorithm for treatment
of coagulopathy in obstetric haemorrhage. Anaesthesia 2019 (in press).
*[14] Charbit B, Mandelbrot L, Samain E, Baron G, Haddaoui B, et al. The decrease of fibrinogen is an early predictor of the
severity of postpartum hemorrhage. J Thromb Haemost 2007 Feb;5(2):266e73. John Wiley & Sons, Ltd., (10.1111).
[15] de Lloyd L, Bovington R, Kaye A, Collis RE, Rayment R, Sanders J, et al. Standard haemostatic tests following major ob-
stetric haemorrhage. Int J Obstet Anesth 2011 Apr;20(2):135e41.
[16] Hartert H. Klin Wochenschr 1948 Oct 1;26(37e38):577e83.
[17] Whiting P, Al M, Westwood M, Ramos IC, Ryder S, Armstrong N, et al. Viscoelastic point-of-care testing to assist with the
diagnosis, management and monitoring of haemostasis: a systematic review and cost-effectiveness analysis. Health
Technol Assess 2015 Jul;19(58):1e228. vevi.
[18] Fahrendorff M, Oliveri RS, Johansson PI. The use of viscoelastic haemostatic assays in goal-directing treatment with
allogeneic blood products - a systematic review and meta-analysis. Scand J Trauma Resusc Emerg Med. BioMed Central
2017 Apr 13;25(1):39.
[19] Serraino GF, Murphy GJ. Routine use of viscoelastic blood tests for diagnosis and treatment of coagulopathic bleeding in
cardiac surgery: updated systematic review and meta-analysis. Br J Anaesth 2017 Jun 1;118(6):823e33.
[20] Chevannes C, Harrod I, Bhalla A, Barclay P, Mallaiah S. Fast rotational thromboelastometry evaluation in major obstetric
haemorrhage. Br J Anaesth 2012;109:484P.
[21] Go€rlinger K, Dirkmann D, Solomon C, Hanke AA. Fast interpretation of thromboelastometry in non-cardiac surgery:
reliability in patients with hypo-, normo-, and hypercoagulability. Br J Anaesth 2013 Feb;110(2):222e30.
*[22] Collins PW, Lilley G, Bruynseels D, Laurent DB-S, Cannings-John R, Precious E, et al. Fibrin-based clot formation as an early
and rapid biomarker for progression of postpartum hemorrhage: a prospective study. Blood 2014 Sep 11;124(11):
1727e36.
[23] Huissoud C, Carrabin N, Audibert F, Levrat A, Massignon D, Berland M, et al. Bedside assessment of fibrinogen level in
postpartum haemorrhage by thrombelastometry. BJOG 2009 Jul;116(8):1097e102. John Wiley & Sons, Ltd., (10.1111).
[24] Gottumukkala VN, Sharma SK, Philip J. Assessing platelet and fibrinogen contribution to clot strength using modified
thromboelastography in pregnant women. Anesth Analg 1999 Dec;89(6):1453e5.
[25] Armstrong S, Fernando R, Ashpole K, Simons R, Columb M. Assessment of coagulation in the obstetric population using
ROTEM® thromboelastometry. Int J Obstet Anesth 2011 Oct;20(4):293e8.
[26] de Lange NM, van Rheenen-Flach LE, Lance MD, Mooyman L, Woiski M, van Pampus EC, et al. Peri-partum reference
ranges for ROTEM(R) thromboelastometry. Br J Anaesth 2014 May;112(5):852e9.
[27] National Institute For Health, Excellence C. Detecting, managing and monitoring haemostasis: viscoelastometric point-of-
care testing (ROTEM, TEG and Sonoclot systems). httpswww.nice.org.ukguidancedg.
*[28] Curry NS, Davenport R, Pavord S, Mallett SV, Kitchen D, Klein AA, et al. The use of viscoelastic haemostatic assays in the
management of major bleeding: a British Society for Haematology Guideline. Br J Haematol 2018 Sep;182(6):789e806.
John Wiley & Sons, Ltd., (10.1111).
*[29] Klein AA, Arnold P, Bingham RM, Brohi K, Clark R, Collis R, et al. AAGBI guidelines: the use of blood components and their
alternatives 2016. Anaesthesia 2016:829e42. John Wiley & Sons, Ltd., (10.1111).
[30] Hiippala S. Replacement of massive blood loss. Vox Sang 1998;74(Suppl. 2):399e407.
[31] Carroll RC, Craft RM, Langdon RJ, Clanton CR, Snider CC, Wellons DD, et al. Early evaluation of acute traumatic coagul-
opathy by thrombelastography. Transl Res 2009 Jul;154(1). 34e9.
*[32] Collins PW, Bell SF, de Lloyd L, Collis RE. Management of postpartum haemorrhage: from research into practice, a
narrative review of the literature and the Cardiff experience. Int J Obstet Anesth 2019 Feb;37:106e17.
[33] Cortet M, Deneux-Tharaux C, Dupont C, Colin C, Rudigoz R-C, Bouvier-Colle M-H, et al. Association between fibrinogen
level and severity of postpartum haemorrhage: secondary analysis of a prospective trial. Br J Anaesth 2012 Jun;108(6):
984e9.
[34] Gayat E, Resche-Rigon M, Morel O, Rossignol M, Mantz J, Nicolas-Robin A, et al. Predictive factors of advanced inter-
ventional procedures in a multicentre severe postpartum haemorrhage study. Intensive Care Med 2011 Nov;37(11):
1816e25. Springer-Verlag.
[35] Barinov SV, Zhukovsky YG, Dolgikh VT, Medyannikova IV. Novel combined strategy of obstetric haemorrhage manage-
ment during caesarean section using intrauterine balloon tamponade. J Matern Fetal Neonatal Med 2017 Jan;30(1):
29e33.
[36] Kaufner L, Henkelmann A, Heymann von C, Feldheiser A, Mickley L, Niepraschk-von Dollen K, et al. Can prepartum
thromboelastometry-derived parameters and fibrinogen levels really predict postpartum hemorrhage? J Perinat Med
2017 May 24;45(4):427e35.
[37] Peyvandi F, Biguzzi E, Franchi F, Bucciarelli P, Acaia B, Zaina B, et al. Elevated prepartum fibrinogen levels are not
associated with a reduced risk of postpartum hemorrhage. J Thromb Haemost 2012 Jul;10(7):1451e3. John Wiley & Sons,
Ltd., (10.1111).
[38] Karlsson O, Jeppsson A, Thornemo M, Lafrenz H, Rådstro € m M, Hellgren M. Fibrinogen plasma concentration before de-
livery is not associated with postpartum haemorrhage: a prospective observational study. Br J Anaesth 2015 Jul;115(1):
99e104.
[39] Bolliger D, Szlam F, Molinaro RJ, Rahe-Meyer N, Levy JH, Tanaka KA. Finding the optimal concentration range for
fibrinogen replacement after severe haemodilution: an in vitro model. Br J Anaesth 2009 Jun;102(6):793e9.
[40] Butwick A, Carvalho B. The effect of colloid and crystalloid preloading on thromboelastography prior to Cesarean delivery.
Can J Anaesth 2007 Mar;54(3):190e5. Springer-Verlag.
[41] Collis RE, Collins PW. Haemostatic management of obstetric haemorrhage. Anaesthesia 2015 Jan;70(Suppl. 1):78e86.
John Wiley & Sons, Ltd., (10.1111), e27e8.
[42] Shields LE, Wiesner S, Fulton J, Pelletreau B. Comprehensive maternal hemorrhage protocols reduce the use of blood
products and improve patient safety. Am J Obstet Gynecol 2015 Mar;212(3):272e80.
[43] Lilley G, Burkett-St-Laurent D, Precious E, Bruynseels D, Kaye A, Sanders J, et al. Measurement of blood loss during
postpartum haemorrhage. Int J Obstet Anesth 2015 Feb;24(1):8e14.
[44] Norfolk D. Handbook of transfusion medicine. Norwich, UK: TSO; 2014.
[45] Wong H, Curry N. Do we need cryoprecipitate in the era of fibrinogen concentrate and other specific factor replacement
options? International Society of Blood Transfusion. ISBT Sci Ser 2018;13:23e8.
[46] WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other mor-
bidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-
controlled trial. Lancet 2017 May 27;389(10084):2105e16.
*[47] Prevention and Management of Postpartum Haemorrhage: Green-top Guideline No. 52. BJOG 2017 Apr;124(5):e106e49.
[48] Borgman MA, Spinella PC, Perkins JG, Grathwohl KW, Repine T, Beekley AC, et al. The ratio of blood products transfused
affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma 2007 Oct;63(4):
805e13.
[49] Spinella PC, Perkins JG, Grathwohl KW, Beekley AC, Niles SE, McLaughlin DF, et al. Effect of plasma and red blood cell
transfusions on survival in patients with combat related traumatic injuries. J Trauma 2008 Feb;64(Suppl. 2).
S69e77ediscussionS77e8.
[50] Stinger HK, Spinella PC, Perkins JG, Grathwohl KW, Salinas J, Martini WZ, et al. The ratio of fibrinogen to red cells
transfused affects survival in casualties receiving massive transfusions at an army combat support hospital. J Trauma
2008 Feb;64(2 Suppl). S79e85ediscussionS85.
[51] Dzik WH, Blajchman MA, Fergusson D, Hameed M, Henry B, Kirkpatrick AW, et al. Clinical review: Canadian national
advisory committee on blood and blood products–massive transfusion consensus conference 2011: report of the panel.
BioMed Central; 2011. p. 242.
[52] Watson GA, Sperry JL, Rosengart MR, Minei JP, Harbrecht BG, Moore EE, et al. Fresh frozen plasma is independently
associated with a higher risk of multiple organ failure and acute respiratory distress syndrome. J Trauma 2009 Aug;67(2):
221e7. discussion228e30.
[53] Johnson JL, Moore EE, Kashuk JL, Banerjee A, Cothren CC, Biffl WL, et al. Effect of blood products transfusion on the
development of postinjury multiple organ failure. Arch Surg. American Medical Association 2010 Oct;145(10):973e7.
[54] Sambasivan CN, Kunio NR, Nair PV, Zink KA, Michalek JE, Holcomb JB, et al. High ratios of plasma and platelets to packed
red blood cells do not affect mortality in nonmassively transfused patients. J Trauma 2011 Aug;71(2 Suppl. 3):S329e36.
[55] Collins PW, Solomon C, Sutor K, Crispin D, Hochleitner G, Rizoli S, et al. Theoretical modelling of fibrinogen supple-
mentation with therapeutic plasma, cryoprecipitate, or fibrinogen concentrate. Br J Anaesth 2014 Oct;113(4):585e95.
[56] Mallaiah S, Barclay P, Harrod I, Chevannes C, Bhalla A. Introduction of an algorithm for ROTEM-guided fibrinogen
concentrate administration in major obstetric haemorrhage. Anaesthesia 2015 Feb;70(2):166e75. John Wiley & Sons, Ltd.,
(10.1111).
[57] Seto S, Itakura A, Okagaki R, Suzuki M, Ishihara O. An algorithm for the management of coagulopathy from postpartum
hemorrhage, using fibrinogen concentrate as first-line therapy. Int J Obstet Anesth 2017 Nov;32:11e6.
[58] Hill JS, Devenie G, Powell M. Point-of-care testing of coagulation and fibrinolytic status during postpartum haemorrhage:
developing a thrombelastography®-guided transfusion algorithm. Anaesth Intensive Care 2012 Nov;40(6):1007e15.
[59] Wikkelsø AJ, Edwards HM, Afshari A, Stensballe J, Langhoff-Roos J, Albrechtsen C, et al. Pre-emptive treatment with
fibrinogen concentrate for postpartum haemorrhage: randomized controlled trial. Br J Anaesth 2015 Apr;114(4):623e33.
*[60] Collins PW, Cannings-John R, Bruynseels D, Mallaiah S, Dick J, Elton C, et al. Viscoelastometric-guided early fibrinogen
concentrate replacement during postpartum haemorrhage: OBS2, a double-blind randomized controlled trial. Br J
Anaesth 2017 Sep 1;119(3):411e21.
*[61] Collins PW, Cannings-John R, Bruynseels D, Mallaiah S, Dick J, Elton C, et al. Viscoelastometry guided fresh frozen plasma
infusion for postpartum haemorrhage: OBS2, an observational study. Br J Anaesth 2017 Sep 1;119(3):422e34.

Coagulopatia

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Coagulopatia

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Best Practice & Research Clinical Obstetrics and Gynaecology 61 (2019) 106e120

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Managing coagulopathy following PPH

Standard laboratory tests (SLTs)

Aspect of clotting assessed ROTEM® parameter TEG® parameter

Initiation Clotting time (CT) Reaction time (R-time)

TEG ROTEM EXTEM ROTEM FIBTEM

Coagulation changes during PPH

Fibrinogen in PPH - cause or effect?

Treating coagulopathy during PPH

Fresh frozen plasma (FFP)

Cryoprecipitate is manufactured by thawing FFP and centrifuging to produce a cryoglobulin rich in

Fibrinogen concentrate is a pasteurized freeze-dried source of ﬁbrinogen from donated plasma. It is

Standard adult dose Volume Fibrinogen content Number of donors

FFP e 4 units 1000 ml ~2 g 4

Tranexamic acid (TXA)

Empiric vs. targeted blood product administration

plasma ﬁbrinogen >2 g/l.

Hypercoagulability in pregnancy prevents signiﬁcant coagulopathy during postpartum haemor-

No funding or sponsorship has been received.

You might also like

Coagulopatia

Uploaded by

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Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

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Coagulopatia

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Best Practice & Research Clinical Obstetrics and Gynaecology 61 (2019) 106e120

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Managing coagulopathy following PPH

Standard laboratory tests (SLTs)

Aspect of clotting assessed ROTEM® parameter TEG® parameter

Initiation Clotting time (CT) Reaction time (R-time)

TEG ROTEM EXTEM ROTEM FIBTEM

Coagulation changes during PPH

Fibrinogen in PPH - cause or effect?

Treating coagulopathy during PPH

Fresh frozen plasma (FFP)

Cryoprecipitate is manufactured by thawing FFP and centrifuging to produce a cryoglobulin rich in

Fibrinogen concentrate is a pasteurized freeze-dried source of ﬁbrinogen from donated plasma. It is

Standard adult dose Volume Fibrinogen content Number of donors

FFP e 4 units 1000 ml ~2 g 4

Tranexamic acid (TXA)

Empiric vs. targeted blood product administration

 plasma ﬁbrinogen >2 g/l.

Hypercoagulability in pregnancy prevents signiﬁcant coagulopathy during postpartum haemor-

No funding or sponsorship has been received.

You might also like

plasma ﬁbrinogen >2 g/l.