Removal of elevated circulating angiopoietin-2 by plasma exchange – A pilot study in critically ill patients with thrombotic microangiopathy and anti-glomerular basement membrane disease
22 February 2010
Accepted after major revision: 15 July 2010
24 November 2017 (online)
In critically ill patients, the massive release of angiopoietin-2 (Ang-2) from Weibel-Palade bodies interferes with protective angiopoietin-1 (Ang-1)/Tie2 signalling in endothelial cells, thus leading to vascular inflammation and subsequent organ-dysfunction. We hypothesised that plasma exchange (PE) is efficient for lowering excess Ang-2 levels in critically ill patients with thrombocytic microangiopathy (TMA) or anti-glomerular basement membrane (anti-GBM) disease. Plasma Ang-1 and Ang-2 were measured by immuno-luminometric assays in patients with TMA (n=9) or anti-GBM disease (n=4) before and after up to four PE sessions. Twenty apparently healthy volunteers served as controls. Median (IQR) plasma levels of Ang-2 were markedly increased in patients with TMA (7.3 (2.4–21.1) ng/ml) and anti-GBM disease (5.8 (3.4–7.0) ng/ml) compared to healthy controls (1.0 (0.9–1.4) ng/ml, p <0.001). Moreover, Ang-1 plasma levels were decreased in both, TMA (1.02 (0.62–1.62) ng/ml) and anti-GBM disease patients (0.74 (0.59–3.62) ng/ml) compared to healthy controls (2.5 (1.93–3.47) ng/ ml, p <0.005). During a total of 32 treatments, PE effectively lowered elevated mean (SD) Ang-2 plasma levels by 36.7 ± 19.6 % per treatment (p <0.0001), whereas low Ang-1 plasma levels remained unchanged (0.3 ± 58.5 %; p =0.147). Ang-2 levels declined to almost normal values during ≤4 PE treatments (Friedman´s test p <0.0001). PE is an effective method to remove excess circulating Ang-2. It remains to be elucidated if the removal of Ang-2 is crucial to ameliorate endothelial damage in critically ill patients with severely altered endothelial integrity.
KeywordsAngiopoietins - critically illness - plasma exchange - thrombotic micro-angiopathy - anti-GBM disease
* SL and AL contributed equally to the manuscript and are joint first authors.
- 1 Benz K, Amann K. Pathological aspects of membranoproliferative glomerulonephritis (MPGN) and haemolytic uraemic syndrome (HUS) / thrombocytic thrombopenic purpura (TTP). Thromb Haemost 2009; 101: 265-270.
- 2 Remuzzi G, Galbusera M, Noris M. et al. von Willebrand factor cleaving protease (ADAMTS13) is deficient in recurrent and familial thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Blood 2002; 100: 778-785.
- 3 Matsuyama T, Kuwana M, Matsumoto M. et al. Heterogeneous pathogenic processes of thrombotic microangiopathies in patients with connective tissue diseases. Thromb Haemost 2009; 102: 371-378.
- 4 Claus RA, Bockmeyer CL, Budde U. et al. Variations in the ratio between von Willebrand factor and its cleaving protease during systemic inflammation and association with severity and prognosis of organ failure. Thromb Haemost 2009; 101: 239-247.
- 5 Kwaan HC. Thrombotic thrombocytopenic purpura. J Am Med Assoc 1982; 247: 3119-3120.
- 6 Shenkman B, Budde U, Angerhaus D. et al. ADAMTS-13 regulates platelet adhesion under flow. A new method for differentiation between inherited and acquired thrombotic thrombocytopenic purpura. Thromb Haemost 2006; 96: 160-166.
- 7 Fiedler U, Krissl T, Koidl S. et al. Angiopoietin-1 and angiopoietin-2 share the same binding domains in the Tie-2 receptor involving the first Ig-like loop and the epidermal growth factor-like repeats. J Biol Chem 2003; 278: 1721-1727.
- 8 Wakui S, Yokoo K, Muto T. et al. Localization of Ang-1, –2, Tie-2, and VEGF expression at endothelial-pericyte interdigitation in rat angiogenesis. Lab Invest 2006; 86: 1172-1184.
- 9 Wong AL, Haroon ZA, Werner S. et al. Tie2 expression and phosphorylation in angiogenic and quiescent adult tissues. Circ Res 1997; 81: 567-574.
- 10 Augustin HG, Koh GY, Thurston G. et al. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol 2009; 10: 165-177.
- 11 Fiedler U, Reiss Y, Scharpfenecker M. et al. Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med 2006; 12: 235-239.
- 12 van Meurs M, Kumpers P, Ligtenberg JJ. et al. Bench-to-bedside review: Angiopoietin signalling in critical illness – a future target?. Crit Care 2009; 13: 207.
- 13 Witzenbichler B, Westermann D, Knueppel S. et al. Protective role of angiopoietin-1 in endotoxic shock. Circulation 2005; 111: 97-105.
- 14 Fiedler U, Scharpfenecker M, Koidl S. et al. The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies. Blood 2004; 103: 4150-4156.
- 15 Scharpfenecker M, Fiedler U, Reiss Y. et al. The Tie-2 ligand angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism. J Cell Sci 2005; 118: 771-780.
- 16 Fiedler U, Augustin HG. Angiopoietins: a link between angiogenesis and inflammation. Trends Immunol 2006; 27: 552-558.
- 17 Kumpers P, Koenecke C, Hecker H. et al. Angiopoietin-2 predicts disease-free survival after allogeneic stem cell transplantation in patients with high-risk myeloid malignancies. Blood 2008; 112: 2139-2148.
- 18 Lukasz A, Hellpap J, Horn R. et al. Circulating angiopoietin-1 and angiopoietin-2 in critically ill patients: development and clinical application of two new immunoassays. Crit Care 2008; 12: R94.
- 19 David S, Kumpers P, Lukasz A. et al. Circulating angiopoietin-2 in essential hyper-tension: relation to atherosclerosis, vascular inflammation, and treatment with olmesartan/pravastatin. J Hypertens 2009; 27: 1641-1647.
- 20 Patel JV, Lim HS, Varughese GI. et al. Angiopoietin-2 levels as a biomarker of cardiovascular risk in patients with hypertension. Ann Med 2008; 40: 215-222.
- 21 Nadar SK, Karalis I, Al YE. et al. Plasma markers of angiogenesis in pregnancy induced hypertension. Thromb Haemost 2005; 94: 1071-1076.
- 22 Lee KW, Lip GY, Blann AD. Plasma angiopoietin-1, angiopoietin-2, angiopoietin receptor tie-2, and vascular endothelial growth factor levels in acute coronary syndromes. Circulation 2004; 110: 2355-2360.
- 23 David S, Kumpers P, Lukasz A. et al. Circulating angiopoietin-2 levels increase with progress of chronic kidney disease. Nephrol Dial Transplant. 2010 Epub ahead of print.
- 24 Kumpers P, Hellpap J, David S. et al. Circulating angiopoietin-2 is a marker and potential mediator of endothelial cell detachment in ANCA-associated vasculitis with renal involvement. Nephrol Dial Transplant 2009; 24: 1845-1850.
- 25 Kumpers P, David S, Haubitz M. et al. The Tie2 receptor antagonist angiopoietin 2 facilitates vascular inflammation in systemic lupus erythematosus. Ann Rheum Dis 2009; 68: 1638-1643.
- 26 Kumpers P, van Meurs M, David S. et al. Time course of angiopoietin-2 release during experimental human endotoxemia and sepsis. Crit Care 2009; 13: R64.
- 27 Kumpers P, Lukasz A, David S. et al. Excess circulating angiopoietin-2 is a strong predictor of mortality in critically ill medical patients. Crit Care 2008; 12: R147.
- 28 Yuan HT, Tipping PG, Li XZ. et al. Angiopoietin correlates with glomerular capillary loss in anti-glomerular basement membrane glomerulonephritis. Kidney Int 2002; 61: 2078-2089.
- 29 Rock GA, Shumak KH, Buskard NA. et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. N Engl J Med 1991; 325: 393-397.
- 30 Gerth J, Schleussner E, Kentouche K. et al. Pregnancy-associated thrombotic thrombocytopenic purpura. Thromb Haemost 2009; 101: 248-251.
- 31 Levy JB, Turner AN, Rees AJ. et al. Long-term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immuno-suppression. Ann Intern Med 2001; 134: 1033-1042.
- 32 David S, Kumpers P, Hellpap J. et al. Angiopoietin 2 and cardiovascular disease in dialysis and kidney transplantation. Am J Kidney Dis 2009; 53: 770-778.
- 33 Kumpers P, Hafer C, David S. et al. Angiopoietin-2 in patients requiring renal replacement therapy in the ICU: relation to acute kidney injury, multiple organ dys-function syndrome and outcome. Intensive Care Med 2010; 36: 462-470.
- 34 Parikh SM, Mammoto T, Schultz A. et al. Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans. PLoS Med 2006; 03: e46.
- 35 Roviezzo F, Tsigkos S, Kotanidou A. et al. Angiopoietin-2 causes inflammation in vivo by promoting vascular leakage. J Pharmacol Exp Ther 2005; 314: 738-744.
- 36 House AA, Ronco C. Extracorporeal blood purification in sepsis and sepsis-related acute kidney injury. Blood Purif 2008; 26: 30-35.
- 37 Busund R, Koukline V, Utrobin U. et al. Plasmapheresis in severe sepsis and septic shock: a prospective, randomised, controlled trial. Intensive Care Med 2002; 28: 1434-1439.
- 38 Stegmayr BG, Banga R, Berggren L. et al. Plasma exchange as rescue therapy in multiple organ failure including acute renal failure. Crit Care Med 2003; 31: 1730-1736.