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
Citation: Breitkopf R, Westermann I, Tauber H, Mittermayr M, Gasteiger L (2017) FXIII Deficiency Occurs Frequently in Major Trauma and Influences Transfusion Requirements While Levels of Von Willebrand Factor are well above Thresholds. Emerg Med Inves: 151. DOI: 10.29011/2475-5605.000051
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; |
|||
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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