Impact of Exercise on Hemostasis in Boys with Hemophilia a (HA) and B (HB): Principal Findings of the Sickkids Hemophilia Exercise Study
Authors: Kumar Riten , Bouskill Vanessa , Kahr Walter H.A. , Craik Allison , Pluthero Fred G , Schneiderman Jane E , Clark Dewi S. , Whitney Kharen , Zhang Christine , Rand Margaret L. , Carcao Manuel 
Published: October 2019

Abstract
Introduction. We undertook a study to assess the impact of exercise on hemostatic parameters [FVIII, FIX, VWF, platelet count and function, thrombin generation time (TGT) and thromboelastography (TEG)] in boys with HA and HB. We did so to explore the hypothesis that subjects with non-severe HA and all subjects with HB would show an increase in platelet count, VWF and FVIII with exercise leading to an overall improvement in hemostasis.
Methods.The study was approved by the institutional ethics board. Subjects (ages 5-18 years) meeting inclusion criteria were invited to participate. Baseline blood-work was drawn and subjects were then exercised on a stationary cycle ergometer using a progressive incremental Godfrey-protocol, aiming to attain 3-minutes of cycling at 85% of predicted maximum heart rate. Blood-work was repeated 5-minutes and 1-hour after exercise completion. Descriptive statistics were used to summarize parameters (mean ± SD). Statistical analyses were performed using the SAS version 9.2 software package. All calculated p-values were two-sided and p-values ≤ 0.05 were considered significant.
Results. Thirty subjects [19 HA (7 mild; 6 moderate; 6 severe); 11 HB (2 mild; 6 moderate; 3 severe)] were enrolled. Mean age at participation was 12.8 (±3.8) years. Mean duration of exercise was 13.9 (±2.6) minutes. Baseline characteristics were similar for HA and HB subjects, except BMI, which was significantly higher in the HA cohort (p=0.01). For the entire study cohort, we found that platelet count, FVIII, VWF:Ag and VWF:RCo levels rose significantly by 5-minutes post-exercise (p values of <0.0001, 0.004, <0.0001 and 0.01 respectively), though only VWF:Ag and VWF:RCo levels remained significantly elevated at 1-hour (p=0.003 and 0.02 respectively). PFA-100 closure time with the collagen/epinephrine cartridge shortened significantly at 5 minutes (n=26; p=0.02), but not with the collagen/ADP cartridge (n=26; p=0.6). Subjects with severe HA showed no significant change in FVIII, VWF:Ag or VWF:RCo levels with exercise, but did show a rise in platelet counts (p=0.03). Post-pubertal boys (>12 years) had a significantly greater increase in FVIII, VWF:Ag and VWF:RCo levels as compared to pre-pubertal boys at both 5-minutes and 1-hour, despite having exercised for a shorter duration of time (13.2 minutes versus 15.1 minutes; p=0.04) (data for non-severe HA and all HB patients is elaborated in Fig. 1). Complete TEG and TGT data were available for 19 subjects (13 HA and 6 HB). No consistent improvement in TEG parameters was noted. TGT studies did show a significant improvement in peak thrombin generation (using 1 pM tissue factor) at 5-minutes post exercise (p=0.01), though this improvement was lost by 1-hour (p=0.9).
Conclusion. Children with hemophilia (excluding severe HA) showed improvements in specific hemostatic parameters with exercise. These improvements were more robust in post-pubertal males. The change in coagulation profile could be discerned using PFA-100 and TGT but not TEG. We conclude that exercise may potentially improve hemostatic parameters (at least for a short time) in subjects with non-severe HA and all subjects with HB thus reducing the risk of bleeding.
Figure 1. Figure 1.
Figure subscript. Impact of exercise on FVIII activity in non-severe HA subjects (1a) and HB subjects (1b); on VWF:RCo activity in non-severe HA subjects (1c) and HB subjects (1d); on VWF:Ag levels in non-severe HA subjects (1e) and HB subjects (1f)

Disclosures
Carcao: Pfizer: This study was an investigator initiated study which was funded by Pfizer Other.