Emergency Medicine Investigations (ISSN: 2475-5605)

research article

FXIII Deficiency Occurs Frequently in Major Trauma and Influences Transfusion Requirements While Levels of Von Willebrand Factor are well above Thresholds

Robert Breitkopf, Isabella Westermann, Helmuth Tauber, Markus Mittermayr, Lukas Gasteiger, Martin Dünser, Petra Innerhofer*                    

Department of Anaesthesiology and Critical Care Medicine, Innsbruck Medical University, Innsbruck, Austria

 *Corresponding author: Petra Innerhofer,Department of Anaesthesiology and Critical Care Medicine, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.Tel: +4351250480407; Fax: +43512 50428430; Email:petra.innerhofer@i-med.ac.at

Received Date: 11 July, 2017; Accepted Date: 5 August, 2017; Published Date: 14 August, 2017

1.      Summary Statement:Monitoring and consequently substituting FXIII may decrease bleeding and transfusion rates in trauma patients

2.      Abstract

2.1.  Background: Coagulation Factor XIII (FXIII) and von Willebrand Factor (VWF) are essential for initial and final clot formation, however, no data on FXIII have been reported so far, and only a few studies addressed VWF in major blunt trauma.

2.2.  Methods:Patients were part of a cohort study including 334 adult trauma patients (DIA-TRE-TIC Study) of whom 274 had severe poly-trauma and measurements of FXIII (n=274) and VWF (n=239) at admission, 4, 6 and 24h thereafter. Study endpoints were FXIII and VWF levels, their association with transfusion (RBC) and clinical outcome.

2.3.  Results: At admission, half the study patients showed FXIII below the reference value of 70%, and 27% had even FXIII <60%. These patients received significantly more RBC/ 24 hours [6 (1, 12) U vs 0 (0, 3) U, p <0.0001] and showed a worse clinical outcome. Logistic regression analysis adjusted for ISS revealed FXIII <60% as independently influencing RBC transfusion. In contrast, the majority of study patients exhibited elevated VWF levels without a detectable association with transfusion requirements or clinical outcome. The immediate available parameters haemoglobin and clot firmness showed a sensitivity of 72 and 74% and a specificity of 83% and 85%, respectively, to predict FXIII plasma levels 60% at admission.

2.4.  Conclusion: In major trauma VWF levels are commonly increased while nearly 30% of trauma patients show FXIII levels <60% at admission and this independently increased transfusion requirements. Further studies should clarify as to whether substituting FXIII may limit blood loss, transfusion requirements and ultimately improve clinical outcome.

3.      Keywords:Coagulation Factors;Factor XIII; Von Willebrand Factor; Trauma; Blood Transfusion



Figure 1:Shows the prevalence of the concentration of coagulation Factor XIII (FXIII, reference range 70-144%), von Willebrand factor antigen (VWF:Ag, referencerange 69-169%) and von Willebrand factor Ristocetin activity (VWF:RiCo, reference range 50-150%) in polytrauma patients at admission to the emergency department. 


Figure 2:(a-c) shows the time course of coagulation Factor XIII (FXIII), von Willebrand factor antigen (VWF:Ag) and von Willebrand factor ristocetin activity (VWF:RiCo) in blunt trauma patients at admission to the Emergency Department (ED), as well as 4, 6, and 24 hours later. Levels of FXIII, VWF:Ag and VWF:RCo changed significantly during the observation period (p<0.001). Reference ranges are indicated as dashed lines.


Figure 3: shows concentration of coagulation factor XIII (F XIII) at admission to emergency department according to ISS grouped as ISS 15-29, 30-50 and >50. (reference ranges are indicated as dashed line). The Kruskal-Wallis test and the Mann- Whitney U Test was used for analysing differences between ISS groups. *p<0.05 as compared to ISS group 15-29, # p<0.05 as compared to ISS group 30-50.


Male gender n (%)

218 (79.6)

Age (years)

42 (27, 54)

ISS (pts)

35 (25, 50)

15-29

104

30-50

116

51-75

54

Pattern of injury n (%)

 

Head

176 (64.2)

Chest

210 (76.6)

Abdomen

148 (54.0)

Extremities

160 (58.4)

GCS (pts)

13 (6, 15)

SBP (mmHg)

120 (100, 140)

Heart rate (bpm)

90 (80, 110)

Shock n (%)

50 (18.2)

Prehospital crystalloids (mL)

1000 (500, 1500)

Prehospital colloids (mL)

500 (0, 1000)

Time until admission (min)

75 (60, 120)

Surgery within 4 hours n (%)

145 (52.9)

24h mortality n (%)

21 (7.7)

ISS: Injury Severity Score; GCS: Glasgow Coma Scale; SBP:Systolic Blood Pressure.Data are given as median values with interquartile ranges or numbers (%).

Table 1: Characteristics of the Study Cohort.

 

pH value

7.33 (7.28, 7.38)

Base excess (mmol/L)

-3.5 (-6.1, -1.6)

Haemoglobin (g/dL)

11.3 (9.4, 12.8)

PT (%)

75 (58, 89)

INR

1.3 (1.1, 1.4)

aPTT (sec)

32 (29, 39)

Antithrombin (%)

66 (53, 79)

Fibrinogen (mg/dL)

203 (148, 246)

Platelets (G/L)

169 (137, 202)

FXIII (%)

75 (57, 93)

VWF:Ag (%)

209 (163, 280)

VWF:RiCo (%)

202 (157, 267)

EXTEM CT (sec)

64 (55, 75)

EXTEM MCF (mm)

51 (45, 56)

FIBTEM MCF (mm)

9 (6, 13)

Hyperfibrinolysis (n)

20 (8.1)

PT:Prothrombin Time; INR:International Normalized Ratio; aPTT:Activated Partial Thromboplastin Time; FXIII: coagulation Factor XIII; VWF: Ag-VWF Antigen, VWF:RiCo, VWF Ristocetin activity, EXTEM:Extrinsically Activated Thrombelastometric Assay, CT:Coagulation Time, MCF: Maximum Clot Firmness, FIBTEM MCF, Fibrinpolymerisation.Data are given as median and interquartile range.

Table 2:Laboratory Values at Emergency Department Admission.

 

 

 

FXIII <60% (n=73)

 

FXIII ≥60% (n=201)

p value

Age (years)

43 (26, 54)

42 (27, 54)

0.813

Male sex n (%)

56 (76.7)

161 (80.5)

0.493

Pattern of injury n (%)

 

 

 

Head/Neck

42 (57.5)

133 (66.5)

0.156

Chest

55 (75.3)

154 (77.0)

0.723

Abdomen/Pelvis

53 (72.6)

95 (47.5)

<0.001

Extremities

51 (69.9)

108 (54)

0.021

Time trauma-ED admission (min)

70 (56, 98)

78 (60, 136)

0.27

Prehospital crystalloids (mL)

1000 (1000, 2000)

1000 (500, 1500)

0.001

Prehospital colloids (mL)

1000 (500, 1000)

500 (0, 500)

<0.001

Injury Severity Score (pts)

43 (34, 59)

34 (24, 41)

<0.001

Glasgow Coma Scale (pts)

11 (5, 15)

13 (7, 15)

0.998

SBP (mm Hg)

103 (90, 121)

120 (110, 140)

<0.001

Heart rate (bpm)

95 (80, 115)

90 (80, 105)

0.008

Shock n (%)

23 (31.5)

27 (13, 5)

<0.001

Temperature (°C)

35.0 (33.2, 36.2)

35 (34.2, 36.1)

0.677

ED:Emergency Department; SPB:Systolic Blood Pressure; Data are given as median values with interquartile ranges, if not otherwise indicated.

Table 3:Characteristics of patients with Factor XIII levels < 60 and ≥ 60% at emergency department admission.

 

 

 

FXIII <60% (n=73)

 

FXIII ≥60% (n=201)

p value

FXIII (%)

47 (40, 54)

82 (70, 98)

<0.001

PT(%)

53 (40, 66)

82 (68, 93)

<0.001

INR

1.5 (1.4, 1.8)

1.2 (1.1, 1.3)

<0.001

aPTT (sec)

43 (37, 64)

30 (27, 34)

<0.001

Antithrombin (%)

48 (39, 56)

72 (62, 82)

<0.001

Fibrinogen (mg dL-1)

122 (100, 156)

217 (186, 262)

<0.001

DD ratio

16.1 (7.5, 32.3)

10.0 (4.7, 21.3)

0.02

EXTEM CT (s)

75 (65, 113)

60 (54, 69)

<0.001

EXTEM CFT (s)

209 (170, 321)

126 (100, 168)

<0.001

EXTEM MCF (mm)

44 (39, 48)

54 (49, 58)

<0.001

FIBTEM MCF (mm)

5 (1, 8)

10 (7, 14)

<0.001

Hyperfibrinolysis n (%)

11 (15.1)

9 (4.5)

0.003

Platelets (G L-1)

132 (110, 168)

182 (154, 214)

<0.001

Haemoglobin (g dL-1)

8.4 (6.7, 10.2)

12.0 (10.4, 13.4)

<0.001

vWF:Ag (%)

181 (137, 255)

223 (173, 290)

0.007

vWF:RiCO (%)

188 (131, 253)

207 (163, 282)

0.091

Arterial pH

7.30 (7.25, 7.35)

7.34 (7.29, 7.39)

<0.001

Base deficit (mmol L-1)

-5.1 (-8.0, -3.2)

-2.9 (-5.2, -1.4)

<0.001

FXIII: Factor XIII; INR: International Normalized Ratio; aPTT:Activated Partial Thromboplastin Time; vWF:Ag- von Willebrand Factor Antigen; vWF:RiCo- von Willebrand Ristocetin Activity; DD ratio: D-Dimer ratio; EXTEM:Extrinsically Activated Thrombelastometric Assay; CT, coagulation time; MCF:Maximum Clot Firmness; FIBTEM MCF:Fibrinpolymerisation. Data are given as median values (interquartile range).

Table 4:Laboratory variables in patients with Factor XIII levels < 60% and ≥ 60% at emergency department admission.

 

 

 

FXIII <60% (n=73)

 

FXIII ≥60% (n=201)

p value

RBC (U)

6 (1, 12)

0 (0, 3)

<0.0001

PC (aphaeresis U)

0 (0, 2)

0 (0, 0)

<0.0001

FFP (U)

5 (0, 10)

0 (0, 0)

<0.0001

Fibrinogen concentrate (g)

4 (2, 7)

0 (0, 3)

<0.0001

PCC (IU)

600 (0, 2000)

0 (0, 0)

<0.0001

MOF n (%)

22 (30.1)

28 (14.0)

0.001

Sepsis n (%)

13 (17.8)

33 (16.5)

0.573

Length of ICU stay (days)

13 (5, 28)

9 (3, 17)

0.009

Ventilator-free days (days)

13 (0, 23)

24 (12, 26)

<0.001

Length of hospital stay (days)

19 (9, 41)

18 (9, 31)

0.52

Hospital mortality n (%)

17 (23.3)

18 (9.0)

0.002

GOS (pts)

4 (2, 5)

5 (4, 5)

<0.001

FXIII: Factor XIII plasma level; RBC, red blood cells; PC:Platelet Concentrate; FFP:Fresh Frozen Plasma; PCC:Prothrombin Complex Concentrate (containing factors II, FVII, IX and X); MOF:Multiple Organ Failure; GOS:Glasgow Outcome Scale; RC:Red Cell Concentrate; PC:Platelet Concentrate; FFP:Fresh Frozen Plasma;
Data are presented as median values with interquartile ranges, if not otherwise indicated.

Table 5:Differences in 24h transfusion and coagulation factor requirements and outcome between trauma patients with FXIII below or above 60% at emergency room admission.

 

 

 

Regression coefficient

 

p value

OR (odds ratio)

95 % CI

 

FXIII (%)

-0.035

<0.001

0.966

0.953

0.978

FXIII <60% (categorical)

1.366

<0.001

3.921

2.084

7.379

PT (%)

0.014

<0.001

0.96

0.945

0.975

aPTT (sec)

0.009

0.272

1.009

0.993

1.024

Fibrinogen (mg/dL)

-0.005

0.003

0.995

0.991

0.998

Platelets (G/L)

-0.007

0.006

0.993

0.988

0.998

EXTEM CT (sec)

-0.001

0.342

0.999

0.996

1.001

EXTEM CFT (sec)

0

0.291

1

0.999

1

EXTEM MCF (mm)

-0.19

0.25

0.981

0.95

1.013

Hyperfibrinolysis (categorical)

1.401

0.012

4.061

1.353

12.19

FIBTEM MCF (mm)

-0.082

0.004

0.921

0.871

0.974

Haemoglobin (g/dL)

-0.47

<0.001

0.954

0.941

0.967

FXIII: coagulation Factor XIII; PT: Prothrombin Time, aPTT:Activated Partial Prothrombin Time; EXTEM:Extrinsically Activated ROTEM assay; CT:Coagulation Time; CFT: Clot Formation Time; MCF:Maximum Clot Firmness; FIBTEM MCF: fibrin polymerization

Table 6:Summary of single logistic regression models (including ISS as a covariate) evaluating the influence of coagulation parameters at admission on 24h red blood cell requirements in patients with severe blunt trauma..

 

 

 

AUC ROC

 

CI 95%

p value

Cut-off value

Sensitivity (%)

Specificity (%)

EXTEM CT (sec)

0.774

0.711-0.835

<0.001

69

67

74

EXTEM CFT (sec)

0.859

0.816-0.903

<0.001

161

81

73

EXTEM MCF (mm)

0.862

0.817-0.908

<0.001

50

74

85

FIBTEM MCF (mm)

0.849

0.796-0.901

<0.001

6

93

57

PT (%)

0.873

0.827-0.919

<0.001

61

88

74

Fibrinogen (mg/dL)

0.886

0.838-0.934

<0.001

154

89

75

Platelets (G/L)

0.785

0.723-0.847

<0.001

148

80

69

Haemoglobin (g/dL)

0.839

0.783-0.895

<0.001

10.7

72

83

Base deficit (mmol/L)

0.665

0.583-0,747

<0.001

-3.3

55

75

CI:Confidence Interval; EXTEM:Extrinsically Activated Thrombelastometry; CT:Coagulation Time; CFT:Clot Formation Time; MCF: Maximum Clot Firmness; FIBTEM MCF: Fibrin Polymerization.

.

Table 7:Results of the Receiver Operator Characteristic Curve Analysis (AUC ROC) for identification of the predictive value and cut-off levels of surrogate laboratory parameters to indicate Factor XIII plasma levels ≥60% at admission.

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