Independent adjudicator assessments of platelet refractoriness and rFVIIa efficacy in bleeding episodes and surgeries from the multinational Glanzmann's thrombasthenia registry

Abstract

Glanzmann's thrombasthenia (GT) is a rare congenital bleeding disorder associated with decreased platelet aggregation due to qualitative/quantitative deficiencies of the fibrinogen receptor. Severe bleeding episodes and perioperative bleeding are typically managed with platelet transfusions, although patients can develop anti-platelet antibodies or experience clinical refractoriness. The GT Registry (GTR) was established to collect efficacy/safety data on hemostatic treatments for GT, including recombinant factor VIIa (rFVIIa). At the request of the United States Food and Drug Administration, three hematology experts evaluated platelet refractoriness, antibody status, and rFVIIa efficacy data on a case-by-case basis to support a potential indication for rFVIIa in GT. Adjudication included 195 patients with 810 events (619 severe bleeding episodes, 192 surgeries), and a consensus algorithm was developed to describe adjudicators' coding of refractoriness and antibody status based on treatment patterns over time. Most rFVIIa-treated events were in patients without refractoriness or antibodies. Adjudicators rated most rFVIIa-treated bleeding episodes as successful (251/266, 94.4%; rFVIIa only, 101/109, 92.7%; rFVIIa ± platelets ± other agents, 150/157, 95.5%); efficacy was consistent in patients with platelet refractoriness ± antibodies (75/79, 94.9%), antibodies only (10/10, 100.0%), and neither/unknown (166/177, 93.8%). Adjudicators also rated most rFVIIa-treated surgeries as successful (159/160, 99.4%; rFVIIa only, 65/66, 98.5%; rFVIIa ± platelets ± other agents, 94/94, 100.0%); efficacy was consistent in patients with platelet refractoriness ± antibodies (69/70, 98.6%), antibodies only (24/24, 100.0%), and neither/unknown (66/66, 100.0%). Unblinding the adjudicators to investigator efficacy ratings changed few assessments. Doses of rFVIIa were narrowly distributed, regardless of other hemostatic agents used.

Low Concentrations of Recombinant Factor VIIa May Improve the Impaired Thrombin Generation of Glanzmann Thrombasthenia Patients

“…The median in both registries was 90 µg/kg. The doses administered were similar to those that are used in haemophilia patients 13,[16][17][18] and similar between bleeding episodes treated solely with rFVIIa as well as those treated with rFVIIa along with other haemostatic agents. Our previous studies regarding rFVIIa-induced thrombin generation using various clinical settings 20,21,36,37,[44][45][46] found that high doses are not required to restore haemostasis for nonhaemophilia patients.…”

“…While the GTR data revealed a good safety profile for rFVIIa use in GT patients, 9,10,18 a serious adverse event, deep vein thrombosis of the leg following an emergency laparotomy, was reported. 10 Moreover, one of the two patients who received higher doses of rFVIIa supplemented by an anti-fibrinolytic agent developed pulmonary embolism and the other developed a ureteric clot.…”

“…From early in its development, recombinant activated factor VII (rFVIIa) has been used to treat severe bleedings in patients with platelets disorders, including GT. 15 The data in international registries of GT 9,10 revealed that a median dose of 90 to 100 µg/kg was applied, in most patients preoperatively as well as in non-surgical bleeding episodes, 13,[16][17][18] although some studies reported increased doses of up to 300 μg/kg. 19 No prospective randomized controlled trial supporting the use of rFVIIa has been conducted thus far due to the rarity of GT.…”

Iron deficiency anemia and bleeding management in pediatric patients with Bernard‐Soulier syndrome and Glanzmann Thrombasthenia: A single‐institution analysis

“…Recombinant FVIIa is approved by the U.S. Food and Drug Administration and European Medicines Agency for the treatment of surgical and non‐surgical bleeding in patients with BSS/GT with platelet refractoriness or alloimmunization 14,15 . Patients with GT achieve effective hemostasis with rFVIIa infusion for acute bleeding events or surgical procedures with or without platelet refractoriness or alloimmunization 12,13,16,17 . Individuals with BSS have also demonstrated significant reduction in or cessation of bleeding following rFVIIa administration 4,5,18 …”

“…14,15 Patients with GT achieve effective hemostasis with rFVIIa infusion for acute bleeding events or surgical procedures with or without platelet refractoriness or alloimmunization. 12,13,16,17 Individuals with BSS have also demonstrated significant reduction in or cessation of bleeding following rFVIIa administration. 4,5,18 Patients with frequent or severe bleeding events (SBE) are at increased risk of developing iron deficiency anemia (IDA) from chronic blood loss.…”