Download PDF
Thromb Haemost 2015; 114(02): 217-227
DOI: 10.1160/TH14-10-0861
Review Article
Schattauer GmbH

Blood coagulation and fibrinolysis in aortic valve stenosis: links with inflammation and calcification

Joanna Natorska
1   Institute of Cardiology, Jagiellonian University School of Medicine, Cracow, Poland
2   John Paul II Hospital, Cracow, Poland
,
Anetta Undas
1   Institute of Cardiology, Jagiellonian University School of Medicine, Cracow, Poland
2   John Paul II Hospital, Cracow, Poland
› Author Affiliations Financial support: The study was supported by the grant from Jagiellonian University Medical College (K/ZDS/002936, to A. U.).
Further Information

Publication History

Received: 16 October 2014

Accepted after major revision: 25 January 2015

Publication Date:
21 November 2017 (online)

    Permissions and Reprints

Summary

Aortic valve stenosis (AS) increasingly afflicts our aging population. However, the pathobiology of the disease is still poorly understood and there is no effective pharmacotherapy for treating those at risk for clinical progression. The progression of AS involves complex inflammatory and fibroproliferative processes that resemble to some extent atherosclerosis. Accumulating evidence indicates that several coagulation proteins and its inhibitors, including tissue factor, tissue factor pathway inhibitor, prothrombin, factor XIII, von Willebrand factor, display increased expression within aortic stenotic valves, predominantly on macrophages and myofibroblasts around calcified areas. Systemic impaired fibrinolysis, along with increased plasma and valvular expression of plasminogen activator inhibitor-1, has also been observed in patients with AS in association with the severity of the disease. There is an extensive cross-talk between inflammation and coagulation in stenotic valve tissue which contributes to the calcification and mineralisation of the aortic valve leaflets. This review summarises the available data on blood coagulation and fibrinolysis in AS with the emphasis on their interactions with inflammation and calcification.

Keywords

Aortic stenosis - blood coagulation - fibrinolysis - fibrin - tissue factor
 

  • References

  • 1 Nkomo VT. et al. Burden of valvular heart diseases: a population-based study. Lancet 2006; 368: 1005-1011.
    CrossrefPubMedGoogle Scholar
  • 2 Yetkin EJ. Molecular and cellular mechanisms of aortic stenosis. Int J Cardiol 2009; 135: 4-13.
    CrossrefPubMedGoogle Scholar
  • 3 Pate GE. Association between aortic stenosis and hypertension. J Heart Valve Dis 2002; 11: 612-614.
    PubMedGoogle Scholar
  • 4 Ngo MV. et al. Smoking and obesity are associated with progression of aortic stenosis. Am J Geriatr Cardiol 2001; 10: 86-90.
    CrossrefPubMedGoogle Scholar
  • 5 Mohty D. et al. Associations between plasma LDL particle size, valvular accumulation of oxidized LDL, and inflammation in patients with aortic stenosis. Arterioscler Thromb Vasc Biol 2008; 28: 187-193.
    PubMedGoogle Scholar
  • 6 Martinsson A. et al. Carotid plaque, intima-media thickness, and incident aortic stenosis: a prospective cohort study. Arterioscler Thromb Vasc Biol 2014; 34: 2343-2348.
    CrossrefPubMedGoogle Scholar
  • 7 Montagnana M. et al. Genetic risk factors of atherothrombosis. Pol Arch Med Wewn 2014; 124: 474-482.
    PubMedGoogle Scholar
  • 8 Goel SS. et al. Severe aortic stenosis and coronary artery disease--implications for management in the transcatheter aortic valve replacement era: a comprehensive review. J Am Coll Cardiol 2013; 02 (62) 1-10.
    PubMedGoogle Scholar
  • 9 Freeman RV, Otto CM. Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies. Circulation 2005; 111: 3316-3326.
    CrossrefPubMedGoogle Scholar
  • 10 Warren BA, Yong JL. Calcification of the aortic valve: its progression and grading. Pathology 1997; 29: 360-368.
    CrossrefPubMedGoogle Scholar
  • 11 Mulholland DL, Gotlieb AI. Cell biology of valvular interstitial cells. Can J Cardiol 1996; 12: 231-236.
    PubMedGoogle Scholar
  • 12 Natorska J. et al. Evidence for tissue factor expression in aortic valves in patients with aortic stenosis. Pol Arch Med Wew 2009; 119: 636-642.
    PubMedGoogle Scholar
  • 13 Schoen FJ. Aortic valve structure-function correlations: role of elastic fibres no longer a stretch of the imagination. J Heart Valve Dis 1997; 06: 1-6.
    PubMedGoogle Scholar
  • 14 Dreger SA. et al. Profile and localisation of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in human heart valves. J Heart Valve Dis 2002; 11: 875-880.
    PubMedGoogle Scholar
  • 15 Desmoulière A, Gabbiani G. Myofibroblast differentiation during fibrosis. Exp Nephrol 1995; 03: 134-139.
    PubMedGoogle Scholar
  • 16 Mohler ER III. Are atherosclerotic processes involved in aortic-valve calcification?. Lancet 2000; 356: 524-525.
    CrossrefPubMedGoogle Scholar
  • 17 Akerström F. et al. Aortic stenosis: a general overview of clinical, pathophysiological and therapeutic aspects. Expert Rev Cardiovasc Ther 2013; 11: 239-250.
    CrossrefPubMedGoogle Scholar
  • 18 Otto CM. et al. Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly. N Engl J Med 1999; 341: 142-147.
    CrossrefPubMedGoogle Scholar
  • 19 Liu AC. et al. The emerging role of valve interstitial cell phenotypes in regulating heart valve pathobiology. Am J Pathol 2007; 171: 1407-1418.
    CrossrefPubMedGoogle Scholar
  • 20 Ngo DT. et al. Prevention of aortic valve stenosis: a realistic therapeutic target?. Pharmacol Ther 2012; 135: 78-93.
    CrossrefPubMedGoogle Scholar
  • 21 Miller JD. et al. Calcific aortic valve stenosis: methods, models, and mechanisms. Circ Res 2011; 108: 1392-1412.
    CrossrefPubMedGoogle Scholar
  • 22 Miller JD. et al. Dysregulation of antioxidant mechanisms contributes to increased oxidative stress in calcific aortic valvular stenosis in humans. J Am Coll Cardiol 2008; 52: 843-850.
    CrossrefPubMedGoogle Scholar
  • 23 Fantus D. et al. Aortic calcification: Novel insights from familial hypercholesterolemia and potential role for the low-density lipoprotein receptor. Atherosclerosis 2013; 226: 9-15.
    CrossrefPubMedGoogle Scholar
  • 24 Leopold JA. Cellular mechanisms of aortic valve calcification. Circ Cardiovasc Interv 2012; 04: 605-614.
    PubMedGoogle Scholar
  • 25 O’Brien KD. Pathogenesis of calcific aortic valve disease: a disease process comes of age (and a good deal more). Arterioscler Thromb Vasc Biol 2006; 08: 1721-1728.
    PubMedGoogle Scholar
  • 26 Maher ER. et al. Aortic and mitral valve calcification in patients with end-stage renal disease. Lancet 1987; 02: 875-877.
    PubMedGoogle Scholar
  • 27 Natorska J. et al. Does diabetes accelerate the progression of aortic stenosis through enhanced inflammatory response within aortic valves?. Inflammation 2012; 35: 834-840.
    CrossrefPubMedGoogle Scholar
  • 28 Linhartová K. et al. Parathyroid hormone and vitamin D levels are independently associated with calcific aortic stenosis. Circ J 2008; 72: 245-250.
    CrossrefPubMedGoogle Scholar
  • 29 Persy V, D’Haese P. Vascular calcification and bone disease: the calcification paradox. Trends Mol Med 2009; 15: 405-416.
    CrossrefPubMedGoogle Scholar
  • 30 Borissoff JI. et al. The haemostatic system as a modulator of atherosclerosis. N Engl J Med 2011; 364: 1746-1760.
    CrossrefPubMedGoogle Scholar
  • 31 Loeffen R. et al. The impact of blood coagulability on atherosclerosis and cardiovascular disease. J Thromb Haemost 2012; 10: 1207-1216.
    CrossrefPubMedGoogle Scholar
  • 32 Kleinegris MC. et al. Coagulation and the vessel wall in thrombosis and atherosclerosis. Pol Arch Med Wewn 2012; 122: 557-566.
    PubMedGoogle Scholar
  • 33 Borissoff JI. et al. Early atherosclerosis exhibits an enhanced procoagulant state. Circulation 2010; 122: 821-830.
    CrossrefPubMedGoogle Scholar
  • 34 Otto CM. et al. Characterisation of the early lesion of “degenerative” valvular aortic stenosis: histological and immunohistochemical studies. Circulation 1994; 90: 844-853.
    CrossrefPubMedGoogle Scholar
  • 35 Marechaux S. et al. Identification of tissue factor in experimental aortic valve sclerosis. Cardiovasc Path 2009; 18: 67-76.
    CrossrefPubMedGoogle Scholar
  • 36 Breyne J. et al. Atherosclerotic-like process in aortic stenosis: activation of the tissue factor-thrombin pathway and potential role through osteopontin alteration. Atherosclerosis 2010; 213: 369-376.
    CrossrefPubMedGoogle Scholar
  • 37 Natorska J. et al. Fibrin presence within aortic valves in patients with aortic stenosis: association with in vivo thrombin generation and fibrin clot properties. Thromb Haemost 2011; 105: 254-260.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Kapusta P. et al. Factor XIII expression within aortic valves and its plasma activity in patients with aortic stenosis: association with severity of disease. Thromb Haemost 2012; 108: 1172-1179.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 39 Balaoing LR. et al. Age-related changes in aortic valve haemostatic protein regulation. Arterioscler Thromb Vasc Biol 2014; 34: 72-80.
    CrossrefPubMedGoogle Scholar
  • 40 Kochtebane N. et al. Expression of uPA, tPA, and PAI-1 in Calcified Aortic Valves. Biochem Res Int 2014; 2014: 658643.
    PubMedGoogle Scholar
  • 41 Levi M. et al. Bidirectional relation between inflammation and coagulation. Circulation 2004; 109: 2698-2704.
    CrossrefPubMedGoogle Scholar
  • 42 Borissoff JI. et al. Genetic and pharmacological modifications of thrombin formation in apolipoprotein E-deficient mice determine atherosclerosis severity and atherothrombosis onset in a neutrophil-dependent manner. PLoS One 2013; 08: e55784.
    CrossrefPubMedGoogle Scholar
  • 43 Lindman BR. et al. Current management of calcific aortic stenosis. Circ Res 2013; 113: 223-237.
    CrossrefPubMedGoogle Scholar
  • 44 Goldsmith IR. et al. Effect of aortic valve replacement on plasma soluble P-selectin, von Willebrand factor, and fibrinogen. Am J Cardiol 2001; 87: 107-110 A9.
    CrossrefPubMedGoogle Scholar
  • 45 Moriyama Y. et al. Influence of low-intensity anticoagulation and low-dose anti-platelet agent on coagulation-fibrinolysis system after mechanical prosthetic valve replacement. J Thorac Cardiovasc Surg 1998; 115: 952-954.
    CrossrefPubMedGoogle Scholar
  • 46 Dimitrow PP. et al. Effect of aortic valve stenosis on haemostasis is independent from vascular atherosclerotic burden. Atherosclerosis 2009; 204: e103-108.
    CrossrefPubMedGoogle Scholar
  • 47 Bischoff J, Aikawa E. Progenitor cells confer plasticity to cardiac valve endothelium. J Cardiovasc Transl Res 2001; 4: 710-719.
    PubMedGoogle Scholar
  • 48 Visconti RP. et al. An in vivo analysis of hematopoietic stem cell potential: hematopoietic origin of cardiac valve interstitial cells. Circ Res 2006; 98: 690-696.
    CrossrefPubMedGoogle Scholar
  • 49 Rafi S. et al. Venous thrombo-embolism and aortic calcifications; more evidence on the link between venous and arterial thrombosis. Thromb Res 2009; 124: 381-382.
    CrossrefPubMedGoogle Scholar
  • 50 Bonow RO. et al. ACC/AHA 2006 guidellin es for the management of patients with valvular heart disease: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidellin es (writing committee to revise the 1998 Guidellin es for the Management of Patients With Valvular Heart Disease). Circulation 2006; 114: e84-231.
    CrossrefPubMedGoogle Scholar
  • 51 Schecter AD. et al. Release of active tissue factor by human arterial smooth muscle cells. Circ Res 2000; 87: 126-132.
    CrossrefPubMedGoogle Scholar
  • 52 Jude B. et al. Relevance of tissue factor in cardiovascular disease. Arch Mal Coeur Vaiss 2005; 98: 667-671.
    PubMedGoogle Scholar
  • 53 Bellows CG. et al. Initiation and progression of mineralisation of bone nodules formed in vitro: the role of alkaline phosphatase and organic phosphate. Bone Miner 1991; 14: 27-40.
    CrossrefPubMedGoogle Scholar
  • 54 Scatena M. et al. Osteopontin: a multifunctional molecule regulating chronic inflammation and vascular disease. Arterioscler Thromb Vasc Biol 2007; 27: 2302-2309.
    CrossrefPubMedGoogle Scholar
  • 55 Rajamannan NM. et al. Human aortic valve calcification is associated with an osteoblast phenotype. Circulation 2003; 107: 2181-2184.
    CrossrefPubMedGoogle Scholar
  • 56 Carmeliet P. et al. Role of tissue factor in embryonic blood vessel development. Nature 1996; 383: 73-75.
    CrossrefPubMedGoogle Scholar
  • 57 Luszczak J. et al. Activated factor XI and tissue factor in aortic stenosis: links with thrombin generation. Blood Coagul Fibrinolysis 2011; 22: 473-479.
    CrossrefPubMedGoogle Scholar
  • 58 Brummel-Ziedins K. et al. Thrombin generation in acute coronary syndrome and stable coronary artery disease: dependence on plasma factor composition. J Thromb Haemost 2008; 06: 104-110.
    PubMedGoogle Scholar
  • 59 Rabiet MJ. et al. Thrombin-induced increase in endothelial permeability is associated with changes in cell-to-cell junction organisation. Arterioscler Thromb Vasc Biol 1996; 16: 488-496.
    CrossrefPubMedGoogle Scholar
  • 60 Borissoff JI. et al. Is thrombin a key player in the ’coagulation-atherogenesis’ maze?. Cardiovasc Res 2009; 82: 392-403.
    CrossrefPubMedGoogle Scholar
  • 61 Colotta F. et al. Expression of monocyte chemotactic protein-1 by monocytes and endothelial cells exposed to thrombin. Am J Pathol 1994; 144: 975-985.
    PubMedGoogle Scholar
  • 62 Tsopanoglou NE. et al. On the mechanism of thrombin-induced angiogenesis: involvement of alphavbeta3-integrin. Am J Physiol Cell Physiol 2002; 283: C1501-C1510.
    CrossrefPubMedGoogle Scholar
  • 63 Al-Jallad HF. et al. Transglutaminase activity regulates osteoblast differentiation and matrix mineralisation in MC3T3-E1 osteoblast cultures. Matrix Biol 2006; 25: 135-148.
    CrossrefPubMedGoogle Scholar
  • 64 Petkow-Dimitrow P, Undas A. Coagulation abnormalities in valvular and subvalvular aortic stenosis – clinical implication. Kardiol Pol 2008; 66: 569-573.
    PubMedGoogle Scholar
  • 65 Sato Y, Hatakeyama K, Yamashita A. et al. Proportion of fibrin and platelets differs in thrombi on ruptured and eroded coronary atherosclerotic plaques in humans. Heart 2005; 91: 526-530.
    CrossrefPubMedGoogle Scholar
  • 66 Salonen EM. et al. Binding of fibronectin by the acute phase reactant C-reactive protein. J Biol Chem 1984; 259: 1496-1501.
    PubMedGoogle Scholar
  • 67 Wolberg AS. et al. Elevated prothrombin results in clots with an altered fibre structure: a possible mechanism of the increased thrombotic risk. Blood 2003; 101: 3008-3013.
    CrossrefPubMedGoogle Scholar
  • 68 Wolberg AS. Thrombin generation and fibrin clot structure. Blood Rev 2007; 21: 131-142.
    CrossrefPubMedGoogle Scholar
  • 69 Gabriel DA. et al. The effect of fibrin structure on fibrinolysis. J Biol Chem 1992; 267: 24259-24263.
    PubMedGoogle Scholar
  • 70 Standeven KF. et al. The molecular physiology and pathology of fibrin structure/function. Blood Rev 2005; 19: 275-288.
    CrossrefPubMedGoogle Scholar
  • 71 Collet JP. et al. The alphaC domains of fibrinogen affect the structure of the fibrin clot, its physical properties, and its susceptibility to fibrinolysis. Blood 2005; 106: 3824-3830.
    CrossrefPubMedGoogle Scholar
  • 72 Muszbek L. et al. Factor XIII: a coagulation factor with multiple plasmatic and cellular functions. Physiol Rev 2011; 91: 931-972.
    CrossrefPubMedGoogle Scholar
  • 73 Töröcsik D. et al. Identification of factor XIII-A as a marker of alternative macrophage activation. Cell Mol Life Sci 2005; 62: 2132-2139.
    CrossrefPubMedGoogle Scholar
  • 74 Cordell PA. et al. Association of coagulation factor XIII-A with Golgi proteins within monocyte-macrophages: implications for subcellular trafficking and secretion. Blood 2010; 115: 2674-2681.
    CrossrefPubMedGoogle Scholar
  • 75 Piercy-Kotb SA. et al. Factor XIIIA transglutaminase expression and secretion by osteoblasts is regulated by extracellular matrix collagen and the MAP kinase signalling pathway. J Cell Physiol 2012; 227: 2936-2946.
    CrossrefPubMedGoogle Scholar
  • 76 Binder BR. et al. Plasminogen activator inhibitor 1: physiological and patho-physiological roles. News Physiol Sci 2002; 17: 56-61.
    PubMedGoogle Scholar
  • 77 Nordt TK. et al. Plasminogen activator inhibitor type-1 (PAI-1) and its role in cardiovascular disease. Thromb Haemost 1999; 82 (Suppl. 01) 14-18.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 78 Natorska J. et al. Impaired fibrinolysis is associated with the severity of aortic stenosis in humans. J Thromb Haemost 2013; 11: 733-740.
    CrossrefPubMedGoogle Scholar
  • 79 Wypasek E. et al. Mast cells in human stenotic aortic valves are associated with the severity of stenosis. Inflammation 2013; 36: 449-456.
    CrossrefPubMedGoogle Scholar
  • 80 Stockschlaeder M. et al. Update on von Willebrand factor multimers: focus on high-molecular-weight multimers and their role in haemostasis. Blood Coagul Fibrinolysis 2014; 25: 206-216.
    CrossrefPubMedGoogle Scholar
  • 81 Vincentelli A. et al. Acquired von Willebrand syndrome in aortic stenosis. N Engl J Med 2003; 349: 343-449.
    CrossrefPubMedGoogle Scholar
  • 82 Warkentin TE. et al. Gastrointestinal bleeding, angiodysplasia, cardiovascular disease, and acquired von Willebrand syndrome. Transfus Med Rev 2003; 17: 272-286.
    CrossrefPubMedGoogle Scholar
  • 83 Undas A. et al. Heyde’s syndrome without a decrease in large von Willebrand factor multimers: a case of intestinal bleedings reversed by valve replacement in a patient with aortic stenosis. Thromb Haemost 2009; 101: 773-774.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 84 Natorska J. et al. Increased thrombin generation and platelet activation are associated with deficiency in high molecular weight multimers of von Willebrand factor in patients with moderate-to-severe aortic stenosis. Heart 2011; 97: 2023-2028.
    CrossrefPubMedGoogle Scholar
  • 85 Petkow-Dimitrow P. Aortic stenosis: new pathophysiological mechanisms and their therapeutic implications. Pol Arch Med Wewn 2014; 124: 723-30.
    PubMedGoogle Scholar
  • 86 Chirkov YY. et al. Association of aortic stenosis with platelet hyperaggregability and impaired responsiveness to nitric oxide. Am J Cardiol 2002; 90: 551-554.
    CrossrefPubMedGoogle Scholar
  • 87 Owens DS, Otto CM. Is it time for a new paradigm in calcific aortic valve disease?. JACC Cardiovasc Imaging 2009; 02: 928-930.
    CrossrefPubMedGoogle Scholar
  • 88 Chan KL. et al. ASTRONOMER Investigators.. Effect of Lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation 2010; 121: 306-314.
    CrossrefPubMedGoogle Scholar
  • 89 O’Brien KD. et al. Angiotensin-converting enzyme inhibitors and change in aortic valve calcium. Arch Intern Med 2005; 165: 858-862.
    CrossrefPubMedGoogle Scholar
  • 90 Innasimuthu AL, Katz WE. Echocardiography. Effect of bisphosphonates on the progression of degenerative aortic stenosis. Echocardiography 2011; 28: 1-7.
    CrossrefPubMedGoogle Scholar
  • 91 Ing SW. et al. Correlates of valvular ossification in patients with aortic valve stenosis. Clin Transl Sci 2009; 02: 431-435.
    CrossrefPubMedGoogle Scholar
  • 92 Yamamoto K. et al. T. Prognostic factors for progression of early- and late-stage calcific aortic valve disease in Japanese: the Japanese Aortic Stenosis Study (JASS) Retrospective Analysis. Hypertens Res 2010; 33: 269-274.
    CrossrefPubMedGoogle Scholar
  • 93 Sweatt A. et al. Matrix Gla protein (MGP) and bone morphogenetic protein-2 in aortic calcified lesions of aging rats. J Thromb Haemost 2003; 01: 178-185.
    CrossrefPubMedGoogle Scholar
  • 94 Mohler 3rd ER. et al. Bone formation and inflammation in cardiac valves. Circulation 2001; 103: 1522-1528.
    CrossrefPubMedGoogle Scholar
  • 95 Kadoglou NP. et al. The beneficial effects of a direct thrombin inhibitor, dabigatran etexilate, on the development and stability of atherosclerotic lesions in apolipoprotein E-deficient mice: dabigatran etexilate and atherosclerosis. Cardiovasc Drugs Ther 2012; 26: 367-374.
    CrossrefPubMedGoogle Scholar
  • 96 Lee IO. et al. The effects of direct thrombin inhibition with dabigatran on plaque formation and endothelial function in apolipoprotein E-deficient mice. J Pharmacol Exp Ther 2012; 343: 253-258.
    CrossrefPubMedGoogle Scholar