THSNA Meeting Proceedings Postpartum hemorrhage: When uterotonics and sutures fail Andra H. James,1* Claire McLintock,2 and Evelyn Lockhart3 Systemic bleeding at the time of postpartum hemorrhage (PPH) is usually the result of coagulopathy that has developed acutely as a result of massive hemorrhage after uterotonics and sutures have failed. Occasionally, the patient has a preexisting coagulopathy, but more often, coagulopathy arises acutely as the result of massive hemorrhage, which is usually related to obstetrical and less often surgical bleeding. Despite being able to identify risk factors for PPH in the antenatal and intrapartum period, the majority of women who ultimately develop PPH do not have any such factors and every pregnancy is at risk. The coagulopathy associated with massive PPH may be due to hemodilution, failure of liver synthetic function as occurs with acute liver failure of pregnancy, or disseminated intravascular coagulation (DIC). There are no data from clinical trials to help guide management of transfusion in PPH, although the management of blood component therapy in severe PPH is similar to that in other massive hemorrhage. Standard practice is to replace fibrinogen to maintain a level of 100 mg/dL, yet recent evidence suggests that the level of fibrinogen needed to prevent PPH is at least 400 mg/dL. Recombinant activated factor VIIa (rFVIIa) has been used in the management of severe PPH unresponsive to blood component therapy. Coagulation laboratory evaluation may be useful in guiding hemostatic management during massive PPH, but for the results to be useful, they must be rapidly available and provide information that would not be available from clinical assessment alone. The hematologist or hemostasis expert has the opportunity to make the difference between life and death for the patient experiencing massive PPH. Am. J. Hematol. 87:S16–S22, C 2012 Wiley Periodicals, Inc. 2012. V

Introduction Pregnancy is the leading cause of death among women of childbearing age worldwide and 25% [1] of the estimated 358,000 women who die in childbirth each year [2] die from postpartum hemorrhage (PPH). The overwhelming majority dies in low-income countries [2], but an unacceptable number of these women die in high-income countries as well [2,3]. Many of the deaths occur in the setting of a coagulopathy when uterotonics and sutures have failed to control PPH. This article will discuss the obstetrical, surgical, and systemic causes of PPH with focus on the management of massive PPH complicated by coagulopathy. Obstetrical Bleeding Obstetrical bleeding has not been defined, but for the purposes of this article, it is defined as abnormal bleeding originating from the blood vessels within the gravid or postpartum uterus. An understanding of obstetrical bleeding requires an understanding of normal placentation as well as separation and expulsion of the placenta. Humans are supported in utero by a hemochorial placenta. Fetal trophoblast (the cells that comprise the outer layer of the evolving placenta) invades, erodes, and dilates maternal blood vessels so that the chorion or outer membranes of the fetal trophoblast are in direct contact with maternal blood. The fetal trophoblast of the hemochorial placenta remodels the spiral arteries (terminal branches of the uterine arteries) so that rather than being narrow and muscular they are wide and flaccid. No matter how advanced the gestation, at the conclusion of pregnancy, the placenta should separate from the wall of the uterus and be expelled. The separation of the placenta is associated with the exposure of the open spiral arteries and bleeding across the entire surface that was previously occupied by the placenta. Contraction of the uterus is the main mechanism by which bleeding from these vessels is controlled. Contraction of the interlacing muscle fibers of the uterus results in external pressure to the open spiral arteries. Other factors, not well understood, lead to vasoconstriction of the open vessels. For the process to succeed and bleed-

ing to be controlled, the placenta must be expelled by uterine contractions and the walls of the uterus be apposed. Bleeding is expected after vaginal delivery with an estimated blood loss of up to 500 mL and at the time of cesarean delivery with an estimated blood loss of up to 1,000 mL [4]. Bleeding is not expected to exceed these amounts at delivery or postpartum. When bleeding is in excess of these amounts at delivery or postpartum, the most common reason is obstetrical bleeding, which accounts for most cases of PPH. The principles of management of obstetrical bleeding include emptying the uterus (delivering the placenta, removing the placenta manually, or curetting the uterine cavity), stimulating the uterus to contract with massage or uterotonics to bring about intrinsic vasoconstriction or extrinsic myometrial compression of the uterine vasculature and, in extreme cases, uterine tamponade or compression using a balloon, or compression sutures. If the uterus is unresponsive, the uterus can be surgically devascularized with ligatures to the uterine and ovarian arteries. Alternatively, the internal iliac (hypogastric)

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

Conflict of Interest: Andra James has received research support, honoraria and served on Advisory Committees for CSL Behring, has received honoraria and research support from Grifols, and received honoraria from Octapharma. Claire McLintock has received honoraria and served on Advisory Committees for CSL Behring and Novo Nordisk and has acted as a Consultant for Novo Nordisk. Evelyn Lockhart has received honoraria and served on 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] Received for publication 4 January 2012; Revised 2 February 2012; Accepted 7 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

C 2012 Wiley Periodicals, Inc. V

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http://wileyonlinelibrary.com/cgi-bin/jhome/35105

THSNA meeting proceedings TABLE I. Rates of Massive Postpartum Hemorrhage from Published Studies Country, Institution (years) The Netherlands, Regional database (1990–1994) [5] Argentina/Uruguay, Multicenter database (hospitals > 1,000 births/yr) (2003–2005) [6] USA, Single tertiary center (2000–2004) [7] Norway, Birth Registry (1999–2004) [8] USA, National discharge database (2004) [9] Scotland, National database (2009) [10]

Deliveries (N)

Definition of PPH

3,464 11,323

PPH 1 transfusion PPH 1 transfusion

12,476

PPH 1 transfusion Coagulopathy >1,500 mL or any transfusion PPH 1 transfusion Coagulopathy >2,500 mL or transfused  5 units red cells or any plasma for coagulopathy

307,415 876,641 59,046

% Pregnancies (n) 2.7% (94) 0.4% (40) 0.9% (108) 0.24% (30) 1.1% (3,333) 0.26% (2,312) 0.15% (1,349) 0.518 % (306 including one miscarriage and two 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 Placenta accreta Lacerations or incisions HELLP syndrome Acute fatty liver Amniotic fluid embolism Fibroids Hemorrhage into ovary Chronic hepatitis B

11 6 6 2 1 1 1 1 1

(37%) (20%) (20%) (7%) (3%) (3%) (3%) (3%) (3%)

arteries can be ligated. Finally, the uterus can be surgically removed (hysterectomy). Surgical Bleeding Surgical bleeding is bleeding due to incisions, lacerations, ruptured vessels, or ruptured viscus and includes the bleeding that accompanies birth trauma or cesarean delivery. Surgical bleeding is successfully treated with ligatures and related procedures including embolization. Besides bleeding from the uterus, bleeding at the time of delivery can occur from ruptured aneurysms or a ruptured viscus other than a ruptured uterus (i.e., ruptured liver) and requires immediate recognition and surgical intervention. Systemic Bleeding Bleeding due to systemic reasons may be due to inadequate platelet function, thrombocytopenia, and/or inadequate clotting factors which may be inherited or acquired and may evolve acutely or chronically. Systemic bleeding at the time of PPH is usually the result of coagulopathy that has developed acutely as a result of massive hemorrhage after uterotonics and sutures have failed. Occasionally, the patient has a preexisting coagulopathy, but more often, coagulopathy arises acutely as a result of massive hemorrhage related to obstetrical and less often surgical bleeding. The published incidence of massive PPH varies but massive PPH requiring transfusion has a reported incidence of 0.26–2.7% [5–10] and massive PPH resulting in coagulopathy has a reported incidence of 0.15–0.5% [7,9,10] (See Table 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 placenta accreta (invasion of the fetal trophoblast through the endometrium into the uterine myometrium and sometimes beyond) and lacerations. Sometimes the patient has a coagulopathy as a result of a condition arising as a consequence of HELLP syndrome (HELLP syndrome 5 hemolysis, elevated liver enzymes, low platelets, or acute liver failure of pregnancy) or abruption of the placenta with or without fetal demise. Rarely, the patient may have suffered

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an amniotic fluid embolism with sudden-onset disseminated intravascular coagulation. Table II lists the incidence of coagulopathy by cause among 12,476 deliveries from 2000 to 2004 at Duke University Medical Center [7]. Risk Factors Documented risk factors for PPH with coagulopathy include an underlying bleeding disorder [8], HELLP syndrome [8], abnormal placentation with placental abruption or placenta previa, anticoagulant use, amniotic fluid embolism [11], and massive bleeding due to uterine atony or lacerations [7,9,10]. Uterine atony is the most common cause of PPH, and accounted for 79% of all PPH events in a United States discharge database [9]. Risk factors for uterine atony include abnormal placentation, a distended uterus, an infected uterus, and prolonged labor. A recent study [12] reported that women with severe PPH requiring transfusion had been exposed to greater amounts of oxytocin during labor than women with no PPH. (Desensitization of the oxytocin receptor to the uterotonic effects of oxytocin after prolonged exposure has been suggested to be the underlying cause. [12]) Documented risk factors for PPH due 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 include obesity [6,16], cardiac disease [8], abnormal placentation with placental abruption or placenta previa, chorioamnionitis, and preeclampsia [9,13]. Sebire et al. reported that a high body mass index (BMI) was an independent risk factor for standard and severe PPH, with women having a BMI >30 almost 50% more likely to have a severe PPH >1,000 mL odds ratio [OR] 1.4 (95% confidence interval [CI] 1.3– 1.6) [16]. Nonetheless, in another study, when mode of delivery was controlled for, BMI >30 was associated with a decreased risk of PPH [17], perhaps because increasing BMI 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 have documented a higher than expected rate of PPH among women with inherited bleeding disorders (von Willebrand disease [VWD], hemophilia carriage, factor XI deficiency and rare bleeding disorders) [19]. One population-based study from the United States found a rate of PPH of 6% among women with VWD compared to 4% among controls [20]. A population-based study from Norway found a threefold increased risk of PPH among women with VWD (OR 5 3.31 [1.01, 10.85]) [8]. Recently, even mild hemostatic abnormalities including low (but not deficient) levels of fibrinogen, low von Willebrand factor antigen, low factor XI, low platelet CD42b, TRAP-induced increase of platelet CD41a, high values of serum residual prothrombin activity, increased closure times using the collagen-ADP cartridge with the PFA-100 system, and blood group O were independently associated with a significantly increased risk for severe PPH [21].

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THSNA meeting proceedings TABLE III. Risk Factors for Uterine Atony Risk Factor Multiple gestation (>1 fetus, e.g., twins, triplets) Retained placenta Fetal macrosomia Polyhydramnios Chorioamnionitis Induction of labor Prolonged labor General anesthesia Antepartum hemorrhage Placental abruption Placental previa

Odds Ratios 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]; 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] 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) 1.9 (1.2, 3.1) [9] 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] 1.6 (1.46, 1.75) [8] 1.14 (1.02, 1.29) [8] 1.89 (1.04, 3.43) at cesarean [15] 2.5 (2.0, 3.2) Primary cesarean [13] 7.2 (5.9, 8.7) Repeat cesarean [13] 3.8 (3.0, 4.8) [9] 2.9 (2.2, 3.7) > 500 mL EBL [13] 2.6 (1.8, 3.7) > 1,000 mL EBL [13] 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 In anticipation of delivery

Immediately postpartum Early PPH

Evolving PPH and possibly early coagulopathy—benefits from multidisciplinary team of obstetrics, anesthesia, transfusion medicine, laboratory medicine, and hematology Unresponsive PPH with coagulopathy—may require pelvic surgeon, general/ vascular/trauma surgeon, interventional radiologist, and intensivist

Intervention Investigate potential risk factors Have baseline complete blood count and type and hold or type and screen Have intravenous access Identify patients at high risk for massive hemorrhage (i.e., those with accreta) and recommend delivery at tertiary care center with specific plan of management Prophylactic oxytocin or other prophylactic uterotonic Ensure that uterus is empty unless precluded by accreta Investigate for bleeding from lacerations or incisions and institute repair if required Transfer to operating room/theatre Administer intravenous oxytocin and administer second-line uterotonic (e.g., the prostaglandin misoprostol) Replace volume Replace red blood cells if needed Obtain coagulation screen (PT/PTT and fibrinogen levels) (Anticipate future role for tranexamic acid before blood component therapy) Replace red blood cells Replace fibrinogen with cryoprecipitate or fibrinogen concentrate Replace 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 Perform laparotomy if abdomen closed Continue replacement blood component therapy and monitoring of clotting factor levels Consider rFVIIa Ligate pelvic vessels Perform hysterectomy if necessary Request embolization of pelvic vessels as necessary Anticipate need for critical care

Other risk factors for PPH that can lead to massive hemorrhage and coagulopathy include factors that interfere with access to optimal care [22–24]; other sociodemographic factors such as age [8,14,15], parity [8] and race/ethnicity [8,13,15], and factors that operate through multiple mechanisms 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 women who ultimately develop PPH do not have any such factors [9] and every pregnancy is at risk. Women at high risk for massive obstetrical hemorrhage (i.e., those with accreta) should deliver at a tertiary care center with a specific plan for multidisciplinary management [27]. Management of PPH Management of PPH depends on the underlying cause or contributing factors. First-line medical therapy for both prevention and treatment of uterine atony is uterine massage and uterotonics. An episiotomy and minor lacerations can be repaired in the birthing room or delivery room. Women who have persistent bleeding despite these basic maneuvers should be transferred to the operating room to allow for examination under appropriate anesthesia and to allow for prompt surgical intervention, including laparotomy, if necessary. The next intervention or interventions may include uterine balloon tamponade, uterine compression

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sutures, pelvic devascularization, or arterial embolization depending on the situation. In a systematic review, these measures were found to be successful in averting hysterectomy in 85–90% of cases [28]. Peripartum hysterectomy is a life-saving intervention performed in women with PPH who might otherwise exsanguinate. The problem is that women have hemorrhaged by the time they undergo the procedure and lose significantly more blood during the procedure 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 PPH and appropriate interventions are summarized in Table IV. Hematologic Management of Massive PPH The coagulopathy associated with massive PPH may be due to hemodilution, failure of liver synthetic function as occurs with acute liver failure of pregnancy, or disseminated intravascular coagulation (DIC). Hemodilution in massive hemorrhage can result from aggressive resuscitation using crystalloid solutions or from incomplete replacement of clotting factors [31]. DIC can accompany placental abruption, retained intrauterine fetal demise or amniotic fluid embolism and may develop acutely. The hypothesis is that under certain conditions, the tissue factor-rich placenta, products of conception, and amniotic fluid enter the maternal circulation and act as a potent activator of the extrinsic

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THSNA meeting proceedings coagulation cascade [32,33]. DIC is frequently rapid and severe in its development. Subsequent fibrinolysis leads to production of D-dimers and fibrin degradation products (FDPs) which may compound the PPH by interfering with uterine contractility and/or platelet function [34]. Transfusion There are no data from clinical trials to help guide management of transfusion in PPH, although the management of blood component therapy in severe PPH is likely similar to that in other massive hemorrhage. The optimal ratio of plasma or cryoprecipitate to units of red blood cells, however, is probably not 1:4 or 1:6 as has been previously assumed, but, extrapolating from retrospective observational studies of trauma victims, may be between 1:1 and 1:3 [35–39]. Similarly, extrapolating from other studies of trauma victims, the optimal ratio of platelets to units of red blood cells in trauma patients is also probably higher than previously assumed [40,41]. The obstetric community is considering the applicability of the lessons learned from trauma victims and military casualties. Relatively few institutions, though, have specific protocols for massive transfusion for PPH [42], and fewer yet have published these protocols. Burtelow et al. at Stanford University described their single-institutional approach, applying their trauma massive transfusion protocol to obstetric patients experiencing PPH [43]. In this protocol, an emergency release blood product package of six packed red blood cells (pRBCs), four thawed plasma, and one apheresis platelet are rapidly prepared and delivered in less than 15 min. This protocol also describes reflexive laboratory assessment of coagulopathy, with initial values for prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, D-dimer, and a complete blood count to be drawn at the time of protocol activation. Additional blood product administration is given either algorithmically based on abnormal lab values in the context of ongoing hemorrhage, with additional blood product packages delivered as needed. The California Maternal Quality Care Collaborative Task Force collated best practices from nine PPH protocols derived from expert opinion in obstetrics and hematology [44,45]. Common elements between these protocols included, (1) partnership between obstetric teams and transfusion services for rapid release of ‘‘obstetrical hemorrhage packs’’ to include pRBCs, platelets, plasma, and cryoprecipitate, (2) availability of a local expert (hematologist or transfusion medicine physician) for consultation as needed, and (3) a scripted protocol in response to PPH which is periodically practiced and evaluated. In addition, laboratory assessment of hemoglobin, platelet count, PT/ PTT, and fibrinogen is recommended every 30 min until the patient is stabilized. Fibrinogen The role of fibrinogen in postpartum hemostasis is receiving renewed attention. Although the investigators acknowledged that it was unclear whether low fibrinogen levels contributed to PPH or reflected the severity of PPH, Charbit et al. [46] demonstrated that fibrinogen levels obtained at the time of PPH were more predictive than other coagulation studies such as the PT, PTT, and platelet counts in determining which women would develop severe PPH. Severe PPH did not develop in any woman who had a fibrinogen level at study entry of >400 mg/dL, but developed in all women with a fibrinogen level of 50,000), and fibrinogen (target fibrinogen level > 100 g/dL) have been optimized, then a second dose of rFVIIa may be administered [62]. Antifibrinolytic Therapy Antifibrinolytic therapy, while used for the prevention of PPH in some patients with bleeding disorders, has not been used in the United States for the prevention or management of PPH. Tranexamic acid, however, has been shown in two randomized trials of uncertain quality to decrease postpartum blood loss after vaginal birth and after cesarean delivery [63]. Recently, tranexamic acid was used in a randomized trial to treat acute PPH. One hundred forty-four women with an estimated blood loss at delivery of > 800 mL following vaginal delivery were randomized to receive intravenous tranexamic acid (loading dose 4 g over 1 h, then an infusion of 1 g/h over 6 h) or to receive no therapy. Other hemostatic treatments were withheld for 2 h unless the estimated blood loss exceeded 2,500 mL or 500 mL in 30 min. Blood loss between enrollment and 6 h later was significantly lower in the tranexamic acid group than in the control group (median, 173 mL; first to third quartiles, 59–377) than in controls (221 mL; first to third quartiles 105–564) (P 5 0.041). Nausea and vomiting was significantly greater in the tranexamic acid group than in the control group. There were two catheter-related thromboses in the tranexamic acid group compared to the control group. This was not a statistically significant difference, but the study was not powered to detect a difference in thromboses [64]. A very large, multicenter, international, randomized-controlled trial, the World Maternal Anitfibrinolytic Trial, or WOMAN Trial, sponsored by the London School of Hygiene and Tropical Medicine is currently recruiting subjects. Inclusion criteria are an estimated blood loss 500 mL after vaginal delivery or 1,000 mL after cesarean delivery. The enrollment is planned for 15,000 subjects who will be randomized to 1–2 g of tranexamic acid intravenously versus saline. The primary outcome measure is hysterectomy or death. Secondary outcome measures will be

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other surgical interventions, transfusions, thromboembolism, and other relevant medical events [65]. Laboratory Evaluation of PPH Coagulation laboratory evaluation may be useful in guiding hemostatic management during massive PPH. To ensure their utility, laboratory results must be rapidly available [61] and provide information that would not be available from clinical assessment alone. In a retrospective study at Duke University Medical Center, we found that the trigger for clotting factor replacement in massive PPH was oozing in 57% of cases versus a PTT > 1.5 times normal in the other 43% of cases. For the patients in which oozing was the trigger for clotting factor replacement, timely laboratory results were not available or not obtained at the time a clinical decision was required [7]. Increasingly, point-of-care coagulation tests such as thromboelastography (TEG1, Haemoscope, Niles, IL) and rotational thromboelastometry (ROTEM1) are being considered as measures to guide transfusion in massive hemorrhage [66]. These tests may be able to identify patients who have hypofibrinogenemia or increased fibrinolysis [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, Munich, Germany] designed to assess fibrinogen level) was significantly lower in women with PPH than in controls. More data from prospective studies are required before these tests can be incorporated into the routine management of blood component therapy in massive PPH. Risk of Thrombosis as a Consequence of PPH Paradoxically, PPH increases the risk of thrombosis. PPH increases the risk of both venous [60,69] and arterial thromboembolism [70,71]. Two population-based studies have found that both PPH and transfusion increase the risk of 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] and 5.0 (0.58, 43) [69] for transfusion. Consequently, patients who have experienced PPH should receive thromboprophylaxis with pneumatic compression devices or graduated compression stockings and, depending on the presence of additional risk factors, pharmacologic prophylaxis as well. Initiation of pharmacologic prophylaxis should be postponed until coagulation studies are normal and the risk of significant bleeding has subsided. The patient who actually experiences a deep vein thrombosis or pulmonary embolism may require temporary postponement of anticoagulation and temporary placement of a vena caval filter. Conclusion By 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 successfully manage PPH in the patient in whom uterotonics and sutures have failed, the hematologist or hemostasis expert should have some understanding of massive PPH; be able to interpret the laboratory results to advise and guide transfusion therapy; make recommendations regarding hemostatic therapy, including the possible need for rFVIIa; and provide critical intrahemorrhage consultation while working with multiple other disciplines and multiple other departments. The hematologist or hemostasis expert, with his or her specialized knowledge, has the opportunity to make the difference between life and death for the patient experiencing massive PPH. References 1. Khan KS, Wojdyla D, Say L, et al. WHO analysis of causes of maternal death: A systematic review. Lancet 2006;367:1066–1074. 2. Hogan MC, Foreman KJ, Naghavi M, et al. Maternal mortality for 181 countries, 1980–2008: A systematic analysis of progress towards Millennium Development Goal 5. Lancet 2010;375:1609–1623.

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THSNA meeting proceedings 3. Knight M, Callaghan WM, Berg C, et al. Trends in postpartum hemorrhage in high resource countries: A review and recommendations from the International Postpartum Hemorrhage Collaborative Group. BMC Pregnancy Childbirth 2009;9:55. 4. ACOG Practice Bulletin: Clinical Management Guidelines for ObstetricianGynecologists Number 76, October 2006: postpartum hemorrhage. Obstet Gynecol 2006;108:1039–1047. 5. Bais JM, Eskes M, Pel M, et al. Postpartum haemorrhage in nulliparous women: Incidence and risk factors in low and high risk women. A Dutch population-based cohort study on standard (> or 5 500 mL) and severe (> or 5 1000 mL) postpartum haemorrhage. Eur J Obstet Gynecol Reprod Biol 2004;115:166–172. 6. Sosa CG, Althabe F, Belizan JM, et al. Risk factors for postpartum hemorrhage in vaginal deliveries in a Latin-American population. Obstet Gynecol 2009;113:1313–1319. 7. James AH, Paglia MJ, Gernsheimer T, et al. Blood component therapy in postpartum hemorrhage. Transfusion 2009;49:2430–2433. 8. Al-Zirqi I, Vangen S, Forsen L, et al. Prevalence and risk factors of severe obstetric haemorrhage. BJOG 2008;115:1265–1272. 9. Bateman BT, Berman MF, Riley LE, et al. The epidemiology of postpartum hemorrhage in a large, nationwide sample of deliveries. Anesth Analg 2010;110:1368–1373. 10. Lenox C, Marr L. Scottish Confidential Audit of Severe Maternal Morbidity, 7th Annual Report. Edinburgh; 2011. pp 1–42. 11. Abenhaim HA, Azoulay L, Kramer MS, et al. Incidence and risk factors of amniotic fluid embolisms: A population-based study on 3 million births in the United States. Am J Obstet Gynecol 2008;199:49 e41–e48. 12. Grotegut CA, Paglia MJ, Johnson LN, et al. Oxytocin exposure during labor among women with postpartum hemorrhage secondary to uterine atony. Am J Obstet Gynecol 2011;204:56 e51–e56. 13. Rouse DJ, MacPherson C, Landon M, et al. Blood transfusion and cesarean delivery. Obstet Gynecol 2006;108:891–897. 14. Jolly M, Sebire N, Harris J, et al. The risks associated with pregnancy in women aged 35 years or older. Hum Reprod 2000;15:2433–2437. 15. Combs CA, Murphy EL, Laros RK Jr. Factors associated with hemorrhage in cesarean deliveries. Obstet Gynecol 1991;77:77–82. 16. Sebire NJ, Jolly M, Harris JP, et al. Maternal obesity and pregnancy outcome: A study of 287,213 pregnancies in London. Int J Obes Relat Metab Disord 2001;25:1175–1182. 17. Paglia MJ, Grotegut CA, Johnson LN, Thames B, James AH. Body mass index and severe postpartum hemorrhage. Gynecol Obstet Invest 2012;73:70–74. 18. Smrtka M, Thames BH, Beckman M, et al. Obesity Increases Fibrinogen Levels in Pregnancy. Boston, MA: International Society on Haemostasis and Thrombosis; 2009. 19. James AH. More than menorrhagia: A review of the obstetric and gynaecological manifestations of bleeding disorders. Haemophilia 2005;11:295–307. 20. James AH, Jamison MG. Bleeding events and other complications during pregnancy and childbirth in women with von Willebrand disease. J Thromb Haemost 2007;5:1165–1169. 21. Chauleur C, Cochery-Nouvellon E, Mercier E, et al. Some hemostasis variables at the end of the population distributions are risk factors for severe postpartum hemorrhages. J Thromb Haemost 2008;6:2067–2074. 22. Owolabi AT, Dare FO, Fasubaa OB, et al. Risk factors for retained placenta in southwestern Nigeria. Singapore Med J 2008;49:532–537. 23. Agwu UM, Umeora OU, Ejikeme BN, et al. Retained placenta aspect of clinical management in a tertiary health institution in Nigeria. Niger J Med 2008;17:146–149. 24. Selo-Ojeme DO, Okonofua FE. Risk factors for primary postpartum haemorrhage. A case control study. Arch Gynecol Obstet 1997;259:179–187. 25. Combs CA, Murphy EL, Laros RK Jr. Factors associated with postpartum hemorrhage with vaginal birth. Obstet Gynecol 1991;77:69–76. 26. Borthen I, Eide MG, Daltveit AK, et al. Obstetric outcome in women with epilepsy: A hospital-based, retrospective study. BJOG 2011;118:956–965. 27. Eller AG, Bennett MA, Sharshiner M, et al. Maternal morbidity in cases of placenta accreta managed by a multidisciplinary care team compared with standard obstetric care. Obstet Gynecol 2011;117:331–337. 28. Doumouchtsis SK, Papageorghiou AT, Arulkumaran S. Systematic review of conservative management of postpartum hemorrhage: What to do when medical treatment fails. Obstet Gynecol Surv 2007;62:540–547. 29. Rossi AC, Lee RH, Chmait RH. Emergency postpartum hysterectomy for uncontrolled postpartum bleeding: A systematic review. Obstet Gynecol 2010;115:637–644. 30. Knight M. Peripartum hysterectomy in the UK: Management and outcomes of the associated haemorrhage. BJOG 2007;114:1380–1387. 31. Cotton BA, Guy JS, Morris JA Jr., et al. The cellular, metabolic, and systemic consequences of aggressive fluid resuscitation strategies. Shock 2006;26:115–121. 32. Bick RL. Disseminated intravascular coagulation: A review of etiology, pathophysiology, diagnosis, and management: Guidelines for care. Clin Appl Thromb Hemost 2002;8:1–31. 33. Thachil J, Toh CH. Disseminated intravascular coagulation in obstetric disorders and its acute haematological management. Blood Rev 2009;23:167–176. 34. Sher G. Pathogenesis and management of uterine inertia complicating abruptio placentae with consumption coagulopathy. Am J Obstet Gynecol 1977;129:164–170. 35. Watson GA, Sperry JL, Rosengart MR, et al. Fresh frozen plasma is independently associated with a higher risk of multiple organ failure and acute

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36.

37.

38.

39.

40.

41.

42. 43.

44.

45.

46.

47. 48.

49.

50.

51. 52.

53.

54.

55. 56.

57.

58.

59.

60.

61.

62.

63. 64. 65.

respiratory distress syndrome. J Trauma 2009;67:221–227; discussion 228– 230. Kashuk JL, Moore EE, Johnson JL, et al. Postinjury life threatening coagulopathy: Is 1:1 fresh frozen plasma:packed red blood cells the answer? J Trauma 2008;65:261–270; discussion 270–261. Stinger HK, Spinella PC, Perkins JG, 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;64:S79–S85; discussion S85. Borgman MA, Spinella PC, Perkins JG, et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma 2007;63:805–813. Stansbury LG, Dutton RP, Stein DM, et al. Controversy in trauma resuscitation: Do ratios of plasma to red blood cells matter? Transfus Med Rev 2009;23:255–265. Perkins JG, Cap AP, Spinella PC, et al. An evaluation of the impact of apheresis platelets used in the setting of massively transfused trauma patients. J Trauma 2009;66:S77–S84; discussion S84–75. Shaz BH, Dente CJ, Nicholas J, et al. Increased number of coagulation products in relationship to red blood cell products transfused improves mortality in trauma patients. Transfusion 2010;50:493–500. Goodnough LT, Daniels K, Wong AE, et al. How we treat: Transfusion medicine support of obstetric services. Transfusion 2011;51:2540–2548. Burtelow M, Riley E, Druzin M, et al. How we treat: Management of lifethreatening primary postpartum hemorrhage with a standardized massive transfusion protocol. Transfusion 2007;47:1564–1572. Bingham D, Lyndon A, Lagrew D, et al. A state-wide obstetric hemorrhage quality improvement initiative. MCN Am J Matern Child Nurs 2011;36: 297–304. Lagrew D, Lyndon A, Main EK. Obstetric Hemorrhage Toolkit: Improving Health Care Response to Obstetric Hemorrhage. California Maternal Quality Care Collaborative website. 2011. Charbit B, Mandelbrot L, Samain E, et al. The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage. J Thromb Haemost 2007;5:266–273. Szecsi PB, Jorgensen M, Klajnbard A, et al. Haemostatic reference intervals in pregnancy. Thromb Haemost 2010;103:718–727. Hiippala ST, Myllyla GJ, Vahtera EM. Hemostatic factors and replacement of major blood loss with plasma-poor red cell concentrates. Anesth Analg 1995;81:360–365. Francois KE, Foley MR.Antepartum and postpartum hemorrhage. In:Gabbe S,Niebyl J,Simpson J, editors. Obstetrics: Normal and Problem Pregnancies,5th ed. Philadelphia, PA: Churchill Livingstone Elsevier; 2007. pp 456–485. Ciavarella D, Reed RL, Counts RB, et al. Clotting factor levels and the risk of diffuse microvascular bleeding in the massively transfused patient. Br J Haematol 1987;67:365–368. Murray DJ, Olson J, Strauss R, et al. Coagulation changes during packed red cell replacement of major blood loss. Anesthesiology 1988;69:839–845. Bolliger D, Szlam F, Molinaro RJ, et al. Finding the optimal concentration range for fibrinogen replacement after severe haemodilution: An in vitro model. Br J Anaesth 2009;102:793–799. Bell SF, Rayment R, Collins PW, et al. The use of fibrinogen concentrate to correct hypofibrinogenaemia rapidly during obstetric haemorrhage. Int J Obstet Anesth 2010;19:218–223. Fenger-Eriksen C, Lindberg-Larsen M, Christensen AQ, et al. Fibrinogen concentrate substitution therapy in patients with massive haemorrhage and low plasma fibrinogen concentrations. Br J Anaesth 2008;101:769–773. Glover NJ, Collis RE, Collins P. Fibrinogen concentrate use during major obstetric haemorrhage. Anaesthesia 2010;65:1229–1230. Thorarinsdottir HR, Sigurbjornsson FT, Hreinsson K, et al. Effects of fibrinogen concentrate administration during severe hemorrhage. Acta Anaesthesiol Scand 2010;54:1077–1082. Fibrinogen Concentrate as Initial Treatment for Postpartum Haemorrhage: A Randomised Clinically Controlled Trial (FIB-PPH). In: Clinical Trials.gov, editor: US National Institute of Health; 2012. Phillips LE, McLintock C, Pollock W, et al. Recombinant activated factor VII in obstetric hemorrhage: Experiences from the Australian and New Zealand Haemostasis Registry. Anesth Analg 2009;109:1908–1915. Alfirevic Z, Elbourne D, Pavord S, et al. Use of recombinant activated factor VII in primary postpartum hemorrhage: The Northern European registry 2000–2004. Obstet Gynecol 2007;110:1270–1278. James AH, Jamison MG, Brancazio LR, et al. Venous thromboembolism during pregnancy and the postpartum period: Incidence, risk factors, and mortality. Am J Obstet Gynecol 2006;194:1311–1315. Meng ZH, Wolberg AS, Monroe DM III, et al. The effect of temperature and pH on the activity of factor VIIa: Implications for the efficacy of high-dose factor VIIa in hypothermic and acidotic patients. J Trauma 2003;55:886–891. Welsh A, McLintock C, Gatt S, et al. Guidelines for the use of recombinant activated factor VII in massive obstetric haemorrhage. Aust N Z J Obstet Gynaecol 2008;48:12–16. Novikova N, Hofmeyr GJ. Tranexamic acid for preventing postpartum haemorrhage. Cochrane Database Syst Rev 2010:CD007872. Ducloy-Bouthors AS, Jude B, Duhamel A, et al. High-dose tranexamic acid reduces blood loss in postpartum haemorrhage. Crit Care 2011;15:R117. World Maternal Antibrinolytic Trial (WOMAN). In: Trials.gov C, editor: US National Institutes of Health; 2012.

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THSNA meeting proceedings 66. Johansson PI, Stissing T, Bochsen L, et al. Thrombelastography and tromboelastometry in assessing coagulopathy in trauma. Scand J Trauma Resusc Emerg Med 2009;17:45. 67. Levrat A, Gros A, Rugeri L, et al. Evaluation of rotation thrombelastography for the diagnosis of hyperfibrinolysis in trauma patients. Br J Anaesth 2008;100:792–797. 68. Huissoud C, Carrabin N, Audibert F, et al. Bedside assessment of fibrinogen level in postpartum haemorrhage by thrombelastometry. BJOG 2009;116: 1097–1102.

S22

69. Danilenko-Dixon DR, Heit JA, Silverstein MD, et al. Risk factors for deep vein thrombosis and pulmonary embolism during pregnancy or post partum: A population-based, case-control study. Am J Obstet Gynecol 2001;184: 104–110. 70. James AH, Bushnell CD, Jamison MG, et al. Incidence and risk factors for stroke in pregnancy and the puerperium. Obstet Gynecol 2005;106:509–516. 71. James AH, Jamison MG, Biswas MS, et al. Acute myocardial infarction in pregnancy: A United States population-based study. Circulation 2006;113: 1564–1571. Epub 2006 Mar 1513.

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