Alexander A. Hanke

Transfusion in trauma: thromboelastometry-guided coagulation factor concentrate-based therapy versus standard fresh frozen plasma-based therapy.

IntroductionThromboelastometry (TEM)-guided haemostatic therapy with fibrinogen concentrate and prothrombin complex concentrate (PCC) in trauma patients may reduce the need for transfusion of red blood cells (RBC) or platelet concentrate, compared with fresh frozen plasma (FFP)-based haemostatic therapy.MethodsThis retrospective analysis compared patients from the Salzburg Trauma Centre (Salzburg, Austria) treated with fibrinogen concentrate and/or PCC, but no FFP (fibrinogen-PCC group, n = 80), and patients from the TraumaRegister DGU receiving ≥ 2 units of FFP, but no fibrinogen concentrate/PCC (FFP group, n = 601). Inclusion criteria were: age 18-70 years, base deficit at admission ≥2 mmol/L, injury severity score (ISS) ≥16, abbreviated injury scale for thorax and/or abdomen and/or extremity ≥3, and for head/neck < 5.ResultsFor haemostatic therapy in the emergency room and during surgery, the FFP group (ISS 35.5 ± 10.5) received a median of 6 units of FFP (range: 2, 51), while the fibrinogen-PCC group (ISS 35.2 ± 12.5) received medians of 6 g of fibrinogen concentrate (range: 0, 15) and 1200 U of PCC (range: 0, 6600). RBC transfusion was avoided in 29% of patients in the fibrinogen-PCC group compared with only 3% in the FFP group (P< 0.001). Transfusion of platelet concentrate was avoided in 91% of patients in the fibrinogen-PCC group, compared with 56% in the FFP group (P< 0.001). Mortality was comparable between groups: 7.5% in the fibrinogen-PCC group and 10.0% in the FFP group (P = 0.69).ConclusionsTEM-guided haemostatic therapy with fibrinogen concentrate and PCC reduced the exposure of trauma patients to allogeneic blood products.

Effects of fibrinogen concentrate as first-line therapy during major aortic replacement surgery: a randomized, placebo-controlled trial.

Background:Fibrinogen is suggested to play an important role in managing major bleeding. However, clinical evidence regarding the effect of fibrinogen concentrate (derived from human plasma) on transfusion is limited. The authors assessed whether fibrinogen concentrate can reduce blood transfusion when given as intraoperative, targeted, first-line hemostatic therapy in bleeding patients undergoing aortic replacement surgery. Methods:In this single-center, prospective, placebo-controlled, double-blind study, patients aged 18 yr or older undergoing elective thoracic or thoracoabdominal aortic replacement surgery involving cardiopulmonary bypass were randomized to fibrinogen concentrate or placebo, administered intraoperatively. Study medication was given if patients had clinically relevant coagulopathic bleeding immediately after removal from cardiopulmonary bypass and completion of surgical hemostasis. Dosing was individualized using the fibrin-based thromboelastometry test. If bleeding continued, a standardized transfusion protocol was followed. Results:Twenty-nine patients in the fibrinogen concentrate group and 32 patients in the placebo group were eligible for the efficacy analysis. During the first 24 h after the administration of study medication, patients in the fibrinogen concentrate group received fewer allogeneic blood components than did patients in the placebo group (median, 2 vs. 13 U; P < 0.001; primary endpoint). Total avoidance of transfusion was achieved in 13 (45%) of 29 patients in the fibrinogen concentrate group, whereas 32 (100%) of 32 patients in the placebo group received transfusion (P < 0.001). There was no observed safety concern with using fibrinogen concentrate during aortic surgery. Conclusions:Hemostatic therapy with fibrinogen concentrate in patients undergoing aortic surgery significantly reduced the transfusion of allogeneic blood products. Larger multicenter studies are necessary to confirm the role of fibrinogen concentrate in the management of perioperative bleeding in patients with life-threatening coagulopathy.

Platelet function following trauma. A multiple electrode aggregometry study.

Platelets play a central role in coagulation. Currently, information on platelet function following trauma is limited. We performed a retrospective analysis of patients admitted to the emergency room (ER) at the AUVA Trauma Centre, Salzburg, after sustaining traumatic injury. Immediately after admission to the ER, blood was drawn for blood cell counts, standard coagulation tests, and platelet function testing. Platelet function was assessed by multiplate electrode aggregometry (MEA) using adenosine diphosphate (ADPtest), collagen (COLtest) and thrombin receptor activating peptide-6 (TRAPtest) as activators. The thromboelastometric platelet component, measuring the contribution of platelets to the elasticity of the whole-blood clot, was assessed using the ROTEM device. The study included 163 patients, 79.7% were male, and the median age was 43 years. The median injury severity score was 18. Twenty patients (12.3%) died. Median platelet count was significantly lower among non-survivors than survivors (181,000/μl vs. 212,000/μl; p=0.01). Although platelet function defects were relatively minor, significant differences between survivors and non-survivors were observed in the ADPtest (94 vs. 79 U; p=0.0019), TRAPtest (136 vs. 115 U; p<0.0001), and platelet component (134 vs.103 MCEEXTEM - MCEFIBTEM; p=0.0012). Aggregometry values below the normal range for ADPtest and TRAPtest were significantly more frequent in non-survivors than in survivors (p=0.0017 and p=0.0002, respectively). Minor decreases in platelet function upon admission to the ER were a sign of coagulopathy accompanying increased mortality in patients with trauma. Further studies are warranted to confirm these results and investigate the role of platelet function in trauma haemostatic management.

Hypothermia and acidosis synergistically impair coagulation in human whole blood.

BACKGROUND:Hypothermia and acidosis were reported to influence coagulopathy in different clinical settings. We evaluated whole blood coagulation to determine the effects of hypothermia and/or acidosis on hemostasis. METHODS:Whole blood samples (3.000 &mgr;L) from 10 healthy volunteers (2 female, 8 male) were acidified by adding 40 &mgr;L of hydrochloric acid of increasing molarity to achieve a blood pH (&agr;-stat) between 7.0 and 7.37, and coagulation was analyzed by rotational thromboelastometry after an incubation period of 30 min using both intrinsically (InTEM ™) and extrinsically (ExTEM ™) activated assays. To assess temperature-dependent effects, all tests were performed at blood/thromboelastometer temperatures of 30, 33, 36, and 39°C, respectively. An additional extrinsically activated test with addition of cytochalasin D was performed to examine clot formation without platelet contribution. RESULTS:Hypothermia at a normal pH produced an increased coagulation time [ExTEM: 65 s ± 3.6 (36°C) vs 85 ± 4 (30°C), P < 0.001; coagulation time, InTEM: 181 s ± 10 (36°C) vs 226 ± 9, P < 0.001] and clot formation time [ExTEM: 105 s ± 5 (36°C) vs 187 ± 6 (30°C), P < 0.001]; clot formation time [InTEM: 101 s ± 5 (36°C) vs 175 ± 7, P < 0.001], as well as decreased &agr; angle [ExTEM: 65.6 ± 1.8 (36°C) vs 58 ± 1.1, P < 0.01, P < 0.01; InTEM: 70.5 ± 1.8 (36°C) vs 60.2 ± 1.5, P < 0.001]. Maximum clot firmness was significantly impaired only in InTEM assays [56.9 mm ± 0.9 (36°C) vs 52.7 ± 0.9, P < 0.05]. In contrast, acidosis per se had no significant effects during normothermia. Acidosis amplified the effects of hypothermia, and synergistically impaired clotting times, &agr; angle, and decreased maximum clot firmness, again in both extrinsically and intrinsically activated assays. Formation of a fibrin clot tested after abolition of platelet function by cytochalasin D was not impaired. Clot lysis decreased under hypothermic and/or acidotic conditions, but increased with hyperthermia. CONCLUSIONS:In this in vitro study, hypothermia produced coagulation changes that were worsened by acidosis whereas acidosis without hypothermia has no significant effect on coagulation, as studied by thromboelastometry. This effect was mediated by the inhibition of coagulation factors and platelet function. Thus, thromboelastometry performed at 37°C overestimated integrity of coagulation during hypothermia in particular in combination with acidosis.

Reduction of Fresh Frozen Plasma Requirements by Perioperative Point-of-Care Coagulation Management with Early Calculated Goal-Directed Therapy

Background: Massive bleeding and transfusion of packed red blood cells (PRBC), fresh frozen plasma (FFP) and platelets are associated with increased morbidity, mortality and costs. Patients and Methods: We analysed the transfusion requirements after implementation of point-of-care (POC) coagulation management algorithms based on early, calculated, goal-directed therapy with fibrinogen concentrate and prothrombin complex concentrate (PCC) in different perioperative settings (trauma surgery, visceral and transplant surgery (VTS), cardiovascular surgery (CVS) and general and surgical intensive care medicine) at 3 different hospitals (AUVA Trauma Centre Salzburg, University Hospital Innsbruck and University Hospital Essen) in 2 different countries (Austria and Germany). Results: In all institutions, the implementation of POC coagulation management algorithms was associated with a reduction in the transfusion requirements for FFP by about 90% (Salzburg 94%, Innsbruck 88% and Essen 93%). Furthermore, PRBC transfusion was reduced by 8.4–62%. The incidence of intraoperative massive transfusion (≧10 U PRBC) could be more than halved in VTS and CVS (2.56 vs. 0.88%; p < 0.0001 and 2.50 vs. 1.06%; p = 0.0007, respectively). Platelet transfusion could be reduced by 21–72%, except in CVS where it increased by 115% due to a 5-fold increase in patients with dual antiplatelet therapy (2.7 vs. 13.7%; p < 0.0001). Conclusions: The implementation of perioperative POC coagulation management algorithms based on early, calculated, goaldirected therapy with fibrinogen concentrate and PCC is associated with a reduction in the transfusion requirements for FFP, PRBC and platelets as well as with a reduced incidence of massive transfusion. Thus, the limited blood resources can be used more efficiently.

Perioperative Coagulation Management and Control of Platelet Transfusion by Point-of-Care Platelet Function Analysis

About one third of all blood components transfused intraoperatively is used in cardiac surgery, whereas mortality of cardiosurgical patients correlates nearly linear with the number of transfused units of packed red blood cells. Acquired platelet function disorders play a major role in perioperative bleeding in cardiac surgery. Therefore, the use of point-of-care-suitable platelet function analyzers seems to be reasonable in this field. Methods: Platelet function analyzer PFA-100®, rotational thrombelastometry (ROTEM®), and multiple platelet function analyzer (Multiplate®) are in principle applicable for point-of-care testing. Since these three analyzers monitor different aspects of platelet function and have different limitations, the selection of the right test system depends on the right question. Results: Perioperative use of platelet function analyzers is helpful in prediction of blood loss in cardiac surgery. Perioperative usage of blood components and their respective costs can be reduced by an appropriate coagulation management. Conclusion: Algorithms for perioperative coagulation management based on point-of-care testing permit a fast diagnostic and goal-directed therapy of coagulation and functional platelet disorders. The possibility to reduce the mortality of patients and the overall cost for hospital stay is subject of further studies.

Potential value of transfusion protocols in cardiac surgery

Purpose of review On the one hand, cardiac and aortic surgery is associated with a high rate of allogeneic blood transfusion. On the other hand, both bleeding and allogeneic blood transfusion is associated with increased morbidity, mortality, and hospital costs in cardiac and aortic surgery. This article reviews the current literature between 1995 and 2012 dealing with transfusion protocols in cardiovascular surgery. The 16 studies fitting these search criteria have evaluated the impact of the implementation of ROTEM/TEG based coagulation management algorithms on transfusion requirement and outcome in overall 8507 cardiovascular surgical patients. Recent findings The use of point-of-care (POC) transfusion and coagulation management algorithms based on viscoelastic tests such as thromboelastometry (ROTEM) and thrombelastography (TEG) in combination with POC platelet function tests such as whole blood impedance aggregometry (Multiplate) have been shown to be associated with reduced allogeneic blood transfusion requirements, reduced incidence of thrombotic/thromboembolic and transfusion-related adverse events, and improved outcomes in cardiac surgery. Summary Implementation of POC algorithms including a comprehensive bundle of POC diagnostics (thromboelastometry and whole blood impedance aggregometry) in combination with first-line therapy using immediately available specific coagulation factor concentrates (fibrinogen and prothrombin complex concentrate) and defining strict indications, calculated dosages, and clear sequences for each haemostatic intervention seems to be complex but most effective in reducing perioperative transfusion requirements and has been shown to be associated with a decreased incidence of thrombotic/thromboembolic events, transfusion-related adverse events, as well as with improved patients’ outcomes including 6-month mortality.

Fibrinogen concentrate reduces intraoperative bleeding when used as first-line hemostatic therapy during major aortic replacement surgery: results from a randomized, placebo-controlled trial.

OBJECTIVES We assessed whether fibrinogen concentrate as targeted first-line hemostatic therapy was more effective than placebo or a standardized transfusion algorithm in controlling coagulopathic bleeding in patients undergoing major aortic surgery. METHODS In this single-center, prospective, double-blind study, adults undergoing elective thoracic or thoracoabdominal aortic replacement surgery involving cardiopulmonary bypass were randomized to intraoperative fibrinogen concentrate (n = 29) or placebo (n = 32). Study medication was given if patients had clinically relevant coagulopathic bleeding, measured by 5-minute bleeding mass, after cardiopulmonary bypass removal, protamine administration, and surgical hemostasis. Fibrinogen concentrate dosing was individualized using the thromboelastometric FIBTEM test. If bleeding continued, a standardized transfusion algorithm was followed. In the placebo group, all 32 patients received 1 transfusion cycle of fresh-frozen plasma/platelets, and 30 patients required a second transfusion cycle; none of these patients received any other procoagulant therapy. Change in bleeding rate after treatment was compared using t tests. RESULTS Mean change in bleeding rate after fibrinogen concentrate was -48.3 g/5 min, compared with 0.4 g/5 min after placebo (P < .001), -16.1 g/5 min after 1 transfusion cycle (fresh-frozen plasma or platelets; P = .003), and -28.0 g/5 min after 2 transfusion cycles (fresh-frozen plasma and platelets; P = .11). Reductions in bleeding rate were greater for patients with higher bleeding rates before treatment, especially with fibrinogen concentrate. CONCLUSIONS FIBTEM-guided intraoperative hemostatic therapy with fibrinogen concentrate is more effective than placebo in controlling coagulopathic bleeding during major aortic replacement surgery. Fibrinogen concentrate is also more effective than 1 cycle of fresh-frozen plasma/platelets and is more rapid than--and at least as effective as--2 cycles of fresh-frozen plasma/platelets.

Tranexamic acid partially improves platelet function in patients treated with dual antiplatelet therapy.

Background Although the impact of tranexamic acid on platelet function remains controversial, tranexamic acid is part of clinical algorithms for the management of platelet dysfunction. The goal of our prospective, observational study was to examine the effects of tranexamic acid on platelet function in patients treated with dual antiplatelet therapy compared to those who ceased antiplatelet therapy for at least 7 days. Methods Forty patients scheduled for cardiac surgery were enrolled in this study. Group 1 consisted of 20 patients who ceased antiplatelet therapy with aspirin and clopidogrel at least 7 days before surgery. Group 2 consisted of 20 patients who were treated with aspirin and clopidogrel until the day before surgery. Using the Multiplate device (Dynabyte, Munich, Germany), multiple electrode aggregometry (MEA) was performed following platelet stimulation with thrombin receptor activating peptide-6 (TRAP-6), arachidonic acid or ADP on blood collected 20 min before and after application of 2 g tranexamic acid. Results Compared with group 1, platelet aggregation was statistically significantly reduced in ASPItest and ADPtest in group 2, whereas there were no significant differences in the TRAPtest. In group 1, platelet aggregation did not differ significantly before and after tranexamic acid treatment. In contrast, in group 2, we observed a significant increase in arachidonic acid-induced [295 (280/470) arbitrary aggregation units × min [AU*min; median (25th/75th percentile) vs. 214 (83/409) AU*min, P = 0.01] and ADP-induced platelet aggregation [560 AU*min (400/760 AU*min) vs. 470 AU*min (282/550 AU*min), P = 0.013], whereas platelet aggregation following stimulation with TRAP-6 did not change significantly [980 (877/1009) AU*min, median (25th/75th percentile) after tranexamic acid vs. 867 (835/961) AU*min before tranexamic acid, P = 0.464]. Conclusion The results of this study indicate that tranexamic acid potentially corrects defects in arachidonic acid-induced and ADP-induced platelet aggregation imposed by dual antiplatelet therapy. However, platelet aggregation in response to arachidonic acid or ADP in the blood of patients who have not received aspirin and clopidogrel is unaffected by tranexamic acid. These results support the use of tranexamic acid to partially reverse platelet aggregation dysfunction due to antiplatelet therapy.

Less impairment of hemostasis and reduced blood loss in pigs after resuscitation from hemorrhagic shock using the small-volume concept with hypertonic saline/hydroxyethyl starch as compared to administration of 4% gelatin or 6% hydroxyethyl starch solution.

BACKGROUND: Small-volume resuscitation using hypertonic saline/hydroxyethyl starch 200/0.62 (HS-HES) has been shown to be an effective alternative to the administration of crystalloids or colloids in trauma patients. All IV fluids cause dose-related dilutional coagulopathy and show intrinsic effects on the hemostatic system, but only few data refer to functional consequences after small-volume resuscitation. METHODS: Using thrombelastometry (ROTEM®), we studied 30 pigs (weighing 35–45 kg) after withdrawal of 60% of blood volume [1484 mL (1369–1624 mL)] and receiving 4 mL/kg HS-HES for compensation of blood loss or 4% gelatin or 6% HES 130/0.4 in a 1:1 ratio to lost blood volume. To compare the ROTEM variables (coagulation time, clot formation time, α angle, clot firmness, and fibrinogen polymerization) with bleeding tendency, a hepatic incision was made and blood loss was measured. RESULTS: Median (25th, 75th percentile) fibrinogen polymerization was significantly higher after HS-HES infusion [11 mm (10, 11), P = 0.0034] when compared with administration of 4% gelatin [4.5 mm (3.0, 5.8)] or HES 130/0.4 [3.5 mm (2.3, 4.0)]. Median blood loss after liver incision was 725 mL (900, 375) after HS-HES, 1625 mL (1275, 1950) after 4% gelatin, and 1600 mL (1500, 1800) after 6% HES 130/0.4 (P = 0.004). Hemodynamic stabilization was traceable in all groups but showed differences regarding filling pressures. CONCLUSIONS: Resuscitation from hemorrhagic shock with HS-HES 200/0.62 results in less impairment of clot formation when compared with compensation of blood loss by administering 6% HES 130/0.4 or 4% gelatin.