Impact of aerobic exercise on haemostatic indices in paediatric patients with haemophilia

Summary

This study investigated the impact of aerobic exercise on laboratory assessments of haemostatic activity in boys (5–18 years of age) with haemophilia A (HA) or B (HB), examining the hypothesis that laboratory coagulation parameters temporarily improve with exercise. Thirty subjects meeting eligibility criteria (19 HA; 11 HB; mean age: 12.8 years) were invited to participate. They underwent a replacement factor washout period and were advised against strenuous activity for three days prior to the planned intervention. At study visit, baseline blood samples were drawn prior to exercise on a stationary cycle ergometer, aiming to attain 3 minutes (min) of cycling at 85 % of predicted maximum heart rate. Blood work was repeated 5 min (t5) and 60 min (t60) post exercise completion. Samples were assessed for platelet count (PC), factor VIII activity (FVIII:C), von Willebrand antigen (VWF:Ag), ristocetin cofactor activity (VWF:RCo) and platelet function analysis (PFA-100); maximum rate of thrombus generation (MRTG) in blood was measured via thromboelastography and plasma peak thrombin generation (PTG) via calibrated automated thrombography. Mean duration of exercise was 13.9 (± 2.6) min. On average, t5 samples showed significant elevation, relative to baseline in PC, FVIII:C, VWF:Ag, VWF:RCo and PTG, while FVIII:C, VWF:Ag, VWF:RCo and MRTG were significantly elevated in t60 samples. Within the cohort, participants with severe HA showed no change in FVIII:C levels with exercise. The greatest improvement in haemostatic indices was observed in post-adolescent males with mild-moderate HA, who thus represent the group most likely to benefit from a reduction of bleeding risk in the setting of exercise.

Keywords

Haemophilia - exercise - factor VIII

• References

• 1 Stonebraker JS, Bolton-Maggs PH, Soucie MJ. et al. A study of variations in the reported haemophilia B prevalence around the world. Haemophilia 2012; 18: e91-94.
• 2 Stonebraker JS, Bolton-Maggs PH, Soucie JM. et al. A study of variations in the reported haemophilia A prevalence around the world. Haemophilia 2010; 16: 20-32.
• 3 Kumar R, Carcao M. Inherited abnormalities of coagulation: haemophilia, von Willebrand disease, and beyond. Paediatr Clin North Am 2013; 60: 1419-1441.
• 4 Manco-Johnson MJ, Abshire TC, Shapiro AD. et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe haemophilia. N Engl J Med 2007; 357: 535-544.
• 5 Nilsson IM, Berntorp E, Lofqvist T. et al. Twenty-five years’ experience of prophylactic treatment in severe haemophilia A and B. J Intern Med 1992; 232: 25-32.
• 6 Souza JC, Simoes HG, Campbell CS. et al. Haemophilia and exercise. Int J Sports Med 2012; 33: 83-88.
• 7 Negrier C, Seuser A, Forsyth A. et al. The benefits of exercise for patients with haemophilia and recommendations for safe and effective physical activity. Haemophilia 2013; 19: 487-498.
• 8 Douma-van Riet DC, Engelbert RH, van Genderen FR. et al. Physical fitness in children with haemophilia and the effect of overweight. Haemophilia 2009; 15: 519-527.
• 9 Greene WB, Strickler EM. A modified isokinetic strengthening program for patients with severe haemophilia. Dev Med Child Neurol 1983; 25: 189-196.
• 10 Pelletier JR, Findley TW, Gemma SA. Isometric exercise for an individual with haemophilic arthropathy. Phys Ther 1987; 67: 1359-1364.
• 11 Beltrame LG, Abreu L, Almeida J. et al. The acute effect of moderate intensity aquatic exercise on coagulation factors in haemophiliacs. Clin Physiol Funct Imaging 2015; 35: 191-196.
• 12 Groen WG, den Uijl IE, van der Net J. et al. Protected by nature? Effects of strenuous physical exercise on FVIII activity in moderate and mild haemophilia A patients: a pilot study. Haemophilia 2013; 19: 519-523.
• 13 Ravanbod RTG, Baghaipour MR, Nad-Ali F. Effects of Ergometric Exercise on F-VIII Coagulant Activity in Mild and Moderate Haemophilia-A: A Chance to Reduce Injective Replacement Therapy. Pakistan J Biol Sci 2006; 09: 2823-2827.
• 14 Nazzaro AM, Owens S, Hoots WK. et al. Knowledge, attitudes, and behaviors of youths in the US haemophilia population: results of a national survey. Am J Public Health 2006; 96: 1618-1622.
• 15 Seuser A, Boehm P, Ochs S. et al. How fit are children and adolescents with haemophilia in Germany? Results of a prospective study assessing the sport-specific motor performance by means of modern test procedures of sports science. Haemophilia 2015; 21: 523-529.
• 16 Sherlock E, O’Donnell JS, White B. et al. Physical activity levels and participation in sport in Irish people with haemophilia. Haemophilia 2010; 16: e202-209.
• 17 Biere-Rafi S, Haak BW, Peters M. et al. The impairment in daily life of obese haemophiliacs. Haemophilia 2011; 17: 204-208.
• 18 Hofstede FG, Fijnvandraat K, Plug I. et al. Obesity: a new disaster for haemophilic patients? A nationwide survey. Haemophilia 2008; 14: 1035-1038.
• 19 Majumdar S, Morris A, Gordon C. et al. Alarmingly high prevalence of obesity in haemophilia in the state of Mississippi. Haemophilia 2010; 16: 455-459.
• 20 Majumdar S, Ostrenga A, Latzman RD. et al. Pharmacoeconomic impact of obesity in severe haemophilia children on clotting factor prophylaxis in a single institution. Haemophilia 2011; 17: 717-718.
• 21 van der Cammen-van Zijp MH, Ijsselstijn H, Takken T. et al. Exercise testing of pre-school children using the Bruce treadmill protocol: new reference values. Eur J Appl Physiol 2010; 108: 393-399.
• 22 van der Cammen-van Zijp MH, van den Berg-Emons RJ, Willemsen SP. et al. Exercise capacity in Dutch children: new reference values for the Bruce treadmill protocol. Scand J Med Sci Sports 2010; 20: e130-136.
• 23 Godfrey S, Davies CT, Wozniak E. et al. Cardio-respiratory response to exercise in normal children. Clin Sci 1971; 40: 419-431.
• 24 Hebestreit H. Exercise testing in children -- what works, what doesn’t, and where to go?. Paediatr Respir Rev 2004; 05 (Suppl A) S11-14.
• 25 Rowland TW. Aerobic Exercise Testing Protocols. Rowland TW. Champaign, IL: Human Kinetics Publishers; 1993
• 26 Luddington R, Baglin T. Clinical measurement of thrombin generation by calibrated automated thrombography requires contact factor inhibition. J Thromb Haemost 2004; 02: 1954-1959.
• 27 Hemker HC, Al Dieri R, Beguin S. Thrombin generation assays: accruing clinical relevance. Curr Opin Haematol 2004; 11: 170-175.
• 28 Revel-Vilk S, Blanchette VS, Sparling C. et al. DDAVP challenge tests in boys with mild/moderate haemophilia A. Br J Haematol 2002; 117: 947-951.
• 29 Seary ME, Feldman D, Carcao MD. DDAVP responsiveness in children with mild or moderate haemophilia A correlates with age, endogenous FVIII:C level and with haemophilic genotype. Haemophilia 2012; 18: 50-55.
• 30 Kaufmann JE, Oksche A, Wollheim CB. et al. Vasopressin-induced von Willebrand factor secretion from endothelial cells involves V2 receptors and cAMP. J Clin Invest 2000; 106: 107-116.
• 31 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: e0140740.
• 32 Lippi G, Maffulli N. Biological influence of physical exercise on haemostasis. Semin Thromb Haemost 2009; 35: 269-276.
• 33 Dimitriadou C, Dessypris A, Louizou C. et al. Marathon run II: Effects on platelet aggregation. Thromb Haemost 1977; 37: 451-455.
• 34 Hilberg T, Schmidt V, Glaser D. et al. Platelet activity, sensitivity to agonist, and platelet--leukocyte conjugate formation after long-term exercise. Platelets 2002; 13: 273-277.
• 35 Kestin AS, Ellis PA, Barnard MR. et al. Effect of strenuous exercise on platelet activation state and reactivity. Circulation 1993; 88: 1502-1511.
• 36 Kratz A, Wood MJ, Siegel AJ. et al. Effects of marathon running on platelet activation markers : direct evidence for in vivo platelet activation. Am J Clin Pathol 2006; 125: 296-300.
• 37 Rock G, Tittley P, Pipe A. Coagulation factor changes following endurance exercise. Clin J Sport Med 1997; 07: 94-99.
• 38 Lin X, El-Sayed MS, Waterhouse J. et al. Activation and disturbance of blood haemostasis following strenuous physical exercise. Int J Sports Med 1999; 20: 149-153.
• 39 van den Burg PJ, Hospers JE, van Vliet M. et al. Unbalanced haemostatic changes following strenuous physical exercise. A study in young sedentary males. Eur Heart J 1995; 16: 1995-2001.
• 40 Ribeiro J, Almeida-Dias A, Ascensao A. et al. Haemostatic response to acute physical exercise in healthy adolescents. J Sci Med Sport 2007; 10: 164-169.
• 41 Andrew M, Carter C, O’Brodovich H. et al. Increases in factor VIII complex and fibrinolytic activity are dependent on exercise intensity. J Appl Physiol 1986; 60: 1917-1922.
• 42 Ferguson EW, Bernier LL, Banta GR. et al. Effects of exercise and conditioning on clotting and fibrinolytic activity in men. J Appl Physiol 1987; 62: 1416-1421.
• 43 Koch B, Luban NL, Galioto Jr FM. et al. Changes in coagulation parameters with exercise in patients with classic haemophilia. Am J Haematol 1984; 16: 227-233.
• 44 van den Burg PJ, Hospers JE, Mosterd WL. et al. Aging, physical conditioning, and exercise-induced changes in haemostatic factors and reaction products. J Appl Physiol 2000; 88: 1558-1564.
• 45 Small M, Tweddel AC, Rankin AC. et al. Blood coagulation and platelet function following maximal exercise: effects of beta-adrenoceptor blockade. Haemostasis 1984; 14: 262-268.
• 46 Stakiw J, Bowman M, Hegadorn C. et al. The effect of exercise on von Willebrand factor and ADAMTS-13 in individuals with type 1 and type 2B von Willebrand disease. J Thromb Haemost 2008; 06: 90-96.
• 47 Posthuma JJ, van der Meijden PE, Ten Cate H. et al. Short- and Long-term exercise induced alterations in haemostasis: a review of the literature. Blood Rev 2015; 29: 171-178.
• 48 Schmidt KG, Rasmussen JW. Exercise-induced changes in the in vivo distribution of 111In-labelled platelets. Scand J Haematol 1984; 32: 159-166.