Sequential therapy with activated prothrombin complex concentrates and recombinant FVIIa in patients with severe haemophilia and inhibitors: update of our previous experience

Abstract

Haemophilia patients with inhibitors can develop bleeding episodes, which are refractory to monotherapy with either recombinant factor VIIa (rFVIIa) or activated prothrombin complex concentrates (APCC). Management of such bleeds is often difficult. We previously reported the safety of using a combination of rFVIIa and APCC given in sequential fashion. In this report, we update our experience with sequential therapy. A retrospective review of medical records was conducted including all reports of sequential therapy defined as receiving both rFVIIa and APCC within 6 h. Data extracted included demographic data, treatment prior to and following hospital admission, clinical data including type and location of bleed, response to therapy, physical examination and laboratory data. In addition, for some patients, thromboelastography was performed to document the effect of sequential therapy on clot formation characteristics. Four patients comprising 35 admissions, 209 hospital days and 115 days of sequential therapy were included in the updated dataset. No patient developed thrombosis or overt disseminated intravascular coagulation (DIC) although elevations in the D-dimer above 5 microg mL(-1) were noted in 42% of the courses that lasted >3 days. Efficacy is suggested by the fact that patients had resolution of their bleeds after a median of 3 days of sequential therapy after failing to respond to a median of 3 days of monotherapy. Thromboelastography demonstrated an additive effect. Sequential therapy is a safe, potentially efficacious approach in the management of refractory bleeding episodes in patients with haemophilia and inhibitors.

International recommendations on the diagnosis and treatment of patients with acquired hemophilia A

“…A few recent case reports describe favorable responses to the administration of both bypassing agents (in alternating sequence) in refractory congenital hemophilia patients with inhibitors and insufficient control of bleeding with a single agent. 56,57 However, these results may not apply to patients with acquired hemophilia. In view of the estimated rate of arterial thrombosis and other thromboembolic complications, 31,43 combination therapy with rFVIIa and aPCC should be restricted to life-or limb-threatening bleeds.…”

Use of recombinant activated factor VII

“…Gydomasis poveikis puikus, didesnis nei 90 proc. ir visuomet nedidelė trombozių rizika (17). Jei kraujavimas refrakteriškas, monoterapijai skiriama rFVIIa (vidutiniškai 3 dienos), tai kartu su rFVIIa skiriama APCC.…”

“…Jei kraujavimas refrakteriškas, monoterapijai skiriama rFVIIa (vidutiniškai 3 dienos), tai kartu su rFVIIa skiriama APCC. Šis derinys per tris dienas paprastai normalizuoja hemostazę (17).…”

“…Pasitikėti tik protrombino laiko ar dalinio aktyvinto tromboplastino laiko (DATL) tyrimais, gydant sergančiuosius inhibitorine hemofilija, negalima. Sergant FVIII stoka, ligonius sekti dėl galimų antikūnių FVII atsiradimo (1,5,6,14,16,17).…”

Prospective Efficacy and Safety of a Novel Bypassing Agent, FVIIa/FX Mixture (MC710) for Hemophilia Patients with Inhibitors

“…In 2002, an anecdotal report suggested that the sequential administration of rFVIIa and prothrombin complex concentrate (PCC) to hemophilia patients with inhibitors in order to obtain a stronger hemostatic effect than with rFVIIa alone [5]. Further, it has been reported that the combination of rFVIIa and APCC appeared to confer beneficial hemostatic synergy in patients refractory to each individual therapy [6][7][8]. However, repeated infusion of APCC may cause an accumulation of prothrombin and factor X (FX), thereby increasing the risk of thrombosis.…”