Keywords
postpartum hemorrhage - bleeding disorder - coagulopathy - maternal morbidity
Postpartum hemorrhage (PPH) remains a leading cause of maternal mortality worldwide.[1] Although the most common causes are uterine atony, obstetric laceration, or retained
placenta, recurrent episodes of hemorrhage despite multiple surgical and pharmacologic
interventions should elicit consideration of rarer etiologies, including coagulopathies.
Here we present two cases of acquired hemophilia A (AHA) diagnosed in the setting
of PPH at a single institution. Both patients provided written consent for publication.
In addition, we review the literature on pregnancy-associated AHA including the workup
and management for the obstetrician.
Case 1
A 50-year-old G2P0010 with dichorionic diamniotic twins was admitted at 29 weeks'
gestation with concern for placental abruption and underwent an uncomplicated low-transverse
caesarean delivery at 31 weeks in the setting of ongoing vaginal bleeding. She had
no history of any bleeding disorder. The patient re-presented on postoperative day
22 with ongoing vaginal bleeding and symptomatic anemia with a hemoglobin of 6.2 g/dL
and platelets of 600,000/µL. She underwent a suction dilation and curettage during
which a uterine scar dehiscence was suspected, and a 3-cm defect was repaired laparoscopically.
After this initial reoperation, her hemoglobin steadily decreased with moderate vaginal
bleeding. On day 25, hemoperitoneum was noted on ultrasound and she underwent an exploratory
laparotomy, supracervical hysterectomy, and evacuation of several liters of hemoperitoneum.
Generalized oozing was noted at all surgical sites including peritoneal and skin incisions.
Intraoperative prothrombin time (PT) and activated partial thromboplastin time (aPTT)
were prolonged, suspected to be secondary to disseminated intravascular coagulation
due to surgical blood loss. However, she continued to have anemia and a persistently
prolonged aPTT despite transfusion, prompting hematology consultation. A mixing study
and measurement of factor activities demonstrated impaired coagulation and a factor
VIII activity of 2% (normal > 50%) consistent with AHA. Recombinant porcine factor
VIII and prednisone were started. Simultaneously, the patient had a computed tomography
(CT) angiogram of the abdomen, which showed active bleeding into the rectus sheath
and a pelvic hematoma. She was transferred to the surgical intensive care unit (ICU)
and interventional radiology (IR) performed a bilateral uterine artery embolization.
The patient was monitored in the hospital for a total of 32 days, during which she
received 16 units of packed red blood cells, 6 units of fresh frozen plasma, and 1
unit of platelets. Her factor VIII levels did not improve despite 15 days of prednisone,
so cyclophosphamide was added. Her factor VIII levels rose to 20%. She received a
total of 10 days of cyclophosphamide and 5 months of prednisone. After stopping steroid
treatment, her factor VIII levels remain normal, and she has had no evidence of recurrence
of her AHA 5 years since her initial diagnosis.
Case 2
This is a 48-year-old G3P1021 with a history of an uncomplicated myomectomy and elevated
titers of cardiolipin antibodies on prophylactic anticoagulation. With an appropriate
window since last dose of heparin (12 hours), neuraxial anesthesia was provided for
the primary delivery. Immediate PPH, suspected due to atony, required multiple uterotonics,
a Bakri uterine tamponade balloon, and, ultimately, reoperation (under general anesthesia)
with placement of a B-lynch suture and coagulation of friable tissue in the vesicouterine
space. She returned on postoperative day 8 after awakening in a pool of blood. Upon
readmission, she received uterotonics, tranexamic acid (TXA), a blood transfusion,
and underwent an exploratory laparotomy with supracervical hysterectomy due to ongoing
uterine atony and bleeding. Intraoperatively, oozing was noted from the surgical bed
as well and skin edges. The patient was transferred to the surgical ICU for postoperative
management given massive hemorrhage and concern for coagulopathy.
Twelve hours later, she had severe abdominal pain and a drop in hemoglobin concerning
for an intra-abdominal bleed and was taken for a second exploratory laparotomy. Venous
bleeding in the vesicovaginal space was cauterized and fresh frozen plasma, platelets,
and packed red blood cells were administered. Postoperatively her hemoglobin continued
to downtrend and increasing abdominal distension was noted. A CT angiogram demonstrated
left epigastric arterial bleeding, and an IR embolization was performed, complicated
by recurrent femoral access site bleeding requiring compressive sutures.
Hematology was consulted for a prolonged aPTT value in the setting of ongoing bleeding.
It was initially presumed that the aPTT was falsely elevated in the setting of a lupus
anticoagulant as she already had cardiolipin antibodies. The mixing study demonstrated
immediate correction but subsequent prolongation in the aPTT with incubation suggestive
of a time-dependent coagulation factor inhibitor. Factor VIII assay showed less than
0.5% activity (normal > 50%) and subsequent inhibitor assay was positive at 82.4 Bethesda
units (BU; titers < 5 BU = low responders; titers > 10 BU = high responders), diagnostic
of AHA. FEIBA (factor VIII inhibitor bypassing activity), TXA, and prednisone were
started. In the setting of persistent arterial bleeding after removal of a radial
arterial line, additional recombinant factor VIIa was given. She was discharged on
hospital day 18. In total, she received 24 units of packed red blood cells, 12 units
of fresh frozen plasma, 2 units of platelets, and 1 unit of cryoprecipitate. One month
after discharge, her factor VIII levels remained undetectable, and cyclophosphamide
was added. Five months after delivery, she remains on cyclophosphamide with no additional
bleeding.
Discussion
AHA is a rare form of coagulopathy with an incidence of 1.5 per million per year.[2] Despite the overall rarity, up to 20% of cases of AHA in women are associated with
pregnancy, and its incidence in pregnancy is 1 per 350,000 births.[3] However, less than 100 cases have been published, the majority being from two large
European registries.[3]
[4] Most are diagnosed in the postpartum period, although it is likely some have autoantibodies
circulating during the antepartum period.[4] Delayed diagnosis is common, with a median time to diagnosis from delivery of 89
days. Other presenting symptoms include subcutaneous, mucosal, or musculoskeletal
bleeding.[5] Although both patients were of advanced maternal age and had pregnancies resulting
from assisted reproductive technology (ART), more data are needed to determine whether
these are risk factors for development of AHA.
AHA is characterized by autoantibodies directed against factor VIII, a key component
of the intrinsic coagulation pathway. This autoantibody inhibits the action of factor
VIII to a variable degree, leading to a wide range of symptoms from no noticeable
bleeding to profound spontaneous bleeding. Pregnancy represents a precipitating event
that can lead to the formation of autoantibodies. The first evidence of AHA is a prolonged
aPTT. Although the aPTT can be prolonged by other common factors including use of
heparin, presence of lupus anticoagulant, or even disseminated intravascular coagulation,
a prolonged aPTT with unexplained bleeding should prompt further workup ([Fig. 1]). First, a mixing study, in which the patient's blood is mixed with normal plasma,
will show a persistently prolonged aPTT, due to the presence of the autoantibody.
Next, coagulation factor levels (e.g., factors VIII, IX, XI, and XII) will reveal
a factor VIII level less than 50% of normal. Finally, a factor VIII antibody assay
will show the titer of the antibody present, which may correlate with the severity
of the condition.[5]
Fig. 1 Algorithm for diagnosis of acquired hemophilia A.
The risk of mortality with AHA is 20%, although it is substantially lower in patients
diagnosed in the peripartum period.[3]
[4] Thus, as soon as AHA is suspected, hematology should be consulted. Multidisciplinary
discussions between obstetrics, hematology, transfusion medicine, anesthesiology,
critical care, and IR should be coordinated as appropriate. As each surgical or procedural
intervention carries a high risk of hemorrhage, there should be careful deliberate
multidisciplinary considerations for managing further bleeding episodes. If possible,
medical management or IR procedures may be preferred to minimize bleeding from surgical
sites. As seen in both cases, pregnancy-associated AHA can present with mucosal, venous,
and arterial bleeding that is refractory to usual first-line interventions.
Due to the ongoing risk of bleeding in the peripartum period, treatment should be
rapidly initiated in patients whose presentations are suspicious for AHA. Treatment
generally involves two components: replacement of depleted factor VIII and reduction
of the inhibitor via immunosuppression ([Table 1]). TXA can be used as an adjunct for acute bleeding, but other traditional hemostatic
agents such as desmopressin have limited utility and should be avoided. Although the
aPTT should begin to normalize once factor VIII levels reach 30 to 50% of normal,
response to treatment should be judged clinically. Failed initial therapy, defined
as failure of inhibitor titer to decline, or factor VIII level to rise in 3 to 5 weeks,
should prompt consideration of second-line therapies. Reasonable second-line options
include calcineurin inhibitors (e.g., cyclophosphamide), rituximab, or a combination
of immunosuppressive agents.[6]
[7]
Table 1
Treatment options for acquired hemophilia A
|
Agent
|
Considerations
|
|
Factor replacement
|
|
Recombinant porcine factor VIII
|
● Easy to monitor
● May require higher doses or may be less effective if autoantibody is cross-reactive
with porcine factor VIII
|
|
Anti-inhibitor coagulant complex
|
● More effective for high factor VIII inhibitor titers (> 10 BU)
● No laboratory value to monitor
● Potential risk of arterial and venous clot
|
|
Recombinant factor VII activated
|
● More effective for high factor VIII inhibitor titers (> 10 BU)
● No laboratory value to monitor
● Potential risk of arterial and venous clot
|
|
Immunosuppression
|
|
Corticosteroid
|
● May take ≥ 3 wk to see clinical benefit
● Typical adverse events associated with steroids
|
|
Cyclophosphamide (+ corticosteroid)
|
● May have faster response than steroids alone
● Highest rate of complete remission
● Needs monitoring for bone marrow suppression
● Breastfeeding contraindicated
|
|
Rituximab[7] (+ corticosteroid)
|
● Fewer and less severe side effects
● Very few cases reported in the literature
● Acceptable for use while breastfeeding
|
The long-term prognosis for patients diagnosed with peripartum AHA is mixed. Mortality
occurs in less than 5% and remission in greater than 90% of cases. However, depending
on the initial immunosuppressive regimen, relapse occurs in approximately 12 to 18%
of patients and long-term follow-up with a hematologist is recommended.[8] Cases of transplacental transmission of antibodies to factor VIII, with neonatal
hemorrhage, have been reported.[9] Neither of the neonates in these cases demonstrated any signs of abnormal bleeding.
In summary, these two cases demonstrate a rare but important consideration for recurrent
or delayed PPH. Any peripartum patient with persistent unexplained bleeding and a
prolonged aPTT should be promptly evaluated for AHA. Including AHA on the differential
in this clinical presentation is critical as (1) failure to quickly diagnose and initiate
treatment can lead to significant morbidity and (2) AHA is unlikely to respond to
traditional medical and surgical management of PPH, as these do not resolve the underlying
coagulopathy. These cases underscore that early initiation of multidisciplinary care
is vital to the successful management of peripartum AHA.
