Management and outcomes for patients with TTP:analysis of 100 cases at a single institution

Shruti Chaturvedi,1 Desiree Carcioppolo,2 Li Zhang,3 and Keith R. McCrae2,4*

The advent of plasma exchange has led to a dramatic improvement in the survival of patients with throm-botic thrombocytopenic purpura (TTP), though approximately 10% of patients still die and a third sufferrelapses. Clinical features that identify poor risk patients have not been clearly identified. We reviewed 100patients who were treated for a first episode of TTP at the Cleveland Clinic between 2000 and 2012 to iden-tify factors predictive of poor outcomes. On multivariate analysis, increasing age, especially age > 60 (RR:7.08, 95% CI: 2.15–23.39, P 5 0.002), severe neurological symptoms at presentation (RR: 18.37, 95% CI:I4.19–80.13, P < 0.001) and a persistently elevated LDH level after two plasma exchanges were predictive ofmortality. Patients with ADAMTS13 activity above or below 5% did not differ in terms of clinical presenta-tion or mortality and relapse rates, although ADAMTS13 activity > 5% was an independent predictor ofadverse renal outcomes (need for dialysis and progression to chronic kidney disease). These variables maybe useful for risk stratification and identification of patients who could potentially benefit from early institu-tion of adjunctive therapy. Am. J. Hematol. 88:560–565, 2013. VC 2013 Wiley Periodicals, Inc.

IntroductionThrombotic thrombocytopenic purpura (TTP) is a rare, life-

threatening disorder characterized by microangiopathic he-molytic anemia, thrombocytopenia, variable degrees of renalinsufficiency, neurologic impairment, and other organ failure.Most cases are associated with an inherited or acquired,antibody-mediated deficiency of ADAMTS13 (A DisintegrinAnd Metalloproteinase with ThromboSpondin-1 like motifs),a von Willebrand factor cleaving protease that cleaves largehemostatically active multimers of von Willebrand factor intosmaller, less adhesive multimers. In the absence ofADAMTS13, large multimers of VWF accumulate in plasmaand promote the formation of platelet rich thrombi in the mi-crovasculature that lead to tissue ischemia and organ dys-function. The rationale for the efficacy of plasma exchangein TTP is based on replacement of ADAMTS13 and removalof ADAMTS13 inhibitory autoantibodies.

Plasma exchange has increased the survival of patientswith TTP from approximately 10% to more than 80% [1].However, 10–20% of patients do not respond to plasmaexchange and another 34–37% relapse after initialresponse to treatment [2,3]. These patients have beentreated with salvage therapies such as corticosteroids [4],vincristine [5], cyclosporine [4,6], and splenectomy withvarying success. More recently, Rituximab has been usedas second line therapy for refractory or relapsing diseasewith significant response rates, few relapses, and noobvious long-term adverse effects [7–11]. A phase II studyof rituximab along with plasma exchange and steroids forinitial therapy of acquired TTP reported a significantlydecreased risk of relapse compared with historical controls[12]. Moreover, other novel therapies for treatment of acuteTTP are currently in clinical trials or under development.

The early initiation of immune-modulatory therapy target-ing the antibody inhibitor of ADAMTS13 could potentiallyreduce the number of plasma exchange proceduresrequired to achieve remission, increase the response rateand decrease the incidence of relapses in patients withTTP. Such approaches would be targeted to patients atgreatest risk for adverse outcomes. Recent studies havereported that severe ADAMTS13 deficiency at the time ofthe initial episode of TTP is associated with an increasedrisk of relapse [13]. There is also evidence that TTP devel-oping in patients with another primary disorder (i.e.

“secondary TTP”) has a worse prognosis than idiopathicacquired TTP, and that TTP associated with hematopoieticstem cell transplant responds poorly to plasma exchange[14]. Some studies have associated male sex [15], age, se-rum creatinine>2 [16], coma [17], and platelet recoveryrate [18] to poor outcomes while others have failed to con-firm these associations [19,20]. Thus, given the emergenceof new options for treatment of acute TTP, additional infor-mation concerning clinical factors that identify patients athigh risk for poor outcomes is needed. This concernprompted a review of all patients with TTP treated at theCleveland Clinic over the last 12 years in an attempt toidentify factors associated with poor prognosis.

Methods

Patients

The study cohort included consecutive patients treated for a first epi-sode of TTP at the Cleveland Clinic from January 2000 to March 2012.Diagnostic criteria were microangiopathic hemolytic anemia character-ized by schistocytes on the peripheral blood film and thrombocytope-nia, with or without fever and neurological or renal impairment. Patientswith alternative causes for MAHA (e.g., disseminated intravascularcoagulation, sepsis, preeclampsia, eclampsia, or HELLP syndrome)were excluded. Only patients who fulfilled the criteria of TTP through-out their hospitalization were included in the study.

Definition of clinical categories

Patients with a diagnosis of TTP were assigned to one or more ofsix predetermined categories based on underlying conditions. Thesewere (1) autoimmune disorder (systemic lupus erythematosus, rheuma-toid arthritis, etc.), (2) solid organ or hematopoietic cell transplant

1Department of Internal Medicine, Cleveland Clinic, Cleveland, Ohio;2Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio; 3QuantitativeHealth Sciences, Cleveland Clinic, Cleveland, Ohio; 4Cellular and MolecularMedicine, Cleveland Clinic, Cleveland, Ohio

Conflict of interest: Nothing to report

*Correspondence to: Keith R. McCrae, Taussig Cancer Institute, R4–018,Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195.E-mail: mccraek@ccf.org

Contract grant sponsor: NIH; Contract grant numbers: U01 HL072033;R01 HL089796.

Received for publication 28 March 2013; Accepted 3 April 2013

Am. J. Hematol. 88:560–565, 2013.

Published online 20 April 2013 in Wiley Online Library (wileyonlinelibrary.com).DOI: 10.1002/ajh.23455

VC 2013 Wiley Periodicals, Inc.

American Journal of Hematology http://wileyonlinelibrary.com/cgi-bin/jhome/35105560

Research Article

recipients, (3) underlying malignancy, (4) pregnancy or the post partumstate, (5) drug related, and (6) idiopathic. All charts were reviewed forassociations with any of the above including a history of exposure todrugs associated with TTP (clopidogrel, ticlopidine, mitomycin, gemci-tabine, carmustine, tacrolimus, and quinine). These categories werenot mutually exclusive.

Definition of clinical outcomes

The primary outcome of the study was death from TTP. Responseto treatment was defined as the achievement of platelet count ofgreater than 150 3 109/l plus normalized serum lactate dehydrogenase(LDH) during plasma exchange. Recurrences of TTP characterized byrecurrent thrombocytopenia (platelet count< 150,000/ml) and elevationin LDH following an initial response were divided into exacerbations(occurring >1 day but <30 days after last plasma exchange) and relap-ses (occurring >30 days after last plasma exchange). Chronic kidneydisease was defined as a persistent elevation of serum creatininegreater than 2 mg/dl or greater than 1.5 times baseline. The need forrenal replacement therapy, e.g. hemodialysis or renal transplant, wasused as a surrogate for end stage renal disease.

Data collection

Study data was collected and managed using REDCap (ResearchElectronic Data Capture), an electronic data capture tool hosted atCleveland Clinic. REDCap is a secure, web-based application designedfor data capture for research studies, providing an intuitive interface forvalidated data entry and audit trails. Information was collected regard-ing demographics and clinical presentation with emphasis on the pres-ence of fever, and neurological symptoms including seizures,obtundation, and focal neurological deficits. Less severe neurologicalsymptoms such as headache, blurred vision, ataxia and transient con-fusion were excluded from the analysis because of inconsistencies indocumentation. Neurological symptoms had to be documented at pre-sentation or within 7 days of starting plasma exchange. Laboratorydata captured at presentation included hemoglobin, platelet count,LDH, ADAMTS13 activity, ADAMTS13 inhibitor and serum creatinine.(ADAMTS13 measurements were performed at the Blood Center ofWisconsin, using the FRETS assay). In addition, the platelet count andLDH levels were measured daily. ADAMTS13 was included in the anal-ysis only if performed prior to the initiation of plasma exchange. Thepatient cohort was followed until death, loss to follow up, or the date ofdata collection. Sixteen patients were lost to follow up.

Statistical analysis

All variables were examined for associations with the outcomesbeing studied. Only data from a first episode of TTP was included inthe analysis. Categorical variables were compared by the Pearson chi-squared or Fisher exact test. Analysis of continuous variables was per-formed by the t-test and Wilcoxon signed rank test for symmetricallydistributed and skewed variables respectively. Data was initially exam-ined by univariate analysis. To predict mortality rate, a multivariate pre-diction model including associations which reached a significance ofP< 0.1 was utilized and the model was internally validated by Boot-strap sampling (n 5 1,000) with an optimism of 2.4% [21] Statisticalanalyses were performed using R (www.r-project.org). A P value of0.05 was considered significant for all analyses.

ResultsOne hundred patients met the inclusion criteria for this

study. Table I shows the clinical characteristics and out-comes of the cohort. Ages ranged from 16 to 79 years(median 49 years) with 73% females. Fifty percent of thepatients were Caucasian, 45% African American, and 2%Hispanic. Sixty-seven percent of cases occurred withoutpredisposing conditions (idiopathic TTP), while 12% wereassociated with autoimmune disease (six with SLE, twowith rheumatoid arthritis, one with SLE and rheumatoid ar-thritis, and one each with Sjogren’s syndrome, dermato-myositis, and mixed connective tissue disorder), 6% withpregnancy, 2% with the postpartum state, 6% each withcancer or solid organ transplantation (four kidney trans-plants, two liver transplants), and 2% each with bone mar-row or stem cell transplant. ADAMTS13 was tested in 57patients before starting plasma exchange; 36 (63%) hadsevere ADAMTS13 deficiency (ADAMTS13 activity< 5%).ADAMTS13 activity in the remaining 21 patients (37%)

ranged from 8% to 56%. Of the 36 patients with severeADAMTS13 deficiency, 27 (75%) had ADAMTS13 inhibitorlevels ranging from 1.0 to 25.0 inhibitory units (referencerange <0.5 inhibitory units). Four of the remaining 9patients had detectable anti-ADAMTS13 IgG by ELISA.

All patients were treated with plasma exchange, and 83received corticosteroids. Eighty-four percent of patientsresponded to plasma exchange therapy. Some receivedadditional therapies including vincristine (n 5 10), rituximab(n 5 15), and splenectomy (n 5 7) in the setting of refrac-tory disease or relapse. Mortality after the first episode ofTTP was 9%, while 13% of patients had exacerbations and18% had relapses (11 patients had a single relapse, 6patients had 2 relapses, and 1 had three relapses).Clinical correlates and outcomes of patients with andwithout severe ADAMTS13 deficiency

The clinical features and outcomes of patients with andwithout severe ADAMTS13 deficiency (ADAMTS13activity<5%) are summarized in Table II. Patients withsevere ADAMTS13 deficiency had heterogeneous clinicalpresentations that were not different from patients withADAMTS13>5% (Fig. 1). There were also no significantdifferences in the levels of hemoglobin, platelets, or LDH inpatients with or without severe ADAMTS13 deficiency. Themean serum creatinine level, however, was significantlyhigher in patients without severe ADAMTS13 deficiency(3.23 vs. 1.94, P 5 0.039). Survival and relapse rates did

TABLE I. Presenting Features and Clinical Outcomes of Patients with TTP

VariableNumber (n 5 100)

or mean 6 SD

Age>60 15Female sex 73Ethnicity

Caucasian 50

African American 46Hispanic 2Other 2

Clinical CategoryAutoimmune disease 12Solid transplant recipient 6Stem cell transplant 2Systemic malignancy 6Pregnancy/postpartum 8

Drug related 16Idiopathic 67

Fever 29Neurological symptomsa

Seizures 9Focal neurological deficits 33Obtundation 16No severe neurological symptoms 54

Laboratory studies

Hemoglobin (g/dl) (11.5–15.5 g/dl) 8.29 6 1.84Platelet count (x 109 /L) (1.5–4.0 3 109 /L) 10.88 6 5.62Serum creatinine (mg/dl) (0.7–1.4 mg/dl) 2.33 6 2.28Lactate Dehydrogenase (IU/ml) (100–220 IU/ml) 1,338 6 945ADAMTS13 (%) (n 5 57) 36 (63%)

OutcomesResponse 84Plasma exchanges needed for remission 12.2 (range: 3–46)Deathb 9

Exacerbation 13Relapse 18Need for hemodialysis during acute episode 19Chronic kidney diseasec 16End-stage kidney diseasec 12

a Only seizures, focal deficits and obtundation were included in the analysessince the assessment of minor neurological symptoms such as headache issubjective 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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not differ between patients with ADAMTS13 activity belowor above 5%.

Of the 21 patients without severe ADAMTS13 deficiency,9 had secondary TTP while 12 had idiopathic TTP. Patientswithout severe ADAMTS13 deficiency had worse renal out-comes with significantly higher rates of acute renal failurerequiring dialysis (RR: 2.89, 95% CI: 1.66–5.05, P 5 0.03),progression to chronic renal insufficiency (RR: 2.86, 95%CI: 1.37–5.96, P 5 0.028), and end-stage renal disease(RR: 3.118, 95% CI: 2.107–4.61, P 5 0.015) at 2 years.

Associations with mortalityOn univariate analysis, increasing age, hematopoietic

stem cell transplant, severe neurological deficits such asobtundation, and persistently elevated LDH after two ormore plasma exchange procedures were associated withincreased mortality (Table III). The absence of neurologicalsymptoms was associated with lower mortality (P 5 0.011).When analyzed in a multivariate model, age and severeneurological impairment (obtundation) remained significantpredictors of mortality (Fig. 2). The mean age difference

between survivors and non-survivors was 10.43 6 5 years;the relative risk (RR) of death was significantly increased inthose above age 60 [RR: 7.08 (2.15–23.39, P 5 0.002)].Non-survivors more frequently displayed severe neurologi-cal symptoms such as obtundation [RR: 18.37 (4.19–80.13,P< 0.001)]. A multivariate model predicted that mortality inthe case of age> 60 years, obtundation at presentation, orboth was 10%, 28%, and 78%, respectively. We internallyvalidated this model by bootstrapping (Fig. 3), whichyielded a mean error of 0.018. Even when the analysis waslimited to patients with undetectable ADAMTS13 activity,obtundation (P 5 0.006) and age >60 years (P 5 0.024)remained significant predictors of mortality. Interestingly, inour cohort, common laboratory parameters at presentation,specifically hemoglobin, platelet count, serum creatinine,LDH, and ADAMTS13 activity did not differ between survi-vors and non-survivors, but non-survivors had significantlyhigher LDH levels after two cycles of plasma exchange(1037 6 516 IU/l vs. 625 6 440 IU/l, P 5 0.005). The aver-age fall in LDH after two plasma exchanges was 703 IU/l insurvivors but only 234 IU/l in non-survivors. As noted previ-ously, severe deficiency of ADAMTS13, or the presence ofan ADAMTS13 inhibitor, did not affect mortality or the rateof relapse. We did find, however, that idiopathic TTP wasassociated with a higher incidence of relapses than sec-ondary TTP (P 5 0.023).

DiscussionThis manuscript describes a cohort of 100 patients with

clinically-diagnosed thrombotic thrombocytopenic purpuratreated at the Cleveland Clinic between 2000 and 2012.This is one of the largest cohorts reported from a singleinstitution, which provides reassurance that the care deliv-ered over this time period was relatively consistent and thatclinical and laboratory data on the entire cohort was avail-able for analysis. Moreover, with the exception of 16patients, follow-up data was available on our entire cohort.

Our patient demographic is similar to that reported inother series in terms of age (mean age: 43 6 4.6 years)and sex distribution (73% females) with secondary TTPcomprising 33% of cases. Other series have reported a

TABLE II. Clinical Features and Outcomes of Patients with and Without Severe ADAMTS13 Deficiency (n 5 57)

Variable ADAMTS13<5% (n 5 36) ADAMTS13> 5% (n 5 21) Relative risk (95% CI) Significance

Age >60 4 (11.11) 6 (28.57) 1.88 (0.98–3.62) 0.190Female sex 24 (66.7) 17 (81) 0.603 (0.24–1.52) 0.362Clinical Category

Autoimmune disease 4 (11.1) 4(19.0) 1.44 (0.65–3.18) 0.449Solid transplant 0 (0.0) 2 (9.5) 2.89 (2.01–4.17) 0.132

Stem cell transplant 0 (0.0) 1 (4.8) 1.000Systemic malignancy 2 (5.5) 1 (4.8) 0.9 (0.175–4.629) 1.000Pregnancy/postpartum 2 (5.5) 2 (9.5) 1.25 (0.433–3.61) 1.000Drug related 2 (5.5) 6 (28.6) 2.45 (1.37–4.38) 0.04Idiopathic 28 (77.8) 12 (57.4) 0.57 (0.30–1.09) 0.100

Fever 12 (33.3) 5 (23.8) 0.74 (0.32–1.68) 0.555Neurological symptoms

Seizures 2 (5.5) 1 (4.8) 0.9 (0.18–4.63) 0.696Focal neurodeficits 18 (50) 3 (14.3) 0.27 (1.97–3.98) 0.010

Obtundation 8 (22.2) 4 (19.0) 0.88 (0.37–2.14) 0.528No severe neurological symptoms 15 (41.7) 13 (61.9) 1.68 (0.83–3.34) 0.140

Laboratory studiesHemoglobin (g/dl) (11.5–15.5 g/dl) 8.64 6 1.95 7.88 6 1.55 0.203Platelet count (x109/L) (1.5–4.0 3 109/L) 20.44 6 13.59 30.63 6 24.62 0.223LDH (IU/L) (100–220 IU/ml) 1,386 6 860 1,269 6 925 0.899S. creatinine (mg/dl) (0.7–1.4 mg/dl) 1.94 6 2.21 3.23 6 2.55 0.012

OutcomesDeath 2 (5.6) 2 (9.5) 1.40 (0.49–3.96) 0.620

Exacerbation 4 (11.1) 1 (4.8) 0.52 (0.09–3.10) 0.642Relapse 6 (16.7) 4 (19.0) 1.10 (0.47–2.58) 1.000Need for hemodialysis during acute episode 2 (5.6) 8 (38.1) 2.89 (1.66–5.05) 0.003Chronic kidney disease 2 (5.5) 5 (23.8%) 2.86 (1.37–5.96) 0.028End-stage kidney disease 0 (0) 4 (19.0) 3.12 (2.10–4.61) 0.015

Figure 1. Proportion of patients with and without severe ADAMTS13 deficiencywho presented with the classical clinical features of TTP.

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562 American Journal of Hematology

wide range in the relative prevalence of secondary TTP, forexample, 67% in the Oklahoma TTP-HUS registry [22],23% in the South East England Registry [23], and 40.9% ina Korean registry [24]. This proportion is significantbecause estimates concerning the prognosis of TTP arevulnerable to bias resulting from the percentage of patientswith secondary TTP, who might respond less well toplasma exchange.

Of the 73 female patients, six were in the third trimesterof pregnancy and two in the postpartum state. The diagno-sis of TTP during pregnancy is challenging because it isdifficult to distinguish affected patients from those with pre-eclampsia, eclampsia, or HELLP syndrome, which aremore common. However, the association between preg-nancy and TTP is well established; 13% of women who de-velop TTP do so during pregnancy or postpartum [25].

While the pathophysiology underlying this association isunknown, it may be related to the procoagulant phenotypeof pregnancy with 1.5- to 3-fold increases in fibrinogen, fac-tor VIII, vWF [26], and factor VIIa [27], and/or the progres-sive decrease in ADAMTS13 activity that occurs duringpregnancy. Mannucci et al. [28] showed that the meanADAMTS13 activity decreased from 94% (range: 40–160%) in the first trimester to 64% (range: 22–135%) in thesecond and third trimesters.

Different series have reported mortality rates in TTP thatrange from 4 to 16% [20,29–31]. Only 9% of the patients inour cohort died. This relatively good outcome might beattributed to the slightly lower proportion of patients withsecondary TTP compared to other series. The exacerba-tion and relapse rates in our study were 13 and 18%respectively, lower than the 34–37% reported in other

TABLE III. Associations of Clinical and Laboratory Parameters with Survival

Clinical variable Survivors Non-survivors Relative risk (95% CI) P value

Age> 60 10 (10.98) 5 (55.56) 7.08 (2.15–23.39) 0.002Female sex 69 (75.8) 4 (44.4) 3.38 (0.98–11.66) 0.057Ethnicity

Caucasian 45 (51.7) 5 (55.56) 1.15 (0.33–4.02) 1.000African American

HispanicOther

Clinical categoryAutoimmune disease 11 (12.1) 1 (11.1) 0.92 (0.13–6.70) 1.000Solid transplant recipient 5 (5.5) 1 (11.1) 1.96 (0.29–13.19) 0.441Stem cell transplant 0 (0) 7 (77.8) 14 (6.86–28.57) 0.007Systemic malignancy 6 (6.6) 0 (0) 1.000Pregnancy/postpartum 8 (87.9) 0 (0) 2.63 (0.73–9.43) 1.000Drug related 13 (14.3) 3 (33.3) 0.39 (0.11–1.37) 0.154

Idiopathic 63 (69.2) 4 (44.4) 0.151Fever 26 (28.6) 3 (33.3) 1.22 (0.33–4.57) 0.716Neurological symptoms

Seizures 8 (8.8) 1 (11.1) 1.26 (0.18–8.99) 0.588Focal neurological deficits 31 (34.1) 2 (22.2) 0.58 (0.13–2.64) 0.714Obtundation 9 (9.9) 7 (77.8) 18.38 (4.19–80.53) <0.001No severe neurologic symptoms 53 (58.2) 1 (11.1) 0.10 (0.01–0.82) 0.011

Laboratory studiesHemoglobin (g/dl) 8.27 6 1.27 8.36 6 1.38 0.868

Platelet count (3 109/l) 27 6 9.84 116 6 29.94 0.160Serum creatinine (mg/dl) 2.20 6 2.15 3.17 6 3.18 0.241Lactate Dehydrogenase (IU/l) 1,344 6 963 1,273 6 783 0.803ADAMTS13 activity (%) (n 5 57) 40.1 6 24.98 55.73 (8.68) 0.096

Figure 2. Association of various clinical and laboratory features with mortalityfrom TTP.

Figure 3. Bootstrap validation of a predictive model for mortality includingage>60 years and severe neurological impairment (obtundation) at presentation.

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American Journal of Hematology 563

cohorts [2,3]. Several patients in our series received a rela-tively slow tapering regimen of plasma exchange afterachieving remission (mean plasma exchanges after remis-sion 12, mean duration 30 days) that may have reducedexacerbation and relapse rates during this vulnerable pe-riod, although this hypothesis remains speculative. Thislower rate of relapse may also, in part, be attributable to arelatively short duration of follow up (2 years) in somepatients causing us to miss late relapses.

Increasing age and severe neurological symptoms atpresentation were associated with increased mortality.However, we did not find an association between mortalityand severity of common laboratory abnormalities at presen-tation. This is in contradistinction to other studies thatobserved associations of mortality from TTP with plateletcount [30], severity of anemia, and fever [32].

Another recent study from the French TMA referencecenter reported that increasing age and high LDH at pre-sentation were predictive of mortality, and developed aprognostic model that included these factors [30]. In ourcohort, we did not find an association of survival with theseverity of thrombocytopenia or LDH at presentation. It is,however, important to note that Benhamou et al. [30]included only patients with severe ADAMTS13 deficiencyand thus their results may not be applicable to the entirespectrum of patients with clinically-diagnosed TTP.Although severe ADAMTS13 deficiency has high specificityfor the diagnosis of TTP, its sensitivity is uncertain. Not allpatients with TTP, even apparent idiopathic TTP, areseverely deficient in ADAMTS13 [13,24]. While the patho-genesis of thrombotic microangiopathy in these individualsis uncertain, potentially reflecting abnormalities in VWF,complement activation, endothelial cell damage, or otherfactors, they are generally considered to have TTP andmanaged as such, and thus were included in our series.

Of the 57 patients who had ADAMTS13 activity deter-mined prior to initiating plasma exchange, 36 (63%) hadsevere deficiency (<5%). Our study has a higher propor-tion of patients with severe ADAMTS13 deficiency than the13% observed in the Oklahoma registry [13] and the 30%in the Korean Registry [24] possibly due to more stringentexclusion of patients with other potential causes of throm-botic microangiopathy. Considering only the patients in ourseries that were considered clinically to have idiopathicTTP, 28/40 (70%) had ADAMTS13 activity<5% while only8/17 (47%) of patients with secondary TTP hadADAMTS13 activity <5% (4 with autoimmune disease and4 each with cancer/chemotherapy-related TTP).

Patients with severe ADAMTS13 deficiency had hetero-geneous clinical presentations that did not differ from thoseof patients with >5% ADAMTS13 activity. Moreover,response to plasma exchange, mortality, exacerbation andrelapse rates in our series did not differ between the twogroups, although patients with ADAMTS13 levels >5% hadsignificantly worse renal outcomes. This trend has previ-ously been observed by Vesely et al. [13] who noted a lin-ear inverse relationship between ADAMTS13 activity andchronic renal disease, but did not describe a distinct differ-ence in renal outcomes in patients with ADAMTS13 activityabove or below 5%. Of the 21 patients with detectableADAMTS13 activity, the majority (12) did not have underly-ing secondary causes for TTP. One might argue that atleast some of these patients may have had atypical hemo-lytic uremia syndrome (aHUS), consistent with their poorerrenal outcomes. .

These results indicate that although ADAMTS13 is im-portant in the pathogenesis of TTP, other mechanismssuch as drug-dependent antibodies to endothelial cells andplatelets [33], changes in the hemostatic system that occur

during pregnancy and activation of the complement system[34,35] also influence outcomes. The latter consideration isof significant interest given the high rate of mutations incomplement and complement regulatory proteins in aHUS,the difficulty of distinguishing different forms of thromboticmicroangiopathy clinically, and recent reports demonstrat-ing responses to complement inhibition in apparent idio-pathic TTP [36].

Prompt diagnosis of patients with TTP is critical becauseof the high mortality (>90%) of untreated cases. Plasmaexchange remains the standard of care but carries a signifi-cant risk of adverse events, particularly in patients receiv-ing extended therapy. In a series of 249 consecutivepatients treated with plasma exchange for TTP from 1996to 2008, 63 (26%) patients had 83 major complications and7 (2.8%) died [37]. A common clinical conundrum inpatients with TTP is how long to continue plasma exchangein patients with an inadequate response prior to the initia-tion of secondary therapies such as Rituximab [12] or cy-closporine [4], or other therapies currently in clinical trialsor development. Our studies provide some information thatmay help to categorize patients at greater risk for relapse,especially those with severely deficient ADAMTS13 activity,who may be candidates for consideration of early additionof adjunctive therapy complementary to plasma exchange.

Some limitations need to be considered while interpretingthis study. First, the study is retrospective. Second, minorneurological manifestations were not included in the analy-sis due to challenges in reproducible documentation. Third,only 57 patients had ADAMTS13 activity measured prior toinitiating plasma exchange, either because the patients pre-sented prior to 2003 when the assay became available, orbecause the test was not ordered. This number may be toosmall to detect differences between patients with and with-out severe ADAMTS13 deficiency. Finally, 16 of the 100patients in our series were lost to follow up within two yearsof diagnosis, so their long-term outcomes are not known.

In conclusion, TTP remains a clinical diagnosis whoseearly recognition can dramatically improve outcomes. Inthis series, we observed that increasing age, severe neuro-logical impairment and persistent elevation of LDH after theinitiation of plasma exchange predict mortality, whileADAMTS13 activity >5% is an independent predictor ofpoor renal outcomes. Ultimately, validation of these findingsin a prospective study should be pursued. Nevertheless,our findings suggest variables that may be used to identifypatients with the potential for poor outcomes who may ben-efit from early institution of adjunctive therapies, leading toimproved outcomes, and decreased morbidity and cost.

Author ContributionsKM and SC conceived the project. SC and DC performed

the research. SC and LZ performed the statistical analysis.SC and KM wrote the manuscript.

AcknowledgmentsWe would like to recognize the contributions of the clini-

cians who cared for these patients. This work was supportedby NIH grant HL072033 and HL089796 (to KRM).

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research article

American Journal of Hematology 565