You are on page 1of 3

International Journal of Gynecology and Obstetrics 119 (2012) 35

Contents lists available at SciVerse ScienceDirect

International Journal of Gynecology and Obstetrics


journal homepage: www.elsevier.com/locate/ijgo

SPECIAL COMMUNICATION

Postpartum hemorrhage management in 2012: Predicting the future


Oluwatoyosi Onwuemene a, David Green a, Louis Keith b,
a
b

Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, USA


Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, USA

a r t i c l e

i n f o

Keywords:
Fibrinogen
Hemorrhage
Massive transfusion protocol
Maternal morbidity
Maternal mortality
Postpartum hemorrhage
Tranexamic acid
Transfusion

a b s t r a c t
Transfusion therapy in postpartum hemorrhage (PPH) traditionally has been modeled after precedents set in
the Vietnam and Korean wars. However, data from recent military combat casualties suggest a different
transfusion strategy. Transfusion of packed red blood cells, fresh frozen plasma, and platelets in a ratio of
1:1:1 improves dilutional coagulopathy and survival. Women who present with low brinogen at the time
of diagnosis of PPH have poorer outcomes and might benet from early brinogen replacement. The
antibrinolytic agent, tranexamic acid, decreases bleeding and progression to severe PPH, but its role in
PPH management is evolving. Observational data suggest that the use of recombinant factor VIIa should be
limited to bleeding that has not responded to an optimal transfusion strategy. Point-of-care testing using
thromboelastography is helpful in guiding the selection of blood products to be transfused. Additionally, massive transfusion protocols can decrease the overall number of products transfused and improve outcomes.
2012 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction
Transfusion is the mainstay of management for postpartum hemorrhage (PPH). However, today's transfusion therapy in PPH is not
based on data from randomized clinical trials but rather on observational data derived from the Vietnam and Korean wars [1,2]. Although
treatment trials for PPH are in progress [3,4], recent studies of military combat casualties in the Iraq and Afghanistan wars encourage us to
reconsider transfusion strategies for the management of PPH.
2. Ratios of products transfused
The relative amounts of the various blood products selected for
transfusion affect the overall survival of patients with massive hemorrhage [57]. Traditionally, volume resuscitation begins with infusions
of crystalloid and colloid followed by transfusion of red blood cells
(RBC). This approach works well to correct hypovolemia; however,
it signicantly worsens existing dilutional coagulopathy and enhances
brinolysis [8,9]. Data from over 8000 patients analyzed in the
German Trauma Registry revealed that up to 34% of patients were
coagulopathic at the time of evaluation in the Emergency Department.
The extent of coagulopathy was proportional to the amount of prior
crystalloid infusion: 40% with 2000 mL and 70% with 4000 mL of intravenous uids administered [9].
Addressing dilutional coagulopathy earlier in the course of hemorrhage by increasing the ratio of fresh frozen plasma (FFP) units to RBC
Corresponding author at: Department of Obstetrics and Gynecology, Feinberg School
of Medicine, Chicago, IL 60611, USA. Tel.: +1 312 432 9880.
E-mail address: lgk395@northwestern.edu (L. Keith).

improves survival [5]. A retrospective review of 246 patients at a


United States Army combat support hospital demonstrated that a
higher median ratio of FFP to RBC transfused produced a statistically
signicant improvement in mortality. The group with the highest median ratio (1:1.4) had less mortality from bleeding than the group
with the lowest ratio (1:8): 37% versus 93%. This trend was also statistically signicant with regard to overall mortality: 19% versus 65%
[5]. Increasing the number of units of platelets relative to RBC also
improves outcomes. A retrospective review of 466 patients receiving
massive transfusion showed greater 30-day survival with a high platelet to RBC ratio ( 1:2) relative to patients with a low platelet to RBC
ratio (b 1:2): 60% versus 40% [6]. A ratio of FFP:platelets:RBC of 1:1:1
appears to best control bleeding and increase survival.
3. Importance of early use of brinogen
Patients with traumatic hemorrhage often have signicant systemic coagulopathy at the time of their initial evaluation. From the
German Trauma Registry, 10% were coagulopathic even with no
more than 500 mL of intravenous uid resuscitation [9]. Women with
a lower level of brinogen at the time of diagnosis of PPH have worse
outcomes. A French multicenter study of 128 women showed that
women with severe PPH had signicantly lower brinogen at the time
of presentation compared with women with nonsevere PPH [10,11].
Similar results were seen in a population-based study of 738 women
with PPH. The brinogen level was independently associated with PPH
severity [11].
Treatment with massive transfusion and resuscitation enhances
brinolysis and further decreases brinogen [12]. Because hemorrhage from raw surfaces is compounded by hypobrinogenemia,

0020-7292/$ see front matter 2012 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ijgo.2012.07.001

O. Onwuemene et al. / International Journal of Gynecology and Obstetrics 119 (2012) 35

early supplementation of brinogen appears to be a rational option


in the management of patients with PPH. Administering brinogen
is expected to control bleeding, but whether it improves overall survival needs to be established. For example, raising brinogen levels
could increase the risk of postpartum thrombotic events. A randomized controlled clinical trial is currently underway to evaluate the
use of brinogen in the early management of patients with PPH [4].
4. Role of tranexamic acid
The use of the antibrinolytic agent, tranexamic acid (TXA), has
only rarely been evaluated as a means to decrease blood loss and maternal morbidity in women with obstetric hemorrhage. This is in stark
contrast to the far greater number of publications addressing the efcacy of this agent in surgical and traumatic interventions [13]. The use
of TXA in women with PPH decreases blood loss and maternal morbidity. A French randomized, open-label study of 144 women undergoing vaginal delivery showed that TXA signicantly decreased blood
loss, bleeding duration, and progression to severe PPH. When compared with controls, the women in the TXA group had a lower median
blood loss (173 mL vs 221 mL), were more likely to have stopped
bleeding after 30 minutes (63% vs 46%), and were less likely to progress to severe PPH (27 vs 37 women) [14]. TXA also reduces blood
loss and the need for oxytocin administration in women undergoing cesarean delivery. A Turkish study of 660 women and an Iranian study of 100 women undergoing cesarean delivery showed that
TXA signicantly lowered intraoperative and postoperative mean
blood loss as well as the use of oxytocin [15,16]. Movafegh et al. [15]
found that there was lower intraoperative blood loss (263 mL vs
405 mL), lower mean postoperative blood loss (67 mL vs 141 mL),
and a lower mean dose of oxytocin administered (39 units vs 43
units) in the TXA group compared with the control group. Gongorduk
et al. [16] found the TXA group to have a lower mean estimated
blood loss (500 mL vs 600 mL), fewer women with blood loss greater
than 1000 mL (2.1% vs 5.8%), and fewer women needing uterotonics
(28 women vs 48 women) compared with controls. Adverse effects
of TXA included nausea, vomiting, and catheter-related thromboses.
TXA is currently being evaluated in a multicenter randomized controlled clinical trial [3].
5. Recombinant human factor VIIa
Recombinant human factor VIIa is US Food and Drug Administrationapproved for the management of bleeding in hemophiliac patients with
inhibitors to clotting factor VIII. It is a potent procoagulant that has been
evaluated in several observational studies of patients with PPH [17].
Current recommendations are that it should be considered when platelets, FFP, and brinogen concentrates fail to control bleeding [18].
6. Monitoring therapy during massive transfusion
Waiting for the results of coagulation tests prior to making decisions about the selection of blood products might jeopardize survival.
However, existing data suggest that the thromboelastograph (TEG) is
useful in guiding the selection of blood products in massively bleeding patients [19,20]. This point-of-care device examines clot formation and dissolution in whole blood. In patients with PPH, it has
been shown to correlate well with the level of brinogen. A prospective observational study of 91 women, including 37 with PPH,
showed that clot amplitude (CA) and maximum clot rmness (MCF)
as assessed by TEG were signicantly lower in the PPH group compared with controls, and showed strong correlation with brinogen
levels. In patients with PPH compared with controls, CA at 5 minutes
was 12 mm vs 16 mm, MCF was 14 mm vs 19 mm, and level of brinogen was 3.4 g/L vs 5.1 g/L [21].

7. Massive transfusion protocols


Patient outcomes improve when massive transfusion protocols
(MTP) are used to guide therapy [22]. Blood product utilization is signicantly decreased, more platelets, plasma and less crystalloid are
transfused, and survival increases. A retrospective evaluation of 211
trauma patients demonstrated a 74% reduction in mortality in the
group treated with MTP compared with matched controls. Patients
treated with MTP had higher intraoperative transfusion of all blood
products and less crystalloid than controls. Additionally, they required
fewer transfusions postoperatively with statistically signicant differences in units of RBC (2.8 vs 8.7), FFP (1.7 vs 7.9), and platelets (0.9
vs 5.7) transfused [23]. Studies in patients with PPH conrm these
impressions [24].
8. Conclusion
Improving outcomes in PPH will require more research and further
coordination at national and international levels. Eagerly anticipated
are the results of ongoing randomized clinical trials [3,4]. As we
wait, however, the evidence to re-examine our current management
of PPH and consider implementing some or all of the measures described is no less than compelling. These include implementing massive transfusion protocols and transfusing blood products in a 1:1:1
ratio of FFP:platelets:RBC, supplementing brinogen when levels are
below those characteristic of pregnancy, and monitoring patients
with thromboelastography.
Conict of interest
The authors have no conicts of interest to declare.
References
[1] Miller RD, Robbins TO, Tong MJ, Barton SL. Coagulation defects associated with
massive blood transfusions. Ann Surg 1971;174(5):794-801.
[2] Schmidt PJ. Transfusion medicine history illustrated. Plasma and prayer in Korea,
1950. Transfusion 2007;47(9):1562-3.
[3] Shakur H, Elbourne D, Gulmezoglu M, Alrevic Z, Ronsmans C, Allen E, et al. The
WOMAN Trial (World Maternal Antibrinolytic Trial): tranexamic acid for the
treatment of postpartum haemorrhage: an international randomised, double
blind placebo controlled trial. Trials 2010;11:40.
[4] Clinical trials website. Fibrinogen Concentrate as Initial Treatment for Postpartum
Haemorrhage: A Randomised Clinically Controlled Trial (FIB-PPH). Available at:
http://clinicaltrials.gov/ct2/show/NCT01359878.
[5] 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;63(4):805-13.
[6] Holcomb JB, Wade CE, Michalek JE, Chisholm GB, Zarzabal LA, Schreiber MA, et al.
Increased plasma and platelet to red blood cell ratios improves outcome in 466
massively transfused civilian trauma patients. Ann Surg 2008;248(3):447-58.
[7] Stinger HK, Spinella PC, Perkins JG, Grathwohl KW, Salinas J, Martini WZ, et al. The
ratio of brinogen to red cells transfused affects survival in casualties receiving massive transfusions at an army combat support hospital. J Trauma 2008;64(2 Suppl.):
S79-85.
[8] Tanaka KA, Szlam F. Treatment of massive bleeding with prothrombin complex
concentrate: argument for. J Thromb Haemost 2010;8(12):2589-91.
[9] Maegele M, Lefering R, Yucel N, Tjardes T, Rixen D, Paffrath T, et al. Early coagulopathy
in multiple injury: an analysis from the German Trauma Registry on 8724 patients. Injury 2007;38(3):298-304.
[10] Charbit B, Mandelbrot L, Samain E, Baron G, Haddaoui B, Keita H, et al. The decrease of brinogen is an early predictor of the severity of postpartum hemorrhage. J Thromb Haemost 2007;5(2):266-73.
[11] Cortet M, Deneux-Tharaux C, Dupont C, Colin C, Rudigoz RC, Bouvier-Colle MH, et al.
Association between brinogen level and severity of postpartum haemorrhage: secondary analysis of a prospective trial. Br J Anaesth 2012;108(6):984-9.
[12] Bolliger D, Szlam F, Levy JH, Molinaro RJ, Tanaka KA. Haemodilution-induced
probrinolytic state is mitigated by fresh-frozen plasma: implications for early
haemostatic intervention in massive haemorrhage. Br J Anaesth 2010;104(3):
318-25.
[13] Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic acid on surgical
bleeding: systematic review and cumulative meta-analysis. BMJ 2012;344:e3054.
[14] Ducloy-Bouthors AS, Jude B, Duhamel A, Broisin F, Huissoud C, Keita-Meyer H,
et al. High-dose tranexamic acid reduces blood loss in postpartum haemorrhage.
Crit Care 2011;15(2):R117.

O. Onwuemene et al. / International Journal of Gynecology and Obstetrics 119 (2012) 35


[15] Movafegh A, Eslamian L, Dorabadi A. Effect of intravenous tranexamic acid administration on blood loss during and after cesarean delivery. Int J Gynecol Obstet
2011;115(3):224-6.
[16] Gungorduk K, Yildirim G, Asicioglu O, Gungorduk OC, Sudolmus S, Ark C. Efcacy
of intravenous tranexamic acid in reducing blood loss after elective cesarean section: a prospective, randomized, double-blind, placebo-controlled study. Am J
Perinatol 2011;28(3):233-40.
[17] Ahonen J. The role of recombinant activated factor VII in obstetric hemorrhage.
Curr Opin Anaesthesiol 2012;25(3):309-14.
[18] James AH, McLintock C, Lockhart E. Postpartum hemorrhage: when uterotonics
and sutures fail. Am J Hematol 2012;87(Suppl. 1):S16-22.
[19] Walsh M, Thomas SG, Howard JC, Evans E, Guyer K, Medvecz A, et al. Blood component therapy in trauma guided with the utilization of the perfusionist and
thromboelastography. J Extra Corpor Technol 2011;43(3):162-7.
[20] DeLoughery TG. Logistics of massive transfusions. Hematology Am Soc Hematol
Educ Program 2010;2010:470-3.

[21] Huissoud C, Carrabin N, Audibert F, Levrat A, Massignon D, Berland M, et al. Bedside


assessment of brinogen level in postpartum haemorrhage by thrombelastometry.
BJOG 2009;116(8):1097-102.
[22] Gutierrez MC, Goodnough LT, Druzin M, Butwick AJ. Postpartum hemorrhage
treated with a massive transfusion protocol at a tertiary obstetric center: a retrospective study. Int J Obstet Anesth 2012;21(3):230-5.
[23] Cotton BA, Gunter OL, Isbell J, Au BK, Robertson AM, Morris Jr JA, et al. Damage
control hematology: the impact of a trauma exsanguination protocol on survival and blood product utilization. J Trauma 2008;64(5):1177-82; discussion
11823.
[24] Burtelow M, Riley E, Druzin M, Fontaine M, Viele M, Goodnough LT. How we treat:
management of life-threatening primary postpartum hemorrhage with a standardized massive transfusion protocol. Transfusion 2007;47(9):1564-72.