3 factor vs 4 factors...
Aside from the excitement of the recently FDA approved four-factor PCC product in the USA, a somewhat obvious, yet important question exists: is why are four factor PCCs better than three factor PCCs?1 Unfortunately in the literature, there is no direct head-to-head data to compare these two classes of PCC. From this broad of a view, it would appear that there is no difference. However, upon further investigation, there are important differences to consider clinically and also for future study.
Through reading, and contemplating this question, I came across a compelling letter to the editor in response to an article asking the same question. This letter to the editor asked, with regard to three or four factor PCCs, what re we really looking for? Specifically, is INR reversal the appropriate outcome measure to analyze?
With regard to normal warfarin therapeutic use, the INR correlates with its antithrombotic effects. Ultimately warfarin’s therapeutic effects are as a result of a reduction in the production of prothrombin (factor II). Since warfarin (and other VKAs) symmetrically inhibit the production/activation of the vitamin K dependent clotting factors (II, VII, IX and X), the INR, a measure of factor deficiencies in the extrinsic and common coagulation pathways (encompassing factors II, V, VII and X), becomes prolonged. This measures simply the presence of factors, rather than generation of prothrombin and thrombin, and is subject to change if factors are supplemented (ex: factor VIIa). In other words, the INR could be ‘corrected’ but the patient may not have achieved hemostasis since more factors are around. From one point of view, this could explain why rFVIIa reverses the INR exquisitely but no change in thrombin generation in animal models and healthy volunteers.2,3
Conversely, measuring actual thrombin generation (and thus activity of warfarin and effectiveness of the entire hemostatic process) is possible and may be a more effective tool once made more accessible and improved turn-around-time. Various thrombogenicity markers have been used for investigational purposes that may not translate into useful clinical tools. Peak thrombin levels and prothrombin activation fragments 1 and 2, endogenous thrombin potential and thrombin-antithrombin complex are some examples of thrombobenicity markers used in the literature.2,4,5 Four factor PCCs such as Beriplex (aka Kcentra) have demonstrated the ability to transiently increase thrombogenicity markers in addition to INR correction.6,7
Thromboelastography (TEG) and rotational thrombelastometry (ROTEM) tests are able to analyze the clot formation in whole blood. Importantly with respect to VKAs, these test are able to analyze the patient’s ability to generate thrombin, thus reflecting the entire hemostatic process. In addition, these test are available and therefore, are of more value in the clinical setting. However, no prospective head-to-head comparisons with INR correlating with clinical hemostasis have been done, just like everything else in this data field.
Never the less, INR may not be the most appropriate surrogate marker for hemostasis after using any of the theorized factors. But considering the available evidence, Beriplex (aka Kcentra), appears to not only reverse the INR, but likewise, thrombogenicity markers and potentially hard outcomes.
More to follow regarding dabigatran, rivaroxaban and apixaban.
1. Marietta M, Pedrazzi P, Luppi M. Three- or four-factor prothrombin complex concentrate for emergency anticoagulation reversal: what are we really looking for? Blood Transfus 2011; 9: 469
2. Taketomi T,Szlam F,Levy JH, et al. Warfarin reversal with prothrombin complex concentrate confers better antifibrinolytic activity compared with recombinant activated factor VII [letter]. Blood Coagul Fibrinolysis 2008; 19 (1): 106-8
3. Skolnick BE, Mathews DR, Khutoryansky NM, Pusateri AE, Carr ME. Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects. Blood 2010;116:693-701
4. Ostermann H, Haertel S, Knaub S, et al. Pharmacokinetics of Beriplex P/N prothrombin complex concentrate in healthy volunteers. Thromb Haemost 2007; 98 (4): 790-7
5. Pabinger I, Brenner B, Kalina U, et al. Prothrombin com- plex concentrate (BeriplexÒ P/N) for emergency antic- oagulation reversal: a prospective multinational clinical trial. J Thromb Haemost 2008; 6 (4): 622-31
6. Staudinger T, Frass M, Rintelen C, et al. Influence of pro- thrombin complex concentrates on plasma coagulation in critically ill patients. Intensive Care Med 1999; 25 (10): 1105-10
7. Evans G, Luddington R, Baglin T. Beriplex P/N reverses severe warfarin-induced overanticoagulation immediately and completely in patients presenting with major bleeding. Br J Haematol 2001; 115 (4): 998-1001
8. Sølbeck S, Ostrowski SR, Johansson PI. A review of the clinical utility of INR to monitor and guide administration of prothrombin complex concentrate to orally anticoagulated patients. Thrombosis Journal 2012, 10:5