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An update on the management of bleeding disorders during pregnancy

Kouides, Peter A.

doi: 10.1097/MOH.0000000000000167
HEMOSTASIS AND THROMBOSIS: Edited by Joseph E. Italiano and Jorge A. Di Paola

Purpose of review The morbidity and mortality of postpartum hemorrhage (PPH) in women with an underlying bleeding disorder requires vigilance by the hematologist.

Recent findings Recent studies suggest that women with underlying bleeding disorders may be ‘undertreated’ at the time of delivery in aiming for too low a target elevation that historically per numerous society guidelines has aimed for VWF/FVIII:C levels to be ‘only’ greater than 50% when in actuality the levels should be akin to what is achieved in a normal pregnancy. The result appears to be an increase in the rate and degree of PPH. In this context, although recent studies imply DDAVP is well tolerated, DDAVP may not be appropriate because it may not raise the levels into the normal supraphysiological range nor maintain it for several days. Particularly in women with rare bleeding disorders, i.e., non-FVIII:C or VWF deficient, adjunctive antifibrinolytic therapy, e.g., tranexamic acid, appears to be in order as a prophylactic measure.

Summary Women with an underlying bleeding disorder appear to be at a heightened risk for PPH if the respective coagulation factor level is not appropriately replaced to the level that is physiologically achieved in a normal pregnancy. Furthermore, there appears to be underuse of tranexamic acid for prophylaxis of PPH in this population.

Mary M. Gooley Hemophilia Center, Inc.

University of Rochester School of Medicine, Rochester, New York, USA

Correspondence to Peter A. Kouides, MD, Rochester General Hospital, 1425 Portland Avenue, Rochester, NY 14621, USA. Tel: +1 585 922 4020; fax: +1 585 563 1832; e-mail:

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Women with an inherited bleeding disorder can have a relatively stable clinical course as there are numerous hemostatic and gynecological options in managing heavy menses with subsequent improvement in quality of life. The care of these patients can, however, be very challenging at the time of childbirth when the underlying coagulopathy precludes the normal supra-physiological compensatory rise that is protective for postpartum hemorrhage (PPH). This review will focus on recent epidemiological and treatment studies in pregnant women with an underlying inherited bleeding disorder.

Box 1

Box 1

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The procoagulant, ‘protective’ state of pregnancy

Near delivery, the VWF antigen (VWF:AG) and VWF ristocetin cofactor (VWF:RCo) activity peak in the 225–250% range [1]. Szecsi et al.[2] reported that the factor VIII activity at 38–42 weeks was 130–430% (2.5th and 97.5th percentiles) (n = 73) compared with 82–291% (n-129) at 13–20-week gestation.

In the past 3 years, several studies have focused on the rate of fall of the FVIII:C and VWF levels postpartum. Huq et al.[3] carried out a prospective study assessing FVIII:C activity, VWF activity, and antigen levels in 95 women (with singleton uncomplicated pregnancies) during labor and postpartum on days 1, 2, and 3. They reported no significant differences in FVIII:C, VWF:Ag, and VWF:collagen binding activity on days 1 and 2 compared with levels during labor. There was a significant decrease in VWF:Ag (P = 0.009) and VWF:collagen binding (P = 0.04) on day 3 (Fig. 1a). Age, ethnicity, duration of labor, and mode of delivery did not have any significant effect on the changes in FVIII:C and VWF levels. Most recently, James et al.[4▪] not only studied comprehensively the rate of fall of FVIII:C and VWF levels postpartum in normal pregnant women but also in pregnant von Willebrand disease (VWD) patients. Patients were matched by race and age. In this prospective observational cohort study, VWF:RCo, VWF:Ag, and FVIII:C levels were obtained in the third trimester of pregnancy, on admission for childbirth, and 10 times postpartum over 6 weeks! Forty women (40 pregnancies) without VWD and 32 women (35 pregnancies) with well documented VWD were enrolled. A total of 15/32 with VWD were treated (30% of those with type 1 and all of those with type 2) in 17 pregnancies. The VWF levels peaked at 250% of baseline at 4 h postpartum in women with VWD and 12 h postpartum in women without VWD. Thereafter, VWF levels fell rapidly, approached baseline at 1 week, and reached baseline at 3 weeks (Fig. 1b). Interestingly, the FVIII:C level fell 20% at 24 h postpartum (perhaps because of consumption) and then rose 30% to a peak the next day (day 3 postpartum). Except immediately postpartum, when the levels among treated patients were higher, levels among women with VWD appeared to parallel, but were lower than those among women without VWD. Interestingly, and to be discussed further in this review, levels were lowest among those who received treatment and this subgroup unlike the untreated type 1 VWD patients had a significantly increased estimated blood loss compared with the control group [4▪].



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The hemorrhagic postpartum state of inherited bleeding disorders

Furthermore, the clinician should be aware that not only may an underlying bleeding disorder be a cause of PPH but that there are additional causes that in general are more common, as outlined in Table 1. A recent novel approach using a candidate gene approach showed a significant association with PPH in a general population of women with PPH of the promoter polymorphism of the tissue factor gene (F3-603A > G) with the G allele exerting a protective effect (P = 0.00053; OR = 0.79, 95% confidence interval (CI) = 0.69–0.90). The authors conclude that the protective effect against PPH of the TF-603A>G polymorphism is biologically plausible as the G allele is associated with an increased protein expression and tissue factor is strongly represented in the placenta at term, particularly in decidual cells of maternal origin [5▪]. This study is a reminder that PPH is ultimately a multifactorial process as outlined in Table 1, with future studies likely to reveal additional genetic polymorphisms that perhaps coupled with clinical risk factors and underlying inherited bleeding disorders result in major PPH.

Table 1

Table 1

These risks notwithstanding, not surprisingly, given the inability of the inherited bleeding disorder patient to mount as high a supraphysiological rise in the coagulation levels peri-partum, historically a higher rate of PPH in women with primarily type 1 VWD of 16–29% [6–8] vs. 3–5% in the general population has been reported, in the first 24 h following delivery. Also, there appears to be a higher rate in type 2, 3 patients compared with type 1 patients [6,8,9]. These studies are from European and US centers and raise the question of whether similar outcomes are seen in non-Western countries. A recent retrospective single center study of 100 Iranian women with inherited bleeding disorders by Shahbazzi et al.[10] also reported an increased rate of PPH. Primary PPH was noted in 47.7% of hemophilia carriers, 32.1% of VWD patients, and 44.0% of patients with rare bleeding disorders compared with 7.5% in the control group of 200 women. Five percent of the patients required a red blood cell transfusion. Secondary PPH (defined as prolonged bleeding beyond 24 h postpartum up to 6 weeks) was noted in 55.3% of hemophilia carriers, 28.6% of VWD patients, and 41.6% of patients with rare bleeding disorders compared with 12.6% in the control group [10].

These retrospective, single institution studies have, however, an inherent selection bias, whereas population-based studies have reported a lower rate of PPH [11]. Regarding the latter, one such study is an analysis of the United States Nationwide Inpatient Sample involving 4067 deliveries among women with VWD (1 in 4000 deliveries). James and Jamison [11] observed that women with VWD were more likely to experience a postpartum hemorrhage (OR, 1.5; 95% CI: 1.1–2.0), and had a five-fold increased risk of being transfused (OR, 4.7; 95% CI: 3.2–7.0). A more recent case–control study from Aberdeen, UK analyzed a total of 62 deliveries in 33 women with VWD compared with controls matched for age, year of delivery, and parity [12]. Primary PPH was reported in 12/62 (19.4%) deliveries in women with VWD and 16/124 (12.9%) controls. The unadjusted odds ratio (OR) for VWD as a risk factor for PPH was 1.62 (95% CI 0.75–3.49, P = 0.22). After adjustment for other risk factors for PPH, the OR for VWD as a risk factor for PPH was 1.31 (95% CI 0.48–3.60, P = 0.60). PPH was observed in 7/24 (29%) deliveries in women known prepregnancy to have VWD. The unadjusted odds for VWD as a risk factor for PPH in this group was significantly greater than the control group (OR 2.78 (95% CI 1.03–7.49), P = 0.043) and remained significant after adjusting for other significant risk factors (OR 3.41 (95% CI 1.07–10.9), P = 0.038). The authors concluded that VWD in itself may not be a significant risk factor for PPH; however, women known to have VWD predelivery may represent an at-risk subgroup consistent with the James and Jamison study [13].

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For an overview, see Fig. 2.



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von Willebrand disease and hemophilia carriers

The use of desmopressin

In cases in which the VWF and or FVIII:C levels have not normalized by the time of active labor, there may be a tight correlation between certain genotypes and biological responsiveness to DDAVP and the risk of postpartum bleeding [14]. Historically, for women whose levels have not exceeded 50%, there are, however, theoretical concerns for administering DDAVP prepartum for the following reasons:

  1. vaso-constrictive effect leading to decreased placental flow,
  2. risk of premature labor as desmopressin has weak V2 receptor activity,
  3. risk of neonatal hyponatremia.

A systematic review of 30 studies of the use of DDAVP for treatment and prophylaxis of bleeding disorders in pregnancy, however, further confirmed its efficacy and safety [15]. They did collect two cases of symptomatic hyponatremia postpartum in 172 pregnancies. Only 5 of 172 patients (3%) of peripartum use were associated with adverse bleeding in two patients with Hermansky Pudlak Syndrome, one case of Ehler Danos, one case of storage pool deficiency, and one case of VWD. This review also included 51 patients in the first or second trimester with no reports of toxicity or adverse bleeding [15]. Most reports have not systematically recorded postpartum sodium levels after administration. Recently in nonpregnant patients, hyponatremia 130 meq/l or less was noted at a relatively high rate of 11% (11/107; 95% CI 5–16%) after a preoperative dose [16▪]. Consequently, caution must be exercised when administering DDAVP peri-partum and to be discussed below factor replacement may be preferable in VWD and hemophilia A in achieving a higher physiological target level noted in normal pregnant patients postpartum.

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Replacement therapy in von Willebrand disease or in hemophilia carriers

Numerous societies and national organizations have developed guidelines as outlined in Table 2[17–19,20▪]. They all consistently state that in the third trimester, the respective level (VWF, FVIII:C) must be greater than 50% to both permit safely epidural analgesia but also to prevent PPH. In those patients who are not desmopressin (DDAVP) responsive, however, which is essentially most patients who by the third trimester do not have a factor VIII or VWF level greater than 50%, specific guidance is lacking in terms of how high a level should be achieved and for how long. Specifically, guidance is lacking on whether a level in the 150–200% range should be targeted with replacement therapy; a range in which levels typically are achieved during a normal pregnancy [1,2,21] as reviewed earlier in this monograph. Furthermore, as noted, VWF levels both in normal patients [3] and VWD patients [4▪] can fall rapidly approaching baseline in 1 week and reach baseline at 3 weeks. In addition, the various present guidelines by and large do not state how long replacement therapy should be given. Some groups also state that delivery should be managed at a tertiary center [18,20▪]. None of the groups specifically advises prophylactic antifibrinolytic therapy postpartum even though bleeding can occur up to 4–6 weeks.

Table 2

Table 2

The national guidelines in The Netherlands have not been that different from other societies advising a target level of 100% level and then a follow-up dose of half the first dose 24 h later. They also advise consultation at a center of specialized care, in other words a Hemophilia Treatment Center, but they do not advise specifically that the delivery be carried out at that specialized center but rather the advisements from that consultation be carried out [22▪▪]. Published his year, Stoof et al.[22▪▪], on behalf of three hemophilia treatment centers in The Netherlands, assessed by retrospective study whether such advisement indeed translates to a normal delivery without excessive PPH. The authors reviewed records of 185 deliveries in 154 women with either previously documented VWD or hemophilia carriership that delivered over a 9-year period. The main endpoint was primary PPH that they defined 500 ml within 24 h postpartum and severe PPH as blood loss at least 1000 ml. Approximately a third of the deliveries were associated with primary PPH and approximately a third of those patients had severe PPH. The authors noted an inverse relationship between the incidence of PPH and third trimester factor levels.

These results are quite provocative, consistent with the results of James et al. [4▪] already mentioned. In that study, the mean estimated blood loss (EBL) at delivery for treated women was 615 ml (473, 758), which was significantly greater than the mean for other women whose mean EBL was 448 ml (379, 517) (P < 0.05). In essence, these women were undertreated [4▪]. In that study, all the patients had VWD, but in the Stoof et al. study, some of these women were hemophilia carriers. Interestingly, PPH was noted in that cohort also in 35 of 114 (31%) pregnancies. In the 14 pregnancies with severe PPH, half had VWD and the remaining half were carriers; five of seven of the carriers had hemophilia A. In the hemophilia B carriers, the third trimester factor IX level, respectively, was 17% and 75% and for the hemophilia A carriers, third trimester factor VIII levels were available on four of five and were 112–165% with the respective nonpregnant factor VIII levels being 50–136%. It is fascinating that there was still severe PPH in these carriers despite the levels being at least 50%. It is possible that these patients are not able to ‘mount’ a level that in normal patients would be protective for hemorrhage. Indirect evidence includes studies in carriers with prolonged bleeding and morbidity with procedures [23,24▪] as well as decreased range of motion and magnetic resonance imaging evidence of joint damage [25] and decreased quality of life despite levels above 40% [26].

Stoof et al.'s study is noteworthy in questioning the ‘status quo’ that specialized care is effective, that a postpartum postreplacement factor VIII level of 100% is adequate, that administration of half the initial dose as follow-up treatment is adequate, and that the obstetric care of hemophilia carriers does not require consideration for aggressive replacement therapy. These results are definitely hypothesis generating, but the clinical researcher in this field must consider several limitations of the Stoof et al. study – the study design was retrospective, there was seemingly a high rate of induction of labor of 34% (though it should be pointed out that induction of labor is not a standard procedure in women with bleeding disorders nor is advised in the Dutch national guidelines), and there were 42 patients without information. Nonetheless, their study is provocative given the high rate of PPH despite treatment. These results should compel one to consider using concurrent antifibrinolytic agent therapy [27▪] and/or double utertonics (oxytocin + misoprostol) [28▪] and/or aiming for a higher trough factor level closer to 200% then 100% and maintaining such a level for several days postpartum (with the implications, for better or worse, being the need to transfer women to specialized centers capable to do on site factor levels). One could also argue that desmopressin should not be used at the time of active labor even apart from the practical concern of inducing hyponatremia as it may not dependably raise the factor level in the physiologic range nor of course maintain it for several days.

Recently, a case of severe hemophilia (0.9%) managed successfully in two pregnancies was reported beginning prophylaxis with recombinant FVIII:C 2 × week 40 u/kg with trough of 7% followed by immediate postpartum infusions to target FVIII:C more than 100% followed by prophylaxis × 6 weeks postpartum initially 25 U/kg every 12 h days 2–5 then daily days 6–14 then every other day until week 6 [29].

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Antifibrinolytic therapy in women with underlying bleeding disorders

As mentioned in the preceding section, antifibrinolytic therapy can be an option for the prevention and control of PPH on the basis of the observation that at the time of delivery, the synthesis of plasminogen activator inhibitor-2 ceases with concurrent elevation of tissue plasminogen activator leading to subsequent fibrin and fibrinogen degradation [30]. Unfortunately, there have not been any randomized control trials of tranexamic acid for the prevention or treatment of tranexamic acid in women with underlying inherited bleeding disorders [31]. One has to extrapolate from studies in pregnant women without an underlying bleeding disorder. A very recent systematic review summarized evidence from randomized controlled trials of 0.5–1.0 g of tranexamic acid intravenously for the prevention of PPH after cesarean section (n = 10) and vaginal deliveries (n = 2) in nonbleeding disorder patients [27▪]. Overall, there was a statistically significant reduction in postpartum blood loss by approximately 20–40%. There were no significant adverse events such as venous thromboembolism (VTE). Regarding the use of tranexamic acid for active PPH, there are fewer published data. In the most robust trial to date, the EXADELI trial, a French group randomly assigned 144 women with PPH at least 800 ml following vaginal delivery to high dose tranexamic acid comprised of a loading dose of 4 g over 1 h and then an infusion of 1 g/h × 6 h or not. There was a 22% reduction in subsequent blood loss, shorter duration of bleeding, and reduced red cell transfusion requirement. There were no major adverse events such as VTE [32]. An ongoing international study double-blind placebo-controlled randomized control trial, the ‘WOMAN’ study with a target accrual of 15 000, should be adequately powered not only for efficacy but also for severe maternal morbidity (hysterectomy, VTE) and maternal death [33].

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Rare bleeding disorders

Table 3 lists the excellent recommendations of the 2014 United Kingdom Haemophilia Centre Doctor's Organization guidelines for pregnancy management of rare bleeding disorders [34▪▪]. As a general measure, the guidelines advise intravenous tranexamic acid at least 2 h before active labor or cesarean section. They advise caution in combination with prothrombin complex concentrates as given for FX deficiency because of potential VTE risk [34▪▪].

Table 3

Table 3

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The care and research of the pregnant patient with an underlying bleeding disorder remains quite challenging because of the lack of adequate data currently in deciding whether such a patient should be aggressively replaced to a factor level normally achieved physiologically in normals. Furthermore, data are needed regarding the optimal dose and duration and schedule of factor replacement in RBDs. Specific study of tranexamic acid as an adjunctive treatment particularly in the RBDs is in order. Despite these challenges, the pregnant patient with an underlying bleeding disorder can benefit from the multidisciplinary model [28▪] of the hematologist, nurse, obstetrician, and anesthesiologist.

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The author thanks the staff of the Mary M. Gooley Hemophilia Center that fosters a very productive environment for the clinical care and research of women with bleeding disorders.

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Financial support and sponsorship


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Conflicts of interest

Dr P.A.K. receives an honorarium for consulting from CSL Behring Inc. that he donates to the Mary M. Gooley Hemophilia Center. CSL Behring Inc. markets intranasal DDAVP and manufactures Humate-P. He also receives an honorarium for consulting from Baxter Inc. Baxter Inc. is developing a recombinant von Willebrand factor product.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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1. Clark P, Brennand J, Conkie JA, et al. Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy. Thromb Haemost 1998; 79:1166–1170.
2. Szecsi PB, Jorgensen M, Klajnbard A, et al. Haemostatic reference intervals in pregnancy. Thromb Haemost 2010; 103:718–727.
3. Huq FY, Kulkarni A, Agbim EC, et al. Changes in the levels of factor VIII and von Willebrand factor in the puerperium. Haemophilia 2012; 18:241–245.
4▪. James AH, Konkle BA, Kouides P, et al. Postpartum von Willebrand factor levels in women with and without von Willebrand disease and implications for prophylaxis. Haemophilia 2015; 21:81–87.

An extensive study of the VWF levels in VWD patients compared with controls. There is also the additional interesting finding that the VWD patients were ‘undertreated’ resulting in a higher degree of PPH.

5▪. Biguzzi E, Franchi F, Acaia B, et al. Genetic background and risk of postpartum haemorrhage: results from an Italian cohort of 3219 women. Haemophilia 2014; 20:e377–e383.

A very interesting study using genome analysis to uncover further markers of PPH, the future is here now!

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12. Chee YL, Townend J, Crowther M, et al. Assessment of von Willebrand disease as a risk factor for primary postpartum haemorrhage. Haemophilia 2012; 18:593–597.
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16▪. Sharma R, Stein D. Hyponatremia after desmopressin (DDAVP) use in pediatric patients with bleeding disorders undergoing surgeries. J Pediatr Hematol Oncol 2014; 36:e371–e375.

A single institution study that is concerning for the clinician using DDAVP!

17. Demers C, Derzko C, David M, Douglas J. Gynaecological and obstetric management of women with inherited bleeding disorders. J Obstet Gynaecol Can 2005; 27:707–732.
18. Nichols WL, Hultin MB, James AH, et al. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA)1. Haemophilia 2008; 14:171–232.
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20▪. Laffan MA, Lester W, O’Donnell JS, et al. The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol 2014; 167:453–465.

Includes recommendations for managing pregnancy in VWD patients.

21. Sanchez-Luceros A, Meschengieser SS, Marchese C, et al. Factor VIII and von Willebrand factor changes during normal pregnancy and puerperium. Blood Coagul Fibrinolysis 2003; 14:647–651.
22▪▪. Stoof CM, van Steenbergen HW, Zwagemaker A, et al. Primary postpartum haemorrhage in women with von Willebrand disease or carriership of haemophilia despite specialised care: a retrospective study. Haemophilia 2015; [Epub ahead of print].

Very provocative study strongly suggesting that we are ‘undertreating’ our patients with known bleeding disorder upon prophylaxis for PPH.

23. Plug I, Mauser-Bunschoten EP, Brocker-Vriends AH, et al. Bleeding in carriers of hemophilia. Blood 2006; 108:52–56.
24▪. Paroskie A, Gailani D, Debaun MR, Sidonio RF Jr. A cross-sectional study of bleeding phenotype in haemophilia A carriers. Br J Haematol 2015; [Epub ahead of print].

Very enlightening study regarding the increased bleeding that has not usually been attributed to hemophilia carriers including obstetrical bleeding.

25. Gilbert L, Rollins L, Hilmes M, et al. Haemophilia A carriers demonstrate pathological and radiological evidence of structural joint changes. Haemophilia 2014; 20:e426–e429.
26. Gilbert L, Paroskie A, Galiani DDM, Sidonio RF. Hemophilia A carriers experience reduced health-related quality of life. Haemophilia 2015; [Epub ahead of print].
27▪. Sentilhes L, Lasocki S, Ducloy-Bouthors AS, et al. Tranexamic acid for the prevention and treatment of postpartum haemorrhage. Br J Anaesth 2015; 114:579–587.

A very well written review of tranexamic acid for the prevention and treatment of PPH in general in pregnant women.

28▪. Abdul-Kadir R, McLintock C, Ducloy AS, et al. Evaluation and management of postpartum hemorrhage: consensus from an international expert panel. Transfusion 2014; 54:1756–1768.

State-of-the-art review and guidelines of the prophylaxis and management of PPH in both normal pregnant women and women with the underlying bleeding disorder.

29. Sharma V, Khalid A, Cohen AJ. Management of pregnancy in a patient with severe hemophilia type a. AJP Rep 2013; 3:29–32.
30. Tengborn L, Blomback M, Berntorp E. Tranexamic acid: an old drug still going strong and making a revival. Thromb Res 2015; 135:231–242.
31. Kadir RA, Davies J, Winikoff R, et al. Pregnancy complications and obstetric care in women with inherited bleeding disorders. Haemophilia 2013; 19 (Suppl 4):1–10.
32. Ducloy-Bouthors AS, Jude B, Duhamel A, et al. High-dose tranexamic acid reduces blood loss in postpartum haemorrhage. Crit Care 2011; 15:R117.
33. Shakur H, Elbourne D, Gulmezoglu M, et al. The WOMAN Trial (World Maternal Antifibrinolytic Trial): tranexamic acid for the treatment of postpartum haemorrhage: an international randomised, double blind placebo controlled trial. Trials 2010; 11:40.
34▪▪. Mumford AD, Ackroyd S, Alikhan R, et al. Guideline for the diagnosis and management of the rare coagulation disorders: a United Kingdom Haemophilia Centre Doctors’ Organization guideline on behalf of the British Committee for Standards in Haematology. Br J Haematol 2014; 167:304–326.

bleeding disorders; postpartum hemorrhage; pregnancy; thrombocytopathy; von Willebrand disease

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