Keywords
anticoagulation - catheter-related thrombosis - factor Xia - gastrointestinal bleeding
- parenteral feeding - osocimab
Introduction
Central venous catheter (CVC) thrombosis is typically managed by CVC removal and short-term
anticoagulation therapy; however, for patients with lifelong CVC dependency management
is difficult, particularly for those who also have a high bleeding risk. Here, we
report the successful management of a 20-year-old woman with ultra-short bowel syndrome
(uSBS) who was dependent on CVCs for parenteral nutrition (PN) and experienced multiple
catheter-related thromboses and bleeding complications throughout her life.
Our patient has jejuno-ileal atresia, a congenital malformation of the small intestine,
which has an estimated prevalence of 0.7/10,000 live births in Europe.[1] Apple-peel syndrome (type IIIb intestinal atresia), characterized by innate jejunal
atresia and the small intestine wrapping spirally around supplying blood vessels,
belongs to the most severe forms and comprises less than 10% of jejuno-ileal atresia
cases.[2]
[3]
[4] Patients with apple peel syndrome often have complex presentations with various
comorbidities.[4]
[5]
Despite the patient receiving daily low-molecular-weight heparin (LMWH; enoxaparin)
injections for more than 15 years since infancy to prevent or treat catheter-related
thrombosis (CRT), clotting of CVCs, CRT, and severe gastrointestinal bleeding remained
a persistent problem, along with repeated catheter replacements and severe osteoporosis.
Patient Clinical History
After diagnosis of apple–peel syndrome at birth, sections from the patient's intestines
were removed surgically by repeated resections and anastomoses, leading to uSBS and
near-complete loss of intestinal function. Subsequent Z-incision surgeries failed
to extend the gut and scarred the small intestine, which later continued to be a recurrent
source of gastrointestinal bleeding events.[6] To provide PN, a Hickman CVC was inserted into the right jugular vein. Subsequently,
the patient experienced recurrent complications of bleeding and thromboembolic events
([Fig. 1]).
Fig. 1 Timeline of patient's medical history, including thrombotic events, bleeding events,
and treatments. Circles represent treatments or interventions. Pink diamonds represent
diagnoses other than thromboembolic events or bleeding events. All other symbols represent
different types of thromboembolic events or bleeding events according to the figure
key. The green shaded area of the timeline represents the duration of osocimab therapy.
ARDS, acute respiratory distress syndrome; CVC, central venous catheter; DVT, deep
vein thrombosis; Fe, ferric carboxymaltose; GI, gastrointestinal; LMWH, low-molecular-weight
heparin; M, mesalamine; PAC, port-a-cath; PICC, peripherally inserted central catheter;
RBC, red blood cells; TA, tranexamic acid.
Aged 2 years, the patient developed jugular deep vein thrombosis (DVT) from catheter
use and initiated once-daily subcutaneous enoxaparin 10 mg. Jugular DVT recurred twice
over the next 12 months, and the patient also experienced subclavian/brachiocephalic
DVT. Repeated enoxaparin dose adjustments were undertaken to balance the risk of thrombosis
versus bleeding. Aged 4 years, she experienced gastrointestinal bleeding, macrohematuria,
and multiple thigh hematomas from enoxaparin injections. Right iliac DVT was discovered—probably
caused by a previous temporary CVC—resulting in the first of many CVC replacements.
Aged 5 and 6 years, she experienced further CRTs, each requiring CVC replacement;
twice-daily enoxaparin was required to maintain vascular access, which increased bleeding
event frequency ([Fig. 1]). Despite a negative family history of venous thromboembolism, a complete thrombophilia
screening was performed at the age of 6 years, which ruled out hereditary or acquired
thrombophilia.
Aged 10 years, another CRT led to a further enoxaparin dosage increase (30 mg twice
daily). The patient experienced a spontaneous distal femoral fracture at 12 years
of age, indicating the advanced stage of osteoporosis, a reported complication of
short-bowel syndrome, and a side effect of proton pump inhibitors and LMWHs.[7]
[8]
[9] Aged 14 years, magnetic resonance imaging revealed known right jugular and brachiocephalic
vein occlusions and a new right subclavian vein occlusion. Persistent iron deficiency
anemia from age 14 (>2 years) was treated with intravenous ferric carboxymaltose.
Aged 17 years, a bone density scan quantitatively documented the presence of severe
osteoporosis (Z-scores: −2.0 [right femur]; −2.3 [left femur]; −4.2 [lumbar spine]).
Height and weight developmental milestones were not achieved and delayed puberty was
diagnosed ([Fig. 1]). Catheter site abscesses and CRT led to a Hickman CVC being inserted into the left
jugular vein. The patient refused further enoxaparin injections and trialed rivaroxaban
15 mg, later decreasing the dose to 10 mg; however, persistent gastrointestinal bleeding
led to treatment discontinuation after 4 weeks. She briefly resumed enoxaparin but
quickly refused further injections.
Following several discussions with the patient and her legal guardian, the clinical
team suggested an individual treatment approach with the experimental drug osocimab,
a human monoclonal antibody inhibitor of factor XIa.[10]
Hereditary FXI deficiency as well as FXI inhibition in animal models have been shown
to reduce arterial and venous thrombosis without increasing bleeding.[11]
[12]
[13] Based on this rationale, several FXI inhibitors are in clinical development.[14] Within this group, osocimab has shown clinical efficacy versus enoxaparin in preventing
postoperative venous thromboembolism in individuals undergoing total knee arthroplasty
and in lowering the risk versus placebo of dialysis conduit clotting in patients with
kidney failure undergoing regular hemodialysis, without increasing the rate of clinically
relevant bleeding.[10]
[15]
[16]
Methods
Following approval from the Clinical Ethics Committee of Dresden University Hospital,
an application was made to the manufacturer (Bayer AG) for compassionate-use access
to osocimab. In November 2021, the patient discontinued enoxaparin and initiated weight-based
(1.2 mg/kg) intravenous therapy with osocimab (total dose 55 mg). Out of ethical considerations
(compassionate use in an underaged patient), and given the limited evidence available
at the time to inform dosage, it was decided to initiate osocimab at 1.2 mg/kg and
only escalate if clinically needed.
Owing to the long half-life, osocimab can be administered at monthly intervals. The
first three doses were administered during day-long hospital stays for close surveillance;
the subsequent 21 doses were administered during regular monthly gastroenterology
outpatient visits and with 3-hour observation windows following each infusion.
This case is reported with the Ethics Committee approval (Dresden University Hospital)
and in accordance with the Declaration of Helsinki[17] and the CARE Checklist.[18] The patient and her legal guardian provided written informed consent.
Results
During 30 months of osocimab treatment, no new thrombotic events occurred. The CVC
dislocated 2 months after treatment initiation leading to insertion of the current
Hickman CVC. During the procedure, sequelae of an old clot (considered unrelated to
osocimab) were discovered in the patient's left jugular vein. In the subsequent 28
months, the Hickman CVC has been uncompromised.
Minor bleeding at the catheter site from a minor skin infection occurred after the
fourth osocimab infusion; the patient was seen at the hospital and discharged with
no further action. A clinically relevant gastrointestinal bleed (considered unrelated
to osocimab treatment) occurred between the seventeenth and eighteenth infusions,
manifesting as hematochezia for 3 days and anemia (treated with tranexamic acid [600 mg]
and 2 units of red blood cells plus ferric carboxymaltose [2 × 500 mg], respectively).
After osocimab injections, the patient demonstrated normal to moderately prolonged
activated partial thromboplastin times (range: 32–42 seconds; reference range: 24–36 seconds).
Factor XI values remained in the normal range during the entire period (range: 78–102%;
reference range: 60–150%). There were no signs of intolerance or allergic reactions
to osocimab.
Aged 20 years, the patient developed acute respiratory distress syndrome, requiring
hospitalization and treatment with high-flow oxygen and low-dose catecholamines. Recurrent
venous thromboembolism and pneumonitis were ruled out, and atypical pneumonia was
diagnosed, considered unrelated to osocimab. The patient fully recovered and osocimab
therapy remained uninterrupted without recurrent respiratory symptoms.
During the 18 months before receiving osocimab, the patient's BMI decreased—probably
owing to CRT, recurrent hospitalizations, and psychological burden—leading to a rapid
deviation from developmental percentiles ([Table 1]). After initiating osocimab, the patient's BMI decline immediately stopped; her
weight increased by more than 10% in 20 months. Also, menarche occurred 3 months later
without signs of menorrhagia. After 24 osocimab infusions, dual-energy X-ray absorptiometry
indicated improved lumbar spine (−2.8) and right femur (−1.3) Z-scores but a somewhat
worsened left femoral Z-score (−3.0) versus the initial scan. The patient reported
a positive change in well-being and quality of life after discontinuing enoxaparin
and continues to receive osocimab under the compassionate use program (extended until
August 2025). To our knowledge, no similar cases have been reported previously.
Table 1
Summary of patient's weight, height, and body mass index from 16 to 20 years of age
|
Age, y
|
Weight, kg
|
Height, cm
|
Body mass index, kg/m2
|
Developmental percentile
|
Treatment notes
|
|
16
|
41.8
|
146.5
|
19.5
|
30th
|
Enoxaparin
|
|
17
|
42.3
|
147
|
19.6
|
29th
|
Enoxaparin
|
|
17
|
40.8
|
148
|
18.6
|
15th
|
Enoxaparin
|
|
17
|
42
|
149.5
|
18.8
|
16th
|
Return to enoxaparin after 4-wks trial of rivaroxaban
|
|
18
|
42.2
|
150.3
|
18.7
|
14th
|
Before osocimab dosing
|
|
18
|
45.0
|
151
|
19.7
|
NA
|
2 mo of osocimab
|
|
18
|
44.7
|
153
|
19.1
|
NA
|
6 mo of osocimab
|
|
19
|
46.7
|
153
|
19.9
|
NA
|
10 mo of osocimab
|
|
19
|
47.2
|
154
|
19.9
|
NA
|
12 mo of osocimab
|
|
19
|
46.2
|
153
|
19.7
|
NA
|
19 mo of osocimab
|
|
19
|
46.5
|
154
|
19.6
|
NA
|
20 mo of osocimab
|
|
19
|
45.3
|
154
|
19.1
|
NA
|
22 mo of osocimab
|
|
20
|
47.5
|
154
|
20
|
NA
|
30 mo of osocimab
|
Abbreviation: NA, not applicable.
Note: There are no developmental percentiles in Germany for adults.
Discussion
This case highlights the therapeutic potential of factor XIa inhibition in preventing
CRT. CVCs are used widely in clinical practice to administer fluids, medications (including
chemotherapy), and PN, and to perform hemodialysis, but they are associated with both
short-term (e.g., infections, sepsis, embolism, thrombus extension) and long-term
complications (e.g., postthrombotic syndrome, thrombosis recurrence, stenosis or occlusion,
vascular access loss).[19]
[20] Patients with short bowel syndrome and uSBS must adhere to potentially life-long
daily PN via CVCs, so the goal in children is to preserve access sites by minimizing
catheter replacement.[21] No anticoagulant drugs are approved for use in children or adults with CRT.[20]
[22] Children undergoing long-term PN who develop CRT may benefit from prophylactic dosing
of LMWH to prevent recurrence[21]; however, ensuring adherence, balancing the increased bleeding risk, and managing
the burden on families can be challenging in children.[21]
The rationale for inhibiting factor XI derives from the observation that on contact
of blood with surfaces of medical devices, FXII is cleaved into activated FXII, which
in turn activates FXI, leading to the formation and propagation of a blood clot.[23] Consequently, inhibition of this contact activation pathway may prevent this frequent
complication in CVC patients.
The patient presented here has received osocimab therapy in clinical practice for
more than 2 years, with maximum adherence. Her outcomes are consistent with those
observed in the recently published CONVERT phase 2b trial evaluating osocimab in patients
with kidney failure on regular hemodialysis, the majority of whom regularly received
concomitant heparin.[16] The limitations associated with a single case report should be addressed with a
randomized controlled trial in patients with CVCs to evaluate quality of life and
treatment burden. Of note, a phase 2 trial of the anti-FXI monoclonal antibody gruticibart
in 22 individuals with cancer undergoing central line placement found that gruticibart
treatment resulted in a lower incidence of catheter-associated thrombosis.[24] In addition, a phase 2 study investigating the efficacy and safety of two FXI antibodies,
REGN7508 and REGN9933, for preventing blood clots in adults with a peripherally inserted
central catheter is currently ongoing (ClinicalTrials.gov: NCT06299111), the results
of which may provide further evidence of the benefits of FXI inhibition in these situations.
Conclusion
These findings suggest that osocimab therapy may be beneficial as part of a multidisciplinary
approach to managing conditions that involve CRT. They also highlight the therapeutic
potential of factor XIa inhibition in preventing the problems associated with clotting
in these patients. With 2.5 years of uninterrupted exposure, this patient has experienced
the longest duration of factor XIa inhibition to date, outside of a clinical trial.
She continues to report a positive change in well-being and quality of life.
Bibliographical Record
Jan Beyer-Westendorf, Katrin Weber, Falk Eckart, Martin W. Laass, Ralf Knöfler, Kate
Benson, László B. Tankó, Martin Bornhäuser. Compassionate Use of Osocimab in Preventing
Thrombotic Complications Without Incremental Bleeding: A Case Report. TH Open 2025;
09: a25774474.
DOI: 10.1055/a-2577-4474
