High prevalence of elevated clotting factor VIII in chronic thromboembolic pulmonary hypertension

Diana Bonderman; Peter L. Turecek; Johannes Jakowitsch; Ansgar Weltermann; Christopher Adlbrecht; Barbara Schneider; Meinhard Kneussl; Lewis J. Rubin; Paul A. Kyrle; Walter Klepetko; Gerald Maurer; Irene M. Lang

doi:10.1160/TH03-02-0067

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2003; 90(03): 372-376
DOI: 10.1160/TH03-02-0067

Rapid Communication

Schattauer GmbH

High prevalence of elevated clotting factor VIII in chronic thromboembolic pulmonary hypertension

Authors

Diana Bonderman

⁷Departments of Cardiology, University of Vienna, Austria
Peter L. Turecek

⁵Baxter BioScience, Austria
Johannes Jakowitsch

⁷Departments of Cardiology, University of Vienna, Austria
Ansgar Weltermann

¹Hematology, University of Vienna, Austria
Christopher Adlbrecht

⁷Departments of Cardiology, University of Vienna, Austria
Barbara Schneider

³Medical Statistics and University of Vienna, Austria
Meinhard Kneussl

⁴Pulmonary Medicine, University of Vienna, Austria
Lewis J. Rubin

⁶Division of Pulmonary and Critical Care Medicine, University of California San Diego, USA
Paul A. Kyrle

¹Hematology, University of Vienna, Austria
Walter Klepetko

²Cardiothoracic Surgery, University of Vienna, Austria
Gerald Maurer

⁷Departments of Cardiology, University of Vienna, Austria
Irene M. Lang

⁷Departments of Cardiology, University of Vienna, Austria

Abstract

Summary

Chronic thromboembolic pulmonary hypertension (CTEPH) is an enigmatic disorder lacking signs, symptoms and classical risk factors for venous thromboembolism.

The objective of the prospective case controlled study, carried out at the Pulmonary Hypertension Unit, University Hospital Vienna, Austria, was to investigate whether plasma FVIII is elevated in CTEPH patients.

The study examined 122 consecutive patients diagnosed with CTEPH. Plasma FVIII was measured and compared with plasma FVIII of healthy controls (n=82) and of patients with non-thromboembolic pulmonary arterial hypertension (PAH, n=88).

Results show that CTEPH patients had higher FVIII levels than controls (233±83IU/dl versus 123±40IU/dl, p<0.0001) and PAH patients (158±61IU/dl, p<0.0001). Plasma FVIII one year after surgery (212±94IU/dl) was statistically unchanged compared with preoperative values (FVIII: 226±88IU/dl, n=25). FVIII>230IU/dl was more prevalent in CTEPH patients (41%) than in controls (5%, p<0.0001) and PAH patients (22%, p=0.022).

We can conclude that elevated plasma FVIII is the first prothrombotic factor identified in a large proportion of CTEPH patients.

Keywords

Factor VIII - pulmonary embolism - thrombophilia

Full Text

References

References
1 Fedullo PF, Auger WR, Kerr KM, Rubin LJ. Chronic thromboembolic pulmonary hyper-tension. N Engl J Med 2001; 345: 1465-72.
2 Wolf M, Boyer-Neumann C, Parent F. et al. Thrombotic risk factors in pulmonary hyper-tension. Eur Respir J 2000; 15: 395-9.
3 Lang IM, Marsh JJ, Olman MA. et al. Parallel analysis of tissue-type plasminogen activator and type 1 plasminogen activator inhibitor in plasma and endothelial cells derived from patients with chronic pulmonary thromboemboli. Circulation 1994; 90: 706-12.
4 Olman MA, Marsh JJ, Lang IM. et al. Endogenous fibrinolytic system in chronic large-vessel thromboembolic pulmonary hypertension. Circulation 1992; 86: 1241-8.
5 O’Donnell J, Tuddenham EG, Manning R. et al. High prevalence of elevated factor VIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction. Thromb Haemost 1997; 77: 825-8.
6 Kyrle PA, Minar E, Hirschl M. et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 2000; 343: 457-62.
7 Koster T, Blann AD, Briet E. et al. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345: 152-5.
8 Friedman R, Mears JG, Barst RJ. Continuous infusion of prostacyclin normalizes plasma markers of endothelial cell injury and platelet aggregation in primary pulmonary hypertension. Circulation 1997; 96: 2782-4.
9 Veyradier A, Nishikubo T, Humbert M. et al. Improvement of von Willebrand factor proteolysis after prostacyclin infusion in severe pulmonary arterial hypertension. Circulation 2000; 102: 2460-2.
10 Austen DEG, Rhymes IL.. A Laboratory Manual of Blood Coagulation. In: Publications OBS, ed. 1975
11 Lang H, Oberreither M, Moritz B. A new chromogenic factor VIII: C-assay based on a system of human proteins. Thromb Haemost 1991; 65: 943 (abstract)
12 Turecek PL, Pichler L, Auer W. et al. Evidence for extracellular processing of pro-von Willebrand factor after infusion in animals with and without severe von Willebrand disease. Blood 1999; 94: 1637-47.
13 Varadi K, Turecek PL, Mitterer A, Dorner F, Schwarz HP. Thrombin-mediated in vitro processing of pro-von Willebrand factor. Thromb Haemost 2001; 86: 1449-58.
14 Gerritsen HE, Turecek PL, Schwarz HP. et al. Assay of von Willebrand factor (vWF)-cleaving protease based on decreased collagen binding affinity of degraded vWF: a tool for the diagnosis of thrombotic thrombocytopenic purpura (TTP). Thromb Haemost 1999; 82: 1386-9.
15 Turecek PL, Gritsch H, Pichler L. et al. In vivo characterization of recombinant von Willebrand factor in dogs with von Willebrand disease. Blood 1997; 90: 3555-67.
16 Knöbl P, Haas M, Laczika K. et al. Kinetics of inhibitors of von Willebrand factor cleaving metalloprotease in three patients with severe thrombotic thrombocytopenic purpura. Ann Hematol 2002; 81: A42.
17 Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001; 344: 1222-31.
18 Thistlethwaite PA, Mo M, Madani MM. et al. Operative classification of thromboembolic disease determines outcome after pulmonary endarterectomy. J Thorac Cardiovasc Surg 2002; 124: 1203-11.
19 Kamphuisen PW, Eikenboom JC, Bertina RM. Elevated factor VIII levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol 2001; 21: 731-8.
20 Martinuzzo ME, Pombo G, Forastiero RR. et al. Lupus anticoagulant, high levels of anti-cardiolipin, and anti-beta2-glycoprotein I antibodies are associated with chronic thromboembolic pulmonary hypertension. J Rheumatol 1998; 25: 1313-9.
21 Egermayer P, Peacock AJ. Is pulmonary embolism a common cause of chronic pulmonary hypertension? Limitations of the embolic hypothesis. Eur Respir J 2000; 15: 440-8.
22 Rabinovitch M, Andrew M, Thom H. et al. Abnormal endothelial factor VIII associated with pulmonary hypertension and congenital heart defects. Circulation 1987; 76: 1043-52.
23 Stoddart Jr. JH, Andersen J, Lynch DC. Clearance of normal and type 2A von Willebrand factor in the rat. Blood 1996; 88: 1692-9.
24 Jeremic M, Weisert O, Gedde-Dahl TW. Factor VIII (AHG) levels in 1016 regular blood donors. The effects of age, sex, and ABO blood groups. Scand J Clin Lab Invest 1976; 36: 461-6.
25 Orstavik KH, Magnus P, Reisner H. et al. Factor VIII and factor IX in a twin population. Evidence for a major effect of ABO locus on factor VIII level. Am J Hum Genet 1985; 37: 89-101.
26 Kamphuisen PW, Houwing-Duistermaat JJ, van Houwelingen HC. et al. Familial clustering of factor VIII and von Willebrand factor levels. Thromb Haemost 1998; 79: 323-7.
27 Brummel KE, Paradis SG, Branda RF. et al. Oral anticoagulation thresholds. Circulation 2001; 104: 2311-7.