Identification of prothrombin as a major thrombogenic agent in prothrombin complex concentrates

Abstract

Prothrombin complex concentrates (PCC) were compared in an in vitro test system for thrombogenicity (thrombin generation assay) employing plasma from coumarin-treated patients. Among these concentrates one had a proven history of thrombogenicity, whereas the remainder did not cause such fatal casualties in the past. Investigations into the thrombogenic component were performed by spiking experiments in which we biased a typical PCC without reported thromboembolic complications into one with a performance in the thrombin generation assay like that with a proven history of thrombogenicity. Hereby, it was possible to identify prothrombin as the most plausible thrombogenic component. Additional experiments performed with anticoagulant components (antithrombin together with heparin) resulted in a perfect reversal of the observed in vitro thrombogenicity. Our in vitro observations corroborate on an experimental basis the widespread medicinal usage of antithrombin administration as a regimen for the avoidance of thromboembolic complications during treatment with PCC and related products, and vice versa. Our observation casts doubts upon the widely accepted idea of activated factor IX as the thromboembolic agent in PCC. Also, our finding may be taken as an example for the feasibility of this test system as an in vitro model for thrombogenicity.

Increasing concentrations of prothrombin complex concentrate induce disseminated intravascular coagulation in a pig model of coagulopathy with blunt liver injury

“…This hypothesis corresponds with in vitro and in vivo data that identified prothrombin overload (and insufficient inhibition of newly generated thrombin by antithrombin) as the most likely cause of thrombosis. 18,44 It is also supported by our observations of prolonged tails as well as large amplitudes in the thrombin generation curves, indicating a lack of thrombin inhibition. In a biochemical comparison of 7 commercially available PCCs, none of the products contained antithrombin at a sufficient level to balance the thrombin-generating potential of prothrombin.…”

“…Excessive concentrations of prothrombin (factor II) in relation to levels of antithrombin have been suggested as the cause of thromboembolic complications. 18,19 The quantity of factor II administered varies among PCCs, and it is not usually monitored. Moreover, the ratio of antithrombin to thrombin is low in all preparations (range 0-1:50), 11 meaning that there is always a risk of factor II overload.…”

Clinical review: Prothrombin complex concentrates - evaluation of safety and thrombogenicity

“…An in vitro model of thrombogenicity has been used recently to systematically examine which components of PCCs contribute to thrombogenicity [29]. Zymogen overload, of prothrombin in particular, was implicated in this study as the main mechanism for the thrombogenic potential of PCCs.…”

Pathophysiology and Treatment of Coagulopathy in Massive Hemorrhage and Hemodilution

“…The prothrombotic risk of PCC may be increased in the presence of antithrombin deficiency caused by hemodilution. 21,137 Additional clinical studies are necessary to establish optimal indications and dosages for PCC in perioperative settings.…”