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Introduction
Thrombotic thrombocytopenic purpura (TTP) is a rare, lifethreatening disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia, variable degrees of renal
insufficiency, neurologic impairment, and other organ failure.
Most cases are associated with an inherited or acquired,
antibody-mediated deficiency of ADAMTS13 (A Disintegrin
And Metalloproteinase with ThromboSpondin-1 like motifs),
a von Willebrand factor cleaving protease that cleaves large
hemostatically active multimers of von Willebrand factor into
smaller, less adhesive multimers. In the absence of
ADAMTS13, large multimers of VWF accumulate in plasma
and promote the formation of platelet rich thrombi in the microvasculature that lead to tissue ischemia and organ dysfunction. The rationale for the efficacy of plasma exchange
in TTP is based on replacement of ADAMTS13 and removal
of ADAMTS13 inhibitory autoantibodies.
Plasma exchange has increased the survival of patients
with TTP from approximately 10% to more than 80% [1].
However, 1020% of patients do not respond to plasma
exchange and another 3437% relapse after initial
response to treatment [2,3]. These patients have been
treated with salvage therapies such as corticosteroids [4],
vincristine [5], cyclosporine [4,6], and splenectomy with
varying success. More recently, Rituximab has been used
as second line therapy for refractory or relapsing disease
with significant response rates, few relapses, and no
obvious long-term adverse effects [711]. A phase II study
of rituximab along with plasma exchange and steroids for
initial therapy of acquired TTP reported a significantly
decreased risk of relapse compared with historical controls
[12]. Moreover, other novel therapies for treatment of acute
TTP are currently in clinical trials or under development.
The early initiation of immune-modulatory therapy targeting the antibody inhibitor of ADAMTS13 could potentially
reduce the number of plasma exchange procedures
required to achieve remission, increase the response rate
and decrease the incidence of relapses in patients with
TTP. Such approaches would be targeted to patients at
greatest risk for adverse outcomes. Recent studies have
reported that severe ADAMTS13 deficiency at the time of
the initial episode of TTP is associated with an increased
risk of relapse [13]. There is also evidence that TTP developing in patients with another primary disorder (i.e.
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research article
recipients, (3) underlying malignancy, (4) pregnancy or the post partum
state, (5) drug related, and (6) idiopathic. All charts were reviewed for
associations with any of the above including a history of exposure to
drugs associated with TTP (clopidogrel, ticlopidine, mitomycin, gemcitabine, carmustine, tacrolimus, and quinine). These categories were
not mutually exclusive.
Definition of clinical outcomes
The primary outcome of the study was death from TTP. Response
to treatment was defined as the achievement of platelet count of
greater than 150 3 109/l plus normalized serum lactate dehydrogenase
(LDH) during plasma exchange. Recurrences of TTP characterized by
recurrent thrombocytopenia (platelet count < 150,000/ml) and elevation
in LDH following an initial response were divided into exacerbations
(occurring >1 day but <30 days after last plasma exchange) and relapses (occurring >30 days after last plasma exchange). Chronic kidney
disease was defined as a persistent elevation of serum creatinine
greater than 2 mg/dl or greater than 1.5 times baseline. The need for
renal replacement therapy, e.g. hemodialysis or renal transplant, was
used as a surrogate for end stage renal disease.
Data collection
Study data was collected and managed using REDCap (Research
Electronic Data Capture), an electronic data capture tool hosted at
Cleveland Clinic. REDCap is a secure, web-based application designed
for data capture for research studies, providing an intuitive interface for
validated data entry and audit trails. Information was collected regarding demographics and clinical presentation with emphasis on the presence of fever, and neurological symptoms including seizures,
obtundation, and focal neurological deficits. Less severe neurological
symptoms such as headache, blurred vision, ataxia and transient confusion were excluded from the analysis because of inconsistencies in
documentation. Neurological symptoms had to be documented at presentation or within 7 days of starting plasma exchange. Laboratory
data captured at presentation included hemoglobin, platelet count,
LDH, ADAMTS13 activity, ADAMTS13 inhibitor and serum creatinine.
(ADAMTS13 measurements were performed at the Blood Center of
Wisconsin, using the FRETS assay). In addition, the platelet count and
LDH levels were measured daily. ADAMTS13 was included in the analysis only if performed prior to the initiation of plasma exchange. The
patient cohort was followed until death, loss to follow up, or the date of
data collection. Sixteen patients were lost to follow up.
Statistical analysis
All variables were examined for associations with the outcomes
being studied. Only data from a first episode of TTP was included in
the analysis. Categorical variables were compared by the Pearson chisquared or Fisher exact test. Analysis of continuous variables was performed by the t-test and Wilcoxon signed rank test for symmetrically
distributed and skewed variables respectively. Data was initially examined by univariate analysis. To predict mortality rate, a multivariate prediction model including associations which reached a significance of
P < 0.1 was utilized and the model was internally validated by Bootstrap sampling (n 5 1,000) with an optimism of 2.4% [21] Statistical
analyses were performed using R (www.r-project.org). A P value of
0.05 was considered significant for all analyses.
Results
One hundred patients met the inclusion criteria for this
study. Table I shows the clinical characteristics and outcomes of the cohort. Ages ranged from 16 to 79 years
(median 49 years) with 73% females. Fifty percent of the
patients were Caucasian, 45% African American, and 2%
Hispanic. Sixty-seven percent of cases occurred without
predisposing conditions (idiopathic TTP), while 12% were
associated with autoimmune disease (six with SLE, two
with rheumatoid arthritis, one with SLE and rheumatoid arthritis, and one each with Sjogrens syndrome, dermatomyositis, and mixed connective tissue disorder), 6% with
pregnancy, 2% with the postpartum state, 6% each with
cancer or solid organ transplantation (four kidney transplants, two liver transplants), and 2% each with bone marrow or stem cell transplant. ADAMTS13 was tested in 57
patients before starting plasma exchange; 36 (63%) had
severe ADAMTS13 deficiency (ADAMTS13 activity < 5%).
ADAMTS13 activity in the remaining 21 patients (37%)
Variable
Age > 60
Female sex
Ethnicity
Caucasian
African American
Hispanic
Other
Clinical Category
Autoimmune disease
Solid transplant recipient
Stem cell transplant
Systemic malignancy
Pregnancy/postpartum
Drug related
Idiopathic
Fever
Neurological symptomsa
Seizures
Focal neurological deficits
Obtundation
No severe neurological symptoms
Laboratory studies
Hemoglobin (g/dl) (11.515.5 g/dl)
Platelet count (x 109 /L) (1.54.0 3 109 /L)
Serum creatinine (mg/dl) (0.71.4 mg/dl)
Lactate Dehydrogenase (IU/ml) (100220 IU/ml)
ADAMTS13 (%) (n 5 57)
Outcomes
Response
Plasma exchanges needed for remission
Deathb
Exacerbation
Relapse
Need for hemodialysis during acute episode
Chronic kidney diseasec
End-stage kidney diseasec
Number (n 5 100)
or mean 6 SD
15
73
50
46
2
2
12
6
2
6
8
16
67
29
9
33
16
54
8.29 6 1.84
10.88 6 5.62
2.33 6 2.28
1,338 6 945
36 (63%)
84
12.2 (range: 346)
9
13
18
19
16
12
a
Only seizures, focal deficits and obtundation were included in the analyses
since the assessment of minor neurological symptoms such as headache is
subjective and difficult to standardize.
b
Eight of nine deaths occurred within 30 days (days 3, 8, 8,11, 12, 16, 25,
27) while one occurred at day 73 during a relapse of TTP.
c
Nine patients died and another 16 were lost to follow up leading to a sample
size of 75 for assessment of long-term (2 year) renal outcomes.
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TABLE II. Clinical Features and Outcomes of Patients with and Without Severe ADAMTS13 Deficiency (n 5 57)
Variable
Age >60
Female sex
Clinical Category
Autoimmune disease
Solid transplant
Stem cell transplant
Systemic malignancy
Pregnancy/postpartum
Drug related
Idiopathic
Fever
Neurological symptoms
Seizures
Focal neurodeficits
Obtundation
No severe neurological symptoms
Laboratory studies
Hemoglobin (g/dl) (11.515.5 g/dl)
Platelet count (x109/L) (1.54.0 3 109/L)
LDH (IU/L) (100220 IU/ml)
S. creatinine (mg/dl) (0.71.4 mg/dl)
Outcomes
Death
Exacerbation
Relapse
Need for hemodialysis during acute episode
Chronic kidney disease
End-stage kidney disease
Significance
4 (11.11)
24 (66.7)
6 (28.57)
17 (81)
1.88 (0.983.62)
0.603 (0.241.52)
0.190
0.362
4 (11.1)
0 (0.0)
0 (0.0)
2 (5.5)
2 (5.5)
2 (5.5)
28 (77.8)
12 (33.3)
4(19.0)
2 (9.5)
1 (4.8)
1 (4.8)
2 (9.5)
6 (28.6)
12 (57.4)
5 (23.8)
1.44 (0.653.18)
2.89 (2.014.17)
0.9 (0.1754.629)
1.25 (0.4333.61)
2.45 (1.374.38)
0.57 (0.301.09)
0.74 (0.321.68)
0.449
0.132
1.000
1.000
1.000
0.04
0.100
0.555
2 (5.5)
18 (50)
8 (22.2)
15 (41.7)
1 (4.8)
3 (14.3)
4 (19.0)
13 (61.9)
0.9 (0.184.63)
0.27 (1.973.98)
0.88 (0.372.14)
1.68 (0.833.34)
0.696
0.010
0.528
0.140
8.64 6 1.95
20.44 6 13.59
1,386 6 860
1.94 6 2.21
7.88 6 1.55
30.63 6 24.62
1,269 6 925
3.23 6 2.55
2 (5.6)
4 (11.1)
6 (16.7)
2 (5.6)
2 (5.5)
0 (0)
2 (9.5)
1 (4.8)
4 (19.0)
8 (38.1)
5 (23.8%)
4 (19.0)
562
0.203
0.223
0.899
0.012
1.40
0.52
1.10
2.89
2.86
3.12
(0.493.96)
(0.093.10)
(0.472.58)
(1.665.05)
(1.375.96)
(2.104.61)
0.620
0.642
1.000
0.003
0.028
0.015
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TABLE III. Associations of Clinical and Laboratory Parameters with Survival
Clinical variable
Survivors
Non-survivors
Age > 60
Female sex
Ethnicity
Caucasian
African American
Hispanic
Other
Clinical category
Autoimmune disease
Solid transplant recipient
Stem cell transplant
Systemic malignancy
Pregnancy/postpartum
Drug related
Idiopathic
Fever
Neurological symptoms
Seizures
Focal neurological deficits
Obtundation
No severe neurologic symptoms
Laboratory studies
Hemoglobin (g/dl)
Platelet count (3 109/l)
Serum creatinine (mg/dl)
Lactate Dehydrogenase (IU/l)
ADAMTS13 activity (%) (n 5 57)
10 (10.98)
69 (75.8)
5 (55.56)
4 (44.4)
7.08 (2.1523.39)
3.38 (0.9811.66)
0.002
0.057
45 (51.7)
5 (55.56)
1.15 (0.334.02)
1.000
11 (12.1)
5 (5.5)
0 (0)
6 (6.6)
8 (87.9)
13 (14.3)
63 (69.2)
26 (28.6)
1 (11.1)
1 (11.1)
7 (77.8)
0 (0)
0 (0)
3 (33.3)
4 (44.4)
3 (33.3)
0.92 (0.136.70)
1.96 (0.2913.19)
14 (6.8628.57)
1.000
0.441
0.007
1.000
1.000
0.154
0.151
0.716
8
31
9
53
1
2
7
1
1.26
0.58
18.38
0.10
(8.8)
(34.1)
(9.9)
(58.2)
8.27 6 1.27
27 6 9.84
2.20 6 2.15
1,344 6 963
40.1 6 24.98
(11.1)
(22.2)
(77.8)
(11.1)
8.36 6 1.38
116 6 29.94
3.17 6 3.18
1,273 6 783
55.73 (8.68)
2.63 (0.739.43)
0.39 (0.111.37)
1.22 (0.334.57)
(0.188.99)
(0.132.64)
(4.1980.53)
(0.010.82)
P value
0.588
0.714
<0.001
0.011
0.868
0.160
0.241
0.803
0.096
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cohorts [2,3]. Several patients in our series received a relatively slow tapering regimen of plasma exchange after
achieving remission (mean plasma exchanges after remission 12, mean duration 30 days) that may have reduced
exacerbation and relapse rates during this vulnerable period, although this hypothesis remains speculative. This
lower rate of relapse may also, in part, be attributable to a
relatively short duration of follow up (2 years) in some
patients causing us to miss late relapses.
Increasing age and severe neurological symptoms at
presentation were associated with increased mortality.
However, we did not find an association between mortality
and severity of common laboratory abnormalities at presentation. This is in contradistinction to other studies that
observed associations of mortality from TTP with platelet
count [30], severity of anemia, and fever [32].
Another recent study from the French TMA reference
center reported that increasing age and high LDH at presentation were predictive of mortality, and developed a
prognostic model that included these factors [30]. In our
cohort, we did not find an association of survival with the
severity of thrombocytopenia or LDH at presentation. It is,
however, important to note that Benhamou et al. [30]
included only patients with severe ADAMTS13 deficiency
and thus their results may not be applicable to the entire
spectrum of patients with clinically-diagnosed TTP.
Although severe ADAMTS13 deficiency has high specificity
for the diagnosis of TTP, its sensitivity is uncertain. Not all
patients with TTP, even apparent idiopathic TTP, are
severely deficient in ADAMTS13 [13,24]. While the pathogenesis of thrombotic microangiopathy in these individuals
is uncertain, potentially reflecting abnormalities in VWF,
complement activation, endothelial cell damage, or other
factors, they are generally considered to have TTP and
managed as such, and thus were included in our series.
Of the 57 patients who had ADAMTS13 activity determined prior to initiating plasma exchange, 36 (63%) had
severe deficiency (<5%). Our study has a higher proportion of patients with severe ADAMTS13 deficiency than the
13% observed in the Oklahoma registry [13] and the 30%
in the Korean Registry [24] possibly due to more stringent
exclusion of patients with other potential causes of thrombotic microangiopathy. Considering only the patients in our
series that were considered clinically to have idiopathic
TTP, 28/40 (70%) had ADAMTS13 activity < 5% while only
8/17 (47%) of patients with secondary TTP had
ADAMTS13 activity <5% (4 with autoimmune disease and
4 each with cancer/chemotherapy-related TTP).
Patients with severe ADAMTS13 deficiency had heterogeneous clinical presentations that did not differ from those
of patients with >5% ADAMTS13 activity. Moreover,
response to plasma exchange, mortality, exacerbation and
relapse rates in our series did not differ between the two
groups, although patients with ADAMTS13 levels >5% had
significantly worse renal outcomes. This trend has previously been observed by Vesely et al. [13] who noted a linear inverse relationship between ADAMTS13 activity and
chronic renal disease, but did not describe a distinct difference in renal outcomes in patients with ADAMTS13 activity
above or below 5%. Of the 21 patients with detectable
ADAMTS13 activity, the majority (12) did not have underlying secondary causes for TTP. One might argue that at
least some of these patients may have had atypical hemolytic uremia syndrome (aHUS), consistent with their poorer
renal outcomes. .
These results indicate that although ADAMTS13 is important in the pathogenesis of TTP, other mechanisms
such as drug-dependent antibodies to endothelial cells and
platelets [33], changes in the hemostatic system that occur
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5. Ziman A, Mitri M, Klapper E, et al. Combination vincristine and plasma
exchange as initial therapy in patients with thrombotic thrombocytopenic purpura: One institutions experience and review of the literature. Transfusion
2005;45:41.
6. Honda K, Hidaka S, Kobayashi S. Successful treatment with cyclosporine of
thrombotic thrombocytopenic purpura refractory to corticosteroids and plasma
exchange. Ther Apher Dial 2011;15:215217.
7. Chemnitz JM, Uener J, Hallek M, Scheid C. Long-term follow-up of idiopathic
thrombotic thrombocytopenic purpura treated with rituximab. Ann Hematol
2010;89:10291033.
8. Sadler J. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic
purpura. Blood 112:1111218.
9. Fakhouri F, Vernant JP, Veyradier A, et al. Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13-deficient thrombotic thrombocytopenic purpura: A study of 11 cases. Blood 2005;106:19321937.
10. Heidel F, Lipka DB, von Auer C, et al. Addition of rituximab to standard therapy improves response rate and progression-free survival in relapsed or refractory thrombotic thrombocytopenic purpura and autoimmune haemolytic
anaemia. Thromb Haemost 2007;97:228233.
11. de la Rubia J. Efficacy and safety of rituximab in adult patients with idiopathic
relapsing or refractory thrombotic thrombocytopenic purpura: Results of a
Spanish multicenter study. Transfus Apher Sci 2010;43:299299303.
12. Scully M, McDonald V, Cavenagh J, et al. A phase 2 study of the safety and
efficacy of rituximab with plasma exchange in acute acquired thrombotic
thrombocytopenic purpura. Blood 2011;118:17461753.
13. Vesely SK, George JN, Lammle B, et al. ADAMTS13 activity in thrombotic
thrombocytopenic purpura-hemolytic uremic syndrome: Relation to presenting
features and clinical outcomes in a prospective cohort of 142 patients. Blood
2003;102:6068.
14. George JN. How I treat patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Blood 2000;96:12231229.
15. Dierkes F, Andriopoulos N, Sucker C, et al. Indicators of acute and persistent
renal damage in adult thrombotic microangiopathy. PLoS One 2012;7:e30886.
16. Dervenoulas J, Tsirigotis P, Bollas G, et al. Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS): Treatment outcome, relapses,
prognostic factors. A single-center experience of 48 cases. Ann Hematol
2000;79:6672.
17. Sarode R, Gottschall JL, Aster RH, McFarland JG. Thrombotic thrombocytopenic purpura: Early and late responders. Am J Hematol 1997;54:102107.
18. Liu C, Kallogjeri D, Dynis M, Grossman BJ. Platelet recovery rate during
plasma exchange predicts early and late responses in patients with thrombotic
thrombocytopenic purpura. Transfusion 2012 [Epub ahead of print].
19. Hollenbeck M, Kutkuhn B, Aul C, et al. Haemolytic-uraemic syndrome
and thrombotic-thrombocytopenic purpura in adults: Clinical findings and prognostic factors for death and end-stage renal disease. Nephrol Dial Transplant
1998;13:7681.
20. Levandovsky M, Harvey D, Lara P, Wun T. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS): A 24-year clinical experience
with 178 patients. J Hematol Oncol 2008;1:23.
21. Austin PC, Tu JV. Bootstrap methods for developing predictive models. Am
Stat 2004;58:131137.
22. George JN, Vesely SK, Terrell DR. The Oklahoma Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome (TTP-HUS) Registry: A community
perspective of patients with clinically diagnosed TTP-HUS. Semin Hematol
2004;41:6067.
23. 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;142:819826.
24. Jang MJ, Chong SY, Kim IH, et al. Clinical features of severe acquired
ADAMTS13 deficiency in thrombotic thrombocytopenic purpura: The Korean
TTP registry experience. Int J Hematol 2011;93:163169.
25. George JN. The association of pregnancy with thrombotic thrombocytopenic
purpura-hemolytic uremic syndrome. Curr Opin Hematol 2003;10:339344.
26. Stirling Y, Woolf L, North WR, et al. Haemostasis in normal pregnancy.
Thromb Haemost 1984;52:176182.
27. de Moerloose P, Amiral J, Vissac AM, Reber G. Longitudinal study on activated factors XII and VII levels during normal pregnancy. Br J Haematol
1998;100:4044.
28. Mannucci PM, Canciani MT, Forza I, et al. Changes in health and disease of
the metalloprotease that cleaves von Willebrand factor. Blood 2001;98:2730
2735.
29. Zhan H, Streiff MB, King KE, Segal JB. Thrombotic thrombocytopenic purpura
at the Johns Hopkins Hospital from 1992 to 2008: Clinical outcomes and risk
factors for relapse. Transfusion 2010;50:868874.
30. Benhamou Y, Assie C, Boelle PY, et al. Development and validation of a predictive model for death in acquired severe ADAMTS13 deficiency-associated
idiopathic thrombotic thrombocytopenic purpura: The French TMA Reference
Center experience. Haematologica 2012;97:11811186.
31. Ramanan AS, Thirumala S, Chandrasekaran V. Thrombotic thrombocytopenia
purpura: A single institution experience. J Clin Apher 1999;14:913.
32. Wyllie BF, Garg AX, Macnab J, et al. Thrombotic thrombocytopenic purpura/
haemolytic uraemic syndrome: A new index predicting response to plasma
exchange. Br J Haematol 2006;132:204209.
33. Kojouri K, Vesely SK, George JN. Quinine-associated thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: Frequency, clinical features, and
long-term outcomes. Ann Intern Med 2001;135:10471051.
34. Reti M, Farkas P, Csuka D, et al. Complement activation in thrombotic thrombocytopenic purpura. J Thromb Haemost 2012;10:791798.
35. Ren G, Hack BK, Minto AW, et al. A complement-dependent model of thrombotic thrombocytopenic purpura induced by antibodies reactive with endothelial
cells. Clin Immunol 2002;103:4353.
36. Chapin J, Weksler B, Magro C, Laurence J. Eculizumab in the treatment of refractory idiopathic thrombotic thrombocytopenic purpura. Br J Haematol
2012;157:772774.
37. Nguyen L, Terrell DR, Duvall D, et al. Complications of plasma exchange in
patients treated for thrombotic thrombocytopenic purpura. IV. An additional
study of 43 consecutive patients, 2005 to 2008. Transfusion 2009;49:392394.
565