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\begin{document}

\title{Sudden-onset gallbladder rupture due to Ceftriaxone-associated
pseudolithiasis in a patient with acquired hemophilia A}



\author[1]{Naonori Harada}%
\author[1]{ Ikumi  Shibano}%
\author[1]{ Daiki  Mukai}%
\author[1]{Yusuke  Kizawa}%
\author[1]{Hiroshi  Shiragami}%
\author[1]{ Shigenori  Takayanagi}%
\author[1]{ Naoki  Hosaka}%
\author[1]{ Atsuko  Mugitani}%
\author[2]{ Masayuki  Hino}%
\affil[1]{Fuchu Byoin}%
\affil[2]{Osaka Shiritsu Daigaku Daigakuin Igaku Kenkyuka Ketsueki Shuyo Seigyogaku}%


\vspace{-1em}



  
  \date{June 13, 2024}


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\selectlanguage{english}
\begin{abstract}
We herein report a 76-year-old man with acquired hemophilia A (AHA) who
developed gallbladder rupture due to Ceftriaxone (CTRX)-associated
pseudolithiasis. The patient was admitted for an examination of systemic
subcutaneous bleeding. A blood test showed a prolonged activated partial
thromboplastin time and sequentially revealed low factor VIII activity
(\textless{}1\%) and a high factor VIII inhibitor level of 143 BU/mL.
The patient was thus diagnosed with AHA. After admission, he developed a
high-grade fever and was administered intravenous CTRX, considering the
possibility of psoas abscess or cellulitis. Although his high-grade
fever was improved, computed tomography incidentally showed a
high-density lesion in the gallbladder, suggestive of CTRX-associated
pseudolithiasis without clinical symptoms. Despite cessation of CTRX,
the pseudolithiasis never disappeared, and the patient suddenly died
after rapid progression of abdominal bloating. An autopsy revealed that
the gallbladder was severely swollen and had ruptured with hemorrhaging
because of hemorrhagic cholecystitis, caused by CTRX-associated
pseudolithiasis with AHA. Our case demonstrated that CTRX-associated
pseudocholelithiasis can unexpectedly induce gallbladder hemorrhaging
and rupture in a patient with a bleeding diathesis, including AHA.
CTRX-associated pseudocholelithiasis can cause a fatal outcome in
patients with a bleeding disorder, even if CTRX is ceased as soon as
pseudocholelithiasis is detected.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Acquired hemophilia A (AHA) is an infrequent autoimmune bleeding
disorder caused by autoantibodies against coagulation factor VIII.
Hemorrhaging can occur anywhere but most predominantly is seen in
subcutaneous and deep muscle \textsuperscript{1}. However, gallbladder
hemorrhaging in a patient with AHA is extremely rare. Rupture of
gallbladder is an infrequent complication, and the majority of cases
have resulted from penetrating wall injures. Rupture of gallbladder can
lead to fatal consequences, but a rapid diagnosis and treatment are
occasionally difficult because of its rare entity and
severity\textsuperscript{2}.

We report a case of sudden-onset gallbladder rupture due to Ceftriaxone
(CTRX)-associated pseudolithiasis in a patient with AHA.



\textbf{Case Presentation}

A 76-year-old male patient was admitted to our institution to
investigate his left lower back pain and systemic subcutaneous bleeding.
On hospital day 1 (HD1), coagulation workup showed no abnormal findings
but revealed a prolonged activated partial thromboplastin time (APTT) of
more than 300 seconds and a low hemoglobin level of 7.6 g/dL. Computed
tomography (CT) showed a low-density lesion, suggestive of left psoas
hematoma, and no gallbladder stones (Figure 1a). The APTT level could
not be corrected by mixing with normal plasma, which was indicative of
the presence of coagulation factor inhibitors. Therefore, intravenous
prednisolone 1~mg/kg/day and recombinant activated factor VII (rFVIIa)
90 mcg/kg every 3 h were administered to eliminate coagulation factor
inhibitors and to prevent life-threatening bleeding, respectively.

Thereafter, laboratory tests revealed low factor VIII activity
(\textless{}1\%) and a high factor VIII inhibitor level of 143 BU/mL.
His bleeding predisposition was attributed to AHA. On the night of HD1,
the patient developed a high-grade fever and was prescribed intravenous
CTRX 2.0 g every 12 h, considering psoas abscess or cellulitis.

After the bypassing agent therapy was administered, his left low back
pain and systemic subcutaneous bleeding were improved. Therefore, we
finished administering rFVIIa to the patient on HD5. CT on HD6
demonstrated that the low-density lesion, suggestive of left psoas
hematoma, had improved, while a high-density lesion in the gallbladder
had emerged (Figure 1b). The patient showed no clinical symptoms of
acute calculous cholecystitis, and there were no remarkable changes in
his laboratory findings. The patient was diagnosed with CTRX-associated
pseudolithiasis, and CTRX was discontinued since his high-grade fever
had improved.

Extensive subcutaneous bleeding of the right back occurred on HD10, and
rFVIIa was promptly resumed. Since the APTT and low factor VIII activity
were not improved and the factor VIII inhibitor level remained high,
intravenous methylprednisolone 1 g/kg/day was administered from HD14 to
HD16. However, despite the further immunotherapy, his bleeding symptoms
and abnormal coagulation-related laboratory data due to AHA were not
improved. Furthermore, CT demonstrated that hematoma of the left psoas
and the right back had expanded, and the high-density area in the
gallbladder remained.

Thus, rFVIIa was switched to activated prothrombin complex concentrates
(APCC) 100 IU/kg every 12 h on HD16. Thereafter, the systemic
subcutaneous bleeding improved, and the dose of APCC was reduced to 100
IU/kg every 12 h on HD21. On the same day, however, the patient
developed a high-grade fever, so piperacillin and tazobactam were
administered. On HD22, the patient complained of abdominal pain in the
right upper quadrant. Enhanced CT with intravenous contrast demonstrated
not only a high-density area, indicative of CTRX-associated
pseudolithiasis but also pericholecystic stranding, a thickened
gallbladder wall, and extravasation of contrast into the gallbladder,
indicative of hemorrhagic cholecystitis (Figure 1c, d). Several hours
later, the patient suddenly died after rapid progression of abdominal
bloating.

At the autopsy, the gallbladder was severely swollen and ruptured with
hemorrhaging and contained a large amount of hematoma. Intra-abdominal
blood clots were connected to the gallbladder, and the primary source of
hemorrhaging was thought to be the gallbladder (Figure 2a, b). Histology
of the gallbladder demonstrated hemorrhagic and necrotic changes with
focal neutrophilic cell infiltration and fresh thrombi (Figure 2c).



\textbf{Discussion}

CTRX, a third-generation cephalosporin antibiotic, is used worldwide to
treat infectious diseases, including lower respiratory tract infections,
bacterial meningitis, and skin and soft tissue infections, since it can
penetrate tissues. CTRX-associated pseudolithiasis is a known
complication, reported mainly in children. The mechanism is ascribed to
a high CTRX concentration in the gallbladder bile, which is 20- to
150-fold higher than that in the serum. When the CTRX concentration in
the gallbladder exceeds its threshold, CTRX can precipitate by binding
to calcium ions secreted along with bile acids. Since CTRX can
precipitate with calcium, CTRX-associated pseudocholelithiasis is
principally composed of calcium-CTRX complexes \textsuperscript{3}.

Subcutaneous, deep muscle, and retroperitoneal bleeding are predominant
bleeding sites in patients with AHA \textsuperscript{1}. However,
gallbladder hemorrhaging and rupture are extremely rare entities, with
only a few previously reported cases, even in patients using
anticoagulants or with bleeding disorders. According to reports,
mechanical irritation of the gallbladder wall due to preceding repeated
cholecystitis can result in hemorrhaging from the gallbladder and its
rupture \textsuperscript{4,5}. Yoshida et al. reported on the outcomes
with CTRX-associated pseudocholelithiasis. The median intervals from
CTRX administration to the diagnosis of CTRX-associated
pseudocholelithiasis and from CTRX cessation to pseudolithiasis
resolution were 10 days and 69 days, respectively. Events related to
pseudocholelithiasis occurred in 29\% patients, but most of the cases
were improved with conservative treatment with CTRX
cessation\textsuperscript{3}. CTRX-associated pseudocholelithiasis can
induce the development of cholecystitis, but no cases with fatal
outcomes, including gallbladder hemorrhaging and rupture, have
previously been reported.

In our case, AHA was a predisposing factor, leading to gallbladder
hemorrhaging and rupture. The gallbladder is not structurally tolerant
of ischemia, since it is maintained by the cystic artery, which is a
terminal artery. Thus, high artery pressure due to a hematoma, boosted
by AHA and local ischemia from massive blood loss caused an ischemic
gallbladder wall, can trigger gallbladder rupture.

In conclusion, our case demonstrated that CTRX-associated
pseudocholelithiasis can unexpectedly induce gallbladder hemorrhaging
and rupture in a patient with a bleeding diathesis. Clinicians should be
alert for CTRX-associated pseudocholelithiasis, which can cause a lethal
outcome in patients with a bleeding disorder, even if CTRX is ceased as
soon as pseudocholelithiasis is detected.

\textbf{Statements}

\textbf{Statement of Ethics}

Written informed consent for publication was obtained from the patient's
wife.

\textbf{Disclosure Statement}

There are no conflicts of interest, financial or otherwise, to disclose
for any the authors.

\textbf{Funding Sources}

The authors declare no funding sources associated with this manuscript.

\textbf{Author Contributions}

All authors contributed the management of the patient, reviewed the
manuscript, and reviewed the literature.

\textbf{Figure Legends}

\textbf{Figure 1.} (a) On day 1 after admission, abdominal computed
tomography with intravenous contrast showed no gallbladder stone. (b) On
day 5 after admission, plain abdominal computed tomography showed a
high-density lesion in the gallbladder, indicative of
ceftriaxone-associated pseudolithiasis. (c, d) On day 22 after
admission, abdominal computed tomography with intravenous contrast
showed a high-density biliary sludge pattern and iodinated contrast
material extravasation into the gallbladder (arrow).

\textbf{Figure 2.} (a, b) The autopsy revealed gallbladder rupture,
resulting in a massive hematoma. (c) Final pathology demonstrated
hemorrhagic and necrotic changes with focal neutrophilic cell
infiltration and fresh thrombi (hematoxylin-eosin staining \selectlanguage{ngerman}×400).



\textbf{References}

1. Menegatti M, Biguzzi E, Peyvandi F. Management of rare acquired
bleeding disorders. \emph{Hematology American Society of Hematology
Education Program.} 2019;2019(1):80-87.

2. Ma Z, Xu B, Wang L, et al. Anticoagulants is a risk factor for
spontaneous rupture and hemorrhage of gallbladder: a case report and
literature review. \emph{BMC surgery.} 2019;19(1):2.

3. Yoshida R, Yoshizako T, Katsube T, Kitagaki H. Computed tomography
findings of ceftriaxone-associated biliary pseudocholelithiasis in
adults. \emph{Japanese Journal of Radiology.} 2019;37(12):826-831.

4. Shimura T, Kojima T, Tsutsumi S, Yoshida T, Uchiumi H, Kuwano H.
Gallbladder hematoma in a patient with hemophilia B, report of a
case.\emph{Hepato-gastroenterology.} 2000;47(34):939-941.

5. Ardu M, Alemanno G, Prosperi P, et al. Hemoperitoneum from
Hemorrhagic Perforated Cholecystitis in a Patient with Acquired
Deficiency of Factor VIII. \emph{The American
surgeon.}2020;86(4):e191-e193.\selectlanguage{english}
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