Table 1.

Clinical Category	All Patients, 1989-2008 (N = 376)	Patients with ADAMTS13 Activity Measurements at the Time of their Initial Diagnosis with TTP, 1995-2008
		Total (n = 261)	ADAMTS13 Activity
		Total (n = 261)	10% or more (n = 201)	< 10% (n = 60)	< 5%* (n = 49)
	No. of patients (no. of patients who survived)
Stem cell transplantation	23 (6)	10 (1)	9 (1)	1 (0)	0
Pregnant/postpartum	27 (25)	15 (14)	12 (11)	3 (3)	2 (2)
Drug association	49 (41)	35 (32)	35 (32)	0	0
Bloody diarrhea	28 (21)	22 (17)	20 (15)	2 (2)	2 (2)
Additional or alternative disorder
Autoimmune disorder	40 (27)	31 (21)	28 (18)	3 (3)	3 (3)
Systemic infection	30 (8)	22 (7)	18 (5)	4 (2)	1 (1)
Systemic malignancy	13 (2)	10 (2)	9 (2)	1 (0)	0
Malignant hypertension	6 (6)	6 (6)	6 (6)	0	0
Multiorgan failure	11 (3)	11 (3)	11 (3)	0	0
Congenital hemolytic anemia	1 (1)	1 (1)	1 (1)	0	0
Idiopathic	148 (118)	98 (79)	52 (42)	46 (37)	41 (33)
Total	376 (258)	261 (178)	201 (136)	60 (47)	*49 (41)**

Clinical Categories of Patients with an Initial Clinical Diagnosis of TTP, 1989-2008

The 376 patients who were enrolled in the Registry for their first episode of clinically diagnosed TTP are presented according to their clinical categories, with the number of surviving patients in parentheses. In addition, the 261 patients who had ADAMTS13 activity measured at the time of their initial diagnosis are presented separately, including the subgroups of 201 patients whose ADAMTS13 activity was ≥ 10%, the 60 patients whose ADAMTS13 activity was < 10%, and the 49 patients whose ADAMTS13 activity was < 5%.
* Patients with < 5% activity (n = 49) are a subset of patients with < 10% activity (n = 60).

Table 2.

Presenting Features and Clinical Outcomes	ADAMTS13 Activity		P
Presenting Features and Clinical Outcomes	10% or more, n = 201	< 10%, n = 60	P
Demographic Features
Age, y	51 (0.6, 86)	41 (9, 72)	.002
Race, % black	16	35	.001
Sex, % female	63	82	.007
Obesity, BMI, kg/m²	24.7 (13.6, 41.1)	30.3 (15.3, 51.4)	< .001
Presenting Clinical and Laboratory Features
Severe neurologic abnormalities, %	44	50	.435
Hematocrit, %	22 (9, 40)	21 (13, 33)	.130
Platelets, /μL	22 (1, 129)	11 (2, 101)	< .001
LDH, U/L	1090 (114, 12 587)	1407 (256, 3909)	.059
Creatinine, mg/dL	4.6 (0.2, 33)	1.6 (0.7, 6.6)	< .001
Acute renal failure, %	54	10	< .001
Clinical Outcomes
Death, %	32	22	.113
Plasma exchange, no.	8 (0, 71)	19 (2, 79)	< .001
Relapse, %*	4 (5/136)	34 (16/47)	< .001

Relation of Presenting Features and Clinical Outcomes to ADAMTS13 Levels

Relation of demographic, clinical, and laboratory features and clinical outcomes to ADAMTS13 levels. Continuous data are presented as median values with the minimum and maximum values in parentheses. Severe neurologic abnormalities are defined as coma, stroke, seizure, or focal neurologic signs.^[9] Laboratory data are the most abnormal values at the time of diagnosis, defined as the day of the first plasma exchange treatment, ± 7 days to account for transient changes resulting from transfusion or worsening renal failure.^[9] Acute renal failure is defined as either (1) an increasing serum creatinine (≥ 44.5 μmol/L [≥ 0.5 mg/dL] per day for 2 consecutive days) or (2) serum creatinine ≥ 353.6 μmol/L (≥ 4.0 mg/dL) plus dialysis that began within 7 days of diagnosis.^[9] The number of plasma exchange treatments and the percent of patients with relapse were analyzed only in surviving patients.
BMI indicates body mass index; and LDH, lactate dehydrogenase.
*Number in parentheses represents the number of patients who relapsed divided by the number of patients who survived.

Table 3.

Clinical, Demographic Features	Survival		P	Relapse		P
Clinical, Demographic Features	Survived (n = 47)	Died (n = 13)	P	Relapsed (n = 16)	No Relapse (n = 31)	P
Age, y	41	45	.10	42	40	.44
Race, % black	38	23	.51	56	29	.07
Sex, % male	19	15	1.00	38	10	.05
Severe neurologic abnormality, %	47	62	.35	50	45	.75
Hematocrit, %	21	22	.49	21	21	.52
Platelets, /μL	11	10	.96	11	10	.80
LDH, U/L	1373	1776	.82	1395	1373	.80
Creatinine, mg/dL	1.2	2.9	< .01	1.2	1.4	.43
ADAMTS13 inhibitor, % 2 or more BU	30	62	.05	13	39	.09
Plasma exchange, no.				21	14	.12
Years of follow-up				8.7	3.7	< .01

Comparison of Patients with ADAMTS13 Activity < 10% at their Initial Diagnosis

Comparison of patients who survived to patients who died among the 60 patients with ADAMTS13 activity < 10% at the time of their initial diagnosis of TTP, and comparison of patients who relapsed to patients who did not relapse among the 47 survivors. Among 60 patients with ADAMTS13 activity < 10% at the time of their initial diagnosis, the 47 patients who survived are compared with the 13 patients who died. Among the 47 survivors, the 16 patients who have relapsed are compared with the 31 patients who have not relapsed. Continuous data are presented as median values. Severe neurologic abnormalities are defined as coma, stroke, seizure, or focal neurologic signs.^[9] Laboratory data are the most abnormal values at the time of diagnosis, defined as the day of the first plasma exchange treatment, ± 7 days to account for transient changes resulting from transfusion or worsening renal failure. LDH indicates lactate dehydrogenase; BU, Bethesda units/mL.

Table 4.

Patient	ADAMTS13 Activity, Inhibitor	Day	Clinical Course
Death attributed to TTP–thrombotic
1	< 5% (F, IB), >> 2 BU	4	30-year-old BM, no response to 3 PEX and corticosteroids, TTP documented by autopsy
2	< 5% (F, IB), >> 2 BU	17	51-year-old WF, response to 7 PEX, died 10 days after PEX stopped from pulmonary emboli^[31]
3	23% (F), 7% (IB), no inhibitor	8	68-year-old WF, cardiac arrest with coma 4 days after cardiac surgery. Platelet count response to 5 PEX, then DNR; died 3 days after PEX stopped.
4	< 5% (F), 18% (IB), inhibitor not tested	1	50-year-old WF, died before PEX begun,^[31] TTP documented by autopsy
5	< 5% (F, IB), > 2 BU	1	37-year-old BF, died after 1st PEX,^[21] TTP documented by autopsy
6	7% (F), < 5% (IB), >> 2 BU	72	70-year-old WF, 4 responses to 45 PEX, corticosteroids, rituximab; none sustained, then DNR. Died 10 days after PEX stopped.
Death attributed to TTP–PEX complications
7	< 5% (F, IB), >> 2 BU	16	41-year-old BF, urine cocaine +, comatose, no response to 12 PEX and corticosteroids, death from sepsis attributed to CVC^[31,32]
8	< 5% (F, IB), > 2 BU	16	25-year-old WF, response to 14 PEX, exacerbation required new CVC, death from hemorrhage caused by CVC insertion^[31,32]
9	< 5% (F, IB), >> 2 BU	26	68-year-old WF, response to PEX then apparent exacerbation, death from sepsis attributed to CVC^[33]
Death not attributed to TTP
10	9% (F), 20% (IB), 1.3 BU	6	39-year-old WF, hepatitis A, hepatic and renal failure, confusion (bilirubin 24 mg/dL). No response to 3 PEX. Autopsy: hepatic necrosis, no evidence of TTP.
11	28% (F), 8% (IB), 1.2 BU	21	65-year-old WF, hypotension, confusion, Candida pneumonia after liver transplantation. Fibrinogen 53 mg/dL. No response to 7 PEX. Death attributed to sepsis.
12	9% (F), 25% (IB), > 2 BU	34	43-year-old WF, relapsed AML after HSCT. Acute GVHD (bilirubin 64 mg/dL), Aspergillus pneumonia. No response to 18 PEX. Death attributed to sepsis and GVHD.
13	6% (F), 13% (IB), 0.9 BU	11	45-year-old WM, HIV infection, pneumonia. No response to 5 PEX. Autopsy: disseminated Kaposi sarcoma, no evidence of TTP.^[29]

Clinical Features and Causes of Death in Patients with ADAMTS13 Activity < 10%

Clinical features and causes of death of the 13 patients with ADAMTS13 < 10% who died. ADAMTS13 activity was determined by the FRETS-VWF73 (F) and immunoblotting (IB) assays. Day indicates day of death; the day of the first plasma exchange (or day of diagnosis in patient 4) was designated as day 1. Citations are provided when patients have been previously described.
ARDS indicates acute respiratory distress syndrome; AML, acute myeloid leukemia; CVC, central venous catheter; DNR, do not resuscitate; GVHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplantation; F, FRETS-VWF73 assay; IB, immunoblotting assay; BU, Bethesda units/mL; PEX, plasma exchange; TTP, thrombotic thrombocytopenic purpura; BF, black female; BM, black male; WF, white female; and WM, white male.

Table 5.

Patient	Clinical Course
1	64-year-old WF (drug [quinine]–associated category), ADAMTS13 56% (F), 50% (IB). 2nd episode caused by repeat quinine ingestion. ADAMTS13 not measured.
2	17-year-old WF (additional or alternative category [autoimmune]) SLE for 5 years; treatment for 2 years. Initial episode: TTP vs SLE flare. Renal biopsy: thrombotic microangiopathy, class IV lupus nephritis. ADAMTS13 70% (F), 80% (IB). 2nd episode: TTP vs SLE flare, renal failure, malignant hypertension. ADAMTS13 > 100% (F, IB).
3	17-year-old WF (additional or alternative category [autoimmune]) SLE for 3 months; renal biopsy: class IV lupus nephritis; immunosuppressive treatment. Initial episode: TTP vs SLE flare, renal failure, malignant hypertension. ADAMTS13 40% (F), 20% (IB). 2nd episode: Klebsiella, cytomegalovirus sepsis. ADAMTS13 62% (F), 65% (IB).
4	41-year-old BM (idiopathic category), incidental discovery of HIV infection, no signs of immunodeficiency. 1st episode: ADAMTS13 53% (F), 60% (IB). 2nd: not measured. 3rd: 15% (F), 50% (IB), INH 1.4 BU. 4th: < 5% (F), 8% (IB), 0.8 BU. 5th and 6th: < 5% (F, IB), INH 1.1 and 1.4 BU.^[29,30]
5	30-year-old WF (idiopathic category). Initial episode, ADAMTS13 16% (F), 100% (IB), INH 1.9 BU. 2nd episode, 29% (F), 100% (IB), INH 1.3 BU.

Clinical Course of the 5 Patients who had ADAMTS13 10% or more at the time of Their Initial Diagnosis with TTP and who were Diagnosed with a Relapse of TTP

Clinical features are described for the 5 patients whose ADAMTS13 activity was ≥ 10% at the time of their initial diagnosis of TTP and who were also diagnosed as having a relapse of TTP. Clinical categories are indicated in parentheses. ADAMTS13 measurements: F, FRETS-VWF73 assay; IB, immunoblotting assay. Citations are provided when patients have been previously described.
SLE indicates systemic lupus erythematosus; TTP, thrombotic thrombocytopenic purpura; INH, inhibitor titer; WF, white female; and BM, black male.

Table 6.

Patient	Initial Episode of TTP	ADAMTS13 Activity During Remission (%)*				Relapse Before Remission Samples	Relapse After Remission Samples	Rituximab Treatment
Patient	Initial Episode of TTP	2004	2006	2007/2008	2009	Relapse Before Remission Samples	Relapse After Remission Samples	Rituximab Treatment
1	1995	< 5⁴	< 5⁰	—	22	1 (1996)	1 (2009, 32 mo after 2006 sample, 2 mo before 2009 sample)	2009
2	1996	100	—	*	*	1 (1996)	0	0
3	1996	100	100	100	85	0	0	0
4	1996	42	87	—	—	1 (1999)	0	0
5	1997	34	100	100	*	4 (1997-2002)	0	0
6	1998	—	—	100	100	0	0	0
7	1999	100	100	100	*	1 (1999)	0	0
8	1999	66	74	49	45	4 (1999-2000)	0	0
9	1999	—	95	*	*	0	0	0
10	1999	85	24	56	58	4 (2000-2004)	1 (2006, 23 mo after 2004 sample)	0
11	2000	8⁰	10⁴	11⁰	17¹	0	0	0
12	2000	—	—	51	80	0	0	0
13	2000	14⁰	*	*	*	0	1 (2004, 1 mo after sample, died)	0
14	2000	90	60	64	100	1 (2003)	2 (2008, 2009, 12 and 18 months after 2007 sample)	2009
15	2000	—	—	85	99	0	0	0
16	2000	—	100	40	10⁰	2 (2001, 2005)	0	2005
17	2000	12¹	11⁰	*	*	0	2 (2008, 17 and 23 months after sample)	0
18	2001	9⁰	17⁰	< 5⁰	*	0	Sudden death (no autopsy) 6 months after sample	0
19	2001	78	100	100	100	0	0	0
20	2001	100	100	100	100	0	0	0
21	2001	20⁰	12¹	15¹	11¹	0	0	0
22	2001	—	—	—	51	3 (2007, 2008, 2008)	0	2008
23	2001	13⁰	100	100	100	0	0	0
24	2001	57	7¹	5¹	< 5⁴	0	0	0
25	2001	13²	100	100	38	1 (2004, 3 mo before sample)	1 (2006, 25 mo after previous sample, 2 mo before next sample)	2006
26	2002	99	26	41	< 5⁴	0	0	0
27	2003	71	96	82	82	0	0	0
28	2003	—	100	—	100	0	0	2003
29	2004	—	93	92	44	1 (2005)	0	2005
30	2005	—	100	100	100	0	0	2005
31	2005	—	36	39	41	0	0	0
32	2006	—	5¹	91	8¹	0	0	2006
33	2006	—	52	59	100	0	0	2006
34	2006	—	75	70	< 5³ ^†	0	1 (2009, diagnosed at ″remission″ visit)	0
35	2006	—	—	< 5⁴	< 5⁴	0	0	0
36	2006	—	—	100	100	0	0	0
37	2007	—	—	100	100	0	0	0
38	2007	—	—	100	90	0	0	2007
39	2008	—	—	—	92	0	0	0
40	2008	—	—	—	88	0	0	0
41	2008	—	—	—	94	0	0	2008

Individual Clinical Course Data for Patients with ADAMTS13 Activity < 10% at their Initial Diagnosis

Clinical course of patients who had ADAMTS13 < 10% at the time of their initial diagnosis with TTP and who had ADAMTS13 activity measured during remission. Data are presented for the 37 patients who had ADAMTS13 activity < 10% at the time of their initial diagnosis of TTP and who also had ADAMTS13 activity measured during clinical remission, documented by clinical evaluation, platelet count, and hematocrit. ADAMTS13 activity and inhibitor were measured by the FRETS-VWF73 method. Nine patients were treated with rituximab for an acute episode, either initial or relapse, in the years indicated. One patient was treated for an acquired factor VIII inhibitor 11 months after her relapse in 2005 (patient 28).
ADAMTS13 inhibitor levels are indicated by superscript numbers: 0 indicates no inhibitor; 1 indicates > 0 to < 1 BU/mL; 2 indicates 1 to < 2 BU/mL; 3 indicates 2 to > 2 BU/mL; and 4 indicates >> 2 BU/mL. — indicates that the patient was not available for the evaluation.
*The patient had died before the planned measurements were performed.
^†Diagnosed with a relapsed acute episode by thrombocytopenia and microangiopathic hemolytic anemia, in spite of being asymptomatic, when she was seen for this scheduled elective evaluation.

Table 7.

	Relapse After Remission Sample	No Relapse After Remission Sample
ADAMTS13 Activity During Remission	(n = 7)	(n = 33)
1 or more samples < 10%	1 (14%)	5 (15%)
1 or more samples 10% to 20%	3 (43%)	3 (9%)
1 or more samples 21% to 49%	1 (14%)	5 (15%)
All samples 50% or more	2 (29%)	20 (61%)
ADAMTS13 Inhibitor During Remission	Inhibitor Measured (n = 4)	Inhibitor Measured (n = 8)
1 or more samples with a strong inhibitor (2 or more BU/mL)	1 (25%)	4 (50%)
1 or more samples with a mild-moderate inhibitor (more than 0 to less than 2)	2 (50%)	2 (25%)
All samples with no inhibitor	1 (25%)	2 (25%)

Group Clinical Course Data for Patients with ADAMTS13 Activity < 10% at their Initial Diagnosis

Data are presented for the 37 patients who had ADAMTS13 activity < 10% at the time of their initial diagnosis of TTP and who also had ADAMTS13 activity measured during clinical remission, documented by clinical evaluation, platelet count, and hematocrit. ADAMTS13 activity and inhibitor were measured by FRETS-VWF73 method. Patient 18 was omitted from this analysis because of the uncertain cause of her death.

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CME

Survival and Relapse in Patients With Thrombotic Thrombocytopenic Purpura

Authors: Johanna A. Kremer Hovinga, MD; Sara K. Vesely, PhD; Deirdra R. Terrell, MPH; Bernhard Lämmle, MD; James N. George, MD
CME Released: 2/26/2010
THIS ACTIVITY HAS EXPIRED
Valid for credit through: 2/26/2011

Start Activity

Target Audience and Goal Statement

This activity is intended for hematologists, primary care physicians, and other physicians who care for patients with thrombotic thrombocytopenic purpura.

The goal of this activity is to identify current rates of survival and relapse of thrombotic thrombocytopenic purpura as well as variables that affect these outcomes.

Upon completion of this activity, participants will be able to:

Describe patterns in ADAMTS13 activity among patients with a history of thrombotic thrombocytopenic purpura (TTP)
List characteristics associated with deficient ADAMTS13 activity
Describe mortality trends in patients with TTP
Describe risk factors for and prognosis of relapse of TTP

Disclosures

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CME Author(s)

Charles P. Vega, MD

Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine

Disclosures

Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

CME Reviewer(s)

Sarah Fleischman

CME Program Manager, Medscape, LLC

Disclosures

Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

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From Blood

CME

Survival and Relapse in Patients With Thrombotic Thrombocytopenic Purpura

Authors: Johanna A. Kremer Hovinga, MD; Sara K. Vesely, PhD; Deirdra R. Terrell, MPH; Bernhard Lämmle, MD; James N. George, MDFaculty and Disclosures

THIS ACTIVITY HAS EXPIRED

CME Released: 2/26/2010

Valid for credit through: 2/26/2011

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Abstract and Introduction

Abstract

Survival of patients with thrombotic thrombocytopenic purpura (TTP) improved dramatically with plasma exchange treatment, revealing risk for relapse. The Oklahoma TTP Registry is a population-based inception cohort of all 376 consecutive patients with an initial episode of clinically diagnosed TTP (defined as microangiopathic hemolytic anemia and thrombocytopenia with or without signs and symptoms of ischemic organ dysfunctions) for whom plasma exchange was requested, 1989 to 2008. Survival was not different between the first and second 10-year periods for all patients (68% and 69%, P = .83) and for patients with idiopathic TTP (83% and 77%, P = .33). ADAMTS13 activity was measured in 261 (93%) of 282 patients since 1995. Survival was not different between patients with ADAMTS13 activity < 10% (47 of 60, 78%) and patients with 10% or more (136 of 201, 68%, P = .11). Among patients with ADAMTS13 activity < 10%, an inhibitor titer of 2 or more Bethesda units/mL was associated with lower survival (P = .05). Relapse rate was greater among survivors with ADAMTS13 activity < 10% (16 of 47, 34%; estimated risk for relapse at 7.5 years, 41%) than among survivors with ADAMTS13 activity of 10% or more (5 of 136, 4%; P < .001). In 41 (93%) of 44 survivors, ADAMTS13 deficiency during remission was not clearly related to subsequent relapse.

Introduction

The introduction of plasma exchange treatment (PEX) dramatically increased the survival of patients with thrombotic thrombocytopenic purpura (TTP). Before the plasma exchange era, only 10% of patients survived^[1]; initial reports of PEX, 1981 to 1991, described survival rates of 70% to 79%.^[2-4] The availability of effective treatment decreased the stringency of criteria required for diagnosis of TTP. Before the plasma exchange era, the characteristic clinical features (anemia, thrombocytopenia, neurologic and renal abnormalities, fever) occurred in 88% to 98% of patients.^[1] For patients in the clinical trial that documented superiority of PEX compared with plasma infusion, only microangiopathic hemolytic anemia and thrombocytopenia without another apparent etiology were required for the diagnosis of TTP; the frequency of each of the other 3 abnormalities decreased to 24% to 63%.^[4] Availability of effective treatment and decreased diagnostic stringency increased the frequency of patients treated for TTP by 7-fold^[5] and may also have increased the heterogeneity of patients diagnosed with TTP.

The discovery of severe ADAMTS13 deficiency as part of the pathogenesis of TTP^[6,7] provided an opportunity for a more specific diagnosis. However, patient heterogeneity has persisted.^[8-11] Patients are described as having idiopathic TTP if they have no apparent other condition that may cause thrombotic microangiopathy; they commonly have severe ADAMTS13 deficiency and they have a higher survival rate.^[9,10] Patients are described as having secondary TTP if other conditions are identified that may cause thrombotic microangiopathy, such as hematopoietic stem cell transplantation (HSCT), pregnancy, drug association, other autoimmune diseases, HIV infection, and cancer; they rarely have severe ADAMTS13 deficiency and they have poor survival.^[9,10] The improved survival rates in recent reports of patients with severe ADAMTS13 deficiency, 82% to 100%,^[10,12-15] compared with the initial reports of patients treated with PEX,^[2-4] may reflect patient selection rather than more effective management.

Soon after the availability of PEX, relapse rates of 37%^[3] and 36%^[16] were reported. Recent studies have reported that severe ADAMTS13 deficiency at the time of the initial episode predicts a risk for relapse^{[9,10,12,13,15,17]} and have suggested that severe ADAMTS13 deficiency during remission may also predict risk for relapse.^[15,17,18]

We report the experience of the Oklahoma TTP Registry, a 20-year population-based inception cohort of all 398 consecutive patients in our 58 county region for whom PEX was requested for a diagnosis of TTP or hemolytic uremic syndrome (HUS), to address questions concerning survival and relapse: (1) What clinical and laboratory features predict survival? (2) Have survival rates changed across the past 20 years? (3) What is the risk for relapse? (4) Who is at risk for relapse? (5) When do relapses occur?

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Methods

CME Information

Abstract and Introduction
Methods
Results
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References

Faculty and Disclosures

CME Author(s)

Charles P. Vega, MD

CME Reviewer(s)

Sarah Fleischman

CME

Survival and Relapse in Patients With Thrombotic Thrombocytopenic Purpura

Target Audience and Goal Statement

Disclosures

CME Author(s)

Charles P. Vega, MD

CME Reviewer(s)

Sarah Fleischman

Accreditation Statements

For Physicians

Instructions for Participation and Credit

Survival and Relapse in Patients With Thrombotic Thrombocytopenic Purpura

Abstract and Introduction

Abstract

Introduction

Table of Contents