Fibrinogen Replacement Therapy Research Articles

Thromboelastography predicts risks of obstetric complication occurrence in (hypo)dysfibrinogenemia patients under non-pregnant state.

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.

Thromboembolic events in patients with severe inherited fibrinogen deficiency

Inherited afibrinogenemia and hypofibrinogenemia are rare bleeding disorders characterized by markedly reduced levels of fibrinogen in blood. Thrombotic complications in these disorders have been rarely described. We performed a multicenter retrospective study and reviewed the occurrence of thrombotic complications among patients with inherited fibrinogen deficiency. Cases were identified during a review of medical records of all patients with inherited fibrinogen deficiency followed at three different university hospitals in Israel. Nine patients were included in this study: five were afibrinogenemic and four hypofibrinogenemic. There were seven thrombotic events, mostly venous, that occurred in four out of nine patients (44%). All thrombotic events occurred in afibrinogenemic patients. Mean age at the time of thrombosis was 45 (range 28-61) years. Thrombophilic evaluation performed was negative in all cases. At the time of thrombosis in five out of seven (71.4%) events, fibrinogen replacement therapy was concurrently given. Therapeutic approach was different among patients ranging from supportive therapy alone, antiplatelet agents and anticoagulant therapy with the concurrent administration of fibrinogen replacement therapy. This study discloses a high rate of thrombosis in patients with afibrinogenemia. Events were both venous and arterial and may be recurrent. Management is highly problematic due to the precarious balance between bleeding and thrombotic risk in these patients. Fibrinogen replacement therapy should be cautiously used in these patients as most thrombotic events followed the administration of fibrinogen replacement therapy. Larger cohorts are warranted to better characterize the best management strategy in these paradoxical events.

Postpartum hemorrhage: a continuing challenge.

Obstetric hemorrhage remains a leading cause of maternal morbidity and mortality worldwide. Many postpartum hemorrhages (PPHs) do not have identifiable risk factors; maternity units should therefore have obstetric hemorrhageprotocols in place for all parturients as every pregnancy has the potential to be complicated by hemorrhage. This review will examine the epidemiology of PPH as well as current recommendations for key elements in obstetric hemorrhage protocols. Recent advances in hematologic management of PPH will be also be reviewed, including: (1) recognition of hypofibrinogenemia as a risk factor for severe PPH, (2) use of antifibrinolytic therapy, and (3) strategies for fibrinogen replacement therapy.

How I use fibrinogen replacement therapy in acquired bleeding

AbstractFibrinogen 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.

In vitro rescue of FGA deletion by lentiviral transduction of an afibrinogenemic patient's hepatocytes

Congenital afibrinogenemia is a rare inherited autosomal recessive disorder in which a mutation in one of three genes coding for the fibrinogen polypeptide chains Aα, Bβ and γ results in the absence of a functional coagulation protein. A patient with congenital afibrinogenemia, resulting from an FGA homozygous gene deletion, underwent an orthotopic liver transplant that resulted in complete restoration of normal hemostasis. The patient's explanted liver provided a unique opportunity to further investigate a potential novel treatment modality. To explore a targeted gene therapy approach for patients with congenital afibrinogenemia. At the time of transplant, the patient's FGA-deficient hepatocytes were isolated and transduced with lentiviral vectors encoding the human fibrinogen Aα-chain. FGA-transduced hepatocytes produced fully functional fibrinogen in vitro. Orthotopic liver transplantation is a possible rescue treatment for failure of on-demand fibrinogen replacement therapy. In addition, we provide evidence that hepatocytes homozygous for a large FGA deletion can be genetically modified to restore Aα-chain protein expression and secrete a functional fibrinogen hexamer.

HYPOFIBRINOGENEMIA COMPLICATING PREGNANCY � CASE REPORT AND REVIEW OF LITERATURE

Congenital fibrinogen disorder may be either afibrinogenemia / hypofibrinogenemia / dysfibrinogenemia. Afibrinogenemia may present at birth as bleeding from umbilical cord. Patients with hypofibrinogenemia may present only during surgical intervention or during pregnancy. Pregnancy with this condition is associated with a very high incidence of abortion & abruption. Fibrinogen replacement can be done using either cryoprecipitate or fibrinogen concentrate. Successful pregnancies have been reported using cryoprecipitate & fibrinogen concentrate (FC). We report a woman with 6 abortions previously who was treated with fibrinogen replacement therapy & delivered a live child.

大量出血と止血凝固検査─フィブリノゲン補充療法とトロンボエラストメトリー（ROTEM&lt;SUP&gt;&amp;reg;&lt;/SUP&gt;）の重要性とその意義─

大量出血と止血凝固検査─フィブリノゲン補充療法とトロンボエラストメトリー（ROTEM&lt;SUP&gt;&amp;reg;&lt;/SUP&gt;）の重要性とその意義─

Postoperative fibrinogen level is associated with postoperative bleeding following cardiothoracic surgery and the effect of fibrinogen replacement therapy remains uncertain

Traditionally, a fibrinogen level > 1 g L(-1) has been viewed as the critical plasma concentration required for hemostasis. No definitive trial has investigated the plasma fibrinogen hemostatic threshold and fibrinogen replacement in complex surgical patients with acquired bleeding. To explore the plasma fibrinogen level required for hemostasis in cardiothoracic surgery patients and assess the association of fibrinogen replacement therapy (using cryoprecipitate or fibrinogen concentrate) with reducing postoperative bleeding rate. Data from a prospectively collated database were used to examine the relationship between postoperative plasma fibrinogen level and the postoperative rate of bleeding within the hour of plasma fibrinogen measurement (n = 430) and to explore the effect of cryoprecipitate infusion (n = 76) or fibrinogen concentrate administration (n = 8) on postoperative bleeding rate. A low plasma fibrinogen level was significantly associated with bleeding, with an odds ratio of 3.06 for every 1 g L(-1) decrease in fibrinogen (95% confidence interval 1.05-8.90) with adjustment for confounders. A fibrinogen threshold associated with excess bleeding was not identified, but this relationship was a continuum. There was no reduction in bleeding following administration of cryoprecipitate or fibrinogen concentrate to raise the post-infusion fibrinogen level to a median of 2.00 and 1.70 g L(-1) , respectively. There is a continuum of bleeding severity with reducing fibrinogen concentration. Fibrinogen concentrate or cryoprecipitate infusion did not significantly reduce bleeding rate; however, confirmation by a randomized controlled trial is required. It remains uncertain whether low postoperative fibrinogen levels are causally associated with postoperative bleeding.

Restoring hemostasis: fibrinogen concentrate versus cryoprecipitate

Fibrinogen plays a key role in the coagulation process, and therefore maintaining adequate quantities of fibrinogen is an essential step in achieving satisfactory hemostasis in patients with acquired hypofibrinogenemia. Potential options for treating acquired hypofibrinogenemia in patients with uncontrolled bleeding include the use of cryoprecipitate or fibrinogen replacement therapy. This review provides a brief overview of the hemostatic process and the methods for assessing coagulopathy and discusses the efficacy and safety of cryoprecipitate and fibrinogen concentrate in restoring fibrinogen levels, achieving hemostasis and reducing transfusion requirements in different patient populations requiring rapid hemostasis. Other issues relevant to the clinical use of these agents in restoring hemostasis, including variations in product composition, preparation time and cost, are also examined.

Epidemiology and treatment of congenital fibrinogen deficiency

Congenital fibrinogen deficiency is a rare bleeding disorder, affecting either the quantity (afibrinogenemia, hypofibrinogenemia) or quality (dysfibrinogenemia) of circulating fibrinogen. There is a strong association between fibrinogen activity levels and clinical bleeding severity. Patients with afibrinogenemia experience frequent, often severe, spontaneous bleeds into the muscles and joints and are at significant risk of intracranial hemorrhage. Patients with hypofibrinogenemia are usually asymptomatic; however, they are vulnerable to bleeding after trauma. Dysfibrinogenemia is associated with both spontaneous bleeding and a relatively high risk of thrombosis. Fibrinogen replacement therapy is effective in treating bleeding episodes in congenital fibrinogen deficiency. Fibrinogen concentrates are the preferred treatment option and guidelines now exist for their on-demand use and to manage surgery. Prophylaxis may benefit patients with afibrinogenemia and others with a severe bleeding tendency. The dose and frequency of administration should be adjusted to maintain a fibrinogen activity level >0.5–1.0 g/L. Pregnant women with afibrinogenemia require prophylactic factor replacement as early as possible during pregnancy, continuing throughout pregnancy, and after the birth. Fibrinogen replacement should also be considered in pregnant women with other fibrinogen deficiencies. The risk of thrombosis presents an additional management challenge in these patients, often necessitating the concurrent use of anticoagulants and fibrinogen. Although basic guidelines have been developed, further studies are needed to help optimize treatment in different patient groups under different clinical circumstances and to improve our understanding of thrombotic events.

Severe bleeding in surgical and trauma patients: the role of fibrinogen replacement therapy

Fibrinogen is in a central position in the coagulation system, playing an important role in platelet aggregation and establishing the fibrin network. Fibrinogen is also the first coagulation factor to become critically low during surgery and after major trauma. Hemostatic support has traditionally involved using transfusion of allogeneic blood products, including fresh frozen plasma; however, there is a lack of conclusive evidence supporting the clinical effectiveness of fresh frozen plasma in these situations. Early, targeted fibrinogen substitution may be preferable in terms of speed of administration and clinical effectiveness, with recent studies adding to the weight of evidence demonstrating the potential to significantly reduce blood loss and transfusion requirements in surgical and severe trauma patients with this approach. The availability of point-of-care testing using viscoelastic techniques to guide fibrinogen substitution has enabled the development of transfusion algorithms that lead to individualized, goal-directed, and targeted use of fibrinogen concentrates to improve clinical outcomes. Fibrinogen replacement has become the standard-of-care in several major surgical centers in Europe and is recommended in current European trauma treatment guidelines. Future prospective studies will help to establish the critical threshold and target levels for fibrinogen substitution in different acute-care situations and should encourage more widespread use of this rational and effective approach to the treatment of bleeding-induced coagulopathies.

Treatment of Congenital Fibrinogen Deficiency; Global Development Plan for a Double Virus Inactivated Fibrinogen Concentrate

AbstractAbstract 4636Congenital afibrinogenaemia and hypofibrinogenaemia are rare inherited disorders occurring in homozygotic patients with an estimated incidence of 1 in 106. Patients present with frequent severe bleeding episodes since birth or early childhood. Bleeding may occur after a minor trauma or a small surgical intervention, into the skin, mucosa, muscles, gastrointestinal tract, or the brain. Therapeutic substitution with human fibrinogen concentrate can correct the haemostatic defect and arrest the bleeding in patients with these fibrinogen deficiencies. Octafibrin is a highly purified, lyophilized, human plasma fibrinogen concentrate, without added albumin. Octafibrin is double virus inactivated using 2 dedicated virus inactivation/removal steps, solvent/detergent treatment, and nanofiltration. A plan for the global development of Octafibrin has been prepared taking into account discussions with European Regulators and the FDA. This plan also involves discussions with the European pediatric committee (PDCO) which oversees the inclusion of pediatric subjects into drug development under the new EMA guidelines.The development plan calls for a prospective, randomized, open label, multinational, pivotal PK comparison of Octafibrin to an existing marketed product in 18 adult and adolescent patients, including comparison of a surrogate efficacy endpoint measured by TEG. In a second study the efficacy and safety of the product in bleeding and invasive procedures will be assessed in 24 adult and adolescent patients. Finally a pediatric PK, efficacy and safety study in patients below 6 years will be performed but because of the rarity of these patients this study will not need to be completed before review and approval by the regulatory agencies. Clinical studies are planned to be started later this year.A double virus inactivated, plasma derived fibrinogen concentrate (Octafibrin) will be globally developed in an ultra rare congenital disease after harmonized discussions with EU and US regulators. Pivotal comparative PK data and interim efficacy and safety data will be available at time of regulatory submissions while the finalization of the pediatric study is deferred.Effective management of congenital fibrinogen deficiencies in bleeding situations is necessary for the prevention of potentially life-threatening bleeding episodes. This clinical program will help to confirm that fibrinogen substitution is able to successfully control bleeding, increase the fibrinogen plasma levels, and reduce the amount of transfusions needed with allogeneic blood products. In addition, it will give additional information on the tolerability and overall safety profile of fibrinogen replacement therapy. Disclosures:Schwartz:Octapharma: Employment. Knaub:Octapharma: Employment.

Fibrinogen replacement therapy: a critical review of the literature.

Fibrinogen is a plasma glycoprotein with a molecular weight of 340 kDa; it is synthesised by the liver. The conversion of fibrinogen to fibrin is catalysed by thrombin and plays a key role in clot formation and stabilisation. In addition, fibrinogen induces platelet activation and aggregation by binding to the platelet fibrinogen receptor glycoprotein GPIIb/IIIa1. Fibrinogen replacement therapy is currently indicated as prophylaxis and therapy of haemorrhage in congenital and acquired fibrinogen deficiency, this latter being associated with liver failure, disseminated intravascular coagulation, massive transfusion and cardiac surgery)2,3. Hypofibrinogenaemia is defined by a decreased level of normal fibrinogen between 0.5 g/L and the lower limit of the normal range for the local laboratory (usually 1.5 g/L)4. Fibrinogen supplementation can be provided by transfusion of fresh-frozen plasma (FFP), cryoprecipitate and fibrinogen concentrate5,6. However, as FFP has several limitations including a low fibrinogen content, which means that large volumes must be given, and the risk of transfusion-related complications (e.g., transfusion-related acute lung injury [TRALI] and viral transmission), this critical analysis is focused on the role of cryoprecipitate and fibrinogen concentrate.

S99 Multiple regression analyses in a cohort of hereditary haemorrhagic telangiectasia patients suggest a novel role for iron in thrombosis

Introduction/objectivesPulmonary emboli (PE) secondary to deep venous thromboses (DVT) are the immediate cause of 10% of hospital deaths. Elevated basal plasma coagulation factor (F) VIII levels, now known to be...

Spontaneous extra-axial intracranial hemorrhage followed by thrombosis in congenital afibrinogenemia: perioperative management of this rare combination

Background Although congenital afibrinogenemia can commonly present with hemorrhage from the umbilical cord at birth, or with spontaneous mucosal or intracranial hemorrhage in the neonatal period, life-threatening intracerebral hemorrhage in adults is infrequent. Case Description We report a 32-year-old woman with congenital afibrinogenemia. Postoperatively, she developed bilateral pulmonary emboli despite the fact that her INR was elevated to 2.3. Highly purified fibrinogen concentrate infusion may have partly contributed to this complication. An inferior vena caval filter was used successfully to prevent further pulmonary emboli. Conclusions Spontaneous intracerebral hemorrhage must be included in the differential diagnosis in patients with known afibrinogenemia presenting with symptoms suggesting raised intracranial pressure. Immediately after surgery, intracranial pressure monitoring of patients is mandatory to pick up further intracranial bleeding early. Fibrinogen replacement therapy is recommended before surgery, but its use as a long-term prophylaxis against hemorrhage should be weighed against the risk of thrombosis.

Postoperative deep venous thrombosis in a woman with congenital afibrinogenaemia treated with fibrinogen concentrates

Postoperative deep venous thrombosis in a woman with congenital afibrinogenaemia treated with fibrinogen concentrates

Congenital hypodysfibrinogenemia and abruptio placentae in a woman with history of cerebral thrombosis

Congenital hypodysfibrinogenemia is characterized by the synthesis of an abnormal fibrinogen molecule that does not function properly when converting fibrinogen into fibrin. The functional defects include: abnormal fibrinopeptide release, defects in fibrin polymerization, abnormal fibrin stabilization, and resistance to fibrin lysis. The most common hypodysfibrinogenemias are those causing polymerization defects. In most cases, congenital hypodysfibrinogenemia is inherited as an autosomal dominant trait with high levels of penetrance, but some patients show an autosomal recessive inheritance. Clinically, patient with hypodysfibrinogenemia will have one of the following phenotypes: no hemorrhagic symptoms, mild bleeding following trauma, thrombosis, or both thrombotic and hemorrhagic symptom manifestations (1). Approximately, 43% of all individuals with congenital hypodysfibrinogenemia are asymptomatic, while about 20% have bleeding symptoms and 17% experience thrombotic manifestations. About 20% of patients have a combination of bleeding and thrombosis (2). Women with congenital hypodysfibrinogenemia are at greater risk of obstetric complications. We report on a 31-year-old woman kept under our observation after having delivered a healthy baby successfully during the 40th gestational week. Thirty days after the end of pregnancy, a cerebral venous thrombosis (occlusion of left transversal sinus) was diagnosed, because of a sudden dyplopia. She was examined for inherited and acquired thrombophilia. Antithrombin III, protein C, protein S, activated protein C resistance, homocysteinemia, lupus-like inhibitor, and anti-phospholipid antibodies were normal. The research for the mutation of Factor V Leiden and the mutation G20210A of prothrombin was negative. The coagulation parameters were Partial Thromboplastin Time (PTT) ratio: 1.15, Prothrombin Time (PT) INR: 1.18, thrombin time: 120 seconds, ratio 4.78, reptilase time: 53 seconds, ratio 2.10, fibrinogen level: 69 mg/dl, fibrinogen antigen level: 90 mg/dl. Then, a diagnosis of hypodysfibrinogenemia was followed, and the patient began oral anticoagulant therapy with warfarin. Then, the patient asked to interrupt warfarin to start a new pregnancy. Therefore, therapy with Enoxaparin 6000 IU antifactor Xa once in day was started (100 IU/kg of body weight). This therapy and the dosage were considered appropriate as prophylaxis of recurrent vein thrombosis. The antifactor Xa activity was in therapeutic range (0.5–1.0 IU) in scheduled controls. At 18th week of pregnancy, the patient was admitted in hospital for sudden abdominal pain and vaginal bleeding. A moderate abruptio placenta was seen by echotomography. The following day, because of a serious vaginal hemorrhage and severe anaemia (Hb: 6.9 g/dl) and increase in the retroplacentar ematoma, the heparin therapy was stopped; a replacement therapy with fibrinogen concentrate and packed red cells was started. On 19th week of pregnancy, the patient delivered a dead fetus of 200 g body weight. No specific therapy is indicated for patients with congenital hypodysfibrinogenemia who are asymptomatic. Hypodysfibrinogenemic patients who have thrombotic episodes require anticoagulation with low molecular weight heparin followed by oral anticoagulants (3). Recurrent thrombotic episodes require prophylactic anticoagulation. Replacement treatment with fresh-frozen plasma, with cryoprecipitate, a rich source of fibrinogen, or with fibrinogen concentrates solvent-detergent treated, is indicated for episodes of active bleeding, preoperatively, and during pregnancy (4, 5). Prophylactic therapy is only recommended during pregnancy, and women with recurrent spontaneous abortions and hypodysfibrinogenemia can be treated with fibrinogen replacement therapy throughout the course of pregnancy. Our case is uncommon, because there were hemorrhagic and thrombotic symptoms in the same patient during the pregnancy period. The first pregnancy was complicated in the immediate postpartum by or because of a thrombotic episode in an unusual site. In the second pregnancy, she had a still birth under dramatic circumstances (placental abruption and serious bleeding). We believe in the case of another pregnancy, the patient must be treated both with heparin and with fibrinogen concentrates to avoid the risk of abortion (and bleeding) and thrombotic complications.

Chronic disseminated intravascular coagulation caused by an aorto-bifemoral aneurysm

This article reports the case of a patient with chronic disseminated intravascular coagulation that led to the diagnosis of an otherwise asymptomatic aorto-bifemoral aneurysm. The bleeding disorder completely resolved with the surgical resection of the aneurysm. Fibrinogen replacement therapy prior to invasive diagnostic procedures resulted in good hemosthasia.

Antifibrinogen IgG, Fibrinogen, and Clq Complexes Circulating in a Hypodysfibrinogenemic Proband

Circulating antifibrinogen antibodies have been reported in rare afibrinogenemic propositi, apparently occurring following fibrinogen replacement therapy, but immune complexes have not been described. In this report we describe circulating immune complexes formed by a monoclonal antifibrinogen IgG in a heterozygous hypodysfibrinogenemic (A alpha 16 Arg-->Cys) proband. Estimated by partial protein sequence and by other analyses, each immune complex consisted of one fibrin(ogen), one C1q, and 3-4 IgG molecules. The complexes were cryoprecipitable, a property also displayed by mixtures of proband IgG and normal fibrinogen. Indicating that both D and E domains were necessary for this behavior, cryoprecipitability was abolished by preincubation of the isolated IgG with either isolated normal fibrinogen fragment D100 or E. Consistent with the crossreactivity of the IgG with normal and mutant fibrinogen, the results suggest that the primary epitope resides on a D-E locus on the fibrin polymer formed by normal and abnormal molecules containing the uncleaved (or mutant) peptide A.

Deletion of the fibrinogen [correction of fibrogen] alpha-chain gene (FGA) causes congenital afibrogenemia.

Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by the complete absence of detectable fibrinogen. Uncontrolled bleeding after birth from the umbilical cord is common, and spontaneous intracerebral bleeding and splenic rupture can occur throughout life. Patients respond well to fibrinogen replacement therapy, either prophylactically or on demand. Because the half-life of infused fibrinogen is essentially normal, the genetic defect is assumed to be at the level of synthesis, but no responsible locus has been identified. Preliminary studies using Southern blotting suggested that no gross structural changes of the fibrinogen genes were present in patients. We report the identification of causative mutations in a nonconsanguineous Swiss family with congenital afibrinogenemia. The four affected male individuals (two brothers and their two first cousins) have homozygous deletions of approximately 11 kb of the fibrinogen alpha-chain gene (FGA). Haplotype data suggest that these deletions occurred separately, on three distinct ancestral chromosomes, implying that the FGA region of the fibrinogen locus is susceptible to deletion by a common mechanism. Furthermore, our results demonstrate that humans, like mice, may be born without the capacity to synthesize functional fibrinogen.