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Clinical Neurology and Neurosurgery 115 (2013) 13– 18

Contents lists available at SciVerse ScienceDirect

Clinical Neurology and Neurosurgery

journa l h omepage: www.elsev ier .com/ locate /c l ineuro

ccurrence and recurrence of spontaneous chronic subdural haematoma isssociated with a factor XIII deficiency

ert Boschea,b,c,∗,1, Marek Molcanyib,1, Thomas Nolld, Matthias Kochaneke, Bastian Kraus f,ernhard Riegerb, Faycal El Majdoubb,g, Christian Dohmenc,h, Mario Löhrb,i,oland Goldbrunnerb, Gerrit Brinkerb

Department of Neurology, University of Duisburg-Essen, GermanyDepartment of Neurosurgery, University of Cologne, GermanyMax Planck Institute for Neurological Research with Klaus-Joachim-Zülch Laboratories of the Max Planck Society and the Medical Faculty of the University of Cologne, GermanyInstitute of Physiology, Medical Faculty Carl Gustav Carus, Technical University Dresden, GermanyDepartment I of Internal Medicine (Haematology, Haemostasiology and Oncology), University of Cologne, GermanyDepartment of Radiology, University of Cologne, GermanyDepartment of Stereotactic and Functional Neurosurgery, University of Cologne, GermanyDepartment of Neurology, University of Cologne, GermanyDepartment of Neurosurgery, University of Würzburg, Germany

r t i c l e i n f o

rticle history:eceived 29 September 2011eceived in revised form 12 January 2012ccepted 25 March 2012vailable online 26 April 2012

eywords:Spontaneous) Chronic subduralaematomaactor XIIIaemostatic disordersifferential diagnosis of strokelood vesselsound healing

a b s t r a c t

Objective: In some patients, chronic subdural haematoma (cSDH) appears to occur spontaneously withfrequent re-bleeding events. The pathophysiology of this phenomenon is still poorly understood. Becausecoagulation factor XIII (FXIII) is known to be involved in vascular integrity, endothelial barrier functionand 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 ofpatients suffering from spontaneous cSDH who were included in this study. We analysed the plasmaactivity of FXIII and standard coagulation parameters and compared these data to age- and sex-matchedhealthy controls. We assessed the occurrence of re-bleeding events using clinical and imaging data andcompared 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. Thepatients 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 didnot differ significantly between the groups. Six patients developed re-bleeding events after haematomaevacuation, and these patients expressed significantly lower FXIII activity compared to the other 12patients (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 suggestinvestigating FXIII activity because it may predict re-bleeding events after treatment. In individuals withconsiderably low FXIII activity, FXIII substitution may mitigate the chronic nature of this disease.

. Introduction

Chronic subdural haematoma (cSDH) frequently occurs inatients who have not experienced a prior traumatic event

∗ Corresponding author at: Klinik für Neurologie, Universitätsklinikum Essen,ufelandstr. 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.

303-8467/$ – see front matter © 2012 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.clineuro.2012.03.045

© 2012 Elsevier B.V. All rights reserved.

[1,2] and in patients who report only a slight trauma in theirhistory [3]. In these specific non-traumatic or spontaneous subdu-ral haematomas, symptoms often occur suddenly and may mimicischaemic stroke [4,5]. Generally, cSDH is known as a typical diseaseof the elderly [1]. In addition to old age and head trauma, commonco-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 beeninvestigated and reviewed in detail in prior publications [3,6]. Nev-ertheless, the aetiology remains unknown in over 25% of cases,

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nd spontaneous re-bleeding events are common and originaterimarily from the membranes covering the cSDH [3,7–9]. Fragileeo-vessels in the membranes that cover the cSDH and an imbal-nce between activated coagulation and fibrinolysis have beeniscussed as possible causes of multiple re-bleeding events andhe chronic nature of the subdural haematoma [10,11]. However,he pathophysiology is still insufficiently understood, particularlyn the case of spontaneous cSDH [3,6,7]. Hence, further studies areequired to identify intrinsic factors for the spontaneous occurrencend recurrence of cSDH.

Coagulation factor XIII (FXIII), also known as clot stabilisingactor [12], is synthesised in cells of bone marrow origin and inepatocytes within the liver and circulates in the blood in the formf a pro-enzyme [13]. Thrombin and Ca2+ convert FXIII to its activeorm. FXIII stabilises fibrin and protects it against fibrinolysis by

echanically cross-linking fibrin chains and the alpha-2 plasminnhibitor at the end of the clotting cascade. This fibrin-stabilisingunction within the coagulation cascade has been broadly investi-ated and is well-established in the literature [13,14]. Additionally,XIII is involved in wound healing [15–17] and plays an importantole in the stabilisation of endothelial barrier function and vascu-ar integrity [15,18–20]. A potential role for FXIII in angiogenesisas also been discussed [21]. However, FXIII plasma activity is notoutinely evaluated in clinical laboratory tests.

We hypothesised that the decreased activity of FXIII may play aole in the pathophysiology and recurrence of spontaneous cSDH.

e aimed to evaluate the initial FXIII plasma activity as a potentialiagnostic parameter for the prediction of further clinical course,nd particularly as a predictor of cSDH recurrence after haematomavacuation.

. Patients and methods

.1. Patient recruitment, inclusion and exclusion criteria

In this prospective study, we consecutively screened 117atients at our centre from 5th October 2006 to 22nd September009. All the patients suffered from focal neurological symptomsuch as limb- or hemiparesis, dysphasia or aphasia and cognitiver neuropsychological disorders caused by a hypodense chronicubdural haematoma, as diagnosed by cranial computed tomog-aphy (CCT) scanning. We scrutinised the origin of the cSDH in ouratients, and all the cSDH patients suffering from spontaneous ornigmatic cSDH (n = 18) were included in this study. To analysenly patients with spontaneous cSDH, the patients (n = 99) whoxpressed one or more of the following criteria were excludedrom the study: (a) any head trauma; (b) chronic alcohol abuse;c) history of any other relevant diseases, such as hepatitis or hep-tocirrhosis, that might cause insufficient protein synthesis in theiver (Child-Pugh < B, [22]); (d) a relevant decrease in Quick/INRQuick < 75%) or a prolonged PTT (>40 s) due to treatment withnticoagulation drugs; (e) decreased thrombocytes (<100,000/�L);f) use of thrombocyte aggregation inhibitors; or (g) history of annherited bleeding disorder (e.g., coagulopathy), leukemia, otherymphoproliferative disorders, Henoch-Schönlein purpura, sys-emic lupus erythematodes or Crohn’s disease.

After the patients were recruited for the study, we analysedhe plasma activity of coagulation factor XIII, Quick/INR, partialhrombin time (PTT), platelet count (thrombocytes) and fibrino-en. We also investigated carbohydrate-deficient transferrin (CDT)

s a marker for frequent alcohol consumption [23,24] and plasmaholinesterase (CHE) levels as an indicator of global liver proteinynthesis dysfunction. Informed consent was obtained in accor-ance with the Declaration of Helsinki. The study was approved

Neurosurgery 115 (2013) 13– 18

and registered by the ethics committee of the medical faculty ofthe 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 aneurological stroke unit, all the patients were admitted and tem-porarily observed in our neurocritical care unit (NCU). Becausethere is no standard scale for the quantification of cSDH symptoms,neurological deficits were assessed using the National Institutes ofHealth Stroke Scale (NIHSS). The initial NIHSS assessment was miss-ing from 3 subjects for logistic reasons. Neurological examinationswere conducted at least twice a day, and short “neurochecks” wereconducted 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 approximately30 mm in diameter, with three 12 mm burr-holes in a typical loca-tion close to the maximum area of cSDH extent. The procedureinvolved the opening and coagulation of the outer (parietal) andinner (visceral) capsule (i.e., membrane) and the full evacuationof all haematoma compartments, including several washing stepswith saline solution. Subsequently, two temporary soft-silicon sub-dural drains were placed into the subdural space and connected to aclosed drain system (Produkte für Medizin AG, Cologne, Germany)for 48–72 h. The drains were then removed carefully, and bothscalp wounds were closed by a suture. The patients with bilateralhaematomas were treated as one case and received the same treat-ment on both sides. We screened patients for relevant re-bleedingevents (thickness clearly larger than the skull bone) using sequen-tial CCT scans on day 1 after surgery, after removal of the drainson day 2 or 3, on day 5–9 and at a 30-day follow-up in the caseof clinical deterioration. A final CCT scan was performed on day 30after surgical treatment in all patients suffering from spontaneouscSDH.

2.3. Cranial imaging analysis

To measure the approximate volume of the subduralhaematoma, we used the maximal extent of the three dimensions,as assessed by the initial CCT images (Amax = maximal length ontransverse CCT slices, Bmax = maximal thickness on transverse CCTslices, 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 thenumber of haematoma compartments clearly separated by mem-branes and by different greyness levels (Hounsfield units) onthe initial CCT. This was performed to assess the complexity ofspontaneous cSDH and to identify the likely number of bleedingincidences that had potentially occurred prior to admission (Fig. 1).One radiologist and one neurosurgeon independently analysedthe cranial imaging results; these individuals were blinded to thebiochemical data of our patients. Average values were used whentwo different imaging measures were obtained.

2.4. Analysis of factor XIII plasma activity

Factor XIII plasma activity was analysed using an assay basedon direct photometric determination according to an establishedmethod described by Fickenscher [25]. We used a commercial

determination system for automatic FXIII analysis (Berichrom®

FXIII, Dade Behring, Marburg, Germany). This approach has beenused broadly in clinical chemistry, and the precision of the methodhas been demonstrated in many studies [26,27]. The biochemical

B. Bosche et al. / Clinical Neurology and

Fig. 1. Cranial CT of a 76-year-old female patient suffering from a spontaneousfronto-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 ofbleeding (hyperdense, asterisks) and a chronic region (hypodense, single arrows). Aseptum (arrowheads) divides the compartments. The space occupied by the cSDHleads to a marked midline shift (multiple arrows). (B) The maximal fronto-parietaland transverse extent of the cSDH is illustrated (distance between both arrowheadptt

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airs). The extent of the cSDH adjacent to the vertex is shown (arrows), furthermorehe swelling of the right hemisphere and the compression of the sulci adjacent tohe motor cortex are visible (asterisks).

nalysts and laboratory staff performing the FXIII investigationsere blinded to all the clinical and imaging data.

.5. Statistics

The results are expressed as median values [1st and 3rd quar-ile]. Due to the advanced age of spontaneous cSDH patients, FXIIIlasma activity and coagulation parameters were additionally com-ared to values of an age- and sex-harmonised healthy control

roup (n = 18, 3 females; age-matched to patients ±2 years). Sub-nalyses were performed for the smaller group of patients withilateral spontaneous cSDH and for patients with relevant re-leeding events. One outsides (FXIII value) was identified that was

able 1atients’ clinical and imaging data.

Age, y/sex Side Bilateral NIHSS Quick, % Platelets, ×109/L

60/m Right Yes – 101 158

66/m Right Yes 12 106 409

70/m Right No 14 115 298

70/m Left Yes 15 116 223

72/m Right No 09 112 173

74/f Left Yes 15 117 269

76/f Right No 10 102 199

76/m Left No 08 114 191

78/m Left No 12 83 201

78/m Left Yes – 88 165

79/m Right No 09 104 172

81/m Right No 11 89 236

81/m Right No – 95 169

82/m Right Yes 13 115 506

83/m Right No 11 93 200

89/m Right No 09 89 129

90/m Left No 09 111 213

93/f Left No 10 107 209

ge/sex: Years/male (m) or female (f); Side: mainly affected hemisphere of the spontaneotroke Scale; “–”: unknown; Quick: quick value (%, INR values are not shown; all values wumber of different hematoma compartments; Volume: approximate volume of the spo

nitial haematoma evacuation.

Neurosurgery 115 (2013) 13– 18 15

not excluded in order to keep the statistical analyses conservative.For non-parametric comparisons of the different groups, we usedthe Fisher exact test for nominal variables and the Mann–WhitneyU test for metrical variables. Correlations between the differentparameters were analysed according to Spearman’s correlationcoefficient. A receiver operating characteristic (ROC) curve wascalculated to discover the optimal FXIII cut-off value and thecorresponding sensitivity and specificity. Positive and negative pre-dictive values were also analysed. We chose P < 0.05 as the levelof significance. Statistical analyses were performed using SPSS forWindows (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 medianage was 78 years [71.5, 82.25]. Three patients were female. Wefound 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 themore strongly affected hemisphere, with a maximum value of156.8 mL. The median number of different compartments withinthe cSDH was 4 [3,5] (maximum of 7 in two patients with unilateralcSDH).

As shown in Fig. 2A, the patients with spontaneous cSDHhad significantly lower FXIII plasma activities than the sex- andage-matched healthy control group (65% [52.75, 80.25], n = 18vs. 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 nocorrelation between age and plasma FXIII activity (Spearman’s cor-relation coefficient: r = −0.002, n = 18, n.s.) or between CHE andFXIII (r = 0.071, n.s.) in our patients. We found no differences inthe 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 activityand the number of haematoma compartments (r = −0.467, n = 18,

PTT, s Fibrinogen, g/L Volume, mL Compartments, x re-cSDH

26 6.3 15.62 5 No23 8.3 17.33 3 No32 2.7 66.78 7 Yes28 5.8 25.35 2 No27 3.8 116.64 3 Yes29 2.8 28.60 3 Yes23 4.0 156.75 4 No26 3.4 3.47 2 No40 7.0 57.33 6 Yes34 2.3 55.08 6 No25 3.5 108.0 4 No30 6.5 58.73 5 No35 4.0 68.45 7 No28 2.5 132.05 5 Yes28 3.1 13.95 3 No28 3.9 11.34 3 No26 3.1 75.6 4 No25 4.0 52.6 4 Yes

us cSDH; Bilateral: bilateral spontaneous cSDH; NIHSS: National Institute of Healthere analysed in the same laboratory); PTT: partial thrombin time; Compartments:ntaneous cSDH (mL); re-cSDH: re-appearance of the spontaneous cSDH after the

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 lowerFXIII 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 patientswith 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 theinitial 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’scorrelation analysis revealed a significant negative correlation between FXIII and the number of different haematoma compartments (r = −0.467, P = 0.046). (B) A significantn the cS

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= 0.046, Fig. 3A). Correspondingly, a significant negative correla-ion was found between FXIII activity and the approximate volumef the cSDH (r = −0.498, n = 18, P = 0.035, Fig. 3B).

After treatment and full evacuation of the cSDH, six patientshowed radiological cSDH progressions and developed relevante-bleeding events that required a second haematoma evacuationTable 1). As illustrated in Fig. 4, these patients had significantlyower initial FXIII activity than the 12 patients who did not expe-ience re-bleeding events (47.5% [33.5, 64], n = 6 vs. 78.5% [58,7], n = 12, P = 0.005). All the standard coagulation parameters (seebove) and measures of fibrinogen showed no significant differ-

nces (data not shown). The largest difference in FXIII activity wasound between patients who suffered from a recurrence of cSDHnd individuals in the healthy control group (47.5% [33.5, 64], n = 6s. 93% [81, 111], n = 18, P < 0.001).

DH (r = −0.498, P = 0.035).

The ROC curve analysis determined an initial FXIII plasmaactivity level of 68.5% (cut-off value) as the best predictor fora relevant re-bleeding event after haematoma evacuation. Thearea under the ROC curve was determined to be 0.903 (arbitraryunits). This cut-off value in elderly patients is nearly equal towhat 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 respectto 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 founda sensitivity of 100% and a specificity of 75%; the positive pre-dictive value was 66%, whereas the negative predictive value was100%.

B. Bosche et al. / Clinical Neurology and

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 patientswith a relevant re-bleeding occurrence (n = 6) show significantly lower factorXIII 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 patientswith FXIII plasma activity ≤68.5% differed significantly from the patients withactivity >68.5% with respect to the occurrence of relevant re-bleeding event afterhaematoma evacuation (n = 6/9 vs. n = 0/9, Fisher’s exact test, P = 0.009). With thecut-off value (FXIII 68.5%) for the prediction of a re-bleeding event, we found a sen-st

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itivity of 100% and a specificity of 75%; the positive predictive value was 66% andhe negative predictive value was 100%.

. Discussion

In this study, we showed that patients suffering from a sponta-eous cSDH displayed significantly decreased levels of plasma FXIIIctivity. A correlation was also found between lower plasma FXIIIctivity and higher cSDH complexity. The patients with re-bleedingvents after haematoma evacuation had considerably lower initialXIII activity than the patients without re-bleeding events.

A three-year recruitment period led to the evaluation of 117SDH patients, 18 of whom (15%) suffered from a spontaneousSDH, which is a rate that varies somewhat from previous reports3,28,29]. According to our strict classification criteria for spon-aneous cSDH, patients on anti-coagulation or anti-aggregationrugs or those with known bleeding disorders were excluded from

his study. The incidence of spontaneous cSDH might be classifiedn different ways in other studies, which could explain our rela-ively small number of patients. Cerebral trauma, chronic alcohol

Neurosurgery 115 (2013) 13– 18 17

consumption, liver disease and anti-coagulation/anti-aggregationdrugs are external co-factors of cSDH [1,3,8,30] and were used asexclusion criteria in this study to isolate true cases of spontaneouscSDH [4]. This strict approach to patient categorisation shouldoffer a clearer view of the intrinsic neurobiology of this enigmaticdisease.

Because cSDH is a disease of the elderly [1,3], the control groupwas matched to the patient group based on age and sex to con-trol for the influences of biological age and gender. Contrary to ourexpectation, no correlation was found between age and FXIII activ-ity. In addition, the age- and sex-matched healthy control group hadonly slightly lower FXIII values compared to the classical healthyadult 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 generalpredisposition for the development of spontaneous subdural bleed-ing or haemorrhage and explains our special interest in bilateralspontaneous cSDH (Fig. 2B) and global FXIII activity (see below). Weexpected a larger decrease of FXIII activity in patients with bilateralspontaneous cSDH compared to individuals with unilateral sponta-neous cSDH, but we did not obtain this result. However, this findingmay partly be explained by the higher number of haematoma com-partments; up to 7 compartments were found in individuals withunilateral spontaneous cSDH (Table 1).

We analysed global FXIII activity to determine whether thismeasurement would be clinically useful. Blood analyses of FXIIIare easy to obtain prior to treatment and may serve as a pre-dictor for later spontaneous re-bleeding events. All the patientswith 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 thedecision for a possible therapeutic global or systemic substitutionof FXIII in individuals with substantially decreased plasma FXIIIactivity. However, caution is necessary due to the potential sideeffects of systemic FXIII substitution, such as thrombosis. Theoret-ically, local intra-operative subdural FXIII substitution might alsobe feasible and effective in some cases.

Nishida measured FXIII in the fluid of cSDH and showed thatFXIII activity was less than 70% of the normal level in nearly allof the recruited patients, providing evidence for locally decreasedFXIII 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 havepreviously 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 havebeen proposed as mechanisms for cSDH, as previously discussed[33]. FXIII is cross-linked with both coagulation and fibrinolysis, andits clot-stabilising function is well understood [13,14,34]. This leadsto the question of what pathophysiological consequences beyondinsufficient clot stabilisation might be expected due to decreasedFXIII activity in spontaneous cSDH. Recent research has uncoveredlesser-known functions of FXIII [15–20]. A previous experimentalstudy showed that activated FXIII stabilises the endothelium of ves-sels by cross-linking single endothelial cells [18]. Considering thepre-existing fragile neo-vascularisation of the membranes cover-ing a potential spontaneous subdural haematoma [10], a decreasein FXIII may result in further vascular leakage, breakdown of vesselintegrity and subsequent local recurrent haemorrhages, which are

arising from the membranes and the subsequent coagulation couldlead to an auxiliary consumption of FXIII, as has been reportedfor blood loss [34,35], thereby leading to a fatal cycle. An initial

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oderate FXIII deficiency may further enhance its own patholog-cal potential due to this intrinsic pathway. Negative correlationsetween FXIII activity and cSDH volume corresponding to the num-er of haematoma compartments support this interpretation. AsXIII is also involved in wound healing [16], protection against fib-inolytic enzymes [14], and potentially in angiogenesis [21]; thisicious cycle could lead to disturbed repair and healing processesesulting in the chronic recurrence of the spontaneous subduralaematoma.

Several limitations of our study should be mentioned. Geneticnfluences [36,37] and possible acquired FXIII deficiency due toXIII inhibitors [34,36] were not included in this investigation.he lack of repeated FXIII measures and the limited number ofatients restricted our insights into the pathophysiology of spon-aneous cSDH. Future studies in patients with both spontaneousnd traumatic cSDH in a multi-centre design using combined localnd systemic FXIII measurements may potentially lead to a deeperathophysiological understanding of spontaneous cSDH. This typef investigation may begin to address causal questions surroundingXIII deficiency and whether it can be attributed to a predispositionor low FXIII or consumption of FXIII by recurrent haemorrhagingnd subsequent coagulation.

Though further research is necessary, our results suggest thatXIII plasma activity may play a pathophysiological role in sponta-eous cSDH, particularly in its recurrence. FXIII could potentially

unction as a valid prognostic indicator to predict clinical out-ome after treatment, and we suggest analysing FXIII in patientsith spontaneous cSDH. In individuals with considerably low FXIII

ctivity, FXIII substitution may be a possible therapeutic optiono prevent re-bleeding events and mitigate the chronic nature ofpontaneous subdural haematoma.

onflict of interest

The authors have no conflicts of interest to declare.

cknowledgements

For their continued support, we thank Dr. H. Stützer of the Insti-ute of Medical Statistics, Informatics and Epidemiology (IMSIE) ofhe University of Cologne, Mr. B. Huth of the Max-Planck-Instituteor neurological Research Cologne, and the staff of our Neurocriticalare Unit and the Institute of Clinical Chemistry of the Universityf Cologne.

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