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.     

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.     

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.     

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.     

Rituximab therapy for refractory thrombotic thrombocytopenic purpura

While most patients of thrombotic thrombocytopenic purpura (TTP) respond to plasma exchange and achieve remission, a subset of the patients experience multiple relapses or develop a persistent disease that may be debilitating and life threatening. We report the experience of rituximab treatment in three consecutive patients who had required periodic plasma exchange for greater than 50-180 days after failing other modalities of treatments. Two patients each received eight doses of rituximab infusion and had clinical remissions that have lasted for 23 months and ongoing in one patient and for 17 months before relapse in the other. The third patient received four doses of rituximab infusion and had improvement of disease for 60 days until her death from unrelated causes. Analysis of the von Willebrand factor-cleaving metalloprotease activity (ADAMTS13) and its inhibitor in two patients showed that rituximab treatment was associated with a rise of the protease level and a decrease of the inhibitor titers in one patient who achieved clinical remission and a decrease of the inhibitor titer but no increase in protease level in the other patient who had a partial response. Based on the responses to rituximab and its mild toxicity in these three patients, and the lack of effective alternative treatments, additional exploration of the role of rituximab in the treatment of refractory TTP is warranted.     

Short- and long-term effects of rituximab for the treatment of thrombotic thrombocytopenic purpura: four case reports

We report four cases of thrombotic thrombocytopenic purpura (TTP) successfully treated with rituximab in combination with plasma exchange and other immunosuppressive agents. All four cases fulfilled the diagnostic criteria of TTP with severe deficiencies in ADAMTS13 activity and a detectable anti-ADAMTS13 inhibitor. Four weekly doses of 375?mg/m² rituximab were initiated on day 3?C29 of presentation as a salvage treatment for relapsing/refractory disease in three patients and as a first-line treatment in one. Resolution of clinical symptoms and hematological abnormalities occurred as early as the second dose and, after the completion of treatment, all four patients achieved complete response (CR). They are currently free from relapse and the duration of CR has been 13?C72?months. During the treatment course, the level of ADAMTS13 activity and the titer of the inhibitor correlated well with resolution or exacerbation of the disease. This report suggests that rituximab exhibits short- and long-term favorable effects for the treatment of TTP and that a severe ADAMTS13 deficiency and ADAMTS13 inhibitor positivity may support early administration of rituximab in both acute/refractory and relapsing cases.     

Rituximab induces remission of cerebral ischemia caused by thrombotic thrombocytopenic purpura

OBJECTIVE: This report describes the experience of a case of atypical thrombotic thrombocytopenic purpura (TTP) whose diagnosis was based on severe deficiency of the von Willebrand factor (vWF) cleaving metalloprotease ADAMTS13. METHODS: The level of ADAMTS13 activity, the titer of the inhibitors of this protease and the size distribution of vWF multimers in plasma samples were analysed in a patient with recurrent episodes of dizziness and blurred vision. RESULTS: In the absence of thrombocytopenia or microangiopathic hemolysis, diagnosis of TTP was established by demonstration of very low ADAMTS13 activity levels and the presence of inhibitors of this protease. After rituximab therapy decreased the inhibitor titer and increased the ADAMTS13 level, the patient has had no relapse of ischemic symptoms in the following 16 months. CONCLUSIONS: Acute neurological deficits may occur in TTP without concurrent thrombocytopenia or microangiopathic hemolysis. The role of rituximab for patients with TTP deserves further exploration.     

Ofatumumab for acute treatment and prophylaxis of a patient with multiple relapses of acquired thrombotic thrombocytopenic purpura

Acquired thrombotic thrombocytopenic purpura (TTP) is an autoimmune disorder resulting in potentially life-threating systemic thrombotic microangiopathy due to production of antibodies directed against the von Willebrand factor-cleaving protease ADAMTS13. Typically managed with plasma exchange, glucocorticoids, and the first-generation anti-CD20 monoclonal antibody rituximab, patients with multiple relapses or refractory disease present unique management challenges. We describe a case of a young woman with multiple relapses of TTP despite standard therapy who was treated with ofatumumab, a second-generation anti-CD20 monoclonal antibody, after developing a severe hypersensitivity reaction to rituximab precluding its use. Ofatumumab was effective for the treatment of an acute relapse of TTP in combination with plasmapheresis and as a single-agent for prophylaxis. The patient has had no evidence of relapse 2 years after completion of acute treatment and 1 year after completing prophylactic therapy. Hypersensitivity to ofatumumab did not develop.     

Rituximab provided long-term remission in a patient with severe thrombotic thrombocytopenic purpura refractory to plasma exchange

We report a patient with severe thrombotic thrombocytopenic purpura (TTP) refractory to plasmapheresis who was successfully treated with rituximab. A 57-year-old male patient was referred to our department for further differential diagnosis and treatment of anemia and severe thrombocytopenia. Progressive psychoneurotic symptoms, hemolytic anemia, thrombocytopenia, renal function insufficiency and fever led us to the diagnosis of TTP. ADAMTS13 activity was below 3% and an inhibitor for ADAMTS13 was detected. Treatment with plasmapheresis and high-dose steroid was initiated but without clinical benefit. Two weeks following the initiation of plasmapheresis, we decided to treat the patient with 7 cycles of rituximab. No severe rituximab-related adverse effects were observed. After treatment with rituximab, the disease remitted, and the ADAMTS13 activity level increased. The patient has remained in complete remission for more than 1 year. Our data suggest that rituximab may be the optimal immunosuppressive therapy for refractory thrombotic thrombocytopenic purpura caused by an anti-ADAMTS 13 inhibitor.     

Epitope mapping of ADAMTS13 autoantibodies in acquired thrombotic thrombocytopenic purpura

Severe deficiency of the von Willebrand factor (VWF)-cleaving protease ADAMTS13 can lead to thrombotic thrombocytopenic purpura (TTP), a disease associated with the widespread formation of platelet-rich thrombi in many organs. Autoantibodies that inactivate ADAMTS13 are the most frequent cause of acquired TTP. Little is known about epitope specificity and reactivity of anti-ADAMTS13 antibodies. In this study, a series of ADAMTS13 domains were expressed in Escherichia coli, and the reactivity of purified recombinant fragments with anti-ADAMTS13 auto-antibodies from 25 patients with severe ADAMTS13 deficiency was evaluated in vitro. All TTP plasmas contained antibodies directed against the cysteine-rich spacer (cys-rich/spacer) domain of ADAMTS13. In the plasma of 3 patients, antibodies were detected that reacted exclusively with the cys-rich/spacer domain, underscoring the importance of this region for functional activity of ADAMTS13. In 64% of the plasmas, antibodies reacted with the 2 CUB domains, and in 56% they reacted with the isolated first thrombospondin type 1 (TSP-1) repeat and with the compound fragment consisting of the catalytic, the disintegrin-like, and the TSP1-1 domain. Less frequently, in 28% of the plasmas, antibodies reacted with the TSP1 repeats 2 to 8. Unexpectedly, antibodies reacted with the propeptide region in 20% of the plasmas. In conclusion, this study shows that even though anti-ADAMTS13 autoantibodies react with multiple domains of the protease, the cys-rich/spacer domain is consistently involved in antibody reactivity.     

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

Therapeutic plasma exchange is an effective empiric treatment for thrombotic thrombocytopenic purpura (TTP), but how therapy affects the level of a disintegrin 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% ( approximately 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.     

Intravenous immunoglobulin as an adjunct to plasma exchange for the treatment of chronic thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease. Therapeutic plasma exchange (TPE) is the most effective therapy; however, despite TPE, about one-third of TTP patients will relapse. A subset of patients with TTP has antibodies to ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) and may become resistant to conventional treatments. We describe a patient with TTP and high-titre anti-ADAMTS13 antibodies who developed a chronic, relapsing course of TTP despite frequent TPE. Once adjuvant treatment with intravenous immunoglobulin (IVIG) was added, remission was achieved. Even during remission, anti-ADAMTS13 antibodies remained elevated. We conclude that IVIG may sustain remission in some patients with chronic, relapsing TTP.     

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.     

Successful treatment of thrombotic microangiopathy after haematopoietic stem cell transplantation with rituximab

Thrombotic microangiopathy (TMA) is a grave complication after haematopoietic stem cell transplantation (HSCT) and effective treatment is undefined. Five patients with postHSCT TMA, which was refractory to at least 1 week of plasma exchange and prednisolone, were treated with rituximab (375 mg/m(2)/week x 4). Remission was achieved in four patients, of whom three remained in remission and one had died of sepsis at a median follow-up of 10 months. ADAMTS13 levels were low in all evaluable patients, and only one patient showed significant anti-ADAMTS13 antibody. The levels of ADAMTS13 and anti-ADAMTS13 antibody did not change significantly with rituximab-induced remission.     

ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases

Autoantibodies neutralizing human ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type 1 motif), the metalloprotease that physiologically cleaves von Willebrand factor, are a major cause of severe deficiency of the protease and of acquired thrombotic thrombocytopenic purpura (TTP). We evaluated prevalence of anti-ADAMTS13 antibodies in 59 patients with thrombotic microangiopathies (TMAs) and in 160 patients with immunologic or thrombocytopenic diseases different from TTP, using an enzyme-linked immunosorbent assay (ELISA). Immunoglobulin G (IgG) antibodies directed against ADAMTS13 were found in 97% of untreated patients with acute acquired TMA who had plasma levels of ADAMTS13 activity below 10%. The corresponding prevalence of IgM antibodies was 11%. In contrast, anti-ADAMTS13 antibodies of G or M isotypes were detected in 20% of patients with TMA with ADAMTS13 activity above 10%. The ELISA was more sensitive than the standard functional inhibitor assay for detecting antibodies against ADAMTS13. Patients with thrombocytopenia from various causes (n = 50), systemic lupus erythematosus (SLE; n = 40), and the antiphospholipid antibody syndrome (APS; n = 55) had prevalences of IgG antibodies of 8%, 13%, and 5% respectively, only slightly higher than the prevalence in 111 healthy donors (4%). A rather high prevalence of anti-ADAMTS13 IgM antibodies was found in patients with SLE and APS (18% each). The clinical significance of IgM antibodies in these groups is unclear. In conclusion, the ELISA method detected anti-ADAMTS13 IgG antibodies in a very large proportion of patients with acquired TMA associated with severe ADAMTS13 deficiency, and was more sensitive than the inhibitor assay.     

Thrombotic thrombocytopenic purpura precipitated by acute pancreatitis: a report of seven cases from a regional UK TTP registry

Thrombotic thrombocytopenic purpura (TTP) may be idiopathic or secondary. We report seven TTP cases precipitated by pancreatitis. The patients were admitted with acute pancreatitis and at that time had no clinical or laboratory features of TTP. The median time to develop TTP after pancreatitis was 3 d. The patients had moderately reduced ADAMTS13 activity (mean activity 49%; normal range 66–126%) with no evidence of anti-ADAMTS13 inhibitory autoantibodies. The median number of plasma exchanges to remission was 10 (range 7–14) and no additional treatment with immunosuppression was required to maintain remission. There have been no relapses to date.     

Efficacy of a rituximab regimen based on B cell depletion in thrombotic thrombocytopenic purpura with suboptimal response to standard treatment: Results of a phase II,multicenter noncomparative study

The standard four‐rituximab infusions treatment in acquired thrombotic thrombocytopenic purpura (TTP) remains empirical. Peripheral B cell depletion is correlated with the decrease in serum concentrations of anti‐ADAMTS13 and associated with clinical response. To assess the efficacy of a rituximab regimen based on B cell depletion, 24 TTP patients were enrolled in this prospective multicentre single arm phase II study and then compared to patients from a previous study. Patients with a suboptimal response to a plasma exchange‐based regimen received two infusions of rituximab 375 mg m^?2 within 4 days, and a third dose at day +15 of the first infusion if peripheral B cells were still detectable. Primary endpoint was the assessment of the time required to platelet count recovery from the first plasma exchange. Three patients died after the first rituximab administration. In the remaining patients, the B cell‐driven treatment hastened remission and ADAMTS13 activity recovery as a result of rapid anti‐ADAMTS13 depletion in a similar manner to the standard four‐rituximab infusions schedule. The 1‐year relapse‐free survival was also comparable between both groups. A rituximab regimen based on B cell depletion is feasible and provides comparable results than with the four‐rituximab infusions schedule. This regimen could represent a new standard in TTP. This trial was registered at www.clinicaltrials.gov (NCT00907751). Am. J. Hematol. 91:1246–1251, 2016. © 2016 Wiley Periodicals, Inc.     

Prognostic value of anti-ADAMTS 13 antibody features (Ig isotype, titer, and inhibitory effect) in a cohort of 35 adult French patients undergoing a first episode of thrombotic microangiopathy with undetectable ADAMTS 13 activity

To study both the pathophysiologic and the prognostic value of ADAMTS13 in thrombotic microangiopathies (TMAs), we enrolled a cohort of 35 adult patients combining a first acute episode of TMA, an undetectable (below 5%) ADAMTS13 activity in plasma, and no clinical background such as sepsis, cancer, HIV, and transplantation. All patients were treated by steroids and plasma exchange, and an 18-month follow-up was scheduled. Remission was obtained in 32 patients (91.4%), and 3 patients died (8.6%) after the first attack. At presentation, ADAMTS13 antigen was decreased in 32 patients (91.4%), an ADAMTS13 inhibitor was detectable in 31 patients (89%), and an anti-ADAMTS13 IgG/IgM/IgA was present in 33 patients (94%). The 3 decedent patients were characterized by the association of several anti-ADAMTS13 Ig isotypes, including very high IgA titers, while mortality was independent of the ADAMTS13 inhibitor titer. In survivors, ADAMTS13 activity in remission increased to levels above 15% in 19 patients (59%) but remained undetectable in 13 patients (41%). Six patients relapsed either once or twice (19%) during the follow-up. High levels of inhibitory anti-ADAMTS13 IgG at presentation were associated with the persistence of an undetectable ADAMTS13 activity in remission, the latter being predictive for relapses within an 18-month delay.     

Low levels of ADAMTS-13 with high anti-ADAMTS-13 antibodies during remission of immune-mediated thrombotic thrombocytopenic purpura highly predict for disease relapse: A multi-institutional study

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a life-threatening immune-mediated thrombotic microangiopathy. Daily therapeutic plasma exchange (TPE) and the optimized use of rituximab have strikingly improved the outcome of this disease, however the rate of disease recurrence remains high. Specific predictors of relapse in patients in remission can be relevant for an optimal patient management. In this study, we aimed to identify predictive variables of disease relapse in a multicenter cohort of 74 out of 153 iTTP patients. They were tested at different time points during remission for the levels of ADAMTS-13 activity and autoantibody, and did not receive pre-emptive treatment for ADAMTS-13 activity deficiency during remission. The results showed that the association of ADAMTS13 activity ≤20% with a high anti-ADAMTS-13 titer at remission, and the time to response to first line treatment ≥13 days, were independent predictive factors of disease relapse. In addition, the use of rituximab in patients with exacerbation or refractoriness to TPE was significantly associated with reduced relapse rate. By Cox regression analysis, patients with ADAMTS-13 activity ≤20% plus anti-ADAMTS13 antibody titer ≥15 U/mL at remission had an increased risk of relapse (HR 1.98, CI 95% 1.087-3.614; P < .02). These findings may help to outline more personalized therapeutic strategies in order to provide faster and sustained responses to first-line iTTP treatment and prevent relapses in these patients.     

ADAMTS13 gene mutation in congenital thrombotic thrombocytopenic purpura with previously reported normal VWF cleaving protease activity

Deficiency of von Willebrand factor (VWF) cleaving protease ADAMTS13 is associated with the development of thrombotic thrombocytopenic purpura (TTP). A case of congenital TTP that was previously reported to have normal ADAMTS13 activity was analyzed at the molecular level. Reanalysis of plasma VWF cleaving protease activity using a different assay revealed that the patient had less than 0.1 U/L ADAMTS13 protease activity, while the parents were both partially deficient. Sequence analysis of DNA amplified by polymerase chain reaction showed that the patient was homozygous for a novel TT deletion in exon 15 of the ADAMTS13 gene resulting in a frameshift, while both parents were heterozygous for the same mutation. Taken together with other recent reports, all the cases of hereditary TTP studied by DNA sequence analysis to date appear to be due to mutations within the ADAMTS13 gene.