An algorithm for the management of coagulopathy from postpartum hemorrhage, using fibrinogen concentrate as first-line therapy

Accepted Manuscript An algorithm for the management of coagulopathy from postpartum hemorrhage, using fibrinogen concentrate as first-line therapy S. Seto, A. Itakura, R. Okagaki, M. Suzuki, O. Ishihar PII: DOI: Reference:

S0959-289X(16)30108-X http://dx.doi.org/10.1016/j.ijoa.2017.03.005 YIJOA 2550

To appear in:

International Journal of Obstetric Anesthesia

Received Date: Revised Date: Accepted Date:

27 October 2016 28 February 2017 10 March 2017

Please cite this article as: Seto, S., Itakura, A., Okagaki, R., Suzuki, M., Ishihar, O., An algorithm for the management of coagulopathy from postpartum hemorrhage, using fibrinogen concentrate as first-line therapy, International Journal of Obstetric Anesthesia (2017), doi: http://dx.doi.org/10.1016/j.ijoa.2017.03.005

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1

An algorithm for the management of coagulopathy from postpartum hemorrhage,

2

using fibrinogen concentrate as first-line therapy

3 4

S. Seto,a A. Itakura,b R. Okagaki,a M. Suzuki,a O. Ishihara

5

a

Department of Obstetrics and Gynecology, Saitama Medical University, Japan

6

b

Department of Obstetrics and Gynecology, Juntendo University, Faculty of Medicine,

7

Japan

8 9 10

Keywords: obstetrical disseminated intravascular coagulation (DIC), freeze-dried fibrinogen, transfusion protocol; postpartum hemorrhage; coagulopathy

11 12

Corresponding author: Atsuo Itakura

13

E-mail address: [email protected]

14 15 16

ABSTRACT

17

Background: We constructed an algorithm for the management of coagulopathy from

18

massive postpartum hemorrhage. Fibrinogen concentrate was administered

19

preferentially, and the dose of both fibrinogen concentrate and fresh frozen plasma

20

given was determined by the plasma fibrinogen concentration and prothrombin time.

21

The efficacy of the algorithm and the amount of fibrinogen concentrate and fresh frozen

22

plasma transfused were determined.

23

Methods: The study was conducted in a single teaching perinatal center. Nineteen

24

patients were included between April 2011 and March 2014 (patient group). For a

25

historical comparison group, we retrospectively analyzed the records of 19 patients who

26

had been treated for coagulopathy from massive postpartum hemorrhage between April

27

2006 and March 2011 (control group).

28

Results: Blood loss was significantly lower in the patient group. No adverse events

29

were associated with this management in either group. The dose of fibrinogen

30

concentrate administered was significantly higher and that of fresh frozen plasma

1

administered was significantly lower in the patient group.

2

Conclusion: This algorithm appeared to help reduce blood loss and the total amount of

3

fresh frozen plasma transfused when treating coagulopathy from postpartum

4

hemorrhage, and may represent another strategy for achieving hemostasis in this setting.

5 6

Introduction

7

Obstetric hemorrhage causes approximately 25% of maternal mortality in Japan and

8

worldwide.1,2 Massive postpartum hemorrhage (PPH) is frequently associated with

9

coagulopathy of dramatic onset. Postpartum hemorrhage is defined as bleeding within

10

24 hours postpartum, with blood loss of more than 500 mL in vaginal delivery and more

11

than 1000 mL in cesarean delivery. Effective substitution with blood products

12

containing coagulation factors, together with circulating volume expansion, are crucial

13

for managing massive PPH.3 4 Fibrinogen is a critical factor for hemostasis in PPH7 and

14

a fall in its concentration is the most sensitive predictor of the severity of surgical blood

15

loss and of PPH.5,6 Previous case series have suggested that fibrinogen concentrate (FC)

16

substitution therapy might be effective in achieving hemostasis for PPH complicated by

17

coagulopathy.8 9 We have reported the efficacy of FC for treating coagulopathy in

18

massive PPH, in combination with conventional methods of management such as fresh

19

frozen plasma (FFP) transfusion.10 However, in previous reports both doses and the

20

priority of blood product administration were not determined by an algorithm, making it

21

difficult to show the most effective transfusion protocol.

22

In this study, therefore, we constructed a novel algorithm to manage coagulopathy in

23

massive PPH. According to this algorithm, FC is administered preferentially and the

24

dose of FC and FFP is determined by plasma fibrinogen levels and prothrombin time

25

(PT) respectively. The primary aims of this study were to evaluate the effectiveness of

26

the algorithm and to estimate suitable FC and FFP doses.

27 28

Methods

29

We designed an algorithm for the treatment of coagulopathy in massive PPH (Fig. 1).

30

Plasma-derived FC, which is purified and virally inactivated, was purchased from Japan

31

Blood Products Organization (Tokyo, Japan). The off-label use of FC and application of

32

this algorithm was approved by the Institutional Review Board of Saitama Medical

1

University Hospital prior to the start of the clinical study, the conduct of which was in

2

compliance with the Declaration of Helsinki.

3

In the protocol, FC is administered preferentially and its initial dose is determined by

4

plasma fibrinogen levels (Fig. 1). It is known that 150–200 mg/dL plasma fibrinogen

5

concentration is needed to achieve hemostasis in patients with coagulopathy,9 11 and the

6

median increase in plasma fibrinogen level is approximately 40 mg/dL/g FC,12 so for

7

example when plasma fibrinogen concentration is <50 mg/dL, 4 g of FC is required.

8

Fresh frozen plasma is simultaneously or additionally administered according to

9

prothrombin time percent (PT%), prothrombin time-international normalized ratio

10

(PT-INR), or clinical status. The FFP transfusion policy in this protocol was based on a

11

previous review.13 An obstetric disseminated intravascular coagulation (DIC) score was

12

calculated according to the Japan Society of Obstetrics and Gynecology (JSOG) clinical

13

guidelines,14 and has three components: the underlying diseases, clinical symptoms and

14

laboratory findings (coagulation tests). Higher scores are given for clinical than for

15

laboratory parameters. The obstetric DIC score aids prompt diagnosis and early

16

treatment prior to obtaining laboratory data.15

17

The algorithm was used for the management of patients with massive PPH and

18

coagulopathy who had been admitted to Saitama Medical University Hospital. Massive

19

PPH was defined as a blood loss of >1000 mL. Patients with massive obstetric

20

hemorrhage, microvascular or continuous uterine bleeding and hypofibrinogenemia

21

(<150 mg/dL) were recruited.

22

All participants either provided written informed consent or, if unconscious, informed

23

consent was obtained from the patient’s family. None of the participants or their family

24

members refused to enter the study. Red blood cells (RBC) or platelet concentrates (PC)

25

were transfused to reach a target appropriate for the patient’s body weight and

26

expectations of additional blood loss (hemoglobin >8.0 g/dL, platelet count >50,000

27

/µL). Uterotonic agents or surgical interventions were used as necessary to achieve

28

hemostasis.

29

Patients included women referred from local clinics or secondary hospitals for the

30

treatment of PPH (16 cases in the control group and 15 cases in the patient group).

31

Exclusion criteria were patients who delivered before 22 weeks’ gestation, had maternal

32

liver dysfunction, blood transfusion therapy other than RBC before the first coagulation

1

tests at our hospital and those with insufficient data for analysis. No patient had a

2

known history of hereditary afibrinogenemia or fibrinogen allergy.

3

Nineteen patients were included between April 2011 and March 2014 (patient group).

4

For historical comparison, 19 patients who had been treated for coagulopathy

5

(fibrinogen <150 mg/mL) from massive PPH between April 2006 and March 2011 were

6

retrospectively analyzed (control group). This group included 10 patients who had been

7

assessed in our previous study,10 when their treatment had been at the discretion of the

8

anesthesiologist delivering care.

9

Fresh frozen plasma was transfused first for cases with primary coagulopathy. If

10

hemostasis was not achieved, fibrinogen concentrate was given. Blood cell counts,

11

platelet levels and blood coagulation parameters, including plasma fibrinogen levels, PT,

12

activated partial thromboplastin time (APTT) and albumin levels were examined just

13

before supplementation with FFP or FC.

14

Data about mode of delivery, estimated blood loss, and complications from DIC-related

15

diseases (placental abruption, amniotic fluid embolism, eclampsia, and diseases listed in

16

the obstetric DIC scoring sheet by the JSOG14) were collected and analyzed. Amniotic

17

fluid embolism was diagnosed clinically or was pathologically confirmed in one case in

18

the control group.

19

Data for RBC, FFP, and PC were examined and the FFP to RBC ratio was calculated.

20

Records were examined for adverse effects such as thromboembolism, allergic reactions,

21

and infection caused by blood products.

22

The results of coagulation testing using the automated Clauss assay (Coapresta 3000:

23

Sekisui Medical Co. Ltd, Tokyo, Japan) are available in approximately 15 minutes at

24

our institution. The centrifugal separation method (2000G 25°C) takes 10 minutes and

25

the automated Clauss assay 1 minute.

26

For demographic variables, results were expressed as mean and standard deviation.

27

Unpaired Welch’s t-test was used to compare means. Chi-square test was used to

28

compare frequencies. Statistical analysis was performed using SPSS version 9.1 (SPSS

29

Inc., Chicago, IL, USA). For single-outcome comparisons, the effect of treatment was

30

considered significant for P-values <0.05.

31

1

Results

2

Patient groups and characteristics are summarized in Figure 2 and Table 1. There was no

3

significant inter-group difference in age, body mass index, and mode of delivery. The

4

possible etiologies of PPH were categorized as complications during pregnancy or

5

perinatal complications for each group.

6

Clinical parameters, including PT and fibrinogen concentrations before treatment, are

7

described in Table 2. No significant difference between groups was noted except for

8

APTT, which was significantly higher in the patient group.

9

Estimated blood loss before and after starting therapy, the number of blood products

10

transfused, clinical outcome, adverse events and response to therapy are shown in Table

11

3. There was no significant difference in total blood loss and blood loss before starting

12

the therapy between the two groups (P=0.051 and 0.052, respectively). Blood loss after

13

starting therapy was significantly lower in the patient group (P=0.023). The dose of FC

14

administered was significantly higher, and that of FFP significantly lower, in the patient

15

group.

16

In two cases, 2 g of FC were given before plasma fibrinogen levels were known because

17

on arrival the patients had unstable vital signs with clinically evident DIC. In both

18

patients, plasma fibrinogen concentration was subsequently found to have been less

19

than 150 mg/dL before treatment, confirming that 2 g of FC was not an excessive dose.

20

No adverse events were associated with management in either group. One patient in the

21

control group died (the details of this case are described in our previous report10, and

22

three cases survived but developed complications, including subarachnoid hemorrhage

23

and Sheehan’s syndrome (Table 3). Several cases in both groups required surgical

24

intervention after blood transfusion, including hysterectomy and interventional

25

radiology (Table 3).

26 27

Discussion

28

This study demonstrates the efficacy of FC as the first-line treatment for coagulopathy

29

from PPH, using a novel algorithm, and the results are in accordance with those of our

30

previous paper.17 The algorithm enables application of a standardized strategy for

31

managing coagulopathy from PPH. A unique feature of the algorithm is that FC is

32

administered according to measured plasma fibrinogen concentrations and PT. Blood

1

loss was reduced after using FC as the first-line treatment. This suggests that the early

2

use of FC promoted the early restoration of hemostasis.

3

The second study goal of this study was to determine the volume of FFP needed to

4

manage coagulopathy when treated according to the protocol. The need to thaw FFP

5

before administration is a disadvantage in an emergency. We speculate that, in the

6

control group of patients who received FFP, fibrinogen supplementation was slow while

7

consumption of coagulation factors continued, making it difficult to determine the

8

amount of blood product required. In addition, large volumes of FFP were needed to

9

restore fibrinogen concentrations, which took time and may have led to volume

10

overload. Massive transfusion for PPH may cause acute lung injury and pulmonary

11

edema.4 This study demonstrated a significant reduction in FFP transfusion requirement,

12

suggesting that FC substitution as the first-line agent may reduce the risk of massive

13

transfusion.

14

One concern was that, in following the algorithm, the supply of other coagulation

15

factors might be compromised, since the use of FFP was decreased. However,

16

prolonged coagulopathy was not seen in the patient group. The algorithm mandates

17

early administration of FFP when the patient is in a critical state, and FFP is given with

18

FC when the PT% is <40% at the first test.

19

There was no significant decrease in the amount of transfused RBC or PC. This may be

20

because the study included patients who were hemodynamically unstable on arrival, and

21

in whom rapid RBC and PC transfusion was started before their coagulation status was

22

known. A case series of placental abruption managed by FC administration using

23

near-patient testing with rotational thromboelastometry (ROTEMTM) has been

24

published,16 as has an algorithm for ROTEMTM-guided fibrinogen concentrate

25

administration during major obstetric hemorrhage.17 ROTEMTM permits dynamic

26

monitoring of clotting abnormalities promptly, potentially a significant advantage over

27

routine laboratory testing in the management of coagulopathy. ROTEMTM has a

28

fibrinogen threshold of 200 mg/dL with 100% sensitivity and greater than 80%

29

specificity.18 Training and quality control are mandatory for performance of these tests,

30

and the requisite equipment has not been installed in all obstetric theaters in tertiary care

31

centers. In our institution, it takes 10–15 minutes to obtain coagulation test results, and

32

the tests are available at any time. Although further studies may enable accurate

1

detection of fibrinogen concentration based on ROTEMTM, conventional coagulation

2

tests are currently the standard used to determine the dosage of fibrinogen given.

3

A limitation of the study is that it was not randomized. A recent study using a broad set

4

of inclusion criteria for pre-emptive treatment did not demonstrate the efficacy of

5

fibrinogen concentrate in treating PPH.19 The incidence of coagulopathy in PPH,

6

although increasing, is still rare.20 Future studies or meta-analyses are needed to clarify

7

the efficacy and safety of this management.

8

In 2009, the Irish Blood Transfusion Service licensed FC use in pregnancy and replaced

9

cryoprecipitate with FC, admitting that FC is as efficacious as cryoprecipitate in

10

correcting hypofibrinogenemia.21 In Japan, FC substitution for acquired

11

hypofibrinogenemia is unlicensed and is not covered by public medical insurance.

12

The algorithm is based on the results of laboratory tests and requires them to be readily

13

available. Currently in Japan, not all medical centers are able to perform urgent

14

laboratory tests. Ahonen et al. insisted that laboratory tests should guide replacement

15

therapy, and that they should be urgently available for the management of obstetric

16

hemorrhage.22

17

An algorithm for the treatment of coagulopathy from PPH, using FC therapy as the

18

first-line, is effective and allows the rapid resolution of coagulopathy. Its use may

19

reduce blood loss after starting treatment of coagulopathy and may reduce the total

20

amount of FFP transfused.

21 22 23

References

24

1) Maternal mortality in World Health Organization

25 26 27 28 29 30 31

http://www.who.int/mediacentre/factsheets/fs348/en/ 2) Maternal deaths. Maternal and child health statistics of Japan, Tokyo: Kamiya K, Mothers’ & Children’s Health & Welfare Association 2014 3) Ahonen J, Stefanovic V, Lassila R. Management of post-partum haemorrhage. Acta Anaesthesiol Scand 2010;54:1164-78. 4) Fuller AJ, Bucklin BA. Blood product replacement for postpartum hemorrhage. Clin Obstet Gynecol 2010;53:196-208.

1

5) Hiippala ST, Myllylä GJ, Vahtera EM. Hemostatic factors and replacement of major

2

blood loss with plasma-poor red cell concentrates. Anesth Analg 1995;81:360-5.

3

6) Charbit B, Mandelbrot L, Samain E et al. The decrease of fibrinogen is an early

4

predictor of the severity of postpartum hemorrhage. J Thromb Haemost 2007;5:

5

266-73.

6

7) Guasch E, Gilsanz F. Treatment of postpartum hemorrhage with blood products in a

7

tertiary hospital: outcomes and predictive factors associated with severe hemorrhage.

8

Clin Appl Thromb Hemost 2016;22:685-92.

9

8) Bell SF, Rayment R, Collins PW, Collis RE. The use of fibrinogen concentrate to

10

correct hypofibrinogenaemia rapidly during obstetric haemorrhage. Int J Obstet

11

Anesth 2010;19:218-23.

12 13 14

9) Weinkove R, Rangarajan S. Fibrinogen concentrate for acquired hypofibrinogenaemic states. Transfus Med 2008;18:151-7. 10) Kikuchi M, Itakura A, Miki A et al. Fibrinogen concentrate substitution therapy for

15

obstetric hemorrhage complicated by coagulopathy. J Obstet Gynaecol Res

16

2013;39:770-6.

17

11) Cortet M, Deneux-Tharaux C, Dupont C et al. Association between fibrinogen

18

level and severity of postpartum haemorrhage: secondary analysis of a prospective

19

trial. Br J Anaesth 2012;108:984-9.

20 21 22 23

12) Obstetrical Hemorrhage. In: Cunningham FG et al., Williams Obstetrics. 24th ed. McGraw-Hill Education 2014;780-828 13) Fuller AJ, Bucklin BA. Blood product replacement for postpartum hemorrhage. Clin Obstet Gynecol 2010;53:196-208

24

14) Minakami H, Maeda T, Fujii T et al. Guidelines for obstetrical practice in Japan:

25

Japan Society of Obstetrics and Gynecology (JSOG) and Japan Association of

26

Obstetricians and Gynecologists (JAOG) 2014 edition. J Obstet Gynaecol Res

27

2014;40:1469-99.

28 29 30 31

15) Kobayashi T. Obstetrical disseminated intravascular coagulation score. J Obstet Gynaecol Res 2014;40:1500-6 16) McNamara H, Mallaiah S, Barclay P et al. Coagulopathy and placental abruption: changing management with ROTEM-guided fibrinogen concentrate therapy. Int J

1 2

Obstet Anesth 2015;24:174-9. 17) Mallaiah S, Barclay P, Harrod I et al. Introduction of an algorithm for

3

ROTEM-guided fibrinogen concentrate administration in major obstetric

4

haemorrhage. Anaesthesia 2015;70:166-75.

5

18) de Lange NM, Lancé MD, de Groot R et al. Obstetric hemorrhage and coagulation:

6

an update. Thromboelastography, thromboelastometry, and conventional coagulation

7

tests in the diagnosis and prediction of postpartum hemorrhage. Obstet Gynecol

8

Surv 2012;67:426-35.

9

19) Wikkelsø AJ, Edwards HM, Afshari A et al. FIB-PPH trial group. Pre-emptive

10

treatment with fibrinogen concentrate for postpartum haemorrhage: randomized

11

controlled trial. Br J Anaesth 2015;114:623-33.

12 13 14

20) Lennox C, Marr L. Scottish Confidential Audit of Severe Maternal Morbidity. Scotland: Healthcare Improvement Scotland 2013 21) Ahmed S, Harrity C, Johnson S et al. The efficacy of fibrinogen concentrate

15

compared with cryoprecipitate in major obstetric haemorrhage--an observational

16

study. Transfus Med 2012;22:344-9.

17 18 19

22) Ahonen J. The role of recombinant activated factor VII in obstetric hemorrhage. Curr Opin Anaesthesiol 2012;25:309-14.

1

Figure Legends

2 3

Fig 1. An algorithm for management of coagulopathy in postpartum hemorrhage

4 5

Fibrinogen: plasma fibrinogen levels

6

FC: fibrinogen concentrate

7

PT: prothrombin time

8

PT-INR: prothrombin time-international normalized ratio

9

FFP: fresh frozen plasma

10 11

Caution：1. When bleeding without blood clot formation, use 2 g of FC first.

12

2. When PT <40％ on initial testing, use 4 units FFP with FC.

13

3. Doses of FFP can be increased when the patient shows signs of hemorrhagic

14 15

shock. 4. When uterine bleeding without coagulopathy exists or a uterovaginal

16

laceration is obvious, surgical intervention should be considered.

17

5. When platelet count is <50,000/µL, transfuse platelet concentrate.

18

6. When hypoproteinemia exists, administer albumin.

19 20 21

Fig 2. Flow of study participants

1

Table 1 Patient characteristics Patient group

Control group

(n = 19

(n = 19

Age (y)

31.6 ± 4.65

34.4 ± 4.70

0.07

Body mass index (kg/m2)

24.4 ± 2.9

24.5 ± 3.7

0.94

P-value

Parity -

0

7

9

-

≥1

12

10

0.8

Referred from another facility -

yes

16

15

-

no

3

4

0.08

Mode of delivery -

vaginal

10

10

-

cesarean

9

9

Mean gestational age (weeks)

37

36

Number of live births

13

11

Number of stillbirths

6

8

0.8

Birthweight of baby (g)

2727 ± 950

2500 ± 844

0.41

Complications during pregnancy -

hypertension

1/1

4/0

-

GDM / DM

1/0

2/0

Perinatal complications -

placenta abruption

8

10

-

amniotic fluid embolism

2

2

-

hemangioma

0

1

-

atonic bleeding

7

2

-

placenta increta

1

1

-

vaginal hematoma

1

1

-

complete previa

0

1

-

cervical laceration

0

1

1

1

Values are mean ± standard deviation (SD) or number.

2

GDM: gestational diabetes mellitus, DM: diabetes mellitus

3

1

Table 2 Laboratory data before the therapy Patient group

Control group

(n=19

(n=19

Hemoglobin (g/dL)

6.1 ± 1.7

5.7 ± 1.3

0.13

Platelets (×104/μL)

7.2 ± 4.0

7.2 ± 2.9

0.49

Plasma fibrinogen (mg/dL)

85 ± 34

84 ± 33

0.48

Prothrombin time (%)

40 ± 19

45 ± 18

0.22

PT-INR

3.4 ± 4.0

3.1 ± 4.0

0.41

APTT (s)

75 ± 37

58 ± 34

0.04

Albumin (g/dL)

2.4 ± 0.4

2.6 ± 0.3

0.08

2

Values are mean ± SD

3

PT-INR: prothrombin time-international normalized ratio

4

APTT: activated partial thromboplastin time

5 6

P-value

1

Table 3 Blood loss, products transfused and patient outcome Patient group

Control group

(n = 19

(n = 19

P-value

Estimated blood loss (mL) -

before starting the therapy

2398 ± 1167

3259 ± 1836

0.051

-

after starting the therapy

229 ± 187

1110 ± 1399

0.023

-

total

2616 ± 1188

3428 ± 1842

0.052

FC (g)

4.4 ± 2.4

2.6 ± 2.3

0.016

FFP (units)

4.3 ± 4.9

9.9 ± 6.7

0.0037

RBC (units)

9.4 ± 6.9

9.4 ± 5.4

0.49

FFP / RBC ratio

0.5 ± 0.6

1.2 ± 1.0

0.0030

PC (units)

5.5 ± 8.3

4.7 ± 9.0

0.37

Albumin (g)

29.6 ± 34.7

14.5 ± 26.8

0.089

Amount of blood product

Prognosis -

alive

19 (100%)

18 (95%)

-

dead

0

1 (94%)

0.59

-

Complications -

Sheehan syndrome

1 (5.3%)

1 (5.6%)

-

subarachnoid hemorrhage

1 (5.3%)

0

0

0

Adverse effects Surgical interventions -

hysterectomy

2 (10.5%)

2 (10.5%)

-

-

intervention radiology

3 (15.8%)

4 (21.1%)

-

2

Values are mean ± standard deviation (SD) or number (percentage).

3

FC: fibrinogen concentrate

4

FFP: fresh frozen plasma

5

RBC: red blood cells

6

PC: platelet concentrate

7

An algorithm for management of coagulopathy in postpartum hemorrhage

Massive hemorrhage with p. fibrinogen < 150 mg/dL When 100≤ p. fib. <150 mg/dL, use 2 g FC When 50≤ p. fib. <100 mg/dL, use 3 g FC When p. fib. <50 mg/dL, use 4 g FC

1: yes

Measure coagulation parameters and check whether 1: PT <50%, PT-INR >2.0, or bleeding resistant to therapy 2: p. fibrinogen <150 mg/dL Both 1 and 2: no Closely observe vital signs and care for additional blood loss

1 2

1: yes, 2: no Give 4 units fresh frozen plasma

Flow of Participants 112 with massive postpartum hemorrhage 74 excluded - 2 delivered before 22 weeks’ gestation - 1 had liver dysfunction - 17 had blood transfusion therapy other than red blood cells before the first coagulation tests at our hospital - 54 did not satisfy the criteria for coagulopathy

38 were analysed

19 were included in the analysis between April 2011 and March 2014 (patient group)

1 2

19 were included in the analysis between April 2006 and March 2011 (control group)

1 2 3

A novel algorithm for the management of postpartum haemorrhage coagulopathy. Preferential use of fibrinogen concentrate is an essential component.