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British Journal of Anaesthesia Dec 2014Cryoprecipitate, originally developed as a therapy for patients with antihaemophilic factor deficiency, or haemophilia A, has been in use for almost 50 yr. However,... (Review)
Review
Cryoprecipitate, originally developed as a therapy for patients with antihaemophilic factor deficiency, or haemophilia A, has been in use for almost 50 yr. However, cryoprecipitate is no longer administered according to its original purpose, and is now most commonly used to replenish fibrinogen levels in patients with acquired coagulopathy, such as in clinical settings with haemorrhage including cardiac surgery, trauma, liver transplantation (LT), or obstetric haemorrhage. Cryoprecipitate is a pooled product that does not undergo pathogen inactivation, and its administration has been associated with a number of adverse events, particularly transmission of blood-borne pathogens and transfusion-related acute lung injury. As a result of these safety concerns, along with emerging availability of alternative fibrinogen preparations, cryoprecipitate has been withdrawn from use in a number of European countries. Compared with the plasma from which it is prepared, cryoprecipitate contains a high concentration of coagulation factor VIII, coagulation factor XIII, and fibrinogen. Cryoprecipitate is usually licensed by regulatory authorities for the treatment of hypofibrinogenaemia, and recommended for supplementation when plasma fibrinogen levels decrease below 1 g litre(-1); however, this threshold is empiric and is not based on solid clinical evidence. Consequently, there is uncertainty over the appropriate dosing and optimal administration of cryoprecipitate, with some guidelines from professional societies to guide clinical practice. Randomized, controlled trials are needed to determine the clinical efficacy of cryoprecipitate, compared with the efficacy of alternative preparations. These trials will allow the development of evidence-based guidelines in order to inform physicians and guide clinical practice.
Topics: Blood Coagulation Disorders; Coagulants; Drug Administration Schedule; Drug Approval; Drug Costs; Drug Monitoring; Factor VIII; Fibrinogen; Humans; Practice Guidelines as Topic
PubMed: 24972790
DOI: 10.1093/bja/aeu158 -
Acta Haematologica 2021Congenital fibrinogen deficiency is an inherited disorder due to genetic mutations with diverse presentations arising from reduced fibrinogen levels... (Review)
Review
Congenital fibrinogen deficiency is an inherited disorder due to genetic mutations with diverse presentations arising from reduced fibrinogen levels (hypofibrinogenemia), absence of fibrinogen in circulation (afibrinogenemia), abnormal functioning (dysfibrinogenemia) or both reduced levels and abnormal functioning (hypodysfibrinogenemia) of fibrinogen. The decreased fibrinogen concentration in congenital fibrinogen deficiency necessitates fibrinogen replacement therapy with fresh frozen plasma, cryoprecipitate, or human fibrinogen concentrate. However, the use of fresh frozen plasma and cryoprecipitate is limited owing to their longer transfusion time, requirement of high doses, volume overload, risk of viral transmission, and other safety concerns. The availability of human fibrinogen concentrate has made it the preferred replacement alternative due to its reduced risk of viral transmission, smaller infusion volume, and accurate dosing. The hemostatic efficacy and safety of human fibrinogen concentrate in congenital fibrinogen deficiency is well established in the literature. We review the prevalence of congenital fibrinogen deficiency in India and the current role of human fibrinogen concentrate in its management.
Topics: Afibrinogenemia; Blood Transfusion; Fibrinogen; Guidelines as Topic; Humans; India; Plasma
PubMed: 34091452
DOI: 10.1159/000516339 -
Seminars in Thrombosis and Hemostasis Mar 2016Fibrinogen has a central role in coagulation. Following trauma and perioperatively, low fibrinogen levels have been found to be risk factors for exaggerated bleeding,... (Review)
Review
Fibrinogen has a central role in coagulation. Following trauma and perioperatively, low fibrinogen levels have been found to be risk factors for exaggerated bleeding, transfusion needs, and adverse outcome. Conversely, treatment with exogenous fibrinogen in critically bleeding patients with low fibrinogen levels has been shown to decrease transfusion needs. Because following trauma and in many perioperative situations fibrinogen is the first coagulation "element" to become critically low, it appears reasonable to target fibrinogen in clinical coagulation algorithms aiming at early specific and goal-directed treatment. A low fibrinogen can be a low plasma concentration or a low functional fibrinogen as assessed by point-of-care techniques such as thromboelastography (TEG) or thromboelastometry (ROTEM). This review summarizes the evidence base for perioperative algorithm-based fibrinogen administration, including the exact thresholds for fibrinogen administration used in the different algorithms. Algorithm-based individualized goal-directed use of fibrinogen resulted in highly significant reduction in transfusion needs, adverse outcomes, in certain studies even mortality, and where investigated reduced costs, with high safety levels at the same time. Best evidence exists in cardiac surgery, followed by trauma, postpartum hemorrhage, and liver transplantation. The introduction of these concepts is highly demanding and requires a tremendous educational effort to familiarize all health care workers with the necessary knowledge and the skills of how to run TEG/ROTEM tests. Future research is needed to compare the efficacy, safety, and costs of different algorithms. This, however, should not prevent us from introducing these expedient point-of-care-based algorithms clinically today.
Topics: Algorithms; Blood Coagulation; Cardiac Surgical Procedures; Female; Fibrinogen; Humans; Male; Perioperative Care; Postpartum Hemorrhage; Wounds and Injuries
PubMed: 26716503
DOI: 10.1055/s-0035-1564841 -
Annales de Biologie Clinique Aug 2016Congenital fibrinogen disorders comprise quantitative disorders defined by a complete absence (afibrinogenemia) or by a decreased level (hypofibrinogenemia) of... (Review)
Review
Congenital fibrinogen disorders comprise quantitative disorders defined by a complete absence (afibrinogenemia) or by a decreased level (hypofibrinogenemia) of circulating fibrinogen and qualitative disorders characterized by a discrepancy between the activity and the antigenic levels of fibrinogen (dysfibrinogenemia and hypodysfibrinogenemia). The biological diagnosis is based on a standard haemostasis assessment. All the coagulation tests that depend on the formation of fibrin as the end point are affected; although in dysfibrinogenemia the specificity and sensitivity of routine test depend on reagent and techniques. A genetic exploration permits to confirm the diagnosis and may enhance the prediction of the patient's phenotype. Homozygous or composite heterozygous null mutations are most often responsible for afibrinogenemia while hypofibrinogenemic patients are mainly heterozygous carrier of an afibrinogenemic allele. Heterozygous missense mutations are prevalent in dysfibrinogenemia, with two hot spot localized in exon 2 of the FGA and in the exon 8 of the FGG. The correlation between phenotype and genotype has been identified in some fibrinogen variants, including six mutations clustered in exons 8 and 9 of the FGG leading to hypofibrinogenemia with hepatic inclusions of abnormal fibrinogen aggregates as well as a few mutations associated with an increase risk of thrombotic events. A familial screening and additional functional assays should be carried out when possible.
Topics: Afibrinogenemia; Blood Coagulation; Blood Coagulation Disorders, Inherited; Clinical Laboratory Techniques; Diagnosis, Differential; Fibrinogen; Fibrinogens, Abnormal; Humans; Molecular Diagnostic Techniques
PubMed: 27492693
DOI: 10.1684/abc.2016.1167 -
Minerva Anestesiologica Dec 2019Two of the most commonly used viscoelastic hemostatic assays, thromboelastometry (ROTEM) and thrombelastography (TEG), have proven to decrease allogenic blood... (Comparative Study)
Comparative Study Review
Two of the most commonly used viscoelastic hemostatic assays, thromboelastometry (ROTEM) and thrombelastography (TEG), have proven to decrease allogenic blood transfusions with cost reduction and possibly decrease mortality and morbidity in cardiac, trauma, and other bleeding patients. This article compares the two devices to provide guidance on the selection and use of these monitoring systems. Their second-generation assays, TEG 6S and ROTEM Sigma, are also discussed.
Topics: Fibrinogen; Fibrinolysis; Hemostatic Techniques; Humans; Thrombelastography; Thrombosis
PubMed: 31630507
DOI: 10.23736/S0375-9393.19.13687-5 -
PloS One 2022Plasma fibrinogen and albumin concentrations initially decrease after abdominal surgery. On postoperative days 3-5 fibrinogen concentration returns to the preoperative...
Plasma fibrinogen and albumin concentrations initially decrease after abdominal surgery. On postoperative days 3-5 fibrinogen concentration returns to the preoperative level or even higher, while albumin stays low. It is not known if these altered plasma concentrations reflect changes in synthesis rate, utilization, or both. In particular a low albumin plasma concentration has often been attributed to a low synthesis rate, which is not always the case. The objective of this study was to determine fibrinogen and albumin quantitative synthesis rates in patients undergoing major upper abdominal surgery with and without intact liver size. Patients undergoing liver or pancreatic resection (n = 9+6) were studied preoperatively, on postoperative days 1 and 3-5. De novo synthesis of fibrinogen and albumin was determined; in addition, several biomarkers indicative of fibrinogen utilization were monitored. After hemihepatectomy, fibrinogen synthesis was 2-3-fold higher on postoperative day 1 than preoperatively. On postoperative days 3-5 the synthesis level was still higher than preoperatively. Following major liver resections albumin synthesis was not altered postoperatively compared to preoperative values. After pancreatic resection, on postoperative day 1 fibrinogen synthesis was 5-6-fold higher than preoperatively and albumin synthesis 1.5-fold higher. On postoperative days 3-5, synthesis levels returned to preoperative levels. Despite decreases in plasma concentrations, de novo synthesis of fibrinogen was markedly stimulated on postoperative day 1 after both hemihepatectomies and pancreatectomies, while de novo albumin synthesis remained grossly unchanged. The less pronounced changes seen following hepatectomies were possibly related to the loss of liver tissue.
Topics: Humans; Abdomen; Fibrinogen; Hemostatics; Hepatectomy; Liver; Serum Albumin; Digestive System Surgical Procedures
PubMed: 36301906
DOI: 10.1371/journal.pone.0276775 -
Blood Mar 2022Fibrinogen plays a pathologic role in multiple diseases. It contributes to thrombosis and modifies inflammatory and immune responses, supported by studies in mice...
Fibrinogen plays a pathologic role in multiple diseases. It contributes to thrombosis and modifies inflammatory and immune responses, supported by studies in mice expressing fibrinogen variants with altered function or with a germline fibrinogen deficiency. However, therapeutic strategies to safely and effectively tailor plasma fibrinogen concentration are lacking. Here, we developed a strategy to tune fibrinogen expression by administering lipid nanoparticle (LNP)-encapsulated small interfering RNA (siRNA) targeting the fibrinogen α chain (siFga). Three distinct LNP-siFga reagents reduced both hepatic Fga messenger RNA and fibrinogen levels in platelets and plasma, with plasma levels decreased to 42%, 16%, and 4% of normal within 1 week of administration. Using the most potent siFga, circulating fibrinogen was controllably decreased to 32%, 14%, and 5% of baseline with 0.5, 1.0, and 2.0 mg/kg doses, respectively. Whole blood from mice treated with siFga formed clots with significantly decreased clot strength ex vivo, but siFga treatment did not compromise hemostasis following saphenous vein puncture or tail transection. In an endotoxemia model, siFga suppressed the acute phase response and decreased plasma fibrinogen, D-dimer, and proinflammatory cytokine levels. In a sterile peritonitis model, siFga restored normal macrophage migration in plasminogen-deficient mice. Finally, treatment of mice with siFga decreased the metastatic potential of tumor cells in a manner comparable to that observed in fibrinogen-deficient mice. The results indicate that siFga causes robust and controllable depletion of fibrinogen and provides the proof-of-concept that this strategy can modulate the pleiotropic effects of fibrinogen in relevant disease models.
Topics: Afibrinogenemia; Animals; Blood Platelets; Disease Models, Animal; Female; Fibrin; Fibrinogen; Gene Knockdown Techniques; Humans; Liposomes; Male; Mice; Nanoparticles; RNA, Small Interfering
PubMed: 34958662
DOI: 10.1182/blood.2021014559 -
Clinical and Applied... 2022Preeclampsia (PE) is a serious complication of pregnancy. The fibrinolytic system play crucial roles regarding placentation and evolution of PE.
OBJECTIVES
Preeclampsia (PE) is a serious complication of pregnancy. The fibrinolytic system play crucial roles regarding placentation and evolution of PE.
AIM
To study comprehensively components of the fibrinolytic system and fibrin lysability in women with PE.
DESIGN AND METHODS
117 women with PE and matched controls were included. Tissue type plasminogen activator (t-PA), plasminogen, PAI-1, plasmin inhibitor (PI), D-dimer, the fibrinolytic potential of dextran sulphate euglobulin fraction (DEF), PAI-2, polymere PAI-2, fibrin clot lysability, thrombin activatable fibrinolysis inhibitor (TAFI) and fibrinogen were assessed.
RESULTS
Women with PE had significantly increased concentrations of t-PA and PAI-1, whereas the plasma concentration of PAI-2 was significantly lower compared to controls, p < 0.0001. Polymere PAI-2 was detected in both groups. DEF, TAFI and fibrinogen were not different between the groups. D-dimer was significantly increased and plasminogen/PI together with fibrin clot lysability time decreased in the PE-group, p = 0.0004 p = 0.04, p = 0.03, p < 0.0001 respectively.
CONCLUSION
This study demonstrates that PE is associated with an affected t-PA/PAI-1 system, decreased PAI-2 and increased fibrin lysability. Furthermore, PAI-2 has the potential to polymerize during pregnancy.
Topics: Female; Humans; Pregnancy; Antifibrinolytic Agents; Carboxypeptidase B2; Dextran Sulfate; Fibrin; Fibrinogen; Fibrinolysis; Plasminogen; Plasminogen Activator Inhibitor 1; Plasminogen Activator Inhibitor 2; Pre-Eclampsia; Thrombosis; Tissue Plasminogen Activator
PubMed: 36217728
DOI: 10.1177/10760296221126172 -
Revista Da Associacao Medica Brasileira... Jun 2020INTRODUCTION Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly described virus responsible for the outbreak of the coronavirus disease 2019... (Review)
Review
INTRODUCTION Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly described virus responsible for the outbreak of the coronavirus disease 2019 (Covid-19), named by the World Health Organization (WHO) in February/2020. Patients with Covid-19 have an incidence of acute respiratory distress syndrome (ARDS) of 15.9-29% and sepsis is observed in all deceased patients. Moreover, disseminated intravascular coagulation (DIC) is one of the major underlying causes of death among these patients. In patients with DIC, there is a decrease in fibrinogen and an increase in D-dimer levels. Some studies have shown that fibrinogen and one of its end products, D-dimer, might have a predictive value for mortality in patients with non-Covid sepsis secondary to complications of DIC. Therefore, anticoagulation, considering its mortality benefits in cases of non-Covid sepsis, may also have an important role in the treatment of Covid-19. METHODS We reviewed the literature of all studies published by April 2020 on patients infected with Covid-19. Our review was limited to D-dimer and fibrinogen changes and anticoagulation recommendations. RESULTS Anticoagulation therapy can be started following the DIC diagnosis in Covid-19 patients despite the bleeding risks. In addition, the current evidence suggests a routine use of anticoagulation, particularly in patients with higher D-dimer levels (> 3.0 μg/mL). CONCLUSION Covid-19 is a systemic, hypercoagulable disease requiring more studies concerning treatment. Aanticoagulation is still an issue to be studied, but D-dimer rise and disease severity are the indicative factors to start treatment as soon as possible.
Topics: Anticoagulants; Betacoronavirus; Biomarkers; Blood Coagulation Disorders; COVID-19; Coronavirus; Coronavirus Infections; Fibrin Fibrinogen Degradation Products; Fibrinogen; Humans; Pandemics; Pneumonia, Viral; SARS-CoV-2
PubMed: 32696883
DOI: 10.1590/1806-9282.66.6.842 -
Clinical and Applied... Sep 2016Cardiac surgery involving cardiopulmonary bypass (CPB) is often associated with important blood loss, allogeneic blood product usage, morbidity, and mortality.... (Review)
Review
Cardiac surgery involving cardiopulmonary bypass (CPB) is often associated with important blood loss, allogeneic blood product usage, morbidity, and mortality. Coagulopathy during CPB is complex, and the current lack of uniformity for triggers and hemostatic agents has led to a wide variability in bleeding treatment. The aim of this review is to provide a simplified picture of the data available on patients' coagulation status at the end of CPB in order to provide relevant information for the development of tailored transfusion algorithms. A nonsystematic literature review was carried out to identify changes in coagulation parameters during CPB. Both prothrombin time and activated partial thromboplastin time increased during CPB, by a median of 33.3% and 17.9%, respectively. However, there was marked variability across the published studies, indicating these tests may be unreliable for guiding hemostatic therapy. Some thrombin generation (TG) parameters were affected, as indicated by a median increase in TG lag time of 55.0%, a decrease in TG peak of 17.5%, and only a slight decrease in endogenous thrombin potential of 7%. The most affected parameters were fibrinogen levels and platelet count/function. Both plasma fibrinogen concentration and FIBTEM maximum clot firmness decreased during CPB (median change of 36.4% and 33.3%, respectively) as did platelet count (44.5%) and platelet component (34.2%). This review provides initial information regarding changes in coagulation parameters during CPB but highlights the variability in the reported results. Further studies are warranted to guide physicians on the parameters most appropriate to guide hemostatic therapy.
Topics: Blood Coagulation; Blood Coagulation Tests; Cardiopulmonary Bypass; Fibrinogen; Humans; Platelet Count; Thrombin
PubMed: 27268940
DOI: 10.1177/1076029616651146