Postpartum hemorrhage: When uterotonics and sutures fail

Postpartum hemorrhage: When uterotonics and sutures failAndra H. James,1* Claire McLintock,2 and Evelyn Lockhart3

Systemic bleeding at the time of postpartum hemorrhage (PPH) is usually the result of coagulopathy thathas developed acutely as a result of massive hemorrhage after uterotonics and sutures have failed. Occa-sionally, the patient has a preexisting coagulopathy, but more often, coagulopathy arises acutely as theresult of massive hemorrhage, which is usually related to obstetrical and less often surgical bleeding. De-spite being able to identify risk factors for PPH in the antenatal and intrapartum period, the majority ofwomen who ultimately develop PPH do not have any such factors and every pregnancy is at risk. The coa-gulopathy associated with massive PPH may be due to hemodilution, failure of liver synthetic function asoccurs with acute liver failure of pregnancy, or disseminated intravascular coagulation (DIC). There are nodata from clinical trials to help guide management of transfusion in PPH, although the management ofblood component therapy in severe PPH is similar to that in other massive hemorrhage. Standard practiceis to replace fibrinogen to maintain a level of �100 mg/dL, yet recent evidence suggests that the level offibrinogen needed to prevent PPH is at least 400 mg/dL. Recombinant activated factor VIIa (rFVIIa) has beenused in the management of severe PPH unresponsive to blood component therapy. Coagulation laboratoryevaluation may be useful in guiding hemostatic management during massive PPH, but for the results to beuseful, they must be rapidly available and provide information that would not be available from clinicalassessment alone. The hematologist or hemostasis expert has the opportunity to make the differencebetween life and death for the patient experiencing massive PPH. Am. J. Hematol. 87:S16–S22,2012. VVC 2012 Wiley Periodicals, Inc.

IntroductionPregnancy is the leading cause of death among women

of childbearing age worldwide and 25% [1] of the estimated358,000 women who die in childbirth each year [2] die frompostpartum hemorrhage (PPH). The overwhelming majoritydies in low-income countries [2], but an unacceptable num-ber of these women die in high-income countries as well[2,3]. Many of the deaths occur in the setting of a coagul-opathy when uterotonics and sutures have failed to controlPPH. This article will discuss the obstetrical, surgical, andsystemic causes of PPH with focus on the management ofmassive PPH complicated by coagulopathy.

Obstetrical BleedingObstetrical bleeding has not been defined, but for the

purposes of this article, it is defined as abnormal bleedingoriginating from the blood vessels within the gravid or post-partum uterus. An understanding of obstetrical bleedingrequires an understanding of normal placentation as wellas separation and expulsion of the placenta.Humans are supported in utero by a hemochorial pla-

centa. Fetal trophoblast (the cells that comprise the outerlayer of the evolving placenta) invades, erodes, and dilatesmaternal blood vessels so that the chorion or outer mem-branes of the fetal trophoblast are in direct contact withmaternal blood. The fetal trophoblast of the hemochorialplacenta remodels the spiral arteries (terminal branches ofthe uterine arteries) so that rather than being narrow andmuscular they are wide and flaccid. No matter howadvanced the gestation, at the conclusion of pregnancy, theplacenta should separate from the wall of the uterus andbe expelled. The separation of the placenta is associatedwith the exposure of the open spiral arteries and bleedingacross the entire surface that was previously occupied bythe placenta. Contraction of the uterus is the main mecha-nism by which bleeding from these vessels is controlled.Contraction of the interlacing muscle fibers of the uterusresults in external pressure to the open spiral arteries.Other factors, not well understood, lead to vasoconstrictionof the open vessels. For the process to succeed and bleed-

ing to be controlled, the placenta must be expelled by uter-ine contractions and the walls of the uterus be apposed.Bleeding is expected after vaginal delivery with an esti-

mated blood loss of up to 500 mL and at the time of cesar-ean delivery with an estimated blood loss of up to 1,000mL [4]. Bleeding is not expected to exceed these amountsat delivery or postpartum. When bleeding is in excess ofthese amounts at delivery or postpartum, the most com-mon reason is obstetrical bleeding, which accounts formost cases of PPH. The principles of management ofobstetrical bleeding include emptying the uterus (deliveringthe placenta, removing the placenta manually, or curettingthe uterine cavity), stimulating the uterus to contract withmassage or uterotonics to bring about intrinsic vasocon-striction or extrinsic myometrial compression of the uterinevasculature and, in extreme cases, uterine tamponade orcompression using a balloon, or compression sutures. Ifthe uterus is unresponsive, the uterus can be surgicallydevascularized with ligatures to the uterine and ovarianarteries. Alternatively, the internal iliac (hypogastric)

Conflict of Interest: Andra James has received research support, honorariaand served on Advisory Committees for CSL Behring, has received honora-ria and research support from Grifols, and received honoraria from Octa-pharma. Claire McLintock has received honoraria and served on AdvisoryCommittees for CSL Behring and Novo Nordisk and has acted as a Consul-tant for Novo Nordisk. Evelyn Lockhart has received honoraria and servedon an Advisory Committee for CSL Behring.

*Correspondence to: Andra James, Division of Maternal-Fetal Medicine,Duke University Medical Center, Box 3967 DUMC, Durham, NC 27710.E-mail: [email protected]

1Department of Obstetrics & Gynecology and Department of Medicine, DukeUniversity Medical Center, Durham, North Carolina; 2National Women’sHealth, Auckland City Hospital, Auckland, New Zealand; 3Department ofPathology, Duke University Medical Center, Durham, North Carolina

Received for publication 4 January 2012; Revised 2 February 2012; Accepted7 February 2012

Am. J. Hematol. 87:S16–S22, 2012.

Published online 15 February 2012 in Wiley Online Library (wileyonlinelibrary.com).DOI: 10.1002/ajh.23156

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VVC 2012 Wiley Periodicals, Inc.

American Journal of Hematology S16 http://wileyonlinelibrary.com/cgi-bin/jhome/35105

arteries can be ligated. Finally, the uterus can be surgicallyremoved (hysterectomy).

Surgical BleedingSurgical bleeding is bleeding due to incisions, lacera-

tions, ruptured vessels, or ruptured viscus and includes thebleeding that accompanies birth trauma or cesarean deliv-ery. Surgical bleeding is successfully treated with ligaturesand related procedures including embolization. Besidesbleeding from the uterus, bleeding at the time of deliverycan occur from ruptured aneurysms or a ruptured viscusother than a ruptured uterus (i.e., ruptured liver) andrequires immediate recognition and surgical intervention.

Systemic BleedingBleeding due to systemic reasons may be due to inad-

equate platelet function, thrombocytopenia, and/or inad-equate clotting factors which may be inherited or acquiredand may evolve acutely or chronically. Systemic bleeding atthe time of PPH is usually the result of coagulopathy thathas developed acutely as a result of massive hemorrhageafter uterotonics and sutures have failed. Occasionally, thepatient has a preexisting coagulopathy, but more often,coagulopathy arises acutely as a result of massive hemor-rhage related to obstetrical and less often surgical bleeding.The published incidence of massive PPH varies but mas-sive PPH requiring transfusion has a reported incidence of0.26–2.7% [5–10] and massive PPH resulting in coagulop-athy has a reported incidence of 0.15–0.5% [7,9,10] (SeeTable I).Uterine atony, or failure of the uterus to contract, is still

the leading cause of both massive PPH and coagulopathy.The next most frequent causes of coagulopathy are pla-centa accreta (invasion of the fetal trophoblast through theendometrium into the uterine myometrium and sometimesbeyond) and lacerations. Sometimes the patient has a coa-gulopathy as a result of a condition arising as a conse-quence of HELLP syndrome (HELLP syndrome 5 hemoly-sis, elevated liver enzymes, low platelets, or acute liver fail-ure of pregnancy) or abruption of the placenta with orwithout fetal demise. Rarely, the patient may have suffered

an amniotic fluid embolism with sudden-onset disseminatedintravascular coagulation. Table II lists the incidence of coa-gulopathy by cause among 12,476 deliveries from 2000 to2004 at Duke University Medical Center [7].

Risk FactorsDocumented risk factors for PPH with coagulopathy

include an underlying bleeding disorder [8], HELLP syn-drome [8], abnormal placentation with placental abruptionor placenta previa, anticoagulant use, amniotic fluid embo-lism [11], and massive bleeding due to uterine atony or lac-erations [7,9,10]. Uterine atony is the most common causeof PPH, and accounted for 79% of all PPH events in aUnited States discharge database [9]. Risk factors for uter-ine atony include abnormal placentation, a distendeduterus, an infected uterus, and prolonged labor. A recentstudy [12] reported that women with severe PPH requiringtransfusion had been exposed to greater amounts of oxyto-cin during labor than women with no PPH. (Desensitizationof the oxytocin receptor to the uterotonic effects of oxytocinafter prolonged exposure has been suggested to be theunderlying cause. [12]) Documented risk factors for PPHdue to uterine atony are listed in Table III.Documented risk factors for PPH due to the increased

likelihood or need for cesarean or operative delivery includeobesity [6,16], cardiac disease [8], abnormal placentationwith placental abruption or placenta previa, chorioamnioni-tis, and preeclampsia [9,13]. Sebire et al. reported that ahigh body mass index (BMI) was an independent risk factorfor standard and severe PPH, with women having a BMI>30 almost 50% more likely to have a severe PPH >1,000mL odds ratio [OR] 1.4 (95% confidence interval [CI] 1.3–1.6) [16]. Nonetheless, in another study, when mode ofdelivery was controlled for, BMI >30 was associated with adecreased risk of PPH [17], perhaps because increasingBMI is associated with higher levels of fibrinogen [18].Both inherited and acquired coagulation disorders have

been shown to increase the risk of PPH. Case series havedocumented a higher than expected rate of PPH amongwomen with inherited bleeding disorders (von Willebrand dis-ease [VWD], hemophilia carriage, factor XI deficiency andrare bleeding disorders) [19]. One population-based studyfrom the United States found a rate of PPH of 6% amongwomen with VWD compared to 4% among controls [20]. Apopulation-based study from Norway found a threefoldincreased risk of PPH among women with VWD (OR 5 3.31[1.01, 10.85]) [8]. Recently, even mild hemostatic abnormal-ities including low (but not deficient) levels of fibrinogen, lowvon Willebrand factor antigen, low factor XI, low plateletCD42b, TRAP-induced increase of platelet CD41a, high val-ues of serum residual prothrombin activity, increased closuretimes using the collagen-ADP cartridge with the PFA-100system, and blood group O were independently associatedwith a significantly increased risk for severe PPH [21].

TABLE I. Rates of Massive Postpartum Hemorrhage from Published Studies

Country, Institution (years) Deliveries (N) Definition of PPH % Pregnancies (n)

The Netherlands, Regional database (1990–1994) [5] 3,464 PPH 1 transfusion 2.7% (94)Argentina/Uruguay, Multicenter database

(hospitals > 1,000 births/yr) (2003–2005) [6]11,323 PPH 1 transfusion 0.4% (40)

USA, Single tertiary center (2000–2004) [7] 12,476 PPH 1 transfusion 0.9% (108)Coagulopathy 0.24% (30)

Norway, Birth Registry (1999–2004) [8] 307,415 >1,500 mL or any transfusion 1.1% (3,333)USA, National discharge database (2004) [9] 876,641 PPH 1 transfusion 0.26% (2,312)

Coagulopathy 0.15% (1,349)Scotland, National database (2009) [10] 59,046 >2,500 mL or transfused

� 5 units red cells or anyplasma for coagulopathy

0.518 % (306 includingone miscarriage andtwo ectopic pregnancies)

Estimated blood loss visually estimated in studies cited.

TABLE II. Reasons for Coagulopathy Among 12,476 deliveries from 2000 to

2004 at Duke University Medical Center

Number (%)

Uterine atony 11 (37%)Placenta accreta 6 (20%)Lacerations or incisions 6 (20%)HELLP syndrome 2 (7%)Acute fatty liver 1 (3%)Amniotic fluid embolism 1 (3%)Fibroids 1 (3%)Hemorrhage into ovary 1 (3%)Chronic hepatitis B 1 (3%)

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Other risk factors for PPH that can lead to massive hem-orrhage and coagulopathy include factors that interfere withaccess to optimal care [22–24]; other sociodemographicfactors such as age [8,14,15], parity [8] and race/ethnicity[8,13,15], and factors that operate through multiple mecha-nisms such as a history of PPH [25], preeclampsia[9,13,15], heart disease [8], and epilepsy [26].Despite being able to identify risk factors for PPH in the

antenatal and intrapartum period, the majority of womenwho ultimately develop PPH do not have any such factors[9] and every pregnancy is at risk. Women at high risk formassive obstetrical hemorrhage (i.e., those with accreta)should deliver at a tertiary care center with a specific planfor multidisciplinary management [27].

Management of PPHManagement of PPH depends on the underlying cause

or contributing factors. First-line medical therapy for bothprevention and treatment of uterine atony is uterine mas-sage and uterotonics. An episiotomy and minor lacerationscan be repaired in the birthing room or delivery room.Women who have persistent bleeding despite these basicmaneuvers should be transferred to the operating room toallow for examination under appropriate anesthesia and toallow for prompt surgical intervention, including laparotomy,if necessary. The next intervention or interventions mayinclude uterine balloon tamponade, uterine compression

sutures, pelvic devascularization, or arterial embolizationdepending on the situation. In a systematic review, thesemeasures were found to be successful in averting hysterec-tomy in 85–90% of cases [28]. Peripartum hysterectomy isa life-saving intervention performed in women with PPHwho might otherwise exsanguinate. The problem is thatwomen have hemorrhaged by the time they undergo theprocedure and lose significantly more blood during the pro-cedure itself [29,30].Optimal management of PPH considers the underlying

etiology of the hemorrhage, the stage of the hemorrhage,and the hematologic needs of the patient. Stages of PPHand appropriate interventions are summarized in Table IV.

Hematologic Management of Massive PPHThe coagulopathy associated with massive PPH may be

due to hemodilution, failure of liver synthetic function asoccurs with acute liver failure of pregnancy, or disseminatedintravascular coagulation (DIC). Hemodilution in massivehemorrhage can result from aggressive resuscitation usingcrystalloid solutions or from incomplete replacement of clot-ting factors [31]. DIC can accompany placental abruption,retained intrauterine fetal demise or amniotic fluid embolismand may develop acutely. The hypothesis is that undercertain conditions, the tissue factor-rich placenta, productsof conception, and amniotic fluid enter the maternalcirculation and act as a potent activator of the extrinsic

TABLE III. Risk Factors for Uterine Atony

Risk Factor Odds Ratios

Multiple gestation (>1 fetus,e.g., twins, triplets)

1.7 (1.3, 2.1) [13];2.34 (2.02, 2.70) [8]; 2.8 (2.2, 3.6) [9]; 2.60 (1.06, 6.39) [5] 4.67 (2.41, 9.05) > 500 mL EBL [6]; 4.34 (1.46, 12.87)> 1,000 mL EBL [6];

Retained placenta 4.1 (3.1, 5.5) [9]; 6.02 (3.50, 10.36) > 500 mL EBL [6]; 16.04 (7.15, 35.99) > 1,000 mL EBL [6]; 7.83 (3.78, 16.22) > 500 mL EBL[5]; 11.73 (5.67, 24..11) > 1,000 mL EBL [5]

Fetal macrosomia 1.93 (1.71, 2.17) [8]; 2.0 (1.93, 2.10) [14]; 2.36 (1.93, 2.88) > 500 mL [6]; 3.41 (2.27, 5.36) > 1,000 mL EBL [6]; 2.11 (1.62, 2.76)Polyhydramnios 1.9 (1.2, 3.1) [9]Chorioamnionitis 2.5 (1.9, 3.3) [9] 2.53 (1.30, 4.93) at cesarean [15] 2.5 (2.0, 3.2) Primary cesarean [13]; 2.5 (1.7, 3.8) Repeat cesarean [13]Induction of labor 1.6 (1.46, 1.75) [8]Prolonged labor 1.14 (1.02, 1.29) [8] 1.89 (1.04, 3.43) at cesarean [15]General anesthesia 2.5 (2.0, 3.2) Primary cesarean [13] 7.2 (5.9, 8.7) Repeat cesarean [13]Antepartum hemorrhage 3.8 (3.0, 4.8) [9]Placental abruption 2.9 (2.2, 3.7) > 500 mL EBL [13] 2.6 (1.8, 3.7) > 1,000 mL EBL [13]Placental previa 4.8 (3.5, 6.5) > 500 mL EBL [13] 15.9 (12.0, 21.0) > 1,000 mL EBL [13]

TABLE IV. Stages of PPH and Appropriate Interventions

Stage Intervention

In anticipation of delivery Investigate potential risk factorsHave baseline complete blood count and type and hold or type and screenHave intravenous accessIdentify patients at high risk for massive hemorrhage (i.e., those with accreta) and recommend delivery at tertiary care

center with specific plan of managementImmediately postpartum Prophylactic oxytocin or other prophylactic uterotonicEarly PPH Ensure that uterus is empty unless precluded by accreta

Investigate for bleeding from lacerations or incisions and institute repair if requiredTransfer to operating room/theatreAdminister intravenous oxytocin and administer second-line uterotonic (e.g., the prostaglandin misoprostol)Replace volumeReplace red blood cells if needed

Evolving PPH and possiblyearly coagulopathy—benefitsfrom multidisciplinary teamof obstetrics, anesthesia,transfusion medicine,laboratory medicine, andhematology

Obtain coagulation screen (PT/PTT and fibrinogen levels) (Anticipate future role for tranexamic acid beforeblood component therapy)

Replace red blood cellsReplace fibrinogen with cryoprecipitate or fibrinogen concentrateReplace other clotting factors with plasma or other factor concentrates (Anticipate future role for fibrinogen

concentrate, and possible other clotting factors, before blood component therapy)Minimize blood loss from uterus with balloon tamponade and uterine compression sutures if abdomen open

Unresponsive PPH withcoagulopathy—may requirepelvic surgeon, general/vascular/trauma surgeon,interventional radiologist,and intensivist

Perform laparotomy if abdomen closedContinue replacement blood component therapy and monitoring of clotting factor levelsConsider rFVIIaLigate pelvic vesselsPerform hysterectomy if necessaryRequest embolization of pelvic vessels as necessaryAnticipate need for critical care

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coagulation cascade [32,33]. DIC is frequently rapid andsevere in its development. Subsequent fibrinolysis leads toproduction of D-dimers and fibrin degradation products(FDPs) which may compound the PPH by interfering withuterine contractility and/or platelet function [34].

TransfusionThere are no data from clinical trials to help guide man-

agement of transfusion in PPH, although the managementof blood component therapy in severe PPH is likely similarto that in other massive hemorrhage. The optimal ratio ofplasma or cryoprecipitate to units of red blood cells, how-ever, is probably not 1:4 or 1:6 as has been previouslyassumed, but, extrapolating from retrospective observatio-nal studies of trauma victims, may be between 1:1 and 1:3[35–39]. Similarly, extrapolating from other studies oftrauma victims, the optimal ratio of platelets to units of redblood cells in trauma patients is also probably higher thanpreviously assumed [40,41].The obstetric community is considering the applicability

of the lessons learned from trauma victims and militarycasualties. Relatively few institutions, though, have specificprotocols for massive transfusion for PPH [42], and feweryet have published these protocols. Burtelow et al. at Stan-ford University described their single-institutional approach,applying their trauma massive transfusion protocol toobstetric patients experiencing PPH [43]. In this protocol,an emergency release blood product package of six packedred blood cells (pRBCs), four thawed plasma, and oneapheresis platelet are rapidly prepared and delivered inless than 15 min. This protocol also describes reflexive lab-oratory assessment of coagulopathy, with initial values forprothrombin time (PT), partial thromboplastin time (PTT),fibrinogen, D-dimer, and a complete blood count to bedrawn at the time of protocol activation. Additional bloodproduct administration is given either algorithmically basedon abnormal lab values in the context of ongoing hemor-rhage, with additional blood product packages delivered asneeded. The California Maternal Quality Care CollaborativeTask Force collated best practices from nine PPH protocolsderived from expert opinion in obstetrics and hematology[44,45]. Common elements between these protocolsincluded, (1) partnership between obstetric teams andtransfusion services for rapid release of ‘‘obstetrical hemor-rhage packs’’ to include pRBCs, platelets, plasma, and cry-oprecipitate, (2) availability of a local expert (hematologistor transfusion medicine physician) for consultation asneeded, and (3) a scripted protocol in response to PPHwhich is periodically practiced and evaluated. In addition,laboratory assessment of hemoglobin, platelet count, PT/PTT, and fibrinogen is recommended every 30 min until thepatient is stabilized.

FibrinogenThe role of fibrinogen in postpartum hemostasis is

receiving renewed attention. Although the investigatorsacknowledged that it was unclear whether low fibrinogenlevels contributed to PPH or reflected the severity of PPH,Charbit et al. [46] demonstrated that fibrinogen levelsobtained at the time of PPH were more predictive thanother coagulation studies such as the PT, PTT, and plateletcounts in determining which women would develop severePPH. Severe PPH did not develop in any woman who hada fibrinogen level at study entry of >400 mg/dL, but devel-oped in all women with a fibrinogen level of <200 mg/dL atstudy entry and was massive in four of five women whohad a fibrinogen level of <200 mg/dL at study entry.Fibrinogen levels are increased during pregnancy (350–

650 mg/dL compared to 197–401 mg/dL among nonpreg-nant individuals [47]) so that significant activation of the

coagulation system and consumption of clotting factors willhave occurred by the time a fibrinogen level has droppedbelow 200 mg/dL. In PPH, depletion of fibrinogen occursquicker than that of other clotting factors or platelets.Whereas the critical levels of prothrombin, factor V, factorVII, and platelets are reached after a blood loss of greaterthan twice a patient’s estimated blood volume, fibrinogendrops to critically low levels after a loss of only 1.4 times apatient’s estimated blood volume [48]. Standard practice,however, is to replace fibrinogen to maintain a level of�100 mg/dL as this level is thought to be sufficient to pro-mote normal hemostasis [49]. Studies that helped derivethis threshold, however, did not include patients with PPHwho may actually require higher levels of fibrinogen [50,51].Further evidence that a higher level of fibrinogen is neededfor optimal hemostasis comes from an in vitro model. Usingan in vitro hemodilution model, the rate of clot formationwas not fully optimized until fibrinogen levels were >250mg/dL [52].Cryoprecipitate is preferred to plasma to correct low fibri-

nogen levels, however, concerns regarding the risk of viraltransmission have led to the substitution or partial substitu-tion of virally inactivated fibrinogen concentrates such asHaemocomplettan or RiaSTAP (CSL Behring, Marberg,Germany), particularly in Europe. At least 24 cases of itsuse in the management of obstetrical hemorrhage havebeen published. Doses, where specified, ranged from 2 to4 g [53–56] and were given alone or in combination withplasma or cryoprecipitate. In no case was fibrinogen admin-istered as part of a controlled study. In three of the fourpublished reports [53–55], the outcomes of PPH weredescribed as improved or normalized with clinical and labo-ratory evidence of resolution of coagulopathy. In the fourthreport, specific data for the obstetric cases were not given[56]. A randomized-controlled trial is underway at four hos-pitals in Denmark that will compare administration of fibri-nogen concentrate, 2 g intravenously versus saline, early inthe course of PPH. Inclusion criteria are an estimated bloodloss �500 mL after vaginal delivery or �1,000 mL after ce-sarean delivery [57].

Recombinant Factor VIIaRecombinant activated factor VIIa (rFVIIa), indicated for

the prevention or treatment of bleeding in hemophiliapatients with inhibitors, has been used in the managementof severe PPH, primarily in cases unresponsive to bloodcomponent therapy. The largest reported series of the off-label use of rFVIIa in obstetrics is from the Australian andNew Zealand Haemostasis Registry [58]. Between January2002 and July 2008, the investigators recorded all off-labeluse of rFVIIa in over 90 participating hospitals in the twocountries. The treatment of acute PPH with rFVIIa wasdocumented in 105 cases. The majority of women (78%)received a single dose (median dose 5 92 mcg/kg). Theclinically determined positive response rate was 76% with64% responding after a single dose. Forty-three patients(41%) had a hysterectomy before administration of thedrug. Only 13 (21%) required hysterectomy followingadministration of the rFVIIa. Two women developed venousthromboembolism after receiving the drug.The Northern Europe Factor 7a in Obstetric Hemorrhage

study reported rFVIIa use in 92 women with obstetric hem-orrhage from 531 maternity units in nine countries. The ma-jority of women (81%) received a single dose of rFVIIa.The most common dose was 90 mcg/kg. The clinicallydetermined positive response rate was 86% with 80%responding after a single dose [59]. Four women developedvenous thromboembolism after receiving rFVIIa. Whetheror not a patient receives rFVIIa, massive PPH is a risk



factor for thrombosis [60] and is an indication for thrombo-prophylaxis once the patient is stable.If rFVIIa does have a role in the management of PPH, it

is in avoiding hysterectomy or achieving hemostasis afterhysterectomy when conventional hemostatic managementhas failed. Whether rFVIIa should be administered to avoidhysterectomy depends on the underlying cause of PPH.Early hysterectomy is essentially unavoidable for severebleeding due to uterine rupture, placenta accreta, or othercircumstances where the uterus cannot be salvaged. Inwomen with uterine atony who have ongoing bleeding de-spite correction of hypothermia, acidosis, hypocalcemia,and replacement of clotting factors, it may be reasonable toconsider a trial of rFVIIa before hysterectomy. It is impor-tant to correct acidosis before administration of rFVIIa assignificant loss of FVIIa has been observed at pH less than7.4 [61]. When effective, an improvement in bleedingshould be seen within 10–15 min after the administration ofthe drug. If the first dose is judged to be ineffective, a sec-ond dose may be tried, but further doses are not recom-mended. The Australia and New Zealand guidelines sug-gest a dosing at 90 mcg/kg [62]. Their specific recommen-dation is that once all surgical and nonsurgical proceduresto arrest active bleeding have been attempted and bleedingcontinues after administration of between 8 and 12 units ofpacked red blood cells and before hysterectomy, then 90mcg/kg per (rounded to the nearest vial) of rFVIIa can beadministered as a single bolus injection over 3–5 min. After20 min, if there is no response and significant bleeding con-tinues, and ph, calcium, platelets (target platelet count >50,000), and fibrinogen (target fibrinogen level > 100 g/dL)have been optimized, then a second dose of rFVIIa may beadministered [62].

Antifibrinolytic TherapyAntifibrinolytic therapy, while used for the prevention of

PPH in some patients with bleeding disorders, has notbeen used in the United States for the prevention or man-agement of PPH. Tranexamic acid, however, has beenshown in two randomized trials of uncertain quality todecrease postpartum blood loss after vaginal birth and aftercesarean delivery [63]. Recently, tranexamic acid was usedin a randomized trial to treat acute PPH. One hundredforty-four women with an estimated blood loss at delivery of> 800 mL following vaginal delivery were randomized toreceive intravenous tranexamic acid (loading dose 4 g over1 h, then an infusion of 1 g/h over 6 h) or to receive notherapy. Other hemostatic treatments were withheld for 2 hunless the estimated blood loss exceeded 2,500 mL or 500mL in 30 min. Blood loss between enrollment and 6 h laterwas significantly lower in the tranexamic acid group than inthe control group (median, 173 mL; first to third quartiles,59–377) than in controls (221 mL; first to third quartiles105–564) (P 5 0.041). Nausea and vomiting was signifi-cantly greater in the tranexamic acid group than in the con-trol group. There were two catheter-related thromboses inthe tranexamic acid group compared to the control group.This was not a statistically significant difference, but thestudy was not powered to detect a difference in thrombo-ses [64]. A very large, multicenter, international, random-ized-controlled trial, the World Maternal Anitfibrinolytic Trial,or WOMAN Trial, sponsored by the London School ofHygiene and Tropical Medicine is currently recruiting sub-jects. Inclusion criteria are an estimated blood loss �500mL after vaginal delivery or �1,000 mL after cesareandelivery. The enrollment is planned for 15,000 subjects whowill be randomized to 1–2 g of tranexamic acid intrave-nously versus saline. The primary outcome measure is hys-terectomy or death. Secondary outcome measures will be

other surgical interventions, transfusions, thromboembo-lism, and other relevant medical events [65].

Laboratory Evaluation of PPHCoagulation laboratory evaluation may be useful in guiding

hemostatic management during massive PPH. To ensuretheir utility, laboratory results must be rapidly available [61]and provide information that would not be available from clin-ical assessment alone. In a retrospective study at Duke Uni-versity Medical Center, we found that the trigger for clottingfactor replacement in massive PPH was oozing in 57% ofcases versus a PTT > 1.5 times normal in the other 43% ofcases. For the patients in which oozing was the trigger forclotting factor replacement, timely laboratory results werenot available or not obtained at the time a clinical decisionwas required [7]. Increasingly, point-of-care coagulation testssuch as thromboelastography (TEG1, Haemoscope, Niles,IL) and rotational thromboelastometry (ROTEM1) are beingconsidered as measures to guide transfusion in massivehemorrhage [66]. These tests may be able to identifypatients who have hypofibrinogenemia or increased fibrinoly-sis [67] which may be relevant in PPH. A case-control study[68] showed that the median clot amplitude of the FIBTEM1

test (the component of the ROTEM1 test [Pentapharm, Mu-nich, Germany] designed to assess fibrinogen level) was sig-nificantly lower in women with PPH than in controls. Moredata from prospective studies are required before thesetests can be incorporated into the routine management ofblood component therapy in massive PPH.

Risk of Thrombosis as a Consequence of PPHParadoxically, PPH increases the risk of thrombosis. PPH

increases the risk of both venous [60,69] and arterialthromboembolism [70,71]. Two population-based studieshave found that both PPH and transfusion increase the riskof venous thromboembolism with odds of 1.3 (1.1, 1.6) [60]and 9.0 (1.1, 71) [69] for PPH and 7.6 (6.2, 9.4) [60] and5.0 (0.58, 43) [69] for transfusion. Consequently, patientswho have experienced PPH should receive thromboprophy-laxis with pneumatic compression devices or graduatedcompression stockings and, depending on the presence ofadditional risk factors, pharmacologic prophylaxis as well.Initiation of pharmacologic prophylaxis should be postponeduntil coagulation studies are normal and the risk of signifi-cant bleeding has subsided. The patient who actually expe-riences a deep vein thrombosis or pulmonary embolismmay require temporary postponement of anticoagulationand temporary placement of a vena caval filter.

ConclusionBy the time a hematologist or hemostasis expert is called,

some combination of obstetrics, anesthesia, general/vascular/trauma surgery, interventional radiology, transfusion medicine,laboratory medicine have already become involved. To suc-cessfully manage PPH in the patient in whom uterotonics andsutures have failed, the hematologist or hemostasis expertshould have some understanding of massive PPH; be able tointerpret the laboratory results to advise and guide transfusiontherapy; make recommendations regarding hemostatic therapy,including the possible need for rFVIIa; and provide critical intra-hemorrhage consultation while working with multiple other disci-plines and multiple other departments. The hematologist orhemostasis expert, with his or her specialized knowledge, hasthe opportunity to make the difference between life and deathfor the patient experiencing massive PPH.

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Postpartum hemorrhage: When uterotonics and sutures fail