Background: Patients with haemophilia have a higher prevalence of hypertension than the general population that cannot be explained by traditional cardiovascular risk factors such as age, race, diabetes or obesity. Patients with severe haemophilia, who are on clotting factor prophylaxis, have a higher prevalence of hypertension compared to patients with milder forms of haemophilia, who infuse clotting factor less frequently. This raises the question of whether there is a link between clotting factor usage and blood pressure in haemophilia patients.
Methods: Data was collected from 193 patients with severe haemophilia presenting to three haemophilia treatment centres in the United States and Canada, including age, body mass index (BMI), blood pressure (BP), Hepatitis C (HCV) and Human Immunodeficiency Virus (HIV) infection status, and clotting factor usage from pharmacy prescriptions (units/kg/year). The correlation between BP and factor usage was examined using quantile regression models.
Results: Systolic and diastolic BP plotted against factor use showed a cone-shaped scatter of points. There was no association between clotting factor usage and higher systolic or diastolic BP.
Conclusion: Our observations provide no evidence for an association between increased clotting factor usage and high BP.
If the inline PDF is not rendering correctly, you can download the PDF file here.
1. Darby SC Kan SW Spooner RJ et al. Mortality rates life expectancy and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV. Blood 2007; 110: 815–25. doi: 10.1182/blood-2006-10-050435.
2. von Drygalski A Kolaitis NA Bettencourt R et al. Prevalence and risk factors for hypertension in hemophilia. Hypertension 2013; 62: 209–15. doi: 10.1161/HYPERTENSIONAHA.113.01174.
3. Fransen van de Putte DE Fischer K Makris M et al. Increased prevalence of hypertension in haemophilia patients. Thromb Haemost 2012; 108: 750–5. doi: 10.1160/TH12-05-0313.
4. Minuk L Jackson S Iorio A et al. Cardiovascular disease (CVD) in Canadians with haemophilia: Age-Related CVD in Haemophilia Epidemiological Research (ARCHER study). Haemophilia 2015; 21: 736–41. doi: 10.1111/hae.12768.
5. Ariesen MJ Claus SP Rinkel GJ Algra A. Risk factors for intracerebral hemorrhage in the general population: a systematic review. Stroke 2003; 34: 2060–5. doi: 10.1161/01.STR.0000080678.09344.8D.
6. Stieltjes N Calvez T Demiguel V et al.; French ICH Study Group. Intracranial haemorrhages in French haemophilia patients (1991-2001): clinical presentation management and prognosis factors for death. Haemophilia 2005; 11: 452–8. doi: 10.1111/j.1365-2516.2005.01090.x.
7. Barnes RF Cramer TJ Sait AS Kruse-Jarres R Quon DV von Drygalski A. The hypertension of hemophilia is not explained by the usual cardiovascular risk factors: results of a cohort study. Int J Hypertens 2016; 2016: 2014201. doi: 10.1155/2016/2014201.
8. Sait AS Kuo A Bettencourt R Bergstrom J Allison M von Drygalski A. Risk assessment for coronary heart disease in patients with haemophilia: a single centre study in the United States. Haemophilia 2014; 20: 763–70. doi: 10.1111/hae.12472.
9. Sun HL Yang M Sait AS von Drygalski A Jackson S. Haematuria is not a risk factor of hypertension or renal impairment in patients with haemophilia. Haemophilia 2016; 22: 549–55. doi: 10.1111/hae.12921.
10. Bhat V Olmer M Joshi S et al. Vascular remodeling underlies rebleeding in hemophilic arthropathy. Am J Hematol 2015; 90: 1027–35. doi: 10.1002/ajh.24133.
11. Barnes RFW Cramer TJ Hughes TH von Drygalski A. The hypertension of hemophilia is associated with vascular remodeling in the joint. Microcirculation 2017; 24. doi: 10.1111/micc.12387.
12. Pickering TG Hall JE Appel LJ et al. Recommendations for blood pressure measurement in humans and experimental animals: part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Circulation 2005; 111: 697–716. doi: 10.1161/01.CIR.0000154900.76284.F6.
13. Koenker R. Quantile regression. 2005. New York: Cambridge University Press.
14. Hao L Naiman D. Quantile regression. 2007. Thousand Oaks CA: Sage Publications.
15. SAS. SAS/STAT 9.22 User's Guide. 2010. Cary NC: SAS Institute Inc. Available from https://support.sas.com/documentation/cdl/en/statug/63347/HTML/default/viewer.htm (accessed 26 August 2019).
16. Statcompute. SAS macro calculating goodness-of-fit statistics for quantile regression. 15 April 2017. Available from https://statcompute.wordpress.com/2017/04/15/sas-macro-calculating-goodness-of-fit-statistics-for-quantile-regression/ (accessed 29 August 2019).
17. Koenker R Machado J. Goodness of fit and related inference processes for quantile regression. J Am Stat Assoc 1999; 94: 1296–310.
18. Whelton PK Carey RM Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention Detection Evaluation and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2018; 138: e426-e83. doi: 10.1161/CIR.0000000000000597.
19. Schroeder V Kohler HP. New developments in the area of factor XIII. J Thromb Haemost 2013; 11: 234–44. doi: 10.1111/jth.12074.
20. Bouma BN Mosnier LO. Thrombin activatable fibrinolysis inhibitor (TAFI) – how does thrombin regulate fibrinolysis? Ann Med 2006; 38: 378–88. doi: 10.1080/07853890600852898.
21. Poli KA Tofler GH Larson MG et al. Association of blood pressure with fibrinolytic potential in the Framingham offspring population. Circulation 2000; 101: 264–9. doi: 10.1161/01.CIR.101.3.264.
22. Sane DC Kontos JL Greenberg CS. Roles of transglutaminases in cardiac and vascular diseases. Front Biosci. 2007; 12: 2530-45.
23. Loof TG Mörgelin M Johansson L et al. Coagulation an ancestral serine protease cascade exerts a novel function in early immune defense. Blood 2011; 118: 2589–98. doi: 10.1182/blood-2011-02-337568.
24. Mian MO Paradis P Schiffrin EL. Innate immunity in hypertension. Curr Hypertens Rep 2014; 16: 413. doi: 10.1007/s11906-013-0413-9.
25. Myles T Nishimura T Yun TH et al. Thrombin activatable fibrinolysis inhibitor a potential regulator of vascular inflammation. J Biol Chem 2003; 278: 51059–67. doi: 10.1074/jbc.M306977200.
26. Mosnier LO Lisman T van den Berg HM et al. The defective down regulation of fibrinolysis in haemophilia A can be restored by increasing the TAFI plasma concentration. Thromb Haemost 2001; 86: 1035–9.
27. Wyseure T Cooke EJ Declerck PJ et al. Defective TAFI activation in hemophilia A mice is a major contributor to joint bleeding. Blood 2018; 132: 1593–603. doi: 10.1182/blood-2018-01-828434.
28. Sharma JN. Hypertension and the bradykinin system. Curr Hypertens Rep 2009; 11: 178–81.
29. Urano T Ihara H Suzuki Y Takada Y Takada A. Coagulation-associated enhancement of fibrinolytic activity via a neutralization of PAI-1 activity. Semin Thromb Hemost 2000; 26: 39–42.
30. Levi M Keller TT van Gorp E ten Cate H. Infection and inflammation and the coagulation system. Cardiovasc Res 2003; 60: 26–39.
31. 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: 3706–13. doi: 10.1182/blood-2014-02-555151.
32. Everett LA Cleuren AC Khoriaty RN Ginsburg D. Murine coagulation factor VIII is synthesized in endothelial cells. Blood 2014; 123: 3697–705. doi: 10.1182/blood-2014-02-554501.
33. Sun H Yang M Fung M et al. Adult males with haemophilia have a different macrovascular and microvascular endothelial function profile compared with healthy controls. Haemophilia 2017; 23: 777–83. doi: 10.1111/hae.13278.
34. Sartori MT Bilora F Zanon E et al. Endothelial dysfunction in haemophilia patients. Haemophilia 2008; 14: 1055–62. doi: 10.1111/j.1365-2516.2008.01808.x.
35. Higashi Y Kihara Y Noma K. Endothelial dysfunction and hypertension in aging. Hypertens Res 2012; 35: 1039–47. doi: 10.1038/hr.2012.138.
36. Srivastava A Brewer AK Mauser-Bunschoten EP et al.; Hemophilia Treatment Guidelines Working Group on Behalf of the World Federation of Hemophilia. Guidelines for the management of hemophilia. Haemophilia 2013; 19: e1–47. doi: 10.1111/j.1365-2516.2012.02909.x.
37. Manco-Johnson MJ Abshire TC Shapiro AD et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007; 357: 535–44. doi: 10.1056/NEJMoa067659.