Download PDF
Thromb Haemost 2009; 102(06): 1176-1182
DOI: 10.1160/TH09-02-0118
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Fibrin clot properties are altered in patients with chronic obstructive pulmonary disease

Beneficial effects of simvastatin treatment
Anetta Undas
1   Institute of Cardiology, Jagiellonian University School of Medicine, Cracow, Poland
2   Department of Medicine, Jagiellonian University School of Medicine, Cracow, Poland
,
Przemyslaw Kaczmarek
2   Department of Medicine, Jagiellonian University School of Medicine, Cracow, Poland
,
Krzysztof Sladek
2   Department of Medicine, Jagiellonian University School of Medicine, Cracow, Poland
,
Ewa Stepien
3   John Paul II Hospital, Cracow, Poland
,
Wojciech Skucha
4   District Hospital Proszowice, Pulmonary Ward, Proszowice, Poland
,
Marcin Rzeszutko
2   Department of Medicine, Jagiellonian University School of Medicine, Cracow, Poland
,
Izabela Gorkiewicz-Kot
3   John Paul II Hospital, Cracow, Poland
,
Wieslawa Tracz
1   Institute of Cardiology, Jagiellonian University School of Medicine, Cracow, Poland
› Author AffiliationsFinancial support: This study was supported by a grant of Polish Ministry of Science (to AU).
Further Information

Publication History

Received: 24 February 2009

Accepted after major revision: 21 September 2009

Publication Date:
28 November 2017 (online)

    Permissions and Reprints

Summary

Increased risk of thrombotic events occurs in chronic obstructive pulmonary disease (COPD). Elevated fibrinogen and C-reactive protein (CRP), being common in COPD, are associated with formation of dense fibrin clots resistant to lysis. Statins have been found to display anti-inflammatory and antithrombotic effects. We investigated fibrin clot properties in COPD patients prior to and following statin therapy. Ex vivo plasma fibrin clot permeability, compaction, and fibrinolysis were assessed in 56 patients with stable COPD,aged 64.9 ±9.2 years (mean FEV1, 54.7 ±15.9% predicted), versus 56 controls matched for age, sex and cardiovascular risk factors. Patients were then randomly assigned to receive simvastatin 40 mg/day (n = 28) or to remain without statins for three months (n = 28). Patients with COPD had lower clot permeability (6.1±1.07 versus 9.2 ±0.9 10−9 cm2; p <0.0001), decreased compaction (44.9 ±4.5 versus 63.9 ± 6.1%; p <0.0001), higher maximum D-dimer levels released from clots (4.23 ±0.55 versus 3.53 ±0.31 mg/l; p <0.0001) with a decreased rate of this release (75.0 ±8.3 versus 80.9 ±8.0 43;g/ l/min; p = 0.03) and prolonged lysis time (9.84 ±1.33 versus 8.02 ±0.84 min; p <0.0001) compared with controls. Scanning electron microscopy confirmed denser clot structure in COPD. Multiple linear regression analysis after adjustment for age and fibrinogen showed that in the COPD patients, CRP was the only independent predictor of permeability (R2 = 0.47; p <0.001) and lysis time (R2 = 0.43; p <0.001). Simvastatin improved clot properties (p <0.05) despite unaltered CRP and irrespective of cholesterol reduction. Our study shows that fibrin clots in COPD patients are composed of much denser networks that are more resistant to lysis, and these properties can be improved by statin administration.

Keywords

Coagulation - fibrin - fibrinolysis - inflammation - statins
 

  • References

  • 1 Sin DD, Anthonisen NR, Soriano JB. et al. Mortality in COPD: role of comorbidities. Eur Respir J 2006; 28: 1245-1257.
    CrossrefPubMedGoogle Scholar
  • 2 Anthonisen NR, Connett JE, Enright PL. et al. Lung Health Study Research Group. Hospitalizations and mortality in the Lung Health Study. Am J Respir Crit Care Med 2002; 166: 333-339.
    CrossrefPubMedGoogle Scholar
  • 3 Huiart L, Ernst P, Suissa S. Cardiovascular morbidity and mortality in COPD. Chest 2005; 128: 2640-2646.
    CrossrefPubMedGoogle Scholar
  • 4 Sin DD, Man SF. Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inflammation in chronic obstructive pulmonary disease. Circulation 2003; 107: 1514-1519.
    CrossrefPubMedGoogle Scholar
  • 5 Undas A, Celinska-Lowenhoff M, Lowenhoff T. et al. Statins, fenofibrate, and quinapril increase clot permeability and enhance fibrinolysis in patients with coronary artery disease. J Thromb Haemost 2006; 04: 1029-1036.
    CrossrefPubMedGoogle Scholar
  • 6 Undas A, Plicner D, Stepien E. et al. Altered fibrin clot structure in patients with advanced coronary artery disease: a role of C-reactive protein, lipoprotein(a), and homocysteine. J Thromb Haemost 2007; 05: 1988-1990.
    CrossrefPubMedGoogle Scholar
  • 7 Bini A, Fenoglio J, Mesa-Tejada E. et al. Identification and distribution of fibrinogen, fibrin, and fibrin(ogen) degradation products in atherosclerosis. Atherosclerosis 1989; 69: 1038-1045.
    PubMedGoogle Scholar
  • 8 Thompson W, Smith E. Atherosclerosis and the coagulation system. J Pathol 1989; 159: 97-106.
    CrossrefPubMedGoogle Scholar
  • 9 Mosesson MW, Siebenlist KR, Meh DA. The structure and biological features of fibrinogen and fibrin. Ann NY Acad Sci 2001; 936: 11-30.
    PubMedGoogle Scholar
  • 10 Blombäck B, Carlsson K, Fatah K. et al. Fibrin in human plasma: gel architecture governed by rate and nature of fibrinogen activation. Thromb Res 1994; 05: 521-538.
    PubMedGoogle Scholar
  • 11 Collet JP, Lesty C, Montalescot G. Dynamic changes of fibrin architecture during fibrin formation and intrinsic fibrinolysis of fibrin-rich clots. J Biol Chem 2003; 278: 21331-21335.
    CrossrefPubMedGoogle Scholar
  • 12 Scott EM, Ariëns RAS, Grant PJ. Genetic and environmental determinants of fibrin structure and function. Relevance to clinical disease. Arterioscler Thromb Vasc Biol 2004; 24: 1558-1566.
    CrossrefPubMedGoogle Scholar
  • 13 Undas A, Zeglin M. Fibrin clot structure and cardiovascular disease. Vasc Dis Prevention 2006; 03: 99-106.
    PubMedGoogle Scholar
  • 14 Undas A, Brozek J, Jankowski M. et al. Plasma homocysteine affects fibrin clot permeability and resistance to lysis in human subjects. Arterioscler Thromb Vasc Biol 2006; 26: 1397-1404.
    CrossrefPubMedGoogle Scholar
  • 15 Undas A, Stepien E, Tracz W. et al. Lipoprotein(a) as a modifier of fibrin clot permeability and susceptibility to lysis. J Thromb Haemost 2006; 04: 973-975.
    CrossrefPubMedGoogle Scholar
  • 16 Salonen EM, Vartio T, Hedman K. Binding of fibronectin by the acute phase C-reactive protein. J Biol Chem 1984; 259: 1496-1501.
    CrossrefPubMedGoogle Scholar
  • 17 Shacter E, Williams JA, Lim M. et al. Differential susceptibility of plasma proteins to oxidative modification: examination by western blot immunoassay. Free Radic Biol Med 1994; 17: 429-437.
    CrossrefPubMedGoogle Scholar
  • 18 Dunn EJ, Ariëns RA, Grant PJ. The influence of type 2 diabetes on fibrin structure and function. Diabetologica 2005; 48: 1198-1206.
    CrossrefPubMedGoogle Scholar
  • 19 Williams S, Fatah K, Ivert T. et al. The effect of acetyl salicylic acid on fibrin gel lysis by tissue plasminogen activator. Blood Coagul Fibrinolysis 1995; 06: 718-725.
    CrossrefPubMedGoogle Scholar
  • 20 Mancini GB, Etminan M, Zhang B. et al. Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease. J Am Coll Cardiol 2006; 47: 2554-2560.
    CrossrefPubMedGoogle Scholar
  • 21 Mills JD, Ariens RA, Mansfield MW. et al. Altered fibrin clot structure in the healthy relatives of patients with premature coronary artery disease. Circulation 2002; 106: 1938-1942.
    CrossrefPubMedGoogle Scholar
  • 22 Collet J-P, Mishal Z, Lesty C. et al. Abnormal fibrin clot architecture in nephritic patients is related to hypofibrinolysis: influence of plasma biochemical modifications. Thromb Haemost 1999; 82: 1482-1489.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Collet J-P, Allali Y, Lesty C. et al. Altered fibrin architecture is associated with hypofibrinolysis and premature coronary atherothrombosis. Arterioscler Thromb Vasc Biol 2006; 26: 2567-2573.
    CrossrefPubMedGoogle Scholar
  • 24 Undas A, Topor-Madry R, Tracz W. Simvastatin increases clot permeability and susceptibility to lysis in patients with LDL cholesterol below 3.4 mmol/l. Pol Arch Med Wewn 2009; 119: 354-359.
    PubMedGoogle Scholar
  • 25 Gonbert S, Malinsky S, Sposito AC. et al. Atorvastatin lowers lipoprotein(a) but not apolipoprotein(a) fragment levels in hypercholesterolemic subjects at high cardiovascular risk. Atherosclerosis 2002; 164: 305-311.
    CrossrefPubMedGoogle Scholar
  • 26 Lee TM, Chen CC, Shan HN. et al. Effects of pravastatin on functional capacity in patients with chronic obstructive pulmonary disease and pulmonary hypertension. Clin Sci (Lond 2009; 116: 497-505.
    PubMedGoogle Scholar
  • 27 Maclay JD, McAlister DA, MacNee W. Cardiovascular risk in chronic obstructive pulmonary disease. Respirology 2007; 12: 634-641.
    CrossrefPubMedGoogle Scholar
  • 28 Lahera V, Goicoechea M, de Vinuesa SG. et al. Endothelial dysfunction, oxidative stress and inflammation in atherosclerosis: beneficial effects of statins. Curr Med Chem 2007; 14: 243-248.
    CrossrefPubMedGoogle Scholar
  • 29 Undas A, Szuldrzynski K, Stepien E. et al. Reduced clot permeability and susceptibility to lysis in patients with acute coronary syndrome: effects of inflammation and oxidative stress. Atherosclerosis 2007; 196: 551-558.
    PubMedGoogle Scholar
  • 30 Ashitani J, Mukae H, Arimura Y. et al. Elevated plasma procoagulant and fibrinolytic markers in patients with chronic obstructive pulmonary disease. Int Medicine 2002; 41: 181-185.
    PubMedGoogle Scholar
  • 31 Joppa P, Petrasova D, Stancak B. et al. Systemic inflammation in patients with COPD and pulmonary hypertension. Chest 2006; 130: 326-333.
    CrossrefPubMedGoogle Scholar
  • 32 Brenner O, Birm MD, Long M. Sclerosis of pulmonary artery with thrombosis. Lancet 1931; 01: 911-914.
    PubMedGoogle Scholar
  • 33 Singh U, Deveraj S, Jialal I. C-reactive protein decreases tissue plasminogen activator activity in human aortic endothelial cells: evidence that CRP is prothrombotic. Arterioscler Thromb Vasc Biol 2005; 25: 2216-2221.
    CrossrefPubMedGoogle Scholar