Shintaro Makino 1,2, Satoru Takeda 1,2, Takao Kobayashi 1,3,MakiMurakami 1,4, Takahiko Kubo 1,5, Toshiyuki Hata 1,6 and Hideaki Masuzaki 1,7.

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1 doi: /jog J. Obstet. Gynaecol. Res. Vol. 41, No. 8: , August 2015 National survey of fibrinogen concentrate usage for postpartum hemorrhage in Japan: Investigated by the Perinatology Committee, Japan Society of Obstetrics and Gynecology Shintaro Makino 1,2, Satoru Takeda 1,2, Takao Kobayashi 1,3,MakiMurakami 1,4, Takahiko Kubo 1,5, Toshiyuki Hata 1,6 and Hideaki Masuzaki 1,7 1 Perinatology Committee, Japan Society of Obstetrics & Gynecology 2 Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo 3 Department of Obstetrics and Gynecology, Hamamatsu Medical Center, Shizuoka 4 Department of Obstetrics and Gynecology, Aiwa Hospital, Saitama 5 Division of Obstetrics, Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Tokyo 6 Department of Perinatology and Gynecology, Kagawa University Graduate School of Medicine, Kagawa and 7 Department of Obstetrics and Gynecology, Nagasaki University Faculty of Medicine, Nagasaki, Japan Abstract Aim: The aim of this study was to provide basic documents applicable to studying the usefulness of administering fibrinogen concentrate to patients with massive post-partum hemorrhage. We investigated the usage of fibrinogen concentrate at training institutions for specialist physicians of the Japan Society of Obstetrics and Gynecology. Material and Methods: The subjects were women who required fibrinogen concentrate for hemostasis of postpartum hemorrhage during the period between April 2008 and March The underlying diseases, obstetric disseminated intravascular coagulation scores, blood loss, amount of blood transfusion, dose of fibrinogen concentrate administered, and plasma fibrinogen levels before and after the administration of fibrinogen concentrate were retrospectively investigated. Results: Ninety-nine (98.0%) patients survived and two died after taking fibrinogen concentrate. Of the surviving 99 cases, the average amount of blood loss at the time of initial fibrinogen administration and total blood loss was 3559 ± 2103 ml and 4562 ± 3198 ml, respectively. The dose per administration was 3 g, and the plasma fibrinogen level before the initial administration of fibrinogen concentrate was 70.5 mg/dl, thereafter increasing to mg/dl. The increase in the fibrinogen level was 32.9 mg/dl/g of fibrinogen concentrate. It was less than 150 mg/dl after the first administration of fibrinogen concentrate only in patients with amniotic fluid embolism and patients with atonic bleeding showed the smallest increase in fibrinogen per gram of fibrinogen concentrate. No adverse events, including thromboembolism, were reported. Conclusion: The results indicated the increase in blood fibrinogen levels to, on occasion, be insufficient even with fibrinogen concentrate use; however, this survey may support the safety and usefulness of fibrinogen concentrate for PPH. Key words: disseminated intravascular coagulation, fibrinogen concentrate, fibrinogen level, national survey, post-partum hemorrhage. Received: December Accepted: February Reprint request to: Dr Shintaro Makino, Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Hongo Bunkyo-ku, Tokyo , Japan. shintaro@juntendo.ac.jp 1155

2 S. Makino et al. Introduction A massive obstetric hemorrhage is responsible for 28% of the estimated maternal deaths in Japan. 1 Post-partum hemorrhage (PPH) occurs unexpectedly and can result in massive blood loss, often progressing to secondary atonic bleeding and rapid onset of disseminated intravascular coagulation (DIC). Massive blood loss induces not only dilutional coagulopathy but also consumptive coagulopathy leading to DIC promptly in cases with abruptio placenta, amniotic fluid embolism, severe pregnancy-induced hypertension, HELLP syndrome, and dead fetus syndrome. 2 Therefore, in the event of massive blood loss, it is essential to confirm the bleeding point and perform appropriate hemostasis procedures, as well as to consider blood transfusion timing by ascertaining the cause of hemorrhage and the general condition of the patient. Plasma fibrinogen levels may become critically low relatively early during delivery and the post-parturition period. 3 The fibrinogen plasma level was identified as the only early independent predictor of the subsequent development of severe PPH. A fibrinogen level of below 2 g/l implied a positive predictive value of 100% for the development of severe PPH. 4 Cryoprecipitate and fibrinogen concentrate are commonly used abroad, as they can replenish large amounts of coagulation factors when a small dose is used for massive PPH. 5 7 In Japan, cryoprecipitate is not currently marketed, and fibrinogen concentrate is indicated only for patients with congenital fibrinogen deficiency. In recent years, however, increasing numbers of research studies and case reports on the efficacy of fibrinogen concentrate for massive PPH have been presented at scientific meetings in Japan. 8 This study aimed to ascertain the actual status of fibrinogen concentrate usage for massive PPH and to provide basic documents applicable to studying the usefulness of administering fibrinogen concentrates to patients with massive PPH. Methods In the primary survey, usage of fibrinogen concentrates at training institutions for specialist physicians of the Japan Society of Obstetrics and Gynecology were investigated. The subjects were patients to whom fibrinogen concentrates (Japan Blood Products Organization) had been administered during the period between April 2008 and March We retrospectively investigated underlying diseases, obstetric DIC scores, 9 blood loss (at the time of initial fibrinogen administration and total), the amount of blood transfusion (red cell concentrate, fresh frozen plasma [FFP], platelet concentrate), the dose (g) of fibrinogen concentrate administered, plasma fibrinogen levels before and after the administration of fibrinogen concentrate (at each administration), additional therapy, adverse events, and peripartum outcomes of the patients. When the lower limit of the fibrinogen measurement was 50 mg/dl, the minimum data were analyzed as 50 mg/dl, otherwise the data were analyzed using the actual measurement value. The present study was conducted with approval from the clinical study review committee of the Japan Society of Obstetrics and Gynecology. Statistical analysis All data were presented as the median or average ± SD. Unpaired t-test was performed to compare two variants. P < 0.05 was considered statistically significant. The statistical analysis was conducted with SPSS 18. Results We received replies from 588 of 667 institutions (88%) in the initial survey. Of the 667 institutions, 44 (6.6%) replied that they had used fibrinogen concentrate, and the total number of patients using fibrinogen concentrate was 101. The number of patients saved was 99 (98.0%), and the causative diseases were premature abruption of normally implanted placenta in 34 patients, atonic bleeding in 19, amniotic fluid embolism in 13, placenta accreta in 10, cervical laceration and uterine rupture in eight, placenta previa in four, and others in 13. The median obstetric DIC score at the time of fibrinogen concentrate administration was 12 points (range, 1 35), and the average amount of blood loss at the time of initial fibrinogen administration and total blood loss was 3559 ± 2103 ml and 4562 ± 3198 ml, respectively. A case with an obstetric DIC score of 1 was congenital afibrinogenemia who needed administration of fibrinogen concentrate because of PPH during elective section. The number of administrations was once in 84 patients, twice in 16, and three times or more in just one. The dose per administration was 3 g (1 15), and the plasma fibrinogen level before the initial administration of fibrinogen concentrate was 70.5 ± 44.7 mg/dl, thereafter increasing to ± 72.3 mg/dl. Thus, the increase in the fibrinogen level was 32.9 ± 34.5 mg/dl/g of fibrinogen concentrate. The plasma fibrinogen levels 1156

3 Fibrinogen concentrate usage for PPH Level of plasma fibrinogen (mg/dl) did not show stepwise increases when comparing between administered doses of fibrinogen concentrate (Figure 1). When the increase was examined by disease, it was less than 150 mg/dl after the first administration of fibrinogen concentrate only in patients with amniotic fluid embolism, while patients with atonic bleeding showed the smallest increase in fibrinogen per g of fibrinogen concentrate (Table 1). Nine patients had an increase of less than 10 mg/dl in fibrinogen per g of fibrinogen concentrate before the initial administration. When these patients were examined as poor responders, five of the nine had received two administrations and several had fibrinogen levels exceeding 150 mg/dl after the final administration (Table 2). Two maternal deaths occurred, and the causes were soft birth canal laceration and amniotic fluid embolism. The final fibrinogen level was 150 mg/dl or less in both of the deceased cases. No adverse events, including thromboembolism, were reported. With regard to health insurance coverage, all institutions replied that they favored an insurance application of the fibrinogen concentrate. Discussion Before Administration of fibrinogen concentrate (g) Figure 1 Increase in plasma fibrinogen level. The plasma fibrinogen levels did not show stepwise increases when compared between administered doses of fibrinogen concentrate. The actual status of fibrinogen concentrate usage for massive PPH was evaluated in the present study. Previous data showed that massive bleeding with severe fibrinogenemia is associated with progression to severe PPH, 4 and thus we believe that many of the women in our study may have died if fibrinogen concentrate had not been administered. Thus, it can be said, fibrinogen concentrate saved 99 lives out of 101. Although the median increase in the fibrinogen level was 32.9 mg/dl/g of fibrinogen concentrate in our study, Kikuchi et al. used approximately 40 mg/dl/g of fibrinogen concentrate in their study. 8 This difference may be caused by the patient population; the cases with minimum fibrinogen levels less than 50 mg/dl were included in the present study. The possible causes of insufficient fibrinogen elevation include: (i) insufficient replenishment; (ii) progression of DIC (with consumption exceeding replenishment); and (iii) hemostasis failure (secondary decrease along with bleeding after replenishment), and these may be present concurrently. In our study, the patients with amniotic fluid embolism had the lowest fibrinogen levels both before and after fibrinogen concentrate administration. This would presumably indicate that coagulation factors, including fibrinogen, are consumed even while being replenished. Coagulopathy associated with massive blood loss is characterized by the presence of a threshold for coagulation factors as indicated by the critical levels of these factors in such patients. 10 Massive blood loss from the uterus is difficult to control in obstetric hemorrhage cases because hemostasis is suddenly impaired when the levels of coagulation factors fall below the threshold instead of a gradual worsening of the bleeding tendency. Furthermore, once coagulopathy develops, a large amount of blood must be transfused to increase levels of coagulation factors to within the safe range allowing hemostasis because FFP, which is one of the main components of treatment, is not a concentrated preparation. Althoughtherewereninepoorresponders,manyof them showed an increase in fibrinogen levels after the second fibrinogen concentrate administration. The rates of increase were similar to those in patients who did not have insufficient fibrinogen elevation. Thus, the ability to identify poor responders is a key factor in successful treatment, and we considered it to be important to administer additional fibrinogen concentrate or FFP on the basis of patient conditions. The fibrinogen levels were below 150 mg/dl in all patients who died, and the difficulty achieving hemostasis due to deficiency of coagulation factors was assumed to be the cause of death. Results from a randomized, placebo-controlled trial revealed that fibrinogen concentrate was more effective than placebo in controlling coagulopathic bleeding during major aortic replacement surgery. Fibrinogen concentrate also enabled more rapid and at least as effective control of intraoperative bleeding when compared with transfusion of four units FFP and two units platelets. 11 In the present study, because FFP and other blood products were administered along with fibrinogen concentrate, the effect of the fibrinogen concentrate alone 1157

4 S. Makino et al. Table 1 Saved patients Disease Case Obstetric DIC scores Fibrinogen level (before) Fibrinogen level (after) Increase in fibrinogen level /g FC Blood loss (ml) (at the time of initial FC administration /total) Blood transfusion RCC FFP PC Administration of FC (g) Placental abruption ± ± ± ± ± / 2915 ± 1647 Atonic bleeding ± ± ± ± ± 1703 / 4634 ± 3269 Amniotic fluid embolism ± ± ± ± ± 2442 / 6642 ± 3859 Placenta accreta ± ± ± ± ± 1497 / 6780 ± 1865 Cervical laceration and uterine rupture ± ± ± ± ± 985 / 4398 ± 1749 Placenta previa ± ± ± ± ± 1391 / 5937 ± 2003 Others ± ± ± ± ± 2512 / 5026 ± (0 60) 6 (0 58) 7 (0 35) 3 (1 6) 16 (6 42) 12 (0 50) 20 (0 40) 3 (1 8) 24 (6 62) 37.5 (8 74) 25 (0 75) 3 (1 9) 15 (6 52) 10 (4 78) 10 (0 30) 2 (1 6) 12.5 (0 28) 12.5 (0 25) 10 (0 25) 3 (1 4) 21 (16 30) 35 (25 52) 25 (15 40) 3 (2 5) 11 (0 42) 14.5 (0 40) 10 (0 70) 3 (1 15) DIC, disseminated intravascular coagulation; FC, fibrinogen concentrate; FFP, fresh frozen plasma; PC, platelet concentrate; RCC, red cell concentrate. 1158

5 Fibrinogen concentrate usage for PPH Table 2 Poor responders of saved patients Disease Placenta abruption Placenta abruption Mode of delivery Fibrinogen Level (mg/dl) Time Vial Before After Emergency Emergency Blood transfusion Additional treatment Total blood loss (ml) RCC 6u FFP 4u FFP 5u 1421 Placenta accreta Elective RCC 10u Compression suture, 5548 FFP 6u hysterectomy Amniotic fluid Emergency RCC 22u 4645 embolism FFP 14u PC 20u Amniotic fluid Vaginal RCC 6u 1071 embolism FFP 8u Atonic bleeding Emergency RCC 6u Atonic bleeding Vaginal RCC 14u FFP 6u Uterine rupture Emergency RCC 10u Hysterectomy 3315 FFP 14u Septic shock, DIC Vaginal RCC 26u Hysterectomy 8637 FFP 40u PC 35u rfviia FC, fibrinogen concentrate; FFP, fresh frozen plasma; PC, platelet concentrate; RCC, red cell concentrate; rfviia, recombinant activated factor VII; u, units. on increasing fibrinogen levels was not examined. It is hoped that efficacy will be evaluated more precisely by randomized controlled trials; however, it is extremely difficult to conduct prospective research or clinical studies for massive PPH. In conclusion, we surveyed the actual status of fibrinogen concentrate usage for massive PPH. The survey results indicated the increase in blood fibrinogen levels to, on occasion, be insufficient even with fibrinogen concentrate use; however, the present survey may support the safety and usefulness of fibrinogen concentrate for massive PPH. Further discussion about the appropriate dose, number, and timing of administrations is needed in future. Disclosure None of the authors has any conflicts of interest to declare. References 1. Japan Association of Obstetricians and Gynecologists. Japanese Maternal Death Registration investigated by Japan Association of Obstetricians and Gynecologists, [Cited August 2013.] Available from URL: all/document/67_ pdf (In Japanese.) 2. Charles J, Lockwood MD. Pregnancy-associated changes in the hemostatic system. Clin Obstet Gynecol 2006; 49: Burtelow M, Riley E, Druzin M, Fontaine M, Viele M, Goodnough LT. How we treat: Management of lifethreatening primary postpartum hemorrhage with a standardized massive transfusion protocol. Transfusion 2007; 47: Charbit B, Mandelbrot L, Samain E et al. The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage. JThrombHaemost2007; 5: Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol 2009; 145: Ducloy-Bouthors A-S, Blondé-Zoonekynd E, Jaillette E et al. Transfusion and postpartum haemorrhage. Transfus Clin Biol 2010; 17: ACOG. Practice Bulletin: Clinical Management Guidelines for Obstetrician-Gynecologists Number 76, 2006: Postpartum hemorrhage. 8. Kikuchi M, Itakura A, Miki A, Nishibayashi M, Ikebuchi K, Ishihara O. Fibrinogen concentrate substitution therapy for obstetric hemorrhage complicated by coagulopathy. JObstet Gynaecol Res 2013; 39: Kobayashi T. Obstetrical disseminated intravascular coagulation score. J Obstet Gynaecol Res 2014; 40:

6 S. Makino et al. 10. Hiippala ST, Myllylä GJ, Vahtera EM. Hemostatic factors and replacement of major blood loss with plasma-poor red cell concentrates. Anesth Analg 1995; 81: Rahe-Meyer N, Hanke A, Schmidt DS, Hagl C, Pichlmaier M. Fibrinogen concentrate reduces intraoperative bleeding when used as first-line hemostatic therapy during major aortic replacement surgery: Results from a randomized, placebocontrolled trial. J Thorac Cardiovasc Surg 2013; 145(3 Suppl): S178 S