Mechanisms and clinical implications of thrombosis in paroxysmal nocturnal hemoglobinuria

Journal of Thrombosis and Haemostasis

Volumn 10, Issue 1, 2012, Pages 1-10

  van Bijnen, S T A ^a   van Heerde, W L ^a   Muus, P ^a  

^a RADBOUD UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

Eculizumab; Paroxysmal nocturnal hemoglobinuria; Thrombosis

Indexed keywords

ACETYLSALICYLIC ACID; ANTIVITAMIN K; BLOOD CLOTTING FACTOR 5 LEIDEN; CD59 ANTIGEN; DECAY ACCELERATING FACTOR; ECULIZUMAB; FIBRINOGEN RECEPTOR ANTAGONIST; GLYCOSYLPHOSPHATIDYLINOSITOL ANCHORED PROTEIN; HEMOGLOBIN; JANUS KINASE 2; LOW MOLECULAR WEIGHT HEPARIN; METHYLENETETRAHYDROFOLATE REDUCTASE (NADPH2); MYELOBLASTIN; NITRIC OXIDE; PHOSPHOLIPID ANTIBODY; PIGA PROTEIN; PLASMINOGEN ACTIVATOR; PROTEIN; TISSUE FACTOR PATHWAY INHIBITOR; UNCLASSIFIED DRUG; WARFARIN;

AFRICAN AMERICAN; ANTICOAGULANT THERAPY; ANTICOAGULATION; ARTERY THROMBOSIS; BLEEDING; BLOOD CELL; BUDD CHIARI SYNDROME; CELL CLONING; CELL DAMAGE; CELL MEMBRANE; CELL SIZE; CHINESE; COMPLEMENT ACTIVATION; DISEASE ASSOCIATION; DRUG EFFECT; ENDOTHELIUM CELL; ERYTHROCYTE; FIBRINOLYSIS; GENE; GENE MUTATION; GRANULOCYTE; HEMOSTASIS; HIGH RISK PATIENT; HUMAN; INTRAVASCULAR HEMOLYSIS; JAPANESE; LATIN AMERICAN MEDICINE; MEMBRANE VESICLE; MORBIDITY; MORTALITY; PAROXYSMAL NOCTURNAL HEMOGLOBINURIA; PATHOPHYSIOLOGY; PIGA GENE; PRIORITY JOURNAL; PROGNOSIS; PROTEIN DEFICIENCY; RACE DIFFERENCE; REVIEW; RISK REDUCTION; THROMBOCYTE ACTIVATION; THROMBOCYTE FUNCTION; THROMBOCYTOPENIA; THROMBOEMBOLISM; THROMBOPHILIA; THROMBOSIS; TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT; VEIN THROMBOSIS;

ANTIBODIES, MONOCLONAL, HUMANIZED; COMPLEMENT ACTIVATION; HEMOGLOBINURIA, PAROXYSMAL; HUMANS; THROMBOSIS;

EID: 84855362194     PISSN: 15387933     EISSN: 15387836     Source Type: Journal    
DOI: 10.1111/j.1538-7836.2011.04562.x     Document Type: Review

References (91)

1. Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, Hillmen P, Luzzatto L, Young N, Kinoshita T, Rosse W, Socie G. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood 2005; 106: 3699-709.
2. de Latour RP, Mary JY, Salanoubat C, Terriou L, Etienne G, Mohty M, Roth S, de Guibert S, Maury S, Cahn JY, Socie G. Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood 2008; 112: 3099-106.
3. Hillmen P, Muus P, Duhrsen U, Risitano AM, Schubert J, Luzzatto L, Schrezenmeier H, Szer J, Brodsky RA, Hill A, Socie G, Bessler M, Rollins SA, Bell L, Rother RP, Young NS. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood 2007; 110: 4123-8.
4. Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med 1995; 333: 1253-8.
5. Socie G, Mary JY, De Gramont A, Rio B, Leporrier M, Rose C, Heudier P, Rochant H, Cahn JY, Gluckman E. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. French Society of Haematology. Lancet 1996; 348: 573-7.
6. Hill A, Reid A, Rother RP, Gladwin MT, Collinson PO, Gaze DC, Lowe A, Guthrie A, Sivananthan MU, Hillmen P. High definition contrast-enhanced MR imaging in paroxysmal nocturnal hemoglobinuria (PNH) suggests a high frequency of subclinical thrombosis. Haematologica 2007; 92(Suppl. 2): 24, Abstract 0066.
7. Hall C, Richards S, Hillmen P. Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH). Blood 2003; 102: 3587-91.
8. Moyo VM, Mukhina GL, Garrett ES, Brodsky RA. Natural history of paroxysmal nocturnal haemoglobinuria using modern diagnostic assays. Br J Haematol 2004; 126: 133-8.
9. Jin JY, Tooze JA, Marsh JC, Gordon-Smith EC. Glycosylphosphatidyl-inositol (GPI)-linked protein deficiency on the platelets of patients with aplastic anaemia and paroxysmal nocturnal haemoglobinuria: two distinct patterns correlating with expression on neutrophils. Br J Haematol 1997; 96: 493-6.
10. Abou AS, El-Haddad B, Wehbe E, Schulz T. Lysis and thrombosis: manifestation of the same disease. Am J Hematol 2008; 83: 505-7.
11. Kumar KS, Malet PF, Rutherford C. Paroxysmal nocturnal hemoglobinuria with no evidence of hemolysis presenting as Budd-Chiari syndrome. Dig Dis Sci 2000; 45: 2238-9.
12. Araten DJ, Thaler HT, Luzzatto L. High incidence of thrombosis in African-American and Latin-American patients with paroxysmal nocturnal haemoglobinuria. Thromb Haemost 2005; 93: 88-91.
13. Le XF, Yang TY, Yang XY, Wang XM. Characteristics of paroxysmal nocturnal hemoglobinuria in China. Clinical analysis of 476 cases. Chin Med J (Engl) 1990; 103: 885-9.
14. Nishimura J, Kanakura Y, Ware RE, Shichishima T, Nakakuma H, Ninomiya H, Decastro CM, Hall S, Kanamaru A, Sullivan KM, Mizoguchi H, Omine M, Kinoshita T, Rosse WF. Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan. Medicine (Baltimore) 2004; 83: 193-207.
15. Ziakas PD, Poulou LS, Rokas GI, Bartzoudis D, Voulgarelis M. Thrombosis in paroxysmal nocturnal hemoglobinuria: sites, risks, outcome. An overview. J Thromb Haemost 2007; 5: 642-5.
16. Poulou LS, Vakrinos G, Pomoni A, Michalakis K, Karianakis G, Voulgarelis M, Ziakas PD. Stroke in paroxysmal nocturnal haemoglobinuria: patterns of disease and outcome. Thromb Haemost 2007; 98: 699-701.
17. Muus P, Szer J, Schrezenmeier H, Brodsky RA, Bessler M, Socie G, Urbano-Ispizua A, Maciejewski J, Rosse W, Kanakura Y, Khursigara G, Karnell A, Bedrosian CL, Hillmen P. Evaluation of paroxysmal nocturnal hemoglobinuria disease burden: the patient's perspective. A Report from the International PNH Registry. Blood (Annual Meeting Abstracts) 2010; 116: Abstract 1525.
18. Ray JG, Burows RF, Ginsberg JS, Burrows EA. Paroxysmal nocturnal hemoglobinuria and the risk of venous thrombosis: review and recommendations for management of the pregnant and nonpregnant patient. Haemostasis 2000; 30: 103-17.
19. Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA 2005; 293: 1653-62.
20. Aharon A, Tamari T, Brenner B. Monocyte-derived microparticles and exosomes induce procoagulant and apoptotic effects on endothelial cells. Thromb Haemost 2008; 100: 878-85.
21. Simak J, Holada K, Risitano AM, Zivny JH, Young NS, Vostal JG. Elevated circulating endothelial membrane microparticles in paroxysmal nocturnal haemoglobinuria. Br J Haematol 2004; 125: 804-13.
22. Grunewald M, Siegemund A, Grunewald A, Schmid A, Koksch M, Schopflin C, Schauer S, Griesshammer M. Plasmatic coagulation and fibrinolytic system alterations in PNH: relation to clone size. Blood Coagul Fibrinolysis 2003; 14: 685-95.
23. Helley D, de Latour RP, Porcher R, Rodrigues CA, Galy-Fauroux I, Matheron J, Duval A, Schved JF, Fischer AM, Socie G. Evaluation of hemostasis and endothelial function in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab. Haematologica 2010; 95: 574-81.
24. Gralnick HR, Vail M, McKeown LP, Merryman P, Wilson O, Chu I, Kimball J. Activated platelets in paroxysmal nocturnal haemoglobinuria. Br J Haematol 1995; 91: 697-702.
25. Tedesco F, Pausa M, Nardon E, Introna M, Mantovani A, Dobrina A. The cytolytically inactive terminal complement complex activates endothelial cells to express adhesion molecules and tissue factor procoagulant activity. J Exp Med 1997; 185: 1619-27.
26. Murasawa S, Asahara T. Endothelial progenitor cells for vasculogenesis. Physiology (Bethesda) 2005; 20: 36-42.
27. la Porta MG, Malcovati L, Rigolin GM, Rosti V, Bonetti E, Travaglino E, Boveri E, Galli A, Boggi S, Ciccone M, Pramparo T, Mazzini G, Invernizzi R, Lazzarino M, Cazzola M. Immunophenotypic, cytogenetic and functional characterization of circulating endothelial cells in myelodysplastic syndromes. Leukemia 2008; 22: 530-7.
28. Mueller RJ, Stussi G, Puga YG, Nikolic M, Soldini D, Halter J, Meyer-Monard S, Gratwohl A, Passweg JR, Odermatt B, Schanz U, Biedermann BC, Seebach JD. Persistence of recipient-type endothelium after allogeneic hematopoietic stem cell transplantation. Haematologica 2011; 96: 119-27.
29. Gao Z, McAlister VC, Williams GM. Repopulation of liver endothelium by bone-marrow-derived cells. Lancet 2001; 357: 932-3.
30. Zhang J, Piro O, Lu L, Broze GJ Jr. Glycosyl phosphatidylinositol anchorage of tissue factor pathway inhibitor. Circulation 2003; 108: 623-7.
31. Maroney SA, Cunningham AC, Ferrel J, Hu R, Haberichter S, Mansbach CM, Brodsky RA, Dietzen DJ, Mast AE. A GPI-anchored co-receptor for tissue factor pathway inhibitor controls its intracellular trafficking and cell surface expression. J Thromb Haemost 2006; 4: 1114-24.
32. Maroney SA, Haberichter SL, Friese P, Collins ML, Ferrel JP, Dale GL, Mast AE. Active tissue factor pathway inhibitor is expressed on the surface of coated platelets. Blood 2007; 109: 1931-7.
33. Basavaraj MG, Gruber FX, Sovershaev M, Appelbom HI, Osterud B, Petersen LC, Hansen JB. The role of TFPI in regulation of TF-induced thrombogenicity on the surface of human monocytes. Thromb Res 2010; 126: 418-25.
34. von Vietinghoff S, Tunnemann G, Eulenberg C, Wellner M, Cristina CM, Luft FC, Kettritz R. NB1 mediates surface expression of the ANCA antigen proteinase 3 on human neutrophils. Blood 2007; 109: 4487-93.
35. Jankowska AM, Szpurka H, Calabro M, Mohan S, Schade AE, Clemente M, Silverstein RL, Maciejewski JP. Loss of expression of neutrophil proteinase-3: a factor contributing to thrombotic risk in paroxysmal nocturnal hemoglobinuria. Haematologica 2011; 96:954-962.
36. Renesto P, Si-Tahar M, Moniatte M, Balloy V, van Dorsselaer A, Pidard D, Chignard M. Specific inhibition of thrombin-induced cell activation by the neutrophil proteinases elastase, cathepsin G, and proteinase 3: evidence for distinct cleavage sites within the aminoterminal domain of the thrombin receptor. Blood 1997; 89: 1944-53.
37. Raife TJ, Cao W, Atkinson BS, Bedell B, Montgomery RR, Lentz SR, Johnson GF, Zheng XL. Leukocyte proteases cleave von Willebrand factor at or near the ADAMTS13 cleavage site. Blood 2009; 114: 1666-74.
38. Villegas-Mendez A, Montes R, Ambrose LR, Warrens AN, Laffan M, Lane DA. Proteolysis of the endothelial cell protein C receptor by neutrophil proteinase 3. J Thromb Haemost 2007; 5: 980-8.
39. Steppich BA, Seitz I, Busch G, Stein A, Ott I. Modulation of tissue factor and tissue factor pathway inhibitor-1 by neutrophil proteases. Thromb Haemost 2008; 100: 1068-75.
40. Almeida AM, Murakami Y, Layton DM, Hillmen P, Sellick GS, Maeda Y, Richards S, Patterson S, Kotsianidis I, Mollica L, Crawford DH, Baker A, Ferguson M, Roberts I, Houlston R, Kinoshita T, Karadimitris A. Hypomorphic promoter mutation in PIGM causes inherited glycosylphosphatidylinositol deficiency. Nat Med 2006; 12: 846-51.
41. Wagener FA, Eggert A, Boerman OC, Oyen WJ, Verhofstad A, Abraham NG, Adema G, van Kooyk Y, de Witte T, Figdor CG. Heme is a potent inducer of inflammation in mice and is counteracted by heme oxygenase. Blood 2001; 98: 1802-11.
42. Hill A, Rother RP, Wang X, Morris SM Jr, Quinn-Senger K, Kelly R, Richards SJ, Bessler M, Bell L, Hillmen P, Gladwin MT. Effect of eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea, and measures of pulmonary hypertension in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 2010; 149: 414-25.
43. Maciejewski JP, Young NS, Yu M, Anderson SM, Sloand EM. Analysis of the expression of glycosylphosphatidylinositol anchored proteins on platelets from patients with paroxysmal nocturnal hemoglobinuria. Thromb Res 1996; 83: 433-47.
44. Vu T, Griscelli-Bennaceur A, Gluckman E, Sigaux F, Carosella ED, Menier C, Scrobohaci ML, Socie G. Aplastic anaemia and paroxysmal nocturnal haemoglobinuria: a study of the GPI-anchored proteins on human platelets. Br J Haematol 1996; 93: 586-9.
45. Sims PJ, Wiedmer T. The response of human platelets to activated components of the complement system. Immunol Today 1991; 12: 338-42.
46. Devine DV, Siegel RS, Rosse WF. Interactions of the platelets in paroxysmal nocturnal hemoglobinuria with complement. Relationship to defects in the regulation of complement and to platelet survival in vivo. J Clin Invest 1987; 79: 131-7.
47. Louwes H, Vellenga E, de Wolf JT. Abnormal platelet adhesion on abdominal vessels in asymptomatic patients with paroxysmal nocturnal hemoglobinuria. Ann Hematol 2001; 80: 573-6.
48. Hill A, Hillmen P, Richards SJ, Elebute D, Marsh JC, Chan J, Mojcik CF, Rother RP. Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria. Blood 2005; 106: 2559-65.
49. Kelly RJ, Hill A, Arnold LM, Brooksbank GL, Richards SJ, Cullen M, Mitchell LD, Cohen DR, Gregory WM, Hillmen P. Long term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood 2011; 117: 6786-92.
50. Sims PJ, Wiedmer T. Induction of cellular procoagulant activity by the membrane attack complex of complement. Semin Cell Biol 1995; 6: 275-82.
51. Sims PJ, Rollins SA, Wiedmer T. Regulatory control of complement on blood platelets. Modulation of platelet procoagulant responses by a membrane inhibitor of the C5b-9 complex. J Biol Chem 1989; 264: 19228-35.
52. Wiedmer T, Hall SE, Ortel TL, Kane WH, Rosse WF, Sims PJ. Complement-induced vesiculation and exposure of membrane prothrombinase sites in platelets of paroxysmal nocturnal hemoglobinuria. Blood 1993; 82: 1192-6.
53. Grunewald M, Grunewald A, Schmid A, Schopflin C, Schauer S, Griesshammer M, Koksch M. The platelet function defect of paroxysmal nocturnal haemoglobinuria. Platelets 2004; 15: 145-54.
54. Hugel B, Martinez MC, Kunzelmann C, Freyssinet JM. Membrane microparticles: two sides of the coin. Physiology (Bethesda) 2005; 20: 22-7.
55. Zwaal RF, Schroit AJ. Pathophysiologic implications of membrane phospholipid asymmetry in blood cells. Blood 1997; 89: 1121-32.
56. Hugel B, Socie G, Vu T, Toti F, Gluckman E, Freyssinet JM, Scrobohaci ML. Elevated levels of circulating procoagulant microparticles in patients with paroxysmal nocturnal hemoglobinuria and aplastic anemia. Blood 1999; 93: 3451-6.
57. Owens AP III, Mackman N. Microparticles in hemostasis and thrombosis. Circ Res 2011; 108: 1284-97.
58. Liebman HA, Feinstein DI. Thrombosis in patients with paroxysmal noctural hemoglobinuria is associated with markedly elevated plasma levels of leukocyte-derived tissue factor. Thromb Res 2003; 111: 235-8.
59. Ninomiya H, Kawashima Y, Hasegawa Y, Nagasawa T. Complement-induced procoagulant alteration of red blood cell membranes with microvesicle formation in paroxysmal nocturnal haemoglobinuria (PNH): implication for thrombogenesis in PNH. Br J Haematol 1999; 106: 224-31.
60. Kozuma Y, Sawahata Y, Takei Y, Chiba S, Ninomiya H. Procoagulant properties of microparticles released from red blood cells in paroxysmal nocturnal haemoglobinuria. Br J Haematol 2011; 152: 631-9.
61. Steppich BA, Hassenpflug M, Braun SL, Schomig K, von Beckerath O, von Beckerath N, Eckstein HH, Ott I. Circulating tissue factor and microparticles are not increased in patients with deep vein thrombosis. Vasa 2011; 40: 117-22.
62. Garcia RP, Eikenboom HC, Tesselaar ME, Huisman MV, Nijkeuter M, Osanto S, Bertina RM. Plasma levels of microparticle-associated tissue factor activity in patients with clinically suspected pulmonary embolism. Thromb Res 2010; 126: 345-9.
63. Zwicker JI, Liebman HA, Neuberg D, Lacroix R, Bauer KA, Furie BC, Furie B. Tumor-derived tissue factor-bearing microparticles are associated with venous thromboembolic events in malignancy. Clin Cancer Res 2009; 15: 6830-40.
64. Thaler J, Ay C, Weinstabl H, Dunkler D, Simanek R, Vormittag R, Freyssinet JM, Zielinski C, Pabinger I. Circulating procoagulant microparticles in cancer patients. Ann Hematol 2011; 90: 447-53.
65. Ploug M, Plesner T, Ronne E, Ellis V, Hoyer-Hansen G, Hansen NE, Dano K. The receptor for urokinase-type plasminogen activator is deficient on peripheral blood leukocytes in patients with paroxysmal nocturnal hemoglobinuria. Blood 1992; 79: 1447-55.
66. Sloand EM, Pfannes L, Scheinberg P, More K, Wu CO, Horne M, Young NS. Increased soluble urokinase plasminogen activator receptor (suPAR) is associated with thrombosis and inhibition of plasmin generation in paroxysmal nocturnal hemoglobinuria (PNH) patients. Exp Hematol 2008; 36: 1616-24.
67. Ronne E, Pappot H, Grondahl-Hansen J, Hoyer-Hansen G, Plesner T, Hansen NE, Dano K. The receptor for urokinase plasminogen activator is present in plasma from healthy donors and elevated in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 1995; 89: 576-81.
68. Ninomiya H, Hasegawa Y, Nagasawa T, Abe T. Excess soluble urokinase-type plasminogen activator receptor in the plasma of patients with paroxysmal nocturnal hemoglobinuria inhibits cell-associated fibrinolytic activity. Int J Hematol 1997; 65: 285-91.
69. Bugge TH, Flick MJ, Danton MJ, Daugherty CC, Romer J, Dano K, Carmeliet P, Collen D, Degen JL. Urokinase-type plasminogen activator is effective in fibrin clearance in the absence of its receptor or tissue-type plasminogen activator. Proc Natl Acad Sci USA 1996; 93: 5899-904.
70. Aird WC. Vascular bed-specific thrombosis. J Thromb Haemost 2007; 5(Suppl 1): 283-91.
71. Rosenberg RD, Aird WC. Vascular-bed - specific hemostasis and hypercoagulable states. N Engl J Med 1999; 340: 1555-64.
72. Maroney SA, Ferrel FP, Mast AE. Expression of tissue factor pathway inhibitor (TFPI) by brain endothelium. Blood (ASH Annual Meeting Abstracts) 2008; 112: Abstract 23.
73. Nafa K, Bessler M, Mason P, Vulliamy T, Hillmen P, Castro-Malaspina H, Luzzatto L. Factor V Leiden mutation investigated by amplification created restriction enzyme site (ACRES) in PNH patients with and without thrombosis. Haematologica 1996; 81: 540-2.
74. Griscelli-Bennaceur A, Gluckman E, Scrobohaci ML, Jonveaux P, Vu T, Bazarbachi A, Carosella ED, Sigaux F, Socie G. Aplastic anemia and paroxysmal nocturnal hemoglobinuria: search for a pathogenetic link. Blood 1995; 85: 1354-63.
75. Dragoni F, Iori AP, Pignoloni P, Minotti C, Chiarotti F, Mazzucconi MG, Mengarelli A, Arcese W, Foa R, Avvisati G. Thrombophilic screening in patients with paroxysmal nocturnal haemoglobinuria: a pilot study. Br J Haematol 2010; 150: 492-4.
76. Baglin T, Gray E, Greaves M, Hunt BJ, Keeling D, Machin S, Mackie I, Makris M, Nokes T, Perry D, Tait RC, Walker I, Watson H. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol 2010; 149: 209-20.
77. Darnige L, de Latour RP, Zemori L, Socie G, Fischer AM, Helley D. Antiphospholipid antibodies in patients with paroxysmal nocturnal haemoglobinuria receiving eculizumab. Br J Haematol 2011; 153: 789-91.
78. Fouassier M, Girodon F, Cleyrat C, Robillard N, Garand R, Hermouet S. Absence of JAK2-V617F in paroxysmal nocturnal haemoglobinuria-associated thrombosis. Thromb Haemost 2009; 102: 180-2.
79. Sugimori C, Shain KH, Caceres G, Sokol L, Araten DJ, Maciejewski JP, Zou J, Epling-Burnette PK, List AF. Co-existence of JAKV617F and PIG-A mutations in primary Budd-Chiari syndrome. Blood (ASH Annual Meeting Abstracts) 2009; 114: 3193.
80. Hoekstra J, Leebeek FW, Plessier A, Raffa S, Darwish MS, Heller J, Hadengue A, Chagneau C, Elias E, Primignani M, Garcia-Pagan JC, Valla DC, Janssen HL. Paroxysmal nocturnal hemoglobinuria in Budd-Chiari syndrome: findings from a cohort study. J Hepatol 2009; 51: 696-706.
81. Luzzatto L, Gianfaldoni G, Notaro R. Management of paroxysmal nocturnal haemoglobinuria: a personal view. Br J Haematol 2011; 153: 709-20.
82. Araten DJ, Notaro R, Kernan NA, Boulad F, Castro-Malaspina H, Small TN, Scaradavou A, Magnan H, Prockop SE, Chaffee S, Gonsky J, Thertulien R, Tarquini R, Luzzatto L. Thrombolytic therapy for reversal of thrombosis in paroxysmal nocturnal hemoglobinuria (PNH). Blood (ASH Annual Meeting Abstracts) 2010; 116: Abstract 4239.
83. Schutgens RE, Pruissen-Peeters KA, Muus P. A cascade of thromboembolic processes in a patient with paroxysmal nocturnal haemoglobinuria terminated by treatment with eculizumab. Thromb Haemost 2011; 106: 383-5.
84. Hillmen P, Hall C, Marsh JC, Elebute M, Bombara MP, Petro BE, Cullen MJ, Richards SJ, Rollins SA, Mojcik CF, Rother RP. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med 2004; 350: 552-9.
85. Hill A, Rother RP, Hillmen P. Improvement in the symptoms of smooth muscle dystonia during eculizumab therapy in paroxysmal nocturnal hemoglobinuria. Haematologica 2005; 90(Suppl. 12): ECR40.
86. Hillmen P, Elebute M, Kelly R, Urbano-Ispizua A, Hill A, Rother RP, Khursigara G, Fu CL, Omine M, Browne P, Rosse W. Long-term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal hemoglobinuria. Am J Hematol 2010; 85: 553-9.
87. Schubert J, Hillmen P, Roth A, Young NS, Elebute MO, Szer J, Gianfaldoni G, Socie G, Browne P, Geller R, Rother RP, Muus P. Eculizumab, a terminal complement inhibitor, improves anaemia in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 2008; 142: 263-72.
88. Brodsky RA, Young NS, Antonioli E, Risitano AM, Schrezenmeier H, Schubert J, Gaya A, Coyle L, de Castro C, Fu CL, Maciejewski JP, Bessler M, Kroon HA, Rother RP, Hillmen P. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood 2008; 111: 1840-7.
89. Weitz IC. Thrombosis in paroxysmal nocturnal hemoglobinuria - insights into the role of complement in thrombosis. Thromb Res 2010; 125(Suppl. 2): S106-7.
90. Brodsky RA. How I treat paroxysmal nocturnal hemoglobinuria. Blood 2009; 113: 6522-7.
91. Emadi A, Brodsky RA. Successful discontinuation of anticoagulation following eculizumab administration in paroxysmal nocturnal hemoglobinuria. Am J Hematol 2009; 84: 699-701.