Activated factor VII: my story

My story starts in the early 1970s when I was appointeda resident in the Hemophilia Clinic at the Malmo¨University Hospital, University of Lund, in Sweden,which at that time was headed by Professor Inga MarieNilsson. This Haemophilia Clinic was very special incombining the clinical investigation and care of haemo-philia patients from all over Sweden together with aresearch programme at the forefront of haemostasis,covering both bleeding and thrombotic disorders. Myown research was focused on ﬁbrinolysis, and Ipresented my dissertation in early 1974. However, inparallel, I was, as the only physician along with IngaMarie in the clinic, deeply involved with the clinicalcare of haemophilic patients. This involved being onduty most of the time dealing with both inpatient andoutpatient care.In the early 1970s, the most serious problem was totreat haemophilia patients who had developed inhibi-tors against factor VIII (FVIII) or factor IX (FIX). Various treatment modalities such as exchange trans-fusions combined with substitution therapy were tried[1–3]. In 1971, David Green described a combination ofsimultaneous administration of large amounts of FVIII/FIX and cyclophosphamide. This regimen was used tocover extensive dental surgery in two haemophilia Bpatients during 1971 [4]. The same treatment modalitywas successfully used in four haemophilia A patientsduring 1972 [5], and later in another ﬁve patients [6]. Inthose patients who had an inhibitor titre too high to besuppressed by the administration of large amounts ofFVIII/FIX concentrates, the addition of an extracor-poral adsorption of the inhibitory gamma globulin asdescribed by Edson et al. [7] was considered.However, in association with the very high doses ofFIX-concentrate (PCC) required in some of the haemo-philia B patients, to achieve a neutralization of theinhibitors as well as a haemostatic plasma level ofFIX:C, there were signs of thrombin activation with asystemic activation of the coagulation system (highlevels of ﬁbrinogen degradation products, decrease ofﬁbrinogen, decreased platelet counts, positive ethanolgelation test, decreased alfa-2-macroglobulin). Theaddition of antithrombin concentrate did not entirelyneutralize these changes [8]. Increasing numbers ofreports with similar ﬁndings following the use ofvarious PCCs were being published [9,10]. As no pureFIX concentrates were commercially available at thetime, this presented a problem for the treatment ofhaemophilia B patients, especially those with high titreinhibitors, who required large doses of the PCCs forhaemostasis.However, reports appeared in the early 1970s on theuse of PCCs in the treatment of mild to moderatebleeding episodes in inhibitor patients. Thus, Feketeet al. [11] reported a haemostatic effect with an‘activated prothrombin complex concentrate’. Thisconcentrate was claimed to include certain amounts ofactivated FIX, FX, FVII as well as traces of thrombin.A high in vitro clotting activity was demonstrated, andthis was called ‘auto-activated FIX’ [12]. In Malmo¨, we were not very satisﬁed with theseconcentrates when used in the treatment of haemophiliaB patients, as we saw changes in the plasma coagulationpattern, indicating activation of systemic coagulation[8], which could cause thrombo-embolic side-effectsincluding disseminated intravascular coagulation (DIC). Furthermore, we did not see any signiﬁcant clinicaleffect in patients with inhibitors. At this time, it wassuggested that the clot promoting effect in PCCs wascaused by the presence of activated coagulation factors,especially FIXa and FXa [10,13,14].