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Fibrinogen Deficiency: A Fundamental Risk Factor for Cardiac Surgery

Hemostatic imbalance is a common occurrence in cardiothoracic surgical patients, particularly those who endure prolonged cardiopulmonary bypass (CPB). Causative factors include consumptive loss of coagulation factors, platelet defects, hemodilution, residual anticoagulation, and fibrinolysis; additional aggravating factors may include anemia, hypothermia, and acidosis. Together, these factors compromise efforts to establish and maintain hemostasis.1,2

Early identification of patients at increased risk of excessive bleeding resulting in transfusion provides clinicians the opportunity to initiate countermeasures and improve outcomes.3 Increasingly, fibrinogen has garnered attention as a potential biomarker for perioperative bleeding in cardiothoracic surgery.3 “Fibrinogen is the precursor to fibrin, which is the basis of clot formation and clot strength,” notes Dr. Aryeh Shander, Chief of Anesthesiology, Critical Care Medicine, Pain Management, and Hyperbaric Medicine at Englewood Hospital and Medical Center in Englewood, New Jersey. “The amount of fibrinogen available to create a clot is very important. Thrombin is responsible for generating fibrin from fibrinogen or factor I, and so a deficiency of factor I is a significant risk factor for bleeding…specifically in cardiac surgery.”4

“A deficiency of factor I is a significant risk factor for bleeding…specifically in cardiac surgery.”


Fibrinogen and Bleeding Risk

Fibrinogen is an acute-phase reactant protein that works by stabilizing platelet plugs at the site of vascular injury. It is a key protein in the coagulation cascade.1-3 The relationship between perioperative fibrinogen plasma concentration and postoperative bleeding after coronary artery bypass grafting (CABG) was the subject of an investigation by Karlsson and colleagues.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 gender (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 to obtain information predictive of bleeding volume and transfusion requirements after CABG
Preoperative fibrinogen concentration, even if it falls within the normal range, is a limiting factor for postoperative hemostasis.


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 blood loss. Such patients seem to benefit from early intervention with fibrinogen concentrate. Acquired fibrinogen deficiency 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.5-7

In a study of preoperative fibrinogen levels in patients undergoing open heart surgery, Ucar and colleagues reported that most hemostatic factors in cardiac surgery are intercorrelated with postoperative bleeding.8 Fibrinogen appears to be the most fundamental hemostatic risk factor in this subset. Study highlights include the following8:
  • A statistically significant relationship exists between fibrinogen level and chest tube drainage r=-0.897; P<.001)
  • Fibrinogen level and relationship to age was statistically significant (P=.015)
  • No statistically significant relationship was found between fibrinogen level 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)
  • Low preoperative fibrinogen level appears to be a useful and potential diagnostic marker for assessing the activity of the coagulation system. The preoperative level of fibrinogen may be a prognostic factor for postoperative bleeding after CABG
“We could potentially utilize preoperative measurement of fibrinogen to assess the risk of bleeding,”4 observes Dr. Shander. He points to emerging data from Europe that support the implementation of measuring preoperative fibrinogen concentration as standard procedure, particularly in the cardiothoracic surgery population.

Correcting Acquired Fibrinogen Deficiency: Current and Emerging Strategies

Strategies for elevating fibrinogen levels in patients with acquired fibrinogen deficiency include the administration of fresh frozen plasma or cryoprecipitate. Fresh frozen plasma administration is routinely used in patients with significant blood loss and has the advantage of containing all of the clotting factors. 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.9 Thus, it is extremely difficult to increase fibrinogen concentrations without inducing volume overload, which may lead to congestive heart failure or interference with oxygenation in vulnerable populations.4

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.9

In a retrospective analysis, Tanaka and colleagues reported that the onset of fibrin formation and thrombin generation was reduced after recombinant factor VIIa (rVIIa) administration, but fibrin clot strength was only improved after supplementation with exogenous fibrinogen.2 The combination of rVIIa and fibrinogen improves the onset and stability of thrombus formation in the cardiac patient, and thus the treatment of bleeding in surgical patients following CPB with rVIIa might be optimized by first normalizing fibrinogen levels.2

Fenger-Eriksen et al noted a significant increase in plasma fibrinogen concentration following fibrinogen concentrate therapy. Platelet counts and fibrin D-dimer values were unchanged, whereas the aPTT and PT were significantly improved. Off-label substitution therapy with a fibrinogen concentrate generally improved global laboratory coagulation results and appeared to lessen requirements for red blood cells, fresh frozen plasma, and platelet substitution when employed as supplementary intervention.1

The optimal level of fibrinogen for managing dilutional coagulopathy is not definitively known 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.9

To study the issue of optimal fibrinogen level for reversing dilutional coagulopathy, Bolliger and colleagues performed an in vitro investigation.9 They found that the rate of clot formation was optimized when the target plasma concentration for fibrinogen replacement was 200 mg/dL or greater—twice the level suggested by 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.9

To date, no studies have demonstrated an increased risk for thrombosis with administration of fibrinogen concentrate, although more and larger studies are needed to demonstrate safety.4 Additional information on fibrinogen deficiency as a fundamental risk factor in cardiac surgery can be found in the Blood CME Center podcast, “Current Trends in Coagulation: The Correlation Between Fibrinogen Levels and Surgical Hemostasis,” featuring expert commentary by Dr. Shander.

References
     
  1. Fenger-Eriksen C, Lindberg-Larsen M, Christensen AQ, Ingerslev J, Sørensen B. Fibrinogen concentrate substitution therapy in patients with massive haemorrhage and low plasma fibrinogen concentrations. Br J Anaesth. 2008;101:769-773.
    2.  
  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.  
  3. Karlsson M, Ternstrom L, Hyllner M, Baghaei F, Nilsson S, Jeppsson A. Plasma fibrinogen level, bleeding, and transfusion after on-pump coronary artery bypass grafting surgery: a prospective observational study. Transfusion. 2008;48:2152-2158.
    4.  
  4. Shander A. Current Trends in Coagulation: The Correlation Between Fibrinogen Levels and Surgical Hemostasis. Available at: www.bloodcmecenter.org.
    5.  
  5. Fenger-Eriksen C, Ingerslev J, Sørensen B. Fibrinogen concentrate—a potential universal hemostatic agent. Expert Opin Biol Ther. 2009;9:1325-1333.
    6.  
  6. 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.
    7.  
  7. Fenger-Eriksen C, Tønnesen E, Ingerslev J, Sørensen B. Recombinant factor VIIa and fibrinogen display additive effect during in vitro haemodilution with crystalloids. Acta Anaesthesiol Scand. 2009;53:332-338.
    8.  
  8. 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.
    9.  
  9. Bolliger D, Szlam F, Molinaro RJ, Rahe-Mayer N, Levy JH, Tanaka KA. Finding the optimal concentration range for fibrinogen replacement after severe haemodilution: an in vitro model. Br J Anaesth. 2009;102:793-799.



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