Control of bleeding in patients with haemophilia A with inhibitors: a systematic review

Abstract

This paper reports a systematic review of the best available evidence of clinical effectiveness in the treatment of acute bleeding in haemophilia A patients with inhibitors. Because of the lack of randomized controlled trials (RCTs) on this topic, broad inclusion criteria with regard to study design were applied in order to assess the best available evidence for each intervention. Because of the clinical and methodological heterogeneity of the evidence, it was not appropriate to pool data across studies; instead, data were synthesized using tabulation and qualitative narrative assessment. No evidence was found to support the use of high-dose factor VIII (FVIII) in bleeding episodes. However in surgery it was found to be highly successful (100%) for low-titre, low-responding inhibitors although not reliable for high-responding inhibitors. Porcine FVIII (pFVIII) was effective in the control of severe bleeding episodes with high-titre or high-responding inhibitors (100%) and in 60-90% of surgical procedures. Activated prothrombin complex concentrates (APCCs) appear to be more effective than prothrombin complex concentrates (PCCs) in the control of mild to severe bleeding episodes. There was no good evidence for the use of PCCs in surgery. APCCs controlled bleeding in approximately 90% of surgical episodes. Recombinant factor VIIa (rFVIIa) controlled 70-100% of mild to severe bleeding episodes with high-responding inhibitors, and achieved better results when used early. It was effective in 60-100% of surgical episodes. Doses varied from study to study, and side-effects from mild to infrequent but serious adverse events were reported. The quality of the evidence is variable. Limited evidence relating to other treatment options is also included in the review.

Bypassing Agents for Bleeding Reduction in Treatment of Bleeding Episodes in Patients With Haemophilia and Inhibitors

“…The efficacy of any bypassing agent varies, as seen in many studies; factor eight inhibitor bypassing activity (FEIBA) is effective in 80-100% of cases (6). On the other hand, other studies have reported more than 90% success, which was close to 60% when rFVIIa was used in treating acute bleeds (7). However, these studies demonstrate that bypassing agents are effective in most cases, although none of them is universally effective (6).…”

Current difficulties and recent advances in bypass therapy for the management of hemophilia with inhibitors: a new and practical formulation of recombinant factor VIIa

“…Pd-aPCC is effective in controlling hemorrhage at a variety of anatomic sites including joint, muscle, mucocutaneous, and central nervous system (CNS) and perioperative bleeding,17–19 and can also be used effectively to achieve hemostasis in a home-treatment setting 14. Mild adverse events, such as chills, fever, nausea, and dizziness, occur in a small proportion of patients,20 and there is a small risk of anaphylactic reactions 21. Thrombotic and thromboembolic events (including disseminated intravascular coagulation [DIC], venous thrombosis, pulmonary embolism, myocardial infarction, and stroke) have been reported following infusion of pd-aPCC 21.…”

“…In addition, pd-aPCC contains trace amounts of factor VIII that may induce an anamnestic rise in factor VIII antibody titers in up to 30% of patients 19,21. This rise in antibody titers does not interfere with the efficacy of pd-aPCC and is transient in the majority of patients 20. Despite these limitations, this product has been widely used for about 30 years and continues to be used in patients who may not respond to rFVIIa.…”

“…An estimate of rFVIIa efficacy for controlling bleeding derived from a recent systematic analysis of available randomized clinical trial data showed an effective treatment response rate of 81% to 91% in patients with inhibitors experiencing acute bleeds 16. The most commonly reported adverse events in clinical studies were mild and included fever, skin reactions, headache, hypertension, epistaxis, shortened prothrombin time, and reduced fibrinogen levels 20. The risk of thromboembolic events with rFVIIa is low and similar to that observed with pd-aPCC 2…”

Sequential therapy with activated prothrombin complex concentrates and recombinant activated factor VII to treat unresponsive bleeding in patients with hemophilia and inhibitors: a single center experience

“…Bleeding episodes are effectively treated by replacing the deficient factor; however, it is common for patients to develop inhibitors to factor VIII or IX, which leads to severe and expensive complications from treatment [2, 3]. The presence of high titer inhibitors, in particular, renders replacement therapy completely ineffective.…”