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Clinical and Practical Aspects of Restoring Thrombin Generation in Acute Coagulopathic Bleeding

Tanaka, Kenichi A. MD, MSc; Bolliger, Daniel MD; Guzzetta, Nina A. MD

doi: 10.1213/ANE.0000000000001766
Letters to the Editor: Letter to the Editor

Department of Anesthesiology, University of Maryland, Baltimore, Maryland,

Department for Anesthesia, Surgical Intensive Care, Prehospital Emergency Medicine and Pain Therapy, University Hospital Basel, Basel, Switzerland

Department of Anesthesiology, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, Georgia

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To the Editor

We have read the work by Mitrophanov et al1 with great interest. Their focus was to model the optimal use of prothrombin complex concentrate (PCC), FVIIa, or antithrombin (AT) to achieve a “balanced thrombin generation (TG) pattern” in dilutional coagulopathy. They performed an in vitro supplementation of specific factors (Factor [F] II, FVII, FIX, FX, activated FVII [FVIIa], and AT) in diluted blood samples from 10 healthy subjects and tested for the recovery of TG. Subsequently, they did extensive computer simulation of TG to determine a best fit modeling by randomizing kinetic parameters using the above data. They concluded that (1) PCC in combination with AT would be more desirable than FVIIa in normalizing TG and (2) PCC without FVII should be preferred because the function of FVII is uncertain. However, we have noted several major discrepancies between their in vitro dilutional model and trauma-induced coagulopathy in vivo. First, severe AT deficiency (mean, 37%)1 is only observed in extremely severe trauma; AT activity in the majority of trauma cases (n = 377, Injury Severity Score [ISS] of 18) is generally close to normal (mean, 68%–79%).2 Further increasing AT may reduce endogenous procoagulant activity as demonstrated in the prolonged lag time of TG by Mitrophanov et al1 (Figure 5B). In vivo activation of protein C and exogenous AT would further reduce TG. Second, the activity of FVII or FVIIa is likely underestimated in the relatively mild FVII deficiency (mean, 39%)1 and moderate TF level (5 pM) on TG assay.3 Hypothermia and acidosis in trauma patients may reduce the rate of procoagulant reactions after PCC 4; thus, there may be a role for FVIIa to increase TG rate. Third, the authors mentioned the static nature of TG assay/simulation as a major limitation of their study. Indeed, lack of blood flow keeps all “generated thrombin” locally, but blood flow itself provides efficient removal of active enzymes from the vascular injury site. Finally, coadministration of PCC and AT concentrates in their model can be costly because roughly 30 international units (IU) per kilogram of PCC ($1.84 per IU) and AT ($4.43 per IU) would be required to increase factors from 40% to 100%. For an 80-kg patient, the total cost amounts to $15,000. A lower dose of 10 to 15 IU per kg of PCC without AT is less costly ($1500–$2200 per dose) and may be sufficient to increase TG in dilutional coagulopathy.5 In conclusion, there is limited clinical evidence to support the addition of AT to PCC in active bleeding situations. The role of AT supplementation for postoperative thromboprophylaxis may be substantiated but requires further investigation.

Kenichi A. Tanaka, MD, MSc

Department of Anesthesiology

University of Maryland

Baltimore, Maryland

Daniel Bolliger, MD

Department for Anesthesia, Surgical Intensive Care,

Prehospital Emergency Medicine and Pain Therapy

University Hospital Basel

Basel, Switzerland

Nina A. Guzzetta, MD

Department of Anesthesiology

Emory University School of Medicine

Children’s Healthcare of Atlanta

Atlanta, Georgia

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1. Mitrophanov AY, Szlam F, Sniecinski RM, Levy JH, Reifman J. A step toward balance: thrombin generation improvement via procoagulant factor and antithrombin supplementation. Anesth Analg. 2016;123:535–546.
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5. Franklin SW, Szlam F, Fernandez JD, Leong T, Tanaka KA, Guzzetta NA. Optimizing thrombin generation with 4-factor prothrombin complex concentrates in neonatal plasma after cardiopulmonary bypass. Anesth Analg. 2016;122:935–942.
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