The Experts below are selected from a list of 309 Experts worldwide ranked by ideXlab platform
Enny Sorense - One of the best experts on this subject based on the ideXlab platform.
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effects of Fibrinogen concentrate as first line therapy during major aortic replacement surgery a randomized placebo controlled trial
Anesthesiology, 2013Co-Authors: Niels Rahemeye, Enny Sorense, Cristina Solomo, Christia Hagl, Alexande A Hanke, Dirk S Schmid, Dietrich Knoerze, Gerald Hochleitne, Maximilia PichlmaieAbstract: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.
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clinical effectiveness of fresh frozen plasma compared with Fibrinogen concentrate a systematic review
Critical Care, 2011Co-Authors: Sibylle Kozeklangenecke, Enny Sorense, John R Hess, Dona R SpahAbstract:Haemostatic therapy in surgical and/or massive trauma patients typically involves transfusion of fresh frozen plasma (FFP). Purified human Fibrinogen concentrate may offer an alternative to FFP in some instances. In this systematic review, we investigated the current evidence for the use of FFP and Fibrinogen concentrate in the perioperative or massive trauma setting. Studies reporting the outcome (blood loss, transfusion requirement, length of stay, survival and plasma Fibrinogen level) of FFP or Fibrinogen concentrate administration to patients in a perioperative or massive trauma setting were identified in electronic databases (1995 to 2010). Studies were included regardless of type, patient age, sample size or duration of patient follow-up. Studies of patients with congenital clotting factor deficiencies or other haematological disorders were excluded. Studies were assessed for eligibility, and data were extracted and tabulated. Ninety-one eligible studies (70 FFP and 21 Fibrinogen concentrate) reported outcomes of interest. Few were high-quality prospective studies. Evidence for the efficacy of FFP was inconsistent across all assessed outcomes. Overall, FFP showed a positive effect for 28% of outcomes and a negative effect for 22% of outcomes. There was limited evidence that FFP reduced mortality: 50% of outcomes associated FFP with reduced mortality (typically trauma and/or massive bleeding), and 20% were associated with increased mortality (typically surgical and/or nonmassive bleeding). Five studies reported the outcome of Fibrinogen concentrate versus a comparator. The evidence was consistently positive (70% of all outcomes), with no negative effects reported (0% of all outcomes). Fibrinogen concentrate was compared directly with FFP in three high-quality studies and was found to be superior for > 50% of outcomes in terms of reducing blood loss, allogeneic transfusion requirements, length of intensive care unit and hospital stay and increasing plasma Fibrinogen levels. We found no Fibrinogen concentrate comparator studies in patients with haemorrhage due to massive trauma, although efficacy across all assessed outcomes was reported in a number of noncomparator trauma studies. The weight of evidence does not appear to support the clinical effectiveness of FFP for surgical and/or massive trauma patients and suggests it can be detrimental. Perioperatively, Fibrinogen concentrate was generally associated with improved outcome measures, although more high-quality, prospective studies are required before any definitive conclusions can be drawn.
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Fibrinogen estimates are influenced by methods of measurement and hemodilution with colloid plasma expanders
Transfusion, 2010Co-Authors: Christia Fengererikse, Jorge Ingerslev, Gary W Moore, Savita Rangaraja, Enny SorenseAbstract:BACKGROUND: Measurement of plasma Fibrinogen is often required in critically ill patients or massively bleeding patients being resuscitated with colloid plasma expander. This study aimed at evaluating different assays of plasma Fibrinogen after in vitro dilution with commonly used plasma expanders and challenged the hypothesis that levels of Fibrinogen are estimated significantly higher in plasma diluted with colloid plasma expander compared with isotonic saline. STUDY DESIGN AND METHODS: Fibrinogen measurements were established in plasma samples each diluted in vitro to 30 or 50% with isotonic saline, hydroxyethyl starch (HES) 130/0.4, and human albumin. Fibrinogen levels were assessed using an antigen determination, three photo-optical Clauss methods, one mechanical Clauss method, a prothrombin-derived method, and viscoelastic measurement through thromboelastometry. RESULTS: Measurement of Fibrinogen levels was significantly different when performed on alternate analytical platforms. By 30 and 50% dilution with HES 130/0.4 coagulation analyzers using the photo-optical Clauss methods significantly overestimated levels of Fibrinogen. Dilution with human albumin did not affect Fibrinogen levels except from one analyzer by 50% dilution level. Viscoelastic measurement of fibrin polymerization was reduced at both dilution levels and appeared to reflect the impairment of fibrin polymerization induced by HES 130/0.4 and to a lesser extent human albumin. CONCLUSION: This study demonstrated that different automated coagulation analyzers revealed significantly different levels of Fibrinogen. The presence of colloid plasma expander gave rise to erroneous high levels of Fibrinogen returned from some coagulation analyzers employing the method of Clauss.
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a critical evaluation of cryoprecipitate for replacement of Fibrinogen
British Journal of Haematology, 2010Co-Authors: Enny Sorense, David EvaAbstract:Maintaining the plasma Fibrinogen concentration is important to limit excessive perioperative blood loss. This article considers the evidence for this statement, and questions the justification for using cryoprecipitate rather than virus-inactivated Fibrinogen concentrate to support plasma Fibrinogen levels. Haemophilia was historically treated with cryoprecipitate, but specific coagulation factor concentrates are now preferred. In contrast, primary fractions of allogeneic donor blood, including cryoprecipitate, are still commonly used to treat perioperative bleeding. When compared with cryoprecipitate and fresh-frozen plasma (FFP), freeze-dried Fibrinogen concentrate offers standardized Fibrinogen content, faster reconstitution and improved efficacy. Pasteurization and purification processes employed in the preparation of Fibrinogen concentrate reduce the risk of pathogen transmission and immune-mediated complications, in comparison with cryoprecipitate and FFP. When all costs associated with administration are taken into consideration, the cost of Fibrinogen concentrate is not substantially different to that of cryoprecipitate. In conclusion, wider availability and use of Fibrinogen concentrate may improve the management of perioperative bleeding. Further benefits may accrue from more rapid and accurate techniques for monitoring Fibrinogen levels. Clinical studies are needed to evaluate methods of measuring Fibrinogen and assessing fibrin polymerization, and to define critical haemostatic plasma Fibrinogen concentrations in different perioperative situations.
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Fibrinogen concentrate substitution therapy in patients with massive haemorrhage and low plasma Fibrinogen concentrations
BJA: British Journal of Anaesthesia, 2008Co-Authors: Christia Fengererikse, Enny Sorense, M Lindberglarse, A Q Christense, Jorge IngerslevAbstract:Abstract Background Patients experiencing massive haemorrhage are at high risk of developing coagulopathy through loss, consumption, and dilution of coagulation factors and platelets. It has been reported that plasma Fibrinogen concentrations may reach a critical low level relatively early during bleeding, calling for replacement Fibrinogen therapy. Cryoprecipitate has been widely used in the past, but more recently, a pasteurized Fibrinogen concentrate has become available. We audited the effects of Fibrinogen concentrate therapy on laboratory and clinical outcome in patients with massive haemorrhage. Methods We identified 43 patients over the previous 2 yr to whom a Fibrinogen concentrate had been administered as treatment for hypoFibrinogenaemia during serious haemorrhage. Platelet count, P-Fibrinogen, activated partial thromboplastin time (APTT), prothrombin time (PT), D-dimer, and volume of blood lost were obtained from medical and laboratory records. Numbers of units of red blood cells (RBC), fresh frozen plasma (FFP), and pooled platelet concentrates were recorded before and after Fibrinogen substitution. Results A significant increase in plasma Fibrinogen concentration was observed after Fibrinogen concentrate therapy. Platelet counts and fibrin D-dimer values remained unchanged, whereas the APTT and PT improved significantly. Requirements for RBC, FFP, and platelets were significantly reduced. Blood loss decreased significantly. Conclusions Off-label substitution therapy with a Fibrinogen concentrate generally improved global laboratory coagulation results and as supplementary intervention, appeared to diminish the requirements for RBC, FFP, and platelet substitution in this patient cohort.
Jerrold H Levy - One of the best experts on this subject based on the ideXlab platform.
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how i use Fibrinogen replacement therapy in acquired bleeding
Blood, 2015Co-Authors: Jerrold H Levy, Lawrence T GoodnoughAbstract:Fibrinogen is a critical protein for hemostasis and clot formation. However, transfusion guidelines have variable recommendations for maintaining Fibrinogen levels in bleeding patients. An increasing number of studies support the practice of Fibrinogen replacement therapy for acquired coagulopathies, and additional studies are underway. Fibrinogen therapy can be administered with cryoprecipitate or Fibrinogen concentrates, and clinical practice varies according to their availability and licensing status. Fibrinogen concentrate therapy has been studied in animal models and clinical trials and supports the critical role of Fibrinogen repletion in bleeding patients. Point-of-care testing will have an important role in guiding Fibrinogen replacement for hemostatic therapy in clinical settings such as cardiovascular surgery, postpartum hemorrhage, and trauma. Fibrinogen therapy is an important component of a multimodal strategy for the treatment of coagulopathic bleeding.
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Fibrinogen as a therapeutic target for bleeding a review of critical levels and replacement therapy
Transfusion, 2014Co-Authors: Jerrold H Levy, Ia J Welsby, Lawrence T GoodnoughAbstract: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.
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Fibrinogen and hemostasis a primary hemostatic target for the management of acquired bleeding
Anesthesia & Analgesia, 2012Co-Authors: Jerrold H Levy, Fania Szlam, Kenichi A Tanaka, Roman M SniecienskiAbstract:Fibrinogen plays several key roles in the maintenance of hemostasis. Its cleavage by thrombin and subsequent polymerization to form fibrin strands provides the structural network required for effective clot formation. During cases of acute blood loss, attempts to maintain circulating volume and tissue perfusion often involve the infusion of crystalloids, colloids, and red blood cells. Intravascular volume resuscitation, although vital, frequently results in dilution of the remaining clotting factors and onset of dilutional coagulopathy. In such cases, Fibrinogen is the first coagulation factor to decrease to critically low levels. There currently is a lack of awareness among physicians regarding the significance of Fibrinogen during acute bleeding and, at many centers, Fibrinogen is not monitored routinely during treatment. We reviewed current studies that demonstrate the importance of considering Fibrinogen replacement during the treatment of acquired bleeding across clinical settings. If depleted, the supplementation of Fibrinogen is key for the rescue and maintenance of hemostatic function; however, the threshold at which such intervention should be triggered is currently poorly defined. Although traditionally performed via administration of fresh frozen plasma or cryoprecipitate, the use of lyophilized Fibrinogen (concentrate) is becoming more prevalent in some countries. Recent reports relating to the efficacy of Fibrinogen concentrate suggest that it is a viable alternative to traditional hemostatic approaches, which should be considered. The prospective study of Fibrinogen supplementation in acquired bleeding is needed to accurately assess the range of clinical settings in which this management strategy is appropriate, the most effective method of supplementation and a comprehensive safety profile of Fibrinogen concentrate used for such an approach.
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finding the optimal concentration range for Fibrinogen replacement after severe haemodilution an in vitro model
BJA: British Journal of Anaesthesia, 2009Co-Authors: Daniel Bolliger, Jerrold H Levy, Fania Szlam, Ross J Molinaro, Niels Rahemeyer, Kenichi A TanakaAbstract:Background Replacement of Fibrinogen is presumably the key step in managing dilutional coagulopathy. We performed an in vitro study hypothesizing that there is a minimal Fibrinogen concentration in diluted whole blood above which the rate of clot formation approaches normal. Methods Blood samples from six healthy volunteers were diluted 1:5 v/v with saline keeping haematocrit at 24% using red cell concentrates. We measured coagulation factors and thrombin generation in plasma at baseline and after dilution. Thromboelastometry was used to evaluate (i) speed and quality of clot formation in diluted samples supplemented with Fibrinogen 50–300 mg dl −1 and (ii) clot resistance to fibrinolysis. Diluted and undiluted samples with no added Fibrinogen served as controls. Results Coagulation parameters and platelets were reduced by 74–85% after dilution. Peak thrombin generation was reduced by 56%. Adding Fibrinogen led to a concentration-dependent improvement of all thromboelastometric parameters. The half maximal effective concentration (EC50) for Fibrinogen replacement in haemodiluted blood was calculated to be 125 mg dl −1 . Adding tissue plasminogen activator, 0.15 μg ml −1 , led to a decrease of clot firmness and lysis time. Conclusions The target plasma concentration for Fibrinogen replacement was predicted by these in vitro results to be greater than 200 mg dl −1 as only these concentrations optimized the rate of clot formation. This concentration is twice the level suggested by the current transfusion guidelines. Although improved, clots were prone to fibrinolysis indicating that the efficacy of Fibrinogen therapy may be influenced by co-existing fibrinolytic tendency occurring during dilutional coagulopathy.
Susan T Lord - One of the best experts on this subject based on the ideXlab platform.
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recombinant Fibrinogen studies reveal that thrombin specificity dictates order of fibrinopeptide release
Journal of Biological Chemistry, 2000Co-Authors: Jennifer L Mullin, Oleg V Gorkun, Cameron G Binnie, Susan T LordAbstract:Abstract During cleavage of Fibrinogen by thrombin, fibrinopeptide A (FpA) release precedes fibrinopeptide B (FpB) release. To examine the basis for this ordered release, we synthesized A′β Fibrinogen, replacing FpB with a fibrinopeptide A-like peptide, FpA′ (G14V). Analyses of fibrinopeptide release from A′β Fibrinogen showed that FpA release and FpA′ release were similar; the release of either peptide followed simple first-order kinetics. Specificity constants for FpA and FpA′ were similar, demonstrating that these peptides are equally competitive substrates for thrombin. In the presence of Gly-Pro-Arg-Pro, an inhibitor of fibrin polymerization, the rate of FpB release from normal Fibrinogen was reduced 3-fold, consistent with previous data; in contrast, the rate of FpA′ release from A′β Fibrinogen was unaffected. Thus, with A′β Fibrinogen, fibrinopeptide release from the β chain is similar to fibrinopeptide release from the α chain. We conclude that the ordered release of fibrinopeptides is dictated by the specificity of thrombin for its substrates. We analyzed polymerization, following changes in turbidity, and found that polymerization of A′β Fibrinogen was similar to that of normal Fibrinogen. We analyzed clot structure by scanning electron microscopy and found that clots from A′β Fibrinogen were similar to clots from normal Fibrinogen. We conclude that premature release of the fibrinopeptide from the N terminus of the β chain does not affect polymerization of Fibrinogen.
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the contribution of the three hypothesized integrin binding sites in Fibrinogen to platelet mediated clot retraction
Blood, 1998Co-Authors: Michael M Rooney, David H Farrell, Bettien M. Van Hemel, Philip G De Groot, Susan T LordAbstract:Fibrinogen is a plasma protein that interacts with integrin α IIb β 3 to mediate a variety of platelet responses including adhesion, aggregation, and clot retraction. Three sites on Fibrinogen have been hypothesized to be critical for these interactions: the Ala-Gly-Asp-Val (AGDV) sequence at the C-terminus of the γ chain and two Arg-Gly-Asp (RGD) sequences in the Aα chain. Recent data showed that AGDV is critical for platelet adhesion and aggregation, but not retraction, suggesting that either one or both of the RGD sequences are involved in clot retraction. Here we provide evidence, using engineered recombinant Fibrinogen, that no one of these sites is critical for clot retraction; Fibrinogen lacking all three sites still sustains a relatively normal, albeit delayed, retraction response. Three Fibrinogen variants with the following mutations were examined: a substitution of RGE for RGD at position Aα 95-97, a substitution of RGE for RGD at position Aα 572-574, and a triple substitution of RGE for RGD at both Aα positions and deletion of AGDV from the γ chain. Retraction rates and final clot sizes after a 20-minute incubation were indistinguishable when comparing the Aα D97E Fibrinogen or Aα D574E Fibrinogen with normal recombinant Fibrinogen. However, with the triple mutant Fibrinogen, clot retraction was delayed compared with normal recombinant Fibrinogen. Nevertheless, the final clot size measured after 20 minutes was the same size as a clot formed with normal recombinant Fibrinogen. Similar results were observed using platelets isolated from an aFibrinogenemic patient, eliminating the possibility that the retraction was dependent on secretion of plasma Fibrinogen from platelet α-granules. These findings indicate that clot retraction is a two-step process, such that one or more of the three putative platelet binding sites are important for an initial step in clot retraction, but not for a subsequent step. With the triple mutant Fibrinogen, the second step of clot retraction, possibly the development of clot tension, proceeds with a rate similar to that observed with normal recombinant Fibrinogen. These results are consistent with a mechanism where a novel site on fibrin is involved in the second step of clot retraction.
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substitution of tyrosine for phenylalanine in fibrinopeptide a results in preferential thrombin cleavage of fibrinopeptide b from Fibrinogen
Biochemistry, 1998Co-Authors: Michael M Rooney, Jennifer L Mullin, Susan T LordAbstract:Phenylalanine at residue 8 in the Aα chain of Fibrinogen is a highly conserved amino acid that is believed to be critical for binding and catalysis by the serine protease thrombin. We have examined the requirement for Phe at this position by constructing a variant recombinant Fibrinogen with a conservative substitution of tyrosine for phenylalanine, Aα F8Y Fibrinogen. We found that the variant fibrinopeptide A (F8Y 1−16) was cleaved by thrombin, in contrast to the lack of cleavage of an Aα 1−23 peptide and an Aα 1−50 fusion protein with the same substitution. This result indicates that Fibrinogen residues other than Aα 1−50 participate in thrombin binding and Fibrinogen proteolysis. We found, for the first time, that thrombin-catalyzed lysis of the Fibrinogen Bβ chain preceded lysis of the Aα chain, such that fibrinopeptide B (FpB) was released prior to F8Y 1−16. Kinetic analysis demonstrated that F8Y 1−16 was a very poor substrate for thrombin, with a specificity constant 280-fold lower than normal fibri...
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the role of putative Fibrinogen aα bβ and γa chain integrin binding sites in endothelial cell mediated clot retraction
Journal of Biological Chemistry, 1997Co-Authors: Richard A Smith, Michael M Rooney, Susan T Lord, M W Mosesson, A U Daniels, Kent T GartnerAbstract:Abstract In this study, endothelial cell-mediated clot retraction was supported by fibrin generated from several purified fractions of plasma Fibrinogen, purified proteolytic fragments of plasma Fibrinogen, recombinant normal Fibrinogen, and recombinant variant Fibrinogen. These results were surprising because some of these Fibrinogens lack domains that are known binding sites for the integrin receptors that support clot retraction. Specifically, Fibrinogens lacking Aα-chain RGD residues at 572–574 or lacking the γ-chain residues AGDV 408–411 supported endothelial cell-mediated clot retraction as well as intact Fibrinogen. Thus, clot retraction mediated by endothelial cells is not dependent on either of these sites. A variety of monoclonal antibodies against the integrin αvβ3 partially inhibited the endothelial cell-mediated retraction of clots formed from plasma Fibrinogen. As expected, an antibody to the platelet integrin αIIbβ3 did not inhibit endothelial cell-mediated clot retraction. These results indicate that this retraction is mediated at least in part by αvβ3. These results support the conclusion that (a) neither of the two Fibrinogen cell binding sites described above is required to support clot retraction or that (b) either site alone or in conjunction with other fibrin(ogen) region(s) can support clot retraction. Thus, endothelial cell-mediated clot retraction appears to be dependent on Fibrinogen cell binding sites other than those required to support adhesion of resting platelets to immobilized Fibrinogen and platelet aggregation.
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dissecting clot retraction and platelet aggregation clot retraction does not require an intact Fibrinogen chain c terminus
Journal of Biological Chemistry, 1996Co-Authors: Michael M Rooney, Leslie V Parise, Susan T LordAbstract:Abstract Fibrinogen mediates the processes of platelet aggregation and clot retraction. Previous studies have demonstrated that Fibrinogen binding to the platelet receptor αβ requires the C-terminal residues of the Fibrinogen chain. We made a recombinant human Fibrinogen that lacks the chain C-terminal four residues (AGDV). As expected this Fibrinogen did not support platelet aggregation. Unexpectedly, this variant did support clot retraction that was indistinguishable from retraction with normal recombinant or plasma Fibrinogen. These results suggest that the site on Fibrinogen that is required for platelet aggregation differs from the site on fibrin that is required for clot retraction.
Nobuo Okumura - One of the best experts on this subject based on the ideXlab platform.
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fibrinopeptide a release is necessary for effective b b interactions in polymerisation of variant Fibrinogens with impaired a a interactions
Thrombosis and Haemostasis, 2012Co-Authors: Keisuke Soya, Fumiko Terasawa, Nobuo OkumuraAbstract:Fibrin polymerisation is mediated by interactions between knobs ‘A’ and ‘B’ exposed by thrombin cleavage, and holes ‘a’ and ‘b’. We demonstrated markedly delayed thrombin-catalysed fibrin polymerisation, through B:b interactions alone, of recombinant γD364H -Fibrinogen with impaired hole ‘a’. To determine whether recombinant variant Fibrinogens with no release of fibrinopeptide A (FpA) polymerise similarly to γD364H -Fibrinogen, we examined two variant Fibrinogens with substitutions altering knob ‘A’, Aα17A- and Aα17C-Fibrinogen. We examined thrombin- or batroxobin-catalysed fibrinopeptide release by HPLC, fibrin clot formation by turbidity and fibrin clot structure by scanning electron microscopy (SEM) and compared the results of the variants with those for γ D364H-Fibrinogen. Thrombin-catalysed FpA release of Aα17A-Fibrinogen was substantially delayed and none observed for Aα17C-Fibrinogen; fibrinopeptide B (FpB) release was delayed for all variants. All variant Fibrinogens showed substantially impaired thrombin-catalysed polymerisation; for Aα17A-Fibrinogen it was delayed less, and for Aα17C more than for γD364H -Fibrinogen. No variants polymerised with batroxobin, which exposed only knob ‘A’. The inhibition of variant Fibrinogens’ polymerisation was dose-dependent on the concentration of either GPRP or GHRP, and both peptides that block holes ‘b’. SEM showed that the variant clots from Aα17A- and γD364H-Fibrinogen had uniform, ordered fibres, thicker than normal, whereas Aα17C -Fibrinogen formed less organised clots with shorter, thinner, and tapered ends. These results demonstrate that FpA release per se is necessary for effective B:b interactions during polymerisation of variant Fibrinogens with impaired A:a interactions.
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Fibrinogens kosai and ogasa bβ15gly cys ggt tgt substitution associated with impairment of fibrinopeptide b release and lateral aggregation
Journal of Thrombosis and Haemostasis, 2003Co-Authors: Masako Hirotakawadobora, Nobuo Okumura, Fumiko Terasawa, Tsutomu Katsuyama, Osamu Yonekawa, N Sahara, E Shimizu, Hidekazu ShigematsuAbstract:Summary. We found two heterozygous dysFibrinogenemias, designated Fibrinogen Kosai and Fibrinogen Ogasa. Kosai was associated with arteriosclerosis obliterans but Ogasa showed no bleeding or thrombotic tendencies. The plasma Fibrinogen concentrations from the two propositi (Ogasa and Kosai) were much lower when determined by the thrombin-time method (0.94 and 1.06 g L−1, respectively) than when determined by the immunological method (2.87 and 2.72 g L−1, respectively). We performed DNA sequencing and functional analyses to clarify the relationship between the structural and functional abnormalities. Genetic analysis of PCR-amplified DNA from the propositi identified the heterozygous substitution Bβ15GlyCys (GGTTGT). Western blotting analysis of purified Fibrinogen revealed the existence of albumin–Fibrinogen complexes. Functional analyses indicated that compared with the normal control, the propositi's Fibrinogen released only half the normal amount of fibrinopeptide B and showed markedly impaired polymerization. In addition, the observation of thinner fibers in fibrin clots (by scanning electron microscopy) indicated markedly defective lateral aggregation in the variant Fibrinogens. The impaired functions may be due to the substitution of Cys for Bβo15Gly plus the existence of some additional disulfide-bonded forms.
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Fibrinogen matsumoto ii γ308asn lys aat aag mutation associated with bleeding tendency
British Journal of Haematology, 1996Co-Authors: Nobuo Okumura, Fumiko Terasawa, Ken-ichi Furihata, Ichiro Ueno, S Ishikawa, Tsutomu KatsuyamaAbstract:: Fibrinogen Matsumoto II is a hereditary dysFibrinogenaemia identified in a woman with Basedow's disease and a bleeding tendency. Coagulation tests of the patient's plasma revealed a prolonged thrombin time and a decreased Fibrinogen level determined by functional method. Release of fibrinopeptide A and B was normal, whereas fibrin monomer polymerization was delayed. Fibrinogen gamma-chain gene of the propositus was heterozygous for a missense mutation that resulted in Asn-->Lys substitution at codon 308. Though the same amino acid substitution was also attributed to Fibrinogen Kyoto I and Bicetre II, Fibrinogen Matsumoto II showed different clinical manifestations from them.
Lawrence T Goodnough - One of the best experts on this subject based on the ideXlab platform.
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how i use Fibrinogen replacement therapy in acquired bleeding
Blood, 2015Co-Authors: Jerrold H Levy, Lawrence T GoodnoughAbstract:Fibrinogen is a critical protein for hemostasis and clot formation. However, transfusion guidelines have variable recommendations for maintaining Fibrinogen levels in bleeding patients. An increasing number of studies support the practice of Fibrinogen replacement therapy for acquired coagulopathies, and additional studies are underway. Fibrinogen therapy can be administered with cryoprecipitate or Fibrinogen concentrates, and clinical practice varies according to their availability and licensing status. Fibrinogen concentrate therapy has been studied in animal models and clinical trials and supports the critical role of Fibrinogen repletion in bleeding patients. Point-of-care testing will have an important role in guiding Fibrinogen replacement for hemostatic therapy in clinical settings such as cardiovascular surgery, postpartum hemorrhage, and trauma. Fibrinogen therapy is an important component of a multimodal strategy for the treatment of coagulopathic bleeding.
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Fibrinogen as a therapeutic target for bleeding a review of critical levels and replacement therapy
Transfusion, 2014Co-Authors: Jerrold H Levy, Ia J Welsby, Lawrence T GoodnoughAbstract: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.
