Impact of severe ADAMTS13 deficiency on clinical presentation and outcomes in patients with thrombotic microangiopathies: the experience of the Harvard TMA Research Collaborative

The Harvard TMA Research Collaborative is a multi‐institutional registry‐based effort to study thrombotic microangiopathies (TMA). Laboratory and clinical parameters were recorded for 254 cases of suspected autoimmune thrombotic thrombocytopenic purpura (TTP). Patients with severe ADAMTS13 deficiency (activity ≤10%, N = 68) were more likely to be young, female and without a history of cancer treatment or transplantation. While all patients with severe deficiency were diagnosed with autoimmune TTP, those without severe deficiency frequently had disseminated intravascular coagulation, drug‐associated TMA and transplant‐related TMA. Patients with severe ADAMTS13 deficiency had superior overall survival at 360 d compared to those without severe deficiency (93·0% vs. 47·5%, P < 0·0001). Almost all patients with severe deficiency received therapeutic plasma exchange (TPE), but the use of TPE in patients with ADAMTS13 activity >10% varied significantly across the institutions in our consortium (13·2–63·8%, P < 0·0001). Nevertheless, 90‐d mortality was not different in patients with ADAMTS13 activity >10% between the three hospitals (P = 0·98). Our data show that patients with severe ADAMTS13 deficiency represent a clinically distinct cohort that responds well to TPE. In contrast, TMA without severe ADAMTS13 deficiency is associated with increased mortality that may not be influenced by TPE.     

Pediatric thrombotic thrombocytopenic purpura

Child‐onset thrombotic thrombocytopenic purpura (TTP) is a rare entity of thrombotic microangiopathy (TMA). The pathophysiology of the disease is based on a severe functional deficiency of ADAMTS13 (activity <10%), the specific von Willebrand factor (VWF)‐cleavage protease. This deficiency may be either acquired (associated anti‐ADAMTS13 autoantibodies) or congenital (resulting from biallelic mutations of ADAMTS13 gene). ADAMTS13 deficiency is responsible for the accumulation of high molecular weight multimers of VWF and the formation of platelet thrombi in the microcirculation. Consequently, microangiopathic hemolytic anemia and consumption thrombocytopenia are associated with organ ischemia. The differential diagnosis with other TMAs, autoimmune cytopenias or hematological malignancies may be challenging. The exploration of ADAMTS13 (activity, antibodies, antigen, ADAMTS13 gene) supports the diagnosis of TTP. The first‐line treatment of the acute phase of TTP is based on plasmatherapy. In congenital TTP, patients with a chronic disease benefit from a prophylactic plasmatherapy. In autoimmune TTP, steroids and B‐cells depleting therapies increasingly are used together with plasma exchange. Long‐term follow‐up including the monitoring of ADAMTS13 activity is mandatory. A severe decrease in ADAMTS13 activity (<10%) may predict relapses and preemptive B‐cell depletion with rituximab can be used to prevent relapses.     

A phase‐II sequential case‐series study of all patients presenting to four plasma exchange centres with presumed relapsed/refractory thrombotic thrombocytopenic purpura treated with rituximab

The primary objective of this phase II study was to evaluate the efficacy of rituximab in the management of adult patients with physician‐diagnosed presumed thrombotic thrombocytopenic purpura (TTP); relapsed or refractory. We conducted a multicentre study in four Canadian hospital‐based apheresis units. Forty patients with presumed TTP (20 refractory and 20 relapsing) were sequentially enrolled and all received rituximab in a standardized manner. A complete response was documented in 14 of 19 refractory patients by week 8 and 15/16 were alive and in remission at 52 weeks (one patient was lost to follow‐up, one was a non‐responder, and three died). Among relapsing patients, 16/18 had a complete response at week 8 and 18/18 at week 52 (one patient lost to follow‐up and one withdrew). At 1 year, all relapsing and 85% of refractory patients survived. Of 38/40 patients who had ADMATS13 testing at study entry, 13/19 refractory and 10/19 relapsing patients had ADAMTS13 < 10% (typical TTP); whereas 6/19 refractory and 9/19 relapsing cases had ADAMTS13 > 10% (other thrombotic microangiopathy; TMA). Refractory‐typical TTP in contrast to refractory‐other TMA and all relapsing patients treated with plasma exchange and rituximab, were less likely to be responsive and more likely to die or relapse.     

Role of ADAMTS13 in the management of thrombotic microangiopathies including thrombotic thrombocytopenic purpura (TTP)

The clinical presentation of thrombotic thrombocytopenia purpura (TTP) and other thrombotic microangiopathies (TMAs) can often be similar. The role of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) in diagnosing TTP is accepted by most researchers but continues to be debated in a few studies. We report the experience of our single‐centre academic institution, where ADAMTS13 is used to diagnose TTP and guide plasma exchange (PLEX). Patients presenting to our institution with thrombotic microangiopathy (60 patients) between January 2006 and December 2012 were divided into two groups based on ADAMTS13 activity and clinical history. Patients with ADAMTS13 activity <10% were included in the TTP (n = 30) cohort while patients with activity >11% were classified as ‘other microangiopathies’ (TMA, n = 30). PLEX was only initiated in patients with a high likelihood of TTP and discontinued when the baseline ADAMTS13 activity was >11%. Patients with severe ADAMTS13 deficiency (TTP group) showed significant presenting differences: lower platelet counts, less renal dysfunction, higher presence of neurological abnormalities, and greater haemolysis markers as compared to non‐deficient patients (TMA group). Most importantly, patients without severe ADAMTS13 deficiency were safely managed without increased mortality despite receiving no PLEX or discontinuing PLEX after a short course (upon availability of ADAMTS13 results). In conclusion, ADAMTS13 can be used to diagnose TTP and guide appropriate PLEX therapy.     

Clinical presentation and management of acquired thrombotic thrombocytopenic purpura: A case series of 55 patients

The aim of this study was to explore the clinical characteristics and treatment of acquired thrombotic thrombocytopenic purpura (TTP). The clinical manifestations, laboratory findings, differential diagnoses, therapeutic methods, and prognosis of 55 patients with acquired TTP were retrospectively analyzed. Among the 55 TTP patients, 17 were males and 38 were females, with a mean age of 40 ± 15 years. Twenty‐one patients had the Triad syndrome, which included neurological syndromes, microangiopathic hemolytic anemia, and thrombocytopenia. Twenty‐three patients had the Quinary syndrome, which included fever, microangiopathic hemolytic anemia, thrombocytopenia, renal insufficiency, and neurological symptoms. Twenty‐eight patients received the measurement for a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity and 23 patients had <10% of the normal range. ADAMTS13 inhibitor was tested in 20 patients and was positive in 18 patients. Both ADAMTS13 activity and ADAMTS13 inhibitor were examined in 20 patients and 90% of the patients showed double positive results. The treatment methods included plasma exchange, glucocorticoids, rituximab, immunosuppressants, and intravenous immunoglobulin. Thirty‐three patients survived, and 22 patients died. Plasma exchange improved the remission rate from 16.7% to 65.3% (P = .022). The combined immunosuppressive therapy based on plasma exchange and glucocorticoids raised the remission rate from 43.8% to 75.8%. Most of acquired TTP patients had the Triad syndrome or the Quinary syndrome. A high proportion of TTP patients had ADAMTS13 activity reduction and ADAMTS13 inhibitor positivity. Plasma exchange and immunosuppressive therapy may improve the prognosis of this disease.     

The utility of ADAMTS13 in differentiating TTP from other acute thrombotic microangiopathies: results from the UK TTP Registry

Thrombotic microangiopathies (TMAs) are frequently difficult to differentiate clinically, and measurement of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) remains vital in thrombotic thrombocytopenic purpura (TTP) diagnosis. We retrospectively reviewed cases referred for ADAMTS13 testing, using UK TTP Registry screening data. Of a total 810 cases, 350 were confirmed as TTP. The 460 non‐TTP cases comprised secondary TMAs (24·57%) and haemolytic uraemic syndrome (HUS) (27·17% aHUS, 2·83% Shiga‐like toxin‐producing E. coli [STEC]‐HUS); the remainder were TMAs with no clear association, not TMAs, or had no confirmed diagnosis. ADAMTS13 levels were significantly lower in TTP than STEC‐HUS, aHUS and other TMAs. TTP patients had significantly lower platelet count (15 × 10⁹/l; range 0–96) than aHUS (57 × 10⁹/l; range 13–145, P < 0·0001) or STEC‐HUS (35 × 10⁹/l; range 14–106, P < 0·0001); they also had lower creatinine levels (92 μmol/l; range 43–374) than aHUS (255 μmol/l; range 23–941, P < 0·0001) and STEC‐HUS (324 μmol/l; range 117–639, P < 0·0001). However, 12/34 (35·3%) aHUS patients had a platelet count <30 × 10⁹/l and 26/150 (17·3%) of TTP patients had a platelet count >30 × 10⁹/l; 23/150 (15·3%) of TTP patients had a creatinine level >150 μmol/l. This study highlights the wide variety of TMA presentations, and confirms the utility of ADAMTS13 testing in TTP diagnosis.     

Refractory thrombotic thrombocytopenic purpura in a 16‐year‐old girl: successful treatment with bortezomib

We present a case of a 16‐year‐old girl with autoimmune thrombotic thrombocytopenic purpura (TTP), refractory to plasma exchange and high‐dose prednisone. Despite the additional treatment with rituximab, she developed renal and neurological complications with ongoing hemolysis and thrombocytopenia. Bortezomib, a proteasome inhibitor and thereby blocking plasma cells, was added, and our patient recovered. We suggest that bortezomib can be of additional value in severe immunologically mediated TTP in adolescents. Its use may prevent the necessity of other invasive therapies, such as splenectomy, with significant side effects.     

Cancer‐associated microangiopathic hemolytic anemia with thrombocytopenia: an important diagnostic consideration

Background: Early initiation of plasma exchange (PE) allows more than 80% of patients with idiopathic thrombotic thrombocytopenic purpura (TTP), most commonly because of severe ADAMTS13 deficiency, to achieve remission and mandates urgency in diagnosis and therapy. Metastatic cancer may present with a microangiopathic hemolytic anemia with thrombocytopenia that is clinically similar to TTP but does not respond to PE. ADAMTS13 activity can be diagnostic but usually not immediately available. Recognition of cancer‐associated microangiopathic hemolytic anemia with thrombocytopenia (CA‐MHA) is paramount to avoid inappropriate PE therapy and delays in cancer‐specific chemotherapy. Objective: To identify distinguishing characteristics of CA‐MHA and TTP to facilitate early recognition of CA‐MHA. Methods: In a retrospective cohort study, baseline clinical and laboratory data of consecutive adult patients with CA‐MHA (n = 7) or autoimmune TTP (n = 7) from a registry of patients with clinically suspected acute TTP referred for PE were compared. Results: The frequencies of bone pain and respiratory symptoms were significantly greater among patients with CA‐MHA compared to patients with TTP; other baseline clinical and laboratory characteristics did not differ significantly between the two groups. Response to PE and mortality at day 30 were significantly worse for CA‐MHA (14% and 71%, respectively) compared to patients with TTP (86% and 14%, respectively). Conclusions: Baseline clinical and laboratory characteristics largely do not distinguish acute CA‐MHA from autoimmune acute TTP. While all suspected acute patients TTP should receive urgent PE, bone pain, respiratory symptoms, or inadequate PE response should prompt an early search for CA‐MHA.     

Demographic and ADAMTS13 biomarker data as predictors of early recurrences of idiopathic thrombotic thrombocytopenic purpura

Objective: Approximately 40% of idiopathic thrombotic thrombocytopenic purpura (TTP) patients will suffer an exacerbation (recurrence of TTP within 30 d after their last plasma exchange (PE) procedure), but there are no data to predict who is at greater risk. We studied the clinical utility of demographic and ADAMTS13 biomarker data to predict the risk for exacerbation. Patients: Forty‐four acute episodes of idiopathic TTP from 26 patients were studied. Methods: PE was performed plus either prednisone (1 mg/kg/d) or cyclosporin (2–3 mg/kg/d) as adjuncts. PE was continued daily until response (platelet count >150 000/μL and normalized lactate dehydrogenase) and tapered uniformly in all patients. ADAMTS13 biomarkers were studied prior to PE and after achieving a response, but within 7 d of the last PE. Results: African American race (AA) was associated with an increased risk for exacerbation (P = 0.046). ADAMTS13 at presentation was also significantly lower in patients experiencing an exacerbation (P = 0.0364). After adjusting for the race effect, ADAMTS13 remained marginally significant (P = 0.0569). Conclusions: AA is significantly associated with an increased risk for exacerbations of TTP. These data also suggest that decreasing pretreatment ADAMTS13 activity was associated with an increased risk for exacerbation, even after accounting for the effect of race.     

Rituximab for chronic recurring thrombotic thrombocytopenic purpura: a case report and review of the literature

Deficiency of von Willebrand factor (VWF) cleaving protease ADAMTS13 has been demonstrated to be the proximate cause of a subset of thrombotic microangiopathic haemolytic anaemias (MAHA) typical for thrombotic thrombocytopenic purpura (TTP). ADAMTS13 gene mutations cause the hereditary form; acquired deficiency has been attributed to presence of an autoantibody, which may represent a specific subset of MAHA best termed 'autoimmune thrombotic thrombocytopenic purpura'. We describe a patient with relapsing TTP because of ADAMTS13 inhibitors, who failed to achieve sustained remission despite therapies with plasma exchange, steroids, vincristine, staphylococcal protein A and splenectomy. The ADAMTS13 inhibitor titre remained elevated and clinical stability was only maintained by plasma exchange every 2-3 d over a period of 268 d. The patient then received rituximab therapy (eight doses of 375 mg/m2 weekly), during which she required five plasma exchanges in the first 10 d, two exchanges in the next 3 weeks, and none thereafter for 450 d and ongoing. The ADAMTS13 inhibitor titre decreased and enzyme activity increased. We compared this case with that of seven previously reported TTP cases also treated with rituximab; experience suggests that rituximab therapy deserves further investigation for patients with either refractory or relapsing TTP caused by ADAMTS13 inhibitors.     

Rituximab for refractory and or relapsing thrombotic thrombocytopenic purpura related to immune‐mediated severe ADAMTS13‐deficiency: a report of four cases and a systematic review of the literature

Thrombotic thrombocytopenic purpura (TTP) is a potentially life‐threatening disorder that in significant proportion of cases is related to the development of autoantibodies to, and resulting severe deficiency of, the ADAMTS13 protease. However, ADAMTS13 deficiency does not account for all cases. Response to plasma exchange (PE) is seen in TTP with and without ADAMTS13 deficiency and is therefore indicated for all with a clinical diagnosis of TTP, although the pathogenesis of the latter group remains to be defined. Although the majority of cases respond to PE, a significant percent are refractory or experience relapse. Rituximab is being increasingly used off‐label in this setting, but many reports do not define the pathogenesis of TTP so treated. We here report our experience with, and systematically review the published experience to date, of rituximab in management of refractory and or relapsing TTP specifically related to immune‐mediated severe ADAMTS13‐deficiency. In total, 73 patients met defined study inclusion criteria. The majority (～95%) achieved complete remission within weeks of the first application of rituximab. The reported relapse rate was low in this patient subgroup, which carry an anticipated relapse rate of up to 60%. However, caution in interpretation of this data is needed given the relatively short median duration of follow‐up of approximately 10 months. Rituximab was generally well tolerated, with few serious adverse events reported. However, three severe infectious complications were identified, including viral reactivation in keeping with black box warnings for this agent. Furthermore, reflecting the rarity of this disorder, only a relatively small number of patients have been treated and data with regards to long‐term follow‐up are largely based on individual case reports. Prospective studies are urgently needed to define the true efficacy and long‐term safety of rituximab.     

The clinical utility of ADAMTS13 activity, antigen and autoantibody assays in thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) has been linked to a severe deficiency in ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) activity. Since the identification of ADAMTS13, and its target cleavage sequence in von Willebrand factor (VWF), several novel ADAMTS13 activity, antigen and autoantibody assays have been developed. Our aim was to evaluate the potential use of these novel assays. ADAMTS13 activity and inhibitors were measured by overnight incubation of patient plasma with pure VWF followed by multimer or collagen binding analysis. ADAMTS13 activity (Rapid peptide assay), antigen and immunoglobulin G anti-ADAMTS13 were measured by enzyme-linked immunosorbent assay. 118 samples from seven TTP patients (six adult idiopathic, one congenital) were studied longitudinally during episodes of TTP, their treatment and prophylaxis. ADAMTS13 antigen levels varied considerably between patients and sample times, but in new cases of acute TTP, rapid assays of ADAMTS13 antigen, on serial samples, maybe helpful in confirming the diagnosis. The rapid peptide ADAMTS13 activity assay showed good concordance of results with the older activity assay methods. The change in ADAMTS13 activity mirrored the autoantibody level and in 5/6 acquired TTP cases, a fall in antibody appeared to predict a rise in ADAMTS13 activity, potentially allowing modification of patient management based on autoantibody levels.     

Consensus opinion on diagnosis and management of thrombotic microangiopathy in Australia and New Zealand

Thrombotic microangiopathy (TMA) arises in a variety of clinical circumstances with the potential to cause significant dysfunction of the kidneys, brain, gastrointestinal tract and heart. TMA should be considered in all patients with thrombocytopenia and anaemia, with an immediate request to the haematology laboratory to look for red cell fragments on a blood film. Although TMA of any aetiology generally demands prompt treatment, this is especially so in thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS), where organ failure may be precipitous, irreversible and fatal. In all adults, urgent, empirical plasma exchange (PE) should be started within 4–8 h of presentation for a possible diagnosis of TTP, pending a result for ADAMTS13 (a disintegrin and metalloprotease thrombospondin, number 13) activity. A sodium citrate plasma sample should be collected for ADAMTS13 testing prior to any plasma therapy. In children, Shiga toxin‐associated haemolytic uraemic syndrome due to infection with Escherichia coli (STEC‐HUS) is the commonest cause of TMA, and is managed supportively. If TTP and STEC‐HUS have been excluded, a diagnosis of aHUS should be considered, for which treatment is with the monoclonal complement C5 inhibitor, eculizumab. Although early confirmation of aHUS is often not possible, except in the minority of patients in whom auto‐antibodies against factor H are identified, genetic testing ultimately reveals a complement‐related mutation in a significant proportion of aHUS cases. The presence of other TMA‐associated conditions (e.g. infection, pregnancy/postpartum and malignant hypertension) does not exclude TTP or aHUS as the underlying cause of TMA.     

Acquired thrombotic thrombocytopenic purpura due to antibody-mediated ADAMTS13 deficiency precipitated by a localized Castleman’s disease: A case report

Acquired ADAMTS13 inhibitor causing thrombotic thrombocytopenic purpura (TTP) may be precipitated by some infections, inflammatory diseases or neoplasia. We reported a case of refractory TTP precipitated by a newly diagnosed localized Castleman’s disease (CD). TTP was initially treated with plasma exchange and immunosuppressive therapy with corticosteroids; however the treatment failed to promote sustained response. During hospitalization, an abdominal tumor was diagnosed and resected; the histological analysis revealed a CD of hyaline-vascular variant rich stroma. After tumor removal, the patient achieved a long-lasting clinical remission and normalized ADAMTS13 activity. This clinical case describes a novel association of acquired ADAMTS13 inhibitor and CD. The antibody to ADAMTS13 developed along with the systemic manifestation of CD and promptly disappeared after the resection of the tumor. There are reports of neoplasia-associated thrombotic microangiopathy however direct evidence of CD-dependent ADAMTS13 inhibitor had not yet been reported.     

Two cases of refractory thrombotic thrombocytopenic purpura associated with collagen vascular disease were significantly improved by rituximab treatment

Thrombotic thrombocytopenic purpura (TTP) is a rare disorder of small vessels. TTP is associated with deficiency of the von Willebrand factor-cleaving protease, ADAMTS13, and its inhibitor. Low ADAMTS13 activity is present in most of idiopathic TTP patients. The prognosis of TTP was improved by plasma exchange treatment, which replaces the ADAMTS13 and removes ADAMTS13 inhibitor. However, ADAMTS13 activity is normal in some TTP patients. These are found among the secondary TTP patients associated with collagen disease, hematopoietic stem cell transplantation, malignancy, or drugs. In addition, most of them do not respond to plasma exchange. On the other hand, several reports demonstrated that rituximab, which is an anti-CD20 monoclonal antibody, is effective for refractory TTP cases caused by ADAMTS13 deficiency. It is considered that the effect of rituximab is associated with disappearance of ADAMTS13 inhibitor. However, rituximab therapy was effective for the TTP patients with normal ADAMTS13 activity in our cases. We considered another mechanism of rituximab for TTP cases.     

Human immunodeficiency virus associated thrombotic thrombocytopenic purpura--favourable outcome with plasma exchange and prompt initiation of highly active antiretroviral therapy

Thrombotic thrombocytopenic purpura (TTP) is an acute prothrombotic disorder. Human immunodeficiency virus (HIV) is an identified precipitant. This study reviewed 30 episodes of HIV-associated TTP in 24 patients from the South-East England Apheresis units, over the last 10 years. All patients were heterosexual Black Africans. First presentation of TTP revealed a new diagnosis of HIV in eight patients. TTP relapse occurred on six occasions (in four patients) as a result of non-adherence to highly active antiretroviral therapy (HAART). Prompt initiation/re-initiation of HAART in parallel with plasma exchange (PEX)±steroid led to prompt remission. Adjunct immunomodulatory agents (e.g. Rituximab) were required in 10% of cases. Once-daily HAART regimens are recommended, being compatible with PEX requirement, maximizing drug exposure between PEX. High viral loads (>500,000 copies/ml) require more PEX to remission. ADAMTS13 activity was reduced (<5%) as detected by collagen-binding assay and anti-ADAMTS13 immunoglobulin G antibodies were raised in 80%. Continued HAART-adherence ensured a durable TTP remission with associated viral control resulting in no evidence of relapse. PEX and HAART are associated with replenishment of ADAMTS13 and viral suppression. More PEX is required in cases with higher viral loads. Continued HAART maintains remission. In a small proportion of cases, further immunomodulatory therapy may be required.     

Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13-deficient thrombotic thrombocytopenic purpura: a study of 11 cases

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease that occurs mainly in young adults. Acquired cases are usually a result of antibodies directed against ADAMTS13 (a disintegrin-like and metalloprotease [reprolysin type] with thrombospondin type 1 motif 13), a protease that cleaves the von Willebrand factor multimers. Prognosis has been improved by plasma therapy, but some acute severe forms are refractory to this treatment and achieving a sustained remission is still a challenge in chronic relapsing forms. We therefore conducted a multicentric open-label prospective trial to test the efficacy of rituximab, an anti-B-cell monoclonal antibody, as a curative and prophylactic treatment in patients with TTP as a result of anti-ADAMTS13 antibodies. Six patients were included during an acute refractory TTP episode. Five patients with severe relapsing TTP and persistent anti-ADAMTS13 antibodies were prophylactically treated during remission. All patients received 4 weekly infusions of rituximab. The target of treatment was to restore a significant ADAMTS13 plasma activity (> 10%). Treatment with rituximab led to clinical remission in all cases of acute refractory TTP. In all patients, anti-ADAMTS13 antibodies disappeared, and a significant (18%-75%) plasma ADAMTS13 activity was detected following treatment. Tolerance of rituximab was good. Rituximab is a promising first-line immunosuppressive treatment in patients with acute refractory and severe relapsing TTP related to anti-ADAMTS13 antibodies.     

A multicenter evaluation of the Technoscreen ADAMTS13 activity semi-quantitative screening test for thrombotic thrombocytopenic purpura diagnosis and exclusion

Introduction

Thrombotic thrombocytopenic purpura (TTP) is a rare but potentially fatal microangiopathy, with an untreated mortality rate of around 90%. TTP is caused by severe deficiency in ADAMTS13, which results in accumulation of ultra large von Willebrand factor multimers, triggering a consumptive thrombocytopenia, microangiopathic hemolytic anemia and end-organ dysfunction and damage. Demonstration of severe ADAMTS13 deficiency is diagnostic for TTP, but long turnaround times for quantitative activity testing often necessitates empirical plasma exchange and/or caplacizumab treatment.

Methods

Multisite (n = 4) assessment of the Technoscreen ADAMTS13 activity assay (semi-quantitative flow through screening assay) for diagnosis/exclusion of TTP compared to current standard practice of quantitative assays (ELISA or chemiluminescence AcuStar).

Results

A total of 128 patient samples were analyzed, with quantitative ADAMTS13 values ranging from 0% to 150%. The Technoscreen assay demonstrated high sensitivity and negative predictive value (NPV) for ADAMTS13 deficiency, but low specificity and positive predictive value (PPV), especially with one lot of reagent. Good inter-observer reliability was demonstrated. Excluding one possibly compromised batch and other test failures, results of 80 samples yielded sensitivity of 100% (95% CI = 84–100), specificity of 90% (80–95), PPV 77% (58–89) and NPV 100% (93–100).

Conclusion

The Technoscreen assay appears to be a reliable screening test for ADAMTS13 activity to exclude TTP in routine clinical practice. However, the assay falsely identified ADAMTS13 deficiency in many cases, partially batch related, which mandates confirmation with a quantitative assay, as well as initial assessment of kits as ‘fit for purpose’ prior to use for patient testing.     

ADAMTS13 content in plasma‐derived factor VIII/von Willebrand factor concentrates

Thrombotic thrombocytopenic purpura (TTP) is a microangiopathy syndrome caused by a congenital or acquired deficiency of ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor (VWF) and thus prevents the formation of platelet‐rich thrombi in the microcirculation. TTP can be fatal if not appropriately and timely treated with the infusion of fresh frozen plasma (FFP) or exchange plasmapheresis, that reverse the process of microangiopathy by removing anti‐ADAMTS13 autoantibodies and replacing functional ADAMTS13. The treatment of TTP with FFP is not free from risks and must be administered in hospitals or clinics, owing to the substantial amount of plasma volume infused or exchanged and the frequent need of catheter application. Moreover, most FFPs are not subjected to treatments to remove or inactivate blood‐borne infectious agents. A number of recent reports indicate that certain plasma‐derived VWF‐factor VIII (FVIII) concentrates are clinically effective in the treatment of congenital TTP. In this study, we measured ADAMTS13 levels in various plasma‐derived VWF‐FVIII concentrates, showing that Koate^®‐DVI (Grifols), contained relatively high amounts of ADAMTS13 and that Alphanate^® (Grifols) was the closest other product in terms of protease content. Koate^®‐DVI contains, on average (five lots tested), 0.091 ± 0.007 Units of ADAMTS13 activity per IU of FVIII. On the basis of this analysis and other reports of VWF‐FVIII concentrate utilization in congenital TTP, potential dosing, and future clinical developments are discussed. Am. J. Hematol. 88:895–898, 2013. © 2013 Wiley Periodicals, Inc.