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Background: Hydroxyethyl starch (HES) administration has resulted in decreased hemostasis and fibrinogen (FI)-thrombin-(FIIa)-Factor XIII (FXIII) interactions. I proposed to determine the hemostatic effect of hemodilution with PentaLyte (6% HES, mean molecular weight 220 kDa) and Voluven (6% HES, 130 kDa)., Methods: Rabbits were intravenously administered 20 ml/kg PentaLyte or Voluven (n = 8 per fluid) over 10 min. Plasma was obtained prior to, 1 min and 1 h after hemodilution. Thrombelastography was performed, with clot initiation (R, sec), clot propagation (alpha, degrees), and clot strength (shear elastic modulus, G, dynes/cm2) determined over 20 min. Celite-activated samples had either no additions or addition of FI, FIIa or activated FXIII (FXIIIa) to restore protein content to pre-diluted values., Results and Conclusions: While there were no significant differences between the groups, R significantly decreased 1 h after hemodilution compared with values observed before and 1 min after hemodilution, whereas alpha and G significantly decreased 1 min after hemodilution and then significantly, but only partially, increased 1 h after hemodilution compared with pre-dilution values. Addition of FI, FIIa and FXIIIa significantly decreased R in both groups. alpha and G 1 min after hemodilution were significantly enhanced by FI, FIIa, FXIIIa in both groups; however, 1 h after hemodilution, rabbits administered PentaLyte had alpha and G enhanced only by FI and FXIIIa addition, whereas animals administered Voluven had alpha and G significantly enhanced by FI addition. PentaLyte and Voluven hemodilution initially diminishes FIIa-FI and FXIIIa-fibrin, but within an hour primarily inhibit FXIIIa-fibrin interactions in the rabbit.

Colloid-mediated hypocoagulability is clinically important, but the mechanisms responsible for coagulopathy have been incompletely defined. Thus, my goal was to elucidate how colloids decrease plasma coagulation function. Plasma was diluted 0% or 40% with 0.9% NaCl, three different hydroxyethyl starches (HES, mean molecular weight 450, 220 or 130 kDa), or 5% human albumin. Samples (n=6 per condition) were activated with celite, and diluted samples had either no additions or addition of fibrinogen (FI), thrombin (FIIa) or activated Factor XIII (FXIIIa) to restore protein function to prediluted values. Thrombelastographic variables measured included clot propagation (angle, alpha), and clot strength (amplitude, A; or shear elastic modulus, G). Dilution with 0.9% NaCl significantly decreased alpha, A and G-values compared to undiluted samples. Supplementation with FI, but not FIIa or FXIIIa, resulted in 0.9% NaCl-diluted thrombelastographic variable values not different from those of undiluted samples. FI supplementation of HES 450, HES 220, HES 130 and albumin-diluted samples only partially restored alpha, A and G-values compared to undiluted samples. FIIa addition only improved clot propagation and strength in albumin-diluted samples. FXIIIa supplementation improved propagation in samples diluted with HES 450, HES 220 and albumin, and clot strength improved in HES 450 and albumin-diluted plasma. Considered as a whole, these data support compromise of FIIa-FI and FXIIIa--fibrin polymer interactions as the mechanisms by which colloids compromise plasma coagulation. Investigation to determine if clinical enhancement of FXIII activity and/or FI concentration (e.g. fresh-frozen plasma, cryoprecipitate) can attenuate colloid-mediated decreases in hemostasis is warranted.

Background: Thrombelastography (TEG) is used to assess coagulopathy. However, a comprehensive characterization of the effects of specific coagulation factor deficiencies and mode of activation on TEG data does not exist., Methods: Thrombelastography was performed for 15 min with control plasma and plasmas deficient (<1% activity) in Factors II, V, VII, VIII, IX, X, XI, XII, or XIII activated with celite (0.28 mg ml(-1)) or tissue factor (TF, 0.1%) (n = 6 per condition). Additional fibrinogen concentration activity (75-345 mg dl(-1)) and Factor II, VII, X and XII activity-response relationships (1%, 6.25%, 12.5%, 25%, 50% and 100% activity) were obtained (n = 8 per condition). Thrombelastography parameters included reaction time (R), angle (alpha), and clot strength (A, amplitude; G, elastic modulus)., Results: Celite activation of FXII-deficient plasma, TF activation of FVII-deficient and FX-deficient plasma, and celite or TF activation of FII-deficient plasma resulted in an almost undetectable clot. Compared to control values, celite activation of plasmas deficient in FXI, FIX and FVIII resulted in prolonged R and decreased alpha values, whereas TF activation resulted in decreased alpha values. Celite and TF activation of FV-deficient plasma resulted in prolonged R and decreased alpha values, whereas FXIII-deficient plasma had decreased alpha, A and G-values compared to control values., Conclusions: The fundamental finding of this study is that coagulation factor deficiencies affect TEG parameters in both a factor-dependent and activation-dependent fashion. Utilizing both celite and TF activation improves the diagnostic power of TEG. Based on such TEG data, more targeted administration of blood products could potentially help improve perioperative hemostatic outcomes.

Abstract: The dog is an important companion animal and also purpose‐bred for research studies. Coagulopathies in dogs are common, although the availability of blood products for therapy is inconsistent throughout the profession. A pro‐coagulant therapeutic that is readily available and easily stored would be useful for the treatment of coagulopathies. Tricarbonyldichlororuthenium (II) dimer [Carbon monoxide‐releasing molecule‐2 (CORM‐2)] acts as a prothrombotic agent in plasma by increasing the velocity of clot formation and clot strength, and by decreasing the clot's vulnerability to fibrinolysis. We sought to test CORM‐2's effect on coagulation and fibrinolysis in vitro in canine plasma using thromboelastography. Measures of the rate of clot formation and clot strength in plasma without CORM‐2 were highly correlated with fibrinogen concentration. We found that CORM‐2 significantly enhanced the rate of clot formation and clot strength and significantly reduced the rate of fibrinolysis and the clot lysis time. The per cent change in rate of clot formation and clot strength was not significantly correlated with fibrinogen concentration, indicating that CORM‐2's pro‐coagulant effect is not dependent on fibrinogen concentration. This study corroborates studies in other species that show that CORM‐2 is pro‐coagulant in plasma, and lays the groundwork for developing CORM‐2 as a therapeutic agent for canine coagulopathies. Future studies will evaluate the effect of CORM‐2 on whole blood both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Several in vitro investigations have demonstrated that anticoagulant effects of fibrinogenolytic snake venom metalloproteinases have been abrogated in human plasma by modifying fibrinogen with iron (Fe) and carbon monoxide (CO) to prevent catalysis or by directly inhibiting these enzymes with CO. To translate these findings, we chose to assess the rabbit as a model of envenomation with Crotalus atrox venom. It was determined with thrombelastography that 15 times the concentration of venom noted to compromise coagulation in plasma in vitro was required to cause coagulopathy in vivo, likely secondary to venom binding to blood cells and being cleared from the circulation rapidly. Unlike human plasma, rabbit plasma pre-treated with Fe/CO was not protected from fibrinogenolysis by venom. Consequently, the administration of purified human fibrinogen (with or without Fe/CO) would be required before venom administration to rabbits. Of greater interest, venom exposed to CO had complete loss of fibrinogenolytic effect in rabbit plasma and partial loss of activity in whole blood, indicative of unbinding of CO from venom and binding to haemoglobin. Thus, venom exposed to CO could remain partially or completely inhibited in whole blood long enough for clearance from the circulation, allowing rabbits to be a useful model to test the efficacy of regional CO administration to the bite site. Future investigations are planned to test these novel approaches to attenuate venom-mediated coagulopathy in the rabbit. [ABSTRACT FROM AUTHOR]

Envenomation by haemotoxic enzymes remains a significant source of human morbidity and mortality worldwide, with administration of long-acting or multiple doses of antivenom first-line therapy. However, coagulopathy can still occur and recur. Of interest, it has been recently demonstrated that direct, isolated exposure of snake venom enzymes with fibrinogenolytic activity to carbon monoxide (CO) abrogates venom-mediated loss of coagulation in human plasma. These observations of CO inhibition of venom fibrinogenolytic activity were subsequently repeated in rabbit whole blood. This study sought to translate these findings in an in vivo rabbit model of envenomation with fibrinogenolytic Crotalus atrox venom. Sedated rabbits were intravenously administered C. atrox venom (400 lg/kg) pre-exposed to 0 or 1000 lM carbon monoxide-releasing molecule-2 (CORM-2) in vitro. Arterial whole-blood samples demonstrated that compared to pre-envenomation values, the CORM-2-na€ıve venom significantly prolonged the onset of coagulation, decreased the velocity of clot growth and decreased clot strength as determined by thromboelastography an hour after venom injection. In contrast, CORM-2 pre-exposure prevented or attenuated C. atrox venom effects on coagulation kinetics. Future studies to determine whether rabbits injected with such venom subcutaneously/intramuscularly can have consequent coagulopathy abrogated by injection of carbon monoxide-releasing molecules into the 'bite site' are justified. [ABSTRACT FROM AUTHOR]

Background: Viscoelastic testing is a method of hemostatic analysis that provides a real-time, holistic view of ex vivo clotting. It allows for examination of both cellular and plasma protein contributions to clotting including platelet number and function, fibrin(ogen) function, and coagulation factor function. The method assesses physical clot properties during the transition of blood from a liquid to a gel state, either by measurement of clot shear modulus using physical force transduction or by measurement of clot resonance frequency using sonometric interrogation. Results are reported in a live trace, with different trace parameters reflecting different contributors to hemostasis. These reported parameters vary between testing platforms.Results: In the United States, there are several commonly used Food and Drug Administration (FDA)-approved viscoelastic instruments available on the market. Those instruments that use sonometric clot assessment are more recently available and allow for improved portability for use near the patient's bedside. These instruments generally feature different reagent kits that allow more specific interrogation of different hemostatic pathways. Viscoelastic testing can predict the results of traditional plasma-based coagulation assays and has the added benefit of detecting hypercoagulability and severe hyperfibrinolysis. Implementation of viscoelastic testing in many clinical settings is becoming widespread and has proven to be efficacious in reducing blood transfusion rates in many settings. An impact on overall mortality and morbidity has not yet been demonstrated.Conclusion: This article provides a narrative review of the basic principles of viscoelastic testing, including the science and technology behind the method, as well as currently available testing platforms and reagents. [ABSTRACT FROM AUTHOR]

Background Functional Fibrinogen assay of the Thromboelastography (FFTEG), a whole blood viscoelastic hemostatic assay, has been used to estimate fibrinogen levels in adult patients undergoing major surgery but its performance in pediatric patients undergoing cardiac surgery requires evaluation. In this study, we evaluate the correlation between FFTEG parameters and standard laboratory tests for fibrinogen and platelet counts before and after cardiopulmonary bypass in children undergoing repair for congenital heart disease. Methods In this prospective observational study, whole blood samples were obtained from children less than 5 years of age undergoing congenital heart surgery with cardiopulmonary bypass before surgical incision and immediately after administration of protamine. Blood samples were analyzed for Thromboelastography, Functional Fibrinogen level measured by FFTEG (FLEV), complete blood counts with platelet count and plasma fibrinogen assay (LFib, Clauss). The primary outcome of this study was to assess the correlation between FFTEG parameters, LFib and platelet counts in neonates, infants, and small children less than 5 years old. Additionally, we studied if postbypass FFTEG parameters could predict critical thresholds of hypofibrinogenemia LFib ≤200 mg•dl-1. Results One hundred and five children (22 neonates, 51 infants, and 32 small children) were included in the final analysis. FLEV estimated higher fibrinogen levels than LFib in all patients. Before bypass, FLEV was on average 133 mg•dl-1 higher than LFib (95% confidence interval, CI, 116-150, P < 0.001) for all the patients; after bypass, FLEV was 48 mg•dl-1 (95% CI: 37-59, P < 0.001) higher than LFib for all the patients. Linear correlation coefficients between FLEV and LFib in all patients were R = 0.41 (95% CI: 0.24-0.56, P < 0.001) before bypass and increased to R = 0.63 (95% CI: 0.51-0.74, P < 0.001) after bypass. Bland Altman analysis performed on postbypass values of FLEV and LFib showed a positive bias of FLEV in estimation of LFib. The magnitude and the variability of the bias for all the patients group was decreased with lower mean of the difference of FLEV and LFib when the average values of FLEV and LFib were <200 mg•dl-1. Low linear correlations were noticed between maximal amplitude of platelet contribution to FFTEG and platelet counts both before and after bypass. For predicting the clinical thresholds of postbypass hypofibrinogenemia at plasma fibrinogen levels ≤200 mg•dl-1, FLEV and maximal amplitude of the fibrinogen clot generated area under receiver operative curves at 0.90 (95% CI = 0.76-1.0) in neonates, 0.6 (95% CI- 0.42-0.78) in infants, and 0.97 (95% CI = 0.91-1.0) in small children. Based on the receiver operative curves, values of postbypass hypofibrinogenemia with LFib ≤200 g•dl-1 corresponded to cutoffs of FLEVPOST ≤245 mg•dl-1 and maximal amplitude of the fibrinogen clot ≤13.4 mm. Conclusion In pediatric patients undergoing cardiac surgery, FLEV derived from Functional Fibrinogen correlated linearly with plasma fibrinogen levels (Clauss) both before and after CPB. FLEV estimation of plasma fibrinogen was improved after CPB in neonates, infants, and small children. After CPB, FFTEG can be used to predict laboratory diagnosis of critical hypofibrinogenemia (≤200 mg•dl-1) during pediatric cardiac surgery. Further studies are required to assess the impact of predictability of FFTEG on component transfusion during pediatric cardiac surgery. [ABSTRACT FROM AUTHOR]

Background: Operative treatment of craniosynostosis is associated with substantial blood loss, often requiring transfusion of packed red blood cells (PRBC) and coagulation products. Aims: The aim of this prospective study was to analyze thromboelastographic (TEG) parameters and platelet fibrinogen product to determine predictors of substantial blood loss, and the need for PRBC transfusion and coagulation products. Methods: With IRB approval, we enrolled 120 children undergoing craniosynostosis repair with a standardized anesthetic, fluid management, and TEG measurements at predefined times. Outcomes of interest were intraoperative blood loss, and need for PRBC transfusion and coagulation products. Multivariable logistic regression and receiver operating characteristic (ROC) curve analysis was applied to determine independent predictors of substantial blood loss and need for coagulation products. Results: One hundred and eighteen children were included in the analysis. Forty-four required PRBC transfusion (median 26 ml kg 2-1; IQR: 22-42) with median blood loss of 56 ml kg 2-1 (IQR: 43-83). Factors associated with the PRBC transfusion included type of surgery, duration of surgery, and three TEG parameters, a-angle, MA, and K-time (all P < 0.001). A predictive algorithm was developed by subgroup analysis of cranial vault reconstruction (CVR) patients for substantial intraoperative blood loss (defined as ≥60 ml kg 2-1) and need for coagulation products with ROC-derived cut-off values: platelet fibrinogen product, <343; a-angle, <62°; MA, <55 mm; Ktime, >2.1 min. The best prognostic combination included at least two of these four predictors (sensitivity 89%, specificity 90%). Multivariable regression identified MA as the only independent predictor of coagulation product administration (P < 0.001) and ROC analysis identified MA <46 mm as the optimal cut-off (sensitivity 86%, specificity 94%). Conclusions: Risk for substantial intraoperative blood loss can be assessed using TEG parameters and platelet fibrinogen product, whereas the need for coagulation products is strongly related to low MA. Patients susceptible to substantial blood loss can be risk stratified based on their TEG/platelet fibrinogen product profile. [ABSTRACT FROM AUTHOR]

Congenital (hypo)dysfibrinogenemia patients may have obstetric complications during their pregnancies. This study aimed to evaluate thromboelastography ( TEG) as a potential tool for assessing the tendency for obstetric complications in those patients in a non-pregnant state. A total of 22 female subjects with congenital (hypo)dysfibrinogenemia were recruited. Nine subjects had histories of obstetric complications and the other 13 subjects had at least one uneventful pregnancy without obstetric complications as yet. Detailed clinical investigation and phenotype/genotype detection were carried out, and both kaolin-activated TEG and functional fibrinogen TEG ( FF- TEG) were applied in all subjects. Significant differences were identified in all TEG parameters except for R and angle between these two groups ( P < 0.05) by covariance analysis. Receiver operating characteristic ( ROC) analysis of discrimination between these two groups of patients was performed for TEG parameters. Significantly high odds ratio ( OR) of obstetric complications occurrence were demonstrated in K ≥ 3.8 min, maximum amplitude ( MA) ≤ 54.2 mm, comprehensive index (CI) ≤ −3 (11.67, 95% CI 1.527-89.121, P < 0.05 in all), and MA- CFF ≤ 12.1 mm (20.00, 95% confidence interval (95% CI) 1.967-203.322, P = 0.002). Moreover, MA- CFF had better prognostic performance, with a corresponding area under the receiver operating curve of 0.923 (range 0.815-1.031, P = 0.001). This study suggests that (hypo)dysfibrinogenemia patients with values outside of the cut-off values of TEG assays under non-pregnant state may have a higher risk of obstetric complications occurring when they are pregnant. No parameters under non-pregnant state in clinical laboratory have ever been reported to be risk factors for obstetric complication occurrence in (hypo)dysfibrinogenemia patients. This study explored such parameters in TEG assays and found that parameters of TEG assays under non-pregnant status might predict the occurrence of obstetric complications, which could provide physicians with important information about whether fibrinogen replacement therapy is required, so as to prevent the occurrence of obstetric complications, especially for patients who are asymptomatic in daily life. [ABSTRACT FROM AUTHOR]

The combined use of immunoadsorption (IA) and membrane filtration (MF) may markedly enhance removal of IgM and complement component C1q, supporting its use as an element of recipient desensitization in antibody-incompatible transplantation. However, coagulation factor removal may contribute to altered hemostasis, posing a risk of bleeding in the perioperative setting. This secondary endpoint analysis of standard coagulation assays and rotational thromboelastometry ( ROTEM®) was performed in the context of a randomized controlled crossover study designed to assess the effect of combined IA (GAM-146-peptide) and MF on levels of ABO antigen-specific IgM. Fourteen patients with autoimmune disorders were randomized to a single treatment with IA+MF followed by IA alone, or vice versa. MF was found to markedly enhance fibrinogen depletion (57% vs. 28% median decrease after IA alone, P < 0.001), whereby four patients showed post-treatment fibrinogen concentrations below 100 mg dL−1. In support of a critical contribution of fibrinogen depletion to impaired coagulation, extrinsically activated ROTEM® analysis revealed a marked reduction in fibrinogen-dependent clot formation upon IA+MF (59% median decrease in FIBTEM mean clot firmness (MCF) as compared to 24% after IA alone, P < 0.001). Moreover, the addition of MF led to a substantial prolongation of activated partial thromboplastin time, possibly due to depletion of macromolecular coagulation factors contributing to intrinsically activated coagulation. Our study demonstrates substantial effects of combined IA+MF on clot formation, which may be mainly attributable to fibrinogen depletion. We suggest that the use of combined apheresis in the setting of transplant surgery may necessitate a careful monitoring of coagulation. J. Clin. Apheresis 31:29-37, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Introduction Bleeding symptoms in severe thrombocytopenia range from mild to severe. The aim of this in vitro study was to improve blood clotting and protect against fibrinolysis in reconstituted severe thrombocytopenia blood. Methods Thrombocytopenia [(16 ± 4) × 106/mL] was created by high-speed centrifugation of normal blood with subsequent mixing plasma with packed cells. The blood samples were subjected to clotting by CaCl2 and tissue factor and to fibrinolysis by the addition of tissue plasminogen activator. Blood was spiked with fibrinogen, activated prothrombin complex concentrate ( FEIBA), thrombin activatable fibrinolysis inhibitor ( TAFI), or their combinations. To mimic the situation that may occur in patients subjected to massive transfusion of plasma substitutes, blood was diluted by 40% of TRIS/saline buffer. Clotting time ( CT), α-Angle, maximum clot firmness ( MCF), and lysis onset time ( LOT) were evaluated using rotation thromboelastometry. Results Spiking thrombocytopenia blood with FEIBA led to reduction of CT. Fibrinogen and FEIBA enhanced α-Angle and MCF both in the absence and in the presence of tPA. LOT values were prolonged by TAFI and to less extent by FEIBA. Dilution of thrombocytopenia blood was followed by reduction of α-Angle and MCF compared to nondiluted blood which partly reversed by either fibrinogen or FEIBA being higher using fibrinogen and FEIBA together. Clot strength was enhanced, and fibrinolysis was inhibited by TAFI. Conclusion The results of this study suggest that combined spiking of blood with fibrinogen and FEIBA may be enough to correct the clot formation disorder in severe thrombocytopenia, whereas in thrombocytopenia and blood dilution, additive inhibition of fibrinolysis may be needed. [ABSTRACT FROM AUTHOR]

Background Postpartum hemorrhage is a potentially life-threatening albeit preventable condition that persists as a leading cause of maternal death. Identification of safe and cost-effective hemostatic treatment options remains crucial as a supplement to surgery and uterotonic agents. Objective This review summarizes the background, current evidence and recommendations with regard to the role of fibrinogen, tranexamic acid, prothrombin complex concentrate, desmopressin, and recombinant factor VIIa in the treatment of patients with postpartum hemorrhage. The benefits and evidence behind traditional standard laboratory tests and viscoelastic hemostatic assays, i.e. thromboelastography TEG® and thromboelastometry ROTEM®, are discussed. In addition we assess and elaborate on the current paradigm and evidence for transfusion of these patients. Data sources Publications between 1994 and 2014 were identified from PubMed, EMBASE, Cochrane Library databases, and ClinicalTrial.gov. Results Viscoelastic hemostatic assays were found to provide a real-time continuum of coagulation and fibrinolysis when introduced as a supplement in transfusion management of postpartum hemorrhage. Fibrinogen should be considered when hypofibrinogenemia is identified. Early administration of 1-2 g tranexamic acid is recommended, followed by an additional dose in cases of ongoing bleeding. Uncontrolled hemorrhage requires early balanced transfusion. Conclusion Despite the lack of conclusive evidence for optimal hemostatic resuscitation in postpartum hemorrhage, the use of viscoelastic hemostatic assays, fibrinogen, tranexamic acid and balanced transfusion therapy may prove to be potentially pivotal in the treatment of postpartum hemorrhage. [ABSTRACT FROM AUTHOR]

Background Blastomycosis is a potentially fatal fungal disease that most commonly affects humans and dogs. The organism causes systemic inflammation and has a predilection for the lungs. The inflammation might lead to a hypercoagulable state with microemboli in the pulmonary circulation which could contribute to inadequate oxygen exchange in infected dogs. Hypothesis/Objectives Dogs with blastomycosis will be hypercoagulable compared with healthy case-matched controls. Animals Client-owned dogs with a diagnosis of blastomycosis (n = 23) and healthy case-matched controls (n = 23). Methods Prospective case-controlled study of client-owned dogs presented to a veterinary teaching hospital with clinical signs compatible with blastomycosis. Complete blood counts, fibrinogen, PT, aPTT, thromboelastometry ( TE), thrombin antithrombin complexes ( TAT), and thrombin generation were evaluated. Results Cases had a leukocytosis compared with controls [mean (SD) 16.6 (7.6) × 103/μL versus 8.2 (1.8) × 103/μL, P < .001], hyperfibrinogenemia [median 784 mg/dL, range 329-1,443 versus median 178 mg/dL, range 82-257, P < .001], and increased TAT concentrations [mean (SD) 9.0 (5.7) μg/L versus 2.0 (2.8) μg/L, P < .001]. As compared to controls, cases were also hypercoagulable as evaluated by thromboelastometry and had increased in vitro thrombin generation on calibrated automated thrombography. Conclusions and Clinical Importance Hypercoagulability occurs in dogs with systemic blastomycosis. Additional studies are needed to explore a possible contribution of thrombogenicity to the clinical manifestations of systemic blastomycosis. [ABSTRACT FROM AUTHOR]

Fibrinogen plays a critical role in achieving and maintaining hemostasis and is fundamental to effective clot formation. There is increasing awareness of the important role of fibrinogen as a key target for the treatment and prevention of acquired bleeding. Fibrinogen is the first coagulation factor to fall to critically low levels (<1.0 g/L) during major hemorrhage (normal plasma fibrinogen levels range from 2.0 to 4.5 g/L), and current guidelines recommend maintaining the plasma fibrinogen level above 1.5 g/L. Fibrinogen supplementation can be achieved using plasma or cryoprecipitate; however, there are a number of safety concerns associated with these allogeneic blood products and there is a lack of high-quality evidence to support their use. Additionally, there is sometimes a long delay associated with the preparation of frozen products for infusion. Fibrinogen concentrate provides a promising alternative to allogeneic blood products and has a number of advantages: it allows a standardized dose of fibrinogen to be rapidly administered in a small volume, has a very good safety profile, and is virally inactivated as standard. Administration of fibrinogen concentrate, often guided by point-of-care viscoelastic testing to allow individualized dosing, has been successfully used as hemostatic therapy in a range of clinical settings, including cardiovascular surgery, postpartum hemorrhage, and trauma. Results show that fibrinogen concentrate is associated with a reduction or even total avoidance of allogeneic blood product transfusion. Fibrinogen concentrate represents an important option for the treatment of coagulopathic bleeding; further studies are needed to determine precise dosing strategies and thresholds for fibrinogen supplementation. [ABSTRACT FROM AUTHOR]

Background: Acquired deficiency of FXIII because of perioperative hemodilution has been described several times in adults; however, data in children are scarce. We performed a prospective observational trial to evaluate the intraoperative course of FXIII in children undergoing elective major surgery. Methods: Blood samples were repeatedly taken from 46 children aged 0.3-16 years undergoing major surgery. Concentrations of FXIII and fibrinogen, thrombelastometry by ROTEM®, and cell count were assessed intraoperatively. Results: A significant decrease in FXIII concentration (median 60%; IQR 49-69%) was already noted at beginning of surgical procedures, while most ROTEM® traces remain unchanged. FXIII levels further deteriorated intraoperatively to minimal levels of 33% (15-61%). Lowest intraoperative clot strength (ExTEM) was 44 mm (34-50 mm), and fibrinogen plasma levels decreased to minimal levels of 130 mg·dl−1 (95-160 mg·dl−1). In 43 of 46 children, transfusion therapy was necessary. Despite of transfusion of fresh frozen plasma (cumulative total dose 22 ml·kg−1 [11-32 ml·kg−1]) in 21 of 46 children, FXIII level remains low in all children till the end of surgery at levels of 39% (20-46%). Conclusions: Coagulation factor XIII decreased early during major surgery owing to hemodilution. Overall intraoperative FXIII levels remain low despite of transfusion of fresh frozen plasma. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To identify the factors influencing blood loss and secondary blood transfusion and to investigate the outcomes of patients who underwent a massive blood transfusion (MBT) following living donor liver transplantation (LDLT). METHODS: Patients who underwent primary adult-to-adult right hepatic lobe LDLT were included in the study, and were divided into the MBT group [≥ 6 red blood cell (RBC) units in 24 h] and the non-massive blood transfusion (NMBT) group (< 6 RBC units in 24 h). All potential risk factors, length of intensive care unit (ICU) stay and long-term survival rate of the patients in the two groups were analyzed. RESULTS: The data of 181 eligible patients were retrospectively analyzed. A decreased long-term survival rate, a higher incidence of postoperative infection and prolonged ICU stay were observed in the MBT group. No significant difference was observed in survival rate between patients having platelet transfusion > 2 units and ≤ 2 units. Hemoglobin < 100 g/L, platelet counts < 70 × 109/L, fibrinogen level < 1.5 g/L and history of upper abdominal surgery were found to be independent risk factors. CONCLUSIONS: Blood transfusion during LDLT can be predicted using preoperative variables. Massive RBC transfusion may lead to poor long-term survival, higher postoperative infection rate and prolonged ICU stay. Platelet transfusion may not be a risk factor for long-term survival. [ABSTRACT FROM AUTHOR]

Background: Hydroxyethyl starches (HES) could differ with regard to the origin, and the influence on the coagulation of the raw material is unknown. This study compared the effects of a new potato-derived HES with a maize-derived HES and two crystalloid solutions. Methods: Whole blood from 10 healthy individuals was diluted by 20% and 40% using either non-balanced potato-derived HES 130/0.42/6 : 1, non-balanced maize-derived HES 130/0.4/9 : 1, isotonic saline or Ringer's lactate solution. Samples were analysed by thromboelastometry ROTEM®: Coagulation was initiated by acid ellagic [intrinsic thromboelastometry (INTEM)] or tissue factor (extrinsic thromboelastometry) with and without cytochalasin to determine the functional component of fibrinogen [cytochalasin-d-modified thromboelastometry (FIBTEM)]. Platelet count and fibrinogen activity were measured. Results: No effect of raw material was found as no difference was detected among the HES solutions. Whatever the solution, progressive haemodilution impaired haemostasis in a dose-dependant manner: For INTEM, the clot formation time was increased up to 308% and the maximum clot firmness (MCF) was decreased down to 49%. As dilution increased, initiation of coagulation was also impaired. Thromboelastometric alterations were more severe with HES than with crystalloids, especially regarding fibrin polymerization explorations: MCF of FIBTEM was considerably reduced from 12[10-14] to 2[2-3] mm ( P<0.05). Fibrinogen activity and platelet count were reduced by dilution in a dose-dependant manner and decreased similarly in all groups. Conclusion: Maize- and potato-derived HES have similar effects on coagulation. Both the starch preparations tested lead to more severe haemostatic defects than crystalloids, and impairment of fibrin polymerization appears to be a leading determinant of this coagulopathy. [ABSTRACT FROM AUTHOR]

Objectives: Despite aggressive measures to miniaturize the cardiopulmonary bypass (CPB) circuit in neonates and infants, the CPB prime volume is often at least as large as the patients’ blood volume. We conducted an observational study to characterize the hemostatic consequences of a CPB prime consisting of either non-fresh or reconstituted whole blood. Methods: Hematocrit, fibrinogen, platelet count, plasminogen, anti-thrombin III (AT-III), and factors (F) II, V, VII, IX, and X of 30 neonates and infants undergoing cardiac surgery with CPB utilizing either a non-fresh or reconstituted whole blood prime were prospectively evaluated at eight time points. Following protamine administration, microvascular bleeding was treated by protocol. Results: The hemostatic composition of the CPB prime was the same following the use of either non-fresh or reconstituted whole blood. The CPB prime platelet count (mean ± sd) was 5.87 ± 2.84 × 103 μl−1 when compared to a preoperative platelet count of 298 ± 142 × 103 μl−1 ( P < 0.0001). Twenty patients received 17.3 ± 9.2 ml·kg−1 (0.86 ± 0.46 units·kg−1) of platelets with significant improvement in platelet count. Nine patients received 16.7 ± 13.4 ml·kg−1 (0.84 ± 0.67 units·kg−1) of cryoprecipitate with significant improvements in FVIII and fibrinogen. Conclusions: Non-fresh or reconstituted whole blood as a component of a small volume CPB prime in neonates and infants induces clinically significant dilutional thrombocytopenia in conjunction with less significant reductions in fibrinogen, FII, FV, FVII, FVIII, FIX, FX, plasminogen, and AT-III. [ABSTRACT FROM AUTHOR]

Background: Gelatin solution impairs coagulation. The mechanism of coagulopathy is incompletely defined. The purpose of this study was to evaluate the capacity of single coagulation factors to reverse gelatin-promoted whole-blood coagulation disorders in vitro. Methods: Venous blood was withdrawn from 12 volunteers in a crossover study. Four percent succinylated gelatin was added to citrated whole-blood samples to make a 40 vol% end-concentration of gelatin. The baseline and 40 vol% samples, and samples with addition of fresh-frozen plasma (FFP), fibrinogen, coagulation factors XIII (FXIII) or VIII, together with the von Willebrand factor (FVIII+vWF), were analysed by thromboelastometry (ROTEM®). Coagulation was initiated by tissue thromboplastin (ExTEM®) with and without cytochalasin to determine the functional component of fibrinogen (FibTEM®). Results: Initiation of coagulation and fibrin formation were delayed at 40 vol% gelatin dilution. At this stage, the median (25th–75th percentiles) maximum clot firmness (MCF) was 76.3 (65.9–80.0) and 32.5 (27.4–45.0)% of the pre-dilution value in ExTEM® and FibTEM® thromboelastometry, respectively. Coagulation time was corrected by addition of fibrinogen and FFP in ExTEM® and FibTEM® analysis, whereas FVIII or FXIII had minimal effects. MCF was partly restored only by FFP in ExTEM®. In FibTEM® analysis, MCF improved more by fibrinogen than by FVIII+VWF, FXIII or FFP. Conclusions: Gelatin-induced whole-blood coagulation disorder in vitro is mainly dependent on the initial fibrinogen–fibrin interaction. The proposed mechanism might suggest not to reverse gelatin coagulopathy solely by fibrinogen administration. The administration of FFP, a mixture of different coagulation factors, reversed the gelatin-induced in vitro coagulopathy the best. [ABSTRACT FROM AUTHOR]

Glanzmann thrombasthenia (GT) is a rare platelet function disorder characterized by a defect in fibrinogen binding to platelet membrane glycoprotein (GP) IIb/IIIa. Recombinant FVIIa (rFVIIa) is a haemostatic agent approved for the treatment of haemophilia patients with inhibitors, patients with acquired haemophilia and in EU also for treatment of factor VII (FVII)-deficient patients and GT patients with antibodies to GPIIb-IIIa. The present study was conducted to evaluate the use of the whole blood test system, rotational thrombelastometry (ROTEM), in measuring the overall haemostasis potential of rFVIIa in 28 GT patients treated with rFVIIa. The correlation of administered rFVIIa and time to start fibrin formation and clot dynamic/stability was assessed and correlation to the clinical response was elucidated. Assessments were performed on predose blood samples spiked with four different concentrations of rFVIIa and whole blood samples taken at 10 and 120 min following dosing. ROTEM parameters clotting time (CT), clot formation time (CFT) and maximum clot firmness (MCF) were measured. Both ex vivo and in vivo data showed beneficial effects on CT in the presence of rFVIIa, but no effect of added rFVIIa was seen on CFT and MCF. In conclusion, the use of thrombelastography at least in the modified form of ROTEM seems to be of limited use in predicting an adequate dose of rFVIIa in GT patients. A good clinical haemostatic response was recorded in spite of the limited changes in the ROTEM pattern supporting the conclusion that ROTEM should not be the method of choice for monitoring rFVIIa therapy in Glanzmann patients. [ABSTRACT FROM AUTHOR]

Background: Hydroxyethyl starch (HES) administration has resulted in decreased hemostasis and fibrinogen (FI)-thrombin-(FIIa)-Factor XIII (FXIII) interactions. I proposed to determine the hemostatic effect of hemodilution with PentaLyte® (6% HES, mean molecular weight 220 kDa) and Voluven® (6% HES, 130 kDa). Methods: Rabbits were intravenously administered 20 ml/kg PentaLyte® or Voluven® ( n = 8 per fluid) over 10 min. Plasma was obtained prior to, 1 min and 1 h after hemodilution. Thrombelastography was performed, with clot initiation (R, sec), clot propagation (α, degrees), and clot strength (shear elastic modulus, G, dynes/cm2) determined over 20 min. Celite-activated samples had either no additions or addition of FI, FIIa or activated FXIII (FXIIIa) to restore protein content to pre-diluted values. Results and conclusions: While there were no significant differences between the groups, R significantly decreased 1 h after hemodilution compared with values observed before and 1 min after hemodilution, whereas α and G significantly decreased 1 min after hemodilution and then significantly, but only partially, increased 1 h after hemodilution compared with pre-dilution values. Addition of FI, FIIa and FXIIIa significantly decreased R in both groups. α and G 1 min after hemodilution were significantly enhanced by FI, FIIa, FXIIIa in both groups; however, 1 h after hemodilution, rabbits administered PentaLyte® had α and G enhanced only by FI and FXIIIa addition, whereas animals administered Voluven® had α and G significantly enhanced by FI addition. PentaLyte® and Voluven® hemodilution initially diminishes FIIa-FI and FXIIIa-fibrin, but within an hour primarily inhibit FXIIIa-fibrin interactions in the rabbit. [ABSTRACT FROM AUTHOR]

Thrombelastography (TEG®) is used to assess coagulopathy. However, a comprehensive characterization of the effects of specific coagulation factor deficiencies and mode of activation on TEG® data does not exist.Thrombelastography® was performed for 15 min with control plasma and plasmas deficient (<1% activity) in Factors II, V, VII, VIII, IX, X, XI, XII, or XIII activated with celite (0.28 mg ml−1) or tissue factor (TF, 0.1%) (n = 6 per condition). Additional fibrinogen concentration activity (75–345 mg dl−1) and Factor II, VII, X and XII activity-response relationships (1%, 6.25%, 12.5%, 25%, 50% and 100% activity) were obtained (n = 8 per condition). Thrombelastography® parameters included reaction time (R), angle (α), and clot strength (A, amplitude; G, elastic modulus).Celite activation of FXII-deficient plasma, TF activation of FVII-deficient and FX-deficient plasma, and celite or TF activation of FII-deficient plasma resulted in an almost undetectable clot. Compared to control values, celite activation of plasmas deficient in FXI, FIX and FVIII resulted in prolonged R and decreasedα values, whereas TF activation resulted in decreasedα values. Celite and TF activation of FV-deficient plasma resulted in prolonged R and decreasedα values, whereas FXIII-deficient plasma had decreasedα, A andG-values compared to control values.The fundamental finding of this study is that coagulation factor deficiencies affect TEG® parameters in both a factor-dependent and activation-dependent fashion. Utilizing both celite and TF activation improves the diagnostic power of TEG®. Based on such TEG® data, more targeted administration of blood products could potentially help improve perioperative hemostatic outcomes. [ABSTRACT FROM AUTHOR]