Review Article

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Unexpected Postpartum Hemorrhage Due to an Acquired Factor VIII Inhibitor Michael J. Paidas, MD1

Nazli Hossain, MBBS, MCPS, FCPS2

1 Department of Obstetrics, Gynecology, and Reproductive Sciences,

Yale Women and Children’s Center for Blood Disorders, Yale University, New Haven, Connecticut 2 Department of Obstetrics and Gynecology, Unit 3, Dow University of Health Sciences, Karachi, Pakistan

Address for correspondence Michael J. Paidas, MD, Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, FMB 339B, New Haven, CT 06520-8063 (e-mail: [email protected]).

Abstract

Keywords

► ► ► ► ►

factor VIII acquired hemophilia pregnancy antibodies postpartum hemorrhage

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.

Postpartum hemorrhage (PPH) that occurs in the absence of a patient bleeding history, apparent risk factors, or preexisting medical conditions can quickly escalate to a life-threatening hemorrhagic complication.1,2 The most common cause of PPH is uterine atony after delivery, accounting for 79% of all cases.3,4 Other causes (►Table 1) can include retained placental tissue, abnormal placental adhesion, lower genital tract laceration or trauma, uterine rupture, and congenital or acquired coagulopathies.5–8 The incidence of PPH has increased significantly over the last 10 to 15 years.3,4,9,10 According to data from the Nationwide Inpatient Sample, the largest inpatient discharge dataset in the United States,

PPH was a significant complication in 2.9% of all deliveries and was associated with 19.1% of all postdelivery in-hospital maternal deaths from 1994 to 2006.3,4 A congenital or acquired bleeding disorder as the cause of PPH might be missed if proper laboratory testing is not performed or the results of this testing are misinterpreted. Recent publication of results from the European Acquired Hemophilia (EACH2) Registry have shown that pregnancy-associated acquired hemophilia A, although rare, may cause severe bleedingrelated morbidity due to prolonged delays in recognition, initiation of appropriate laboratory investigation, diagnosis, and treatment.11 While the risk of PPH is very high in women

received May 14, 2013 accepted after revision September 11, 2013 published online December 11, 2013

Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

DOI http://dx.doi.org/ 10.1055/s-0033-1358768. ISSN 0735-1631.

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Am J Perinatol 2014;31:645–654.

Postpartum Hemorrhage Due to an Acquired Factor VIII Inhibitor

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Table 1 Categories of postpartum hemorrhage (PPH)a PPHb Category Uterine tone

c

Abnormality

Cause of hemorrhagic complication

Uterine atony

Uterine muscle fatigue or overdistension; effects of anesthesia on uterine muscle

Retained tissuec

Placental tissue or clots

Abnormal attachment of placenta to uterine wall

Obstetric trauma

Genital tract lacerations

Injury at delivery with lacerations and hematomas of the perineum, vagina, and cervix

Coagulation

Coagulopathy

Congenital defects or deficiencies of clotting factors (vWD; prothrombin; fibrinogen; factors V, VII, X, XI) Acquired inhibitors of clotting factors (factor VIII) Use of anticoagulation or antiplatelet agents

Abbreviation: vWD, Von Willebrand disease. a Based on information in Walfish et al.6 b Primary PPH occurs within the first 24 hours after delivery and is most likely to result in maternal morbidity and mortality; secondary PPH occurs after the first 24 hours up to 6 weeks after delivery. c Most common causes of PPH and hysterectomy.

with inherited bleeding disorders, such as von Willebrand disease, and those who are carriers of congenital hemophilia or have factor XI (FXI) deficiency,12 a bleeding diathesis due to acquired FVIII inhibitors can be an unusual cause of severe and unexpected PPH in mother and child. The pathogenesis of acquired pregnancy-associated hemophilia A is still undetermined, although FVIII inhibitor development has been hypothesized to occur as a result of maternal exposure to fetal FVIII during pregnancy or delivery.13,14 Primigravid women postpartum have an increased incidence of acquired hemophilia A, a bleeding diathesis due to the development of neutralizing autoantibodies that inhibit FVIII procoagulant activity.11,13,15–17 Although considered rare, postpartum acquired hemophilia A is a significant clinical challenge.11,15 Persistent unexplained vaginal bleeding and/or unusual bleeding into the skin, limb muscles, or mucosal or soft internal tissues should trigger suspicion for postpartum acquired hemophilia A, prompting a rapid investigation to confirm the presence of FVIII inhibitory antibodies.16,18–23 If left untreated or if standard hemostatic interventions fail, postpartum acquired hemophilia A may lead to costly intensive care, invasive procedures, and gynecologic surgeries, including emergency hysterectomy, adding to any complications from the original bleeding episode.3,5 There is also increasing recognition of the potential bleeding threat posed to newborns if FVIII inhibitors are transferred to the fetus during the last trimester of pregnancy.11,15,24 While this cause of neonatal bleeding is rare, the well-being of the newborn is at risk (e.g., intracranial bleeding) if cardinal signs and symptoms are not recognized, appropriate laboratory testing is not conducted, and prompt treatment is not initiated to restore hemostasis.11 Significant patient morbidity and mortality, as well as loss of fertility, may result from postpartum acquired hemophilia A if bleeding is severe and appropriate strategies for restoring hemostasis and eradicating inhibitors are not rapidly implemented.11,13,15,25 The aim of this review is to highlight advances in the knowledge and understanding of acquired FVIII inhibitors as a cause of PPH, underscoring the importance of American Journal of Perinatology

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prompt recognition and collaboration with experienced hematology specialists to obtain an accurate diagnosis and appropriate treatment, as well as management of patients with postpartum acquired hemophilia A. A patient case scenario is used throughout this review to highlight and illustrate the clinical complexities of the presentation, recognition, testing, diagnosis and treatment approaches utilized to control bleeding, and restore hemostasis.

Maternal Bleeding Complications from Acquired FVIII Inhibitors Patient Clinical Scenario A 34-year-old woman without a prior personal or family history of bleeding presented at term in active labor. She had an uncomplicated vaginal delivery but experienced a PPH on postpartum day 2 that was not responsive to uterotonic agents. She required transfusion of 2 units of packed red blood cells (RBCs) due to symptomatic anemia. Coagulation studies were not performed during her postpartum stay in the hospital. She was discharged on postpartum day 3 despite intermittent vaginal bleeding. Her vaginal bleeding increased and became persistent at home, and on postpartum day 9 she returned to the hospital and was readmitted with suspicion of retained placental tissue. She underwent curettage; only clot, but not placental tissue, was appreciated by visual inspection of uterine contents at the time of evacuation and was confirmed by pathologic examination. Her infant experienced a normal, uneventful postpartum course. As depicted in the patient scenario above, childbirth and puerperium present major bleeding challenges to women of childbearing age, and excessive bleeding or hemorrhage is a common postpartum symptom encountered by obstetricians/ gynecologists.5,6,12 Persistent postpartum vaginal bleeding is of particular concern, especially when it is refractory to standard hemostatic interventions.12,13,26,27 Massive PPH from uterine atony or vaginal lacerations may even lead to life-threatening hemorrhagic shock.28 As such, PPH is a major cause of maternal morbidity and mortality worldwide. If efforts to control diffuse

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rate.2,13,16,37,38,40–43 Spontaneous inhibitor remission and decreased mortality in postpartum patients appear to be linked with lower plasma FVIII inhibitor concentrations and low inhibitor potency for FVIII inactivation.13 The occurrence of FVIII inhibitors during subsequent pregnancies and deliveries is rare, suggesting a lack of anamnesis (i.e., a subsequent, more rapid immune response that is antigen-specific based on immunological memory) for autoantibody redevelopment.13 In a small number of cases, postpartum FVIII inhibitors have been reported in subsequent pregnancies, resulting in severe uterine bleeding; however, those instances most likely represent inhibitor persistence from the prior pregnancy due to eradicative treatment failure.13,14

Clinical Presentation of Acquired FVIII Inhibitors Women with postpartum bleeding due to an acquired FVIII inhibitor usually present within days to up to 3 months (and in some cases, up to 1 year) after delivery.13,15,17 Persistent vaginal bleeding is the first cardinal sign of an acquired bleeding diathesis (►Table 2), if it occurs in the absence of other clinical factors, potential anatomic causes, or patient history of bleeding.5,6,13,15 The location of a hematoma and variable patterns of bleeding (variable sites and severity) may also provide important clues as to whether bleeding is due to an FVIII inhibitor or any other cause (►Table 2).16,20,21,23 Retrospective studies have shown that postpartum acquired hemophilia A can present with ecchymoses and soft tissue bleeds and mortality can be related to uncontrollable bleeding shortly after delivery, respiratory obstruction from laryngeal or sublingual hemorrhage, or severe retroperitoneal bleeding resulting in acute impairment of renal, cardiac, and respiratory function.38,40,44,45 Bleeding severity in patients with postpartum acquired hemophilia A can vary from mild (e.g., vaginal bleeding, epistaxis, ecchymoses, hematuria) to limb-threatening (e.g., intramuscular compartment syndrome) or life-threatening (e.g., abdominal compartment syndrome, intracerebral hemorrhage).13,16,46 FVIII inhibitor-related epistaxis or profuse gastrointestinal or urological bleeding can be extremely difficult to diagnose because bleeding in each of these anatomic regions is associated with many other disorders.20,23 Plasma levels (i.e., titer) of FVIII inhibitors appear to predict the magnitude of symptomatic postpartum bleeding. Low titers are usually associated with mild bleeding symptoms,

Table 2 Cardinal signs that should raise suspicion of a postpartum acquired FVIII inhibitor Vaginal bleeding that is not controlled by standard hemostatic approaches No previous personal or family bleeding history Bleeding or hemorrhage that is persistent and excessive in the absence of known risk factors An isolated, prolonged aPTT A variable bleeding pattern Bleeding or hemorrhage into unusual sites: skin, intramuscular areas, soft tissues, and mucosal tissues An underlying disease state, infection, or drug therapy linked with possible inhibitor development Abbreviations: aPTT, activated partial thromboplastin time; FVIII, factor VIII. American Journal of Perinatology

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pelvic and vaginal bleeding with conventional first-line (i.e., uterotonic drugs, suturing, transfusions of blood and blood products) or second-line (i.e., dilation and curettage, internal iliac artery ligation, tamponade or packing of the uterus, hysterectomy) hemostatic approaches fail,28 then coagulopathy may be the underlying cause of PPH.5 Coagulopathies are an uncommon cause of PPH; however, defective coagulation should be suspected in patients with a history of menorrhagia, a family history of bleeding disorders, or a predisposing medical condition such as an autoimmune disorder, and in patients without evidence of uterine atony, retained placental remnants, significant gynecological trauma, or other direct causes of obstetrical hemorrhage.5,6 Maternal coagulation disorders are one of the less common causes of PPH but may include disseminated intravascular coagulation (DIC), platelet disorders, or a coagulation factor deficiency or defect.5,6,29 Low fibrinogen levels in women diagnosed with PPH have been implicated as a factor determining the course of PPH and may provide an early predictor of its severity.30–34 The correct diagnosis of a coagulopathy as the underlying cause for PPH might be missed if conventional laboratory tests are not conducted in a timely fashion, or the results of key tests are misinterpreted, leading to delays in hemostatic treatment decisions. Data from the EACH2 registry has shown that delayed diagnosis of acquired hemophilia A as the cause of PPH, even in women with typical clinical and laboratory findings, has a significant impact on treatment initiation, patient morbidity, and outcomes.11,35 Point-of-care coagulation tests (i.e., thromboelastography and rotational thromboelastometry) are gaining increased interest as potential approaches to more rapid determination of the patient’s actual coagulation state that could guide the selection of blood products to be transfused or the use of other hemostatic treatments to improve outcomes.30,31,36 Postpartum FVIII inhibitors account for 7 to 21% of all confirmed cases of acquired hemophilia A.37–41 While the clinical picture for postpartum acquired hemophilia A can often be severe and life-threatening, the prognosis for patients with postpartum FVIII inhibitors is quite favorable if acute bleeding is quickly controlled.1,5,6,13 The natural history of postpartum acquired hemophilia A is typically benign once hemostasis is restored with a high percentage of spontaneous remissions (> 60% of cases) within a median of 30 months after delivery and a low (< 10%) mortality

Paidas, Hossain

Postpartum Hemorrhage Due to an Acquired Factor VIII Inhibitor and high titers with more severe bleeding.13,14,16–18,23,47 FVIII inhibitor titers can be used to guide treatment for a given patient, especially one with a high titer and severe bleeding who is more likely to develop complications requiring surgery and intensive care and may also experience inhibitor persistence, despite aggressive treatment.13,15 Bleeding is related to the timing of inhibitor development, with early postpartum development associated with persistent vaginal bleeding and later postpartum development usually associated with severe bleeding involving nongynecologic tissues.13,15,16 Clinical heterogeneity in the anatomic sites and patterns of bleeding in patients with postpartum acquired hemophilia A may contribute significantly to the difficulty in making this diagnosis, setting the stage for delayed treatment, persistent bleeding, and increased morbidity.47 Taken together, unexplained persistent postpartum bleeding should heighten clinical suspicion and motivate an immediate collaboration with a hematology specialist or bleeding disorders treatment center to determine an accurate diagnosis and the best course of patient treatment, management, and follow-up.

Diagnostic and Laboratory Testing Strategies The patient’s hemoglobin was 5.6 g/dL (normal, 12.1–15.1 g/dL), activated partial thromboplastin time (aPTT) 95 seconds (normal, 26–36 seconds), prothrombin time (PT) 11 seconds (normal, 8–12 seconds), and bleeding time 7 minutes 42 seconds (normal, < 10 minutes). She was transfused with two additional

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units of RBCs. She underwent a dilation and second curettage, but the bleeding persisted and 8 hours later she had a total abdominal hysterectomy. She received additional intraoperative transfusions of RBCs, cryoprecipitate, and fresh frozen plasma. On postoperative day 2, she presented with extensive ecchymoses on her upper torso and extremities and an abdominal ultrasound showed signs of retroperitoneal bleeding. She was promptly transferred to the intensive care unit and was referred to the hematology center for laboratory studies to evaluate abnormalities of coagulation. The patient in the scenario was readmitted to the hospital with the cause of her persistent vaginal bleeding undetermined. To prevent further deterioration of her condition due to the unexplained ongoing loss of blood, prompt investigation to pinpoint the cause of bleeding and to determine the most appropriate treatment approach is imperative. Knowledge of the cardinal sites and patterns of bleeding (►Table 2) must be combined with an appropriate laboratory testing strategy (►Fig. 1) to facilitate timely diagnosis and treatment of an acquired FVIII inhibitor in postpartum patients with persistent bleeding.16,20,22,48 Obstetricians/gynecologists need to be aware of the importance and urgency of early collaboration with a hematology specialist to allow accurate interpretation of key initial coagulation test results and rapid assessment of whether PPH is due to an anatomic cause or a coagulopathy. Initial laboratory tests should include a comprehensive panel of conventional hematologic blood tests, including a

Fig. 1 An algorithm for the recognition, diagnosis, testing, and treatment of a postpartum acquired FVIII inhibitor. aPTT, activated partial thromboplastin time; BU/mL, Bethesda units per milliliter plasma; CBC, complete blood count; DIC, disseminated intravascular coagulation; FVIII, factor VIII; Hgb, hemoglobin; PT, prothrombin time; vWD, von Willebrand disease. American Journal of Perinatology

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Postpartum Hemorrhage Due to an Acquired Factor VIII Inhibitor

Neonatal Bleeding Complications from Acquired FVIII Inhibitors It is important to note that, while sporadic, several case reports have described transplacental transfer of maternal FVIII autoantibodies to the fetus that can result in clinically significant infant bleeding and morbidity.11,15,24,51–55 The mechanism most likely involves a specialized transplacental immunoglobulin transport process normally active during late-stage pregnancy to provide maternal antibodies for early newborn humoral immunity.56,57 The incidence of

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acquired neonatal postpartum acquired hemophilia A is unknown, although morbidity, if it occurs, can range from mild epistaxis and ecchymoses to life-threatening intracranial hemorrhage.11,15,24,51–53 Neonatal postpartum acquired hemophilia A also has a benign course with rapid clearance and elimination of maternal FVIII inhibitors once bleeding is controlled with appropriate hemostatic medical intervention.11,15,54,55

Management of the Patient with a Confirmed Acquired FVIII Inhibitor Diagnosis Control of Acute Bleeding To stop the bleeding, the patient was treated with activated recombinant factor VIIa (rFVIIa) at a dose of 90 μg/kg every 2 hours. After 48 hours, the rFVIIa dose was increased to 120 μg/kg every 2 hours for persistent bleeding. After 6 days, bleeding was controlled and hemoglobin level returned to normal. The patient was also started on an immunosuppressive (IS) regimen with rituximab once weekly (weekly dose ¼ patient body surface area [m2]  375 mg) for 4 weeks once the diagnosis of postpartum acquired hemophilia A was confirmed. After the final dose of rituximab, the patient’s inhibitor titer level decreased from its highest level of 114 to 8 BU/mL. The management strategy for the patient with postpartum acquired hemophilia A in the scenario is based on bleeding severity and inhibitor titer. The most immediate goal of treatment is to control acute bleeding. The inhibitor titer is often used to guide the initial choice of therapy for restoration of hemostasis.16,21,46,49 Patients with a low-titer FVIII inhibitor (< 5 BU/mL) and minor bleeding can be managed with desmopressin, a synthetic arginine-vasopressin analogue that causes release of von Willebrand factor (vWF) from the vascular endothelium and acts as a carrier protein for plasma FVIII. Desmopressin causes a transient rise in plasma FVIII: vWF to hemostatic levels ( 50%), but patients must be carefully monitored for tachyphylaxis to its hemostatic effect after 3 to 4 days of use, as well as for potential antidiuretic and vasomotor side effects.47 Intravenous human recombinant FVIII (rFVIII) concentrate may also be administered alone or in combination with desmopressin to stop the bleeding and achieve hemostasis; however, no data are available from controlled studies on the use of high-dose rFVIII replacement therapy in acquired hemophilia.47 As a result, rFVIII has been recommended for use only in patients with a low inhibitor titer with minor bleeding and when bypassing agents are unavailable. This recommendation is also based on the unpredictability of rFVIII plasma half-life and observed variability in the pharmacokinetics of infused rFVIII concentrate.47 Patients with PPH due to a high-titer FVIII inhibitor (> 5 BU/mL) or severe bleeding regardless of inhibitor titer should promptly be treated with a bypassing agent. First-line therapies include administration of either rFVIIa or plasma-derived activated prothrombin complex concentrate (pd-aPCC) to control acute bleeding and restore hemostasis. Both bypassing agents have shown high rates of patient response (response rates  80%) successfully achieving hemostasis in American Journal of Perinatology

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complete blood count with differential, platelets, and a reticulocyte count; and coagulation studies, including PT, aPTT, and fibrinogen. Results should provide an initial presumptive diagnosis by exclusion of other potential causes of bleeding such as thrombocytopenia and DIC. An initial aPTT that is prolonged, while the PT and other laboratory measures of bleeding tendency are normal should immediately heighten suspicion of an acquired clotting factor deficiency, possibly one mediated by a FVIII inhibitor.16,20,49 A prolonged aPTT may also be due to a heparin or warfarin overdose, lupus-type inhibitors with or without antiphospholipid syndrome, or DIC necessitating further laboratory testing and additional patient history.19,20 Results of a mixing study failed to show a correction of the aPTT to the normal range after incubation for 2 hours at 37°C suggesting an acquired clotting factor inhibitor. Further testing, using the Bethesda assay expressed as Bethesda units (BU) per mL, confirmed an inhibitor titer of 78 BU/mL (normal, 0 BU/mL). Specific assay of plasma FVIII showed a decrease to 3% (normal, 50–150%); plasma FIX level was normal. Fibrinogen level was 425 mg/dL (normal, 200–350 mg/dL). The patient in our scenario has a prolonged aPTT that cannot be corrected in a mixing study by addition of an equal volume of normal plasma to the patient’s plasma after incubation at 37°C for at least 2 hours, which is indicative of an acquired FVIII inhibitor (►Fig. 1).20,21 The mixing study should be followed up with a modified in vitro Bethesda assay, which is used to quantify the plasma titer of the FVIII antibody inhibitor, and an assay to measure the patient’s plasma FVIII level.20,21 It is important to note that the in vivo potency of the inhibitor may be underestimated by the Bethesda assay due to the incomplete and complex nature of autoantibody inactivation of FVIII (type II kinetics) which is different from the complete inactivation of FVIII achieved by alloantibody interaction in patients with mild and moderate hemophilia (type I and type II kinetics).16,50 The kinetic properties of FVIII autoantibodies can complicate both the choice of therapy and the ability to monitor a therapeutic response.16 The severity of bleeding must also be factored into therapeutic decision-making regardless of inhibitor titer.16,18,46 These critical complexities of making the diagnosis of an acquired FVIII inhibitor highlight the importance of early consultation and collaboration with an experienced hematology specialist to facilitate a thorough but efficient diagnostic evaluation and determine the best course of therapy once the diagnosis is established.

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Postpartum Hemorrhage Due to an Acquired Factor VIII Inhibitor postpartum acquired hemophilia A patients with moderate to severe bleeding.13,28,47 The benefit of rFVIIa in the setting of hemorrhage due to acquired hemophilia A is consistent with rFVIIa’s success in treatment of massive postpartum hemorrhage, especially where limited therapeutic options such as interventional radiology are available.58 Analysis of data from the EACH2 supports the use of bypassing agents as first-line therapies for bleeding control in patients with acquired FVIII inhibitors.11 EACH2 is a large, prospective database tracking the characteristics, diagnosis, treatment, and outcomes of patients (n ¼ 501, males and females, included between 2003 and 2008) with bleeding due to acquired FVIII inhibitors.35,59,60 Forty-two acquired hemophilia A cases (8.4%) from EACH2 were associated with the peripartum period in women who had a median FVIII level at diagnosis of 2.5 IU/dL, an inhibitor titer of 7.8 BU/mL, and a median time to diagnosis of acquired hemophilia A after delivery of 89 days.11 Control of bleeding episodes was significantly higher in patients treated with bypassing agents compared with those treated with FVIII and desmopressin (93.3 and 68.3%, respectively; p ¼ 0.003).11,59 For rFVIIa and pd-aPCC, rates of bleeding control (93.0% for both) and the incidence of thrombotic events (2.9 and 4.8%, respectively) were similar.59 Use of pd-aPCC and rFVIIa concomitantly in a sequential or combined dosing regimen for severe bleeding has been reported to achieve hemostasis in patients where monotherapy with either agent alone has failed.61 However, the concomitant use of these bypassing agents in the same patient can pose an increased risk of adverse thromboembolic events that can be serious or life-threatening, and data from prospective, randomized, and controlled studies are lacking.62–65 The combined use of bypassing agents is still considered experimental and poses a significant thrombotic risk in patients with acquired hemophilia or severe congenital hemophilia with high titer inhibitors.66 In the absence of appropriately controlled safety and efficacy studies, the US Food and Drug Administration (FDA) has warned against concomitant use of these agents and considers it outside their labeled indications.66 Taken together, increased risk of thrombogenesis in certain patients with thrombophilic comorbidities or drug sensitivities coupled with the unpredictability of patient response highlight the need for early consultation and collaboration with a hematology specialist.47

Eradication of Inhibitors After 2 months in the hospital undergoing an aggressive therapeutic regimen, the patient’s inhibitor titer was 0.4 BU/mL, and her plasma FVIII concentration was 40% at discharge. Six months after delivery, the patient had a sustained response to IS therapy with no detectable FVIII inhibitor and her plasma FVIII concentration was within normal range at 90%. (A sustained or complete response to IS therapy has been defined as an inhibitor level < 0.6 BU/mL and an FVIII level > 50%.)21 For this patient with postpartum acquired hemophilia A, the other immediate goal of therapy is the eradication of the acquired FVIII inhibitor. The strategy to achieve this goal American Journal of Perinatology

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involves initiation and management of IS therapy by the hematology specialist or team, as soon as possible after diagnosis, with corticosteroids used as first-line treatment. While the response to IS therapy does not appear to correlate with bleeding severity or baseline inhibitor titer,13,47,67 positive predictive indices for IS response have been shown to consist of a low initial inhibitor titer and a short time interval between symptomatic bleeding and the start of an IS regimen.47 The decision to initiate aggressive IS therapy is not a clear-cut one and must be carefully weighed against the likelihood of a benign course and spontaneous inhibitor remission or potential contraindications in some postpartum patients due to the chances for adverse effects, infection, potential drug interactions, or agent toxicity.2,13,21,47,50 In particular, the use of agents that have broad cytotoxic effects, such as cyclophosphamide, may pose an increased risk for infertility.13,21,22,68,69 While the benefit of IS treatment of patients with postpartum acquired hemophilia A has been called into question by retrospective studies and registry data,13,14,38–41,70 recent expert recommendations have advocated IS treatment for inhibitor eradication in all acquired hemophilia A patients at diagnosis, including those with postpartum acquired hemophilia A, due to the high risk for recurrent bleeding and the inability to accurately predict which patients will undergo spontaneous inhibitor remission once bleeding is controlled.21,69 Overall, the risks of IS treatment of postpartum patients with drugs such as corticosteroids, cyclophosphamide, or azathioprine as first-line IS therapies are considered minimal relative to the grave risks associated with major, persistent bleeding.12 In some cases, patients with postpartum acquired hemophilia A may present with a persistent high-titer inhibitor that fails to respond to corticosteroid treatment or other firstline therapies. When this occurs, second-line therapeutic options can include rituximab, a selective biologic IS agent or immune tolerance induction (ITI), a complex therapeutic strategy aimed at physical inhibitor depletion combined with concurrent FVIII replacement and IS treatment. Rituximab, which has become an important agent for the treatment of other autoimmune disorders such as rheumatoid arthritis, selectively eliminates the autoreactive CD20 positive B-lymphocytes involved in FVIII autoantibody production.43,47,48,71–75 Recent reports from a limited number of cases suggest that rituximab, alone or combined with other IS agents such as a corticosteroid or cyclophosphamide, can be highly effective in eradicating postpartum acquired FVIII inhibitors in patients refractory to first-line IS regimens.43,71–74,76,77 Zeitler et al78 reported the successful use of ITI for achieving inhibitor remission in four cases of postpartum acquired hemophilia A. The presentation of a postpartum patient with a persistent high-titer FVIII inhibitor mandates immediate collaboration with experienced hematology experts because IS regimens are complex, treatment responses are unpredictable, and there are currently no evidence-based guidelines.21,47,69 Recent analyses of data from EACH2 have shown that achievement of stable, complete inhibitor remission (defined as undetectable titer, an FVIII level > 70 IU/dL, and discontinued

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Fig. 2 Proposed immunologic mechanism of autoantibody generation against FVIII leading to a state of acquired hemophilia A that may be involved in postpartum hemorrhage. sPIF, synthetic preimplantation factor. Coagulation factors: FI, fibrinogen; FIa, fibrin; FII, prothrombin; FIIa, thrombin; FV, factor V; FVa, activated FV; FVIIa, activated FVII; FVIII, coagulation factor VIII; FIX, factor IX; FIXa, activated FIX; FX, factor X; FXa, activated FX; FXIa, activated FXI; FXIIIa, activated FXIII.

IS) occurred with highest frequency in patients treated with steroids combined with cyclophosphamide (70%) compared with steroids alone (48%) or rituximab alone (59%).11,60 When controlled for age, sex, FVIII level, inhibitor titer, and underlying bleeding etiology, stable remission was more likely with the combination of steroids and cyclophosphamide than the use of steroids alone (odds ratio ¼ 3.25; 95% CI, 1.51–6.96; p < 0.003).11,60 Key factors influencing stable remission included the patient’s initial inhibitor titer and FVIII level. The median time to complete remission was twice as long for a rituximab regimen compared with a regimen of steroids plus cyclophosphamide (10 weeks and 5 weeks, respectively).60 More effective and safer immune modulatory agents would have a profound impact on the eradication of FVIII inhibitors. We are actively pursuing the treatment of FVIII inhibitors in an animal model. Specifically, a new mutation in the FVIII gene in the WAG-F8m1Ycb rat has resulted in decreased FVIII levels and a severe bleeding tendency.79 Our research involves creation of FVIII inhibitors in this WAG-F8m1Ycb rat, and the application of a novel synthetic analogue of a mammalian embryo-derived peptide, preimplantation factor (PIF), with potent immune modulatory properties that have characterized.80 PIF promotes embryo-decidual adhesion and influences critical peri-implantation events.81 Synthetic PIF (sPIF) orchestrates a systemic anti-inflammatory effect in humans. In naive human peripheral blood mononuclear cells (PBMCs), sPIF binds avidly to CD4þ monocytes/leucocytes, and in activated PBMCs binding to T and B cells increasing both TH2/TH1 cytokine secretion and gene expression.82 Several animal models confirm sPIF’s beneficial effects in immune-mediated diseases, including murine models of diabetes, multi-

ple sclerosis, and graft-versus-host disease. 83–85 sPIF not only favorably alters the TH2/TH1 cytokine balance by decreasing pro-inflammatory cytokines (IL-6, IL-17, IL-12, and IFNγ), it also affects B-cell–mediated pathways.84 Interestingly, sPIF may play a key role in altering FVIII inhibitor development, as sPIF has been demonstrated to significantly affect B7H1 surface receptor expression on bone marrow derived monocytes (►Fig. 2).85 Required FDA pretoxicology studies for human application of sPIF are now complete, paving the way for human clinical trials of sPIF.

Conclusions PPH is a leading cause of maternal morbidity and mortality worldwide, and in the United States it has accounted for 19.1% of all inpatient maternal deaths from 1994 to 2006.3,9,10 Unexplained PPH that does not respond to standard interventions for restoring hemostasis should promptly alert obstetricians/gynecologists to suspect an acquired FVIII inhibitor. The proportion of PPH-related mortality attributable to postpartum acquired hemophilia A is unknown due to its rare occurrence; however, postpartum acquired hemophilia A can have catastrophic consequences, including loss of fertility, debilitating morbidity, or death, if not rapidly recognized and promptly treated. Transplacental transfer of FVIII inhibitors is an emerging bleeding threat to newborns that must also be promptly recognized and treated if it presents after delivery.11,15,54 Despite the grave hemorrhagic risk of postpartum acquired hemophilia A, the natural history of acquired FVIII inhibitors is relatively benign, with a high rate of spontaneous inhibitor American Journal of Perinatology

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Postpartum Hemorrhage Due to an Acquired Factor VIII Inhibitor

Postpartum Hemorrhage Due to an Acquired Factor VIII Inhibitor remission and a low mortality rate in mothers and rapid inhibitor clearance in infants, if acute bleeding is controlled early after delivery.2,11–13,15,40,41,54 Increased awareness and understanding of acquired FVIII inhibitor development and persistence is needed by obstetricians/gynecologists because unchecked, persistent postpartum bleeding can quickly escalate and become a serious bleeding threat to mother and child if conventional medical or surgical hemostatic interventions fail. To optimize clinical outcomes in adult female patients with postpartum acquired hemophilia A, the two immediate goals of treatment are to control bleeding and eradicate systemic FVIII inhibitors; this will restore hemostasis. To attain these goals, close collaboration with an expert hematologist or hemostasis center is absolutely essential because of the major challenges involved in the prompt and appropriate management of postpartum acquired hemophilia A. The key challenges include the difficult diagnosis and accurate interpretation of laboratory results, variable and unpredictable treatment responses, the recurrence of bleeding, and a lack of evidence-based treatment guidelines. A hematologist will provide valuable input to the diagnosis and interpretation of laboratory results, the risk-benefit assessment of patient treatment, and this expertise integral to the successful long-term management and follow-up care of women and children affected by postpartum acquired hemophilia A.

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Acknowledgments Editorial and writing assistance was provided by Jeffrey M. Palmer, PhD, ETHOS Health Communications, Newtown, PA, with financial assistance from Novo Nordisk, Inc., in compliance with international good publication practice guidelines.

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References

23

1 Borna S, Hantoushzadeh S. Acquired hemophilia as a cause of

2

3

4

5 6 7

8

primary postpartum hemorrhage. Arch Iran Med 2007;10(1): 107–110 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 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 Callaghan WM, Kuklina EV, Berg CJ. Trends in postpartum hemorrhage: United States, 1994-2006. Am J Obstet Gynecol 2010; 202(4):e1–e6 Silver RM, Major H. Maternal coagulation disorders and postpartum hemorrhage. Clin Obstet Gynecol 2010;53(1):252–264 Walfish M, Neuman A, Wlody D. Maternal haemorrhage. Br J Anaesth 2009;103(Suppl 1):i47–i56 Mecacci F, Pieralli A, Bianchi B, Paidas MJ. The impact of autoimmune disorders and adverse pregnancy outcome. Semin Perinatol 2007;31(4):223–226 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

American Journal of Perinatology

Vol. 31

No. 8/2014

24 25

26

27

28

29 30

31

Paidas, Hossain

Gynecology. 1st ed. Oxford, UK: Blackwell Publishing (Wiley Blackwell); 2011 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 Oyelese Y, Ananth CV. Postpartum hemorrhage: epidemiology, risk factors, and causes. Clin Obstet Gynecol 2010;53(1):147–156 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 Kadir RA, Aledort LM. Obstetrical and gynaecological bleeding: a common presenting symptom. Clin Lab Haematol 2000;22 (Suppl 1):12–16, discussion 30–32 Franchini M. Postpartum acquired factor VIII inhibitors. Am J Hematol 2006;81(10):768–773 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 Lulla RR, Allen GA, Zakarija A, Green D. Transplacental transfer of postpartum inhibitors to factor VIII. Haemophilia 2010;16(1): 14–17 Franchini M, Gandini G, Di Paolantonio T, Mariani G. Acquired hemophilia A: a concise review. Am J Hematol 2005;80(1):55–63 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 Franchini M, Lippi G. Acquired factor VIII inhibitors. Blood 2009; 113(21):5368 Ma AD, Carrizosa D. Acquired factor VIII inhibitors: pathophysiology and treatment. Hematology (Am Soc Hematol Educ Program) 2006:432–437 Kessler CM. Hemophilia Acquired. eMedicine Hematology Web site. 2008http://emedicine.medscape.com/article/211186-overview. Accessed April 7, 2010 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 Collins PW, Percy CL. Advances in the understanding of acquired haemophilia A: implications for clinical practice. Br J Haematol 2010;148(2):183–194 Boggio LN, Green D. Acquired hemophilia. Rev Clin Exp Hematol 2001;5(4):389–404, quiz 431 Broxson EH, Hathaway WE. Transplacental transfer of acquired factor VIII: C inhibitor. Thromb Haemost 1987;57(1):126 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 Franchini M, Lippi G, Franchi M. The use of recombinant activated factor VII in obstetric and gynaecological haemorrhage. BJOG 2007;114(1):8–15 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 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 Levi M, Opal SM. Coagulation abnormalities in critically ill patients. Crit Care 2006;10(4):222 Onwuemene O, Green D, Keith L. Postpartum hemorrhage management in 2012: predicting the future. Int J Gynaecol Obstet 2012;119(1):3–5 de Lange NM, Lancé MD, de Groot R, Beckers EA, Henskens YM, Scheepers HC. Obstetric hemorrhage and coagulation: an update.

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

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Postpartum Hemorrhage Due to an Acquired Factor VIII Inhibitor

33

34

35

36

37 38

39 40

41

42

43

44

45

46

47 48

49 50

51

52

653

53 Frick PG. Hemophilia-like disease following pregnancy with trans-

54 55

56 57

58

59

60

61

62 63

64

65

66

67

68 69

70

71

72

73

74

placental transfer of an acquired circulating anticoagulant. Blood 1953;8(7):598–608 Moraca RJ, Ragni MV. Acquired anti-FVIII inhibitors in children. Haemophilia 2002;8(1):28–32 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 Simister NE. Placental transport of immunoglobulin G. Vaccine 2003;21(24):3365–3369 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 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 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 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 Miranda GG, Rodgers GM. Treatment of an acquired factor VIII inhibitor with sequential recombinant factor VIIa and FEIBA. Haemophilia 2009;15(1):383–385 Aledort LM. Factor VIII inhibitor bypassing activity (FEIBA) addressing safety issues. Haemophilia 2008;14(1):39–43 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 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 Roberts HR, Monroe DM, White GC. The use of recombinant factor VIIa in the treatment of bleeding disorders. Blood 2004;104(13): 3858–3864 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 Barnett B, Kruse-Jarres R, Leissinger CA. Current management of acquired factor VIII inhibitors. Curr Opin Hematol 2008;15(5): 451–455 Green D. The management of acquired hemophilia. Haemophilia 2006;12(Suppl 5):32–36 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 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 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 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 Santoro C, Rago A, Biondo F, et al. Efficacy of rituximab treatment in postpartum acquired haemophilia A. Haemophilia 2008;14(1): 147–149 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 American Journal of Perinatology

Vol. 31

No. 8/2014

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

32

Thromboelastography, thromboelastometry, and conventional coagulation tests in the diagnosis and prediction of postpartum hemorrhage. Obstet Gynecol Surv 2012;67(7):426–435 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 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 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 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 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 Solymoss S. Postpartum acquired factor VIII inhibitors: results of a survey. Am J Hematol 1998;59(1):1–4 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 Michiels JJ, Bosch LJ, van der Plas PM, Abels J. Factor VIII inhibitor postpartum. Scand J Haematol 1978;20(2):97–107 Michiels JJ. Acquired hemophilia A in women postpartum: clinical manifestations, diagnosis, and treatment. Clin Appl Thromb Hemost 2000;6(2):82–86 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 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 Santoro RC, Prejanò S. Postpartum-acquired haemophilia A: a description of three cases and literature review. Blood Coagul Fibrinolysis 2009;20(6):461–465 Shear W, Rosner MH. Acute kidney dysfunction secondary to the abdominal compartment syndrome. J Nephrol 2006;19(5): 556–565 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 Franchini M, Lippi G. Recent improvements in the clinical treatment of coagulation factor inhibitors. Semin Thromb Hemost 2009;35(8):806–813 Baudo F, Caimi T, de Cataldo F. Diagnosis and treatment of acquired haemophilia. Haemophilia 2010;16(102):102–106 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 Collins PW. Treatment of acquired hemophilia A. J Thromb Haemost 2007;5(5):893–900 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 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 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

Paidas, Hossain

Postpartum Hemorrhage Due to an Acquired Factor VIII Inhibitor 75 Stasi R, Brunetti M, Stipa E, Amadori S. Selective B-cell depletion

76

77 78

79

80

81

with rituximab for the treatment of patients with acquired hemophilia. Blood 2004;103(12):4424–4428 Holme PA, Brosstad F, Tjønnfjord GE. Acquired haemophilia: management of bleeds and immune therapy to eradicate autoantibodies. Haemophilia 2005;11(5):510–515 Toschi V, Baudo F. Diagnosis, laboratory aspects and management of acquired hemophilia A. Intern Emerg Med 2010;5(4):325–333 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 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 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 Barnea ER, Kirk D, Paidas MJ. Preimplantation factor (PIF) promoting role in embryo implantation: increases endometrial integrin-

American Journal of Perinatology

Vol. 31

No. 8/2014

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83

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α2β3, amphiregulin and epiregulin while reducing betacellulin expression via MAPK in decidua. Reprod Biol Endocrinol 2012; 10:50 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 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 Weiss L, Or R, Jones RC, et al. Preimplantation factor reduces graftversus-host disease by regulating immune response and lowering oxidative stress (murine model). J Neurol Sci 2012;312(1–2): 146–157 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

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