Fibrinogen is a critical protein in hemostasis and clot formation. However, there is considerable variation among transfusion guidelines as to what levels of fibrinogen should be maintained in bleeding patients.
A growing body of research supports the use of fibrinogen replacement therapy in patients with acquired coagulation disorders, including cold precipitation or fibrinogen concentrates, which vary in clinical practice depending on institutional availability and authorization status.
Fibrinogen concentrate therapy has been studied in animal models and clinical trials, and both support its important role in patients with bleeding disorders. Immediate testing is an important guide for fibrinogen replacement therapy in clinical situations such as cardiac surgery, postpartum hemorrhage, and trauma. Fibrinogen therapy is one of the key strategies in the management of patients with coagulation disorders with hemorrhage.
A review of how to supplement fibrinogen in bleeding disorders by Professor Levy of Stanford University was published online in the journal Blood on February 26, 2015.
Fibrinogen is an essential protein in clot formation, providing the necessary matrix and reticular mesh for clot contraction. Maintaining stable fibrinogen levels is an important therapeutic measure for patients with bleeding, especially during surgery. Previous studies have found that fibrinogen supplementation restores clot contraction strength.
Fibrinogen levels are elevated during pregnancy, and studies have found that fibrinogen supplementation is effective in treating postpartum hemorrhage. In addition numerous published or ongoing studies support fibrinogen supplementation in acquired coagulopathies. Although used as a therapeutic tool, the precise level of fibrinogen supplementation should be achieved is still not well defined.
Role of fibrinogen and related proteins in clot formation
Case: A 62-year-old, 110-kg male patient required aortic root replacement with preservation of the aortic valve, and preoperative treatment included inhibitors and beta-blockers. A total of 52,000 U of heparin was administered intraoperatively and subsequently neutralized with 250
mg of fisetin was used for neutralization. The patient received an empirical transfusion of 4 U of plasma and 2 U of platelets.
In the intensive care unit (ICU), the patient was hemodynamically stable but bleeding with a bleeding volume of approximately 150 ml/h. Coagulation tests on arrival at the ICU were: activated clotting time of 120 s, platelet count of 115 × 109/L, international normalized ratio (INR) of 1.3, partial thromboplastin time of 37 s, and fibrinogen of 1.2 g/L.
Question: How should a bleeding patient be treated?
Fibrinogen is a liver-synthesized, 350 kD plasma glycoprotein that is a substrate for prothrombin, fibrinolytic enzymes and activated FXIII, with an in vivo half-life of 3-5 days. After tissue injury, thrombin cleaves it into soluble fibrin monomers, which build a meshwork structure capable of uptake into red blood cells and thus forming a blood clot.
The fibrin polymer is cross-linked by FXIIIa, which increases the clot’s firmness and prevents fibrinolysis. Fibrinogen can also bind to platelet glycoprotein IIb/IIIa receptors to promote platelet aggregation, which further promotes cross-linking and clot stability. Thus, fibrinogen is an important component and substrate for clot formation, expansion and stabilization.
As the most concentrated coagulation factor in plasma, hypofibrinogenemia often occurs after massive blood loss and bleeding due to hemodilution caused by volume replacement, fibrinogen depletion due to clot formation, or diffuse intravascular coagulation. Therefore, in patients with bleeding, fibrinogen supplementation to maintain normal plasma levels is an important component of ensuring normal clot formation.
The similarly reduced levels of other coagulation factors make for complex coagulopathies in patients with major bleeding such as surgery, trauma, and extracorporeal circulation. FXIII deficiency due to dilution or depletion can also lead to perioperative bleeding, and coagulation elastography has shown that FXIII can significantly affect the firmness of the clot.
Therefore, the treatment of bleeding in patients with coagulopathies should involve a variety of measures, not only fibrinogen supplementation, but also an emphasis on associated coagulation abnormalities, including antifibrinolytic therapy and supplementation with other coagulation factors.
Target levels of fibrinogen supplementation
Question: To what target level should fibrinogen be increased in surgical and postoperative patients?
Normal fibrinogen levels range from 2-4.5 g/L and are increased in special circumstances such as pregnancy. Studies have reported that hypofibrinogenemia is a high risk factor for bleeding in clinical conditions such as cardiac surgery, perinatal and trauma. The level of fibrinogen required depends on a variety of factors and clinical conditions, and clinical studies have been conducted to explore how best to determine the target level of fibrinogen.
Because many patients with congenital fibrinogen deficiency do not bleed, most clinicians do not monitor fibrinogen levels during active bleeding or consider the threshold level for treatment to be 1 g/L. In addition, coagulation markers such as prothrombin time and activated partial thromboplastin time are affected only when fibrinogen is <1 g/L.
Previous guidelines recommended a target fibrinogen level of 1 g/L in trauma and postoperative settings; current studies and guideline consensus recommend higher target levels in cardiovascular surgery, trauma, and other clinical states.
Immediate application of clot strength viscoelasticity measurements for clotting assays depends on the concentration of fibrinogen. In vitro, the fibrinogen threshold to achieve optimal clot formation is 2 g/L. Studies have shown that higher levels of fibrinogen supplementation are required in surgical patients.
The post-2013 European Trauma Guidelines recommend fibrinogen supplementation at fibrinogen levels <1.5-2 g/L. In other clinical conditions, such as pregnancy, different therapeutic thresholds need to be taken into account. For perinatal patients, fibrinogen levels should reach 5-6 g/L, and a level of <2 g/L predicts a high risk of postpartum hemorrhage.
Testing fibrinogen levels
For patients with perioperative bleeding, what are the ways to measure fibrinogen levels?
A variety of methods for measuring plasma fibrinogen levels are functional assays, which determine clot formation by spectrophotometry or viscoelastic clot detection. clot formation time is recorded by spectroscopic analysis through the addition of thrombin to citrate-containing plasma by the Clauss assay.
Thromboelastography has been increasingly used as an immediate monitoring device during surgery and trauma, where functional fibrinogen levels are determined by platelet activation inhibitors.
Fibrinogen concentrations measured by Clauss analysis can be falsely reduced by direct thrombin inhibitors and falsely increased by starch solutions, making photometric and turbidimetric methods more susceptible than mechanical assays.
Fibrinogen supplementation
What blood products are used for fibrinogen supplementation in bleeding patients?
In most European countries, lyophilized fibrinogen concentrates are used; in North America, the United Kingdom, and some other European countries, plasma and cold precipitation are used.
Plasma
Plasma is now widely transfused in trauma and surgical patients, however, recent systematic reviews have shown that it does not benefit patients in most clinical indications, except for trauma. Some studies have also reported that it may also increase the rate of transfusion-related morbidity.
A variety of plasma products are available, including single-donor fresh frozen plasma (FFP), frozen-thawed plasma collected within 24 hours, and frozen-thawed plasma within 5 days. However, none of these are ideal sources of fibrinogen supplementation, as fibrinogen concentrations may fluctuate between 1 and 3 g/L.
Fibrinogen supplementation by plasma transfusion also requires larger volumes and may be beneficial in patients with trauma-induced coagulopathy, where bleeding requires volume replenishment. 12.2 ml/kg can increase plasma fibrinogen levels by 0.4 g/L and 33.5
A dose of 12.2 ml/kg can increase plasma fibrinogen levels by 0.4 g/L and 33.5 mL/kg can increase fibrinogen levels by 1 g/L.
Despite these data, clinicians continue to use plasma as a treatment modality for fibrinogen supplementation. A recent study comparing plasma with fibrinogen concentrate in patients requiring fibrinogen supplementation during trauma and surgery included a total of 70 observational studies of plasma infusion and 21 fibrinogen concentrate infusions.
Heterogeneity was evident in the effectiveness or benefit of plasma infusion, with 28% of the studies suggesting a benefit and 22% showing an unfavorable prognosis. The results showed that plasma transfusion reduced mortality in approximately 50% of studies of patients with major bleeding and trauma, and significantly increased mortality in 20% of studies of patients with surgical and non-major bleeding.
Fibrinogen concentrate infusion was included in only five studies comparing fibrinogen concentrate with placebo, and 70% of patients had improved prognosis.
Overall, the two risk factors of circulatory overload associated with transfusion and the inability to effectively raise fibrinogen levels have prevented plasma from being an effective treatment, and fibrinogen concentrate and cold precipitation are more effective than fibrinogen supplementation.
Cold precipitation
Cold precipitation was first used in the treatment of patients with hemophilia A before the advent of lyophilized clotting factor concentrates. Cold precipitation was obtained primarily by thawing FFP at 1-6°C, followed by centrifugation and resuspension and refreezing of the precipitated plasma proteins. Cold precipitation contains fibrinogen, vascular hemophilia factor (vWF) and human coagulation factor VIII (F VIII), which is an important source of fibrinogen.
One unit (U) of cold precipitate contains 200-250 mg of fibrinogen. Although the concentration of fibrinogen in each unit of cold sediment varies, 8-10 U of cold sediment is a standard therapeutic dose for adults. In addition to fibrinogen supplementation, cold precipitation can be used for the treatment of patients deficient in vWF and F VIII.
Because cold precipitate is a non-antiviral treated, multiple donor-sourced blood product, it is not available to patients in some countries due to safety concerns. However, there is no alternative to cold precipitation in almost all countries. Cold precipitation must be stored on a blood group compatible basis and requires time to dissolve and concentrate prior to transfusion.
Therefore, despite its widespread use, research and guidelines strictly limit its use. If fibrinogen concentrate is available, guidelines recommend that plasma not be transfused to control bleeding associated with low fibrinogen levels.
Fibrinogen Concentrates
Commercial fibrinogen concentrates are sterilized and lyophilized blood products obtained from multiple donors that undergo purification, virus inactivation and removal processes without cross-matching.
Four fibrinogen concentrates have been approved, with Haemocomplettan being the only fibrinogen concentrate available worldwide and approved in several countries for acute bleeding due to hypofibrinogenemia.
Fibrinogen dosing
What dosing strategy and testing method should be given to patients with bleeding?
The dose of fibrinogen can be based on the degree of bleeding and the initial fibrinogen concentration. In patients with suspected bleeding due to low fibrinogen concentration and function, the initial supplementation is 1-2 g. However, the dose should depend on the bleeding status, laboratory tests and immediate monitoring results.
Thromboelastometer/thromboelastography (ROTEM/TEG) is increasingly used for targeted supplementation of coagulation factors in trauma and surgical patients. In clinical trials, the FIBTEM test performed with the ROTEM instrument has been widely used to determine the level of fibrinogen and to calculate the dose required for treatment.
The maximum amplitude, which is the equivalent parameter of the maximum clot hardness (MCF), can be measured by functional fibrinogen analysis on the TEG instrument. The required dose of fibrinogen is calculated as fibrinogen concentrate dose (g) = (target MCF value – actual MCF value) x (kg body weight/70) x 0.5.
Depending on the normal fibrinogen level, the normal MCF value is between 9 and 25 mm, and in patients undergoing aortic surgery, the target MCF value is 22 mm. in the Weber algorithm, if EXTEM
A10 and FIBTEM
A10 are below 40mm and 8mm respectively, the recommended dose of fibrinogen is 25mg/kg; EXTEM
A10 <40mm and FIBTEM
The recommended dose should be increased to 50mg/kg when EXTEM A10 <40mm and FIBTEM A10 <6mm.
Fibrinogen supplementation has a risk of inducing thromboembolic events. Excessive fibrinogen application, especially with high thrombin production, has an increased risk of systemic microvascular thrombosis. However, a post hoc study of a randomized clinical trial of fibrinogen concentrate supplementation reported that fibrinogen supplementation did not significantly correlate with changes in hemostatic parameters.
In a model in pigs, no hypercoagulable state or thrombosis was reported in a study with fibrinogen application up to 600 mg/kg.
Clinical studies evaluating the therapeutic effects of fibrinogen
What data support the use of fibrinogen supplementation in surgical, trauma and postoperative patients?
Trauma
Trauma patients with reduced fibrinogen levels on admission to the hospital often have a poor prognosis. Fibrinogen supplementation, especially with concentrates, has increasingly become the hemostatic treatment for trauma-induced coagulopathy.
However, patients with hypovolemia initially require massive plasma transfusions to restore blood volume. Other treatments include measurement of fibrinogen levels, supplementation with specific amounts of fibrinogen, antifibrinolytic therapy, and surgical treatment.
Concentrates of fibrinogen and other factors have been extensively studied and reported for use in surgery and trauma as a management option for bleeding. In a retrospective report of 131 patients, results showed that the application of fibrinogen concentrate and prothrombin complex for goal-directed coagulation management resulted in better survival than trauma severity scores.
Another retrospective analysis found that 601 patients treated with FFP rather than concentrates had greater red blood cell and platelet concentrate transfusion requirements than 60 trauma patients treated with fibrinogen concentrate and thrombospondin complex.
A prospective study of 144 patients with large blunt trauma also reported corrective coagulopathy and reduced red blood cell and platelet transfusions in patients receiving coagulation factor concentrates compared with those receiving FFP, and fewer patients developed multi-organ failure. However, another retrospective analysis of 294 patients with trauma found that fibrinogen concentrate infusion did not reduce overall mortality.
Current European guidelines for the management of patients bleeding from trauma with fibrinogen levels of 1.5-2 g/L recommend an initial supplementation of 3-4 g of fibrinogen concentrate, with laboratory test results to guide the subsequent dose application. There are multiple ongoing trials to guide the supplementation regimen of fibrinogen concentrate in trauma patients. In addition, we likewise need to consider a variety of other therapeutic avenues, including the use of antifibrinolytic drugs.
Cardiovascular Surgery
Patients undergoing cardiovascular surgery often have a combination of bleeding because of multiple coagulation defects including cardiopulmonary bypass, tissue injury, and dilutional changes. A number of factors influence bleeding in these patients, including reoperation, surgical procedures, timing of cardiopulmonary bypass, renal insufficiency, and other related factors.
In addition, patients undergoing cardiac surgery have hemostatic changes consistent with diffuse intravascular coagulation (DIC), such as increased D-dimer, reduced fibrinogen, prolonged PT and APTT, reduced platelets, and low antithrombin levels.
Studies have reported that for coronary artery bypass grafting, preoperative fibrinogen levels are an independent predictor of postoperative bleeding and the need for bleeding. Preoperative fibrinogen levels below 3 g/L were associated with significantly increased intraoperative blood loss and the need for postoperative transfusion.
A prospective, observational study of 1956 patients undergoing cardiac surgery found a significant increase in extensive bleeding in patients with low fibrinogen. The study recommended transfusion of allogeneic blood products to replenish fibrinogen and thereby reduce bleeding.
A study of 61 patients with bleeding after extracorporeal circulation found that for half of the patients, preoperative transfusion of fibrinogen concentrate avoided postoperative transfusion compared with placebo. Other prospective and retrospective studies of cardiac surgery have shown that fibrinogen concentrate reduces postoperative bleeding and allogeneic blood product transfusions.
Obstetric bleeding
Postpartum hemorrhage (PPH) is an important cause of death in women and has been the focus of research in clinical trials. Severe, persistent PPH is defined as active bleeding greater than 1,000 ml 24 h after delivery, despite the use of hemostatic measures such as contractions and uterine massage.
Several studies have reported that fibrinogen is an important predictor of PPH and severe PPH, and that low fibrinogen levels are associated with PPH progression. Low fibrinogen levels and FIBTEM values imply longer bleeding, the need for invasive maneuvers, longer transfusion dependence and the need for earlier transfusions.
Fibrinogen was the only laboratory parameter associated with severe PPH, with a 2.63-fold increase in risk for every 1 g/L reduction in fibrinogen. The negative predictive value for fibrinogen >4 g/L was 79%, and the positive predictive value for fibrinogen ≤2 g/L was 100%.
A case-control study that included three groups of female patients with severe PPH, non-severe PPH, and asymptomatic controls showed that fibrinogen <2 g/L was an independent correlate of increased risk of severe PPH. Another report showed that fibrinogen <2g/L was 99% specific in predicting severe PPH.
Further studies found an important role for fibrinogen concentrate therapy in PPH patients with hypofibrinogenemia. Patients with fibrinogen <2g/L often have severe bleeding, in which case they can be treated rapidly with fibrinogen concentrate without the need for blood type matching.
Studies have been conducted to investigate whether early treatment with fibrinogen concentrate can reduce blood transfusions in patients with PPH. Preliminary studies have found that it can reduce the transfusion of allogeneic blood products.
Plastic surgery
Plastic surgery is often combined with blood loss, dilutional coagulopathy, and impaired fibrin polymerization. A prospective study of 66 patients found that supplementation with fibrinogen concentrate may maintain clot firmness. Another study of pediatric patients undergoing cranial attachment repair showed that repeated supplementation of fibrinogen concentrate could achieve hemostasis without blood transfusion.
In conclusion
Fibrinogen is an important hemostatic protein in the prevention and treatment of bleeding, and fibrinogen levels are best supplemented by cold precipitation and commercial fibrinogen concentrates. A growing number of studies are exploring the application of fibrinogen as a therapeutic target for acquired coagulopathies.
A variety of modalities should be used to treat bleeding patients, including supplementation with other coagulation proteins, antifibrinolytic drugs, and blood product transfusions such as red blood cells and platelets. For coagulopathy bleeding, fibrinogen concentrates are an important therapeutic option that may reduce allogeneic blood product transfusions. Future multicenter studies are still needed to determine, for different clinical situations, the optimal dose and targeting threshold for fibrinogen therapy.