Re: Three versus four-factor prothrombin complex concentrates for “factor-based” resuscitation in a porcine hemorrhagic shock model

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To the Editor:
In reporting their study of 3- and 4-factor prothrombin complex concentrate (PCC) in hemorrhagic shock and coagulopathy, Moe et al1 have made an important contribution to the question whether PCCs can be used as an alternative to therapeutic plasma in trauma-related bleeding. Compared with therapeutic plasma, coagulation factor concentrates provide much higher concentrations of coagulation factors, enabling treatment with smaller infusion volumes. Coagulation factor concentrates can also be administered considerably more rapidly than therapeutic plasma. However, in the case of PCC, there are some important safety considerations as highlighted by the study of Moe et al. PCC was administered to pigs at a dose of 45 IU/kg, and consumptive coagulopathy was observed in 67% of animals receiving 3-factor PCC and 25% of those receiving 4-factor PCC.1 As mentioned in the discussion, it is possible that consumptive coagulopathy was a sign of disseminated intravascular coagulopathy.
PCCs supplement levels of coagulation factors II, IX, and X (with 4-factor PCCs, factor VII as well), and the principal effect is increased thrombin generation potential. In one arm of the Moe et al. study, animals received therapeutic plasma in addition to 4-factor PCC. Coadministration of the range of coagulation factors in plasma may have been expected to improve outcomes, but this was not observed. One explanation might be that because fresh frozen plasma (FFP) provides similar levels of procoagulants and anticoagulants, it cannot correct for an overload of procoagulants caused by PCC.
In patients with low thrombin generation but normal levels of anticoagulants (as in patients receiving warfarin), PCC therapy has been shown help to restore hemostasis. However, in other clinical settings, where levels of anticoagulants as well as procoagulants may be depleted, the dose of PCC must be selected more carefully. In trauma patients treated with PCCs, increased thrombin generation potential has been shown to persist for several days.2 Moreover, in an animal study, we showed that PCC at a dose of 50 IU/kg after trauma and dilution coagulopathy led to protracted activation of coagulation, with thromboembolic complications and signs of disseminated intravascular coagulopathy.3 Thrombin generation measurements revealed insufficient inhibition of thrombin by antithrombin (AT).
In vitro studies performed more than 10 years ago identified factor II (FII) as the most likely thrombogenic component in PCC, and showed that the ratio of procoagulants to anticoagulants needs to be within the physiologically normal range for normal levels of thrombin generation.4 PCC therapy is more likely to raise the ratio of procoagulants to anticoagulants when it is being used for treatment of trauma-related bleeding than for anticoagulant reversal. Because PCCs contain trace or non-existent levels of AT, their administration is likely to increase the patient’s plasma FII/AT ratio above physiologically normal levels.
Studies by Mitrophanov et al.5 suggest that coadministration of AT with PCC may reduce hypercoagulopathic tendency. Currently there is no evidence regarding the best approach to coadministering AT with PCC (e.g. triggers for treatment, optimal dosing). Further possible means of optimizing the benefit-risk ratio include measuring variables such as clotting time/r-time in viscoelastic coagulation assays, so that PCC is administered only when the patient’s need for increased thrombin generation has been confirmed.
PCC may be considered as preferable to therapeutic plasma for increasing patients’ thrombin generation, but other deficiencies of the coagulation system must be treated separately. Moreover, the potential risk of hypercoagulation must be minimized whenever administering PCC.
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