Petra Innerhofer

Hemostatic changes after crystalloid or colloid fluid administration during major orthopedic surgery: the role of fibrinogen administration.

BACKGROUND:To explore whether disturbed fibrin polymerization is the main problem underlying dilutional coagulopathy and can be reversed by fibrinogen administration, we conducted a prospective study using modified thrombelastography (ROTEM®). METHODS:Sixty-six orthopedic patients randomly received modified gelatin solution, hydroxyethyl starch 130/0.4, or exclusively Ringer lactate solution. ROTEM® analysis was performed, concentrations of coagulation factors and markers of thrombin generation were measured. Fibrinogen concentrate (Hemocomplettan®) was administered (30 mg/kg) when thrombelastographically measured fibrinogen polymerization was critically decreased. RESULTS:The α angle, clot firmness, and fibrinogen polymerization (median [min to max]) significantly decreased in the patients receiving hydroxyethyl starch (area under the curve minus baseline (−5 [−9 to −2]), followed by gelatin solution (−3 [−8 to 0]), with the least reductions seen for Ringer lactate solution (−2 [− 4 to 1]) (colloids versus Ringer lactate P < 0.0001). Thirteen patients in the colloid groups but none in the Ringer lactate group needed fibrinogen concentrate to maintain borderline clot firmness. Activity of FVII, FVIII, FIX, and von Willebrand ristocetin activity decreased significantly with colloids. Thrombelastographically measured coagulation time, molecular markers of thrombin generation, and activity of all other coagulation factors were comparable in all groups. CONCLUSION:Disturbance of fibrinogen/fibrin polymerization is the primary problem triggering dilutional coagulopathy during major orthopedic surgery. The magnitude of clot firmness reduction is determined by the type of fluid used, with hydroxyethyl starch showing the most pronounced effects. These undesirable effects of intravascular volume therapy can be reversed by increasing fibrinogen concentration by administering fibrinogen concentrate, even during continuing blood loss and intravascular volume replacement.

Risk for postoperative infection after transfusion of white blood cell-filtered allogeneic or autologous blood components in orthopedic patients undergoing primary arthroplasty.

BACKGROUND:  This study was designed to obtain data on the incidence of postoperative infection in patients undergoing elective orthopedic surgery and receiving white blood cell (WBC)‐filtered blood components prepared according to current standards.

Prevalence and impact of abnormal ROTEM® assays in severe blunt trauma: results of the ‘Diagnosis and Treatment of Trauma-Induced Coagulopathy (DIA-TRE-TIC) study’

BACKGROUND ROTEM(®)/TEG(®) (rotational thromboelastometry) assays appear to be useful for the treatment of bleeding trauma patients. However, data on the prevalence and impact of abnormal ROTEM(®) assays are scarce. METHODS This is a prospective cohort study of blunt trauma patients (Injury Severity Score ≥15 or Glasgow Coma Score ≤14) admitted to Innsbruck Medical University Hospital between July 2005 and July 2008. Standard coagulation tests, antithrombin (AT), prothrombin fragments (F1+2), thrombin-antithrombin complex (TAT), and ROTEM(®) assays were measured after admission. Data on 334 patients remained for final analysis. RESULTS ROTEM(®) parameters correlated with standard coagulation tests (all Spearman r>0.5), and significant differences in mortality were detected for defined ROTEM(®) thresholds [FIBTEM 7 mm (21% vs 9%, P=0.006), EXTEM MCF (maximum clot firmness) 45 mm (25.4% vs 9.4%, P=0.001)]. EXTEM MCF was independently associated with early mortality [odds ratio (OR) 0.94, 95% confidence interval (CI) 0.9-0.99] and MCF FIBTEM with need for red blood cell transfusion (OR 0.92, 95% CI 0.87-0.98). In polytrauma patients with or without head injury (n=274), the prevalence of low fibrinogen concentrations, impaired fibrin polymerization, and reduced clot firmness was 26%, 30%, and 22%, respectively, and thus higher than the prolonged international normalized ratio (14%). Hyperfibrinolysis increased fatality rates and occurred as frequently in isolated brain injury (n=60) as in polytrauma (n=274) (5%, 95% CI 1.04-13.92 vs 7.3%, 95% CI 4.52-11.05). All patients showed elevated F1+2 and TAT and low AT levels, indicating increased thrombin formation. CONCLUSIONS Our data enlarge the body of evidence showing that ROTEM(®) assays are useful in trauma patients. Treatment concepts should focus on maintaining fibrin polymerization and treating hyperfibrinolysis.

The Effect of Fibrinogen Substitution on Reversal of Dilutional Coagulopathy: An In Vitro Model

Colloids and crystalloids are usually administered as treatment for hypovolemia in severely injured patients. However, dilution of clotting factors and platelets together with impaired fibrinogen polymerization are associated with fluid therapy and may aggravate hemorrhage, thus worsening final outcome of these patients. We investigated, in an in vitro model, whether the addition of fibrinogen to diluted blood samples can reverse dilutional coagulopathy. Blood from 5 healthy male volunteers was diluted by 60% using lactated Ringers solution, 4% modified gelatin solution, or 6% hydroxyethyl starch 130/0.4, as well as the combination of lactated Ringers solution with either of the 2 colloid solutions. Thereafter, aliquots of diluted blood samples were incubated with 3 different concentrations of fibrinogen (0.75, 1.5, and 3.0 mg/mL). Measurements were performed by modified thrombelastography (ROTEM®; Pentapharm, Munich, Germany). After 60% dilution, clotting times increased, whereas clot firmness and fibrin polymerization decreased significantly. After administration of fibrinogen, clotting times decreased and clot firmness, as well as fibrin polymerization, increased in all diluted blood samples. The effect of in vitro fibrinogen substitution on ROTEM® variables was dependent on the fibrinogen dosage and the type of solution used to dilute the blood samples.

The effect of the combined administration of colloids and lactated Ringer's solution on the coagulation system: an in vitro study using thrombelastograph coagulation analysis (ROTEG.

Gelatin solutions are often given in clinical practice once the maximal dose of a median-weight hydroxyethyl starch (HES) has been reached. Colloids are usually combined with lactated Ringer’s solution (RL). Whether the combined administration of colloids and/or crystalloids affects blood coagulation is not known. We diluted blood by 20%, 40%, and 60% with RL, gelatin (Gelofusin®), 6% HES 130/0.4 (Voluven®), and 6% HES 200/0.5 (Iso-Hes®), as well as with combinations of these solutions at a ratio of 1:1 (gelatin/RL, 6% HES 130/0.4:RL, 6% HES 200/0.5:RL, 6% HES 130/0.4:gelatin, 6% HES 200/0.5:gelatin). Thereafter, blood was analyzed by using modified thrombelastograph® coagulation analysis (ROTEG®) and clotting time, clot formation time, and maximal clot firmness were determined. RL had the least effect on hemostasis. Gelatin administered alone impaired the coagulation system significantly less than each median-weight HES administered alone. We conclude that gelatin combined with 6% HES 200/0.5 or 6% HES 130/0.4 decreases hemostasis <6% HES 200/0.5 or 6% HES 130/0.4 administered alone.

The impact of fresh frozen plasma vs coagulation factor concentrates on morbidity and mortality in trauma-associated haemorrhage and massive transfusion

INTRODUCTION Clinical observations together with recent research highlighted the role of coagulopathy in acute trauma care and early aggressive treatment has been shown to reduce mortality. METHODS Datasets from severely injured and bleeding patients with established coagulopathy upon emergency room (ER) arrival from two retrospective trauma databases, (i) TR-DGU (Germany) and (ii) Innsbruck Trauma Databank/ITB (Austria), that had received two different strategies of coagulopathy management during initial resuscitation, (i) fresh frozen plasma (FFP) without coagulation factor concentrates, and (ii) coagulation factor concentrates (fibrinogen and/or prothrombin complex concentrates) without FFP, were compared for morbidity, mortality and transfusion requirements using a matched-pair analysis approach. RESULTS There were no major differences in basic characteristics and physiological variables upon ER admission between the two cohorts that were matched. ITB patients had received substantially less packed red blood cell (pRBC) concentrates within the first 6h after admission (median 1.0 (IQR(25-75) 0-3) vs 7.5 (IQR(25-75) 4-12) units; p<0.005) and the first 24h as compared to TR-DGU patients (median 3 (IQR(25-75) 0-5) vs 12.5 (8-20) units; p<0.005). Overall mortality was comparable between both groups whilst the frequency for multi organ failure was significantly lower within the group that had received coagulation factor concentrates exclusively and no FFP during initial resuscitation (n=3 vs n=15; p=0.015). This translated into trends towards reduced days on ventilator whilst on ICU and shorter overall in-hospital length of stays (LOS). CONCLUSION Although there was no difference in overall mortality between both groups, significant differences with regard to morbidity and need for allogenic transfusion provide a signal supporting the management of acute post-traumatic coagulopathy with coagulation factor concentrates rather than with traditional FFP transfusions. Prospective and randomised clinical trials with sufficient patient numbers based upon this strategy are advocated.

Fibrinogen in Craniosynostosis Surgery

BACKGROUND: During craniosynostosis repair, massive blood loss, consumption and dilution of clotting factors often result in coagulopathy, for which cryoprecipitate, fresh frozen plasma (FFP), and platelets are recommended for treatment. However, cryoprecipitate is not available in most European countries, and the efficacy of FFP in correcting fibrinogen deficiency is limited. We report our experience with human fibrinogen concentrate (Hemocomplettan®) used to improve impaired fibrinogen polymerization in children. METHODS: Results of routine coagulation tests, thrombelastometry (ROTEM®), transfusion requirements, administration of fibrinogen concentrate, and data on the postoperative course of nine consecutive children undergoing major craniofacial surgery were retrospectively collected from anesthesia protocols, medical charts, laboratory and ROTEM® databases. RESULTS: The nine children aged 12 (8, 22) mo (median [25th, 75th percentile]), weighing 9.5 (9, 10) kg had a calculated blood loss of 80 (49, 92)% of calculated blood volume during the surgery lasting 6.4 (4.5, 7.2) h. Impaired fibrinogen polymerization detected by ROTEM® was the main problem underlying dilutional coagulopathy. In all cases, sufficient hemostasis was achieved without adverse effects by administering (if necessary), repeated doses of fibrinogen concentrates (each single dose 30 mg/kg) without FFP or platelet transfusions. All children were successfully weaned from mechanical ventilation within a few hours and were able to be discharged early from the Intensive Care Unit. CONCLUSIONS: Administration of fibrinogen concentrate effectively improves fibrinogen polymerization and total clot strength, which were the main underlying problems of dilutional coagulopathy in children undergoing craniosynostosis surgery.

Time for changing coagulation management in trauma-related massive bleeding.

Purpose of review New insights into the pathophysiology of trauma-induced coagulopathy, the increasing availability of point-of-care devices and awareness of side effects of intravenous fluids and traditional fresh frozen plasma therapy has encouraged new concepts for managing massive blood loss. Recent findings Trauma-induced coagulopathy primarily results from blood loss, hypovolemia-induced activation of the protein C system and consequent increase of the fibrinolytic potential, whereas hemodilution, localized consumption of clotting factors and platelets, hypothermia, acidosis, anemia and hypocalcemia further decrease the hemostatic potential. The widespread use of viscoelastic devices highlighted the importance of the contribution of fibrinogen to clot firmness, a precondition for cessation of bleeding. The evidence is growing that targeted therapy using coagulation factor concentrates guided by viscoelastic measurements enables effective correction of severe coagulopathy. Summary During massive blood loss, viscoelastic measurements should guide aggressive treatment of deficiency or hyperfibrinolysis or both. In addition, the impact of contributing factors should be considered and as far as possible corrected. New data underscore the importance of avoiding hypoperfusion, and the use of coagulation factor concentrates should enable more effective correction of coagulopathy.

Hemostasis and Hemodilution: A Quantitative Mathematical Guide for Clinical Practice

Quantitative changes of hemostasis during hemodilution remain unclear. With the increasing popularity of artificial blood substitutes (ABS), which solely provide oxygen-transport capacity, this issue becomes even more complex. We developed a mathematical model to quantitatively analyze hemostasis during hemodilution and validated it by recalculating patient data. We calculated and compared maximal allowable blood losses (MABL) related to minimal acceptable hematocrit, platelet concentration, and plasma fibrinogen concentration. MABL is the maximal blood loss that can be tolerated without any additional blood products. The variable with the smallest MABL thus limits hemodilution foremost. Hemodilution included isovolemic replacement of blood loss with colloid or acute normovolemic hemodilution (ANH) followed by isovolemic replacement of blood loss with colloid and ABS. We also related our findings to preoperative patient data (n = 204). The decline in platelet concentrations rarely (<2% of all patients) limits hemodilution. By contrast, critical plasma fibrinogen (≤100 mg/dL) concentrations can often (≤20% of all patients) limit hemodilution if their initial concentrations are within the lower normal range (<300 mg/dL). These findings become more frequent if ANH is combined with ABS. Under those circumstances ANH blood products are solely required for stabilization of hemostasis, thereby defeating the original purpose of combining ANH with ABS.

Point-of-care whole blood impedance aggregometry versus classical light transmission aggregometry for detecting aspirin and clopidogrel: the results of a pilot study.

BACKGROUND:We determined whether whole blood impedance aggregometry using the Multiplate® detects the effects of antiplatelet drugs as reliably as does classical light transmission aggregometry (LTA) or the platelet function analyzer PFA-100®. METHODS:Multiplate (M) assays, measuring changes in electrical resistance as aggregation units over time (AU*min), and LTA assays induced by collagen (COL), adenosine diphosphate (ADP) or arachidonic acid (AA) and PFA-100 testing, using epinephrine (PFA100-EPI) or ADP (PFA100-ADP) cartridges, were performed simultaneously using arterial blood samples obtained before induction of anesthesia in 70 consecutive patients scheduled for elective coronary artery bypass grafting. Patients in group A (n = 48) served as controls, patients in group B (n = 11) received aspirin 100 mg/d and those in group C (n = 11) aspirin 100 mg/d and clopidogrel 75 mg/d until the day before surgery. RESULTS:In controls the median (1st, 3rd quartiles) change in impedance AU*min for M-COL (374 [231–469]) was significantly greater than in patients receiving aspirin (164 [86–211], P = 0.0009) or receiving aspirin and clopidogrel (118 [101–244], P = 0.004). M-ADP values in controls were 258 (158–389), in patients receiving aspirin 261 (159–393), and in patients receiving aspirin and clopidogrel 88 (48–231, P = 0.054). M-AA values were significantly lower in patients receiving aspirin alone (45 [28–60], P = 0.0004) or aspirin and clopidogrel (44 [26–221], P = 0.008) than in controls (200 [86–345]). The areas under the receiver operating characteristic curves indicating the ability to discriminate patients taking aspirin from those not taking aspirin were comparable for COL and AA assays using whole blood impedance aggregometry or classical LTA (M-COL 0.84 [P = 0.001], LTA-COL 0.85 [P = < .001], M-AA 0.84 [P = < .001] and LTA-AA 0.87 [P = < .001]), but only 0.74 for PFA-100-EPI (P = 0.03). Similarly, for discrimination of patients not taking antiplatelet drugs from patients taking clopidogrel and aspirin the areas under the receiver operating characteristic curve were also comparable for both aggregometry methods M-COL 0.77 (P = 0.006), LTA-COL 0.78 (P = 0.004), M-ADP 0.74 (P = 0.015), LTA-ADP 0.73 (P = 0.018). CONCLUSION:Results achieved with the bedside Multiplate assays were not different than those obtained with classical aggregometry for detecting the effects of aspirin and clopidogrel in preoperative patients scheduled for elective cardiac surgery.