Table 2.
Summary of key papers involving clinical experience with FXIII
| References | Year | Indication | Study type | Patients | Protocol | Key outcomes | |
|---|---|---|---|---|---|---|---|
| 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% |