Arch Iranian Med 2007; 10 (1): 107 110

Case Report

Acquired Hemophilia as a Cause of Primary Postpartum Hemorrhage

Sedigheh Borna MD *, Sedigheh Hantoushzadeh MD*

A 32-year-old primigravid woman developed acquired factor VIII inhibitor after delivery. She presented with postpartum hemorrhage and large hematoma in episiotomy site. Laboratory examinations showed markedly prolonged activated partial thromboplastin time, low levels of factor VIII (8%), and factor VIII inhibitor (2 Bethesda units). The bleeding was controlled successfully using combined treatment with factor VIII, intravenous immunoglobulin, steroids, and recombinant factor VIIa. Six months after delivery, factor VIII inhibitor was not present and factor VIII concentration increased to normal range. Acquired hemophilia is a life-threatening disorder. Precise screening of coagulation factors is essential for diagnosis of persisting postpartum hemorrhage.
Archives of Iranian Medicine, Volume 10, Number 1, 2007: 107 110.

Keywords: Acquired hemophilia A factor VIII inhibitor postpartum hemorrhage

Introduction
cquired hemophilia A is an uncommon hemorrhagic disorder caused by spontaneous occurrence of autoantibodies directed against the factor VIII. These inhibitors that develop in nonhemophilic patients are associated with various underlying conditions such as pregnancy, lymphoproliferative or myeloproliferative disorders, solid tumors, autoimmune diseases, and allergic reactions to medications (penicillin, chloramphenicol, and phenytoin).1, 2 Acquired hemophilia A is rare. Its incidence is about 1 per 5 million individuals per year. About 14% of cases with acquired hemophilia can be identified in the postpartum period. Such patients usually show postpartum hemorrhage (PPH) or uncontrolled bleeding after surgical interventions. The clinical picture is often severe and lifethreatening with a death rate between 10 22% depending on case series.3 Severe, prompt, and
Authors affiliation: *Department of Obstetrics and Gynecology, Tehran University of Medical Sciences, Tehran, Iran. Corresponding author and reprints: Sedigheh Borna MD, 2nd Floor, Vali-e-Asr Hospital, Imam Khomeini Hospital Complex, Keshavarz Blvd., Tehran 14194, Iran. Tel: +98-216-6937766, Fax: +98-218-8718062, E-mail: s_borna@hotmail.com. Accepted for publication: 19 April 2006

accurate diagnosis is necessary in order to provide adequate treatment.

Case Report
A 32-year-old primigravida woman, with no significant medical history delivered a 3,500 g female neonate at 40th gestational week in a local hospital, 12 days prior to admission. The pregnancy was uncomplicated until 2 days after delivery. Two days after discharge, she developed intermittent vaginal bleeding, with passage of a large clot along with large hematoma in the episiotomy site. A dilatation and curettage was performed for the presumed retained products of conception. The large hematoma was evacuated and the site was sutured. A few days later, the patient continued to have heavy spotting and passage of clots, along with large hematoma in the vulva. She received methylergonovine plus oxytocin and dilatation and curettage was performed again. The patient required multiple transfusions for persistent blood loss. Because of the uncontrollable bleeding and prolonged partial thromboplastin time (PTT) (89 second), the patient was referred to our academic hospital 12 days after delivery. On admission, she was severely anemic and had

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Acquired hemophilia as a cause of primary PPH

Table 1. Laboratory values at admission.

Hemoglobin Hematocrit Platelet PTT PT Fibrinogen D-dimers Fibrin split products Factor VIII inhibitor Factor VIII 5.6 g/dL 15% 16010/L 89 seconds 12 seconds 358 mg/dL 0.2 0.4 g/mL < 5 mg/L 2 Bethesda units 8%

intermittent vaginal bleeding. Vaginal ultrasonography of the pelvis did not reveal any abnormal findings in the uterus and pelvis. The laboratory results showed hemoglobin = 5.6 g/dL, and an activated PTT = 89 seconds. Other laboratory tests, including prothrombin time (PT), platelet count, and D-dimers, were within normal limits. The results of the other tests such as rheumatoid factor, antinuclear antibody, anticardiolipin IgG, and HIV were all normal or negative. Further work-up revealed low levels of factor VIII (8%). A factor inhibitor screen was performed, and the result was positive, with a titer of 2 Bethesda units (BU). Laboratory data are summarized in Table 1. The absence of familial and personal bleeding history plus normal vaginal ultrasonography of pelvis and laboratory tests, accompanied by the fact that the PTT was not corrected following the infusion of normal plasma led us to presume that a coagulation inhibitor was involved. After consultation with senior hematologists, we decided to transfuse packed red blood cell and human factor VIII. Intravenous immune globulin (IVIG) 40 g/day for 2 days and tranexamic acid l g every 12 hours were used too. Immune suppression was started at the same time with prednisone 50 mg per day. The patient received uterotonic drugs such as oxytocin and ergot alkaloids. We also began a course of intravenous antibiotics for possible endometritis and wound infections. After 3 days, the patient continued to have
Table 2. Treatment modalities.
Agents Human factor VIII IVIG Tranexamic acid Prednisone rFVIIa (Novo seven) Day 1 50 U/kg daily 40 g 1 g/BID 50 mg 60 g/kg QID Day 2 50 U/kg daily 40 g 1 g/BID 50 mg 60 g/kg QID Day 3 50 U/kg daily 1 g/BID 50 mg 60 g/kg QID

vaginal bleeding and passage of clots. The laboratory results showed a prolonged activated PTT (77 second). Recombinant factor VIIa (Novo seven) was commenced as the final attempt to control the bleeding. An intravenous bolus injection of 90 g/kg Novo seven was started, followed by 60 g/kg after 2 hours. The same dose was then administered every 4 hours for 48 hours, then every 8 hours for 2 days more. Using this method of treatment, the vaginal bleeding was quickly controlled and hemoglobin levels stabilized. Novo seven and factor VIII were discontinued after 8 days (Table 2). Ten days after admission, the patient was discharged from the hospital in good clinical condition. Prednisone was continued for 4 weeks and then gradually tapered. Three months after delivery, factor VIII inhibitor was 1 BU and factor VIII concentration was 50% (normal range: 60 120%). Six months after delivery, factor VIII inhibitor was not present and factor VIII concentration had increased to normal range (Table 3).

Discussion
PPH is a major cause of maternal mortality and morbidity worldwide. The most common cause of PPH is uterine atony.3 Other causes include retained placental tissues, abnormal adhesion of the placenta, lower genital laceration, uterine rupture, and coagulopathy. Our patient had acquired hemophilia A, which was a result of factor VIII inhibitor production. The patients disease was diagnosed by a coagulation profile, which showed isolated elevation of the PTT. Other coagulation parameters were normal. The next test done was a check of individual factor levels, which revealed low factor VIII activity. The factor inhibitor screen showed a titer of 2 BU. Michiels et al2 have reviewed 27 patients with postpartum factor VIII inhibitors; these patients had over 100 bleeding episodes and only one patient had significant bleeding during pregnancy. Six patients

Day 4 50 U/kg daily 1 g/BID 50 mg

Day 5 50 U/kg daily 1 g/BID 50 mg

Day 6 50 U/kg daily 1 g/BID 50 mg

Day 7 50 U/kg daily 1 g/BID 50 mg

Day 8 50 U/kg daily 1 g/BID 50 mg

rFVIIa = recombinant activated factor VII.

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S. Borna, S. Hantoushzadeh

Table 3. Laboratory values after treatment.

PTT after 3 days PTT after 8 days Factor VIII inhibitor after 3 months Factor VIII inhibitor after 6 months Factor VIII after 3 months Factor VIII after 6 months
BU = Bethesda unit.

77 seconds 41 seconds 1 BU Negative 50% 90%

had significant PPH and in five of these patients the PPH lasted for several weeks. Two of these patients had undergone laparotomy with hysterectomy before the coagulation defect was detected. Mortality occurred in three patients; one patient died shortly after delivery due to uncontrollable bleeding and two other patients died due to respiratory obstruction following laryngeal hemorrhage and retroperitoneal bleeding, respectively. In a more recent survey, 14 additional new cases of postpartum acquired hemophilia have been analyzed. These patients had a total of 80 bleeding episodes, 34 of which were severe and five were life-threatening. One patient had severe PPH requiring hysterectomy .3 When medical treatments and conservative surgical procedures fail to control the bleeding, hysterectomy is usually needed. 3, 4 Emergency hysterectomy is associated with significant blood loss, and more postoperative complications. Our presented case showed that early recognition of a prolonged activated PTT in a bleeding patient is essential for the diagnosis and initiation of adequate treatment. Our case also showed that accurate diagnosis and adequate treatment could successfully control life-threatening PPH in women who had acquired hemophilia A and emergency hysterectomy was not needed. Patients who develop hemophilia A during postpartum period usually present within 1 to 4 weeks after delivery. Acquired postpartum hemophilia usually affects the first pregnancy and future pregnancies are rarely affected.3, 4 The prognosis of acquired hemophilia A depends on the underlying disorder and the inhibitor titer. Postpartum and idiopathic forms as well as those with low inhibitor titer, have more favorable prognosis.4 The antenatal transplacental transmission of factor VIII has been reported in a case of severe neonate intracranial hemorrhage,4 but in our case the neonatal had normal factor VIII levels and there were no neonatal sequel. Management of this disease should be aimed at

stopping the hemorrhage, raising endogenous factor VIII levels, and reducing the inhibitor levels.5, 6 Treatment consists of blood products to replace the blood loss, coagulation factors, and immunosuppressants. Human factor VIII concentrate may seem a logical choice for treatment, but it can be dangerous in patients whose immune system responds to the infusion of factor VIII by increasing the antibody levels (high responders). An animal-derived product, porcine factor VIII, has been used to maintain the patients clotting ability while other treatments are used to stop antibody production. Before administering porcine factor VIII, it has to be determined that the patients antibody does not cross-react with the animal-derived factor VIII. This treatment usually works best in patients who have antibody titers lower than 50 BU. Prothrombin complex concentrates (e.g., Konyne, Autoplex T) are available now. These are a combination of clotting factors that contain activated forms of factors X and VII, which bypass the inhibited intrinsic arm of the cascade. Because the patients receive activated coagulating factors, there is a risk of converting the situation to a thrombotic state. So, the patients must be monitored for signs of disseminated intravascular coagulation or deep venous thrombosis. Another available treatment is a recombinant form of factor VIIa (Novo seven). It reacts with tissue factor and activates factor X, stimulating the common coagulation cascade and bypassing the inhibited intrinsic arm. 7, 8 Steroids and in most cases cytotoxic chemotherapy are given in the same way they are used for the treatment of other autoimmunemediated disorders. In addition, IVIGs have been used with some success but the exact mechanism of action is not clear. However, it is thought that anti-idiotypic antibodies are present in pooled human immunoglobulin that neutralize the acquired inhibitor.1 Plasmapheresis and plasma exchange measures are not useful in the treatment of this disorder.9 Most patients receive a combination of these treatments.9 As recombinant factor VIIa was not immediately available, and our case had lifethreatening bleeding, she was initially treated with blood products, IVIG, high dose of factor VIII, and prednisone, but bleeding was not controlled. Finally, recombinant factor VIIa (Novo seven) was prescribed, which was effective in controlling the

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bleeding. In our reported case, the bleeding was successfully controlled with a combination of these treatments. Recombinant factor VIIa is an effective treatment in postpartum acquired hemophilia A. This case highlights the importance of hematologic investigations in persisting PPH.

factor VIII inhibitors as a cause of primary postpartum hemorrhage. Eur J Obstet Gynecol. 2002; 103: 97 98. 5

Wiestner A, Cho HJ, Asch AS, Michelis MA, Zeller JA, Peerschke EI, et al. Rituximab in the
treatment of acquired factor VIII inhibitors. Blood. 2002; 100: 3426 3428. Schaffer LG, Philips MD. Successful treatment of acquired hemophilia with oral immunosuppressive therapy. Ann Intern Med. 1997; 127: 206 209. 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: 105 109. Michiels JJ. Acquired hemophilia A in women postpartum: clinical manifestations, diagnosis, and treatment. Clin Appl Thromb Hemost. 2000; 6: 82 86. Hauser I, Schneider B, Lechner K. Postpartum factor VIII inhibitors. A review of the literature with special reference to the value of steroid and immunosuppressive treatment. Thromb Haemost. 1995; 73: 1 5.

References
1 Boudo F. Acquired factor VIII inhibitors in pregnancy: data from the Italian Hemophilia Register relevant to clinical practice. Int J Obstet Gynecol. 2003; 110: 311 314. Michiels JJ, Bosch LJ, van der Plas PM, Abels J. Factor VIII inhibitor postpartum. Scand J Haematol. 1978; 20: 97 107. Solymoss S. Postpartum acquired factor VIII inhibitors: results of a survey. Am J Hematol. 1998; 59: 1 4. Howland EJ, Palmer J, Lumley M, Keay SD. Acquired

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