Skip to main content

Advertisement

SpringerLink
Log in

Whole blood viscosity in systemic sclerosis: a potential biomarker of pulmonary hypertension?

  • Original Article
  • Published:
Clinical Rheumatology Aims and scope Submit manuscript

Abstract

Objective

Our goal was to determine if whole blood viscosity (WBV) can be used to predict the risk of pulmonary arterial hypertension (PAH) in patients with systemic sclerosis (SSc).

Methods

Patients with SSc were analyzed. Out of 107 patients, 26 patients, found to have confirmed diagnosis of PAH, were classified as those with (n = 26, PAH group) and without PAH (n = 81, non-PAH group). We calculated estimated WBV at both high (HSR) and low shear rates (LSR) from hematocrit and total serum protein levels.

Results

Total protein levels were significantly higher and the anti-centromere antibody (ACA) was more frequent in the PAH group. Furthermore, anti-topoisomerase antibody (anti-scl-70) was significantly less frequent in the PAH group. The WBV values were significantly higher at HSR (16.68 ± 0.38 vs. 16.24 ± 0.58; p < 0.001) and at LSR (51.81 ± 7.21 vs. 42.97 ± 11.76; p < 0.001) in PAH group. The multivariate analysis revealed that the WBV at both shear rates independently designated the presence of PAH in SSc patients. The ROC curve showed that the sensitivity and specificity of LSR and HSR were 92.3% and 61.7% (AUC 0.759, p < 0.001), and 88.5% and 65.4% (AUC 0.770, p < 0.001) with a cutoff value of 43.56 and 16.32 for WBV, respectively.

Conclusion

Higher WBV levels in SSc patients were an independent indicator for PAH development in this cohort. WBV-LSR and WBV-HSR values might help exclude the PAH possibility in patients diagnosed with SSc and remain as an independently associated biomarker for follow-up of these patients for future risk of PAH development. Findings remain to be confirmed by other cohorts.

Key Points

• The most important cause of morbidity and mortality in systemic sclerosis patients is considered to be pulmonary arterial hypertension.

• When the symptoms of PAH are not recognized earlier in the course of the SSc, the prognosis might be worse.

• Higher whole blood viscosity levels in scleroderma patients with PAH was an independent indicator for PAH development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. McLaughlin VV, McGoon MD (2006) Pulmonary arterial hypertension. Circulation 114(13):1417–1431. https://doi.org/10.1161/circulationaha.104.503540

    Article  PubMed  Google Scholar 

  2. Mukerjee D, St George D, Coleiro B, Knight C, Denton CP, Davar J, Black CM, Coghlan JG (2003) Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis 62(11):1088–1093. https://doi.org/10.1136/ard.62.11.1088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hachulla E, Gressin V, Guillevin L, Carpentier P, Diot E, Sibilia J, Kahan A, Cabane J, Frances C, Launay D, Mouthon L, Allanore Y, Tiev KP, Clerson P, de Groote P, Humbert M (2005) Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study. Arthritis Rheum 52(12):3792–3800. https://doi.org/10.1002/art.21433

    Article  PubMed  Google Scholar 

  4. Steen VD, Medsger TA (2007) Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum Dis 66(7):940–944. https://doi.org/10.1136/ard.2006.066068

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hao Y, Hudson M, Baron M, Carreira P, Stevens W, Rabusa C, Tatibouet S, Carmona L (2017) Early mortality in a multinational systemic sclerosis inception cohort. Arthritis Rheum 69(5):1067–1077. https://doi.org/10.1002/art.40027

    Article  Google Scholar 

  6. Fisher MR, Mathai SC, Champion HC, Girgis RE, Housten-Harris T, Hummers L, Krishnan JA, Wigley F, Hassoun PM (2006) Clinical differences between idiopathic and scleroderma-related pulmonary hypertension. Arthritis Rheum 54(9):3043–3050. https://doi.org/10.1002/art.22069

    Article  PubMed  Google Scholar 

  7. Clements PJ, Tan M, McLaughlin VV, Oudiz RJ, Tapson VF, Channick RN, Rubin LJ, Langer A (2012) The pulmonary arterial hypertension quality enhancement research initiative: comparison of patients with idiopathic PAH to patients with systemic sclerosis-associated PAH. Ann Rheum Dis 71(2):249–252. https://doi.org/10.1136/annrheumdis-2011-200265

    Article  CAS  PubMed  Google Scholar 

  8. Ramjug S, Hussain N, Hurdman J, Billings C, Charalampopoulos A, Elliot CA, Kiely DG, Sabroe I, Rajaram S, Swift AJ, Condliffe R (2017) Idiopathic and systemic sclerosis-associated pulmonary arterial hypertension: a comparison of demographic, hemodynamic, and MRI characteristics and outcomes. Chest 152(1):92–102. https://doi.org/10.1016/j.chest.2017.02.010

    Article  PubMed  Google Scholar 

  9. Chung L, Liu J, Parsons L, Hassoun PM, McGoon M, Badesch DB, Miller DP, Nicolls MR, Zamanian RT (2010) Characterization of connective tissue disease-associated pulmonary arterial hypertension from REVEAL: identifying systemic sclerosis as a unique phenotype. Chest 138(6):1383–1394. https://doi.org/10.1378/chest.10-0260

    Article  PubMed  PubMed Central  Google Scholar 

  10. Yaqub A, Chung L (2013) Epidemiology and risk factors for pulmonary hypertension in systemic sclerosis. Curr Rheumatol Rep 15(1):302. https://doi.org/10.1007/s11926-012-0302-2

    Article  PubMed  Google Scholar 

  11. Budhiraja R, Tuder RM, Hassoun PM (2004) Endothelial dysfunction in pulmonary hypertension. Circulation 109(2):159–165. https://doi.org/10.1161/01.cir.0000102381.57477.50

    Article  PubMed  Google Scholar 

  12. Cool CD, Stewart JS, Werahera P, Miller GJ, Williams RL, Voelkel NF, Tuder RM (1999) Three-dimensional reconstruction of pulmonary arteries in plexiform pulmonary hypertension using cell-specific markers. Evidence for a dynamic and heterogeneous process of pulmonary endothelial cell growth. Am J Pathol 155(2):411–419. https://doi.org/10.1016/s0002-9440(10)65137-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Proudman SM, Stevens WM, Sahhar J, Celermajer D (2007) Pulmonary arterial hypertension in systemic sclerosis: the need for early detection and treatment. Intern Med J 37(7):485–494. https://doi.org/10.1111/j.1445-5994.2007.01370.x

    Article  CAS  PubMed  Google Scholar 

  14. Goldberg A (2010) Pulmonary arterial hypertension in connective tissue diseases. Cardiol Rev 18(2):85–88. https://doi.org/10.1097/CRD.0b013e3181cbcde7

    Article  PubMed  Google Scholar 

  15. Lowe GD, Lee AJ, Rumley A, Price JF, Fowkes FG (1997) Blood viscosity and risk of cardiovascular events: the Edinburgh artery study. Br J Haematol 96(1):168–173. https://doi.org/10.1046/j.1365-2141.1997.8532481.x

    Article  CAS  PubMed  Google Scholar 

  16. de Simone G, Devereux RB, Chien S, Alderman MH, Atlas SA, Laragh JH (1990) Relation of blood viscosity to demographic and physiologic variables and to cardiovascular risk factors in apparently normal adults. Circulation 81(1):107–117. https://doi.org/10.1161/01.CIR.81.1.107

    Article  PubMed  Google Scholar 

  17. Kensey KR, Cho YI, Chang M (1997) Effects of whole blood viscosity on Atherogenesis. J Invasive Cardiol 9(1):17–24

    CAS  PubMed  Google Scholar 

  18. Ciuffetti G, Schillaci G, Lombardini R, Pirro M, Vaudo G, Mannarino E (2005) Prognostic impact of low-shear whole blood viscosity in hypertensive men. Eur J Clin Investig 35(2):93–98. https://doi.org/10.1111/j.1365-2362.2005.01437.x

    Article  CAS  Google Scholar 

  19. Koenig W, Sund M, Filipiak B, Doring A, Lowel H, Ernst E (1998) Plasma viscosity and the risk of coronary heart disease: results from the MONICA-Augsburg cohort study, 1984 to 1992. Arterioscler Thromb Vasc Biol 18(5):768–772. https://doi.org/10.1161/01.ATV.18.5.768

    Article  CAS  PubMed  Google Scholar 

  20. Velcheva I, Antonova N, Titianova E, Damianov P, Dimitrov N, Ivanov I (2006) Hemorheological parameters in correlation with the risk factors for carotid atherosclerosis. Clin Hemorheol Microcirc 35(1–2):195–198

    PubMed  Google Scholar 

  21. Silber HA, Bluemke DA, Ouyang P, Du YP, Post WS, Lima JA (2001) The relationship between vascular wall shear stress and flow-mediated dilation: endothelial function assessed by phase-contrast magnetic resonance angiography. J Am Coll Cardiol 38(7):1859–1865. https://doi.org/10.1016/S0735-1097(01)01649-7

    Article  CAS  PubMed  Google Scholar 

  22. Tietjen GW, Chien S, Leroy EC, Gavras I, Gavras H, Gump FE (1975) Blood viscosity, plasma proteins, and Raynaud syndrome. Arch Surg 110(11):1343–1346. https://doi.org/10.1001/archsurg.1975.01360170083011

    Article  CAS  PubMed  Google Scholar 

  23. McGrath MA, Peek R, Penny R (1977) Blood hyperviscosity with reduced skin blood flow in scleroderma. Ann Rheum Dis 36(6):569–574. https://doi.org/10.1136/ard.36.6.569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jacobs MJ, Jorning PJ, van der Kloot EJ VR, Kitslaar PJ, Lemmens HA, Slaaf DW, Reneman RS (1991) Plasmapheresis in Raynaud's phenomenon in systemic sclerosis: a microcirculatory study. Int J Microcirc Clin Exp 10(1):1–11

    CAS  PubMed  Google Scholar 

  25. Jacobs MJ, Breslau PJ, Slaaf DW, Reneman RS, Lemmens JA (1987) Nomenclature of Raynaud's phenomenon: a capillary microscopic and hemorheologic study. Surgery 101(2):136–145

    CAS  PubMed  Google Scholar 

  26. Vaya A, Todoli J, Calvo J, Romagnoli M, Ricart JM (2008) Haemorheological profile in patients with systemic sclerosis. Clin Hemorheol Microcirc 40(3):243–248

    Article  CAS  PubMed  Google Scholar 

  27. Johnson SR (2015) New ACR EULAR guidelines for systemic sclerosis classification. Curr Rheumatol Rep 17(5):32. https://doi.org/10.1007/s11926-015-0506-3

    Article  CAS  PubMed  Google Scholar 

  28. Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M (2016) 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 37(1):67–119. https://doi.org/10.1093/eurheartj/ehv317

    Article  PubMed  Google Scholar 

  29. Price LC, Wort SJ, Perros F, Dorfmuller P, Huertas A, Montani D, Cohen-Kaminsky S, Humbert M (2012) Inflammation in pulmonary arterial hypertension. Chest 141(1):210–221. https://doi.org/10.1378/chest.11-0793

    Article  CAS  PubMed  Google Scholar 

  30. Patan S (2000) Vasculogenesis and angiogenesis as mechanisms of vascular network formation, growth and remodeling. J Neuro-Oncol 50(1–2):1–15

    Article  CAS  Google Scholar 

  31. Risau W (1997) Mechanisms of angiogenesis. Nature 386(6626):671–674. https://doi.org/10.1038/386671a0

    Article  CAS  PubMed  Google Scholar 

  32. Ranchoux B, Harvey LD, Ayon RJ, Babicheva A, Bonnet S, Chan SY, Yuan JX, Perez VJ (2018) Endothelial dysfunction in pulmonary arterial hypertension: an evolving landscape (2017 Grover conference series). Pulm Circ 8(1):2045893217752912. https://doi.org/10.1177/2045893217752912

    Article  CAS  PubMed  Google Scholar 

  33. Kim J, Chung H, Cho M, Lee BK, Karimi A, Shin S (2013) The role of critical shear stress on acute coronary syndrome. Clin Hemorheol Microcirc 55(1):101–109. https://doi.org/10.3233/ch-131694

    Article  PubMed  Google Scholar 

  34. Antonova N, Velcheva I (1999) Hemorheological disturbances and characteristic parameters in patients with cerebrovascular disease. Clin Hemorheol Microcirc 21(3–4):405–408

    CAS  PubMed  Google Scholar 

  35. Cecchi E, Giglioli C, Valente S, Lazzeri C, Gensini GF, Abbate R, Mannini L (2011) Role of hemodynamic shear stress in cardiovascular disease. Atherosclerosis 214(2):249–256. https://doi.org/10.1016/j.atherosclerosis.2010.09.008

    Article  CAS  PubMed  Google Scholar 

  36. Korsten P, Niewold TB, Zeisberg M, Utset TO, Cho D, Zachary LS, Sweiss NJ, Volkov S (2017) Increased whole blood viscosity is associated with the presence of digital ulcers in systemic sclerosis: results from a cross-sectional pilot study. Autoimmune diseases 2017(3529214):1–5. https://doi.org/10.1155/2017/3529214

    Article  CAS  Google Scholar 

  37. Wei A, Gu Z, Li J, Liu X, Wu X, Han Y, Pu J (2016) Clinical adverse effects of endothelin receptor antagonists: insights from the meta-analysis of 4894 patients from 24 randomized double-blind placebo-controlled clinical trials. J Am Heart Assoc 5(11). https://doi.org/10.1161/jaha.116.003896

  38. Hughes M, Herrick AL (2017) Digital ulcers in systemic sclerosis. Rheumatology (Oxford, England) 56(1):14–25. https://doi.org/10.1093/rheumatology/kew047

    Article  CAS  Google Scholar 

  39. Kolstad KD, Li S, Steen V, Chung L (2018) Long-term outcomes in systemic sclerosis-associated pulmonary arterial hypertension from the pulmonary hypertension assessment and recognition of outcomes in scleroderma registry (PHAROS). Chest 154(4):862–871. https://doi.org/10.1016/j.chest.2018.05.002

    Article  PubMed  PubMed Central  Google Scholar 

  40. Launay D, Sitbon O, Hachulla E, Mouthon L, Gressin V, Rottat L, Clerson P, Cordier JF, Simonneau G, Humbert M (2013) Survival in systemic sclerosis-associated pulmonary arterial hypertension in the modern management era. Ann Rheum Dis 72(12):1940–1946. https://doi.org/10.1136/annrheumdis-2012-202489

    Article  PubMed  Google Scholar 

  41. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J, Harrington RA, Anderson JL, Bates ER, Bridges CR, Eisenberg MJ, Ferrari VA, Grines CL, Hlatky MA, Jacobs AK, Kaul S, Lichtenberg RC, Lindner JR, Moliterno DJ, Mukherjee D, Pohost GM, Rosenson RS, Schofield RS, Shubrooks SJ, Stein JH, Tracy CM, Weitz HH, Wesley DJ (2009) ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation task force on expert consensus documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation 119(16):2250–2294. https://doi.org/10.1161/circulationaha.109.192230

    Article  PubMed  Google Scholar 

  42. Williams MH, Handler CE, Akram R, Smith CJ, Das C, Smee J, Nair D, Denton CP, Black CM, Coghlan JG (2006) Role of N-terminal brain natriuretic peptide (N-TproBNP) in scleroderma-associated pulmonary arterial hypertension. Eur Heart J 27(12):1485–1494. https://doi.org/10.1093/eurheartj/ehi891

    Article  CAS  PubMed  Google Scholar 

  43. Harris ES, Meiselman HJ, Moriarty PM, Metzger A, Malkovsky M (2018) Therapeutic plasma exchange for the treatment of systemic sclerosis: a comprehensive review and analysis. J Scleroderma Relat Disord 3(2):132–152. https://doi.org/10.1177/2397198318758606

    Article  PubMed  PubMed Central  Google Scholar 

  44. Hunzelmann N, Genth E, Krieg T, Lehmacher W, Melchers I, Meurer M, Moinzadeh P, Muller-Ladner U, Pfeiffer C, Riemekasten G, Schulze-Lohoff E, Sunderkoetter C, Weber M, Worm M, Klaus P, Rubbert A, Steinbrink K, Grundt B, Hein R, Scharffetter-Kochanek K, Hinrichs R, Walker K, Szeimies RM, Karrer S, Muller A, Seitz C, Schmidt E, Lehmann P, Foeldvari I, Reichenberger F, Gross WL, Kuhn A, Haust M, Reich K, Bohm M, Saar P, Fierlbeck G, Kotter I, Lorenz HM, Blank N, Grafenstein K, Juche A, Aberer E, Bali G, Fiehn C, Stadler R, Bartels V (2008) The registry of the German network for systemic scleroderma: frequency of disease subsets and patterns of organ involvement. Rheumatology (Oxford, England) 47(8):1185–1192. https://doi.org/10.1093/rheumatology/ken179

    Article  CAS  Google Scholar 

  45. Denton CP, Hachulla E (2011) Risk factors associated with pulmonary arterial hypertension in patients with systemic sclerosis and implications for screening. Eur Respir Rev 20(122):270–276. https://doi.org/10.1183/09059180.00006111

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cardiology, Faculty of Medicine, Dokuz Eylül University, Izmir, Turkey

    Bihter Senturk, Bahri Akdeniz & Mehmet Birhan Yilmaz

  2. School of Physical Therapy and Rehabilitation, Dokuz Eylül University, Izmir, Turkey

    Buse Ozcan Kahraman

  3. Department of Cardiology, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey

    Burak Acar

  4. Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Dokuz Eylül University, Izmir, Turkey

    Sadettin Uslu & Merih Birlik

Authors
  1. Bihter Senturk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bahri Akdeniz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mehmet Birhan Yilmaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Buse Ozcan Kahraman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Burak Acar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sadettin Uslu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Merih Birlik
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bihter Senturk.

Ethics declarations

Disclosures

None.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Senturk, B., Akdeniz, B., Yilmaz, M.B. et al. Whole blood viscosity in systemic sclerosis: a potential biomarker of pulmonary hypertension?. Clin Rheumatol 39, 49–56 (2020). https://doi.org/10.1007/s10067-019-04603-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-019-04603-4

Keywords

Search

Navigation