1. Clinical Neurology and Neurosurgery 115 (2013) 13–18
Contents lists available at SciVerse ScienceDirect
Clinical Neurology and Neurosurgery
journal homepage: www.elsevier.com/locate/clineuro
Occurrence and recurrence of spontaneous chronic subdural haematoma is
associated with a factor XIII deficiency
Bert Boschea,b,c,∗,1
, Marek Molcanyib,1
, Thomas Nolld
, Matthias Kochaneke
, Bastian Krausf
,
Bernhard Riegerb
, Faycal El Majdoubb,g
, Christian Dohmenc,h
, Mario Löhrb,i
,
Roland Goldbrunnerb
, Gerrit Brinkerb
a
Department of Neurology, University of Duisburg-Essen, Germany
b
Department of Neurosurgery, University of Cologne, Germany
c
Max Planck Institute for Neurological Research with Klaus-Joachim-Zülch Laboratories of the Max Planck Society and the Medical Faculty of the University of Cologne, Germany
d
Institute of Physiology, Medical Faculty Carl Gustav Carus, Technical University Dresden, Germany
e
Department I of Internal Medicine (Haematology, Haemostasiology and Oncology), University of Cologne, Germany
f
Department of Radiology, University of Cologne, Germany
g
Department of Stereotactic and Functional Neurosurgery, University of Cologne, Germany
h
Department of Neurology, University of Cologne, Germany
i
Department of Neurosurgery, University of Würzburg, Germany
a r t i c l e i n f o
Article history:
Received 29 September 2011
Received in revised form 12 January 2012
Accepted 25 March 2012
Available online 26 April 2012
Keywords:
(Spontaneous) Chronic subdural
haematoma
Factor XIII
Haemostatic disorders
Differential diagnosis of stroke
Blood vessels
Wound healing
a b s t r a c t
Objective: In some patients, chronic subdural haematoma (cSDH) appears to occur spontaneously with
frequent re-bleeding events. The pathophysiology of this phenomenon is still poorly understood. Because
coagulation factor XIII (FXIII) is known to be involved in vascular integrity, endothelial barrier function
and wound healing, we evaluated the role of FXIII in spontaneous cSDH.
Methods: We prospectively scrutinised the origin of cSDH in 117 patients and identified a subgroup of
patients suffering from spontaneous cSDH who were included in this study. We analysed the plasma
activity of FXIII and standard coagulation parameters and compared these data to age- and sex-matched
healthy controls. We assessed the occurrence of re-bleeding events using clinical and imaging data and
compared FXIII activity in patients with and without re-bleeding events.
Results: Out of 117 cSDH patients, 18 individuals suffered from spontaneous cSDH in this study. The
patients with spontaneous cSDH showed significantly lower FXIII activity than the control group (65%
[52.75, 80.25] (median [IQR]) vs. 93% [81, 111], P = 0.001), whereas standard coagulation parameters did
not differ significantly between the groups. Six patients developed re-bleeding events after haematoma
evacuation, and these patients expressed significantly lower FXIII activity compared to the other 12
patients (47.5% [33.5, 64] vs. 78.5% [58, 87], P = 0.005). The patient group with FXIII ≤ 68.5% differed
significantly from the group with FXIII > 68.5% when categorised by the occurrence of re-bleeding events
(n = 6/9 vs. n = 0/9, P = 0.009). This cut-off value predicted the re-bleeding events with a sensitivity of 100%
and a specificity of 75% (positive predictive value: 66%, negative predictive value: 100%).
Conclusion: FXIII deficiency may play a pathophysiological role in spontaneous cSDH, so we suggest
investigating FXIII activity because it may predict re-bleeding events after treatment. In individuals with
considerably low FXIII activity, FXIII substitution may mitigate the chronic nature of this disease.
© 2012 Elsevier B.V. All rights reserved.
1. Introduction
Chronic subdural haematoma (cSDH) frequently occurs in
patients who have not experienced a prior traumatic event
∗ Corresponding author at: Klinik für Neurologie, Universitätsklinikum Essen,
Hufelandstr. 55, 45147 Essen, Germany. Tel.: +49 201 723 83586.
E-mail addresses: bert.bosche@gmail.com, bert.bosche@uk-essen.de (B. Bosche).
1
These authors contributed equally to this work.
[1,2] and in patients who report only a slight trauma in their
history [3]. In these specific non-traumatic or spontaneous subdu-
ral haematomas, symptoms often occur suddenly and may mimic
ischaemic stroke [4,5]. Generally, cSDH is known as a typical disease
of the elderly [1]. In addition to old age and head trauma, common
co-factors observed in conjunction with cSDH include alcoholism,
liver disease and therapeutic anti-coagulation or anti-aggregation.
Risk factors for the occurrence and recurrence of cSDH have been
investigated and reviewed in detail in prior publications [3,6]. Nev-
ertheless, the aetiology remains unknown in over 25% of cases,
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2. 14 B. Bosche et al. / Clinical Neurology and Neurosurgery 115 (2013) 13–18
and spontaneous re-bleeding events are common and originate
primarily from the membranes covering the cSDH [3,7–9]. Fragile
neo-vessels in the membranes that cover the cSDH and an imbal-
ance between activated coagulation and fibrinolysis have been
discussed as possible causes of multiple re-bleeding events and
the chronic nature of the subdural haematoma [10,11]. However,
the pathophysiology is still insufficiently understood, particularly
in the case of spontaneous cSDH [3,6,7]. Hence, further studies are
required to identify intrinsic factors for the spontaneous occurrence
and recurrence of cSDH.
Coagulation factor XIII (FXIII), also known as clot stabilising
factor [12], is synthesised in cells of bone marrow origin and in
hepatocytes within the liver and circulates in the blood in the form
of a pro-enzyme [13]. Thrombin and Ca2+ convert FXIII to its active
form. FXIII stabilises fibrin and protects it against fibrinolysis by
mechanically cross-linking fibrin chains and the alpha-2 plasmin
inhibitor at the end of the clotting cascade. This fibrin-stabilising
function within the coagulation cascade has been broadly investi-
gated and is well-established in the literature [13,14]. Additionally,
FXIII is involved in wound healing [15–17] and plays an important
role in the stabilisation of endothelial barrier function and vascu-
lar integrity [15,18–20]. A potential role for FXIII in angiogenesis
has also been discussed [21]. However, FXIII plasma activity is not
routinely evaluated in clinical laboratory tests.
We hypothesised that the decreased activity of FXIII may play a
role in the pathophysiology and recurrence of spontaneous cSDH.
We aimed to evaluate the initial FXIII plasma activity as a potential
diagnostic parameter for the prediction of further clinical course,
and particularly as a predictor of cSDH recurrence after haematoma
evacuation.
2. Patients and methods
2.1. Patient recruitment, inclusion and exclusion criteria
In this prospective study, we consecutively screened 117
patients at our centre from 5th October 2006 to 22nd September
2009. All the patients suffered from focal neurological symptoms
such as limb- or hemiparesis, dysphasia or aphasia and cognitive
or neuropsychological disorders caused by a hypodense chronic
subdural haematoma, as diagnosed by cranial computed tomog-
raphy (CCT) scanning. We scrutinised the origin of the cSDH in our
patients, and all the cSDH patients suffering from spontaneous or
enigmatic cSDH (n = 18) were included in this study. To analyse
only patients with spontaneous cSDH, the patients (n = 99) who
expressed one or more of the following criteria were excluded
from the study: (a) any head trauma; (b) chronic alcohol abuse;
(c) history of any other relevant diseases, such as hepatitis or hep-
atocirrhosis, that might cause insufficient protein synthesis in the
liver (Child-Pugh < B, [22]); (d) a relevant decrease in Quick/INR
(Quick < 75%) or a prolonged PTT (>40 s) due to treatment with
anticoagulation drugs; (e) decreased thrombocytes (<100,000/␮L);
(f) use of thrombocyte aggregation inhibitors; or (g) history of an
inherited bleeding disorder (e.g., coagulopathy), leukemia, other
lymphoproliferative disorders, Henoch-Schönlein purpura, sys-
temic lupus erythematodes or Crohn’s disease.
After the patients were recruited for the study, we analysed
the plasma activity of coagulation factor XIII, Quick/INR, partial
thrombin time (PTT), platelet count (thrombocytes) and fibrino-
gen. We also investigated carbohydrate-deficient transferrin (CDT)
as a marker for frequent alcohol consumption [23,24] and plasma
cholinesterase (CHE) levels as an indicator of global liver protein
synthesis dysfunction. Informed consent was obtained in accor-
dance with the Declaration of Helsinki. The study was approved
and registered by the ethics committee of the medical faculty of
the University of Cologne.
2.2. Clinical care and neurosurgical treatment
After routine diagnostics including neurological examination,
blood analysis and cranial imaging at the emergency room or at a
neurological stroke unit, all the patients were admitted and tem-
porarily observed in our neurocritical care unit (NCU). Because
there is no standard scale for the quantification of cSDH symptoms,
neurological deficits were assessed using the National Institutes of
Health Stroke Scale (NIHSS). The initial NIHSS assessment was miss-
ing from 3 subjects for logistic reasons. Neurological examinations
were conducted at least twice a day, and short “neurochecks” were
conducted every 2 h by the nursing staff in the NCU.
All the patients underwent a standardised neurosurgical pro-
cedure with an extended burr-hole trepanation approximately
30 mm in diameter, with three 12 mm burr-holes in a typical loca-
tion close to the maximum area of cSDH extent. The procedure
involved the opening and coagulation of the outer (parietal) and
inner (visceral) capsule (i.e., membrane) and the full evacuation
of all haematoma compartments, including several washing steps
with saline solution. Subsequently, two temporary soft-silicon sub-
dural drains were placed into the subdural space and connected to a
closed drain system (Produkte für Medizin AG, Cologne, Germany)
for 48–72 h. The drains were then removed carefully, and both
scalp wounds were closed by a suture. The patients with bilateral
haematomas were treated as one case and received the same treat-
ment on both sides. We screened patients for relevant re-bleeding
events (thickness clearly larger than the skull bone) using sequen-
tial CCT scans on day 1 after surgery, after removal of the drains
on day 2 or 3, on day 5–9 and at a 30-day follow-up in the case
of clinical deterioration. A final CCT scan was performed on day 30
after surgical treatment in all patients suffering from spontaneous
cSDH.
2.3. Cranial imaging analysis
To measure the approximate volume of the subdural
haematoma, we used the maximal extent of the three dimensions,
as assessed by the initial CCT images (Amax = maximal length on
transverse CCT slices, Bmax = maximal thickness on transverse CCT
slices, Cmax = n × 9 mm, n: sum of slices with visible haematoma,
one slice ∼9 mm) and the following formula: approximate vol-
ume = [Amax × Bmax × Cmax/2] × 10−3 mL. We also counted the
number of haematoma compartments clearly separated by mem-
branes and by different greyness levels (Hounsfield units) on
the initial CCT. This was performed to assess the complexity of
spontaneous cSDH and to identify the likely number of bleeding
incidences that had potentially occurred prior to admission (Fig. 1).
One radiologist and one neurosurgeon independently analysed
the cranial imaging results; these individuals were blinded to the
biochemical data of our patients. Average values were used when
two different imaging measures were obtained.
2.4. Analysis of factor XIII plasma activity
Factor XIII plasma activity was analysed using an assay based
on direct photometric determination according to an established
method described by Fickenscher [25]. We used a commercial
determination system for automatic FXIII analysis (Berichrom®
FXIII, Dade Behring, Marburg, Germany). This approach has been
used broadly in clinical chemistry, and the precision of the method
has been demonstrated in many studies [26,27]. The biochemical

3. B. Bosche et al. / Clinical Neurology and Neurosurgery 115 (2013) 13–18 15
Fig. 1. Cranial CT of a 76-year-old female patient suffering from a spontaneous
fronto-parietal chronic subdural haematoma in the right hemisphere. (A) Two dif-
ferent compartments of the cSDH are shown next to each other: an acute region of
bleeding (hyperdense, asterisks) and a chronic region (hypodense, single arrows). A
septum (arrowheads) divides the compartments. The space occupied by the cSDH
leads to a marked midline shift (multiple arrows). (B) The maximal fronto-parietal
and transverse extent of the cSDH is illustrated (distance between both arrowhead
pairs). The extent of the cSDH adjacent to the vertex is shown (arrows), furthermore
the swelling of the right hemisphere and the compression of the sulci adjacent to
the motor cortex are visible (asterisks).
analysts and laboratory staff performing the FXIII investigations
were blinded to all the clinical and imaging data.
2.5. Statistics
The results are expressed as median values [1st and 3rd quar-
tile]. Due to the advanced age of spontaneous cSDH patients, FXIII
plasma activity and coagulation parameters were additionally com-
pared to values of an age- and sex-harmonised healthy control
group (n = 18, 3 females; age-matched to patients ±2 years). Sub-
analyses were performed for the smaller group of patients with
bilateral spontaneous cSDH and for patients with relevant re-
bleeding events. One outsides (FXIII value) was identified that was
not excluded in order to keep the statistical analyses conservative.
For non-parametric comparisons of the different groups, we used
the Fisher exact test for nominal variables and the Mann–Whitney
U test for metrical variables. Correlations between the different
parameters were analysed according to Spearman’s correlation
coefficient. A receiver operating characteristic (ROC) curve was
calculated to discover the optimal FXIII cut-off value and the
corresponding sensitivity and specificity. Positive and negative pre-
dictive values were also analysed. We chose P < 0.05 as the level
of significance. Statistical analyses were performed using SPSS for
Windows (SPSS, Surrey, UK).
3. Results
Of the 117 cSDH patients, 18 experienced spontaneous cSDH.
Table 1 summarises the clinical and imaging data. Six patients suf-
fered from bilateral cSDH, and 12 had unilateral cSDH. The median
age was 78 years [71.5, 82.25]. Three patients were female. We
found normal values for CDT (1.5% [1.2, 2.1]) and a normal or mod-
erately decreased CHE value (4.56 kU/l [3.95, 6.00]) in our patients.
The approximate volume of cSDH was 52.6 mL [16.5, 72.0] in the
more strongly affected hemisphere, with a maximum value of
156.8 mL. The median number of different compartments within
the cSDH was 4 [3,5] (maximum of 7 in two patients with unilateral
cSDH).
As shown in Fig. 2A, the patients with spontaneous cSDH
had significantly lower FXIII plasma activities than the sex- and
age-matched healthy control group (65% [52.75, 80.25], n = 18
vs. 93% [81,111], n = 18, P = 0.001). However, standard coagula-
tion parameters, i.e., Quick (105% [92, 114.25] vs. 107% [96, 119],
not significant (n.s.)), PTT (28 s [25.75, 30.5] vs. 26 s [24.5, 28.5],
n.s.), thrombocytes (200.0 × 103/␮L [170.5, 252.5] vs. 189 × 103/␮L
[144.5, 226], n.s.), and fibrinogen (3.9 g/L [3.025, 5.925] vs. 3.3 g/L
[2.725, 4,45], n.s.) showed no significant differences. There was no
correlation between age and plasma FXIII activity (Spearman’s cor-
relation coefficient: r = −0.002, n = 18, n.s.) or between CHE and
FXIII (r = 0.071, n.s.) in our patients. We found no differences in
the sub-analyses that compared the FXIII activity of the smaller
patient group with bilateral cSDH to the group with unilateral cSDH
(66.5% [49.5, 78.25] n = 6 vs. 68.5% [48.25, 87], n = 12, n.s., Fig. 2B).
We found a significant negative correlation between FXIII activity
and the number of haematoma compartments (r = −0.467, n = 18,
Table 1
Patients’ clinical and imaging data.
Age, y/sex Side Bilateral NIHSS Quick, % Platelets, ×109
/L PTT, s Fibrinogen, g/L Volume, mL Compartments, x re-cSDH
60/m Right Yes – 101 158 26 6.3 15.62 5 No
66/m Right Yes 12 106 409 23 8.3 17.33 3 No
70/m Right No 14 115 298 32 2.7 66.78 7 Yes
70/m Left Yes 15 116 223 28 5.8 25.35 2 No
72/m Right No 09 112 173 27 3.8 116.64 3 Yes
74/f Left Yes 15 117 269 29 2.8 28.60 3 Yes
76/f Right No 10 102 199 23 4.0 156.75 4 No
76/m Left No 08 114 191 26 3.4 3.47 2 No
78/m Left No 12 83 201 40 7.0 57.33 6 Yes
78/m Left Yes – 88 165 34 2.3 55.08 6 No
79/m Right No 09 104 172 25 3.5 108.0 4 No
81/m Right No 11 89 236 30 6.5 58.73 5 No
81/m Right No – 95 169 35 4.0 68.45 7 No
82/m Right Yes 13 115 506 28 2.5 132.05 5 Yes
83/m Right No 11 93 200 28 3.1 13.95 3 No
89/m Right No 09 89 129 28 3.9 11.34 3 No
90/m Left No 09 111 213 26 3.1 75.6 4 No
93/f Left No 10 107 209 25 4.0 52.6 4 Yes
Age/sex: Years/male (m) or female (f); Side: mainly affected hemisphere of the spontaneous cSDH; Bilateral: bilateral spontaneous cSDH; NIHSS: National Institute of Health
Stroke Scale; “–”: unknown; Quick: quick value (%, INR values are not shown; all values were analysed in the same laboratory); PTT: partial thrombin time; Compartments:
number of different hematoma compartments; Volume: approximate volume of the spontaneous cSDH (mL); re-cSDH: re-appearance of the spontaneous cSDH after the
initial haematoma evacuation.

4. 16 B. Bosche et al. / Clinical Neurology and Neurosurgery 115 (2013) 13–18
Fig. 2. Box-plot comparisons between factor XIII plasma activities in different patient groups. (A) Patients with chronic subdural haematoma (n = 18) show significantly lower
FXIII activities than the age- and sex-matched healthy control group (n = 18, Mann–Whitney U-test, P = 0.001). (B) No significant difference was found between the patients
with bilateral cSDH (n = 6) and the patients with only one affected hemisphere (n = 12, n.s.). represent an outsider.
Fig. 3. Scatterplots of factor XIII plasma activities correlated with the number of haematoma compartments and the approximate volume of the spontaneous cSDH on the
initial cranial CT. Scatterplots (n = 18) are depicted with regression slopes and 95% confidence intervals. *Please note that symbols are overlaid in some cases. (A) Spearman’s
correlation analysis revealed a significant negative correlation between FXIII and the number of different haematoma compartments (r = −0.467, P = 0.046). (B) A significant
negative correlation was also found between FXIII and the approximate volume of the cSDH (r = −0.498, P = 0.035).
P = 0.046, Fig. 3A). Correspondingly, a significant negative correla-
tion was found between FXIII activity and the approximate volume
of the cSDH (r = −0.498, n = 18, P = 0.035, Fig. 3B).
After treatment and full evacuation of the cSDH, six patients
showed radiological cSDH progressions and developed relevant
re-bleeding events that required a second haematoma evacuation
(Table 1). As illustrated in Fig. 4, these patients had significantly
lower initial FXIII activity than the 12 patients who did not expe-
rience re-bleeding events (47.5% [33.5, 64], n = 6 vs. 78.5% [58,
87], n = 12, P = 0.005). All the standard coagulation parameters (see
above) and measures of fibrinogen showed no significant differ-
ences (data not shown). The largest difference in FXIII activity was
found between patients who suffered from a recurrence of cSDH
and individuals in the healthy control group (47.5% [33.5, 64], n = 6
vs. 93% [81, 111], n = 18, P < 0.001).
The ROC curve analysis determined an initial FXIII plasma
activity level of 68.5% (cut-off value) as the best predictor for
a relevant re-bleeding event after haematoma evacuation. The
area under the ROC curve was determined to be 0.903 (arbitrary
units). This cut-off value in elderly patients is nearly equal to
what Fickenscher [25] termed a pathologically low FXIII activ-
ity level in adults. Fig. 5 shows a specific four-fold distribution
(using scale bars: FXIII ≤ 68.5% vs. >68.5% and re-cSDH vs. cSDH,
no re-bleeding events); the patient group with FXIII ≤ 68.5% dif-
fered significantly from the group with FXIII > 68.5% with respect
to the occurrence of a relevant re-bleeding event (n = 6/9 vs.
n = 0/9, P = 0.009). Using this FXIII cut-off value (68.5%), we found
a sensitivity of 100% and a specificity of 75%; the positive pre-
dictive value was 66%, whereas the negative predictive value was
100%.

5. B. Bosche et al. / Clinical Neurology and Neurosurgery 115 (2013) 13–18 17
Fig. 4. Box-plot comparisons of factor XIII plasma activities in patients with or with-
out relevant re-bleeding after the evacuation of spontaneous cSDH. The patients
with a relevant re-bleeding occurrence (n = 6) show significantly lower factor
XIII activities than the cSDH patients who did not develop re-bleeding (n = 12,
Mann–Whitney U-test, P = 0.005). represent an outsider.
Fig. 5. Bar scale visualisation of the specific fourfold distribution (FXIII ≤ 68.5% vs.
FXIII > 68.5% and re-cSDH vs. cSDH, no re-bleeding event). The group of patients
with FXIII plasma activity ≤68.5% differed significantly from the patients with
activity >68.5% with respect to the occurrence of relevant re-bleeding event after
haematoma evacuation (n = 6/9 vs. n = 0/9, Fisher’s exact test, P = 0.009). With the
cut-off value (FXIII 68.5%) for the prediction of a re-bleeding event, we found a sen-
sitivity of 100% and a specificity of 75%; the positive predictive value was 66% and
the negative predictive value was 100%.
4. Discussion
In this study, we showed that patients suffering from a sponta-
neous cSDH displayed significantly decreased levels of plasma FXIII
activity. A correlation was also found between lower plasma FXIII
activity and higher cSDH complexity. The patients with re-bleeding
events after haematoma evacuation had considerably lower initial
FXIII activity than the patients without re-bleeding events.
A three-year recruitment period led to the evaluation of 117
cSDH patients, 18 of whom (15%) suffered from a spontaneous
cSDH, which is a rate that varies somewhat from previous reports
[3,28,29]. According to our strict classification criteria for spon-
taneous cSDH, patients on anti-coagulation or anti-aggregation
drugs or those with known bleeding disorders were excluded from
this study. The incidence of spontaneous cSDH might be classified
in different ways in other studies, which could explain our rela-
tively small number of patients. Cerebral trauma, chronic alcohol
consumption, liver disease and anti-coagulation/anti-aggregation
drugs are external co-factors of cSDH [1,3,8,30] and were used as
exclusion criteria in this study to isolate true cases of spontaneous
cSDH [4]. This strict approach to patient categorisation should
offer a clearer view of the intrinsic neurobiology of this enigmatic
disease.
Because cSDH is a disease of the elderly [1,3], the control group
was matched to the patient group based on age and sex to con-
trol for the influences of biological age and gender. Contrary to our
expectation, no correlation was found between age and FXIII activ-
ity. In addition, the age- and sex-matched healthy control group had
only slightly lower FXIII values compared to the classical healthy
adult reference group [25].
Bilateral cSDH has a higher recurrence rate than unilateral cases
[31], and one-third of our patients suffered from bilateral sponta-
neous cSDH. In our patients, this may reflect a multi-focal or general
predisposition for the development of spontaneous subdural bleed-
ing or haemorrhage and explains our special interest in bilateral
spontaneous cSDH (Fig. 2B) and global FXIII activity (see below). We
expected a larger decrease of FXIII activity in patients with bilateral
spontaneous cSDH compared to individuals with unilateral sponta-
neous cSDH, but we did not obtain this result. However, this finding
may partly be explained by the higher number of haematoma com-
partments; up to 7 compartments were found in individuals with
unilateral spontaneous cSDH (Table 1).
We analysed global FXIII activity to determine whether this
measurement would be clinically useful. Blood analyses of FXIII
are easy to obtain prior to treatment and may serve as a pre-
dictor for later spontaneous re-bleeding events. All the patients
with re-bleeding events showed an FXIII plasma activity of <68.5%
(sensitivity: 100%), while no patients with an FXIII activity >68.5%
suffered from re-bleeding events after treatment (negative predic-
tive value: 100%). Therefore, FXIII plasma activity may guide the
decision for a possible therapeutic global or systemic substitution
of FXIII in individuals with substantially decreased plasma FXIII
activity. However, caution is necessary due to the potential side
effects of systemic FXIII substitution, such as thrombosis. Theoret-
ically, local intra-operative subdural FXIII substitution might also
be feasible and effective in some cases.
Nishida measured FXIII in the fluid of cSDH and showed that
FXIII activity was less than 70% of the normal level in nearly all
of the recruited patients, providing evidence for locally decreased
FXIII activity [32]. This local FXIII activity is comparable to the sys-
temic activity found in our spontaneous cSDH patients (Fig. 2A).
In the present study, the patients with re-bleeding events (Fig. 4)
had even lower FXIII activities. Other coagulation factors have
previously been found to be decreased in the cSDH fluid, in addi-
tion to an increase in fibrinogen degradation products [11]. Thus,
locally increased activation of coagulation and fibrinolysis have
been proposed as mechanisms for cSDH, as previously discussed
[33]. FXIII is cross-linked with both coagulation and fibrinolysis, and
its clot-stabilising function is well understood [13,14,34]. This leads
to the question of what pathophysiological consequences beyond
insufficient clot stabilisation might be expected due to decreased
FXIII activity in spontaneous cSDH. Recent research has uncovered
lesser-known functions of FXIII [15–20]. A previous experimental
study showed that activated FXIII stabilises the endothelium of ves-
sels by cross-linking single endothelial cells [18]. Considering the
pre-existing fragile neo-vascularisation of the membranes cover-
ing a potential spontaneous subdural haematoma [10], a decrease
in FXIII may result in further vascular leakage, breakdown of vessel
integrity and subsequent local recurrent haemorrhages, which are
known to be characteristic of cSDH. The subdural haemorrhages
arising from the membranes and the subsequent coagulation could
lead to an auxiliary consumption of FXIII, as has been reported
for blood loss [34,35], thereby leading to a fatal cycle. An initial

6. 18 B. Bosche et al. / Clinical Neurology and Neurosurgery 115 (2013) 13–18
moderate FXIII deficiency may further enhance its own patholog-
ical potential due to this intrinsic pathway. Negative correlations
between FXIII activity and cSDH volume corresponding to the num-
ber of haematoma compartments support this interpretation. As
FXIII is also involved in wound healing [16], protection against fib-
rinolytic enzymes [14], and potentially in angiogenesis [21]; this
vicious cycle could lead to disturbed repair and healing processes
resulting in the chronic recurrence of the spontaneous subdural
haematoma.
Several limitations of our study should be mentioned. Genetic
influences [36,37] and possible acquired FXIII deficiency due to
FXIII inhibitors [34,36] were not included in this investigation.
The lack of repeated FXIII measures and the limited number of
patients restricted our insights into the pathophysiology of spon-
taneous cSDH. Future studies in patients with both spontaneous
and traumatic cSDH in a multi-centre design using combined local
and systemic FXIII measurements may potentially lead to a deeper
pathophysiological understanding of spontaneous cSDH. This type
of investigation may begin to address causal questions surrounding
FXIII deficiency and whether it can be attributed to a predisposition
for low FXIII or consumption of FXIII by recurrent haemorrhaging
and subsequent coagulation.
Though further research is necessary, our results suggest that
FXIII plasma activity may play a pathophysiological role in sponta-
neous cSDH, particularly in its recurrence. FXIII could potentially
function as a valid prognostic indicator to predict clinical out-
come after treatment, and we suggest analysing FXIII in patients
with spontaneous cSDH. In individuals with considerably low FXIII
activity, FXIII substitution may be a possible therapeutic option
to prevent re-bleeding events and mitigate the chronic nature of
spontaneous subdural haematoma.
Conflict of interest
The authors have no conflicts of interest to declare.
Acknowledgements
For their continued support, we thank Dr. H. Stützer of the Insti-
tute of Medical Statistics, Informatics and Epidemiology (IMSIE) of
the University of Cologne, Mr. B. Huth of the Max-Planck-Institute
for neurological Research Cologne, and the staff of our Neurocritical
Care Unit and the Institute of Clinical Chemistry of the University
of Cologne.
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