The use of ADAMTS13 activity, platelet count, and serum creatinine to differentiate acquired thrombotic thrombocytopenic purpura from other thrombotic microangiopathies

Abstract Background and Aims Caplacizumab, a bivalent Nanobody, targets the A1 domain of von Willebrand Factor, inhibiting the interaction between ultra-large vWF and platelets in the treament of Acquired Thrombotic Thrombocytopenic Purpura (aTTP). Results of the Phase 3 HERCULES study confirm that treatment with caplacizumab reduces the time to platelet count response, resulting in faster resolution of aTTP. Treatment with caplacizumab also resulted in a highly clinically meaningful reduction in aTTP-related death, recurrence of aTTP, or a major thromboembolic event during study drug treatment. Data from clinical practice confirming the clinical trial data is still scarce. We report here the first real world evidence collected in the French thrombotic microangiopathies network. Method Patients with an acute episode of aTTP were included in an observational prospective multicentric study. The diagnosis of aTTP was done according to the French score (platelet count < 30 g/l and serum creatinine< 200µmol/l) or ADAMTS13 activity if available. Adult patients were proposed to be treated with daily plasma exchange (PE) in addition to corticosteroid and frontline rituximab plus early initiation of caplacizumab. PE was stopped after 2 days of platelet count normalization. Results Fifty patients (36 females, median age of 46 years old) were treated for aTTP. 30 patients (60%) had cerebral involvement and 13 (26%) had cardiac involvement. Cardiac troponin I was above upper normal value for 61% of patients. Before treatment, median platelet count was 16 g/l and median serum creatinine was 86 µmol/l. Three initial clinical suspicions of aTTP were finally diagnosed as HUS (2 patients) or vitamin deficiency (1 patient) resulting in the stop of treatment. A median number of 6 plasma exchanges was administered (min:3 - max:16). 375mg/m rituximab injections (3 to 4 for 35/43 patients with reported data) were mostly initiated within 3 days after the first plasma exchange. Caplacizumab treatment was initiated early (37/42 patients with reported data within 2 days after 1st plasma exchange) with a total median duration of treatment of 33 days (min:18 - max:35). The median platelet count normalization was 5 days (min:4 - max:6). 6/41 (14,6%) experienced exacerbations. No deaths and no patients refractory to therapy were reported. Eight adverse events related to caplacizumab therapy were reported, all with good outcomes. Conclusion Concomitant start of additional treatments allow to target severe ADAMTS13 deficiency and platelet aggregation which causes early mortality. The clinical French score seems useful in clinical practices.

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Pregnancy onset congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome) mimicking HELLP syndrome: a case report

Perinatal Journal ◽

10.2399/prn.21.0293013 ◽

2021 ◽

Vol 29 (3) ◽

pp. 270-273

Author(s):

Başak Ergin ◽

Berna Buse Kobal ◽

Zeynep Yazıcı ◽

Ali Hakan Kaya ◽

Sezin Canbek ◽

...

Keyword(s):

Thrombotic Thrombocytopenic Purpura ◽

Hellp Syndrome ◽

Epigastric Pain ◽

Novel Mutation ◽

Adamts13 Activity ◽

Thrombotic Microangiopathies ◽

Thrombocytopenic Purpura ◽

Uremic Syndrome ◽

Congenital Thrombotic Thrombocytopenic Purpura ◽

Low Platelet Count

Objective Thrombotic thrombocytopenic purpura is a thrombotic microangiopathic condition characterized by hemolytic anemia, thrombocytopenia, neurologic abnormalities, fever and renal dysfunction. Thrombotic microangiopathies such as preeclampsia and HELLP syndrome are pregnancy-specific, whereas others such as thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome are not. In this report, we present a case at which we identified a novel mutation which led to a significant reduction of ADAMTS13 activity. Case(s) A nulliparous pregnant woman of 32-year-old presenting with epigastric pain, hypertension and low platelet count was first suspected of HELLP syndrome, but was diagnosed with congenital TTP after delivery. Conclusion HELLP syndrome co-existed with undiagnosed TTP in this case. We strive to have sufficient awareness in order to distinguish these two pathologies from each other on an antenatal basis, because the causes of the managements are entirely different.

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Clinical Characteristics of Thrombotic Thrombocytopenic Purpura with Severe ADAMTS13 Deficiency

Blood ◽

10.1182/blood.v116.21.4666.4666 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4666-4666

Author(s):

Moon Jang ◽

So Young Chong ◽

Inho Kim ◽

Chul W. Jung ◽

Doyeun Oh

Keyword(s):

Mortality Rate ◽

Serum Creatinine ◽

Thrombotic Thrombocytopenic Purpura ◽

Clinical Significance ◽

Sodium Dodecyl ◽

Prognostic Significance ◽

Adamts13 Activity ◽

Lower Serum ◽

Thrombocytopenic Purpura ◽

Adamts13 Deficiency

Abstract Abstract 4666 The clinical significance of ADAMTS13 activity for response to treatment, mortality rate, recurrence, and prognosis is unclear. Therefore, we investigated the characteristics of severe ADAMTS13 deficiency and evaluated its clinical significance in Thrombotic thrombocytopenic purpura (TTP). The Korean TTP Registry includes 66 patients from 13 teaching hospitals in Korea who received the diagnosis of TTP from January 2005 to December 2008. Blood samples obtained upon admission were sent for ADAMTS13 analysis (multimer analysis by sodium dodecyl sulfate electrophoresis and/or ELISA) to a central laboratory along with patient clinical information. After 6 months, patient data regarding treatment, response, and prognosis were collected on standardized report forms. Patients with severe ADAMTS13 deficiency had lower serum creatinine levels (P=0.001) and WBC counts (P=0.050) than patients with non-severe ADAMTS13 deficiency. Although severe ADAMTS13 deficiency was associated with better response rate (75% vs 53%, P=0.145), remission rate (81% vs 61%, P=0.209), and mortality rate (19% vs 31%, P=0.508) than non-severe ADAMTS13 deficiency, treatment outcomes did not differ significantly between groups. After adjusting for clinical and laboratory features, multivariate analysis did not reveal any independent risk factors for TTP-associated mortality. Patients with severe ADAMTS13 deficient had lower serum creatinine levels and WBC counts at presentation but Severe ADAMTS13 activity deficiency at TTP diagnosis does not appear to have prognostic significance. Disclosures: No relevant conflicts of interest to declare.

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Relative incidence of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome in clinically suspected cases of thrombotic microangiopathy

Clinical Kidney Journal ◽

10.1093/ckj/sfz066 ◽

2019 ◽

Vol 13 (2) ◽

pp. 208-216 ◽

Cited By ~ 1

Author(s):

Ulf Schönermarck ◽

Wolfgang Ries ◽

Bernd Schröppel ◽

Lars Pape ◽

Malgorzata Dunaj-Kazmierowska ◽

...

Keyword(s):

Serum Creatinine ◽

Thrombotic Thrombocytopenic Purpura ◽

Haemolytic Uraemic Syndrome ◽

Primary Objective ◽

Adamts13 Activity ◽

Cross Sectional ◽

Thrombocytopenic Purpura ◽

Relative Incidence ◽

Severe Deficiency ◽

Post Hoc

Abstract Background Data are lacking on the relative incidence of thrombotic thrombocytopenic purpura (TTP), haemolytic uraemic syndrome (HUS) caused by Shiga toxin–producing Escherichia coli (STEC) and atypical HUS (aHUS) in patients presenting with thrombotic microangiopathies (TMAs). Methods This was a prospective, cross-sectional, multicentre and non-interventional epidemiological study. Patients fulfilling criteria for TMAs (platelet consumption, microangiopathic haemolytic anaemia and organ dysfunction) were included in the study. The primary objective was to assess the relative incidence of TTP, STEC-HUS, aHUS and ‘other’ physician-defined diagnoses. The secondary objective was to develop an algorithm to predict a severe deficiency in ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity (≤10%) using routine laboratory parameters. A post hoc classification using the recent Kidney Disease: Improving Global Outcomes diagnostic criteria was then undertaken to further classify patient groups. Results aHUS was diagnosed with a relative incidence of 61%, whereas TTP, STEC-HUS and ‘other’ were diagnosed in 13, 6 and 20% of patients, respectively. In the post hoc analysis, 27% of patients with a TMA were classified as ‘primary aHUS’ and 53% as ‘secondary aHUS’. Multivariate analysis revealed that severe deficiency in ADAMTS13 activity (≤10%) was unlikely to underlie TMA if platelet and serum creatinine were above threshold values of 30 × 109/L and 1.8 mg/dL, respectively (negative predictive value of 92.3 and 98.1, respectively, if one or both values were above the threshold). Conclusions In this study, aHUS was the most common single diagnosis among patients presenting with a TMA. In the absence of an ADAMTS13 activity result, platelet count and serum creatinine may aid in the differential diagnosis.

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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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Clinical Features of Severe Acquired ADAMTS13 Deficiency in Thrombotic Thrombocytopenic Purpura: Second Report of the Korean TTP Registry.

Blood ◽

10.1182/blood.v120.21.2188.2188 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2188-2188

Author(s):

Doyeun Oh ◽

Moon Ju Jang ◽

Inho Kim ◽

Soo-Mee Bang ◽

Chul-Won Jung ◽

...

Keyword(s):

Mortality Rate ◽

Serum Creatinine ◽

Thrombotic Thrombocytopenic Purpura ◽

Conflicts Of Interest ◽

Prognostic Significance ◽

Response To Treatment ◽

Adamts13 Activity ◽

Lower Serum ◽

Thrombocytopenic Purpura ◽

Adamts13 Deficiency

Abstract Abstract 2188 The clinical utility of ADAMTS13 activity for TTP has been extensively studied for last years. However, the clinical significance of ADAMTS13 activity for response to treatment, mortality rate, recurrence, and prognosis is still unclear. We previously reported the characteristics of severe ADAMTS13 deficiency in thrombotic thrombocytopenic purpura (TTP) and patients with severe ADAMTS13 deficiency had lower serum creatinine levels than patients with non-severe ADAMTS13 deficiency using 66 patients enrolled from January 2005 to December 2008. (Jang MJ et al, Int J Hematol 2011;93:163–9). In this second report, we enrolled 65 additional patients from January 2009 to June 2012 and analyzed 131 TTP patients using same methods. Patients with severe ADAMTS13 deficiency had lower serum creatinine levels (P=0.001), lower platelet counts (P<0.0001), and high total bilirubin levels (P=0.018) at presentation. However, as same as previous results, treatment outcomes did not differ significantly between severe and non-severe ADAMTS13 deficiency groups in response rate (82 vs. 65%, P = 0.256), remission rate (70 vs. 63%, P = 0.781), and mortality rate (23 vs. 18%, P = 0.820). After adjusting for clinical and laboratory features, multivariate analysis did not reveal any independent risk factors for TTP-associated mortality. In conclusion, although TTP with severe ADAMTS13 deficiency is a unique subgroup characterized by lower platelet count and relatively good renal function, the prognostic significance of ADAMTS13 is still unclear and further study would be required to clarify it. Disclosures: No relevant conflicts of interest to declare.

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Heparin-induced thrombocytopenia as a cause of prolonged low platelet count in patient with thrombotic thrombocytopenic purpura treated with plasmapheresis

Acta Biochimica Polonica ◽

10.18388/abp.2016_1428 ◽

2017 ◽

Vol 64 (2) ◽

Cited By ~ 1

Author(s):

Agata Winiarska ◽

Norbert Kwella ◽

Tomasz Stompór

Keyword(s):

Platelet Count ◽

Thrombotic Thrombocytopenic Purpura ◽

Low Molecular Weight Heparin ◽

Careful Analysis ◽

Low Molecular Weight ◽

Thrombotic Microangiopathies ◽

Thrombocytopenic Purpura ◽

Heparin Induced Thrombocytopenia ◽

Low Platelet Count ◽

Functional Deficiency

Thrombotic thrombocytopenic purpura (TTP) is a rare disorder belonging to thrombotic microangiopathies (TMA) and is caused by functional deficiency of metalloproteinase ADAMTS-13. Plasma exchange (PE) remains the treatment of choice in this disease. Here were describe the case of patient who apparently recovered from TTP following multiple sessions of PE, but remained thrombocytopenic. Careful analysis revealed the development of heparin-induced thrombocytopenia (HIT) that precluded platelet count (PLT) normalization. Full normalization of PLT followed discontinuation of PE and low-molecular weight heparin.

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Evaluation of the Plasmic Score for the Prediction of Adamts13 Activity in Patients with Thrombotic Microangiopathies

Proceedings ◽

10.3390/proceedings2090533 ◽

2018 ◽

Vol 2 (9) ◽

pp. 533 ◽

Cited By ~ 1

Author(s):

Giovanni Tiscia ◽

Filomena Cappucci ◽

Potito Scalzulli ◽

Nicola Cascavilla ◽

Cosima Battista ◽

...

Keyword(s):

Thrombotic Thrombocytopenic Purpura ◽

Diagnostic Tool ◽

Adamts13 Activity ◽

Thrombotic Microangiopathies ◽

Thrombocytopenic Purpura ◽

Adamts13 Deficiency

The PLASMIC score for the prediction of a likelihood of a severe ADAMTS13 deficiency represents a valid pre-test diagnostic tool to identify patients with thrombotic thrombocytopenic purpura.

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Evolution of Anti-ADAMTS13 Antibodies in a Refractory Case of Thrombotic Thrombocytopenic Purpura with Fatal Outcome

Blood ◽

10.1182/blood.v112.11.4568.4568 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4568-4568

Author(s):

Barbara Plaimauer ◽

Paul Knoebl ◽

Susanna Skalicky ◽

Silvia Ferrari ◽

Katalin Varadi ◽

...

Keyword(s):

Platelet Count ◽

Thrombotic Thrombocytopenic Purpura ◽

Clinical Laboratory ◽

Fatal Case ◽

Fatal Outcome ◽

Laboratory Data ◽

Postoperative Phase ◽

Adamts13 Activity ◽

Plasma Therapy ◽

Thrombocytopenic Purpura

Abstract Thrombotic thrombocytopenic purpura (TTP) is characterized by systemic microvascular thrombosis leading to life-threatening ischemia of multiple organs, and is associated with a severe deficiency of the von Willebrand factor (VWF)-cleaving protease ADAMTS13, which permits highly adhesive ultra-large VWF multimers to accumulate in the circulation. Inhibitory and less frequent non-inhibitory anti-ADAMTS13 autoantibodies have been detected in patients suffering from acquired idiopathic TTP. Current treatment with plasma exchange therapy is considered to remove the autoantibodies while concomitantly supplying plasma with the deficient protease. Plasma therapy greatly reduces mortality, nevertheless, still about 10% of the patients die from refractory TTP. To explore the cause of treatment failure in a fatal case of idiopathic acquired TTP we investigated retrospectively the anti-ADAMTS13 immunological profile of a 70-year-old female patient during the course of disease progression. At admittance, she presented with schistocytes, thrombocytopenia and severe neurological disturbances. ADAMTS13 antigen and activity were borderline low in the presence of initially non-inhibiting anti-ADAMTS13 IgG and IgM antibodies, no ADAMTS13 gene aberrations were detected. She had had no previous episodes of TTP. During treatment, the patient received repeated plasma exchanges, supportive extracorporal immunoadsorption and corticosteroid therapy. Despite ongoing treatment anti-ADAMTS13 antibodies still developed and ADAMTS13 activity remained less than 0.1U/ml. After 5 weeks of therapy, during which time the patient was seriously ill with striking neurological limitations, her platelet count dropped and a splenectomy was performed. The patient’s state improved despite a complicated postoperative phase. During the next 4 weeks, her platelet count increased gradually up to 780 G/L, a moderately low ADAMTS13 activity of 0.24U/ml (0.57ng/ml ADAMTS13 antigen) was detected and ADAMTS13-specific antibodies were not measurable. However, within a few days her platelet count dramatically dropped to 20G/L, anti-ADAMTS13 antibodies reappeared and ADAMTS13 activity again was undetectable. The patient’s state deteriorated and she died 2 days later from multiple organ failure. We show the results of the fluctuating anti-ADAMTS13 antibody profile (functional inhibitors and total IgG, IgG subtypes, IgA and IgM) and the pattern of the ADAMTS13 domain-specific reactivity superimposed with the common clinical laboratory data over the patient’s 9-week clinical course.

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Thrombotic Thrombocytopenic Purpura: Mechanism for Effectiveness of Plasmapheresis

10.1055/s-0038-1665810 ◽

1979 ◽

Author(s):

J. G. Kelton ◽

P. B. Neame ◽

I. Walker ◽

A. G. Turpie ◽

J. McBride ◽

...

Keyword(s):

Platelet Count ◽

Thrombotic Thrombocytopenic Purpura ◽

The Other ◽

Unknown Etiology ◽

Normal Range ◽

Antiplatelet Antibody ◽

Thrombocytopenic Purpura ◽

Serious Illness ◽

Normal Platelet ◽

Very High

Thrombotic thrombocytopenic purpura (TTP) is a rare but serious illness of unknown etiology. Treatment by plasmapheresis has been reported to be effective but the mechanism for benefit is unknown. We have investigated the effect of plasmapheresis in 2 patients with TTP by quantitating platelet associated IgG (PAIgG) levels prior to and following plasmapheresis. Both patients had very high levels of PAIgG at presentation (90 and A8 fg IgG/platelet respectively, normal 0-5). in both, the PAIgG levels progressively fell to within the normal range and the platelet count rose following plasmapheresis. One patient remained in remission with normal platelet counts and PAIgG levels. The other relapsed after plasmapheresis and the PAIgG level rose prior to the fall in platelet count. Plasmapheresis was repeated and resulted in normalization of both the platelet count and PAIgG level. It is suggested that plasmapheresis removes antiplatelet antibody or immune complexes which may be of etiological importance in this illness.

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