RSS-Feed abonnieren
DOI: 10.1160/TH17-01-0004
Pathophysiological Mechanisms of Endogenous FVIII Release following Strenuous Exercise in Non-severe Haemophilia: A Review
Publikationsverlauf
04. Januar 2017
22. August 2017
Publikationsdatum:
06. Dezember 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201712/lookinside/thumbnails/10-1160-th17-01-0004_170004-1.jpg)
Abstract
Introduction Non-severe haemophilia A is characterized by coagulation Factor VIII activity (FVIII:C) levels of 1 to 40 IU/dL. It has been reported that strenuous exercise increases the plasma FVIII:C in haemophilia A patients. This review highlights current knowledge about the pathophysiological mechanisms of endogenous FVIII release following strenuous exercise.
Methods A literature search was performed to include relevant studies with data on pathophysiological mechanisms of FVIII release following strenuous exercise in haemophilia.
Results The source of the released FVIII is most likely endothelial cells (ECs) from different vascular beds. ECs from human lung, lymph, heart, intestine, skin and pulmonary artery can release and even produce FVIII in response to activation by epinephrine. Ex vivo evidence suggests that FVIII is co-stored with von Willebrand factor in Weibel–Palade bodies in some forms of non-severe haemophilia. The β-adrenergic receptor pathway is involved in increased FVIII levels following strenuous exercise.
Conclusion The current available ex vivo and in vivo evidence suggests that endogenous FVIII is released by ECs from different vascular beds in response to epinephrine following strenuous exercise in patients with non-severe haemophilia.
-
References
- 1 Spiegel Jr PC, Stoddard BL. Optimization of factor VIII replacement therapy: can structural studies help in evading antibody inhibitors?. Br J Haematol 2002; 119 (02) 310-322
- 2 Lenting PJ, van Mourik JA, Mertens K. The life cycle of coagulation factor VIII in view of its structure and function. Blood 1998; 92 (11) 3983-3996
- 3 Groen WG, den Uijl IE, van der Net J, Grobbee DE, de Groot PG, Fischer K. Protected by nature? Effects of strenuous physical exercise on FVIII activity in moderate and mild haemophilia A patients: a pilot study. Haemophilia 2013; 19 (04) 519-523
- 4 Mannucci PM, Tuddenham EG. The hemophilias: from royal genes to gene therapy. N Engl J Med 2001; 344 (23) 1773-1779
- 5 Lethagen S. Desmopressin in mild hemophilia A: indications, limitations, efficacy, and safety. Semin Thromb Hemost 2003; 29 (01) 101-106
- 6 Shahani T, Lavend'homme R, Luttun A, Saint-Remy JM, Peerlinck K, Jacquemin M. Activation of human endothelial cells from specific vascular beds induces the release of a FVIII storage pool. Blood 2010; 115 (23) 4902-4909
- 7 Bontempo FA, Lewis JH, Gorenc TJ. , et al. Liver transplantation in hemophilia A. Blood 1987; 69 (06) 1721-1724
- 8 Madeira CL, Layman ME, de Vera RE, Fontes PA, Ragni MV. Extrahepatic factor VIII production in transplant recipient of hemophilia donor liver. Blood 2009; 113 (21) 5364-5365
- 9 Everett LA, Cleuren AC, Khoriaty RN, Ginsburg D. Murine coagulation factor VIII is synthesized in endothelial cells. Blood 2014; 123 (24) 3697-3705
- 10 Fahs SA, Hille MT, Shi Q, Weiler H, Montgomery RR. A conditional knockout mouse model reveals endothelial cells as the principal and possibly exclusive source of plasma factor VIII. Blood 2014; 123 (24) 3706-3713
- 11 Spencer HT, Riley BE, Doering CB. State of the art: gene therapy of haemophilia. Haemophilia 2016; 22 (Suppl. 05) 66-71
- 12 Aronovich A, Tchorsh D, Katchman H. , et al. Correction of hemophilia as a proof of concept for treatment of monogenic diseases by fetal spleen transplantation. Proc Natl Acad Sci U S A 2006; 103 (50) 19075-19080
- 13 Kennedy A, Ng CT, Biniecka M. , et al. Angiogenesis and blood vessel stability in inflammatory arthritis. Arthritis Rheum 2010; 62 (03) 711-721
- 14 Jacquemin M, Neyrinck A, Hermanns MI. , et al. FVIII production by human lung microvascular endothelial cells. Blood 2006; 108 (02) 515-517
- 15 Pan J, Dinh TT, Rajaraman A. , et al. Patterns of expression of factor VIII and von Willebrand factor by endothelial cell subsets in vivo. Blood 2016; 128 (01) 104-109
- 16 Rosenberg JB, Greengard JS, Montgomery RR. Genetic induction of a releasable pool of factor VIII in human endothelial cells. Arterioscler Thromb Vasc Biol 2000; 20 (12) 2689-2695
- 17 Turner NA, Moake JL. Factor VIII is synthesized in human endothelial cells, packaged in Weibel-Palade bodies and secreted bound to ULVWF strings. PLoS One 2015; 10 (10) e0140740
- 18 Haberichter SL, Shi Q, Montgomery RR. The biology of von Willebrand factor and factor VIII-regulated release. Haematol Rep 2005; 1: 9-14
- 19 Bloom AL. The biosynthesis of factor VIII. Clin Haematol 1979; 8 (01) 53-77
- 20 van den Biggelaar M, Bouwens EA, Kootstra NA, Hebbel RP, Voorberg J, Mertens K. Storage and regulated secretion of factor VIII in blood outgrowth endothelial cells. Haematologica 2009; 94 (05) 670-678
- 21 Shi Q, Fahs SA, Kuether EL, Cooley BC, Weiler H, Montgomery RR. Targeting FVIII expression to endothelial cells regenerates a releasable pool of FVIII and restores hemostasis in a mouse model of hemophilia A. Blood 2010; 116 (16) 3049-3057
- 22 Vischer UM, Wollheim CB. Epinephrine induces von Willebrand factor release from cultured endothelial cells: involvement of cyclic AMP-dependent signalling in exocytosis. Thromb Haemost 1997; 77 (06) 1182-1188
- 23 Ingram GI, Jones RV. The rise in clotting factor 8 induced in man by adrenaline: effect of alpha- and beta-blockers. J Physiol 1966; 187 (02) 447-454
- 24 Hoppener MR, Kraaijenhagen RA, Hutten BA, Büller HR, Peters RJ, Levi M. Beta-receptor blockade decreases elevated plasma levels of factor VIII:C in patients with deep vein thrombosis. J Thromb Haemost 2004; 2 (08) 1316-1320
- 25 van den Biggelaar M, Bouwens EAM, Voorberg J, Mertens K. Storage of factor VIII variants with impaired von Willebrand factor binding in Weibel-Palade bodies in endothelial cells. PLoS One 2011; 6 (08) e24163
- 26 Mannucci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years. Blood 1997; 90 (07) 2515-2521
- 27 Warrier AI, Lusher JM. DDAVP: a useful alternative to blood components in moderate hemophilia A and von Willebrand disease. J Pediatr 1983; 102 (02) 228-233
- 28 Stoof SC, Sanders YV, Petrij F. , et al. Response to desmopressin is strongly dependent on F8 gene mutation type in mild and moderate haemophilia A. Thromb Haemost 2013; 109 (03) 440-449
- 29 Mannucci PM. Hemostatic drugs. N Engl J Med 1998; 339 (04) 245-253
- 30 Arai M, Yorifuji H, Ikematsu S. , et al. Influences of strenuous exercise (triathlon) on blood coagulation and fibrinolytic system. Thromb Res 1990; 57 (03) 465-471
- 31 Lin X, El-Sayed MS, Waterhouse J, Reilly T. Activation and disturbance of blood haemostasis following strenuous physical exercise. Int J Sports Med 1999; 20 (03) 149-153
- 32 Ikarugi H, Shibata M, Shibata S, Ishii H, Taka T, Yamamoto J. High intensity exercise enhances platelet reactivity to shear stress and coagulation during and after exercise. Pathophysiol Haemost Thromb 2003; 33 (03) 127-133
- 33 Urhausen A, Coen B, Weiler B, Kindermann W. Individual anaerobic threshold and maximum lactate steady state. Int J Sports Med 1993; 14 (03) 134-139
- 34 Meyer T, Gabriel HH, Kindermann W. Is determination of exercise intensities as percentages of VO2max or HRmax adequate?. Med Sci Sports Exerc 1999; 31 (09) 1342-1345
- 35 Menzel K, Hilberg T. Blood coagulation and fibrinolysis in healthy, untrained subjects: effects of different exercise intensities controlled by individual anaerobic threshold. Eur J Appl Physiol 2011; 111 (02) 253-260
- 36 Li KX, Xiao J, Zhao YQ. , et al. Moderate-intensity exercise improves the thromboelastography coagulation index in children with severe hemophilia A. Blood Coagul Fibrinolysis 2016; 27 (07) 797-803
- 37 Beltrame LG, Abreu L, Almeida J, Boullosa DA. The acute effect of moderate intensity aquatic exercise on coagulation factors in haemophiliacs. Clin Physiol Funct Imaging 2015; 35 (03) 191-196
- 38 Kumar R, Bouskill V, Schneiderman JE. , et al. Impact of aerobic exercise on haemostatic indices in paediatric patients with haemophilia. Thromb Haemost 2016; 115 (06) 1120-1128
- 39 Koch B, Luban NL, Galioto Jr FM, Rick ME, Goldstein D, Kelleher Jr JF. Changes in coagulation parameters with exercise in patients with classic hemophilia. Am J Hematol 1984; 16 (03) 227-233
- 40 Zourikian N, Merlen C, Bonnefoy A, St-Louis J, Rivard GE. Effects of moderate-intensity physical exercise on pharmacokinetics of factor VIII and von Willebrand factor in young adults with severe haemophilia A: a pilot study. Haemophilia 2016; 22 (03) e177-e183
- 41 Ravanbod R, Torkaman G, Baghaipour MR. , et al. Effects of ergometric exercise on F-VIII coagulant activity in mild and moderate haemophilia A: a chance to reduce injective replacement therapy. Pak J Biol Sci 2006; 9: 2823-2827
- 42 van den Burg PJ, Hospers JE, Mosterd WL, Bouma BN, Huisveld IA. Aging, physical conditioning, and exercise-induced changes in hemostatic factors and reaction products. J Appl Physiol (1985) 2000; 88 (05) 1558-1564
- 43 Mandalaki T, Dessypris A, Louizou C, Panayotopoulou C, Dimitriadou C. Marathon Run III: effects on coagulation, fibrinolysis, platelet aggregation and serum cortisol levels. A 3-year study. Thromb Haemost 1980; 43 (01) 49-52