Paroxysmal nocturnal hemoglobinuria: pathophysiology, natural history and treatment options in the era of biological agents.
Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal non-malignant hematological disease characterized by the expansion of hematopoietic stem cells (HSCs) and progeny mature cells, whose surfaces lack all the proteins linked through the glycosyl-phosphatidyl inositol anchor. This defect arises from an acquired somatic mutation in the X-linked phosphatidylinositol glycan class A gene, with subsequent clonal expansion of the mutated HSCs as a result of a concomitant, likely immune-mediated, selective pressure. The disease is characterized by complement-mediated chronic intravascular hemolysis, resulting in hemolytic anemia and hemosiderinuria; capricious exacerbations lead to recurrent gross hemoglobinuria. Additional cardinal manifestations of PNH are a variable degree of bone marrow failure and an intrinsic propensity to thromboembolic events. The disease is markedly invalidating, with chronic symptoms requiring supportive therapy - usually including periodical transfusions; possible life-threatening complications may also ensue. The biology of PNH has been progressively elucidated in the past few years, but therapeutic strategies remained unsatisfactory for decades, the only exception being stem cell transplantation, which is restricted to selected patients and retains significant morbidity and mortality. Recently, a biological agent to treat PNH has been developed - the terminal complement inhibitor eculizumab - which has been tested in a number of clinical trials, with exciting results. All the data from worldwide clinical trials confirm that eculizumab radically modifies the symptoms, the biology, and the natural history of PNH, strongly improving the quality of life of PNH patients.
Risitano
Antonio M
AM
Hematology, Department of Biochemistry and Medical Biotechnologies, Federico II, University of Naples, Italy.
Rotoli
Bruno
B
Br J Haematol. 1999 May;105(2):497-504
10233427
Exp Hematol. 1990 Dec;18(11):1204-8
2226680
Am J Hematol. 1987 May;25(1):77-83
3578265
Blood. 2005 Dec 1;106(12):3699-709
16051736
J Exp Med. 2001 Sep 3;194(5):581-9
11535627
Exp Hematol. 2004 Mar;32(3):261-9
15003311
Baillieres Clin Haematol. 1989 Jan;2(1):113-38
2645958
Br J Haematol. 1997 May;97(2):356-65
9163602
Rev Invest Clin. 1993 Sep-Oct;45(5):457-61
8134727
Blood. 2005 Oct 1;106(7):2559-65
15985537
Blood. 2002 Aug 15;100(4):1185-91
12149196
Acta Haematol. 1994;91(2):62-5
8023644
Blood. 1991 Aug 1;78(3):820-9
1713516
Leukemia. 2005 May;19(5):862-8
15759038
Blood. 1997 May 15;89(10):3691-9
9160674
Blood. 1992 Mar 15;79(6):1400-3
1372185
Blood. 2005 May 15;105(10):3848-54
15687243
Br J Haematol. 2001 Dec;115(4):1023-31
11843845
Leukemia. 2005 Feb;19(2):217-22
15668701
J Clin Invest. 1966 May;45(5):736-48
5935361
Am J Hematol. 1997 Feb;54(2):149-54
9034290
J Exp Med. 1984 Nov 1;160(5):1558-78
6238120
Nat Med. 1995 Aug;1(8):839-42
7585191
Blood. 2002 Apr 15;99(8):2748-51
11929762
Int J Hematol. 1997 Apr;65(3):285-91
9114600
Crit Rev Oncol Hematol. 2000 Jan;33(1):25-43
10714960
Blood. 1992 Jul 15;80(2):337-45
1627795
Blood Rev. 1993 Jun;7(2):75-86
8369662
Cytometry B Clin Cytom. 2007 May;72(3):167-77
17285629
Br J Haematol. 2007 May;137(3):181-92
17408457
Haematologica. 1996 Nov-Dec;81(6):540-2
9009443
Blood. 1982 Jul;60(1):20-3
7044450
Blood. 2007 Dec 1;110(12):4123-8
17702897
Blood. 1990 Nov 1;76(9):1853-9
2145990
Lancet. 2004 Jul 24-30;364(9431):355-64
15276395
Proc Natl Acad Sci U S A. 1986 Sep;83(18):6975-9
2428045
Blood. 1999 May 15;93(10):3451-6
10233897
Haematologica. 2007 Mar;92(3):e31-3
17405753
Am J Hematol. 2001 Dec;68(4):280-3
11754418
J Clin Invest. 2001 Sep;108(5):765-73
11544283
Leukemia. 2002 Nov;16(11):2243-8
12399968
Science. 1993 Feb 26;259(5099):1318-20
7680492
N Engl J Med. 1985 Jan 31;312(5):257-65
2981406
Haematologica. 2000 Jan;85(1):59-62
10629593
Circulation. 2004 Apr 20;109(15):1819-22
15066953
Blood. 2001 Oct 1;98(7):2248-55
11568013
JAMA. 2005 Apr 6;293(13):1653-62
15811985
Hum Immunol. 2002 Oct;63(10):813-20
12368033
Blood. 2002 Jul 1;100(1):178-83
12070025
Blood. 1982 Jul;60(1):157-9
7082835
J Clin Invest. 2000 Sep;106(5):637-41
10974016
Br J Haematol. 1999 Feb;104(2):392-6
10050724
Blood. 2000 Oct 1;96(7):2613-20
11001919
Clin Exp Immunol. 1990 Apr;80(1):109-13
1691059
Medicine (Baltimore). 2004 May;83(3):193-207
15118546
J Immunol. 1985 Jan;134(1):506-11
3964820
J Clin Invest. 1997 Sep 1;100(5):1028-36
9276719
Nat Med. 2006 Jul;12(7):846-51
16767100
Blood. 2002 Dec 1;100(12):4116-22
12393537
N Engl J Med. 2006 Sep 21;355(12):1233-43
16990386
N Engl J Med. 1990 Oct 25;323(17):1184-9
1699124
N Engl J Med. 2007 Apr 19;356(16):1641-7
17442906
Blood. 2007 Jun 1;109(11):5036-42
17284529
Cell. 1997 Jan 10;88(1):1-4
9019395
J Exp Med. 1987 Feb 1;165(2):572-7
2434597
Br J Haematol. 2004 Jun;125(6):804-13
15180871
Blood. 2002 May 15;99(10):3668-75
11986222
Cell. 1993 May 21;73(4):703-11
8500164
Am J Hematol. 2007 Feb;82(2):98-107
17013814
Blood. 2003 Nov 15;102(10):3587-91
12893760
J Clin Invest. 1989 Nov;84(5):1387-94
2478585
Br J Haematol. 2004 Jul;126(1):133-8
15198744
Blood. 1970 Aug;36(2):145-52
5448520
Blood. 1993 Aug 15;82(4):1192-6
7688991
J Immunol. 1986 Mar 1;136(5):1777-82
2419414
Cytometry. 2000 Aug 15;42(4):223-33
10934341
Hematology. 2003 Jun;8(3):173-81
12745651
N Engl J Med. 2004 Feb 5;350(6):552-9
14762182
Blood. 1990 Apr 15;75(8):1595-601
2183885
Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6025-9
1378620
N Engl J Med. 1995 Nov 9;333(19):1253-8
7566002
Hum Mol Genet. 1994 May;3(5):751-7
8081362
Blood. 2002 Aug 1;100(3):1031-7
12130519
Lancet. 1996 Aug 31;348(9027):573-7
8774569
Br J Haematol. 1996 Mar;92(4):815-7
8616071
Nat Biotechnol. 2007 Nov;25(11):1256-64
17989688
Blood. 1995 Aug 15;86(4):1487-92
7632956
Blood. 1984 Oct;64(4):847-51
6478058
Blood. 2008 Feb 15;111(4):1840-7
18055865
Curr Opin Hematol. 1996 Mar;3(2):101-10
9372059
Br J Haematol. 2001 Nov;115(2):360-8
11703336
Haematologica. 2005 Dec;90(12 Suppl):ECR40
16464755
Leukemia. 1996 Aug;10(8):1326-30
8709638
J Intern Med. 1994 Jan;235(1):85-9
8283166
Lancet. 1996 Aug 31;348(9027):560
8774563
Blood. 1997 Feb 15;89(4):1173-81
9028939
J Exp Med. 1993 Feb 1;177(2):517-21
8426120
Nature. 1988 Jun 9;333(6173):565-7
2967435
J Neurol. 2005 Nov;252(11):1379-86
16021362
Blood. 2006 Mar 1;107(5):2131-7
16322479
Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):5209-14
10220445
Blood. 1998 Nov 1;92(9):3422-7
9787183
Br J Haematol. 1999 May;105(2):366-8
10233405
Circulation. 1996 Jan 15;93(2):327-32
8548906
J Immunol. 1981 Jan;126(1):232-5
6778916
Blood. 1996 Mar 15;87(6):2546-57
8630422
Br J Haematol. 1999 Feb;104(2):303-6
10050712
Blood. 2005 Oct 1;106(7):2399-408
15956278
Ann Hematol. 2003 May;82(5):299-302
12707719
Immunology. 2006 Dec;119(4):522-8
16999828
Am J Clin Pathol. 2000 Sep;114(3):459-66
10989647
N Engl J Med. 1985 Apr 25;312(17):1091-7
3845321
Proc Natl Acad Sci U S A. 1983 Aug;80(16):5066-70
6576376