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Beyond uterine atony: characterizing postpartum hemorrhage coagulopathy

Published:November 30, 2022DOI:https://doi.org/10.1016/j.ajogmf.2022.100822

      BACKGROUND

      Postpartum hemorrhage is a leading cause of morbidity and mortality worldwide, yet the associated early coagulopathy is not well defined.

      OBJECTIVE

      We hypothesized that women who develop postpartum hemorrhage have a distinct derangement of thrombin generation and coagulation factors compared with postpartum women without postpartum hemorrhage.

      STUDY DESIGN

      This prospective study of pregnant patients with postpartum hemorrhage was completed at a single urban hospital. Blood was drawn on postpartum hemorrhage diagnosis and 2 and 4 hours later. Assays of patients with postpartum hemorrhage included thrombelastography, whole blood thrombin generation, coagulation factor activity, tissue factor levels and activity, and tissue factor pathway inhibitor levels, which were compared with that of patients without postpartum hemorrhage.

      RESULTS

      A total of 81 patients were included in this study. Of those patients, 66 had postpartum hemorrhage, and 15 served as controls. Compared with patients without PPH, patients with postpartum hemorrhage had lower fibrinogen levels (469.0 mg/dL vs 411.0 mg/dL; P=.02), increased tissue plasminogen activator resistance (fibrinolysis 30 minutes after maximal clot strength: 8.7% vs 4.2%; P=.02), decreased peak thrombin concentration (150.2 nM vs 40.7 nM; P=.01), and decreased maximal rate of thrombin generation (60.1 nM/minute vs 2.8 nM/minute; P=.02). Furthermore, compared with patients without postpartum hemorrhage, patients with postpartum hemorrhage had decreased tissue factor levels (444.3 pg/mL vs 267.1 pg/mL; P=.02) and increased tissue factor pathway inhibitor levels (0.6 U/mL vs 0.8 U/mL; P=.04), with decreased tissue factor pathway inhibitor ratios (624 vs 299; P=.01).

      CONCLUSION

      PPH is not only an issue of uterine tone and mechanical bleeding but also a distinct coagulopathy that is characterized by decreased fibrinogen level, clot breakdown resistance, and markedly low thrombin generation. This pathology seemed to be driven by low tissue factor and high tissue factor pathway inhibitor levels.

      Keywords

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      References

        • Oyelese Y
        • Ananth CV.
        Postpartum hemorrhage: epidemiology, risk factors, and causes.
        Clin Obstet Gynecol. 2010; 53: 147-156
        • Khan KS
        • Wojdyla D
        • Say L
        • Gülmezoglu AM
        • Van Look PF.
        WHO analysis of causes of maternal death: a systematic review.
        Lancet. 2006; 367: 1066-1074
        • Bateman BT
        • Berman MF
        • Riley LE
        • Leffert LR.
        The epidemiology of postpartum hemorrhage in a large, nationwide sample of deliveries.
        Anesth Analg. 2010; 110: 1368-1373
        • Callaghan WM
        • Creanga AA
        • Kuklina EV.
        Severe maternal morbidity among delivery and postpartum hospitalizations in the United States.
        Obstet Gynecol. 2012; 120: 1029-1036
        • Collins P
        • Abdul-Kadir R
        • Thachil J
        Subcommittees on Women' s Health Issues in Thrombosis and Haemostasis and on Disseminated Intravascular Coagulation. Management of coagulopathy associated with postpartum hemorrhage: guidance from the SSC of the ISTH.
        J Thromb Haemost. 2016; 14: 205-210
        • James AH
        • McLintock C
        • Lockhart E.
        Postpartum hemorrhage: when uterotonics and sutures fail.
        Am J Hematol. 2012; 87: S16-S22
        • Sohn CH
        • Kim SR
        • Kim YJ
        • et al.
        Disseminated intravascular coagulation in emergency department patients with primary postpartum hemorrhage.
        Shock. 2017; 48: 329-332
        • 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
        • Cortet M
        • Deneux-Tharaux C
        • Dupont C
        • et al.
        Association between fibrinogen level and severity of postpartum haemorrhage: secondary analysis of a prospective trial.
        Br J Anaesth. 2012; 108: 984-989
        • de Lange NM
        • Lancé MD
        • de Groot R
        • Beckers EA
        • Henskens YM
        • Scheepers HC.
        Obstetric hemorrhage and coagulation: an update. Thromboelastography, thromboelastometry, and conventional coagulation tests in the diagnosis and prediction of postpartum hemorrhage.
        Obstet Gynecol Surv. 2012; 67: 426-435
        • Butwick AJ
        • Goodnough LT.
        Transfusion and coagulation management in major obstetric hemorrhage.
        Curr Opin Anaesthesiol. 2015; 28: 275-284
        • Collins PW
        • Bell SF
        • de Lloyd L
        • Collis RE.
        Management of postpartum haemorrhage: from research into practice, a narrative review of the literature and the Cardiff experience.
        Int J Obstet Anesth. 2019; 37: 106-117
        • McNamara H
        • Kenyon C
        • Smith R
        • Mallaiah S
        • Barclay P.
        Four years’ experience of a ROTEM® -guided algorithm for treatment of coagulopathy in obstetric haemorrhage.
        Anaesthesia. 2019; 74: 984-991
        • Gonzalez E
        • Moore EE
        • Moore HB
        • et al.
        Goal-directed hemostatic resuscitation of trauma-induced coagulopathy: a pragmatic randomized clinical trial comparing a viscoelastic assay to conventional coagulation assays.
        Ann Surg. 2016; 263: 1051-1059
        • Bingham DMK
        • Main E.
        CMQCC obstetric hemorrhage toolkit hospital level implementation guide.
        The California Maternal Quality Care Collaborative (CMQCC) Stanford University, Palo Alto, CA2010
        • Haemonetics Corporation
        TEG® 5000 system - user manual.
        Haemonetics Corporation, Haemoscope Division, Niles, IL2010
        • Durila M
        • Lukáš P
        • Bronský J
        • Cvachovec K.
        Time impact on non-activated and kaolin-activated blood samples in thromboelastography.
        BMC Anesthesiol. 2015; 15: 50
        • Yang Lu S
        • Tanaka KA
        • Abuelkasem E
        • Planinsic RM
        • Sakai T
        Clinical applicability of rapid thrombelastography and functional fibrinogen thrombelastography to adult liver transplantation.
        Liver Transpl. 2014; 20: 1097-1105
        • Moore HB
        • Moore EE
        • Huebner BR
        • et al.
        Fibrinolysis shutdown is associated with a fivefold increase in mortality in trauma patients lacking hypersensitivity to tissue plasminogen activator.
        J Trauma Acute Care Surg. 2017; 83: 1014-1022
        • Coleman JR
        • Moore EE
        • Samuels JM
        • et al.
        Whole blood thrombin generation is distinct from plasma thrombin generation in healthy volunteers and after severe injury.
        Surgery. 2019; 166: 1122-1127
        • Mann KG
        • Whelihan MF
        • Butenas S
        • Orfeo T.
        Citrate anticoagulation and the dynamics of thrombin generation.
        J Thromb Haemost. 2007; 5: 2055-2061
        • R Foundation for Statistical Computing
        R: A Language and Environment for Statistical Computing.
        2010 (Available at) (Accessed August 9, 2022)
        • Butwick AJ.
        Postpartum hemorrhage and low fibrinogen levels: the past, present and future.
        Int J Obstet Anesth. 2013; 22: 87-91
        • Era S
        • Matsunaga S
        • Matsumura H
        • Murayama Y
        • Takai Y
        • Seki H.
        Usefulness of shock indicators for determining the need for blood transfusion after massive obstetric hemorrhage.
        J Obstet Gynaecol Res. 2015; 41: 39-43
        • Ducloy-Bouthors AS
        • Duhamel A
        • Kipnis E
        • et al.
        Postpartum haemorrhage related early increase in D-dimers is inhibited by tranexamic acid: haemostasis parameters of a randomized controlled open labelled trial.
        Br J Anaesth. 2016; 116: 641-648
        • Moore HB
        • Moore EE
        • Neal MD
        • et al.
        Fibrinolysis shutdown in trauma: historical review and clinical implications.
        Anesth Analg. 2019; 129: 762-773
        • Moore EE
        • Moore HB
        • Gonzalez E
        • et al.
        Postinjury fibrinolysis shutdown: rationale for selective tranexamic acid.
        J Trauma Acute Care Surg. 2015; 78: S65-S69
        • Moore HB
        • Moore EE
        • Huebner BR
        • et al.
        Tranexamic acid is associated with increased mortality in patients with physiological fibrinolysis.
        J Surg Res. 2017; 220: 438-443
        • Moore EE
        • Moore HB
        • Gonzalez E
        • Sauaia A
        • Banerjee A
        • Silliman CC.
        Rationale for the selective administration of tranexamic acid to inhibit fibrinolysis in the severely injured patient.
        Transfusion. 2016; 56: S110-S114
        • Coleman JR
        • Moore EE
        • Moore HB
        • et al.
        Tranexamic acid disturbs the dynamics of postinjury fibrinolysis.
        ANZ J Surg. 2020; 90: 420-422
        • MacDonald S
        • White D
        • Langdown J
        • Downes K
        • Thomas W.
        Investigation of patients with unclassified bleeding disorder and abnormal thrombin generation for physiological coagulation inhibitors reveals multiple abnormalities and a subset of patients with increased tissue factor pathway inhibitor activity.
        Int J Lab Hematol. 2020; 42: 246-255
        • Wada T
        • Shiraishi A
        • Gando S
        • et al.
        Disseminated intravascular coagulation immediately after trauma predicts a poor prognosis in severely injured patients.
        Sci Rep. 2021; 11: 11031
        • Rugeri L
        • Quélin F
        • Chatard B
        • De Mazancourt P
        • Negrier C
        • Dargaud Y.
        Thrombin generation in patients with factor XI deficiency and clinical bleeding risk.
        Haemophilia. 2010; 16: 771-777
        • Ruberto MF
        • Piras MS
        • Sorbello O
        • et al.
        Chronic intravascular coagulation in liver cirrhosis predicts a high hemorrhagic risk.
        Eur Rev Med Pharmacol Sci. 2021; 25: 5518-5524
        • Abildgaard U.
        Relative roles of tissue factor pathway inhibitor and antithrombin in the control of thrombogenesis.
        Blood Coagul Fibrinolysis. 1995; 6: S45-S49
        • Maroney SA
        • Mast AE.
        Expression of tissue factor pathway inhibitor by endothelial cells and platelets.
        Transfus Apher Sci. 2008; 38: 9-14
        • Audu P
        • Nielsen VG
        • Armstead V
        • et al.
        The impact of tissue factor pathway inhibitor on coagulation kinetics determined by thrombelastography.
        Anesth Analg. 2006; 103: 841-845
        • Karaszi K
        • Szabo S
        • Juhasz K
        • et al.
        Increased placental expression of Placental Protein 5 (PP5) /Tissue Factor Pathway Inhibitor-2 (TFPI-2) in women with preeclampsia and HELLP syndrome: relevance to impaired trophoblast invasion?.
        Placenta. 2019; 76: 30-39
        • Godoi LC
        • Gomes KB
        • Alpoim PN
        • Md Carvalho
        • Lwaleed BA
        • Sant'Ana Dusse LM
        Preeclampsia: the role of tissue factor and tissue factor pathway inhibitor.
        J Thromb Thrombolysis. 2012; 34: 1-6
        • Xiong Y
        • Zhou Q
        • Jiang F
        • et al.
        Changes of plasma and placental tissue factor pathway inhibitor-2 in women with preeclampsia and normal pregnancy.
        Thromb Res. 2010; 125: e317-e322
        • Aharon A
        • Brenner B
        • Katz T
        • Miyagi Y
        • Lanir N.
        Tissue factor and tissue factor pathway inhibitor levels in trophoblast cells: implications for placental hemostasis.
        Thromb Haemost. 2004; 92: 776-786
        • Barg AA
        • Brutman-Barazani T
        • Avishai E
        • et al.
        Anti-TFPI for hemostasis induction in patients with rare bleeding disorders, an ex vivo thrombin generation (TG) guided pilot study.
        Blood Cells Mol Dis. 2022; 95102663
        • Mast AE.
        Tissue factor pathway inhibitor: multiple anticoagulant activities for a single protein.
        Arterioscler Thromb Vasc Biol. 2016; 36: 9-14
        • Shapiro AD.
        Concizumab: a novel anti-TFPI therapeutic for hemophilia.
        Blood Adv. 2021; 5: 279
        • Patel-Hett S
        • Martin EJ
        • Mohammed BM
        • et al.
        Marstacimab, a tissue factor pathway inhibitor neutralizing antibody, improves coagulation parameters of ex vivo dosed haemophilic blood and plasmas.
        Haemophilia. 2019; 25: 797-806