Abstract
Immune thrombotic thrombocytopenic purpura (iTTP) caused by an autoantibody-mediated deficiency of ADAMTS13 and atypical hemolytic syndrome (aHUS) caused by alternative complement dysregulation are the most common primary thrombotic microangiopathies (TMAs). The evaluation of a patient with TMA is a medical emergency since it is critical to quickly distinguish iTTP and aHUS from other causes of TMA. Untreated iTTP is rapidly fatal, and delays in initiating complement inhibition in aHUS increase the risk of irreversible renal failure. An ADAMTS13 activity level of less than 10% is diagnostic of iTTP in the appropriate clinical setting. In settings where rapid-turnaround ADAMTS13 testing is not available, clinical features and clinical prediction tools are useful to identify patients who should receive emergent plasma exchange. We present an evidence-based approach to the initial (first 24 hours) diagnosis and management of iTTP and review the clinical and laboratory features that can be used to identify patients with aHUS who will benefit from early C5 blockade. We also discuss the potential use of complement blockade to improve outcomes in selected patients with secondary TMA.
Bibliography
1.
Zini
G
, d'Onofrio
G
, Briggs
C
, et al; International Council for Standardization in Haematology (ICSH)
. ICSH recommendations for identification, diagnostic value, and quantitation of schistocytes
. Int J Lab Hematol
. 2012
;34
(2
):107
-116
. doi:10.1111/j.1751-553X.2011.01380.x.
2.
Fakhouri
F
, Schwotzer
N
, Frémeaux-Bacchi
V.
How I diagnose and treat atypical hemolytic uremic syndrome
. Blood
. 2023
;141
(9
):984
-995
. doi:10.1182/blood.2022017860.
3.
Joly
BS
, Coppo
P
, Veyradier
A.
Thrombotic thrombocytopenic purpura
. Blood
. 2017
;129
(21
):2836
-2846
. doi:10.1182/blood-2016-10-709857.
4.
Maga
TK
, Nishimura
CJ
, Weaver
AE
, Frees
KL
, Smith
RJ
. Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome
. Hum Mutat
. 2010
;31
(6
):E1445
-E1460
. doi:10.1002/humu.21256.
5.
Palma
LMP
, Sridharan
M
, Sethi
S.
Complement in secondary thrombotic microangiopathy
. Kidney Int Rep
. 2021
;6
(1
):11
-23
. doi:10.1016/j.ekir.2020.10.009.
6.
Page
EE
, Kremer Hovinga
JA
, Terrell
DR
, Vesely
SK
, George
JN
. Thrombotic thrombocytopenic purpura: diagnostic criteria, clinical features, and long-term outcomes from 1995 through 2015
. Blood Adv
. 2017
;1
(10
):590
-600
. doi:10.1182/bloodadvances.2017005124.
7.
Scully
M
, Yarranton
H
, Liesner
R
, et al. Regional UK TTP registry: correlation with laboratory ADAMTS 13 analysis and clinical features
. Br J Haematol
. 2008
;142
(5
):819
-826
. doi:10.1111/j.1365-2141.2008.07276.x.
8.
El Karoui
K
, Boudhabhay
I
, Petitprez
F
, et al. Impact of hypertensive emergency and rare complement variants on the presentation and outcome of atypical hemolytic uremic syndrome
. Haematologica
. 2019
;104
(12
): 2501
-2511
. doi:10.3324/haematol.2019.216903.
9.
Noris
M
, Caprioli
J
, Bresin
E
, et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype
. Clin J Am Soc Nephrol
. 2010
;5
(10
):1844
-1859
. doi:10.2215/CJN.02210310.
10.
Timmermans
SAMEG
, Wérion
A
, Damoiseaux
JGMC
, Morelle
J
, Reutelingsperger
CP
, van Paassen
P.
Diagnostic and risk factors for complement defects in hypertensive emergency and thrombotic microangiopathy
. Hypertension
. 2020
;75
(2
):422
-430
. doi:10.1161/HYPERTENSIONAHA.119.13714.
11.
Coppo
P
, Schwarzinger
M
, Buffet
M
, et al; French Reference Center for Thrombotic Microangiopathies
. Predictive features of severe acquired ADAMTS13 deficiency in idiopathic thrombotic microangiopathies: the French TMA reference center experience
. PLoS One
. 2010
;5
(4
):e10208
. doi:10.1371/journal.pone.0010208.
12.
Bendapudi
PK
, Hurwitz
S
, Fry
A
, et al. Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: a cohort study
. Lancet Haematol
. 2017
;4
(4
):e157
-e164
. doi:10.1016/S2352-3026(17)30026-1.
13.
Paydary
K
, Banwell
E
, Tong
J
, Chen
Y
, Cuker
A.
Diagnostic accuracy of the PLASMIC score in patients with suspected thrombotic thrombocytopenic purpura: a systematic review and meta-analysis
. Transfusion
. 2020
;60
(9
):2047
-2057
. doi:10.1111/trf.15954.
14.
Liu
A
, Dhaliwal
N
, Upreti
H
, et al. Reduced sensitivity of PLASMIC and French scores for the diagnosis of thrombotic thrombocytopenic purpura in older individuals
. Transfusion
. 2021
;61
(1
):266
-273
. doi:10.1111/trf.16188.
15.
Favaloro
EJ
, Pasalic
L
, Henry
B
, Lippi
G.
Laboratory testing for ADAMTS13: utility for TTP diagnosis/exclusion and beyond
. Am J Hematol
. 2021
; 96
(8
):1049
-1055
. doi:10.1002/ajh.26241.
16.
Hassan
S
, Westwood
JP
, Ellis
D
, et al. The utility of ADAMTS13 in differentiating TTP from other acute thrombotic microangiopathies: results from the UK TTP Registry
. Br J Haematol
. 2015
;171
(5
):830
-835
. doi:10.1111/bjh.13654.
17.
Zheng
XL
, Vesely
SK
, Cataland
SR
, et al. ISTH guidelines for treatment of thrombotic thrombocytopenic purpura
. J Thromb Haemost
. 2020
;18
(10
):2496
-2502
. doi:10.1111/jth.15010.
18.
Aibar
J
, Castro
P
, Espinosa
G
, et al. ADAMTS-13 in critically ill patients with septic syndromes and noninfectious systemic inflammatory response syndrome
. Shock
. 2015
;43
(6
):556
-562
. doi:10.1097/SHK.0000000000000341.
19.
Masias
C
, Cataland
SR
. The role of ADAMTS13 testing in the diagnosis and management of thrombotic microangiopathies and thrombosis
. Blood
. 2018
;132
(9
):903
-910
. doi:10.1182/blood-2018-02-791533.
20.
Thomas
MR
, de Groot
R
, Scully
MA
, Crawley
JT
. Pathogenicity of anti-ADAMTS13 autoantibodies in acquired thrombotic thrombocytopenic purpura
. EBioMedicine
. 2015
;2
(8
):942
-952
. doi:10.1016/j.ebiom.2015.06.007.
21.
Scheiflinger
F
, Knöbl
P
, Trattner
B
, et al. Nonneutralizing IgM and IgG antibodies to von Willebrand factor-cleaving protease (ADAMTS-13) in a patient with thrombotic thrombocytopenic purpura
. Blood
. 2003
;102
(9
): 3241
-3243
. doi:10.1182/blood-2003-05-1616.
22.
Rieger
M
, Mannucci
PM
, Kremer Hovinga
JA
, et al. ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases
. Blood
. 2005
;106
(4
):1262
-1267
. doi:10.1182/blood-2004-11-4490.
23.
Moore
GW
, Meijer
D
, Griffiths
M
, et al. A multi-center evaluation of TECHNOSCREEN® ADAMTS-13 activity assay as a screening tool for detecting deficiency of ADAMTS-13
. J Thromb Haemost
. 2020
;18
(7
):1686
-1694
. doi:10.1111/jth.14815.
24.
Favaloro
EJ
, Mohammed
S
, Chapman
K
, et al. A multicenter laboratory assessment of a new automated chemiluminescent assay for ADAMTS13 activity
. J Thromb Haemost
. 2021
;19
(2
):417
-428
. doi:10.1111/jth.15157.
25.
Valsecchi
C
, Mirabet
M
, Mancini
I
, et al. Evaluation of a new, rapid, fully automated assay for the measurement of ADAMTS13 activity
. Thromb Haemost
. 2019
;119
(11
):1767
-1772
. doi:10.1055/s-0039-1696718.
26.
Bu
F
, Meyer
NC
, Zhang
Y
, et al. Soluble c5b-9 as a biomarker for complement activation in atypical hemolytic uremic syndrome
. Am J Kidney Dis
. 2015
;65
(6
):968
-969
. doi:10.1053/j.ajkd.2015.02.326.
27.
Noris
M
, Galbusera
M
, Gastoldi
S
, et al. Dynamics of complement activation in aHUS and how to monitor eculizumab therapy
. Blood
. 2014
;124
(11
): 1715
-1726
. doi:10.1182/blood-2014-02-558296.
28.
Volokhina
EB
, Westra
D
, van der Velden
TJ
, van de Kar
NC
, Mollnes
TE
, van den Heuvel
LP
. Complement activation patterns in atypical haemolytic uraemic syndrome during acute phase and in remission
. Clin Exp Immunol
. 2015
;181
(2
):306
-313
. doi:10.1111/cei.12426.
29.
Cataland
SR
, Holers
VM
, Geyer
S
, Yang
S
, Wu
HM
. Biomarkers of terminal complement activation confirm the diagnosis of aHUS and differentiate aHUS from TTP
. Blood
. 2014
;123
(24
):3733
-3738
. doi:10.1182/blood-2013-12-547067.
30.
Gavriilaki
E
, Yuan
X
, Ye
Z
, et al. Modified Ham test for atypical hemolytic uremic syndrome
. Blood
. 2015
;125
(23
):3637
-3646
. doi:10.1182/blood-2015-02-629683.
31.
Galbusera
M
, Noris
M
, Gastoldi
S
, et al. An ex vivo test of complement activation on endothelium for individualized eculizumab therapy in hemolytic uremic syndrome
. Am J Kidney Dis
. 2019
;74
(1
):56
-72
. doi:10.1053/j.ajkd.2018.11.012.
32.
Doreille
A
, Rafat
C
, Rondeau
E
, Mesnard
L.
How I treat thrombotic microangiopathy in the era of rapid genomics
. Blood
. 2023
;141
(2
):147
-155
. doi:10.1182/blood.2022015583.
33.
Scully
M
, Cataland
SR
, Peyvandi
F
, et al; HERCULES Investigators
. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura
. N Engl J Med
. 2019
;380
(4
):335
-346
. doi:10.1056/NEJMoa1806311.
34.
Dutt
T
, Shaw
RJ
, Stubbs
M
, et al. Real-world experience with caplacizumab in the management of acute TTP
. Blood
. 2021
;137
(13
):1731
-1740
. doi:10.1182/blood.2020007599.
35.
Peyvandi
F
, Scully
M
, Kremer Hovinga
JA
, et al; TITAN Investigators
. Caplacizumab for acquired thrombotic thrombocytopenic purpura
. N Engl J Med
. 2016
;374
(6
):511
-522
. doi:10.1056/NEJMoa1505533.
36.
Goshua
G
, Sinha
P
, Hendrickson
JE
, Tormey
C
, Bendapudi
PK
, Lee
AI
. Cost effectiveness of caplacizumab in acquired thrombotic thrombocytopenic purpura
. Blood
. 2021
;137
(7
):969
-976
. doi:10.1182/blood.2020006052.
37.
Hughes
M
, Prescott
C
, Elliott
N
, Adler
AI
. NICE guidance on caplacizumab for treating acute acquired thrombotic thrombocytopenia purpura
. Lancet Haematol
. 2021
;8
(1
):e14
-e15
. doi:10.1016/S2352-3026(20)30406-3.
38.
Chaturvedi
S.
Counting the cost of caplacizumab
. Blood
. 2021
;137
(7
): 871
-872
. doi:10.1182/blood.2020009250.
39.
Goel
R
, Ness
PM
, Takemoto
CM
, Krishnamurti
L
, King
KE
, Tobian
AA
. Platelet transfusions in platelet consumptive disorders are associated with arterial thrombosis and in-hospital mortality
. Blood
. 2015
;125
(9
): 1470
-1476
. doi:10.1182/blood-2014-10-605493.
40.
Legendre
CM
, Licht
C
, Muus
P
, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome
. N Engl J Med
. 2013
; 368
(23
):2169
-2181
. doi:10.1056/NEJMoa1208981.
41.
Licht
C
, Greenbaum
LA
, Muus
P
, et al. Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies
. Kidney Int
. 2015
;87
(5
):1061
-1073
. doi:10.1038/ki.2014.423.
42.
Ryan
M
, Donato
BMK
, Irish
W
, Gasteyger
C
, L'Italien
G
, Laurence
J.
Economic impact of early-in-hospital diagnosis and initiation of eculizumab in atypical haemolytic uraemic syndrome
. Pharmacoeconomics
. 2020
;38
(3
): 307
-313
. doi:10.1007/s40273-019-00862-w.
43.
Fakhouri
F
, Hourmant
M
, Campistol
JM
, et al. Terminal complement inhibitor eculizumab in adult patients with atypical hemolytic uremic syndrome: a single-arm, open-label trial
. Am J Kidney Dis
. 2016
;68
(1
):84
-93
. doi:10.1053/j.ajkd.2015.12.034.
44.
Fremeaux-Bacchi
V
, Fakhouri
F
, Garnier
A
, et al. Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults
. Clin J Am Soc Nephrol
. 2013
;8
(4
):554
-562
. doi:10.2215/CJN.04760512.
Copyright © 2023 by The American Society of Hematology
2023
You do not currently have access to this content.
