The Importance of Fibrinogen in the Management of Cardiac Surgical Bleeding

Definition and Etiology

Figure 1.

Fibrinogen is a plasma glycoprotein which plays pivotal roles in clot formation and wound healing. It is synthesized by the liver, and is also known as factor I. The fibrinogen molecule (molecular weight ~340 kDa) is comprised of two sets of three polypeptide (Aα, Bβ, γ) chains bonded together by disulfides.^1,2 In the early phase of hemostatic reaction, fibrinogen is necessary to stabilize platelet aggregates that are anchored by von Willebrand factor at the site of vascular injury (Figure 1). During coagulation, fibrinogen is converted into fibrin by thrombin, and fibrin fibers are cross-linked by activated factor XIII to form polymerized chains (clot). Fibrinogen also plays an important role in maintaining plasma viscosity, which increases the shear rate of blood flow, and supports procoagulant responses. Age, gender and race seem to play some roles in the homeostasis of fibrinogen.¹ Chronically elevated fibrinogen levels are associated with the risk of cardiovascular events.¹ However, patients who become acutely deficient of fibrinogen after major surgery or trauma are likely to experience increased bleeding as a result of impaired clot formation, often due to fibrinogen levels below 60-70 mg/dL.³

The deficiency of fibrinogen is categorized as either acquired or congenital. Acquired deficiency is typically encountered after hemorrhagic or dilutional loss of fibrinogen, and after excessive fibrinolysis (e.g., fibrinolytic therapy).^2,3 A consumptive loss of fibrinogen can result from disseminated intravascular coagulation in sepsis or from a complication of pregnancy (e.g, abruptio placentae). Acquired fibrinogen deficiency may be also caused by decreased hepatic synthesis of fibrinogen.

There are three forms of congenital (hereditary) fibrinogen deficiency: afibrinogenemia, hypofibrinogenemia and dysfibrinogenemia.^4,5 Afibrinogenemia is diagnosed as a complete absence of fibrinogen, while hypofibrinogenemia is characterized by significantly low levels of fibrinogen. Dysfibrinogenemia, diagnosed in approximately one person per one million, is a qualitative defect in which circulating fibrinogen levels are normal, yet fibrinogen does not function properly.

Standard coagulation testing, prothrombin time (PT) and activated partial thromboplastin time (aPTT), may indicate a deficiency of fibrinogen by showing absent or delayed clot formation when fibrinogen is below 100 mg/dL (< 60 – 70 mg/dL for aPTT). Thrombin-activated clotting time (thrombin time, TT) also detects hypofibrinogenemia (< 100 mg/dL).

Causes of Fibrinogen Depletion in Cardiac Surgical Procedures

Maintaining the proper levels of fibrinogen is critical in preventing major hemorrhage. This is especially important during cardiac surgery, as cardiac patients normally are administered antithrombotic therapies to prevent their blood from clotting.⁶

Cardiac surgical procedures often involve major hemodynamic and hematologic perturbations that affect plasma fibrinogen levels. Complex anastomoses and hemorrhage during surgery and the duration of extracorporeal circulation result in a major loss of fibrinogen and other coagulation factors. The shed blood becomes depleted of plasma proteins once it is processed through the cell salvage unit (e.g., Cell Saver) to recover red blood cells.⁷

In particular, fluid resuscitation after cardiac surgery may result in extensive hemodilution and coagulopathy. The amount of fluid, including crystalloids, albumin and synthetic colloids (hydroxyethyl starch), can be significant during cardiac surgery, resulting in low plasma fibrinogen levels (below 100–150 mg/dL).⁸ Adequate fibrinogen levels are necessary to successfully manage dilutional coagulopathy. Normal clot firmness is measured by normal platelet and fibrinogen levels, which are calculated at 2.0 to 4.5g/l in healthy patients.^9,10 There is a noticeable decrease in clot firmness when platelet count and fibrinogen levels decline. Even when normal platelet count is maintained, the fibrinogen level of approximately 100 mg/dL is associated with severe hemorrhage.¹⁰ The threshold level of fibrinogen at 100 mg/dL is observed after a loss of 100–150% of circulating blood volume depending on the preoperative fibrinogen levels and the body size.^11,12 Further, fibrin clots are more prone to fibrinolysis because major antifibrinolytic proteins are decreased after extensive hemodilution.¹³

Figure 2.

The deficiencies of fibrinogen and antithrombin in severe hemodilution can be detrimental to the control of procoagulant activity. Without adequate fibrin polymerization, thrombin and activated FX generated at the injury site are released into systemic circulation. These activated proteases exacerbate disseminated intravascular coagulation in conjunction with low levels of anticoagulant factors. It is not known what minimal levels of fibrinogen should be kept to minimize perioperative bleeding. The international guidelines before 2009 recommended minimal fibrinogen levels between 80 and 100 mg/dL; however, more recent European guidelines recommend higher fibrinogen cutoffs (150–200 mg/dL) for perioperative coagulopathy (Figure 2).

Additional Considerations When Treating the Cardiac Surgical Patient

The preoperative use of oral anticoagulants, common for the prevention of atrial fibrillation, ischemic strokes and venous thromboembolism can result in decreased fibrin formation.⁶ Warfarin is a vitamin K inhibitor that decreases plasma factors II (prothrombin), VII, IX and X, all of which are critical in generating hemostatic levels of thrombin.¹⁴ Novel oral anticoagulants including dabigatran (thrombin inhibitor) and rivaroxaban (factor Xa inhibitor) also affect thrombin generation. The conversion of fibrinogen to fibrin is delayed or decreased by these anticoagulant agents. A rapid restoration of thrombin generation in warfarin-treated patients can be most efficiently achieved with prothrombin complex concentrate along with vitamin K.¹⁵ Fresh-frozen plasma (FFP) is often used for acute warfarin reversal with vitamin K, but large amounts (15–30 ml/kg) may be required to restore PT. No direct antidote is available for dabigatran or rivaroxaban.

Treatment

Timely and effective hemostatic management is important in cardiac and other major surgery because excess uses of allogeneic blood transfusion worsen clinical outcomes.^16,17 Antifibrinolytic agents such as ε-aminocaproic acid and tranexamic acid are prophylactically used to reduce bleeding during cardiac surgery. These agents prevent the break-down of fibrin by plasmin, but they are only effective if sufficient fibrin polymers are formed for hemostasis at the site of vascular injury. Desmopressin (1-deamino-8-d-arginine vasopressin) has been used during cardiac surgery with inconsistent hemostatic results and with a potentially increased risk of myocardial infarction.¹⁸ Several recent literatures indicated that a rapid fibrinogen replacement using purified human fibrinogen concentrate to achieve plasma fibrinogen level of ~360 mg/dL improved hemostasis after aortic replacement surgery.¹⁹

In North America, acquired fibrinogen deficiency has been treated primarily with the infusion of FFP or cryoprecipitate. While these plasma products contain fibrinogen, the dosage and duration of each therapy is dependent upon each patient’s bleeding condition and the surgical procedure.¹⁴ Precise dosing for replacement is preferable, but it is often difficult to determine because the fibrinogen content is variable among different units of FFP or cryoprecipitate.²⁰

FFP transfusions are utilized specifically in cases of severe coagulopathy to increase the plasma level of all coagulation factors above 30 percent.^10,21 The general recommendation for this therapy is two units in an adult, which will raise each factor approximately 2 to 3 percent.²² Each unit of FFP contains fibrinogen in the range of 400 to 800 mg (per 250 ml), and thus each bag administered will raise fibrinogen levels an average of 8.0 mg/dL in an average adult (70 kg body weight).²³

Cryoprecipitate therapy is administered using 10 units of frozen plasma thawed at a controlled temperature of 4ºC.²⁴ Each unit of cryoprecipitate contains approximately 350 milligrams of fibrinogen.²⁵ The use of cryoprecipitate can rapidly increase plasma fibrinogen; however, there are few clinical studies that support its efficacy and safety because the thawing and pooling process that must be completed prior to treatment can delay the replacement up to two hours. ²⁶

While FFP (in sufficient volumes) and cryoprecipitate can be used to raise fibrinogen levels, some countries are restricting the use of either therapy because of their practical limitations.²⁷ Besides obvious needs for thawing and blood type matching, these products carry potential risks for immunomodulation, and volume overload. Immunoglobulins and other proteins in these components have been shown to cause anaphylaxis and/or allergic reactions that cause symptoms such as itching, hives and rash in 20 to 30 percent of patients.²⁸ Other studies have shown that large volumes of FFP and cryoprecipitate transfusion can cause intravascular hemolysis and increase risk of transfusion-associated circulatory overload (TACO), which occurs in an estimate of 1 in 100 to 1 in 100,000 transfusions.^29-31 Furthermore, FFP, cryoprecipitate and other plasma products are not routinely treated with the virus elimination procedure. While strict donor selection and sensitive testing of each donation have reduced the risk of infection, it still remains a potential threat to patients.³²

Conclusion

Understanding the impacts of preoperative anticoagulation, intraoperative hemorrhage and hemodilution on fibrinogen levels is pivotal in the management of clinical bleeding after complex cardiac surgery. Hemostatic roles of fibrinogen are diverse; therefore its interactions with platelets and other coagulation factors need to be optimized to establish hemostasis without causing thrombotic complications. The cardiac surgery care team should be aware of perioperative fibrinogen levels, so that timely and effective therapies can be implemented to correct fibrinogen deficiencies. Given current limitations on the monitoring and therapies related to acquired fibrinogen deficiency, it is also important for the professional societies and biological industries to invest in the research and development of new modalities and strategies for the management of this challenging and potentially life-threatening coagulation disorder.

References

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Publication Date: 3-Jul-2012
Last Modified: 20-Jun-2012