Unexpected Postpartum Hemorrhage Due to an Acquired Factor VIII Inhibitor

Abstract

Unexplained postpartum hemorrhage (PPH) refractory to standard hemostatic measures should trigger a heightened clinical suspicion of an acquired bleeding disorder. When hemostatic medical interventions and surgical procedures fail to control the bleeding, then significant postoperative blood loss, debilitating morbidity, loss of fertility, and death may occur. In the setting of an autoantibody inhibitor to factor VIII (FVIII), control of life-threatening PPH and avoidance of subsequent bleeding episodes depends on a timely and accurate diagnosis, prompt hemostatic treatment and eradication of FVIII inhibitors, and appropriate long-term patient care and management. Acquired postpartum hemophilia due to a FVIII inhibitor is a rare cause of PPH; however, delayed treatment can lead to increased maternal morbidity and mortality. Acquired FVIII inhibitors also pose an emerging bleeding threat to the neonate as a result of possible transplacental transfer of FVIII autoantibodies to the fetus during the last trimester of pregnancy. The purpose of this review is to increase awareness among hematologists and obstetricians/gynecologists regarding the occurrence of FVIII neutralizing autoantibodies as a cause of PPH, and emphasize the importance of collaboration between obstetrician/gynecologists and hematology specialists to optimize the diagnostic evaluation, treatment, and long-term management of women who experience PPH due to an acquired FVIII inhibitor.

Keywords

factor VIII - acquired hemophilia - pregnancy - antibodies - postpartum hemorrhage

• References

• 1 Borna S, Hantoushzadeh S. Acquired hemophilia as a cause of primary postpartum hemorrhage. Arch Iran Med 2007; 10 (1) 107-110
• 2 Baudo F, de Cataldo F ; Italian Association of Haemophilia Centres (AICE): Register of acquired factor VIII inhibitors (RIIA). Acquired factor VIII inhibitors in pregnancy: data from the Italian Haemophilia Register relevant to clinical practice. BJOG 2003; 110 (3) 311-314
• 3 Bateman BT, Berman MF, Riley LE, Leffert LR. The epidemiology of postpartum hemorrhage in a large, nationwide sample of deliveries. Anesth Analg 2010; 110 (5) 1368-1373
• 4 Callaghan WM, Kuklina EV, Berg CJ. Trends in postpartum hemorrhage: United States, 1994-2006. Am J Obstet Gynecol 2010; 202 (4) e1-e6
• 5 Silver RM, Major H. Maternal coagulation disorders and postpartum hemorrhage. Clin Obstet Gynecol 2010; 53 (1) 252-264
• 6 Walfish M, Neuman A, Wlody D. Maternal haemorrhage. Br J Anaesth 2009; 103 (Suppl. 01) i47-i56
• 7 Mecacci F, Pieralli A, Bianchi B, Paidas MJ. The impact of autoimmune disorders and adverse pregnancy outcome. Semin Perinatol 2007; 31 (4) 223-226
• 8 Hossain N, Langhoff Roos L, Paidas MJ. Postpartum hemorrhage. In: Paidas MJ, Hossain N, Shamsi TS, Rodger MA, Langhoff-Roos J, Lockwood CJ, , eds. Hemostasis and Thrombosis in Obstetrics and Gynecology. 1st ed. Oxford, UK: Blackwell Publishing (Wiley Blackwell); 2011
• 9 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
• 10 Oyelese Y, Ananth CV. Postpartum hemorrhage: epidemiology, risk factors, and causes. Clin Obstet Gynecol 2010; 53 (1) 147-156
• 11 Tengborn L, Baudo F, Huth-Kühne A , et al; EACH2 registry contributors. Pregnancy-associated acquired haemophilia A: results from the European Acquired Haemophilia (EACH2) registry. BJOG 2012; 119 (12) 1529-1537
• 12 Kadir RA, Aledort LM. Obstetrical and gynaecological bleeding: a common presenting symptom. Clin Lab Haematol 2000; 22 (Suppl. 01) 12-16 , discussion 30–32
• 13 Franchini M. Postpartum acquired factor VIII inhibitors. Am J Hematol 2006; 81 (10) 768-773
• 14 Coller BS, Hultin MB, Hoyer LW , et al. Normal pregnancy in a patient with a prior postpartum factor VIII inhibitor: with observations on pathogenesis and prognosis. Blood 1981; 58 (3) 619-624
• 15 Lulla RR, Allen GA, Zakarija A, Green D. Transplacental transfer of postpartum inhibitors to factor VIII. Haemophilia 2010; 16 (1) 14-17
• 16 Franchini M, Gandini G, Di Paolantonio T, Mariani G. Acquired hemophilia A: a concise review. Am J Hematol 2005; 80 (1) 55-63
• 17 Shobeiri SA, West EC, Kahn MJ, Nolan TE. Postpartum acquired hemophilia (factor VIII inhibitors): a case report and review of the literature. Obstet Gynecol Surv 2000; 55 (12) 729-737
• 18 Franchini M, Lippi G. Acquired factor VIII inhibitors. Blood 2009; 113 (21) 5368
• 19 Ma AD, Carrizosa D. Acquired factor VIII inhibitors: pathophysiology and treatment. Hematology (Am Soc Hematol Educ Program) 2006; 432-437
• 20 Kessler CM. Hemophilia Acquired. eMedicine Hematology Web site. 2008 http://emedicine.medscape.com/article/211186-overview . Accessed April 7, 2010
• 21 Huth-Kühne A, Baudo F, Collins P , et al. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A. Haematologica 2009; 94 (4) 566-575
• 22 Collins PW, Percy CL. Advances in the understanding of acquired haemophilia A: implications for clinical practice. Br J Haematol 2010; 148 (2) 183-194
• 23 Boggio LN, Green D. Acquired hemophilia. Rev Clin Exp Hematol 2001; 5 (4) 389-404 , quiz 431
• 24 Broxson EH, Hathaway WE. Transplacental transfer of acquired factor VIII: C inhibitor. Thromb Haemost 1987; 57 (1) 126
• 25 Franchini M, Franchi M, Bergamini V , et al. The use of recombinant activated FVII in postpartum hemorrhage. Clin Obstet Gynecol 2010; 53 (1) 219-227
• 26 Franchini M, Lippi G, Franchi M. The use of recombinant activated factor VII in obstetric and gynaecological haemorrhage. BJOG 2007; 114 (1) 8-15
• 27 Franchini M, Franchi M, Bergamini V, Salvagno GL, Montagnana M, Lippi G. A critical review on the use of recombinant factor VIIa in life-threatening obstetric postpartum hemorrhage. Semin Thromb Hemost 2008; 34 (1) 104-112
• 28 Bouwmeester FW, Jonkhoff AR, Verheijen RH, van Geijn HP. Successful treatment of life-threatening postpartum hemorrhage with recombinant activated factor VII. Obstet Gynecol 2003; 101 (6) 1174-1176
• 29 Levi M, Opal SM. Coagulation abnormalities in critically ill patients. Crit Care 2006; 10 (4) 222
• 30 Onwuemene O, Green D, Keith L. Postpartum hemorrhage management in 2012: predicting the future. Int J Gynaecol Obstet 2012; 119 (1) 3-5
• 31 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 (7) 426-435
• 32 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 (6) 984-989
• 33 Charbit B, Mandelbrot L, Samain E , et al; PPH Study Group. The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage. J Thromb Haemost 2007; 5 (2) 266-273
• 34 Paidas MJ. New approaches to transfusion therapy for postpartum hemorrhage. In: Aurulkumaran S, Karoshi M, Keith LG, Lalonde AB, Lynch CB, , eds. A Comprehensive Textbook of Postpartum Hemorrhage, An Essential Clinical Reference for Effective Management. 2nd ed. London, UK: Sapiens Publishing; 2012: 48-51
• 35 Knoebl P, Marco P, Baudo F , et al; EACH2 Registry Contributors. Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2). J Thromb Haemost 2012; 10 (4) 622-631
• 36 Pacheco LD, Saade GR, Gei AF, Hankins GD. Cutting-edge advances in the medical management of obstetrical hemorrhage. Am J Obstet Gynecol 2011; 205 (6) 526-532
• 37 Solymoss S. Postpartum acquired factor VIII inhibitors: results of a survey. Am J Hematol 1998; 59 (1) 1-4
• 38 Michiels JJ, Hamulyak K, Nieuwenhuis HK, Novakova I, van Vliet HH. Acquired haemophilia A in women postpartum: management of bleeding episodes and natural history of the factor VIII inhibitor. Eur J Haematol 1997; 59 (2) 105-109
• 39 Michiels JJ, Bosch LJ, van der Plas PM, Abels J. Factor VIII inhibitor postpartum. Scand J Haematol 1978; 20 (2) 97-107
• 40 Michiels JJ. Acquired hemophilia A in women postpartum: clinical manifestations, diagnosis, and treatment. Clin Appl Thromb Hemost 2000; 6 (2) 82-86
• 41 Hauser I, Schneider B, Lechner K. Post-partum factor VIII inhibitors. A review of the literature with special reference to the value of steroid and immunosuppressive treatment. Thromb Haemost 1995; 73 (1) 1-5
• 42 Delgado J, Jimenez-Yuste V, Hernandez-Navarro F, Villar A. Acquired haemophilia: review and meta-analysis focused on therapy and prognostic factors. Br J Haematol 2003; 121 (1) 21-35
• 43 Santoro RC, Prejanò S. Postpartum-acquired haemophilia A: a description of three cases and literature review. Blood Coagul Fibrinolysis 2009; 20 (6) 461-465
• 44 Shear W, Rosner MH. Acute kidney dysfunction secondary to the abdominal compartment syndrome. J Nephrol 2006; 19 (5) 556-565
• 45 Cullen DJ, Coyle JP, Teplick R, Long MC. Cardiovascular, pulmonary, and renal effects of massively increased intra-abdominal pressure in critically ill patients. Crit Care Med 1989; 17 (2) 118-121
• 46 Franchini M, Lippi G. Recent improvements in the clinical treatment of coagulation factor inhibitors. Semin Thromb Hemost 2009; 35 (8) 806-813
• 47 Baudo F, Caimi T, de Cataldo F. Diagnosis and treatment of acquired haemophilia. Haemophilia 2010; 16 (102) 102-106
• 48 Bitting RL, Bent S, Li Y, Kohlwes J. The prognosis and treatment of acquired hemophilia: a systematic review and meta-analysis. Blood Coagul Fibrinolysis 2009; 20 (7) 517-523
• 49 Collins PW. Treatment of acquired hemophilia A. J Thromb Haemost 2007; 5 (5) 893-900
• 50 Franchini M, Capra F, Nicolini N , et al. Drug-induced anti-factor VIII antibodies: a systematic review. Med Sci Monit 2007; 13 (4) RA55-RA61
• 51 Ries M, Wölfel D, Maier-Brandt B. Severe intracranial hemorrhage in a newborn infant with transplacental transfer of an acquired factor VII:C inhibitor. J Pediatr 1995; 127 (4) 649-650
• 52 Vicente V, Alberca I, Gonzalez R, Alegre A. Normal pregnancy in a patient with a postpartum factor VIII inhibitor. Am J Hematol 1987; 24 (1) 107-109
• 53 Frick PG. Hemophilia-like disease following pregnancy with transplacental transfer of an acquired circulating anticoagulant. Blood 1953; 8 (7) 598-608
• 54 Moraca RJ, Ragni MV. Acquired anti-FVIII inhibitors in children. Haemophilia 2002; 8 (1) 28-32
• 55 Kotani Y, Shiota M, Umemoto M, Koike E, Tsuritani M, Hoshiai H. Case of acquired hemophilia with factor VIII inhibitor in a mother and newborn. J Obstet Gynaecol Res 2011; 37 (8) 1102-1105
• 56 Simister NE. Placental transport of immunoglobulin G. Vaccine 2003; 21 (24) 3365-3369
• 57 Radulescu L, Antohe F, Jinga V, Ghetie V, Simionescu M. Neonatal Fc receptors discriminates and monitors the pathway of native and modified immunoglobulin G in placental endothelial cells. Hum Immunol 2004; 65 (6) 578-585
• 58 Hossain N, Shansi T, Haider S , et al. Use of recombinant activated factor VII for massive postpartum hemorrhage. Acta Obstet Gynecol Scand 2007; 86 (10) 1200-1206
• 59 Baudo F, Collins P, Huth-Kühne A , et al; EACH2 registry contributors. Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry. Blood 2012; 120 (1) 39-46
• 60 Collins P, Baudo F, Knoebl P , et al; EACH2 registry collaborators. Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2). Blood 2012; 120 (1) 47-55
• 61 Miranda GG, Rodgers GM. Treatment of an acquired factor VIII inhibitor with sequential recombinant factor VIIa and FEIBA. Haemophilia 2009; 15 (1) 383-385
• 62 Aledort LM. Factor VIII inhibitor bypassing activity (FEIBA) - addressing safety issues. Haemophilia 2008; 14 (1) 39-43
• 63 Sumner MJ, Geldziler BD, Pedersen M, Seremetis S. Treatment of acquired haemophilia with recombinant activated FVII: a critical appraisal. Haemophilia 2007; 13 (5) 451-461
• 64 O'Connell KA, Wood JJ, Wise RP, Lozier JN, Braun MM. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 2006; 295 (3) 293-298
• 65 Roberts HR, Monroe DM, White GC. The use of recombinant factor VIIa in the treatment of bleeding disorders. Blood 2004; 104 (13) 3858-3864
• 66 Ingerslev J, Sørensen B. Parallel use of by-passing agents in haemophilia with inhibitors: a critical review. Br J Haematol 2011; 155 (2) 256-262
• 67 Barnett B, Kruse-Jarres R, Leissinger CA. Current management of acquired factor VIII inhibitors. Curr Opin Hematol 2008; 15 (5) 451-455
• 68 Green D. The management of acquired hemophilia. Haemophilia 2006; 12 (Suppl. 05) 32-36
• 69 Collins P, Baudo F, Huth-Kühne A , et al. Consensus recommendations for the diagnosis and treatment of acquired hemophilia A. BMC Res Notes 2010; 3: 161
• 70 Mazzucconi MG, Bizzoni L, Giorgi A , et al. Postpartum inhibitor to factor VIII: treatment with high-dose immunoglobulin and dexamethasone. Haemophilia 2001; 7 (4) 422-427
• 71 Field JJ, Fenske TS, Blinder MA. Rituximab for the treatment of patients with very high-titre acquired factor VIII inhibitors refractory to conventional chemotherapy. Haemophilia 2007; 13 (1) 46-50
• 72 Mei-Dan E, Walfisch A, Martinowitz U, Hallak M. A rapidly progressive, life-threatening postpartum hemorrhage: successful treatment with anti-CD-20 monoclonal antibody. Obstet Gynecol 2009; 114 (2, Pt 2) 417-419
• 73 Santoro C, Rago A, Biondo F , et al. Efficacy of rituximab treatment in postpartum acquired haemophilia A. Haemophilia 2008; 14 (1) 147-149
• 74 Berezné A, Stieltjes N, Le-Guern V , et al. Rituximab alone or in association with corticosteroids in the treatment of acquired factor VIII inhibitors: report of two cases. Transfus Med 2006; 16 (3) 209-212
• 75 Stasi R, Brunetti M, Stipa E, Amadori S. Selective B-cell depletion with rituximab for the treatment of patients with acquired hemophilia. Blood 2004; 103 (12) 4424-4428
• 76 Holme PA, Brosstad F, Tjønnfjord GE. Acquired haemophilia: management of bleeds and immune therapy to eradicate autoantibodies. Haemophilia 2005; 11 (5) 510-515
• 77 Toschi V, Baudo F. Diagnosis, laboratory aspects and management of acquired hemophilia A. Intern Emerg Med 2010; 5 (4) 325-333
• 78 Zeitler H, Ulrich-Merzenich G, Hess L , et al. Treatment of acquired hemophilia by the Bonn-Malmo Protocol: documentation of an in vivo immunomodulating concept. Blood 2005; 105 (6) 2287-2293
• 79 Booth CJ, Brooks MB, Rockwell S , et al. WAG-F8(m1Ycb) rats harboring a factor VIII gene mutation provide a new animal model for hemophilia A. J Thromb Haemost 2010; 8 (11) 2472-2477
• 80 Paidas MJ, Krikun G, Huang SJ , et al. A genomic and proteomic investigation of the impact of preimplantation factor on human decidual cells. Am J Obstet Gynecol 2010; 202 (5) e1-e8
• 81 Barnea ER, Kirk D, Paidas MJ. Preimplantation factor (PIF) promoting role in embryo implantation: increases endometrial integrin-α2β3, amphiregulin and epiregulin while reducing betacellulin expression via MAPK in decidua. Reprod Biol Endocrinol 2012; 10: 50
• 82 Barnea ER, Kirk D, Ramu S, Rivnay B, Roussev R, Paidas MJ. PreImplantation Factor (PIF) orchestrates systemic antiinflammatory response by immune cells: effect on peripheral blood mononuclear cells. Am J Obstet Gynecol 2012; 207 (4) e1-e11
• 83 Weiss L, Bernstein S, Jones R , et al. Preimplantation factor (PIF) analog prevents type I diabetes mellitus (TIDM) development by preserving pancreatic function in NOD mice. Endocrine 2011; 40 (1) 55
• 84 Weiss L, Or R, Jones RC , et al. Preimplantation factor reduces graft-versus-host disease by regulating immune response and lowering oxidative stress (murine model). J Neurol Sci 2012; 312 (1–2) 146-157
• 85 Azar Y, Shainer R, Almogi-Hazan O , et al. Preimplantation factor reduces graft-versus-host disease by regulating immune response and lowering oxidative stress (murine model). Biol Blood Marrow Transplant 2013; 19 (4) 519-528