PDF herunterladen
Hamostaseologie 2019; 39(02): 195-202
DOI: 10.1055/s-0038-1673415
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Endothelial Function in Patients with Severe and Moderate Haemophilia A and B

Stephanie Böhmert
1   Division of Haemostaseology, Department of Internal Medicine II, University Hospital Frankfurt, Frankfurt, Germany
,
Ralf Schubert
2   Department for Children and Adolescents Medicine, University Hospital Frankfurt, Frankfurt, Germany
,
Stephan Fichtlscherer
3   Division of Cardiology, Department of Internal Medicine III, University Hospital Frankfurt, Frankfurt, Germany
,
Sonja Alesci   *
4   IMD Blood Coagulation Centre, Bad Homburg, Germany
,
Wolfgang Miesbach   *
1   Division of Haemostaseology, Department of Internal Medicine II, University Hospital Frankfurt, Frankfurt, Germany
› Institutsangaben
Weitere Informationen

Publikationsverlauf

09. März 2018

13. August 2018

Publikationsdatum:
09. Oktober 2018 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Abstract

The life expectancy of patients with haemophilia has increased and therefore the interest in age-related comorbidities has grown. The aim of this study was to determine whether haemophilia patients have a different endothelial function compared with the general population. A total of 26 patients with severe or moderate haemophilia A or B, 14 controls and 36 patients with coronary artery disease (CAD) were included in this study. Five markers of endothelial dysfunction (MOEDs) were determined. Moreover, the endothelial function was examined using the Itamar Endo-PAT, and the reactive hyperemia index (RHI) was calculated from the results. The MOEDs soluble intercellular adhesion molecule-1 (p = 0.0095) and interleukin-6 (p = 0.010) were significantly higher for patients with haemophilia compared with the control group. The presence of increased adhesion molecule levels and low-grade inflammation is suggestive of a decreased endothelial function. RHI is impaired in CAD patients (1.862), whereas haemophilia patients have an RHI of 1.958 in comparison with 2.112 in controls (p = 0.127). Therefore, laboratory and functional measurements imply a possible higher risk for CAD in haemophilia patients.

Zusammenfassung

Die Lebenserwartung der Hämophilie-Patienten und das Interesse an altersbedingten Begleiterkrankungen ist gestiegen. Die Fragestellung war, ob sich die endotheliale Funktion bei Hämophilie-Patienten und der Allgemeinbevölkerung unterscheiden. 26 Patienten mit mittelschwerer/schwerer Hämophilie A/B, 36 Patienten mit Koronarer Herzkrankheit (KHK) und 14 Normalpersonen wurden eingeschlossen. Fünf Marker für endotheliale Dysfunktion (MFED) wurden bestimmt. Die Endothelfunktion wurde mittels des Itamar Endo-PAT-Geräts gemessen und aus den Ergebnissen der Reaktive-Hyperämie-Index (RHI) berechnet. Bei den MFED zeigten sich signifikant höhere Werte für soluble intercellular adhesion molecule-1 (p = 0,0095*) und Interleukin-6 (p = 0,010*) bei Hämophilie-Patienten im Vergleich zur Kontrollgruppe. Das Vorhandensein von erhöhten Leveln von Adhäsionsmolekülen und geringgradiger Entzündung deuten auf eine verminderte endotheliale Funktion hin. Diese Tendenz spiegelt sich auch in den RHI-Ergebnissen wider (mittlerer RHI: KHK 1,862; Hämophilie 1,958; Kontrolle 2,112; p = 0,127). Laborchemische und funktionelle Untersuchungen deuten auf ein mögliches höheres Risiko für KHK bei Hämophilie-Patienten hin.

Keywords

Haemophilia - endothelial function - comorbidity - coronary artery disease

Schlüsselwörter

Hämophilie - endotheliale Funktion - Komorbidität - koronare Herzkrankheit

Authors' Contributions

S. B. collected the data, analysed and interpreted the data, drafted and wrote the manuscript; S. A. designed the study and reviewed the manuscript; R. S. helped with data collection, assisted with data analysis and reviewed the manuscript; S. F. reviewed the manuscript; W. M. assisted in writing the manuscript, revised and reviewed the manuscript. All authors approved the submitted and final version.


* Sonja Alesci and Wolfgang Miesbach are sharing last authorship.


 

  • References

  • 1 Fransen van de Putte DE, Fischer K, Makris M. , et al. Unfavourable cardiovascular disease risk profiles in a cohort of Dutch and British haemophilia patients. Thromb Haemost 2013; 109 (01) 16-23
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 2 Casaña P, Cabrera N, Cid AR. , et al. Severe and moderate hemophilia A: identification of 38 new genetic alterations. Haematologica 2008; 93 (07) 1091-1094
    CrossrefPubMedGoogle Scholar
  • 3 Miesbach W, Müller M, Geisen C, Seifried E. Die “Krankheit der Könige” verstehen und behandeln. Forschung Frankfurt; 2010: 54-60
    Google Scholar
  • 4 Miesbach W, Alesci S, Krekeler S, Seifried E. Comorbidities and bleeding pattern in elderly haemophilia A patients. Haemophilia 2009; 15 (04) 894-899
    CrossrefPubMedGoogle Scholar
  • 5 Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med 1999; 340 (02) 115-126
    CrossrefPubMedGoogle Scholar
  • 6 Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol 2003; 23 (02) 168-175
    CrossrefPubMedGoogle Scholar
  • 7 Srámek A, Reiber JHC, Gerrits WBJ, Rosendaal FR. Decreased coagulability has no clinically relevant effect on atherogenesis: observations in individuals with a hereditary bleeding tendency. Circulation 2001; 104 (07) 762-767
    CrossrefPubMedGoogle Scholar
  • 8 Kamphuisen PW, ten Cate H. Cardiovascular risk in patients with hemophilia. Blood 2014; 123 (09) 1297-1301
    CrossrefPubMedGoogle Scholar
  • 9 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 (03) 815-825
    PubMedGoogle Scholar
  • 10 Tuinenburg A, Rutten A, Kavousi M. , et al. Coronary artery calcification in hemophilia A: no evidence for a protective effect of factor VIII deficiency on atherosclerosis. Arterioscler Thromb Vasc Biol 2012; 32 (03) 799-804
    CrossrefPubMedGoogle Scholar
  • 11 Bilora F, Zanon E, Petrobelli F. , et al. Does hemophilia protect against atherosclerosis? A case-control study. Clin Appl Thromb Hemost 2006; 12 (02) 193-198
    CrossrefPubMedGoogle Scholar
  • 12 Rosendaal FR, Briët E, Stibbe J. , et al. Haemophilia protects against ischaemic heart disease: a study of risk factors. Br J Haematol 1990; 75 (04) 525-530
    CrossrefPubMedGoogle Scholar
  • 13 Heitzer T, Ylä-Herttuala S, Luoma J. , et al. Cigarette smoking potentiates endothelial dysfunction of forearm resistance vessels in patients with hypercholesterolemia. Role of oxidized LDL. Circulation 1996; 93 (07) 1346-1353
    CrossrefPubMedGoogle Scholar
  • 14 Britten MB, Zeiher AM, Schaechinger V. Endothelfunktion und körperliche Aktivität. Dtsch Z Sportmed 2000; 51 (04) 118-122
    PubMedGoogle Scholar
  • 15 Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 2000; 87 (10) 840-844
    CrossrefPubMedGoogle Scholar
  • 16 Heitzer T, Schlinzig T, Krohn K, Meinertz T, Münzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 2001; 104 (22) 2673-2678
    CrossrefPubMedGoogle Scholar
  • 17 Igel M, Sudhop T, von Bergmann K. Nichtlipidsenkende Effekte von Statinen. Dtsch Arztebl 2004; 101 (06) 352-356
    PubMedGoogle Scholar
  • 18 Eickmeier O, Huebner M, Herrmann E. , et al. Sputum biomarker profiles in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) and association between pulmonary function. Cytokine 2010; 50 (02) 152-157
    CrossrefPubMedGoogle Scholar
  • 19 Flammer AJ, Anderson T, Celermajer DS. , et al. The assessment of endothelial function: from research into clinical practice. Circulation 2012; 126 (06) 753-767
    CrossrefPubMedGoogle Scholar
  • 20 Fischer-Rasokat U, Spyridopoulos I, Walter J, Honold J, Zeiher AM, Fichtlscherer S. Microvascular dysfunction and pulse wave reflection characterize different vascular pathologies in patients at cardiovascular risk. Vasa 2012; 41 (03) 192-199
    CrossrefPubMedGoogle Scholar
  • 21 Hamburg NM, Keyes MJ, Larson MG. , et al. Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study. Circulation 2008; 117 (19) 2467-2474
    CrossrefPubMedGoogle Scholar
  • 22 Itmar Medical. EndoPAT FAQ [cited May 10, 2016]. Available from: http://www.itamar-medical.com/endopat-faq/
    PubMedGoogle Scholar
  • 23 Rubinshtein R, Kuvin JT, Soffler M. , et al. Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J 2010; 31 (09) 1142-1148
    CrossrefPubMedGoogle Scholar
  • 24 de Faria AP, Ritter AMV, Sabbatini AR. , et al. Deregulation of soluble adhesion molecules in resistant hypertension and its role in cardiovascular remodeling. Circ J 2016; 80 (05) 1196-1201
    CrossrefPubMedGoogle Scholar
  • 25 Lowe GDO, Rumley A, McMahon AD, Ford I, O'Reilly DSJ, Packard CJ. ; West of Scotland Coronary Prevention Study Group. Interleukin-6, fibrin D-dimer, and coagulation factors VII and XIIa in prediction of coronary heart disease. Arterioscler Thromb Vasc Biol 2004; 24 (08) 1529-1534
    CrossrefPubMedGoogle Scholar
  • 26 Roifman I, Beck PL, Anderson TJ, Eisenberg MJ, Genest J. Chronic inflammatory diseases and cardiovascular risk: a systematic review. Can J Cardiol 2011; 27 (02) 174-182
    CrossrefPubMedGoogle Scholar
  • 27 Acharya SS. Exploration of the pathogenesis of haemophilic joint arthropathy: understanding implications for optimal clinical management. Br J Haematol 2012; 156 (01) 13-23
    CrossrefPubMedGoogle Scholar
  • 28 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 (06) 535-544
    CrossrefPubMedGoogle Scholar
  • 29 Oldenburg J. Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens. Blood 2015; 125 (13) 2038-2044
    CrossrefPubMedGoogle Scholar
  • 30 Barnes RFW, Cramer TJ, Hughes TH, von Drygalski A. The hypertension of hemophilia is associated with vascular remodeling in the joint. Microcirculation 2017; 24 (07) xx
    PubMedGoogle Scholar
  • 31 Dysangco A, Liu Z, Stein JH, Dubé MP, Gupta SK. HIV infection, antiretroviral therapy, and measures of endothelial function, inflammation, metabolism, and oxidative stress. PLoS One 2017; 12 (08) e0183511
    CrossrefPubMedGoogle Scholar
  • 32 Iantorno M, Schär M, Soleimanifard S. , et al. Coronary artery endothelial dysfunction is present in HIV-positive individuals without significant coronary artery disease. AIDS 2017; 31 (09) 1281-1289
    CrossrefPubMedGoogle Scholar
  • 33 Currier JS, Lundgren JD, Carr A. , et al; Working Group 2. Epidemiological evidence for cardiovascular disease in HIV-infected patients and relationship to highly active antiretroviral therapy. Circulation 2008; 118 (02) e29-e35
    PubMedGoogle Scholar
  • 34 Garg H, Joshi A, Mukherjee D. Cardiovascular complications of HIV infection and treatment. Cardiovasc Hematol Agents Med Chem 2013; 11 (01) 58-66
    CrossrefPubMedGoogle Scholar
  • 35 Stein JH, Klein MA, Bellehumeur JL. , et al. Use of human immunodeficiency virus-1 protease inhibitors is associated with atherogenic lipoprotein changes and endothelial dysfunction. Circulation 2001; 104 (03) 257-262
    CrossrefPubMedGoogle Scholar
  • 36 Bonetti PO, Pumper GM, Higano ST, Holmes Jr DR, Kuvin JT, Lerman A. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol 2004; 44 (11) 2137-2141
    CrossrefPubMedGoogle Scholar
  • 37 Matsuzawa Y, Sugiyama S, Sugamura K. , et al. Digital assessment of endothelial function and ischemic heart disease in women. J Am Coll Cardiol 2010; 55 (16) 1688-1696
    CrossrefPubMedGoogle Scholar
  • 38 Sartori MT, Bilora F, Zanon E. , et al. Endothelial dysfunction in haemophilia patients. Haemophilia 2008; 14 (05) 1055-1062
    CrossrefPubMedGoogle Scholar
  • 39 Tuinenburg A, Mauser-Bunschoten EP, Verhaar MC, Biesma DH, Schutgens REG. Cardiovascular disease in patients with hemophilia. J Thromb Haemost 2009; 7 (02) 247-254
    CrossrefPubMedGoogle Scholar