- Open Access
The impact of acquired coagulation factor XIII deficiency in traumatic bleeding and wound healing
Critical Care volume 26, Article number: 69 (2022)
Factor XIII (FXIII) is a protein involved in blood clot stabilisation which also plays an important role in processes including trauma, wound healing, tissue repair, pregnancy, and even bone metabolism. Following surgery, low FXIII levels have been observed in patients with peri-operative blood loss and FXIII administration in those patients was associated with reduced blood transfusions. Furthermore, in patients with low FXIII levels, FXIII supplementation reduced the incidence of post-operative complications including disturbed wound healing. Increasing awareness of potentially low FXIII levels in specific patient populations could help identify patients with acquired FXIII deficiency; although opinions and protocols vary, a cut-off for FXIII activity of ~ 60–70% may be appropriate to diagnose acquired FXIII deficiency and guide supplementation. This narrative review discusses altered FXIII levels in trauma, surgery and wound healing, diagnostic approaches to detect FXIII deficiency and clinical guidance for the treatment of acquired FXIII deficiency.
Factor XIII (FXIII) is an enzyme of the coagulation cascade which plays a key role in maintaining the functional integrity of fibrin clots . Additionally, FXIII has a range of other functions, including wound healing and tissue repair (Fig. 1). FXIII circulates in plasma as a protransglutaminase comprising two catalytic A and two carrier B subunits [1,2,3] and intracellularly as a homodimer of constitutively active A subunits . Plasma FXIII is activated by thrombin which cleaves the activation peptide from the A subunits; binding of Ca2+ ions and fibrin substrate results in a conformational change exposing the active site [1,2,3]. After tissue injury and fibrin clot formation, thrombin-activated FXIII catalyses covalent cross-linking of fibrin chains, stabilising the clot . FXIII also exerts antifibrinolytic activity through cross-linking of α2-antiplasmin to fibrin (Fig. 2) [5,6,7].
The role of FXIII in wound healing is known from preclinical studies (Fig. 3) [8, 9]. In FXIII-deficient mice, excisional wound healing was delayed compared to controls or FXIII-deficient mice receiving FXIII supplementation . Moreover, FXIII cross-links fibrin to surface proteins of invading bacteria (e.g. Streptococcus , Staphylococcus and Escherichia ), trapping bacteria in the clot and reducing the risk of tissue infection [9, 11, 12]. FXIII also binds to αvβ3 integrin, resulting in VEGFR-2 activation, promotion of endothelial cell proliferation and survival, and angiogenesis .
FXIII activity varies between individuals; activities as high as 250% of the reference range have rarely been reported . Inherited FXIII deficiency is graded according to FXIII activity into (1) severe: undetectable FXIII associated with spontaneous major bleeding, (2) moderate: < 30% FXIII activity associated with mild spontaneous or triggered bleeding, and (3) mild: > 30% FXIII activity, usually asymptomatic. Plasma FXIII levels in acquired FXIII deficiency are typically 30–70%, but a clear association with spontaneous bleeding complications has not been demonstrated . Lower-than-reference FXIII levels prior to, or hyper-consumption during and after, trauma or surgery, may be associated with increased bleeding risk . Potential causes include immune-mediated inhibition and non-immune hyper-consumption or hypo-synthesis. Acquired FXIII deficiency may likewise be idiopathic or linked to co-morbidities such as malignancies or autoimmune diseases (Table 1) .
This narrative review considers the clinical evidence for the role of FXIII in wound healing and trauma in a range of settings and provides the authors’ opinion on diagnosis and treatment of acquired FXIII deficiency. The diagnosis and treatment of congenital and immune-acquired FXIII deficiency, use of FXIII supplementation to correct defective cellular FXIII function, and use in paediatric patients, are beyond the scope of this review.
Due to limited availability of level 1 evidence and the variable nature of data reported, with differing outcome measures, a formal approach using PICO and GRADE methodology was not considered appropriate. Therefore, our aim was to summarise available clinical evidence. A literature search was conducted in PubMed on 21 January 2021. The search term factor XIII was combined with: trauma; complication; postpartum haemorrhage; cancer AND surgery; cardiac surgery; infection; sepsis; fistula; ulcer; burn; wound healing; diagnosis AND (test OR assay); (guidelines OR guidance OR recommendations OR algorithm). Exclusion criteria included: congenital FXIII deficiency; immune-mediated FXIII deficiency (with auto-antibodies); other clinical settings; fibrin glue; non-clinical studies; reviews; articles in a language other than English or German; full text not available.
Overall, 789 articles were retrieved, including 129 duplicates, leaving 660 articles. Following screening to identify relevant clinical studies with sufficient patient numbers and adequate reporting of results, 563 articles were excluded (Additional file 1: Fig. S1). The authors reviewed all 97 resulting articles to identify 18 papers (Table 2) [18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35].
Patients who have sustained severe trauma are at increased risk of trauma-induced coagulopathy (TIC), usually triggered by acute trauma-haemorrhagic shock (THS). THS leads to reduced blood volume, resulting in tissue hypoxia and risk of organ damage. Therefore, early identification and intervention is critical to prevent widespread organ damage [7, 31]. TIC is characterised by activation and consumption of clotting factors (notably fibrinogen), dilutional coagulopathy, hyperfibrinolysis and inflammation [36, 37]. In addition, significant loss and consumption of FXIII has been reported [36, 37]. Preclinical studies in models of THS and experimental burn have suggested that FXIII supplementation may ameliorate THS-induced organ failure [38, 39]. Furthermore, in preclinical studies using an experimental haemorrhagic shock model high doses of FXIII promoted effective haemostasis for trauma-associated coagulopathy in vitro and in vivo [40, 41]. FXIII also improved clot adhesion in wounds in a standardised bleeding model . In vitro, FXIII improved clot strength and increased resistance to hyperfibrinolysis (measured by rotational thromboelastometry [ROTEM]) and significantly decreased bleeding and prolonged survival in vivo .
Although use of FXIII concentrate has been investigated clinically in major trauma patients, no double-blind, randomised trials could be identified. FFP contains approximately 1.2 U/mL of FXIII , Administration of FXIII concentrate (15 U/kg body weight) to major trauma patients with ongoing bleeding and FXIII activity < 60% as part of a goal-directed transfusion algorithm, led to a reduction in the proportion of patients requiring massive transfusions and an overall reduction of red blood cell (RBC) and fresh frozen plasma (FFP) transfusion . However, with changes to acute trauma care over time, including novel goal-directed coagulation management strategies and modified surgical approaches, the specific contribution of FXIII to improved outcomes could not be confirmed . FXIII administration was also part of coagulation factor (CF)-based algorithms guided by viscoelastic tests for reversal of TIC, where use of CF concentrates was superior in reducing organ failure, reversal of TIC and transfusion requirements compared to FFP only [45, 46]. In the RETIC trial , 27/50 patients (54%) in the CF group had plasma FXIII < 60% and either diffuse microvascular bleeding or massive bleeding requiring transfusion of > 3 U RBCs/hour and received FXIII concentrate (20 IU/kg) with every other fibrinogen dose. In the FFP group, 11 patients (25%) received FXIII as rescue therapy. In the Swiss observational study, application of a target haematocrit range was associated with increased use of FXIII (15/172 patients [9%] vs. 6/172 [3.5%], p = 0.004), with a reduction in the proportion of patients requiring RBC transfusions (11.6% vs. 29.7% of patients, p < 0.001) and the number of transfusions . In both studies, FXIII was part of an algorithmic approach and it was not possible to identify the specific contribution of individual components.
Opinion and experiences differ regarding the timing and potential effects of FXIII deficiency in major trauma. One view is that FXIII deficiency may be a late (typically 2–3 weeks) complication of major trauma due to hepatic dysfunction; another is that FXIII deficiency occurs 3–7 days post-trauma, particularly in cases of major surgery. However, ~ 30% of trauma patients exhibit FXIII activity < 60% on admission with a clear association to the degree of blood loss suggesting FXIII activity decreases shortly after trauma .
Consequently, evaluation of FXIII activity should be conducted following trauma. Depending on clinical risk factors, magnitude of the traumatic impact and incidence of further bleeding, FXIII measurements may be required every 5–7 days or at shorter intervals in settings with higher dynamics and turnover, e.g. major trauma or severe burns. Conversely, lower risk patients may require less frequent monitoring as plasma FXIII has a half-life of 11–14 days .
An association between lower FXIII levels and peri-operative blood loss has been reported [16, 48, 49]. FXIII deficiency is associated with post-operative haemorrhagic events and requirement for post-operative transfusion [21, 35, 50]. Observational data from neurosurgical patients identified a post-operative FXIII level < 60% as an independent risk factor for post-operative intracranial bleeding [21, 35]. In a retrospective study of 34 patients with suspected coagulopathy and recorded post-operative FXIII levels, eight patients had FXIII levels < 60% and all had a major post-operative haemorrhage compared to 3/26 patients with FXIII levels within reference ranges; this difference was highly significant . In a prospective study post-operative haematoma occurred in 39/910 neurosurgical procedures. Thirteen patients (33.3%) with post-operative haematoma had post-operative FXIII levels < 60% compared with 61 (7%) without haematoma, a relative risk of 6.4 .
A retrospective study evaluated whether FXIII along with fibrinogen or platelet count affected the probability of intra-operative RBC transfusions in patients during non-cardiac surgery. In total, 443/1023 patients received RBCs; FXIII deficiency (FXIII level < 70%) was associated with a significantly increased probability of RBC transfusion, as was platelet count but not fibrinogen depletion . An observational study of CFs after coronary artery bypass graft demonstrated that pre- and post-operative FXIII activity and plasma fibrinogen levels at two hours after surgery may inversely correlate with post-operative blood loss . Furthermore, in 49 post-surgical patients with suspected acquired FXIII deficiency, FXIII levels < 50% were identified in 55% of patients. FXIII deficiency was associated with decreased haematocrit, increased transfusion requirement and delayed bleeding . Conversely, treatment with FXIII reduced post-operative blood loss and blood transfusion after coronary surgery in patients where post-medication levels of FXIII ≥ 70% could be achieved . FXIII administration was only beneficial if plasma levels were below reference ranges and it was suggested that plasma levels should be measured prior to FXIII administration .
A more recent prospective case control study evaluated potential risk factors for surgical re-exploration due to bleeding after elective cardiac surgery. Multivariate analysis revealed reduced FXIII activity was independently associated with surgical re-exploration . Reduced post-operative FXIII activity was also significantly associated with increased 30-day mortality in univariate, but not multivariate, analysis . Finally, in a prospective, randomised, proof-of-concept study in patients undergoing surgery for gastrointestinal cancer who were at risk of increased intra-operative blood loss (preoperative fibrin monomer > 3 µg/L), reductions in the secondary endpoints of blood loss and fibrinogen consumption were observed in patients who received FXIII .
Data from randomised controlled trials (RCTs) using recombinant FXIII (rFXIII) suggest that peri-operative FXIII supplementation has a varying impact on transfusion requirements; however, these trials were either unsuitable to evaluate FXIII or produced non-significant results [32,33,34]. In a study primarily designed to assess the safety and pharmacokinetics of rFXIII, there was less chest tube drainage in patients who received rFXIII following cardiopulmonary bypass (CPB) compared to placebo . In a double-blind, placebo-controlled, multicentre trial involving 409 patients undergoing CPB surgery, rFXIII administration had no effect on blood transfusion requirement or re-operation compared to placebo; however, the cohort was limited to patients with a moderate risk for transfusion and transfusion avoidance was higher than anticipated with mean FXIII levels around 80% prior to drug administration. The efficacy of rFXIII may be better demonstrated in patients with a higher transfusion risk, in those with severe FXIII deficiency, or instead of antifibrinolytic drugs .
In post-operative intensive care patients with low FXIII and high fibrinogen levels, in vitro supplementation of FXIII to supraphysiological levels increased clot firmness and stability, and accelerated clot formation .
Surgical wound healing
Prolonged reduction in plasma FXIII levels following surgery has been demonstrated [18, 23, 54, 55] and FXIII supplementation reduced the incidence of post-operative complications including disturbed wound healing [18, 23,24,25]. In 70% of patients with prolonged air leak following pulmonary lobectomy, air leaks resolved when FXIII was administered for five days. In patients who responded, post-operative FXIII levels were lower compared to those who did not respond to administration of FXIII indicating two potential mechanisms for prolonged air leak; one of which is related to FXIII consumption . In an open-label, randomised study in 310 patients with disturbed post-operative wound healing or fistulae after surgery of the gastrointestinal tract, FXIII treatment for five days reduced wound size compared to controls . Similarly, in an open-label study of 71 patients with post-operative wound healing disturbances, wound size at day 15 remained largely unchanged from baseline in controls, but decreased in the FXIII-treated groups; findings were similar for patients with fistulae . In a double-blind placebo-controlled study of 55 patients undergoing laparotomy, 35.7% of patients in the FXIII group had wound healing complications compared to 48.1% of controls. This difference was not statistically significant, potentially due to the relatively small sample size .
FXIII deficiency has also been associated with impaired healing of non-surgical wounds, such as leg ulcers [27,28,29, 56,57,58], burns [30, 59], and pressure sores . Topical treatment of venous leg ulcers with FXIII has shown promising results in small trials and case studies [27,28,29, 56, 57]. In a study of 54 patients with ulcers of the lower extremities, including a subgroup with post-thrombotic ulcus cruris venosum that had pre-existed for a mean of 11.8 months, in-hospital treatment with FXIII for a mean of 3.15 weeks permitted out-of-hospital management, and skin transplantation could be accomplished in many cases . Furthermore, locally applied FXIII promoted healing of acute, small leg ulcers (< 1000 mm2) in a trial of 24 patients . Similarly, a randomised, double-blind, age-matched study in patients with venous leg ulcers confirmed a faster healing rate and significantly reduced lesional fibrinolytic activity with topical FXIII treatment compared to controls .
Refractory wounds and fistulae
In line with the role of FXIII in limiting the spread of invading bacteria and promoting wound healing, FXIII levels were reduced in patients with post-operative non-healing fistulae or anastomotic leaks [20, 24, 61]. Furthermore, the use of FXIII concentrate has been shown to be beneficial for the treatment of post-operative wounds [20, 24, 61], as well as serious skin infections . Thus, in a study evaluating FXIII treatment for post-operative, refractory wounds, improvements occurred in patients with FXIII levels > 70% while deterioration was observed in those with FXIII levels < 50% . In a patient with decreased FXIII activity and multiple intractable enterocutaneous fistulae, FXIII administration after further surgery resulted in no fistula recurrence or other complications . In another study, FXIII administration increased levels to > 70% in 64.7% of patients with anastomotic leaks or fistulae and low plasma FXIII activity levels; improved wound healing was associated with increased levels of plasma epidermal growth factor and transforming growth factor-β, and it was suggested that FXIII may accelerate wound healing through increasing circulating levels of growth factors .
Conversely, other studies have not demonstrated benefits from FXIII administration. In a single-centre study of 43 patients undergoing pancreatoduodenectomy, post-operative morbidity, including pancreatic fistulae, were comparable between patients with < 70% or ≥ 70% FXIII activity . Similarly, in an RCT in 50 patients with post-operative pancreatic fistulae and FXIII levels ≤ 70%, early administration of FXIII concentrate did not facilitate fistulae healing .
In 34 patients with severe burns (20–64% total body surface), there was a rapid fall of FXIII activity to ~ 35% during the first three days and this level remained < 50% until day 14  (Fig. 4), suggesting that bleeding episodes, disturbed re-epithelialisation of mesh-graft harvesting areas and other clinical problems may be likely under these circumstances. Two studies have reported reduced transfusion requirements with FXIII supplementation in burn patients [30, 63]; the earlier study also reported reduced blood loss and accelerated epithelial growth, particularly around skin harvesting areas .
Abnormal bleeding may imply FXIII deficiency, but diagnosis requires specific laboratory tests . Importantly, in cases of FXIII deficiency, routine coagulation tests such as prothrombin time, activated partial thromboplastin time, and thrombin time remain within their reference ranges, so it is essential to apply specific tests to assess FXIII levels [64, 65].
In 2011, the International Society on Thrombosis and Haemostasis (ISTH) recommended an algorithm for diagnostic testing to classify and grade congenital and acquired FXIII deficiencies . In clinical practice standard activity tests based on transglutaminase activity (ammonia release and amine incorporation assays), isopeptidase activity or direct quantitative antigen assays are most commonly available . Clot solubility tests may also be used, despite a lack of standardisation and inability to measure less prominent FXIII deficiency. Autoantibody assays may be performed if FXIII activity is below the reference range [65,66,67].
Clot strength and resistance to hyperfibrinolysis in vitro can be measured by ROTEM [36, 42] but direct measurement of FXIII by ROTEM has not, to-date, been possible [68, 69]. A study in cardiac surgery patients reported a close correlation between fibrinogen levels and FXIII and further suggested FXIII levels could be estimated using MCF-FIBTEM measured by ROTEM . In addition, an unpublished study combined in vitro observation and FXIII measurement by ROTEM (EXTEM and INTEM) with a prospective evaluation in patients with severe trauma (personal communication C. Kleber). This approach requires confirmation and has not yet reached widespread clinical application.
Clinical guidelines for the management of acquired FXIII deficiency are limited. However, recommendations for the use of FXIII concentrate are covered in guidelines for the management of bleeding during surgery [71,72,73], postpartum haemorrhage , and following trauma . Blood conservation guidelines from the US Society of Thoracic Surgeons state that FXIII concentrate may be considered after CPB in bleeding patients when other routine blood conservation measures prove unsatisfactory . The European Society of Anaesthesiology recommends administration of FXIII concentrate (30 IU/kg) in cases of peri-operative bleeding and FXIII activity < 30% . In contrast, the ISTH recommends against the use of FXIII concentrate for management of peri-operative bleeding, on the basis that the benefits remain unproven in the context of acquired FXIII deficiency . The European guideline for the management of major bleeding following trauma suggests including FXIII monitoring in coagulation support algorithms and supplementation in bleeding patients with a functional FXIII deficiency . However, there is no consensus on what level of FXIII indicates FXIII deficiency or when FXIII concentrate should be prescribed in these settings.
The limited inclusion of FXIII therapy into critical care guidelines suggests low awareness of potential FXIII deficiency in acquired bleeding and wound healing. Although data from RCTs remain limited, a considerable body of clinical evidence and expert knowledge has been accumulated over recent years on the use of FXIII in acquired bleeding and wound healing that could guide current treatment approaches. Due to the limitations of the published literature, we were unable to apply full systematic methodologies to evaluate the literature. However, every effort was made to accurately represent the data and the limitations therein. A supplementary search of clinicaltrials.gov and EU Clinical Trials register (conducted November 2021) found no ongoing clinical trials or substantive studies not already identified by our literature review.
It is the authors’ opinion that diagnostic measures concerning FXIII levels in the peri-operative setting are underrepresented and that there is less FXIII supplementation than current evidence would support. Increasing awareness of FXIII testing could help identify patients with acquired FXIII deficiency. Current recommendations for the management of FXIII deficiency are largely based on data from patients with congenital FXIII deficiency, which may not be transferable to patients with acquired FXIII deficiency in bleeding and wound healing. It is also not clear whether differences in the pathophysiological response to acute soft tissue trauma compared to elective surgery could affect the response to FXIII therapy. Therefore, tests should always be interpreted in the context of the clinical course of the disorder, concomitant diseases, operative/surgical trauma and bleeding characteristics and phenotype. In cases of ongoing bleeding with global test results and platelet counts within reference ranges, FXIII deficiency should be considered and a quantitative functional FXIII activity test performed. Although opinions and protocols may vary, a cut-off for FXIII activity of < 50–70% may be appropriate to diagnose acquired FXIII deficiency.
Current international treatment guidelines offer limited and seemingly contradictory recommendations regarding the use of FXIII in acquired bleeding and intensive care and some focus only on its use when congenital deficiency is present. Prices of FXIII products vary across Europe according to the source (plasma derived/recombinant) and licensed indications. However, costs are similar to other coagulation factor concentrates. Despite lack of consensus in clinical guidelines, the studies summarised in this narrative review indicate it may be beneficial to administer FXIII to patients with low FXIII levels. In the setting of active bleeding, prolonged wound healing, substantial soft tissue injury, or persistent infection/bacteraemia treatment with FXIII should be considered only if reduced activity is detected.
Regarding safety, FXIII is widely used to treat FXIII deficiency with few adverse events reported. The most common adverse events reported during use of Factor XIII Concentrate (Fibrogammin/Corifact; CSL Behring GmbH, Marburg, Germany) are allergoid-anaphylactoid reactions (e.g. generalised urticaria, rash, fall in blood pressure, dyspnoea) and rise in temperature, reported at an incidence of between 1/10,000 and 1/1000 . The safety of Factor XIII Concentrate has also been confirmed through > 20 years of pharmacovigilance data, with a low risk of thromboembolic events reported over this period . Although formal controlled trials in trauma are limited, studies in patients with acquired FXIII deficiency due to traumatic injury or post-operatively have indicated a good safety profile [21, 23, 24, 26, 28, 31, 32, 34]. Further information on the safety of FXIII in patients with severe trauma would be useful, although challenging to obtain due to the devastating nature of trauma and the multi-modal treatment employed.
FXIII is a haemostatic protein that stabilises blood clots and has a range of functions in wound healing, tissue repair, haemostasis, bleeding and trauma. A recent review has described three pools of FXIII within the circulation, in plasma, and within the cellular compartments of platelets and monocytes/macrophages, providing additional insights into the complex roles of FXIII in these physiological processes . Although beyond the scope of this review, studies have indicated that FXIII levels/activity are impaired before and during extra-corporeal membrane oxygenation [79,80,81]. Moreover, acquired coagulopathy and reduced FXIII levels have been reported in patients with COVID-19 [82,83,84].
There is also increasing evidence that FXIII may be of use in areas beyond the scope of this narrative review, e.g. bone healing. Preclinical experimental models have demonstrated a positive effect during early stages of bone healing, with increased FXIII levels correlating with an increase in tensile strength and number of newly formed osteons [85, 86]. Studies in patients with inflammatory bowel disease suggest FXIII activity may vary according to disease activity [87,88,89,90,91] with initial clinical data suggesting a potential role for FXIII therapy – although results are conflicting [92,93,94,95,96,97].
There remain substantial research gaps and opportunities to further explore the role and use of FXIII in acquired bleeding and wound healing. Topical treatment as well as systemic application of FXIII in the impaired healing of non-surgical wounds merits further research and an RCT in this field would be of great interest. Further clinical studies are also vital in major abdominal surgery, septic infection and burn care to clarify the function of FXIII. Additionally, case series to identify risk factors for acquired FXIII deficiency would be of value, as would a prospective, multi-centre study with FXIII substitution dependent on activity cut-off, in patients that have bacteraemia and in trauma patients to leverage the knowledge on anti-infective properties. If such trials were conducted, a formal meta-analytical approach would be useful to confirm the utility of FXIII in specific clinical settings.
In patients with low plasma FXIII levels, FXIII supplementation reduced the incidence of post-operative complications including delayed haemorrhage and disturbed wound healing. Several studies with positive outcomes have used ~ 60–70% activity as a trigger for FXIII supplementation. Increasing the awareness of FXIII testing could help identify patients with acquired FXIII deficiency in cases of acquired bleeding and delayed wound healing. Creating in-house standard operating procedures for the diagnosis and treatment of acquired FXIII deficiency could be highly beneficial.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.
Fresh frozen plasma
Red blood cell
Randomised controlled trial
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Kleber, C., Sablotzki, A., Casu, S. et al. The impact of acquired coagulation factor XIII deficiency in traumatic bleeding and wound healing. Crit Care 26, 69 (2022). https://doi.org/10.1186/s13054-022-03940-2
- Factor XIII
- Wound healing
- Acquired bleeding
- Factor XIII deficiency