Bergeijk, L van

Huijgens, P.C.

Nijenhuis, AV

Zweegman, S.

Nijenhuis, A. V.

van Bergeijk, L.

Huijgens, P. C.

NARCIS 

Acquired factor XIII deficiency due to an inhibitor: a case report and review of the literature.

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A.V.M. Nijenhuis et al.
| 46 | haematologica/the hematology journal | 2004; 89(online)
Acquired factor XIII deficiency due to an
inhibitor: a case report and review of the 
literatureHaematologica 2004; 89:(4)e46-e48
When a bleeding disorder is suspected, performing rou-
tine coagulation tests is not sufficient, as a normal
Activated Partial Thromboplastin Time (APTT) and
Protrombin Time (PT) do not exclude clinically relevant
deficiencies of various coagulation factors and anti-fibri-
nolytic factors. In this report we describe a patient who
presented with spontaneous bleeding and a normal
APTT and PT. Analysis showed the presence of an
acquired inhibitor to factor XIII. The pathogenesis, clini-
cal features and treatment modalities will be discussed.
A 75 year old woman was referred to our hospital
because of multiple subcutaneous haematomas and a
painful swollen upper left thigh a few days after a fall.
Her medical history revealed recurrent depressions, for
which she had been admitted to a psychiatric clinic and
for which a selective serotonin uptake inhibitor (fluvox-
amine) was prescribed. A cholecystectomy was per-
formed 30 years earlier without bleeding complications.
Physical examination showed a healthy but pale looking
woman. Examination of heart, lungs and abdomen was
unremarkable. There were indeed multiple haematomas
on her entire body. A swollen and tense left thigh was
found (diameter 61 cm compared to 56 cm on the right).
Laboratory studies showed a normocytic anemia (haemo-
globin 4.6 mmol/L). Platelet count, APTT and PT were
normal. An ultrasound of the left upper thigh showed an
intramuscular haematoma. 
As multiple units of red blood cells were necessary to
maintain a stable hemoglobin level (Figure 1) a coagula-
tion disorder was suspected. However, additional tests
were found to be within normal limits: bleeding time,
von Willebrand factor activity (ristocetin cofactor activity
>100%) and antigen (>125%), platelet aggregation tests
(using ADP, collagen, arachidonic acid and ristocetin as
stimulators) and fibrinogen (6 g/L). A clotting disorder
was reconsidered when an intramuscular bleeding in the
left arm occurred, probably caused by vein punctures.
The consulted haematologist ordered factor XIII and
alpha-2-antiplasmin tests (108%). Photometric determi-
nation of factor XIII activity revealed a severe deficiency
(Berichrom F XIII®, Dade Behring, Marburg, Germany:
6%, ref 70-140% of normal plasma). As the patient never
experienced bleeding before, the factor XIII deficiency
was most likely to be acquired, which could be confirmed
by determination of an inhibitor in mixing studies
(inhibitor titer of >20 U/mL). The factor XIII activity in a
1:1 mixture of patient and normal plasma remained
extremely low (2%). 
Underlying malignant, lympho-proliferative or auto-
immune diseases were found to be unlikely as computer
tomographic scanning of thorax and abdomen showed
no abnormalities, protein analysis excluded the presence
of a M-protein and no anti-nuclear factor or anti rheuma
factor antibodies were present. Therapy was started with
prednisone (1 mg/kg). In order to quickly raise factor XIII
levels, human immunoglobins (1 g/kg, for 2 days) were
administered. This resulted in an increase of factor XIII
from 2% to 16% six days later. Because it was possible to
maintain adequate Hb-levels with transfusion of <3 units
of red cells/week, it was decided not to administer fXIII-
concentrate. The patient redeveloped a severe depres-
sion. At that time, at persistent low fXIII levels of about
10%, a painful haematoma developed in the right flank.
The patient refused any therapy because of her wish to
die. A psychiatric consultant judged her to be competent
and her chronic depression to be therapy resistant. A few
days later she died due to rectal bleeding and accompa-
nying hypovolemic shock. An autopsy, including section
of the brain, was performed. Besides large haematomas
in the left upper thigh and the right intercostal muscles
autopsy revealed no abnormalities. 
This case report emphasizes that in a patient with per-
sistent bleeding a normal APTT and PT does not exclude
a clinical relevant deficiency of a coagulation factor is not
excluded. Although levels of nearly all coagulation factors
can be subnormal despite normal APTT and PT, those
levels are generally not accompanied with spontaneous
serious bleeding. In case of bleeding, especially distur-
bances in platelet aggregation/adhesion or a deficiency of
factor XIII or alpha-2-antiplasmin have to be considered.
In our patient an acquired inhibitor to factor XIII was
diagnosed. Factor XIII is a specific transamidase that cross
links fibrin molecules by forming ?(?-glutamyl)lysine
bridges that stabilize the clot. Moreover, it incorporates
fibronectin, collagen and alfa-2-antiplasmin into the clot,
thereby making the clot more suitable for the ingrowth of
fibroblasts and more resistant to fibrinolysis. That
patients with factor XIII deficiency generally start bleed-
ing some time after trauma is probably accounted for by
the fact that fibrinolysis of clots occurs more rapidly
because of less alfa-2-antiplasmin incorporated into the
clot 1. Furthermore, non cross-linked fibrin has a higher
affinity for plasminogen.2 Hereditary factor XIII deficien-
cy is a rare severe bleeding disorder (incidence
1:3.000.000). The inheritance is autosomal recessive. In
80% the first and almost pathognomonic sign is bleeding
from the umbilical cord a few days after birth. There is a
tendency to bleed in the skin, muscles and subcutaneous
tissues. Patients bleed several days after minor trauma or
surgery. In up to 30% of cases intracranial bleeding
occurs.1 In addition to hereditary factor XIII deficiency,
acquired factor XIII deficiency has been described.3
Acquired partial deficiencies, usually in the range of 50-
75% of normal have been reported in association with
various diseases (see Table 1). Whether these mild defi-
ciencies are of clinical importance has been differently
reported on 1,4. Severe deficiencies, leading to sponta-
Figure 1. Haemoglobin level and timing of transfusion of filtered
units of red cells and fresh frozen plasma.
The patient was admitted to the hospital at July the 11th with an
intramuscular haematoma. On the 12th of Augusts she developed
a haematoma in the left arm due to vein punctures. The diagno-
sis of acquired factor XIII deficiency was made at August the 22th
after a haematologist was consulted. The patient was treated
thereafter with immunoglobulins (IG: 1g/kg for 2 days). In the
beginning of September a painful haematoma developed in the
right flank. Further therapy was refused by the patient. 
neous bleeding are most often caused by acquired
inhibitors to factor XIII. The first patient was described in
1967.5 We could identify 21 cases of inhibitor induced
acquired factor XIII deficiency in the literature.6-25 Six of
these patients used isoniazide, which is presumed to play
a causative role. Autoimmune diseases were present in 5
patients. In only two cases a Monoclonal Gammopathy
of Undetermined Significance (MGUS) was found, one
patient also using isoniazide. In most8 of described cases
no underlying disease could be determined, although is
has to be emphasised that no generally no extensive
investigations were performed. Concerning our patient;
no association between fluvoxamine and acquired fXIII
deficiency has been reported. To our knowledge, this
would be the first report. However, as it is not unusual
that an underlying disease is absent, it might well be
coincidence. Factor XIII deficiency can be diagnosed with
functional assays showing increased clot solubility in 1%
monochloroacetic acid or in 5M urea can be used.5
However, these tests do not differentiate heterozygotes
or patients with acquired partial deficiency. Quantization
of factor XIII activity levels can be easily determined by a
photometric assay such as we used. The presence of an
inhibitor against fXIII can be investigated in mixing stud-
ies with normal plasma, in which the remaining fXIII
level is lowered by the presence of the inhibitor, leading
to persistent low fXIII levels. Furthermore, the inhibitor
can be quantified by use of the Bethesda assay, in which
control and patient plasma in different dilutions are incu-
bated with normal human plasma for 2 hours at 37°C.
Subsequently, the remaining level of factor XIII is deter-
mined. The Bethesda inhibitor titer is defined as the
reciprocal of the plasma dilution that yields a residual fac-
tor XIII of 50%.
The treatment of patients with an acquired factor XIII
inhibitor aims at controlling bleeding by an acute increase
in factor XIII and by elimination of the inhibitor. Acute
increases in factor XIII can be obtained by administration
of factor XIII, either as fresh frozen plasma or as pas-
teurised factor XIII concentrate derived from human pla-
centa (Fibrogammin-P®). Because of a long in vivo half life
(11-14 days), in hereditary factor XIII deficiency 1000 U
of Fibrogammin-P® can be given very 6 weeks. This dose
normally raises the plasma level to above 30% of normal,
providing levels of 3-5% at week 6, which, in hereditary
deficiency, is sufficient to prevent bleeding. However, in
inhibitor patients, the half life is considerably shorter.
Therefore, higher and more frequent dosages are neces-
sary. Control of hemorrhagic symptoms has been
obtained with factor XIII doses from 50-150 U/kg.17,22
Administration of factor XIII can be combined with
plasmapheresis to remove antibodies. However, as most
of the antibodies are IgG antibodies rapid repletion from
extravascular sites occurs. An increase in antibody deple-
tion can be achieved with the use of staphylococcus A
columns, which selectively binds to the Fc portion of the
human IgG.19 Although the value of gammaglobulins in
patients with a factor XIII inhibitor is unknown, in view
of the described effect in patients with acquired hemofil-
ia A and von Willebrand disease, we treated our patient
with intravenous gammaglobulins.26,27 The proposed
mechanisms of action are direct complex formation of
the gammaglobulins with the neutralizing antibody (idio-
type anti-idiotype interaction) and blockade of the Fc
receptors of the reticuloendothelial system thereby
reducing the plasma clearance of antigen-antibody com-
plexes. Effect is generally observed after several days,
which indeed appeared to be the case in our patient,
showing a rise in fXIII activity of 14%. Furthermore,
although no clinical data are available it would be reason-
able to treat patients with anti-fibrinolytic therapy (e.g.
tranexaminic acid), as clots are more vulnerable to fibri-
nolysis.1,2
Similar to treatment of acquired inhibitors to factor
VIII, inhibition of the formation of antibodies can be tried
by administration of high doses of corticosteroids, cyclo-
fosfamide, ciclosporin or combinations.3,28 The success
rate is unknown because of the rarity of this disease and
the fact that spontaneous remissions have been reported.
In the 21 described cases the fatality rate was high: 50%
of patients of whom the outcome was reported died.
However, the current possibility to treat patients with
high dose factor XIII concentrate might lead to a lower
mortality, which is supported by recent reports. 15,17,18,22
In conclusion, although substitution therapy is easy in
hereditary factor XIII deficiency because of the long half
life of factor XIII concentrate, treatment of patients with
inhibitors is more complicated. High and frequent dosing
of factor XIII concentrates (Fibrogammin-P®) is necessary.
As the pharmacokinetics of transfused factor XIII concen-
trate is unpredictable, monitoring of factor XIII levels is a
prerequisite. There might be a role for human
immunoglobulines to decrease the clearance of factor
XIII-antibody complexes, thereby minimizing the neces-
sary dosages of factor XIII administration.
A.V.M. Nijenhuis,1 L. van Bergeijk,1 P.C. Huijgens,2 S. Zweegman2
1Department of Internal Medicine, Hospital Twenteborg, Almelo and 
2Department of Haematology, VU University Medical Center,
Amsterdam, the Netherlands
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haematologica/the hematology journal | 2004; 89(online) | 47 |
Table 1. Causes of acquired factor XIII deficiency.
Impaired synthesis
Liver disease
Increased turn-over and consumption
Acute and chronic leukemia
Myeloproliferative and myelodysplastic syndrome
Disseminated intravascular coagulation
Septic infections
Unknown or combined etiology
Major surgery
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Idiopathic
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A.V.M. Nijenhuis et al.
| 48 | haematologica/the hematology journal | 2004; 89(online)


Acquired factor XIII deficiency due to an inhibitor: a case report and review of the literature.

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