ADAMS-TS13 Inhibitor Level and Risk of Relapse in Acquired Idiopathic Thrombotic Thrombocytopenic Purpura

Abstract Introduction: Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy due to reduced activity of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, 13). This disorder can be due to a congenital deficiency state or be acquired (immune TTP (iTTP)) due to an antibody which either inhibits or causes clearance of ADAMTS13. The aim of our study was to determine whether ADAMTS13 inhibitor titer at initial presentation could serve as a predictor of refractory disease and relapse in iTTP. We also measured clinical outcomes across different gender and racial subgroups. Methods: The United States Thrombotic Microangiopathy (USTMA) iTTP registry was used to extract patient information for two academic institutions in Eastern North Carolina. Descriptive statistics were used to analyze the data. The first iTTP episode recorded in the data base was used as the index episode. All patients included in the final analysis had an ADAMTS13 activity of <10%. An inhibitor level of 5 Bethesda units was arbitrarily chosen as the cutoff between low (<5) and high (>/5) inhibitor level. Response time was defined as the number of days of plasma exchange (PEX) required to achieve a platelet count of 150,000 for two consecutive days. Relapse was defined as occurrence of a new episode of iTTP 30 days after achievement of response. Refractory disease was defined as persistence of thrombocytopenia or absence of a sustained platelet count increment or platelet counts of < 50,000 despite 4-7 days of plasma exchanges and steroid treatment. Rituximab resistance was defined as lack of platelet recovery to more than 150,000 within 11 to 14 days of administration of the first dose of Rituximab. Results: A total of 161 patients with iTTP were identified. Ten patients had ADAMTS13 activity >10% and 15 patients did not have a reported inhibitor level. These subjects were not included in the final analysis. The cohort had 28% male (n =38/136) and 72% (n=98/136) female patients. There were more African American patients 73% (n=99/136) than Caucasians 24% (n=32/136). There were also 2 Hispanic, 1 Native American and 2 patients with unidentified race. Median ADAMTS3 inhibitor titer was 1.05 (Range 0-87). Forty three patients with ADAMTS13 activity <10 % had an inhibitor level of 0 (i.e undetectable).They were included in the low inhibitor group. Overall, 88% patients (n=120/136) had low inhibitor level and only 12% (n=16/136) had a high inhibitor. Thirteen percent females (n=13/98) and 8% (n=3/38) males had a high inhibitor level (p=0.387). Fourteen percent (n=14/99) African Americans and 6 % (n=2/32) Caucasians had a high inhibitor, p=0.23. In the low inhibitor group 30% (n=36/120) patients suffered at least one episode of relapse whereas 31% (n=5/16) had relapsed in the high inhibitor group. The median time to response was 6 days (range 1-76) in the low inhibitor group and 7 days (range 4-20) in the high inhibitor group (p=0.61). While looking at the various subgroups, median time to response for males was 6 days (range 4-21), females 6 days (range 1-76) , African Americans 6 days (range 3-29) , and Caucasians 6 days (range 1-76). The frequency of refractory disease was 31 % (n=5/16) in the high inhibitor group and 29% (n=34/119) in the low inhibitor group. At the time of enrollment in the registry, Rituximab was not a part of first line therapy. Only 26 out of 136 patients had received Rituximab. In the low inhibitor group 5 patients displayed Rituximab resistance whereas there were no patients in the high inhibitor group with Rituximab resistance. Conclusion: When evaluating patients presenting with iTTP in two centers in North Carolina, no correlation was found between a high inhibitor levels of >/ 5 Bethesda units and risk of relapse or refractory disease. A larger study is needed to evaluate this further. Disclosures No relevant conflicts of interest to declare.

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Haemolytic uraemic syndrome

Oxford Textbook of Medicine ◽

10.1093/med/9780198746690.003.0496 ◽

2020 ◽

pp. 5027-5032

Author(s):

Edwin K.S. Wong ◽

David Kavanagh

Keyword(s):

Escherichia Coli ◽

Acute Kidney Injury ◽

Complement System ◽

Shiga Toxin ◽

Thrombotic Microangiopathy ◽

Initial Treatment ◽

Haemolytic Uraemic Syndrome ◽

Kidney Injury ◽

Adamts13 Activity ◽

Thrombocytopenic Purpura

Haemolytic uraemic syndrome (HUS) is a thrombotic microangiopathy characterized by the triad of thrombocytopenia, microangiopathic haemolytic anaemia, and acute kidney injury. It is most often caused by Shiga toxin-producing Escherichia coli (STEC-HUS), and any HUS not caused by this is often termed atypical HUS (aHUS). aHUS may be caused by an underlying complement system abnormality (primary aHUS) or by a range of precipitating events, such as infections or drugs (secondary aHUS). Management of STEC-HUS is supportive. In aHUS, plasma exchange is the initial treatment of choice until ADAMTS13 activity is available to exclude thrombotic thrombocytopenic purpura as a diagnosis. Once this has been done, eculizumab should be instigated as soon as possible.

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N-Acetylcysteine Treatment in Two Patients with Relapsed Thrombotic Thrombocytopenic Purpura Increased ADAMTS13 Activity, Free Thiol Concentration in Plasma, and Inhibited Platelet Activation

Blood ◽

10.1182/blood.v126.23.239.239 ◽

2015 ◽

Vol 126 (23) ◽

pp. 239-239

Author(s):

Junmei Chen ◽

Tahsin Özpolat ◽

Colette Norby ◽

Jennie Le ◽

Minhua Ling ◽

...

Keyword(s):

Platelet Count ◽

Plasma Exchange ◽

Platelet Activation ◽

Research Funding ◽

Specific Activity ◽

High Dose ◽

Adamts13 Activity ◽

Thrombocytopenic Purpura ◽

Platelet Counts ◽

Free Thiol

Abstract Introduction: Thrombotic thrombocytopenic purpura (TTP) is a catastrophic and potentially fatal disorder caused by systemic microvascular thrombosis due to von Willebrand factor (VWF)-platelet thrombi. TTP is caused by congenital or acquired deficiency of the plasma metalloprotease ADAMTS13. Based on an earlier study (Chen J et al., J Clin Invest 2011, 121:593-603), we proposed N-acetylcysteine (NAC) as an adjunct treatment for TTP. This study showed that NAC reduced the size and activity of VWF in vitro in human plasma and in vivo in a TTP mouse model. In 2013 and 2014, two case reports described treatment of refractory TTP patients with NAC, one receiving a low dose of NAC [300 mg/kg (total 15 g) for the 1st 24 hrs, followed by 2.5 g/day for two weeks concurrently with plasma exchange] (Shortt J et al., N Engl J Med 2013, 368: 90-92; Shortt J et al., Transfusion 2014, 54:2362-2363) and the other receiving high-dose NAC [300 mg/kg/day (11 g/day) for 10 days between plasma exchanges] (Li GW et al. Transfusion 2014, 54: 1221-1224). The patient treated with high-dose NAC improved rapidly (the patient woke up from coma 18 hr after NAC treatment was initiated), but the patient treated with lower dose NAC did not appear to respond. Thus, it is as yet unclear whether NAC is an effective treatment for TTP. Therefore, more clinical studies and detailed analyses are required to examine the effects of NAC in TTP patients. Here we report the results of clinical and biochemical studies on two patients with relapsed TTP treated with NAC. Before, during, and after NAC treatment, we determined the concentrations of NAC, cysteine, and glutathione in plasma; VWF concentration, multimer structure, and functions; ADAMTS13 concentration and activity; and platelet counts and activation status (P-selectin expression and phosphatidylserine exposure). Methods: Two females with a history of prior episodes of TTP presented with acute TTP [ADAMTS13 < 10%, positive for ADAMTS13 inhibitors, platelet count ≤ 10,000/uL, lactate dehydrogenase (LDH) > 600 IU/L] and both were treated with NAC per IRB-approved protocol [150 mg/kg bolus over 1 hr and 150 mg/kg as continuous infusion until the next therapeutic plasma exchange (TPE)]. They received daily TPE until their platelet counts normalized, and intravenous NAC during days 2-5. Blood was collected daily for 8 days for research assays. ADAMTS13 concentrations in patient plasma were measured by ELISA. ADAMTS13 activity was measured using HRP-conjugated A2 peptide substrate (Wu J-J et al. J Thromb Haemost 2006, 4:129-136). Concentrations of NAC, total cysteine, and total free thiols (free thiol cysteine and free thiol NAC) in plasma were determined by mass spectrometry. Plasma VWF multimer patterns were analyzed by 1.5% agarose gel electrophoresis followed by western blotting with an HRP-conjugated polyclonal VWF antibody. Platelets in whole blood were labeled for platelet markers (CD41a or CD42b) together with one of the activation markers, P-selectin or phosphatidylserine (lactadherin). The labeled platelets were analyzed by flow cytometry. Results: Platelet counts in both patients started to increase 1 day after NAC infusion and continued to increase after discontinuation of NAC and TPE. After NAC infusion, the free thiol concentration (NAC and cysteine) in plasma increased 4 and 59 fold in patients 1 and 2, respectively. This was accompanied by increasing ADAMTS13 specific activity (ADAMTS13 activity/ADAMTS13 antigen). In patient 1, the specific activity increased from 127% (prior to NAC infusion but after TPE) to 270% during NAC infusion; in patient 2, the specific activity increased from 56% to 86%. In patient 1, the VWF multimer size decreased during NAC treatment and the VWF multimers migrated slightly faster. NAC also appeared to inhibit platelet activation. Before NAC infusion, the platelets in both patients were positive for phosphatidylserine (PS, > 30%) and P-selectin (> 15%), compared to 2% and 5%, respectively, in a normal control. The percentages of PS- and P-selectin-positive platelets decreased to less than 18% and 10% respectively, during NAC treatment. Summary: NAC treatment of two patients with TTP in conjunction with TPE was well tolerated and associated with recovery of platelet count and LDH, increased ADAMTS13 specific activity and total free thiol concentration in plasma, reduced platelet activation, and decreased VWF multimer size in one patient. Disclosures Konkle: CSL Behring: Consultancy; Pfizer: Consultancy; Baxalta: Consultancy, Research Funding; Biogen: Consultancy, Research Funding; Octapharma: Research Funding; Novo Nordisk: Consultancy.

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Identification of ADAMTS13 Peptide Sequences Recognized by Autoantibodies in Patients with Acquired Thrombotic Thrombocytopenic Purpura.

Blood ◽

10.1182/blood.v112.11.2286.2286 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2286-2286

Author(s):

Yusuke Yamaguchi ◽

Takanori Moriki ◽

Hideo Wada ◽

Masanori Matsumoto ◽

Yoshihiro Fujimura ◽

...

Keyword(s):

Thrombotic Thrombocytopenic Purpura ◽

Peptide Sequence ◽

Adamts13 Activity ◽

Lambda Phage ◽

Thrombocytopenic Purpura ◽

C Terminus ◽

Epitope Sequence ◽

Von Willebrand ◽

The Impact ◽

Inhibitor Titer

Abstract Anti-ADAMTS13 autoantibodies are considered to play pivotal roles in the pathophysiology of acquired thrombotic thrombocytopenic purpura (TTP). They inhibit the ADAMTS13 function resulting in the appearance of ultra-large von Willebrand factor (VWF) multimers. Major binding sites of the autoantibodies were reported to be in the cysteine-rich/spacer domains. To clarify the precise peptide sequences recognized by anti-ADAMTS13 IgG autoantibodies, we constructed a random cDNA fragment library expressing various peptides of ADAMTS13 on the surface of lambda phage and screened the library using purified IgG from 13 TTP patients. Diverse peptide sequences were obtained from almost entire ADAMTS13 domains such as metalloprotease, disintegrin, TSP1-1, cysteine-rich, spacer, TSP1- 2, 3, 4, 5, 7, 8 and CUB1. In particular, we detected an identical 26 amino-acid epitope sequence in the C-terminus of spacer domain from Gly662 to Val687 (sp662–687) shared by 5 TTP patients. Moreover, the peptide sequence was exactly included in one of the VWF binding epitope sites that we previously determined (Blood110 (11), 795a, 2007). We then assessed the impact of specific autoantibody to ADAMTS13 activity measured by FRETS-VWF73 or EIA and ADAMTS13 inhibitor titer in each of TTP patient plasma. However, both of the ADAMTS13 activity and inhibitor titer seemed not correlated with the existence of specific sp662–687 IgG autoantibody. These observations suggest that the autoantibody to sp662–687 may be one specific feature of TTP, although other epitopes are also involved in the pathogenesis of the disorder.

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First-Line Rituximab Efficacy and Safety in Patients with Acquired Idiopathic Thrombotic Thrombocytopenic Purpura Experiencing a Non Optimal Response to Therapeutical Plasma Exchange: Results of a Prospective Multicenter Phase 2 Study From the French Reference Center for the Management of Thrombotic Microangiopathies.

Blood ◽

10.1182/blood.v114.22.890.890 ◽

2009 ◽

Vol 114 (22) ◽

pp. 890-890

Author(s):

Antoine Froissart ◽

Marc Buffet ◽

Agnes Veyradier ◽

Pascale Poullin ◽

François Provot ◽

...

Keyword(s):

Platelet Count ◽

Peripheral Blood ◽

Refractory Disease ◽

Phase 2 ◽

Adamts13 Activity ◽

Efficacy And Safety ◽

Optimal Response ◽

The Mean ◽

Count Recovery

Abstract Abstract 890 Background: Acquired idiopathic thrombotic thrombocytopenic purpura (TTP) is a rare form of thrombotic microangiopathy (TMA) resulting from an autoantibody-mediated defect in the von Willebrand factor-cleaving protease ADAMTS13. Therapeutical monoclonal antibodies directed against B-lymphocytes (rituximab) provided interesting results on preliminary studies. Objectives: We assessed rituximab efficacy and safety in adult patients with acquired idiopathic TTP who experienced a non optimal response to daily TPE, as defined by a refractory disease at day 5 or a flare-up of the disease within the first 15 days of standard intensive TPE treatment. Design: We conducted a prospective multicenter open-label single arm phase 2 trial. Patients with a non optimal response received 4 rituximab infusions at days 1, 4, 8 and 15, along with daily TPE continuation (R+ group). Peripheral blood B-lymphocyte count was evaluated before each rituximab administration, and then at 3, 6, 9 and 12 months. Outcome from the first TPE session was compared to this of 57 historical patients (R- group) treated by TPE alone (36 cases) or associated with vincristine (21 cases) for the same indication. ADAMTS13 activity was assessed at 3, 6, 9 and 12 months in both groups. Results: Both groups had comparable features on admission. Twenty-two patients were included to receive rituximab. All received 4 rituximab infusions. One patient died in a context of refractory disease, whereas the 21 others achieved durable remission. The median time to durable platelet count recovery was 20 days (extremes: 14-33), which required a median plasma volume of 950 mL/kg (extremes: 310-1940). The median time from the first rituximab infusion to durable platelet count recovery was 10 days (extremes: 5-27). All patients recovered platelet count before day-35. No relapse was observed during the first year. However, 3 (14.3%) patients relapsed after a mean follow-up of 21.2±13.8 months. In R- group, 4 patients died beyond day-5. The mean time to platelet count recovery and the mean plasma volume required to achieve remission did not significantly differ between survivors in R+ and R- groups (p=0.28 and 0.67, respectively). However, 13 (21.6%) patients of R- group were still thrombocytopenic at day-35 (p=0.01). Rituximab allowed a profound and sustained peripheral blood B-cell depletion as early as day day-4 despite associated daily plasmapheresis. Peripheral blood B-cells were undetectable from day-8 to the 6th or 9th month, and recovered at 1 year. Consistently, ADAMTS13 activity was significantly higher at 3, 6 and 9 months in R+ patients (85% [0-150], 90% [42-150], and 89% [92-125], respectively) when compared to R- patients (49% [0-150], 54% [0-130] and 40% [0-90], respectively, p<0.01, <0.05 and <0.001, respectively), which correlated with significantly lower levels of serum anti-ADAMTS13 antibodies (16 [0-77], 8 [0-18] and 10 [0-25] U/L, respectively, in R+ group and 44 [7-100], 33 [12-100] and 34 [10-130] U/L, respectively, in R- group; p=0.003, 0.007 and 0.04, respectively). However, these differences vanished at 12 months. Neither patient experienced side effects related to rituximab during infusions. No patient developed hypogammaglobulinemia. No significant infectious complications occurred during follow-up. Conclusion: In patients with acquired idiopathic TTP, rituximab allows to shorten treatment duration in slow responders and prevents 1-year relapses by allowing a higher increase in ADAMTS13 activity. However, rituximab does not prevent long term relapses. Whether rituximab should be introduced systematically on diagnosis or only in patients identified as being slow responders with standard treatment remains a matter of debate which should be accurately assessed through larger, randomized trials. Disclosures: No relevant conflicts of interest to declare.

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Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura

Blood ◽

10.1182/blood-2003-11-4035 ◽

2004 ◽

Vol 103 (11) ◽

pp. 4043-4049 ◽

Cited By ~ 318

Author(s):

X. Long Zheng ◽

Richard M. Kaufman ◽

Lawrence T. Goodnough ◽

J. Evan Sadler

Keyword(s):

Plasma Exchange ◽

Thrombotic Thrombocytopenic Purpura ◽

High Titer ◽

Patient Treatment ◽

Adamts13 Activity ◽

Thrombocytopenic Purpura ◽

Hematopoietic Stem ◽

Complete Clinical Remission ◽

Inhibitor Level

Abstract Therapeutic plasma exchange is an effective empiric treatment for thrombotic thrombocytopenic purpura (TTP), but how therapy affects the level of adisintegrin and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) or inhibitor has not been reported in many patients. We prospectively analyzed ADAMTS13 activity and inhibitor levels in 37 adults with TTP. ADAMTS13 level at presentation was lower than 5% in 16 of 20 patients with idiopathic TTP and in none of 17 patients with TTP associated with hematopoietic stem cell transplantation, cancer, drugs, or pregnancy (P < .00001). Seven of the 16 patients with ADAMTS13 activity lower than 5% (≈ 44%) had inhibitors. For 8 patients followed serially with ADAMTS13 activity lower than 5% but no inhibitor at presentation, plasma exchange led to complete clinical remission and a rise in ADAMTS13 level. In contrast, 4 patients with low ADAMTS13 activity but high-titer inhibitor (> 5 units/mL) had neither a rise in ADAMTS13 activity nor a reduction in the inhibitor titer: 3 had recurrent disease and 1 died. Among 17 patients with AD-AMTS13 activity at presentation higher than 25%, 10 died. Mortality rate for idiopathic TTP was 15%, whereas mortality for nonidiopathic TTP was 59% (P < .02). We conclude that assays of ADAMTS13 activity and inhibitors in addition to the clinical categories (idiopathic TTP and nonidiopathic TTP) are predictive of outcome and may be useful to tailor patient treatment.

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Case Report: Two Cases of Pediatric Thrombotic Thrombocytopenic Purpura Treated With Combined Therapy

Frontiers in Pediatrics ◽

10.3389/fped.2021.743206 ◽

2021 ◽

Vol 9 ◽

Author(s):

Costanza Tripiciano ◽

Paola Zangari ◽

Mauro Montanari ◽

Giovanna Leone ◽

Laura Massella ◽

...

Keyword(s):

Platelet Count ◽

Thrombotic Thrombocytopenic Purpura ◽

Combined Therapy ◽

Laboratory Data ◽

Adamts13 Activity ◽

Laboratory Findings ◽

Thrombocytopenic Purpura ◽

Life Threatening ◽

Successful Clinical Outcome ◽

Von Willebrand

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy caused by a severely reduced activity of the von Willebrand factor-cleaving protease ADAMTS13. Over 95% of TTPs are acquired, due to autoantibody inhibitors. In children, acquired TTP is a very rare, life-threatening disease. To date, no consensus exists on the treatment strategy of pediatric TTP. We report the cases of two pediatric patients with a diagnosis of TTP, successfully treated with a combination of various therapeutic approaches. Although the patients complained of different sets of symptoms, laboratory data showed Coombs negative hemolytic anemia, renal impairment, and low platelet count in both cases. The diagnosis of acquired TTP was supported by the PLASMIC score and confirmed by the reduction of the ADAMTS13 activity and the presence of anti-ADAMTS13 antibodies. Intravenous immunoglobulin, corticosteroids, and plasma exchange (PEX) were performed without delay. As soon as available, caplacizumab was added to the therapy, with a prompt normalization of platelet count. Nevertheless, ADAMTS13 activity was persistently low, and anti-ADAMTS13 antibodies level was high; thus, a course of rituximab was administered, with persistent normalization of laboratory findings. No adverse events were observed during the treatment. In our experience, the combined use of PEX, caplacizumab, and immunosuppressive therapy during the acute phase of the disease is safe and may have a significant impact on the prognosis with successful clinical outcome and decrease in life-threatening events.

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Relapse Prediction Model for Immune-Mediated Thrombotic Thrombocytopenic Purpura

Blood ◽

10.1182/blood-2020-142117 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 8-9

Author(s):

Camila Masias ◽

Shangbin Yang ◽

Senthil Sukumar ◽

Alcinda Flowers ◽

Haiwa Wu ◽

...

Keyword(s):

Complement Activation ◽

Research Funding ◽

Factor Model ◽

Factor Models ◽

Preemptive Therapy ◽

Adamts13 Activity ◽

Thrombocytopenic Purpura ◽

Asymptomatic Patients ◽

Immune Mediated ◽

Risk Of Relapse

Background: Immune mediated thrombotic thrombocytopenic purpura (iTTP) is defined by thrombocytopenia and microangiopathic hemolytic anemia caused by severely deficient ADAMTS13 activity (<10%). After resolution of their initial episode, patients remain at risk for relapse. Relapse is most common during the first year, but can occur at any point in their lives. In asymptomatic patients, severely deficient ADAMTS13 activity in remission has been shown to be a risk factor for relapses and can guide consideration of preemptive therapy with Rituximab. However, severely deficient ADAMTS13 activity alone does not uniformly lead to relapse, and patients with non-deficient ADAMTS13 activity in remission may still relapse in the following months. The aim of this study was to develop a multivariable model to identify patients at high risk of relapse, using other biomarkers known to have a role in the pathophysiology of iTTP. Patients/Methods: This analysis utilized samples from patients enrolled in the Ohio State University TMA registry beginning in 2003 until 2014. Patients were followed every 3 months to monitor for relapse and for the development of long-term complications. Clinical data (CBC, chemistry, LDH, ADAMTS13 biomarkers) were obtained on each visit to confirm remission in addition to research samples. Clinical and demographic data in addition to biomarkers of complement activation that were performed on banked samples were used to develop a model to quantify the risk for relapse in the following 3 months. A Lasso logistic regression model (Tibshirani et al 1996) with relapse in the following 3 months as the response variable using the R package glmnet (https://cran.r-project.org/web/packages/glmnet/index.html) was used to identify those variables most predictive of relapse from the 17 studied (Table 1). The data from all subjects were split into training data (75%) and testing data (25%) to develop and subsequently test the performance of the model. The final predictors were then standardized to develop the final model and the program to predict the risk of relapse (%) in the following 3 months. Results: Data from a total of 131 patient encounters from 42 patients in a clinical remission were included in the study to develop the statistical model (Table 2). 31(75.6%) were White and 10 (24.4%) were African American. The average age was 42 (18-69), and 31 (75.6%) were women. The median number of encounters from each patient was 2 (range, 1 to 10). From these 131 encounters, 39 relapses occurred in 20 patients over the next 3 months following their clinic visit. The 39 relapse encounters were compared to the 92 encounters where no relapse occurred to develop the model. The performance of both the 11-factor and 6-factor models are shown in Table 3. Given the comparable data in terms of the AUC, sensitivity and specificity to the 11-factor model to predict relapse, the 6-factor model was judged to be more practical given the fewer number of variables. Both the 11-factor and 6-factor models performed better than the ADAMTS13 activity alone. In this model, the presence of ULVWF multimers, increased levels of LDH, complement activation as measured by C3a (log transformed), a lower ADAMTS13 activity (log transformed), ADAMTS13 antigen (log transformed), and younger age increased the risk for relapse. These variables would be entered into the model with the result being read out as a percent risk for relapse in the following 3 months as described in the hypothetical examples in Table 4. Conclusion: Utilizing a model that includes a combination of biomarkers in asymptomatic patients in remission from iTTP provides more accurate identification of patients at increased risk of relapse in the next 3 months, when compared to using the ADAMTS13 activity alone. This model would allow physicians to initiate preemptive therapy with rituximab to patients at the greatest risk for relapse, and potentially avoiding therapy in patients whose risk may be lower than what would be predicted by the ADAMTS13 activity alone. Disclosures Cataland: Ablynx/Sanofi: Consultancy, Research Funding; Alexion: Consultancy, Research Funding.

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Simultaneous Development of Thrombotic Thrombocytopenic Purpura and Immune Thrombocytopenia in a Pediatric Patient with Systemic Lupus Erythematosus.

Blood ◽

10.1182/blood.v106.11.4017.4017 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4017-4017

Author(s):

Shannon L. Carpenter ◽

Joe Cole

Keyword(s):

Platelet Count ◽

Lupus Erythematosus ◽

Immune Thrombocytopenia ◽

Blood Smear ◽

Peripheral Blood Smear ◽

Adamts13 Activity ◽

Laboratory Examination ◽

Systemic Lupus ◽

Thrombocytopenic Purpura ◽

Hematological Abnormalities

Abstract Patients with systemic lupus erythematosus can experience multiple hematological complications. Autoimmune hemolytic anemia, immune thrombocytopenia (ITP) and thrombotic thrombocytopenic purpura (TTP) have been described in patients with this disease. Hematologic abnormalities may precede joint or renal manifestations of the disease. In TTP, decrease in the level of von Willebrand cleaving protease (ADAMTS13) activity and the presence of an inhibitor to this enzyme have been shown to correlate with disease activity. For the diagnosis of ITP, the presence of platelet antibodies is not required, but they are strongly suggestive of the diagnosis in combination with a falling platelet count. We present a young lady who developed multiple hematological abnormalities simultaneously against a background of well-controlled SLE. WC is a 13 yo female who was diagnosed with SLE after developing lupus nephritis at the age of 12. She was treated successfully with immunosuppression and had been maintained on cyclophosphamide every three months. At a routine clinic visit, a CBC was obtained that showed a hemoglobin of 6.7 g/dL, white blood cells of 7,500/mm3 and platelets of 22,000/mm3. Reticulocyte count was 18.8%. Direct antiglobulin test was negative. The patient complained of fatigue and headache of one week’s duration. The peripheral blood smear showed 7–10 schistocytes per high power field and thrombocytopenia. A complete blood count performed one month prior to this visit showed a hemoglobin of 11.6 gm/dL and a platelet count of 353,000/mm3. The patient underwent plasmapheresis for 5 days for a presumptive diagnosis of TTP. She responded to plasmapheresis with increase in her hemoglobin level to 10.2 gm/dL and platelets to 153,000/mm3. On laboratory examination obtained prior to beginning plasmapheresis therapy, anti-platelet IgM antibody titer was elevated; ADAMTS13 inhibitor was elevated at 0.9 inhibitor units, and ADAMTS13 activity was decreased at 30%. After cessation of plasmapheresis the patient’s platelet count decreased over one week to a nadir of 74,000/mm3. However, the patient’s hemoglobin increased to 11.1 gm/dL over that same time period. Haptoglobin was normal at this time at 142 mg/dL. Lactate dehydrogenase was also normal at 204 U/L. No schistocytes were evident on peripheral blood smear. Therefore, we felt that the patient at this point was experiencing autoimmune destruction of her platelets only, without active TTP. The patient was monitored closely and her platelet count increased to 214,000/mm3 without intervention. She currently has stable blood counts in the normal range. This case is an unusual example of the hematological complications of SLE with the simultaneous development of two abnormalities in one patient. In this situation, presence of anti-platelet antibody and the stability of the patient’s hemoglobin prevented reinitiation of plasmapheresis. The measurement of anti-platelet antibody was obtained as part of the screening laboratory examination for lupus and would not normally have been obtained in a patient with this clinical picture who presented to our clinic. This raises the questions of how often multiple autoantibodies coexist in these complex patients with SLE and whether we should consider examining for them more closely at the time of development of hematological abnormalities or at diagnosis of their rheumatologic disease.

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Impact of Pregnancy On the Course of Immune Thrombocytopenic Purpura: An Observational Study On 44 Cases.

Blood ◽

10.1182/blood.v114.22.1320.1320 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1320-1320 ◽

Cited By ~ 1

Author(s):

Lilia Baili ◽

Mehdi Khellaf ◽

Laetitia Languille ◽

Philippe Bierling ◽

Bertrand Godeau ◽

...

Keyword(s):

Platelet Count ◽

Previous History ◽

Third Trimester ◽

Thrombocytopenic Purpura ◽

The Third ◽

Short Course ◽

History Of ◽

The Mean ◽

Mucosal Bleeding ◽

Risk Of Relapse

Abstract Abstract 1320 Poster Board I-342 Backgound Adult's immune thrombocytopenic purpura (ITP), now referred as immune thrombocytopenia, is an autoimmune disease affecting preferentially women of child-bearing age. The risk of relapse or worsening of the disease during pregnancy in women with a previous history of ITP or followed for a chronic ITP is not well known and the monitoring of such patients is therefore not consensual. In order to better asses the impact of pregnancy on ITP' course and natural history, a study was initiated at the national referral center for adult's immune cytopenias at Creteil, France. Patients and Methods This was an observational single center study. To be included into the study, all women had to fulfill the following inclusion criteria: 1) A previous history of definite ITP outside pregnancy with a platelet count < 50×109/L at time of diagnosis and 2) Occurrence of at least one pregnancy within 10 years after ITP diagnosis. Patients diagnosed with secondary ITP (lupus-associated or other) or in whom ITP was diagnosed during a previous pregnancy could not be included. All available clinical and biological ITP-related data available before, during and after each pregnancy were extensively reviewed and analyzed. Results Data on 44 pregnancies in 33 women (mean age: 25 ± 7 years) were analyzed. The mean delay between ITP diagnosis and first pregnancy was 52 ± 19,8 months. At the beginning of pregnancy, ITP was considered “active” (i.e platelet count <100×109/L) in 11/44 (25%) cases, with a platelet count below 50 ×109/L in 6 cases whereas ITP was in remission (platelet count > 100 × 109/L) in 75% of the cases, either off therapy (82%) or on treatment (18% of the cases). In total, the platelet count remained stable during pregnancy In 25/44 of the cases (57%) without the need of any treatment except for one patient who received corticosteroids for an associated autoimmune hemolytic anemia diagnosed during pregnancy (Evans' syndrome). A slight decrease in the platelet count (between 50 and 100×109/L) was observed in 12 cases (27%), 6 of which occurred at the end of pregnancy. In nine of these cases, patients were given a short course of corticosteroids in preparation for delivery. Lastly, a decrease of the platelet count below 50×109/L was observed in only 7 of the 44 pregnancies (16%). In 6 of these 7 cases, patients were given corticosteroids, either alone (n=2) or in combination with intravenous immunoglobulin (n=4 cases); one patient was also given a platelet transfusion. No severe bleeding episode (mucosal bleeding or any hemorrhage) occurred in any of these cases prior to, during or after delivery. A miscarriage occurred in 6 of the 44 pregnancies (13.5%), a C-section was performed in 18% of the cases which is the usual average rate in France. In total, a treatment for ITP had been considered useful in 15 pregnancies (34%) mainly at the end of the third trimester. The mean platelet count at time of delivery was 107 ± 17 × 109/L, None of the patients had a relapse or a significant decrease of the platelet count within 6 months after delivery except for a one patient who presented with a severe (platelet count < 20 × 109/L) and symptomatic (cutaneous and mucosal bleeding) thrombocytopenia on day 2 after delivery. Conclusion Based on these preliminary data, pregnancy does not seem to have a negative impact on the course of the disease in women with chronic non-refractory ITP nor to increase the risk of relapse in those with a previous history of ITP. A significant decrease of the platelet count may occur in about 15% of the cases, mainly during the third trimester. In women with a platelet count between 50 and 100 × 109/L at term, a short course of treatment could be indicated in preparation for delivery and especially if an epidural analgesia is planned. Disclosures No relevant conflicts of interest to declare.

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Anti-ADAMTS13 Inhibitor Boosting During Plasma Exchange Therapy in Acquired TTP Is the Expression of a General Dysregulation of the Immune Response,

Blood ◽

10.1182/blood.v118.21.3299.3299 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3299-3299 ◽

Cited By ~ 1

Author(s):

Monica Schaller ◽

Irmela Sulzer ◽

Magnus Mansouri ◽

MD student ◽

Bernhard Lämmle ◽

...

Keyword(s):

Immune Response ◽

Platelet Count ◽

Plasma Exchange ◽

Strong Increase ◽

Line Treatment ◽

Adamts13 Activity ◽

First Line ◽

Antibody Titers ◽

Inhibitor Titer ◽

First Line Treatment

Abstract Abstract 3299 Background. Thrombotic thrombocytopenic purpura (TTP) is a rare disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia with schistocytes on the peripheral blood smear and a variable degree of ischemic organ dysfunction due to microvascular thrombosis. In the case of acquired TTP, circulating autoantibodies inhibit ADAMTS13 activity and/or increase ADAMTS13 clearance. The first-line treatment of an acute TTP bout is plasma exchange (PEX) therapy with the replacement of fresh frozen plasma. Up to 30% of TTP patients show an exacerbation under PEX. After initial improvement, platelet counts drop again which is typically associated with a strong increase of ADAMTS13 inhibitor titers, and therefore the phenomenon is also referred to as inhibitor boosting. Interestingly it is apparently not seen in other autoimmune diseases treated with PEX, like acquired hemophilia A or myasthenia gravis. The aim of this study was therefore to investigate if inhibitor boosting in acquired TTP is a general or ADAMTS13 specific phenomenon. Methods. Plasma samples, obtained day-to-day during PEX therapy supplemented with steroids until remission, of 9 patients suffering from acute TTP due to severe acquired ADAMTS13 deficiency, were analyzed for the following laboratory parameters: (a) C-reactive protein (CRP) and total IgG, (b) ADAMTS13 activity, (c) anit-ADAMTS13 antibody titers by ELISA, (d) functional inhibitor titers by FRETS assay, and (e) anti-TG and anti-TPO antibody titers. Results. At initial presentation inhibitor titers ranged from 0.7 - >10 BU/ml (a positive functional inhibitor titer is defined as >0.4 BU/ml by FRETS). All patients initially improved when PEX was started, however, in 7/9 cases a drop in platelet count was noted on day 7 (n=5), 8 or 9 (each n=1), which was associated with a substantial increase in anti-ADAMTS13 antibody and functional inhibitor titer in all seven patients. CRP was increased (>30mg/L) in one patient only, during the three days before the raise in inhibitor titer and a drop in platelet count was noted, while total IgG remained stable in all 9 patients throughout PEX. At presentation none of the patients had a positive result for the thyroid antibodies, however, all 9 patients developed positive anti-TPO antibody titers during treatment and three patients tested positive for anti-TG antibodies at the same time. Anti-TPO antibody peaks occurred after the anti-ADAMTS13 antibody peak in all patients (range days 9–17), except the two patients where no raise in anti-ADAMTS13 antibody titers was observed (anti-TPO peak on day 3 in both). The two patients without inhibitor boosting required only five and six PEX sessions, respectively to get into remission, of the other seven patients two didn't overcome the inhibitor boosting and became refractory and were subsequently successfully treated by splenectomy or Rituximab, and one patient died of sepsis on day 11. Conclusions. Inhibitor boosting in acquired TTP due to antibody-mediated severe ADAMTS1313 deficiency treated with PEX is common (78%) and cannot be overcome by standard first line treatment in half of the patients. The fact that significant titers of other autoantibodies than anti-ADAMTS13 antibodies occur during the acute disease episode is striking and points to a more general dysregulation of the immune response in acquired TTP. Investigation of further autoantibodies, cytokines, etc. to explore the role of B-cells and T-cells in this phenomenon in more detail are underway. Disclosures: No relevant conflicts of interest to declare.

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