Unresponsiveness to factor VIII inhibitor bypassing agents during haemostatic treatment for life‐threatening massive bleeding in a patient with haemophilia A and a high responding inhibitor

Abstract

We report a case of haemophilia A with a high responding inhibitor of factor VIII (FVIII) who had a serious retroperitoneal haematoma caused by penetration of a duodenal ulcer. Inhibitor-bypassing therapy was commenced immediately on admission. On the 17th day of treatment with activated prothrombin complex concentrate (APCC; FEIBA, re-bleeding occurred and thrombelastography (TEG) demonstrated resistance to therapy. Treatment was changed to recombinant activated factor VII (rFVIIa; NovoSeven and resulted in clinical improvement together with an improvement in TEG parameters. On the 10th day of continuous infusion with NovoSeven, however, TEG again showed resistance to therapy. FEIBA infusions were re-introduced and TEG results remained satisfactory for 7 days. On day 34, however, further retroperitoneal bleeding was evident and a decline in the haemostatic efficiency of FEIBA was recorded by TEG. NovoSeven was again successfully administered for 7 days. There were no laboratory findings to indicate disseminated intravascular coagulation (DIC), hypercoagulability or abnormal fibrinolysis. The plasma-based clotting tests did not show any additional prolongation on the occasions when the TEG demonstrated unresponsiveness to FEIBA or NovoSeven. These findings suggested that some component of whole blood, other than plasma might have governed the TEG data. The long-term use of APCC such as FEIBA or rFVIIa, requires careful monitoring in terms of FVIII inhibitor bypassing activity as well as the tendency to DIC.

Factor VIIa analog has marked effects on platelet function and clot kinetics in blood from patients with hemophilia A

“…Although both tests have been proposed to be useful for rFVIIa monitoring in hemophilia patients [12][13][14], prospective clinical trials linking a specific laboratory parameter to the rFVIIa clinical response are lacking. With regard to the clinical effect of rFVIIa no such correlation exists although there are a few anecdotal case reports [3,15]. Both thromboelastography [16] and the thrombin generation tests are subject to great variability, and the lack of standardized assay conditions makes comparison between laboratories difficult.…”

“…Clinical experience however has shown that there can be a wide variation in the hemostatic response, and in some cases a low response to rFVIIa has been observed [3][4][5].…”

The use of thromboelastography, thrombin generation test and clotting tests to evaluate the efficacy of hemostatic therapy with recombinant activated factor VII in hemophilia patients with inhibitor

“…Поэтому ТЭГ в настоящее время является од-ним из наиболее принятых методов мониторинга те-рапии rFVIIa у пациентов с ингибиторной формой гемофилии [9,13,14]. Использование ТЭГ позволяет не только мониторировать терапию шунтирующими препаратами, но и выявлять резистентность к одно-му из них, вовремя изменить тактику гемостатиче-ской терапии, индивидуализировать лечение [6,15]. Наиболее информативной для этого является оценка таких параметров ТЭГ, как период R и интервал МА, они позволяют даже дифференцировать больных ге-мофилией с тяжелой формой, умеренной тяжести и легкого течения [5].…”

Successful self‐infusion of activated prothrombin complex concentrate for prophylaxis in a child with a factor VIII inhibitor

“…Thus, as an alternative to APCC therapy, successful control of hemostasis by rFVIIa was documented in patients with inhibitors [16]. The short half-life of rFVIIa (3.5 hr) [17], however, makes it difficult to optimize the interval of regular infusion for prophylaxis. Sequential administration of APCC and rFVIIa has been effectively used on occasion.…”

“…Sequential administration of APCC and rFVIIa has been effectively used on occasion. Hayashi et al [17] and Schneiderman et al [18] reported that a regimen that alternated between APCC and rFVIIa was effective for treatment of inhibitor-positive patients with refractory bleeding that was not effectively controlled with either agent alone. However, the sequential use of PCCs/APCCs and FVIIa may be problematic, as illustrated by the development of thrombotic events, one of which was fatal, in two patients receiving PCCs and rVIIa [19].…”