Skip to main content

Advertisement

SpringerLink
Log in

Hyperhomocysteinemia in patients with pulmonary embolism is associated with impaired plasma fibrinolytic capacity

  • Published:
Journal of Thrombosis and Thrombolysis Aims and scope Submit manuscript

Abstract

Hyperhomocysteinemia (HHcy) affects haemostasis and shifts its balance in favour of thrombosis. In vitro and in vivo studies suggested that HHcy may impair fibrinolysis either by influencing the plasma levels of fibrinolytic factors or by altering the fibrinogen structure. We investigated the influence of mild HHcy levels on plasma fibrinolytic potential by using clot lysis time (CLT) and fibrin susceptibility to plasmin-induced lysis in 94 patients with previous pulmonary embolism and no pulmonary hypertension. CLT was measured as lysis time of tissue factor induced clots exposed to exogenous tissue plasminogen activator (t-PA). The rate of in vitro plasmin-mediated cleavage of fibrin β-chain was assessed over a 6-h period on fibrin clots, which were obtained by exposition to thrombin of purified fibrinogen. Homocysteine plasma levels were measured by Abbott Imx immunoassay and we considered as altered the values above 15 μmol/L according to the literature. In 68 patients homocysteine levels were below 15 μmol/L (NHcy) and in 26 they were above (HHcy). Significant differences were observed between the two groups regarding plasma fibrinolytic potential (p = 0.016), TAFIact (expressed as clot lysis ratio) (p = 0.02), t-PA (0.008) and PLG (0.037), but not for the other assessed components. The HHcy-patients had a threefold higher risk to have an impaired fibrinolysis. Instead, a multivariate logistic regression analysis adjusted for significances of univariate showed that HHcy (OR 5.2 95 % CI 1.7–15.9; p = 0.003) and BMI (OR 5.0 95 % CI 1.6–15.9; p = 0.006) resulted independently associated with impaired fibrinolytic activity. HHcy affects TAFI-mediated hypofibrinolysis but not fibrin(ogen) structure or function as documented by fibrin degradation analysis.

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.

Institutional subscriptions

Similar content being viewed by others

References

  1. Lisman T, de Groot PG, Meijers JC, Rosendaal FR (2005) Reduced plasma fibrinolytic potential is a risk factor for venous thrombosis. Blood 105:1102–1105

    Article  CAS  PubMed  Google Scholar 

  2. Guimarães AH, de Bruijne EL, Lisman T, Dippel DW, Deckers JW, Poldermans D, Rijken DC, Leebeek FW (2009) Hypofibrinolysis is a risk factor for arterial thrombosis at young age. Br J Haematol 145:115–120

    Article  PubMed  Google Scholar 

  3. Meltzer ME, Doggen CJ, de Groot PG, Rosendaal FR, Lisman T (2007) Fibrinolysis and the risk of venous and arterial thrombosis. Curr Opin Hematol 14:242–248

    Article  CAS  PubMed  Google Scholar 

  4. Cellai AP, Lami D, Fedi S, Marcucci R, Mannini L, Cenci C, Rogolino A, Sodi A, Menchini U, Abbate R, Prisco D (2012) A hypercoagulable and hypofibrinolytic state is detectable by global methods in patients with retinal vein occlusion. Atherosclerosis 224:97–101

    Article  CAS  PubMed  Google Scholar 

  5. Grifoni E, Marcucci R, Ciuti G, Cenci C, Poli D, Mannini L, Liotta AA, Miniati M, Abbate R, Prisco D (2012) The thrombophilic pattern of different clinical manifestations of venous thromboembolism: a survey of 443 cases of venous thromboembolism. Semin Thromb Hemost 38:230–234

    Article  PubMed  Google Scholar 

  6. Naess IA, Christiansen SC, Romundstad PR, Cannegieter SC, Blom HJ, Rosendaal FR, Hammerstrøm J (2008) Prospective study of homocysteine and MTHFR 677TT genotype and risk for venous thrombosis in a general population-results from the HUNT 2 study. Br J Haematol 141:529–535

    Article  CAS  PubMed  Google Scholar 

  7. Bezemer ID, Doggen CJ, Vos HL, Rosendaal FR (2007) No association between the common MTHFR 677C->T polymorphism and venous thrombosis: results from the MEGA study. Arch Intern Med 167:497–501

    Article  CAS  PubMed  Google Scholar 

  8. Durga J, Verhoef P, Anteunis LJ, Schouten E, Kok FJ (2007) Effects of folic acid supplementation on hearing in older adults: a randomized, controlled trial. Ann Intern Med 146:1–9

    Article  PubMed  Google Scholar 

  9. Kołodziejczyk J, Malinowska J, Nowak P, Olas B (2010) Comparison of the effect of homocysteine and its thiolactone on the fibrinolytic system using human plasma and purified plasminogen. Mol Cell Biochem 344:217–220

    Article  PubMed  Google Scholar 

  10. Undas A, Brozek J, Jankowski M, Siudak Z, Szczeklik A, Jakubowski H (2006) Plasma homocysteine affects fibrin clot permeability and resistance to lysis in human subjects. Arterioscler Thromb Vasc Biol 26:1397–1404

    Article  CAS  PubMed  Google Scholar 

  11. Colucci M, Cattaneo M, Martinelli I, Semeraro F, Binetti BM, Semeraro N (2008) Mild hyperhomocysteinemia is associated with increased TAFI levels and reduced plasma fibrinolytic potential. J Thromb Haemost 6:1571–1577

    CAS  PubMed  Google Scholar 

  12. Cellai AP, Lami D, Antonucci E, Fiorillo C, Becatti M, Olimpieri B, Bani D, Grifoni E, Cenci C, Marcucci R, Mannini L, Poli D, Abbate R, Prisco D (2013) Fibrinolytic inhibitors and fibrin characteristics determine a hypofibrinolytic state in patients with pulmonary embolism. Thromb Haemost 109:565–567

    Article  CAS  PubMed  Google Scholar 

  13. Miniati M, Fiorillo C, Becatti M, Monti S, Bottai M, Marini C, Grifoni E, Formichi B, Bauleo C, Arcangeli C, Poli D, Nassi PA, Abbate R, Prisco D (2010) Fibrin resistance to lysis in patients with pulmonary hypertension other than thromboembolic. Am J Respir Crit Care Med 181:992–996

    Article  CAS  PubMed  Google Scholar 

  14. Galiè N, Torbicki A, Barst R, Dartevelle P, Haworth S, Higenbottam T, Olschewski H, Peacock A, Pietra G, Rubin LJ, Simonneau G, Priori SG, Garcia MA, Blanc JJ, Budaj A, Cowie M, Dean V, Deckers J, Burgos EF, Lekakis J, Lindahl B, Mazzotta G, McGregor K, Morais J, Oto A, Smiseth OA, Barbera JA, Gibbs S, Hoeper M, Humbert M, Naeije R, Pepke-Zaba J, Task Force (2004) Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The task force on diagnosis and treatment of pulmonary arterial hypertension of the European Society of Cardiology. Eur Heart J 25:2243–2278

    Article  PubMed  Google Scholar 

  15. Cellai AP, Lami D, Magi A, Liotta AA, Rogolino A, Antonucci E, Bandinelli B, Abbate R, Prisco D (2010) Assessment of fibrinolytic activity by measuring the lysis time of a tissue-factor-induced clot: a feasibility evaluation. Clin Appl Thromb Hemost 16:337–344

    Article  PubMed  Google Scholar 

  16. Lisman T, Leebeek FW, Mosnier LO, Bouma BN, Meijers JC, Janssen HL, Nieuwenhuis HK, De Groot PG (2001) Thrombin activatable fibrinolysis inhibitor deficiency in cirrhosis is not associated with increased plasma fibrinolysis. Gastroenterology 121:131–139

    Article  CAS  PubMed  Google Scholar 

  17. Buckell M (1958) The effect of citrate on euglobulin methods of estimating fibrinolytic activity. J Clin Pathol 11:403–405

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Ranucci M, Ballotta A, Frigiola A, Boncilli A, Brozzi S, Costa E, Mehta RH (2009) Pre-operative homocysteine levels and morbidity and mortality following cardiac surgery. Eur Heart J 30:995–1004

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Meltzer ME, Lisman T, de Groot PG, Meijers JC, le Cessie S, Doggen CJ, Rosendaal FR (2010) Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1. Blood 116:113–121

    Article  CAS  PubMed  Google Scholar 

  20. Morris TA, Marsh JJ, Chiles PG, Auger WR, Fedullo PF, Woods VL (2006) Fibrin derived from patients with chronic thromboembolic pulmonary hypertension is resistant to lysis. Am J Respir Crit Care Med 173:1270–1275

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Conflict of interest

None declared.

Author information

Authors and Affiliations

  1. Department of Heart and Vessels, Thrombosis Centre, Azienda Ospedaliero-Universitaria Careggi, Viale Morgagni 85, 50134, Florence, Italy

    Anna Paola Cellai, Agatina Alessandrello Liotta & Angela Rogolino

  2. Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy

    Donatella Lami, Emilia Antonucci, Sandra Fedi, Caterina Cenci, Rossella Marcucci, Rosanna Abbate & Domenico Prisco

  3. Department of Biochemical Sciences, University of Florence, Florence, Italy

    Claudia Fiorillo & Matteo Becatti

Authors
  1. Anna Paola Cellai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Donatella Lami
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Emilia Antonucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Agatina Alessandrello Liotta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Angela Rogolino
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sandra Fedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Claudia Fiorillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Matteo Becatti
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Caterina Cenci
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Rossella Marcucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Rosanna Abbate
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Domenico Prisco
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anna Paola Cellai.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cellai, A.P., Lami, D., Antonucci, E. et al. Hyperhomocysteinemia in patients with pulmonary embolism is associated with impaired plasma fibrinolytic capacity. J Thromb Thrombolysis 38, 45–49 (2014). https://doi.org/10.1007/s11239-013-0981-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11239-013-0981-1

Keywords

Search

Navigation