10.4081/btvb.2023.53
Acquired factor XIII (FXIII) deficiency is an extremely rare and potentially fatal bleeding disorder. Immune-mediated FXIII deficiency is due to the development of anti-FXIII autoantibodies which may develop with concomitant conditions that cause immune dysregulation such as malignancies or autoimmune disorders. Clinical presentation includes delayed post-operative bleeding or spontaneous soft tissue hematomas and/or cerebral bleeding. Since screening coagulation laboratory tests (prothrombin time, activated partial thromboplastin time, and fibrinogen) are typically normal, acquired FXIII deficiency is likely to be overlooked and underdiagnosed. The management of immune-mediated FXIII deficiency is based on hemostatic therapy, autoantibody removal and eradication of the underlying etiology; however, no treatment guidelines are still available. Here we report a case of acquired FXIII deficiency associated with plasmablastic lymphoma, in order to raise awareness of this rare bleeding disorder and consent prompt life-saving management.
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Luca Puccetti
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Bleeding, Thrombosis and Vascular Biology
Myeloma
A case of acquired factor XIII deficiency secondary to plasmablastic lymphoma
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Case Reports
2023-03-09
2022-10-25
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Bleed Thromb Vascul Biol
Luca Puccetti
2023/03/09
10.4081/btvb.2023.53
Hemostasis and Thrombosis Unit, “Santa Maria alle Scotte” University Teaching Hospital of Siena, University of Siena
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Myeloma
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Kariyawasan CC, Hughes DA, Jayatillake MM, Mehta AB. Multiple myeloma: causes and consequences of delay in diagnosis. QJM 2007;100:635-40.
A case of acquired factor XIII deficiency secondary to plasmablastic lymphoma
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                                                                                                                  CASE REPORT

A case of acquired factor XIII deficiency secondary to plasmablastic lymphoma
Vincenzo Sammartano,1 Adele Santoni,1 Elisabetta Zappone,1 Paola Calzoni,2 Daniela Fineschi,2 Eleonora Franceschini,2
Federico Caroni,1 Anna Sicuranza,1 Monica Bocchia,1 Luca Puccetti3
1
 Hematology Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, “Santa Maria alle Scotte” University
Teaching Hospital of Siena, Italy; 2Coagulative Disorders Laboratory Unit, “Santa Maria alle Scotte” University Teaching Hospital of
Siena, Italy; 3Hemostasis and Thrombosis Unit, “Santa Maria alle Scotte” University Teaching Hospital of Siena, University of Siena,
Italy



ABSTRACT
    Acquired factor XIII (FXIII) deficiency is an extremely rare and potentially fatal bleeding disorder. Immune-mediated FXIII defi-
ciency is due to the development of anti-FXIII autoantibodies which may develop with concomitant conditions that cause immune dys-
regulation such as malignancies or autoimmune disorders. Clinical presentation includes delayed post-operative bleeding or spontaneous
soft tissue hematomas and/or cerebral bleeding. Since screening coagulation laboratory tests (prothrombin time, activated partial throm-
boplastin time, and fibrinogen) are typically normal, acquired FXIII deficiency is likely to be overlooked and underdiagnosed. The
management of immune-mediated FXIII deficiency is based on hemostatic therapy, autoantibody removal and eradication of the un-




                                                                                                       ly
derlying etiology; however, no treatment guidelines are still available. Here we report a case of acquired FXIII deficiency associated




                                                                                               on
with plasmablastic lymphoma, in order to raise awareness of this rare bleeding disorder and consent prompt life-saving management.




                                                                                         e
    Correspondence: Luca Puccetti, Hemostasis and Thrombosis Unit,
    “Santa Maria alle Scotte” University Teaching Hospital of Siena,
    University of Siena, Viale Bracci 16, 53100, Siena, Italy.
                                                                                   us
                                                                              INTRODUCTION
                                                                                  Acquired factor XIII (FXIII) deficiency is an ex-
                                                                              al
    Tel: +39.0577586185.                                                      tremely rare and potentially fatal bleeding disorder due to
    E-mail: luca.puccetti@unisi.it
                                                                              either FXIII hyper-consumption, hypo-synthesis or in-
                                                                    ci

    Citation: Sammartano V, Santoni A, Zappone E, et al. A case of ac-        hibitor related to an immune-mediated process. The con-
                                                                  er


    quired factor XIII deficiency secondary to plasmablastic lym-             dition can be idiopathic or associated with several
    phoma. Bleeding, Thrombosis, and Vascular Biology 2023;2:53.              pathologic states such as malignancies or autoimmune
                                                                 m




    Key words: Factor XIII, Bleeding, Myeloma.                                disorders. Immune-mediated FXIII deficiency is typically
                                                                              symptomatic and clinical presentation includes delayed
                                                      om




    Conflicts of interest: The authors declare no potential conflict of       post-operative bleeding or spontaneous soft tissue
    interest.                                                                 hematomas and/or cerebral hemorrhages. Acquired FXIII
                                               -c




    Funding: None                                                             deficiency is likely to be overlooked as traditional coag-
                                                                              ulation tests [prothrombin time (PT), activated partial
                                      on




    Availability of data and material: Data and materials are available       thromboplastin time (aPTT), thrombin time and fibrino-
    by the Authors.
                                                                              gen] are in range. Treatment is based on FXIII replace-
                                N




    Informed consent: The manuscript does not contain any individual          ment, anti-fibrinolytic administration and/or inhibitor
    person’s data in any form.                                                eradication.1-3
                                                                                  Here we report a case of acquired FXIII deficiency as-
    Received for publication: 13 October 2022.
                                                                              sociated to plasmablastic lymphoma (PBL), which has
    Accepted for publication: 20 February 2023.
                                                                              never been described in current literature.
    Publisher’s note: All claims expressed in this article are solely those
    of the authors and do not necessarily represent those of their affili-
    ated organizations, or those of the publisher, the editors and the re-    CASE REPORT
    viewers. Any product that may be evaluated in this article or claim
    that may be made by its manufacturer is not guaranteed or endorsed            In May 2020 a 67-year-old woman with a recent di-
    by the publisher.                                                         agnosis of IgG/k PBL was transferred to our Hematology
    ©
     Copyright: the Author(s), 2023                                           Unit for progressive and severe anemia [hemoglobin
    Licensee PAGEPress, Italy                                                 (Hb) 6.5 g/dL]. Her medical history revealed the occur-
    Bleeding, Thrombosis and Vascular Biology 2023; 2:53                      rence of diffuse and atraumatic lumbar and rib cage pain
    doi:10.4081/btvb.2023.53
                                                                              six months earlier (November 2019), for which she was
    This work is licensed under a Creative Commons Attribution-               referred to the emergency room (ER) of a District-Hos-
    NonCommercial 4.0 International License (CC BY-NC 4.0).                   pital. Chest X-ray showed a 5th rib fracture and a lumbar
                                                                              Magnetic Resonance Imaging (MRI) scan revealed a ver-

                                                Bleeding, Thrombosis and Vascular Biology 2023; 2:53
                         A case of acquired factor XIII deficiency secondary to plasmablastic lymphoma                       27



tebral failure of D8. At that time, laboratory investiga-          dysfunction syndromes and von Willebrand disease, a
tions did not show abnormalities, yet serum protein elec-          factor XIII deficiency was detected with a FXIII activity
trophoresis was not performed, and the patient started             level of 3% by quantitative activity assay (Berichrom
analgesic therapy (ketorolac) with limited benefit. Two            Factor XIII test kit, Siemens, Marburg, Germany). The
months later (January 2020), she consulted both a neu-             clot solubility assay evaluating the stability of crosslinked
rosurgeon and an orthopedic that suggested the use of a            fibrin was abnormal and was not corrected by mixing
corset and she also repeated an X-ray showing a new ver-           with normal plasma, thus suggesting the presence of
tebral failure of D12. In April 2020 back pain worsened            FXIII inhibitor which was then confirmed by Bethesda
further, and the patient was admitted again to the ER,             assay at the level of 40 units.4-6 The patient had no history
where laboratory tests showed the presence of acute renal          of bleeding and previous surgeries (cholecystectomy in
failure (creatinine of 14 mg/dL). She immediately started          2012 and transurethral resection of bladder papillary le-
dialysis as an outpatient and developed a large hematoma           sion in 2016) were not complicated by bleeding, so we
in the catheter insertion site. Chest X-ray showed lung            concluded that the acquired FXIII deficiency was second-
consolidations in the upper right lobe, while abdominal            ary to her recent malignancy. As FXIII concentrates were
ultrasound evidenced splenic and hepatic focal lesions             not available, we used fresh frozen plasma (FFP) daily at
and lymphadenopathy. A bone marrow biopsy revealed                 the dosage of 15 ml/kg body weight (80 kg) to correct the




                                                                                    ly
80% monoclonal IgG/k plasmablastic plasma cells with               FXIII deficiency and to continue the PAD-regimen with




                                                                             on
t (14;16) by fluorescent in situ hybridization. Suddenly           the aim of eliminating the cause that had triggered the in-
just after the biopsy she developed a large hematoma               hibitor (Table 1). However, the patient’s clinical condition
around the incision site. A staging MRI of the spine and           worsened in three days with increasing dyspnea and de-




                                                                       e
the pelvis showed multiple vertebral lesions (D8, D9,              creasing oxygen saturation (SaO2) to 90%. Chest high-
D12 and L4), while 18F-fluorodeoxyglucose (FDG)
positron emission tomography revealed increased FDG
                                                                 usresolution CT showed expanding hematoma in the left
                                                                   hemithorax with signs of recent bleeding as well as a
                                                                   bronchopneumonia finding in the upper right lobe asso-
uptake in dorsal and lumbar spine, pelvis, ribs and stern.
                                                          al
Vertebroplasty of D9 was performed for worsening pain,             ciated with pleural effusion (Figure 2). The patient re-
                                                                   ceived consequently empiric antibiotic therapy with
                                              ci

but immediately the patient developed a huge hematoma
around the surgical site. A few days later, while she was          meropenem and linezolid and a CT angiography was per-
                                            er


on dialysis outpatient program waiting to start plas-              formed revealing minimal blood spread in the arterial
mablastic lymphoma therapy, she was urgently admitted              phase in the para-costal area in correspondence with the
                                           m




to ER for extreme asthenia and dyspnea. Blood tests                IX left intercostal space without clear evidence of the
                                                                   branch of origin, thus suggesting bleeding secondary to
                                  om




showed severe anemia (6 g/dL) and chest Computed To-
mography (CT) demonstrated a large hematoma of the                 the recent vertebroplasty of D9. The patient immediately
left hemithorax with spots of bleeding at the level of the         underwent embolization of the left intercostal arteries (V
                            -c




5th and the 7th rib. Only at this time, she was transferred        to IX) with the sandwich technique, achieving the reso-
to our hematology unit. On physical examination, the pa-
                     on




tient presented a huge purplish hematoma extending from
the neck to the hips, also involving the left arm and the
                 N




left leg (Figure 1). Laboratory tests still showed severe
anemia (Hb 6.5 g/dL) despite two packed red blood cell
(PRBC) units received while in ER, moderate thrombo-
cytopenia (platelet count 130000/mm3), increased serum
creatinine (5.95 mg/dL) and a monoclonal component
IgGk of 2.5 g/dL on serum protein electrophoresis and
immunofixation. Serum-free light chain assay demon-
strated k 5880 mg/L and λ 3.96 mg/L with a k/λ free light
chain ratio of 1458. Thus, induction therapy with borte-
zomib, PEGylated doxorubicin and dexamethasone (PAD
regimen) was started and dialysis continued.
    Although the initial screening had shown normal val-
ues of PT, aPTT and fibrinogen, we decided to investigate
further the coagulation profile considering her recent
bleedings and her poor transfusion yield stable Hb of 6
g/dL despite daily transfusions of 2 PRBC units. While             Figure 1. Huge purplish hematoma extending from the neck to
laboratory investigations ruled out the presence of platelet       the hips, also involving the left arm and the left leg.


                                     Bleeding, Thrombosis and Vascular Biology 2023; 2:53
28                                                             V. Sammartano et al.




lution of the bleeding. Despite an initial rise in hemoglo-
bin levels and a decrease of the monoclonal component                          DISCUSSION AND CONCLUSIONS
(0.44 g/dL), the ventilatory dynamics of the patient were                          Acquired FXIII deficiency is rare and can be classified
too compromised due to the organized hematoma and the                          as non-immune or immune-mediated. The former is
bronchopneumonia pattern in the remaining non-at-                              caused by FXIII hyper-consumption (such in case of sur-
electatic lung parenchyma. Our patient died of respiratory                     gery, inflammatory bowel disease or sepsis) or hypo-syn-
arrest five days after embolization.                                           thesis (such in case of liver disease or leukemia) and it is
                                                                               typically asymptomatic. Instead, immune-mediated FXIII
                                                                               deficiency is due to the development of anti-FXIII autoan-
                                                                               tibodies which may develop with concomitant conditions
                                                                               that cause immune dysregulation (such as autoimmune
                                                                               disease, malignancy or Monoclonal Gammopathy of Un-
                                                                               determined Significance (MGUS). Immune-mediated
                                                                               FXIII deficiency often presents with spontaneous or de-
                                                                               layed post-operative bleeding, especially in subcutaneous
                                                                               and intramuscular compartments.1,4,5




                                                                                                               ly
                                                                                   Both congenital and acquired conditions have normal




                                                                                                    on
                                                                               screening coagulation laboratory tests (PT, aPTT and fib-
                                                                               rinogen) and no evidence of platelet deficiency/dysfunc-
                                                                               tion.1,3 Clot solubility assays were traditionally used as the




                                                                                              e
                                                                               initial screening test, however, they can only detect severe
                                                                                      us
                                                                               FXIII deficiency. In fact, the International Society on
                                                                               Thrombosis and Haemostasis Scientific and Standardiza-
Figure 2. Computed tomography scan: expanding hematoma in                      tion Committee (ISTH-SSC) recommends a quantitative
                                                                              al
the left hemithorax with signs of recent bleeding as well as a                 functional FXIII activity assay as the first-line screening
bronchopneumonia finding in the upper right lobe associated
                                                              ci

                                                                               test. As regards autoimmune-mediated acquired defi-
with pleural effusion.
                                                                               ciency, ISTH-SSC also recommends the detection of neu-
                                                            er
                                                           m




Table 1. Laboratory data.
                                                 om




                                                                              T0                         T1                        T2
Hb (g/dl)                                                                     6.5                        8                         8.3
                                           -c




PLT (1x103/µL)                                                                130                       152                        161
WBC (1x103/µL)                                                                7.9                       10.4                      11.2
                                   on




PT (%)                                                                        96                         94                        91
INR                                                                          1.02                       1.03                      1.07
                             N




PTT (secs)                                                                    29                         33                        32
PTT Ratio                                                                      1                        1.13                       1.1
Fibrinogen (mg/dl)                                                            325                       290                        330
vWF:Ag (%)                                                                    124                       109                        136
vWF:RiCof (%)                                                                 130                       116                        124
Factor XIII (%)                                                                3                         11                        26
FXIII-inhibitor (Bethesda Units)                                              40                                                   15
ADP-induced platelet aggregation (10 nmol/L) (%)                              86
ADP-induced platelet aggregation (2 nmol /L) (%)                              78
Arachidonate-induced platelet aggregation (1.6 µmol /L) (%)                   80
Collagene-induced platelet aggregation (0.2 mg/ml) (%)                        84
Ristocetin-induced platelet aggregation (1.2 g/L) (%)                         78
Ristocetin-induced platelet aggregation (0.6 g/L) (%)                          7
T0, baseline; T1, five days after beginning of therapy*; T2, nine days after beginning of therapy* (day before exitus); Hb, hemoglobin; PLT, platelets;
WBC, white blood cells; PT, prothrombin time; INR, international normalized ratio; vWF (Ag: antigen, RiCof: ristocetin cofactor activity); ADP:
adenosine diphosphate. *Bortezomib, PEGylated doxorubicin and dexamethasone (PAD regimen). Fresh frozen plasma (FFP) was used daily at the
dosage of 15 mL/kg body weight (80 kg) between T0 and T2.


                                            Bleeding, Thrombosis and Vascular Biology 2023; 2:53
                         A case of acquired factor XIII deficiency secondary to plasmablastic lymphoma                          29



tralizing antibodies through mixing studies and Bethesda           we suggest that FXIII deficiency should be considered,
assay and non-neutralizing antibodies through binding as-          together with platelet dysfunction syndromes and von
says.1,6 In 2015 the ISTH-SSC proposed a diagnostic cri-           Willebrand disease (type 1 and 2), in patients presenting
terion for immune-mediated acquired FXIII deficiency.5             with unexplained bleeding symptoms with normal coag-
    The management of immune-mediated FXIII defi-                  ulation profile and platelet count. Even more, rapid recog-
ciency is dual: hemostatic therapy and autoantibody re-            nition of the factor XIII deficiency as the main cause of
moval. Since the rarity of this disorder, no guidelines are        an important hemorrhagic tendency could allow at least
available. Anti-fibrinolytic administration and FXIII re-          one attempt at correction perhaps by trying to reach cir-
placement with FXIII concentrates, cryoprecipitate and             culating levels considered to be at lower bleeding risk for
FFP are used to treat active bleeding. Autoantibody re-            invasive procedures/surgery.3
moval can be achieved by immunosuppressive therapies,                  In conclusion, we report here for the first time an asso-
such as corticosteroids, cyclophosphamide or rituximab,            ciation between PBL and acquired FXIII deficiency. Both
or through plasma exchange. In addition, therapy directed          conditions are rare and require aggressive and prompt man-
at the underlying etiology is suggested.1,7                        agement given the life-threatening risk. However, delayed
    PBL shares a reported median survival of 10 months             diagnosis is common and can negatively impact the clinical
and current treatment includes a combination of anti-              course. Our aim is to increase awareness of both diseases




                                                                                     ly
myeloma agents and chemotherapy.8                                  and to highlight the importance of extending coagulation




                                                                             on
    To date the association between FXIII deficiency and           work-up including FXIII deficiency investigation when an
PBL has never been reported in the literature, however,            unexpected bleeding diathesis is present, avoiding in the
the association between FXIII deficiency and other                 meantime every invasive procedure.




                                                                       e
plasma-cell dyscrasias, such as MGUS and Amyloid
Light-chain (AL) amyloidosis, has been described.9
    Our patient was transferred to our Hematology Unit
when the PBL was in a very advanced stage as the diag-
                                                                 usREFERENCES
                                                          al
nosis was made five months after the onset of symptoms.             1. Yan MTS, Rydz N, Goodyear D, Sholzberg M. Acquired
                                                                       factor XIII deficiency: A review. Transfus Apher Sci
This could be the reason for the poor outcome and, prob-
                                             ci

                                                                       2018;57:724-30.
ably, the cause that had triggered the FXIII inhibitor. In          2. Chou SC, Lin CY, Yen CT, et al. Acquired FXIII inhibitor:
                                           er


fact, a prolonged delay before the diagnosis is associated             Patient characteristics and treatment outcome, a case series
with a significant negative impact on the clinical course              in Taiwan. J Formos Med Assoc 2021;120:411-4.
                                          m




of multiple myeloma, especially in terms of an increased            3. Dorgalaleh A, Rashidpanah J. Blood coagulation factor XIII
number of complications, Durie-Salmon stage III and re-
                                 om




                                                                       and factor XIII deficiency. Blood Rev 2016;30:461-75.
duced disease-free survival.10 In our case, a common                4. Muszbek L, Katona É. Diagnosis and Management of Con-
serum protein electrophoresis might have anticipated the               genital and Acquired FXIII Deficiencies. Semin Thromb He-
                            -c




diagnosis and, thus, the specific treatment, avoiding fur-             most 2016;42:429-39.
ther complications or even the exitus. For this reason, we          5. Ichinose A, Kohler HP, Philippou H. Factor XIII and Fib-
                     on




                                                                       rinogen SSC Subcommittee of the ISTH. Recommendation
suggest that a blood test comprehensive of full blood cell
                                                                       for ISTH/SSC Criterion 2015 for autoimmune acquired fac-
count, creatinine, calcium and serum and urine protein
                                                                       tor XIII/13 deficiency. Thromb Haemost 2016;116:772-4.
                N




electrophoresis should be performed in case of bone pain            6. Durda MA, Wolberg AS, Kerlin BA. State of the art in factor
resistant to usual pain medications to rule out a plasma               XIII laboratory assessment. Transfus Apher Sci 2018;57:
cell disorder, which should be taken in consideration by               700-4.
the physician in every patient with persistent bone pain.           7. Ichinose A. Japanese Collaborative Research Group on
    As described, our case was complicated by acquired                 AH13. Autoimmune acquired factor XIII deficiency due to
FXIII deficiency which resulted to be lethal for the pa-               anti-factor XIII/13 antibodies: A summary of 93 patients.
tient. Indeed, the first bleeding was considered to be re-             Blood Rev 2017;31:37-45.
lated exclusively to an invasive procedure (catheter                8. Suarez-Londono JA, Rohatgi A, Antoine-Pepeljugoski C,
insertion) and not a possible underlying bleeding diathe-              Braunstein MJ. Aggressive presentation of plasmablastic
                                                                       myeloma. BMJ Case Rep 2020;13:e234436.
sis, despite an uncommon bleeding pattern, especially
                                                                    9. Ferretti A, Baldacci E, Fazio F, et al. Acquired FXIII defi-
with normal baseline coagulation tests, as observed in the             ciency and AL amyloidosis: A case of a rare association.
reported case. Extensive coagulation tests were not inves-             Transfus Apher Sci 2020;59:102903.
tigated, and two other invasive procedures were per-               10. Kariyawasan CC, Hughes DA, Jayatillake MM, Mehta AB.
formed, a bone marrow biopsy and vertebroplasty, the                   Multiple myeloma: causes and consequences of delay in di-
latter responsible for the patient’s fatal hematoma. Thus,             agnosis. QJM 2007;100:635-40.




                                    Bleeding, Thrombosis and Vascular Biology 2023; 2:53
