REGULAR ARTICLE

Obstetric and perioperative management of patients with factor XI

deficiency: a retrospective observational study

Shivani Handa,1 Michelle Sterpi,2 Guilherme Sacchi De Camargo Correia,2 David S. Frankel,3 Yaakov Beilin,4 Lawrence Cytryn,1
Katherine Hawkins,1 and Etta Frankel1
1
Division of Hematology-Oncology, Icahn School of Medicine at Mount Sinai, New York, NY; 2 Department of Medicine, Icahn School of Medicine/Mount Sinai Morningside-

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West Hospital, New York, NY; 3 Division of Electrophysiology, University of Pennsylvania, Philadelphia, PA; and 4 Department of Anesthesia, Icahn School of Medicine at Mount
Sinai, New York, NY

Key Points
• Personal history of
bleeding strongly
predicts perioperative
or obstetric bleeding
risk in patients with FXI
deficiency.
• Higher FXI levels may
be associated with
lower bleeding risk;
however, there is no
optimal sensitivity level
to rule out bleeding
risk.
Factor XI (FXI) deficiency is an autosomal inherited, milder bleeding disorder that may
predispose to a potential risk of life-threatening bleeding during childbirth or surgery.
Unfortunately, data regarding obstetric and perioperative management of this condition
are scarce, with limited cases reviewed in the last decade. Therefore, the present study
aimed to expand this database and identify factors associated with increased bleeding risk.
We performed a retrospective chart review of patients with FXI deficiency who underwent
childbirth or other surgical procedures between August 2011 and April 2021 within a single
academic health system and identified 198 patients who underwent 252 procedures,
including 143 vaginal deliveries, 63 cesarean deliveries, and 46 other surgical procedures.
Thirty-three of the 252 procedures resulted in bleeding complications. On multivariable
logistic regression analysis, personal history of bleeding was the strongest predictor of
perioperative or obstetric bleeding (odds ratio [OR], 5.92; P = .001). Higher FXI levels
were correlated with lower odds of bleeding (OR, 0.72 with every 10 U/dL increase in FXI
level; P = .05). On receiver operative characteristic analysis, FXI level of >40 U/dL predicted
a lower bleeding risk with reasonable specificity (75%) but lacked sensitivity (47%). A family
history of bleeding, ethnicity, genotype, preprocedural partial thromboplastin time, and
platelet levels were not associated with bleeding risk. There were no cases of epidural or
spinal hematoma associated with neuraxial anesthesia. FXI levels remain stable during
pregnancy and repeated measurements may not be necessary.

Introduction

Factor XI (FXI) deficiency, also known as hemophilia C, is a rare bleeding disorder that Rosenthal and
Dreskin first described in 1955. It was distinguished from the better-known hemophilia A and B by its
presence in both genders due to its autosomal inheritance, a milder bleeding tendency, and the
conclusion that the laboratory defect could be corrected by mixing tests with hemophilia A and B
plasma.1

Submitted 26 July 2022; accepted 4 November 2022; prepublished online on Blood
Advances First Edition 15 December 2022. https://doi.org/10.1182/
bloodadvances.2022008648.
Presented in abstract form at the 63rd annual meeting of the American Society of
Hematology, Atlanta, GA, 12 December 2021.
Partial data from our patient cohort were also presented in poster form (#869), Factor
XI Deficiency in Pregnant Women: A Case-Series from a New York City Hospital, at
the American Society of Hematology 2020 conference.
Data from this study were previously published as oral abstract.34
Data can be made available in deidentified Excel sheets on request to the corre-
sponding author, Shivani Handa (shivani.handa@mountsinai.org).
© 2023 by The American Society of Hematology. Licensed under Creative Commons
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0),
permitting only noncommercial, nonderivative use with attribution. All other rights
reserved.

23 MAY 2023 • VOLUME 7, NUMBER 10 1967

Although uncommon in the general population, with a frequency of
~1 per million, it is more prevalent in Ashkenazi and Iraqi Jewish
populations, with a rate of heterozygosity as high as 8% to 9%.2,3
Moreover, with the advent of expanded prenatal genetic profiling
and direct-to-consumer genetic testing, people with or without a
bleeding history and FXI deficiency are increasingly recognized,
creating a need to understand this condition better.4
In the existing literature, severe deficiency in homozygous or
compound heterozygous carriers is classified as FXI activity <20
international unit (IU)/dL and partial deficiency in heterozygous
carriers is defined as FXI levels between 20 and 70 IU/dL. How-
ever, even in its most severe form, coagulation factor deficiency is
not associated with a spontaneous bleeding tendency, unlike
severe FVIII or FIX deficiency; therefore, it is not usually classified
as a severe bleeding disorder.5 Instead, bleeding in FXI deficiency
is usually injury or surgery related, particularly at sites with high
local fibrinolytic activity, such as the genitourinary tract, nasal cavity,
and oral cavity.
The management of patients with FXI deficiency is challenging for
multiple reasons. There is a lack of correlation between plasma
levels of FXI activity and the patient’s tendency to bleed. Multiple
studies have attempted to establish an association between
bleeding risk and FXI levels; however, ultimately the bleeding ten-
dency remains unpredictable, with no clear correspondence to FXI
levels, genotype, or consistency, even within an individual or fam-
ily.6-8 This discordance leads to important questions about who
needs to receive factor replacement in the perioperative or peri-
partum setting. Some evidence points to plasma replacement
therapy during labor not being mandatory even for women with
severe FXI deficiency, as observed by Salomon et al9 Furthermore,
some anesthesiologists may be reluctant to administer neuraxial
anesthesia to healthy women with FXI deficiency and no bleeding
history despite growing evidence pointing toward its safety.10-13
Second, the management of bleeding episodes and prevention of
bleeding related to surgery are not straightforward because of the
risks of currently available therapies and the significant differences
in the availability of FXI concentrates in different regions of the
world. FXI concentrates carry a significant thrombotic risk and are
not available for use in the United States. Lastly, as easily deduced
by the rarity of this bleeding disorder and its underdiagnosis due to
its intrinsically unpredictable clinical presentation, there is a paucity
of data surrounding it, with <500 cases reviewed in the last
decade. Therefore, this study aimed to expand this database to
identify the factors associated with increased bleeding risk, assess
neuraxial anesthesia safety, and analyze the impact of prophylactic
administration of hemostatic agents on the incidence and severity
of clinically significant bleeding.
Methods
We retrospectively evaluated the electronic medical records of
patients with FXI deficiency who underwent childbirth or other sur-
gical procedures between August 2011 and April 2021, within the
Mount Sinai Health System in New York. We used the Mount Sinai
Data Warehouse to collect the demographic and health-related
data. This study was granted a waiver of informed consent and
approved by our institutional review board (#IRB-20-03750). The
criteria used to diagnose FXI deficiency in our patients included low
1968 HANDA et al
FXI activity, that is, below the lower limit of the normal range in our
laboratory (70-150 IU/dL) or the identification of a mutation in the
FXI gene. Subsequently, a database of patients with a definitive
diagnosis of FXI deficiency was created.
Health-related data included laboratory data on hematological
parameters and clinical data, including surgical details, delivery,
and bleeding complications. The non–health-related data included
age, gender, and ethnicity. Laboratory data collected included FXI
level, genotype, prothrombin time, partial thromboplastin time
(PTT), hemoglobin, platelet count, and ABO Rh blood group.
Clinical data included mode of delivery (vaginal or cesarean), sur-
gical procedure, type of anesthesia (spinal, epidural, or combined
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spinal-epidural), periprocedural complications, estimated blood
loss, administration of hemostatic products (fresh frozen plasma
[FFP] or tranexamic acid ([TXA]), and packed red blood cell (RBC)
transfusions. We collected available data on the personal history of
bleeding and family history of bleeding. We used the 2017
American Congress of Obstetricians and Gynecologists guidelines
that define postpartum hemorrhage (PPH) as a cumulative blood
loss ≥1000 mL or associated with signs/symptoms of hypovolemia
regardless of the route of birth.14 Early PPH occurred within 24
hours of delivery and late PPH occurred >24 hours after delivery.
History of bleeding phenotype was defined as ≥1 of the following:
(1) unexplained easy bruisability, (2) epistaxis requiring medical
attention, (3) heavy menstrual bleeding, (4) bleeding with dental
procedures requiring intervention, (5) obstetrical bleeding, and (6)
postoperative bleeding requiring intervention.15
Statistical methods
Categorical variables are presented as counts with percentages.
Continuous variables are presented as means with standard devi-
ations or medians with interquartile ranges. Categorical values
were compared using the Fisher exact test. Continuous variables
were compared using the paired t test or Mann-Whitey U test. We
performed logistic regression to test the association between his-
torical, laboratory, and procedural variables with the bleeding end
point (defined as acute PPH or postoperative hemorrhage or any
bleeding warranting nonprophylactic administration of packed
RBCs, FFP, or TXA). Separate logistic regression analyses were
performed for the entire population and only for obstetric patients.
Receiver operative characteristic (ROC) curves were plotted for
FXI levels to identify the cutoff with optimal sensitivity and speci-
ficity for the bleeding end point. Analyses were performed using
SPSS software (SPSS Inc, Chicago, IL).
Results
Patient characteristics
We identified 198 patients who underwent 252 procedures
including 143 vaginal deliveries, 63 cesarean deliveries, and 46
other surgical procedures. The mean age was 36 years, with 94%
(186) females. Data on ethnicity were available for 177 of 198
patients. The majority (77%) were Ashkenazi Jewish, 8 patients
identified as Hispanic, and 2 were African American. Only 12%
of patients had severe FXI deficiency (defined as a FXI level of
<20 U/dL). Median FXI level was 50 U/dL (2-190 U/dL). Median
PTT was 33.1 seconds (20.5-47.3 seconds). Mutational analysis was
available for 51% of the patients, with type II (c.403G>T p.E135X)
23 MAY 2023 • VOLUME 7, NUMBER 10
and type III (c.901T>C p.F301L) being the most common mutations Table 2. Baseline characteristics according to the presence of
identified in 46 and 43 patients, respectively. A total of 16 different bleeding complication
mutations were reported, with 1 patient harboring both type II and III Bleeding complication, No bleeding
mutations. There was no difference in FXI levels based on the N (%)* complication, N (%) P

underlying mutations (Table 1). Forty-three (21.7%) patients met at 33 219

least 1 criterion for the bleeding phenotype, and 31 (15.7%) patients Obstetrical 26 (78.8) 180 (82.2) .6
reporting prior surgical bleeding related to dental/obstetric or other Nonobstetrical 7 (21.2) 39 (17.8)
procedures. Only 14 (7%) patients had a family history significant for
Age ± standard 37.9 (26-49) 36.1 (25-47) .4
bleeding. deviation, y

Bleeding complications and factors predicting Female 28 (84.8) 207 (94.5) .06

bleeding risk Ethnicity .5

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Ashkenazi Jewish 22 (66.7) 154 (70.3)
Thirty-three procedures (13%) resulted in bleeding complications.
Of these 33 patients, 21 had acute PPH and 2 had delayed PPH, Hispanic 4 (12.1) 11 (5.0)

whereas acute and delayed postsurgical bleeding (in nonpregnant African American 0 3 (1.4)
patients) were reported in 3 and 2 cases, respectively. Surgical Other White 3 (9.1) 20 (9.1)
cases associated with bleeding included knee arthroplasty (n = 1), Other non-White 2 (6.1) 6 (2.7)
laparoscopy with proctopexy (n = 1), gastrectomy (n = 1), Hart-
Unknown 2 (6.1) 25 (11.4)
mann procedure (n = 1), and laminectomy with posterior spinal
Blood group .6
fusion (n = 1). Five additional patients required nonprophylactic
FFP transfusion to achieve hemostasis, which were also recorded A 17 (51.5) 82 (38.1)

as bleeding complications. Of the 21 patients with acute PPH, 8 B 8 (24.2) 45 (20.9)

patients had additional known risk factors for PPH besides FXI AB 2 (6.1) 13 (6.0)
deficiency. Six patients had uterine atony, with 1 requiring hyster- O 6 (18.2) 75 (34.9)
otomy with dilatation and curettage, 1 had retained placenta, and 1
Genotype .08
sustained a second-degree perineal laceration.
c.403G>T p.E135X 6 (18.2) 51 (23.3)
Only 8 of these 33 bleeding events were observed in patients with (type II)
FXI levels <20 U/dL. Baseline characteristics such as age, gender, c.901T>C p.F301L 7 (21.2) 54 (24.7)
ethnicity, genotype, and blood group were equally distributed (type III)
among patients with and without bleeding events (Table 2). Table 3 Other genotype 4 (12.1) 13 (5.9)
compares the laboratory parameters, procedure type, and hemo- Unknown 16 (48.5) 101 (46.1)
static interventions in patients with and without bleeding compli- Personal history of <.001
cations. The median preprocedural PTT value was higher for those bleeding
with bleeding complication (32.8 vs 31.0 U/dL, P = .03). Median 1 type† 14 (42.4) 34 (15.5)
FXI activity was significantly different in patients with a bleeding
≥2 types 2 (6.3) 7 (3.4)
complication compared to those without (41.5 vs 49.0 U/dL,
Family history of bleeding 3 (9.4) 14 (7.0) .6
P = .03). A significantly higher number of cesarean deliveries were
associated with bleeding events (23.8%) than vaginal deliveries Data are presented as count (percentage) or mean ± standard deviation.
*Bleeding complication defined as acute bleeding or nonprophylactic transfusion of
(7.6%, P = .006). Use of prophylactic FFP was significantly higher RBCs, FFP, or TXA.
in the group with bleeding events (24.2% vs 5.9%, P = .002). †Types of bleeding include heavy menstrual bleeding, dental bleeding, easy bruising,
epistaxis, obstetrical bleeding, or postoperative bleeding.
Among the entire population, cesarean delivery, prophylactic FFP
administration, and personal history of bleeding were associated
with higher odds of bleeding in the univariable logistic regression
(Table 4). On multivariate logistic regression, a personal history of
point. When confined to obstetric patients alone (Table 5), only
bleeding (odds ratio [OR], 5.92; P = .001), FXI levels (OR, 0.72
cesarean deliveries (OR, 3.40; P = .03) and personal history of
per 10 U/dL increase; P = .05), and cesarean deliveries (OR, 2.83;
bleeding (OR, 6.10; P = .002) remained significantly associated
P = .04) remained significantly associated with the bleeding end
with the bleeding end point in the multivariable analysis. Age,
ethnicity, genotype, family history of bleeding, preprocedural PTT,
and platelet levels were not associated with bleeding risk.
Table 1. Median FXI level as per genetic mutation
Genetic mutation FXI level Hemostatic interventions
c.403G>T p.E135X (type II) 49.5 [44.5-54.8] Prophylactic FFP was administered before 21 (8.3%) procedures
c.901T>C p.F301L (type III) 52.5 [45.0-61.0] in 17 patients. Mean FXI level for patients receiving prophylactic
FFP was 25.6 U/dL (range, 1-71 U/dL) (Figure 1). Eleven of the 17
Other genotype 43.0 [32.0-50.0]
patients had severe FXI deficiency, whereas 6 patients had a partial
Unknown 44.0 [17.0-56.0]
deficiency. All patients with partial deficiency who were given
Data are presented as median [interquartile range]. empiric FFP were known to have a bleeding phenotype except 2, 1
with an FXI level of <40 and no prior surgical history, and another

23 MAY 2023 • VOLUME 7, NUMBER 10 FXI DEFICIENCY IN OBSTETRIC AND SURGICAL PATIENTS 1969
Table 3. Hematological and surgical data according to presence of bleeding complication
Bleeding complication No bleeding complication P

33 219
Laboratory values before delivery/procedure
FXI (U/dL) 41.5 [14.0-52.0] 49.0 [40.0-57.3] .03

Activated PTT (sec) 32.8 [29.9-41.8] 31.0 [28.7-34.2] .03

Hemoglobin (g/dL) 12.0 [11.3-13.0] 12.3 [11.6-13.3] .2
9
Platelets (10 /L) 186 [152-240] 199 [173-232] .3
Blood loss during delivery/procedure (mL) 659 [213-1000] 286 [124-400] <.001

Blood loss following delivery/procedure (mL) 58 [0-809] 0 [0-36] <.001

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Hemoglobin decrease following delivery/procedure 2.8 [1.3-3.5] 1.6 [1.0-2.6] .003
(g/dL)
Procedure type .006

Vaginal delivery 11 (33.3) 132 (60.3)

Cesarean delivery 15 (45.5) 48 (21.9)
Other surgical procedure 7 (21.2) 39 (17.8)

Hemostatic interventions
Prophylactic FFP 8 (24.2) 13 (5.9) .002

Prophylactic TXA 1 (3.0) 6 (2.8) .9

Prophylactic RBC 0 2 (0.1) .8

Nonprophylactic FFP 10 (30.3) 0 <.001

Nonprophylactic TXA 9 (27.3) 0 <.001

Nonprophylactic RBC 8 (24.2) 0 <.001

Data are presented as count (percentage) or median [interquartile range].

woman who was treated with a heparin infusion for a history of
factor V Leiden mutation and was given a unit of FFP before urgent
cesarean delivery.
Eight of these 21 (38%) procedures resulted in bleeding compli-
cations, despite prophylactic FFP use. Three of these 8 bleeding
events occurred in patients who had previously undergone surgery,
with prophylactic FFP without any hemorrhagic complications, and
3 events occurred in patients who received <10 mL/kg FFP dose
periprocedurally. Only 7 patients in the study received prophylactic
TXA. One of them experienced a bleeding complication. Post-
procedural FFP and TXA were administered in 10 and 9 patients,
respectively, to arrest bleeding or follow high-risk surgeries. Eight
patients also required packed RBC transfusions for significant PPH
or postprocedural hemorrhage.

Table 4. Factors predicting bleeding complication among entire population

Univariable logistic regression Multivariable logistic regression

OR 95% CI P value OR 95% CI P value

Pre-procedure FXI level (per 1 U/dL increase) 0.98 0.96-1.00 .1 0.97 0.95-1.00 .05

Pre-procedure FXI level (per 10 U/dL increase) 0.83 0.68-1.02 .1 0.72 0.54-0.97 .05
Pre-procedure PTT 1.01 0.99-1.04 .4

Pre-procedure platelet count 1.00 0.99-1.00 .2

Cesarean delivery (compared to vaginal delivery) 3.74 1.61-8.70 .002 2.83 10.4-7.72 .04

Use of prophylactic FFP 1.28 1.00-1.65 .05 2.05 0.33-12.80 .4

Use of prophylactic TXA 1.10 0.13-9.43 .9
Blood type O+ 0.44 0.17-1.12 .08 0.39 0.12-1.24 .1

Personal history of bleeding 4.07 1.88-8.82 <.001 5.92 1.98-17.71 .001

Family history of bleeding 1.37 0.37-5.05 .6

Type III mutation 0.83 0.30-2.33 .7

CI, confidence interval.

1970 HANDA et al 23 MAY 2023 • VOLUME 7, NUMBER 10

Table 5. Factors predicting bleeding complication among obstetric population
Univariable logistic regression Multivariable logistic regression

OR 95% CI P value OR 95% CI P value

Pre-procedure FXI level (per 1 U/dL increase) 0.97 0.95-1.00 .02 0.99 0.96-1.02 .5

Pre-procedure FXI level (per 10 U/dL increase) 0.73 0.57-0.94 .02 0.84 0.60-1.19 .5
Pre-prcedure PTT 1.11 1.03-1.19 .004 1.14 1.00-1.31 .06

Pre-procedure platelet count 1.00 0.99-1.00 .8

Cesarean delivery (compared to vaginal delivery) 3.75 1.61-8.73 .002 3.40 1.15-10.03 .03

Use of prophylactic FFP 1.76 1.06-2.95 .03 0.32 0.03-3.38 .3

Blood type O+ 0.61 0.23-1.60 .3

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Personal history of bleeding 3.42 1.36-8.62 .009 6.10 1.90-19.57 .002

Family history of bleeding 1.21 0.25-5.81 .9

Type III mutation 0.67 0.28-2.25 .7

Neuraxial anesthesia ROC analysis

Neuraxial anesthesia was administered before 174 (70%) pro-
cedures. Mean FXI level for patients receiving neuraxial anesthesia
was 50 U/dL (3-118 U/dL). There were no cases of epidural or
spinal hematoma associated with neuraxial anesthesia in our
cohort. Five patients with a negative bleeding history despite
surgical challenges received neuraxial anesthesia at FXI levels of
<10 U/dL without any complications. Only one of them received
prophylactic FFP before surgery. In general, the majority of pro-
cedures in patients (78.7%) with FXI levels >30 U/dL were per-
formed under neuraxial anesthesia, as compared to only 32.2% of
procedures in patients with levels ≤30 U/dL. Among the obstetric
procedures alone, most deliveries (168/206 or 81.5%) were per-
formed under neuraxial anesthesia. Eighty-six percent of patients
with preoperative FXI levels >30 U/dL received spinal/epidural
anesthesia. Figure 2 illustrates the distribution of deliveries in which
neuraxial anesthesia was administered to patients across various
FXI levels.
ROC curves were plotted for FXI levels to identify the cutoff with
optimal sensitivity and specificity for predicting bleeding risk. The
results were similar for all patients and obstetric patients only
(Table 6). For the entire cohort, the area under the curve was 0.62,
with a sensitivity of 47% and specificity of 75%, using an FXI cutoff
value of 40 U/dL.
FXI trend in pregnancy
At least 2 FXI levels measured at different timepoints during
pregnancy were available for the 81 women. The mean FXI level did
not change between these 2 measurements (49.7 U/dL at first
measurement vs 48.3 U/dL later in pregnancy, P = .3).
Discussion
Our study assessed a large cohort of patients and investigated the
risk factors of bleeding in patients with FXI deficiency. In a mixed

Figure 1. Distribution of procedures in which prophylactic FFP

was administered to patients across various FXI levels. Empiric
Prophylactic FFP use
90
FFP was administered before 47.6% vs 4.7% of the procedures 80
performed in patients with severe FXI and partial FXI deficiency, 80
respectively. 70
58
60 55
Procedures

50

40

30

20 17
10 8
10 6 4 3 3 2 3 3
0
0
1-10 11-20 21-30 31-40 41-50 !50 Unknown
Pre-op factor XI level
Prophylactic FFP administered Prophylactic FFP not administered

23 MAY 2023 • VOLUME 7, NUMBER 10 FXI DEFICIENCY IN OBSTETRIC AND SURGICAL PATIENTS 1971
 Figure 2. Distribution of deliveries in which neuraxial anesthesia
Neuraxial Anesthesia Use was administered to patients across various FXI levels. Eighty-
90
six percent of patients with preoperative (pre-op) FXI levels >30 U/dL
80 received spinal/epidural anesthesia before delivery.
70
60
Deliveries

50
40
30
20

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10
0
1-10 11-20 21-30 31-40 41-50 !50 Unknown
Pre-op factor XI level
Deliveries without neuraxial 6 1 5 3 4 12 7
anesthesia
Deliveries with neuraxial
5 1 3 16 49 71 23
anesthesia

cohort of parturients and other surgical patients, 13% of proced- significantly increased risk of PPH as compared with vaginal
ures were complicated by bleeding events. The most common deliveries (OR, 3.4; P = .003). Other analyses have also highlighted
bleeding event was PPH, which was found to be almost twice as the importance of reviewing a patient’s personal history in
high for the parturients with FXI deficiency as in the general pop- conjunction with a family history of bleeding events while also
ulation of women undergoing labor (11% vs 6%).16,17 PPH rates of evaluating the proposed intervention to be performed, as seen in
17% and 18% have been reported in recent systematic reviews the retrospective study conducted by Santoro et al.19 Family his-
including 490 and 372 deliveries in the studies by Davies et al and tory of bleeding was not found to be a significant risk factor in our
Wiewel-Verschueren et al, respectively.5,18 Similarly, postoperative study.
bleeding was reported in ~11% (5/46) of the other surgical pro-
Irrespective of an early series published in 199720 demonstrating a
cedures in our study as compared to 21% in the study by Santoro
strong negative correlation between bleeding and FXI levels
et al.19 On the other hand, the use of prophylactic interventions
(r = −0.36, P = .0001), more recent studies have failed to establish
such as FFP or TXA was lower than the aforementioned studies
such an association.9,19,21 Our data do not provide an unequivocal
(11% vs 20%).5,18
answer as to how to interpret FXI levels in this context. We found a
A personal history of bleeding was found to be the strongest risk statistically significant but weaker association between FXI con-
factor for perioperative or obstetric bleeding events in this popu- centration and bleeding risk (OR, 0.72 for 10 U/dL of FXI level
lation (OR, 5.9; P = .001). This finding is consistent with the cur- increase). Although an FXI level cutoff of 40 U/dL can predict a
rent literature that indicates a significant correlation between lower bleeding risk with reasonable specificity (75%), no clear FXI
bleeding history and an increased risk of PPH.9,17-22 Moreover, a level is adequately sensitive to detect all patients who are at an
case-control study conducted by Stoeckle et al not only argued in increased risk of bleeding. The lack of a reliable correlation
favor of this correlation, but also pinpointed an increase in PPH between FXI levels and bleeding risk renders the management of
only among cesarean deliveries compared with the control cohort.4 patients with mild FXI deficiency without a bleeding history
Similarly, in our study, cesarean deliveries were associated with a particularly challenging when screening patients for prophylactic
interventions. This calls for the development of a disease specific
bleeding score (BS) that can assist in standardizing this assess-
Table 6. ROC analyses for FXI level cutoffs as a predictor of ment. A recent Dutch study assessing bleeding severity in rare
bleeding risk bleeding disorders showed no correlation between the Interna-
All patients Obstetrical patients only tional Society of Thrombosis and Hemostasis Bleeding Assess-
Area under the curve, 0.62 Area under the curve, 0.64 ment Tool (BAT) score and FXI activity.23 A specific Rare Bleeding
Disorders BAT developed by the European Network of Rare
Cutoff Sensitivity Specificity Cutoff Sensitivity Specificity
Bleeding Disorders group was shown to have a higher predictive
10 0.16 0.93 10 0.16 0.96 power when compared to International Society of Thrombosis and
20 0.28 0.89 20 0.24 0.95 Hemostasis BAT for rare bleeding diathesis, however, this remains
30 0.34 0.85 30 0.32 0.91 to be validated in FXI deficiency.24 As of now, the only reliable BS
40 0.47 0.75 40 0.44 0.80
standardized for bleeding disorders is the one published for von
Willebrand disease by Tosetto et al,25 which was successfully
50 0.69 0.46 50 0.68 0.48
employed by Guéguen et al26 to quantitatively evaluate the

1972 HANDA et al 23 MAY 2023 • VOLUME 7, NUMBER 10

bleeding tendency in a small cohort of patients with FXI deficiency.
Future studies attempting to develop and validate a clinical BS
customized for FXI deficiency in a larger patient population would
be particularly useful.
There is no established straightforward correlation between the
genotype, FXI levels, and bleeding tendency. The most common
FXI gene mutations described are type I mutations involving a
splice site; type II, a Glu117stop mutation; and type III, a
Phe283Leu substitution. In our study, there was no difference
between FXI levels based on the underlying mutation, although it
should be noted that mutational analysis was available for only half
of the cases. Similarly, in the study by Salomon et al, type II/III
mutation was associated with the highest frequency of PPH,
although homozygotes with type II/II mutation had the lowest FXI
levels.9 However, these differences were not statistically signifi-
cant.9 In another cohort study, the genotype II/II had a stronger
association with injury and surgery related bleeding than II/III,
whereas another study did not find any difference in bleeding
tendency in relation to genotype.2,15
Traditionally blood group O has been associated with a higher
bleeding risk attributed to lower baseline von Willebrand factor
(VWF) levels, with a suboptimal rise of VWF levels during preg-
nancy and a higher risk of PPH.27 More recently, a large obser-
vational study on the association of ABO blood group with
bleeding severity in patients with bleeding of unknown cause
showed that blood group O was associated with increased
bleeding severity, independently from VWF and FVIII levels.28 As
per the authors, the lack of an explanation for the increased
bleeding severity in patients with blood group O was the greatest
limitation of the study. In our study, no association between blood
group type and the risk of bleeding was identified.
In an attempt to further identify and describe the most commonly
encountered clinical dilemmas in this patient population, we spe-
cifically assessed patients undergoing neuraxial anesthesia. In our
analysis, no significant adverse events resulted from this proced-
ure, and there were no instances of epidural or spinal hematoma in
174 cases. These data are in line with growing evidence sup-
porting the safety of epidural/spinal anesthesia during delivery in
this population. In our study, a substantial majority (81.5%) of
deliveries were performed under neuraxial anesthesia. This is
higher than that previously reported in other studies on patients
with FXI deficiency. The systematic review conducted by Davies
et al in 2016, which looked at the use of labor analgesia in 6
different studies totaling 236 deliveries, showed no reported
complications in any of the 73 procedures (31% of the deliveries)
where regional block was administered.5 Similarly, Gerber et al
appreciated in their study, more frequent use of neuraxial anes-
thesia (up to 59% of the deliveries) with no bleeding complications
related to the analgesia even in women who experienced
concomitant PPH.21 The latter also described 5 patients with
severe FXI deficiency undergoing neuraxial anesthesia without
bleeding complications, even though only 2 received FFP. Like-
wise, a small subset of 5 patients in our study with a negative
bleeding history despite surgical challenges received neuraxial
anesthesia at an FXI level <10 U/dL without any complications, and
only one of them received prophylactic FFP before surgery. Yet, a
considerable number of patients with severe deficiency, 50% in the
recent study by Gerber et al and 70% in our cohort, did not receive
23 MAY 2023 • VOLUME 7, NUMBER 10
epidural injections due to concerns for adverse reaction.21 On the
other hand, patients with partial deficiency have consistently been
demonstrated to not be at risk for more severe complications
originating from this anesthesia modality. In a single-center report
from Israel where >30% of women who delivered were of Ashke-
nazi Jewish ancestry, FXI levels were checked on a random sample
of 261 Ashkenazi women, and 15% of these women were found to
have partial deficiency with levels <70 U/dL. Because no epidural/
spinal hematomas were documented among 57 722 women who
received neuraxial anesthesia during the span of a decade at this
institute, the authors extrapolated the numbers to estimate that at
least 2150 women with unknown partial FXI deficiency have safely
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undergone labor analgesia at their center.10 In sum, these data
challenge the practice of withholding neuraxial anesthesia solely
based on low FX1 levels.
The abovementioned results, in conjunction with the evidence that
emerged from our study, are significant and should also be
considered when evaluating the indications and actual benefits of
prophylactic treatment in patients with FXI deficiency in the peri-
partum setting. Although clinically relevant, indications have not yet
been objectively and consistently determined. It has been shown
that prophylaxis may reduce the absolute number of bleeding
events and complications in parturient patients, most importantly in
those with severe deficiency or those with a personal history of
bleeding.9,18
Other studies have directly investigated and discussed the avail-
able modalities for prophylaxis. These include antifibrinolytic
agents, plasma-derived products, and recombinant FVIIa. Patients
who are heterozygous, with a less prominent history of bleeding in
the past, may safely be treated with TXA.17 Meanwhile, FFP has
traditionally been indicated for patients with severe deficiency. The
indication for FFP use, although beneficial, is not devoid of risks,
especially in patients with cardiovascular conditions, because the
large volume of plasma required for treatment may lead to fluid
overload. Furthermore, the additional use of FFP is sometimes
predicated on the follow-up of postinfusion FXI levels, which often
cannot be obtained in a timely fashion.5,29 Given the lack of insti-
tutional or national guidelines on the use of prophylactic FFP for
FXI deficiency, the practice of FFP prescription varied among
providers within our institution. In general, the doses ranged from
10 to 20 mL/kg, with the lower end of the range being used for
patients with an FXI >20 U/dL or no significant bleeding history,
whereas a dose of 20 mL/kg was prescribed for those with levels
<20 U/dL or prior bleeding history. No specific FXI was targeted,
given the time lag in laboratory assessments.
Finally, we observed again that FXI activity levels remain stable
during pregnancy. This indicates that trending these levels
throughout pregnancy may be unnecessary, further sparing
expenses and expediting clinical decision making in these cases.
The consistent FXI levels before and during pregnancy have also
been demonstrated by other authors in different settings.5,30-32
Given its retrospective design, our study has some limitations.
Although we analyzed a large population, this study may have
lacked the power to fully establish an FXI level cutoff for meriting
prophylaxis. Setting up an international registry with an even larger
cohort would allow for different results. This may help determine
the impact of different mutations by analyzing a more diverse
population from a genotypic perspective. Prospective studies
FXI DEFICIENCY IN OBSTETRIC AND SURGICAL PATIENTS 1973
aimed at investigating when to prescribe preoperative prophylactic
treatment to patients with FXI deficiency would help to draw
definitive conclusions. Nevertheless, such a study may not be
feasible, considering the eventual severity of side effects from
bleeding in these settings, particularly in obstetrical cases. Another
important limitation is that TXA was not consistently administered in
the setting of PPH in our study cohort despite TXA use being a
standard practice among obstetricians since the WOMAN study
established its efficacy in 2017.33 This reflects an important real-
world scenario in which the standard of care measures may be
overlooked due to a lack of familiarity with their applicability in rare
bleeding disorders.
patients with severe FXI deficiency. FXI levels remain stable
during pregnancy.
Authorship
Contribution: E.F. and K.H. conceived and designed the study; S.H.
and M.S. collected data; D.S.F. performed statistical analyses and
interpretation of results; S.H., M.S., and G.S.D.C.C. performed the
literature review and prepared the first draft of the manuscript; Y.B.,
L.C., D.S.F., K.H., and E.F. reviewed and revised the manuscript;
and all authors reviewed the results and approved the final
manuscript.

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In summary, our study highlights the importance of the careful Conflict-of-interest disclosure: The authors declare no
evaluation of individual patients. Personal history of bleeding competing financial interests.
was the strongest predictor of bleeding risk. In the absence of
ORCID profiles: S.H., 0000-0002-1932-6209; L.C., 0000-
prior surgical challenges, FXI levels play a role in clinical decision
0002-4172-6858.
making, as higher levels confer some degree of protection
against hemorrhagic complications. Although an optimally sen- Correspondence: Shivani Handa, Division of Hematology-
sitive cutoff remains to be established, an FXI level of 40 U/dL is Oncology, Department of Medicine, Icahn School of Medicine at
reasonably specific for a nonbleeding end point. Our study Mount Sinai, 1 Gustave Levy Pl, New York, NY 10029; email:
reinforces the safety of neuraxial anesthesia in carefully selected shivani.handa@mountsinai.org.

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23 MAY 2023 • VOLUME 7, NUMBER 10 FXI DEFICIENCY IN OBSTETRIC AND SURGICAL PATIENTS 1975