Table 2 Summary of key papers involving clinical experience with FXIII

Trial 1

Baer et al. [18]

1980

Wound healing (surgery)

Randomised controlled trial

95 patients undergoing major abdominal or vascular surgery or patients with risk factors for development of wound healing disturbances

15 patients had FXIII levels within reference ranges whilst 80 patients had a pre- or post-operative deficit in FXIII (< 87.5%) and were randomised to receive either FXIII supplementation or no supplementation according to the formula:

FXIII units for supplementation = 0.5 × body weight x FXIII deficit (%)

All patients showed a post-operative decrease in FXIII levels, the incidence of wound healing disturbance correlated with decreased FXIII levels, severity of FXIII decrease correlated with severity of surgical intervention and supplementation with FXIII concentrate reduced the incidence of post-operative surgical complications

FXIII supplementation: 10 wound healing disorders/38 patients

No supplementation: 19 wound healing disorders/42 patients

Trial 2

Chaoui et al. [19]

1999

Wound healing (surgery)

Randomised controlled trial

100 patients after surgery of head/neck tumours

1250 IU FXIII on post-operative day 2, 4 and 6 or no FXIII supplementation

Results are displayed for patients with high-risk for wound healing disorders (17 controls, 20 FXIII supplementation)

FXIII plasma levels not predictive of wound healing disturbances. In FXIII group, plasma levels increased by ~ 30% (not significant) 10/20 (50%) of patients had primary wound healing compared to 7/17 (35%) controls

Trial 3

Fujita et al. [20]

2006

Wound healing (surgery)

Single-centre, open-label study

17 patients with anastomotic leaks (n = 16) or non-healing fistulas (n = 1) after gastrointestinal surgery who had serum protein and albumin levels within reference ranges but low FXIII activity after the resolution of post-operative acute inflammation

A 240 U dose of FXIII concentrate was administered intravenously for 5 days

Improvement following treatment was observed in 15 cases (88.2%). FXIII activity increased to > 70% of the reference range in 11 cases (64.7%) but was 40–70% of the reference range in six cases (35.3%). Levels of plasma EGF and TGF-β increased in patients with improvement but did not change in patients without improvement

Trial 4

Gerlach et al. [21]

2000

Wound healing (surgery)

Retrospective study

1264 patients underwent intracranial operations

FXIII testing was carried out post-operatively in 34 patients in whom coagulopathies were suspected despite platelets, fibrinogen, prothrombin and partial thromboplastin time being within the reference ranges

Of the 1264 patients, a total of 20 patients (1.6%) had a post-operative haemorrhage; of the 34 patients with suspected coagulopathies and FXIII post-operative testing, 11 suffered a major post-operative haemorrhage. Levels of FXIII were within the reference ranges (> 60%) in 26 of the 34 patients whilst FXIII deficiency (< 60%) was found in eight patients. All eight patients with FXIII deficiency had a major post-operative haemorrhage whilst of the remaining 26 patients with FXIII levels within the reference ranges only three had a post-operative haemorrhage (p < 0.00001)

Trial 5

Gierhake et al. [22]

1974

Wound healing (surgery)

Double-blind, placebo-controlled trial

300 patients undergoing abdominal surgery

Patients received one dose of FXIII or placebo, 1 day pre-operatively and on day 1 to 3 post-operatively; the first 200 patients received 500 IU FXIII or placebo at each time-point and the next 100 patients received 750 IU FXIII or placebo

7.8% of patients in the FXIII group and 18.5% of patients in the placebo group developed wound healing disturbances (statistically significant, p < 0.01), post-operative FXIII levels fell further in the placebo group (62.3%) compared to the FXIII group (88.7%)

Trial 6

Muto et al. [23]

1997

Wound healing (surgery)

Multi-centre, open, randomised controlled study

310 patients: 196 with non-healing post-operative wounds and 114 with fistulae

Patients had FXIII levels < 70%, each received 1500 IU FXIII concentrate over 5 days or no treatment (controls)

In non-healing post-operative wounds and fistulae, the rate of improvement was significantly higher for patients treated with FXIII compared to controls (non-healing wounds 72% vs 32%; p < 0.01; fistulae 69% vs 38%, p < 0.01)

Trial 7

Mishima et al. [24]

1984

Wound healing (surgery)

Controlled, randomised, open trial

71 patients with post-operative wound healing disturbance e.g. fistulae, dehiscence of skin wounds without improvement after at least 14 days and with FXIII plasma levels < 70% at 3–5 days prior to inclusion

5 days after inclusion subjects were randomised to three groups:

Control: no factor XIII supplementation; Group 1: FXIII 750 IU/day on days 6, 7 and 8; Group 3: FXIII 1500 IU/day on days 6, 7 and 8

Improvements occurred when FXIII plasma levels were > 70% whilst subjects with < 50% FXIII deteriorated; rate of relevant general improvement of wounds in blind evaluation: 61.9% (750 IU FXIII, Group 1); 76.2% (1500 IU FXIII, Group 2); 10.5% (no FXIII, control)

Trial 8

Schramm et al. [25]

1982

Wound healing (surgery)

Double-blind, randomised, placebo-controlled study

80 patients with cancer surgery of stomach, colon and rectum of which 55 patients were evaluable

Patients were randomised to receive either 1250 IU of FXIII immediately post-operatively and on post-operative days 2 and 4 or corresponding placebo

Overall, in the placebo group, 48.1% of patients had abdominal wall dehiscence or rupture compared to 35.7% in the FXIII group, a difference which was not statistically significant

Trial 9

Takeda et al. [26]

2018

Wound healing (surgery)

Randomised controlled trial

50 patients with post-operative pancreatic fistula

Patients randomly assigned in a 1:1 ratio to receive FXIII concentrate the day after randomisation or a control group that received no FXIII concentrate within 2 weeks

There was no significant difference in the duration of drain placement between groups, early administration of exogenous FXIII does not facilitate the healing of post-operative pancreatic fistula

Trial 10

Herouy et al. [27]

2000

Wound healing (ulcers)

Randomised, double blind, age-matched study

30 patients with venous leg ulcers that had been resistant to therapy and had existed for a mean of 1.5 years: 15 patients underwent FXIII treatment and 15 patients received placebo

Beside compression bandage therapy, wound surfaces were treated once daily with FXIII or with placebo (isotonic sodium chloride solution). Ulcers were debrided and topical treatment started 24 h later

A significant decrease in the wound surface was observed after topical treatment with FXIII compared with placebo with total closure of venous leg ulcers achieved within a mean of 6 weeks. A significant reduction in fibrinolytic activity was also observed after 96 h of FXIII treatment whilst the placebo group showed the typical activity of venous leg ulcers with no significant decrease in fibrinolytic activity

Trial 11

Wozniak et al. [28]

2001

Wound healing (chronic leg ulcer)

Open study

54 patients with ulcers of the lower extremity

Initial regimen was 2 × 250 IU FXIII in the first week; however, this was reduced to 1 × 250 IU FXIII in the first week, followed by 250 IU every 2 days in the second week and 250 IU every 3 days from the third week up to 6 weeks

Patients with venous ulcers due to post-thrombotic syndrome admitted after infections, pain or unsuccessful treatment required FXIII treatment in hospital for 3–15 weeks and could then continue out-of-hospital treatment

Trial 12

Peschen et al. [29]

1998

Wound healing (chronic leg ulcer)

Placebo-controlled clinical study

24 patients were placed into 2 groups each made up of 12 patients with leg ulcers > 1000 mm² or < 1000 mm²

In each group 8 of 12 patients were given additional topical treatment of FXIII twice daily for 10 days (treatment groups)

Results demonstrate that locally applied FXIII promotes wound healing of more acute, smaller venous leg ulcers (< 1000 mm²); it is suggested that FXIII is inactivated rapidly after topical application since immunohistochemical staining of FXIII showed no significant difference before and after therapy

Trial 13

Erlebach et al. [30]

1999

Wound healing (burns)

Treatment report

93 patients with burns between 41 and 89% of body surface area

Patients with 41–60% burn area (n = 87) received 1250–2500 IU FXIII on the day of surgery and on the first two post-operative days after each surgery; patients with 61–89% burn area (n = 6) received 1250–2500 IU FXIII on the day of surgery and 1250 IU FXIII daily until wound healing was complete

FXIII at admission 61–78%, at day of first surgery (approx. day 3): 17–37%; Perceived benefits of treatment with FXIII were reduced blood loss and a lesser need for transfusion in addition to accelerated epithelial regrowth especially of skin harvesting areas

Trial 14

Godje et al. [31]

2006

Surgery

Double-blind placebo-controlled clinical trial

75 patients, after coronary surgery with extracorporeal circulation

2500 U FXIII, 1250 U FXIII and a placebo given to 25 patients each

FXIII administration decreases post-operative blood loss and the level of blood transfusion after coronary surgery; however, administration is only advantageous if plasma levels are below the reference ranges

Trial 15

Karkouti et al. [32]

2013

Surgery

Double-blind placebo-controlled clinical trial

409 cardiac surgery patients at moderate risk for transfusion

17.5 IU/kg (n = 143), 35 IU/kg (n = 138) or placebo (n = 128) after cardiopulmonary bypass

Administration of FXIII levels after cardiac surgery restored levels in patients at moderate risk for transfusion to pre-operative levels; replenishment of FXIII levels had no effect on transfusion avoidance, transfusion requirements or need for re-operation

Trial 16

Korte et al. [33]

2009

Surgery

Double-blind placebo-controlled clinical trial

22 patients were evaluated after elective gastrointestinal cancer surgery

FXIII (30 U/kg) or placebo

In patients at increased risk for intra-operative bleeding, clot firmness was decreased by ~ 8% in patients that received FXIII and for patients in the placebo group it was reduced by 38% (p = 0.004); patients at high risk for intra-operative blood loss demonstrated reduced loss of clot firmness when FXIII was given early during surgery

Trial 17

Levy et al. [34]

2009

Surgery

Randomised controlled trial

35 patients were randomised to FXIII and 8 to placebo after cardiopulmonary bypass

11.9, 25, 35 or 50 IU/kg FXIII or placebo in a 4:1 ratio

In the FXIII group, dosing with 25–50 IU/kg restored FXIII levels to those seen pre-operatively with a tendency towards overshoot in the 50 IU/kg group and for post-operative FXIII replenishment 35 IU/kg may be the most appropriate dose

Trial 18

Gerlach et al. [48]

2002

Surgery

Prospective study

876 patients undergoing 910 neurosurgical procedures who developed 39 post-operative intracranial haematomas (4.3% of surgeries)

Prothrombin time, partial thromboplastin time, platelet count, fibrinogen, and FXIII activity were tested in each patient pre- and post-operatively

13/39 (33.3%) patients with post-operative haematoma had post-operative FXIII < 60% vs. 61/867 (7%) without (p < 0.01). The relative risk for a post-operative haematoma was increased 6.4-fold in patients with post-operative FXIII deficiency. The risk was increased 12-fold in patients who also had post-operative decreases in fibrinogen levels (< 1.5 g/L) and 9-fold in patients with platelet count < 150 × 10⁹/L and FXIII < 60%