Clinical Brief from the Blood CME Center Faculty

• Preoperative measurement of fibrinogen concentration provides information about bleeding volume and transfusion requirements after coronary artery bypass grafting (CABG)
• New data suggest that fibrinogen plays a critical role in achieving and maintaining hemostasis
• CABG patients experiencing massive hemorrhage are at high risk of developing coagulopathy

Fibrinogen is an important coagulation factor that plays a major role in producing effective clot in surgical patients, although this role is often overlooked. Fibrinogen levels represent an important predictor of perioperative bleeding.¹

In surgical patients who endure prolonged cardiopulmonary bypass, hemostatic imbalance often results. Contributing factors include consumptive loss of coagulation factors, hemodilution, hypothermia, residual anticoagulation, and fibrinolysis. These clinical conditions cause reductions from baseline of 40% to 50% in most procoagulant plasma factors, and platelet numbers and function are also often reduced.²

The early identification of patients who are at increased risk of excessive bleeding and transfusion requirements after cardiac surgery presents the surgical team with an opportunity to assess patients' plasma fibrinogen levels as part of the strategy for restoring and maintaining perioperative hemostasis.

Fibrinogen is a key protein in the coagulation cascade and thus a potential biomarker for bleeding. Karlsson and colleagues investigated the relationship between perioperative fibrinogen plasma concentration and postoperative bleeding and transfusion after CABG.³ They found that postoperative bleeding volume correlated univariately with preoperative fibrinogen concentration (r=-0.53; P<.001) and platelet count (r=-0.26; P=.001). However, only preoperative fibrinogen concentration was an independent predictor of postoperative bleeding volume. Preoperative fibrinogen concentration was also an independent predictor of transfusion (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.1—3.7 per 1-unit decrease; P=.027) as were female sex (OR, 5.0; 95% CI, 1.8-14.7; P=.002) and aortic cross-clamp time (OR, 1.03; 95% CI, 1.01-1.06 per minute; P=.013).³

The investigators concluded that:

• Preoperative fibrinogen concentration, even if it falls within the normal range, is a limiting factor for postoperative hemostasis
• Preoperative measurement of fibrinogen concentration is important in order to obtain information predictive of bleeding volume and transfusion requirements after CABG

Recent data suggest that fibrinogen plays a critical role in achieving and maintaining hemostasis, particularly in patients in whom acquired fibrinogen deficiency develops during massive bleeding. Such patients appear to benefit from early intervention with fibrinogen concentrate. Acquired deficiency of fibrinogen appears to be an early event in seriously bleeding patients and precedes the development of critically low levels of platelets and alterations in other coagulation factors.^4-6

Ucar and colleagues studied preoperative fibrinogen levels in patients undergoing open heart surgery.⁷ They reported that most hemostatic factors in cardiac surgery are intercorrelated with postoperative bleeding. Fibrinogen seems to be the most fundamental hemostatic risk factor for patients undergoing open heart surgery.⁷

The investigators concluded that:

• There was a statistically significant relationship between fibrinogen levels and drainage (r=-0.897; P<.001)
• Mean chest drainage was 972 mL (range, 240-2445 mL) in the first 48 hours after sternotomy closure
• Fibrinogen level and relationship to age was statistically significant (P=.015)
• There was no statistically significant relationship between fibrinogen levels and gender (male=400.7 ± 123.0 vs female=395.6 ± 148.1; P=.877) or between drainage and gender (male=968.2 ± 538.5 vs female=990.0 ± 554.7; P=.876)
• Study results suggest that low preoperative fibrinogen level is a useful diagnostic marker for assessing the activity of the coagulation system. The preoperative level may be a prognostic factor for postoperative bleeding after CABG

Blome and colleagues confirmed that chest-tube bleeding following CABG was significantly correlated with both preoperative and postoperative fibrinogen level. They concluded that fibrinogen level may modulate postoperative bleeding.⁸

Emerging Data on Fibrinogen Replacement Therapy

The role of fibrinogen as a critical coagulation factor in ensuring adequate hemostasis has been the subject of recent clinical interest. Emerging data suggest that fibrinogen is important in maintaining perioperative hemostasis, especially in patients with acquired fibrinogen deficiency who develop massive hemorrhage.⁹ Patients experiencing massive hemorrhage are at high risk of developing coagulopathy through loss, consumption, and dilution of coagulation factors and platelets.⁹

For more information on managing perioperative hemostasis, click on the following programs that feature cardiothoracic and hepatic surgical procedures.

The optimal level of fibrinogen for managing dilutional coagulopathy remains unclear, because most studies have been performed using a single concentration of fibrinogen to reverse this condition. International guidelines suggest a minimal fibrinogen concentration above 80 to 100 mg/dL, but there is very little information to support this recommendation.¹⁰

After major blood loss, fresh frozen plasma is frequently administered for the stated purpose of improving “hemostasis.”¹⁰ However, administration of 10 to 15 mL/kg, the recommended dosage, increases fibrinogen by only 40 mg/dL, whereas 30 mL/kg of fresh frozen plasma increases fibrinogen by 100 mg/dL. Thus, it is extremely difficult to increase fibrinogen concentrations without inducing volume overload. Cryoprecipitate provides more concentrated fibrinogen (about 150 to 250 mg/10 mL), but it is not available in a pathogen-inactivated form. Pasteurized fibrinogen concentrate is preferred for instances of low volume requirement (2 g in 50 mL) and low infectious risks.¹⁰

To study the issue of the optimal level of fibrinogen for reversing dilutional coagulopathy, Bolliger and colleagues performed an in vitro investigation.¹⁰ They concluded that the target plasma concentration for fibrinogen replacement was 200 mg/dL or greater, as only these concentrations optimized the rate of clot formation. This concentration is twice the level suggested by the current transfusion guidelines. Although clotting was improved, the clots were prone to fibrinolysis, indicating that co-existing fibrinolytic tendency occurring during dilutional coagulopathy may influence the efficacy of fibrinogen therapy.¹⁰




References

1. Levy JH, Tanaka KA. Prohemostatic agents to prevent perioperative blood loss. Semin Thromb Hemost. 2008;34:439-444. 
 
2. Tanaka KA, Taketomi T, Szlam F, et al. Improved clot formation by combined administration of activated factor VII (NovoSeven) and fibrinogen (Haemocomplettan P). Anesth Analg. 2008;106:732-738.
 
3. Karlsson M, Ternström L, Hyllner M, et al. Plasma fibrinogen level, bleeding, and transfusion after on-pump coronary artery bypass grafting surgery: a prospective observational study. Transfusion. 2008;48:2152-2158.
 
4. Fenger-Eriksen C, Ingerslev J, Sørensen B. Fibrinogen concentrate–a potential universal hemostatic agent. Expert Opin Biol Ther. 2009;9:1325-1333.
 
5. Fenger-Eriksen C, Jensen TM, Kristensen BS, et al. Fibrinogen substitution improves whole blood clot firmness after dilution with hydroxyethyl starch in bleeding patients undergoing radical cystectomy: a randomized, placebo-controlled clinical trial. J Thromb Haemost. 2009;7:795-802.
 
6. Fenger-Eriksen C, Tønnesen E, Ingerslev J, et al. Recombinant factor VIIa and fibrinogen display additive effect during in vitro haemodilution with crystalloids. Acta Anaesthesiol Scand. 2009;53:332-338.
 
7. Ucar HI, Oc M, Tok M, et al. Preoperative fibrinogen levels as a predictor of postoperative bleeding after open heart surgery. Heart Surg Forum. 2007;10:E392-E396.
 
8. Blome M, Isgro F, Kiessling AH, et al. Relationship between factor XIII activity, fibrinogen, haemostasis screening tests and postoperative bleeding in cardiopulmonary bypass surgery. Thromb Haemost. 2005;93:1101-1107.
 
9. Fenger-Eriksen C, Lindberg-Larsen M, Christensen AQ, et al. Fibrinogen concentrate substitution therapy in patients with massive haemorrhage and low plasma fibrinogen concentrations. Br J Anaesth. 2008;101:769-773.
 
10. Bolliger D, Szlam F, Molinaro RJ, et al. Finding the optimal concentration range for fibrinogen replacement after severe haemodilution: an in vitro model. Br J Anaesth. 2009;102:793-799.