Shortened Lifespan and Lethal Hemorrhage in a Hemophilia A Mouse Model

Abstract

Background: Hemophilia A animal models have helped advance our understanding of factor VIII deficiency. Previously, factor VIII deficient mouse models were reported to have a normal life span without spontaneous bleeds. However, the bleeding frequency and survival in these animals has not been thoroughly evaluated.

Objective: To investigate the survival and lethal bleeding frequency in two strains of E-16 hemophilia A mice.

Methods: We prospectively studied factor VIII deficient hemizygous affected males (n = 83) and homozygous affected females (n = 55) for survival and bleeding frequency. Animals were evaluated for presence and location of bleeds as potential cause of death.

Results and conclusions: Hemophilia A mice had a median survival of 254 days, which is significantly shortened compared to wild type controls (p < 0.0001). In addition, the hemophilia A mice experienced hemorrhage in several tissues. This previously-underappreciated shortened survival in the hemophilia A murine model provides new outcomes for investigation of therapeutics and also reflects the shortened lifespan of patients if left untreated.

Fig 1. Hemophilia A mice sustain lethal bleeding events.

(A) Illustration depicts sites of lethal bleeds which include intracranial, joint/soft tissue, thoracic, and intra-abdominal. (B) and (C) are representative pictures of gross bleeding observed during the study. (B) Mouse discovered dead in cage with swollen joint visibly noticeable (arrow indicates the affected joint). (C) Grossly visible joint/soft tissue bleed noted on necropsy (arrow indicates same joint as in (B)).

Fig 2. Hemophilia A mice have a shortened lifespan compared to wild type controls.

(A) Hemophilia A mice have a median survival of 254 days. n = 138 (total from both backgrounds), p < 0.0001 (log-rank [Mantel-Cox] test) compared to wild type mice, n = 96. (B) C57Bl/6 F8 null mice have a median survival of 236 days. n = 67, p < 0.0001 (log-rank [Mantel-Cox] test) compared to wild type mice, n = 54. (C) B6129 F8 null mice have a median survival of 288 days. n = 71, p < 0.0001 (log-rank [Mantel-Cox] test) compared to wild type mice, n = 39. (D) Factor VIII deficient animals have decreased median lifespan regardless of gender. Median survival of F8 null female mice (361.5 days) was significantly longer than that of F8 null male mice (207 days). p = 0.0009, log-rank [Mantel-Cox] test. (E) Female C57Bl/6 F8 null mice have a median survival of 236 days, n = 29 (p < 0.0001 when compared to wild type controls, n = 31). Male C57Bl/6 F8 null mice have a median survival of 245.5 days, n = 38 (p < 0.0001 when compared to wild type controls, n = 23). (F) Female B6129 F8 null mice have a median survival of 654 days, n = 26 (p = 0.022 when compared to wild type controls, n = 16). Male B6129 F8 null mice have a median survival of 173 days, n = 45 (p < 0.0001 when compared to wild type controls, n = 23).