Hypoxia and Altered Platelet Behavior Influence von Willebrand Factor Multimeric Composition in Secondary Pulmonary Hypertension

Abstract

In pulmonary hypertension (PH), defective plasma von Willebrand factor (vWF) lacking the larger multimers with increased concentration of low-molecular-weight fractions (LMW) has been reported, although the mechanisms involved are not completely known. Altered platelet behavior may be involved in this alteration; this hypothesis was investigated in 10 patients with PH associated with chronic hypoxemia and erythrocytosis (age 13 to 51 years, mean pulmonary artery pressure 38 to 98 mmHg). The possible influence of the hematocrit (Hct) and decreased oxygen saturation (SpO₂) on vWF abnormalities was examined. Patients were evaluated before and after therapeutic hemodilution. vWF alterations were quantified using the ratio of LMW/total multimers (densitometric analysis of luminographs after Western blotting). Platelet count and activation state (plasma levels of f-thromboglobulin, enzyme-linked immunosorbent assay), the Hct and SpO₂ were also assessed before and after hemodilution. Platelet activation and consumption were suggested by increased plasma β-thromboglobulin (p=0.0444) with decreased platelet count (p<0.001). Altered vWF LMW/total ratio correlated significantly with decreased platelet count (p=0.0066) and low SpO₂ (p=0.0088). The effects of both variables were independent and additive (p=0.0031, multiple regression). Hemodilution was followed by an increase in platelet count (p=0.0013) associated with improvement of LMW/total ratio (p=0.0079). Residual vWF alterations were associated with persistent hypoxemia and residual platelet activation (plasma β-thromboglobulin still increased). These data suggest a common mechanism for platelet and vWF abnormalities in these chronically hypoxic PH patients. Hypoxia itself may play a role, possibly inducing endothelial release of unprocessed (LMW) vWF molecules.

Keywords

von Willebrand factor Pulmonary hypertension Platelet Hypoxia Thrombosis

References

1. Sadler JE . von Willebrand factor. J Biol Chem 1991; 266:22777-22777.

2. Ruggeri ZM , Zimmerman TS . The complex multimeric composition of factor VIII/von Willebrand factor. Blood 1981;57:1140-1140.

3. Furlan M , Robles R , Galbusera M , et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med 1998;339:1578-1578.

4. Mannucci PM , Lombardi R , Lattuada A , et al. Supranormal von Willebrand factor multimers in scleroderma. Blood 1989;73:1586-1586.

5. Moake JL . von Willebrand factor in the pathophysiology of thrombotic trombocytopenic purpura. Clin Lab Sci 1998; 11:362-362.

6. Sadler J . A revised classification of von Willebrand disease. Thromb Haemost 1994;71:520-520.

7. Rinder MR , Richard RE , Rinder HM . Acquired von Willebrand's disease: A concise review. Am J Hematol 1997;54: 139-139.

8. Rabinovitch M , Andrew M , Thom H , et al. Abnormal endothelial factor VIII associated with pulmonary hypertension and congenital heart defects. Circulation 1987; 76:1043-1043.

9. Lopes AA , Maeda NY , Bydlowski SP . Abnormalities in circulating von Willebrand factor and survival in pulmonary hypertension. Am J Med 1998;105:21-21.

10.

10. Veyradier A , Nishikubo T , Humbert M , et al. Improvement of von Willebrand factor proteolysis after prostacyclin infusion in severe pulmonary arterial hypertension. Circulation 2000;102:2460-2460.

11.

11. Lopes AAB , Maeda NY , Ebaid M , et al. Effect of intentional hemodilution on platelet survival in secondary pulmonary hypertension. Chest 1989;95:1207-1207.

12.

12. Lopes AAB , Maeda NY . Abnormal degradation of von Willebrand factor main subunit in pulmonary hypertension. Eur Respir J 1995;8:530-530.

13.

13. Friedman R , Mears G , Barst R . Continuous infusion of prostacyclin normalizes plasma markers of endothelial cell injury and platelet aggregation in primary pulmonary hypertension. Circulation 1997;96:2782-2782.

14.

14. Pareti Fl , Lattuada A , Bressi C , et al. Proteolysis of von Willebrand factor and shear stress-induced platelet aggregation in patients with aortic valve stenosis. Circulation 2000;102:1290-1290.

15.

15. Tsai H-M . Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and required calcium ion. Blood 1996;87:4235-4235.

16.

16. Siedlecki CA , Lestini BJ , Kottke-Marchant KK , et al. Sheardependent changes in the three-dimensional structure of human von Willebrand factor. Blood 1996;88:2939-2939.

17.

17. Dent JA , Berkowitz SD , Ware J , et al. Identification of a cleavage site directing the immunochemical detection of molecular abnormalities in type IIA von Willebrand factor. Proc Natl Acad Sci USA 1990;87:6306-6306.

18.

18. Goto S , Salomon DR , Ikeda Y , et al. Characterization of the unique mechanism mediating the shear-dependent binding of soluble von Willebrand factor to platelets. J Biol Chem 1995;270:23352-23352.

19.

19. Ruggeri ZM , Pareti Fl , Mannucci PM , et al. Heightened interaction between platelets and factor VIII/von Willebrand factor in a new subtype of von Willebrand's disease. N Engl J Med 1980;302:1047-1047.

20.

20. Ruggeri ZM , Mannucci PM , Lombardi R , et al. Multimeric composition of factor VIII/von Willebrand factor following administration of DDAVP: Implications for pathophysiology and therapy of von Willebrand's disease subtypes. Blood 1982;59:1272-1272.

21.

21. Zimmerman TS , Dent JA , Ruggeri ZM , et al. Subunit composition of plasma von Willebrand factor: Cleavage is present in normal individuals, increased in IIA and IIB von Willebrand disease, but minimal in variants with aberrant structure of individual oligomers (types IIC, IID and IIE). J Clin Invest 1986;77:947-947.

22.

22. De Marco K , Mazzucato M , De Roia D , et al. Distinct abnormalities in the interaction of purified IIA and IIB von Willebrand factor with the two platelet binding sites GP Ib-IX and GP IIb-Illa. J Clin Invest 1990;86:785-785.

23.

23. Michiels C , Arnould T , Remacle J . Endothelial cell responses to hypoxia: Initiation of a cascade of cellular interactions. Biochim Biophys Acta 2000;1497: 1-1.

24.

24. Tsai H-M , Nagel RL , Hatcher VB , et al. Endothelial cellderived high molecular weight von Willebrand factor is converted into the plasma multimer pattern by granulocyte proteases. Biochem Biophys Res Commun 1989; 158:980-980.

25.

25. Blann AD , Seigneur M , Adams RA , et al. Neutrophil elastase, von Willebrand factor, soluble thrombomodulin and percutaneous oxygen in peripheral atherosclerosis. Eur J Vasc Endovasc Surg 1996;12:218-218.

26.

26. Pinsky DJ , Naka Y , Liao H , et al. Hypoxia-induced exocytosis of endothelial cell Weibel-Palade bodies. A mechanism for rapid neutrophil recruitment after cardiac preservation. J Clin Invest 1996;97:493-493.

27.

27. Goerge T , Niemeyer A , Rogge P , et al. Secretion pores in human endothelial cells during acute hypoxia. J Membr Biol 2002;187:203-203.

28.

28. Vongpatanasin W , Brickner E , Hillis LD , et al. The Eisenmenger syndrome in adults. Ann Intern Med 1998; 128:745-745.

29.

29. Fuster V , Steele PM , Edwards WD , et al. Primary pulmonary hypertension: Natural history and the importance of thrombosis. Circulation 1984;70:580-580.

30.

30. Chaouat A , Weitzenblum E , Higenbottam T . The role of thrombosis in severe pulmonary hypertension. Eur Respir J 1996;9:356-356.

31.

31. Hassell KL . Altered hemostasis in pulmonary hypertension. Blood Coag Fibrinolysis 1998;9:107-107.

32.

32. Herve P , Humbert M , Sitbon O , et al. Pathobiology of pulmonary hypertension. The role of platelets and thrombosis. Clin Chest Med 2001;22:451-451.

33.

33. Lopes AAB , Maeda NY , Almeida A , et al. Circulating platelet aggregates indicative of in vivo platelet activation in pulmonary hypertension. Angiology 1993;44:701-701.

34.

34. Herve P , Launay JM , Scrobohaci ML , et al. Increased plasma serotonin in primary pulmonary hypertension. Am J Med 1995;99:249-249.

35.

35. Eddahibi S , Humbert M , Sediame S , et al. Imbalance between platelet VEGF and PDGF in pulmonary hypertension, effect of prostacyclin therapy. Am J Respir Crit Care Med 2000;162:1493-1493.