An exploratory study of the effects of strenuous exercise on markers of coagulation activation, circulating microparticles, and inflammation in sickle cell trait

Abstract This exploratory study evaluated the effect of intense exercise on biomarkers of inflammation and coagulation activation in subjects with and without sickle cell trait (SCT). Fifteen healthy African American men (18‐35 years, 5 SCT, 10 control) completed a strenuous exercise protocol. Microparticle‐associated prothrombinase and tissue factor activities, as well as soluble VCAM, total white cell and monocyte count increased transiently in all subjects following exercise. In the SCT group, exercise resulted in increased d‐dimer, erythrocyte phosphatidylserine exposure, as well as increased circulating erythrocyte‐ and endothelial‐derived microparticle numbers. These alterations could contribute to exercise‐related complications in people with SCT.


INTRODUCTION
It is well established that regular exercise training lowers cardiovascular, metabolic, and thromboembolic disease risk [1,2]. Paradoxically, strenuous acute exercise may transiently increase the risk of cardiovascular and thromboembolic complications, and is associated with a transient hypercoaguable state and elevated markers of inflammation [3]. Microparticles (MPs), membrane-derived vesicles (0.1-1 µm) that are released from cells during apoptosis or upon activation, have been shown to contribute to coagulation activation following acute exercise [4]. The prothrombotic properties of MPs may be related to several mechanisms, including the exposure of phosphatidylserine (PS) or tissue factor (TF) on the outer membrane leaflet [5]. PS exposure provides a docking surface for coagulation enzymatic complexes, and provides a catalytic surface for assembly of the tenase and prothrom-This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. binase complexes, thereby promoting thrombin generation. TF is an integral-membrane protein that triggers the extrinsic pathway of coagulation, when bound to activated factor VII.
Accumulating evidence suggests that sickle cell trait (SCT), the heterozygous form of sickle cell anemia (SCA), could be a risk factor for exercise-related complications, including rhabdomyolysis or sudden death [6]. Although SCT has generally been considered to be benign, previous studies have shown that hemorheological and inflammatory responses to exercise may be altered in individuals with SCT [7]. However, the pathogenesis of exercise-related complications in SCT has not been explored, and the effect of exercise on red blood cell (RBC) physiology and circulating MP concentrations in this population remains unknown.
The present study set out to explore short-term effects of a single bout of vigorous exercise on a variety of biomarkers of eJHaem. 2020;1:251-254.
wileyonlinelibrary.com/journal/jha2 activation of coagulation and inflammation in subjects with and without SCT.

METHODS
The study included 15 healthy African American males (18-35 years).
Ten of the subjects had normal adult hemoglobin (controls), while 5 had SCT. During a primary visit, subjects completed a graded exercise test to determine maximal oxygen consumption (VO 2 max). Then, during a second visit, subjects completed a single bout of exercise, composed of 30 min of treadmill running at 65% of their VO 2 max, followed by an

RESULTS
Subjects with SCT were similar to controls with respect to age, BMI,

DISCUSSION
This study demonstrates that an acute bout of strenuous exercise results in a transient increase in MPTF procoagulant activity accompanied by increased MP-prothrombinase activity, WBC and monocyte counts, leucocyte MP counts, and sVCAM. Therefore, our results are similar to previous findings that strenuous exercise causes acute systemic activation of coagulation and inflammation [3], while providing insight into an additional mechanism through which rigorous exercise could increase thrombin generation. Elevated MPTF procoagulant activity has been observed in a number of prothrombotic and inflammatory disorders, indicating a potentially important role in the pathogenesis of thrombosis [10]. Although the cellular source of MPTF seen in this study is unknown, previous research has shown that the majority of TF-expressing MPs are leucocyte-derived, and that leukocytes are prone to microvesiculation when they are exposed to inflammatory cytokines [5]. In our study, both sVCAM and LMPs increased significantly post-exercise. Therefore, it is possible that exercise-related inflammation stimulated LMP formation, which contributed to increased MPTF activity. Future studies will need to be carried out to confirm this hypothesis.
The findings of this study also show that exercise resulted in trends for increased RBC PS exposure and elevated levels of circulating RBCMPs and EMPs in individuals with SCT. Elevated PS exposure could potentially increase the risk of exercise-related complications in two ways. First, PS exposure increases erythrocyte adhesion, which can impede blood flow in the microcirculation [11]. Second, PS exposure activates coagulation by providing a surface for prothrombinase and tenase to assemble [10]. The elevated RBCMPs and EMPs could also potentially play a role in coagulation activation through TF-dependent and independent mechanisms, and thereby increase the risk of developing exercise-related complications [8].